Small Animal Critical Care Medicine [2 ed.] 9781455703067

Table of contents :
Small Animal Critical Care Medicine
Copyright page
Contributors
Preface
Acknowledgments
Dedication
Reference Ranges
Part I: Key Critical Care Concepts
1 Evaluation and Triage of the Critically Ill Patient
Key Points
Introduction
Triage Systems
Initial Patient Triage
Primary Survey
Respiratory system evaluation
Cardiovascular system evaluation
Neurologic system evaluation
Urinary system evaluation
Additional considerations
Triage Diagnostics: Vascular Access, Emergency Database, and Focused Ultrasound
Secondary Survey
Summary
References
2 Physical Examination and Daily Assessment of the Critically Ill Patient
Key Points
Physical Examination
Airway and Breathing
Circulation
Heart rate
Mucous membrane color
Capillary refill time
Venous distention
Pulse quality
Auscultation
Level of Consciousness
Temperature
Hydration
Abdominal Palpation and Gastrointestinal Assessment
Monitoring and Laboratory Data
Oncotic Pull, Total Protein, and Albumin
Glucose
Electrolyte and Acid-Base Balance
Oxygenation and Ventilation
Red Blood Cell and Hemoglobin Concentrations
Blood Pressure
Coagulation
Renal Function and Urine Output
Immune Status, Antibiotic Dosage and Selection, and White Blood Cell Count
Drug Dosages and Metabolism
Nutrition
Nursing Care
References
3 Cardiopulmonary Resuscitation
Key Points
Preparedness and Prevention
Basic Life Support
Circulation: Chest Compressions
Airway and Breathing—Ventilation
Monitoring
Electrocardiography
Capnography
Advanced Life Support
Drug Therapy
Vasopressors
Parasympatholytics
Antiarrhythmic drugs
Reversal agents
Intravenous fluids
Corticosteroids
Alkalinizing agents
Electrical Defibrillation
Open-chest CPR
Prognosis
References
4 Post–Cardiac Arrest Care
Key Points
Propagating Sustained Rosc
Systemic Response to Ischemia and Reperfusion: Sepsis-Like Syndrome
Hemodynamic Optimization
Glycemic Control
Adrenal Dysfunction
Post–Cardiac Arrest Brain Injury
Brain Injury Sustained During Ischemia Versus During Reperfusion
Controlled Reoxygenation
Mild Therapeutic Hypothermia
Other Neuroprotective Treatment Strategies
Neurologic Assessment and Prognostication
Myocardial Dysfunction
Persistent Precipitating Pathology
References
5 Shock
Key Points
Clinical Presentation
Diagnostics and Monitoring
Monitoring Tissue Perfusion and Oxygen Delivery
Blood Lactate Levels
Cardiac Output Monitoring and Indices of Oxygen Transport
Mixed Venous Oxygen Saturation (SvO2) and Central Venous Oxygen Saturation (ScvO2)
Treatment
References
6 Systemic Inflammatory Response Syndrome
Key Points
Systemic Inflammation
The Consequences of Systemic Inflammation
SIRS and Sepsis
Potential Markers of Sepsis
Treatment of SIRS in Humans
SIRS in Small Animals
Summary
References
7 Multiple Organ Dysfunction Syndrome
Key Points
Epidemiology
Pathophysiology
Immune Dysregulation
Coagulation
Mitochondria
Gastrointestinal Tract
Specific Organ Dysfunction
Lung
Cardiac
Liver
Gastrointestinal
Kidneys
Central Nervous System
Coagulation and the Endothelium
Scoring Systems
Sequential Organ Failure Assessment (SOFA)
Multiple Organ Dysfunction (MOD) Score
Logistic Organ Dysfunction System (LODS)
Predisposition Infection Response Organ (PIRO) Dysfunction
Which Score To Use?
Management
Cardiovascular Support
Ventilatory Strategies
Renal Replacement Therapy
Nutritional Support and Glucose Control (see Chapters 127 to 130)
Corticosteroids
Novel Therapeutic Approaches
References
8 Hypotension
Key Points
Normal Determinants of Blood Pressure
Potential Causes of Hypotension
Reduction in Preload
Reduction in Cardiac Function
Reduction in Systemic Vascular Resistance
Response to Decreases in Blood Pressure
Diagnosis of Hypotesion
Physical Examination
Measurement of Blood Pressure
Direct blood pressure monitoring
Indirect blood pressure measurement
Doppler ultrasonography
Oscillometric sphygmomanometry
Additional Diagnostics
Treatment of Hypotension
Fluid Resuscitation
Positive Inotropes
Vasopressor Agents
Summary
References
9 Hypertensive Crisis
Key Points
Pathophysiology
Blood Pressure Measurement
Target Organ Damage
Ocular
Neurologic
Renal
Cardiovascular
Patients at Risk for Hypertension
Hypertensive Urgency
Hypertensive Emergency
Treatment
Therapeutic Goals
Follow-up
References
10 Hyperthermia and Fever
Key Points
Thermoregulation
Hyperthermia
True Fever
Exogenous Pyrogens
Endogenous Pyrogens
Inadequate Heat Dissipation
Heat Stroke
Hyperpyrexic Syndrome
Exercise-Induced Hyperthermia
Pathologic and Pharmacologic Hyperthermia
Benefits and Detriments of Fever
Benefits
Detriments
Clinical Approach to the Hyperthermic Patient
Nonspecific Therapy for Febrile Patients
The Febrile Intensive Care Patient
References
11 Interstitial Edema
Key Points
Microvascular Filtration
Lymphatic Drainage
Serosal Transudation
Antiedema Mechanisms
Mechanisms of Edema Formation
Venous Hypertension
Hypoproteinemia
Increased Microvascular Permeability
Impaired Lymph Flow
Inflammatory Edema
Chronic Edemagenic Conditions
Conclusion
References
12 Patient Suffering in the Intensive Care Unit
Key Points
Maslow’s Hierarchy of Needs and Primal Alert Signals
Impact of Symptom Relief
Palliative Measures
References
13 Illness Severity Scores in Veterinary Medicine
Key Points
Applications of Illnes Severity Scores
Applications for the Individual Patient
Inappropriate Score Use
Applications in Triage and Clinician Performance Benchmarking
Research Applications
Use of Illness Severity Scores in the Management of Confounding
Demonstration of Effective or Ineffective Randomization
Provision of Objective Context
Reduction of Required Sample Sizes
Critical Evaluation of Illness Severity Scores
Assessment of Model Validity
Discrimination and Calibration
Model Transferability
Veterinary Models: Disease Specific and Disease Independent
Features of Model Construction
Selection of Predictive Variables
Outcome Selection
Model-Building Process
APPLE Scores
Summary
References
Part II: Respiratory Disorders
14 Oxygen Therapy
Key Points
Arterial Oxygen Content
Indications for Oxygen Therapy
Methods of Oxygen Administration
Humidification
Noninvasive Methods
Flow-by oxygen
Face mask
Oxygen hood
Oxygen cage
Invasive Methods
Nasal prongs
Nasal and nasopharyngeal oxygen
Transtracheal oxygen
Hyperbaric Oxygen
Complications of Oxygen Therapy
Oxygen Toxicity
References
15 Hypoxemia
Key Points
Collection of Blood Samples for In Vitro Measurement
Recognition of Hypoxemia
PaO2
SpO2
Cyanosis
Mechanisms of Hypoxemia
Low Inspired Oxygen
Hypoventilation
Venous Admixture
Regions of low ventilation-perfusion (V/Q) ratio
Regions of zero V/Q
Diffusion impairment
Anatomic Shunts
Estimating the Magnitude of the Venous Admixture
PaCO2 + PaO2 Added Value (“The 120 rule”)
Alveolar-Arterial PO2 Gradient
PaO2/FiO2 Ratio
Venous Admixture (Shunt) Calculation
References
16 Hypoventilation
Key Points
Definitions
Control of Breathing
Central Neuronal Control of Breathing
Central and Peripheral Chemoreceptors
Lung Receptors
Respiratory Mechanics and Muscular Control
Differential Diagnosis
Clinical Signs
Diagnosis
Treatment
References
17 Upper Airway Disease
Key Points
History and Clinical Signs
Emergency Stabilization
Diagnostics
Diseases of the Upper Airway
Brachycephalic Airway Syndrome
Nasopharyngeal Polyps
Nasopharyngeal Stenosis
Congenital Choanal Atresia
Nasopharyngeal Foreign Bodies and Infection
Laryngeal Paralysis
Inflammatory Laryngeal Disease
Tracheal Collapse
Tracheal Stenosis/Stricture
Tracheal Foreign Bodies
Upper Airway Neoplasia
Complications of Upper Airway Obstruction
References
18 Brachycephalic Syndrome
Key Points
Pathophysiology
Respiratory Consequences
Consequences of Chronic Upper Airway Obstruction
Management of Upper Airway Obstructive Crises in BD
Gastrointestinal Consequences
Systemic Consequences
Summary
References
19 Tracheal Trauma
Key Points
Causes
Pathophysiology
Clinical Signs
Differential Diagnosis and Diagnostic Testing
Treatment
Outcome and Prognosis
References
20 Allergic Airway Disease in Dogs and Cats and Feline Bronchopulmonary Disease
Key Points
Definition of Allergic Airway Disease
Human Asthma
Pathogenesis of Small Animal Allergic Respiratory Disease
Parasitic Allergic Airway Disease
Canine Allergic Bronchitis or Eosinophilic Bronchopneumopathy
Pulmonary Infiltrates with Eosinophils
Feline Bronchopulmonary Disease
Pathogenesis
Clinical Signs
Laboratory Diagnostic Tests
Radiology
Bronchoscopy
Treatment of Allergic Airway Disease and Feline Bronchopulmonary Disease
Glucocorticoids
Bronchodilators
Miscellaneous Drugs and Other Therapies
Prognosis
References
21 Pulmonary Edema
Key Points
Pathophysiology
Clinical Presentation
High-Pressure Edema
Cardiogenic edema
Fluid therapy
Increased-Permeability Edema
Mixed-Cause Edema
Diagnostic Tests
Treatment
Oxygen Therapy
Medical Therapy
Fluid Therapy
Prognosis
References
22 Pneumonia
Key Points
Clinical Presentation
Initial Evaluation
History
Physical Examination
Diagnostic Testing
Pathophysiology
Mechanism
Causes
Treatment
Additional Management Considerations
Contagion and Zoonosis
Monitoring
Prognosis and Outcome
References
23 Aspiration Pneumonitis and Pneumonia
Key Points
Definitions
Aspiration Pneumonitis
Aspiration Pneumonia
Aspiration Pneumonitis and Pneumonia
Epidemiology
Pathophysiology
Diagnosis
History
Physical examination
Radiography and computed tomography
Tracheal wash
Bronchoscopy and bronchoalveolar lavage
Complete blood cell count and serum biochemistry
Oxygenation status
Biomarkers
Treatment
Airway management
Oxygen therapy
Mechanical ventilation
Antimicrobial therapy
Bronchodilators
Cardiovascular support
Chest physiotherapy
Glucocorticoids
Prevention
References
24 Acute Lung Injury and Acute Respiratory Distress Syndrome
Key Points
The Human Perspective
Criteria for the Diagnosis of ALI/ARDS
Pathophysiology
Treatment
The Canine Perspective
Criteria for the Diagnosis of ALI/ARDS
Treatment
References
25 Pulmonary Contusions and Hemorrhage
Key Points
Pathophysiology and Pathology
Diagnosis
Physical Findings
Imaging: Radiology, Computed Tomography, and Ultrasound
Blood Gas Analysis and Pulse Oximetry
Management
Initial Approach
Oxygen Therapy and Ventilation
Fluid Therapy
Analgesia
Antimicrobial Therapy
Glucocorticoids
Other Therapies
Prognosis and Outcome
Atraumatic Pulmonary Hemorrhage
Diagnostic Evaluation
Treatment
Prognosis and Outcome
References
26 Pulmonary Thromboembolism
Key Points
Pathophysiology
History and Clinical Signs
Physical Examination
Diagnostic Testing
Treatment and Prophylaxis
Summary
References
27 Chest Wall Disease
Key Points
Chest Wall Anatomy and Function
Diagnosis of Chest Wall Disease
Diseases of the Chest Wall
Congenital
Neoplasia
Rib Fractures
Trauma
Flail chest and intercostal muscle damage
Penetrating wounds
Nontraumatic rib fractures
Cervical Spine Disease
Neuromuscular Disease (see Chapter 85)
Tick paralysis
Acute idiopathic polyradiculoneuritis
Botulism
Fulminant myasthenia gravis
Elapidae snake envenomation
References
28 Pleural Space Disease
Key Points
Pleural Space
Clinical Evaluation
Pleural Effusion
Pure Transudates and Modified Transudates
Exudates
Feline Infectious Peritonitis
Pyothorax
Chylothorax
Hemothorax
Neoplastic Effusions and Pleural Neoplasia
Fibrosing Pleuritis
Pneumothorax
Space-Occupying Lesions
Diaphragmatic Hernia
References
29 Nonrespiratory Look-Alikes
Key Points
PH and PCO2 Receptor Activation
PO2 Receptor Activation
Cortical Modification of Respiration
Thermal Receptor Changes
Electrolyte Imbalances and Metabolic Disease
Peripheral Nervous System Disease
Central Nervous System Disease
Clinical Evaluation
Summary
References
Part III: Mechanical Ventilation
30 Basic Mechanical Ventilation
Key Points
Compliance
The Ventilator Breath
Ventilator Settings
Indications for Mechanical Ventilation
Approach to Initiation of Mechanical Ventilation
Goals
Carbon Dioxide
Oxygen
Maintenance of Mechanical Ventilation
Complications
Troubleshooting
Prognosis
References
31 Advanced Mechanical Ventilation
Key Points
Ventilator Concepts
Respiratory Cycle
Equation of Motion
Defining the Ventilator Mode
Breath Type
Control Variable
Phase Variables
Trigger variable
Cycle variable
Limit variable
Baseline variable
Breath Pattern
Continuous mandatory ventilation
Continuous spontaneous ventilation
Intermittent mandatory ventilation
Ventilator Mode
Respiratory Rate and Inspiratory-to-Expiratory Ratio
Positive End-Expiratory Pressure
Ventilator Alarms
Low Airway Pressure Alarm
High Airway Pressure Alarm
Low Tidal Volume Alarm
High Tidal Volume Alarm
Lung-Protective Ventilation
Setting Optimal PEEP
Recruitment Maneuvers
Patient–Ventilator Asynchrony
References
32 Jet Ventilation
Key Points
Physics and Physiology
Equipment
Indications
Disadvantages
Monitoring of Gas Exchange during Jet Ventilation
Ventilator Settings
References
33 Ventilator Waveforms
Key Points
Waveform Types
General
Waveforms in Different Ventilation Modes
Pressure Waveform
Flow Waveform
Volume Waveform
Pressure-Volume Loops
Flow-Volume Loops
Patient–Ventilator Dyssynchrony
Summary
References
34 Care of the Ventilator Patient
Key Points
Anesthesia
Monitoring
Airway Management
Endotracheal Tube
Humidification
Airway Suctioning
Oral Care
Eye Care
Urinary Care
Gastrointestinal Tract
Recumbent Patient Care
Apparatus Care
References
35 Discontinuing Mechanical Ventilation
Key Points
When to Wean
Anesthetic Considerations
Weaning Prediction
Weaning a Patient From Mechanical Ventilation
Spontaneous Breathing Trials
Pressure Support Ventilation
Synchronized Intermittent Mandatory Ventilation
Tracheostomy and Weaning
Monitoring
Failure to Wean
Extubation
Prognosis
References
36 Ventilator-Induced Lung Injury
Key Points
Definitions
Introduction
Evidence From Experimental Models
Stretch Injury
Shear Injury
Biotrauma
Histopathology
Pneumothorax
Oxygen Toxicity
Clinical Relevance
Prevention
Conventional Mechanical Ventilation Strategies
Low tidal volume
Positive end-expiratory pressure
Limitation of plateau pressure
Using the Pressure-Volume Loop to Guide Settings
Avoid Patient–Ventilator Asynchrony
Other Strategies
Advanced Pulmonary Support Techniques
References
37 Ventilator-Associated Pneumonia
Key Points
Pathogenesis
Diagnosis
Prevention
Nonpharmacologic Strategies
Pharmacologic Strategies
Treatment
References
Part IV: Cardiac Disorders
38 Mechanisms of Heart Failure
Key Points
Neurohormonal Aspects of Heart Failure
Renin-Angiotensin-Aldosterone System
Sympathetic Nervous System
Natriuretic Peptide System
Endothelin and Vasopressin Systems
Myocardial Remodeling
Abnormal Calcium Ion Handling
Abnormal Myocardial Energy Production
Global Cardiac Function
The Frank-Starling Mechanism as a Key to Understanding Heart Failure
Diastolic Heart Dysfunction
Clinical Staging and Assessment of Heart Failure
Clinical Manifestations of Heart Failure
Low output versus congestive failure
Left-sided versus right-sided heart failure
References
39 Cardiogenic Shock
Key Points
Pathophysiology
Clinical Signs and Diagnosis
Systolic Dysfunction
Failure of Contractility
Dilated cardiomyopathy
Sepsis
Endomyocarditis
Myocardial infarction
Mechanical Failure
Diastolic Failure
Cardiac Tamponade
Hypertrophic Cardiomyopathy
Tachyarrhythmias
Bradyarrhythmias
References
40 Ventricular Failure and Myocardial Infarction
Key Points
Basic Terminology
Causes of Ventricular (Systolic) Failure
Primary Causes
Secondary to Other Cardiac Disease
Extracardiac Causes
Myocardial Infarction
Physical Examination
Diagnostic Tests
Pathophysiology
Treatment
Supporting Contractility and Maintaining Blood Pressure
Relieving Signs of Congestion
Suppressing Arrhythmias
Treating the Underlying Cause
References
41 Feline Cardiomyopathy
Key Points
Etiopathogenesis
Pathophysiology
Diastolic Dysfunction
Systolic Anterior Motion of the Mitral Valve
Feline Arterial Thromboembolism (FATE)
Clinical Presentation
Patient History and Physical Findings
Electrocardiography
Radiography
Echocardiography
Systemic Blood Pressure
Bloodborne Cardiac Biomarkers
Diagnostic Approach
Therapeutic Approach
Management of FATE
Management of Acutely Decompensated Heart Failure
Management of Chronic Heart Failure
References
42 Canine Cardiomyopathy
Key Points
Dilated Cardiomyopathy
Physical Examination
Thoracic Radiography
Electrocardiography
Routine Blood Tests
Effusion Analysis
Echocardiography
Acute Treatment of Congestive Heart Failure
Long-Term Treatment of Dilated cardiomyopathy
Diuretics
Angiotensin-Converting Enzyme Inhibitors
Digoxin
Pimobendan
Novel Therapy
Diet
Supplements
Treatment of Arrhythmias
Breed Variations with DCM
Cocker Spaniels
Doberman Pinschers
Dalmatians
Great Danes and Irish Wolfhounds
Portuguese Water Dogs
Arrhythmogenic Right Ventricular Cardiomyopathy in Boxers
Electrocardiography
Treatment of Arrhythmogenic Right Ventricular Cardiomyopathy
Hypertrophic Cardiomyopathy in Dogs
Pathologic Features
Important Differentials for Concentric Hypertrophy of the Left Ventricle
Uncommon Myocardial Diseases of Dogs
Duchenne Cardiomyopathy
Atrioventricular Myopathy
Toxic Myocardial Disease
References
43 Valvular Heart Disease
Key Points
Pathology
Pathophysiology
History and Physical Examination
Laboratory Evaluation
Electrocardiographic Findings
Radiographic Findings
Echocardiographic Findings
Emergency Management
Cardiac Output
Tissue Oxygenation
Arrhythmia Management and Adjunctive Therapy
Monitoring
Long-Term Therapy
Prognosis
Infectious Endocarditis
References
44 Myocardial Contusion
Key Points
Incidence
Etiology, Mechanism of Injury, and Pathophysiology
Diagnosis
Treatment
Summary
References
45 Pericardial Diseases
Key Points
Pericardial Effusion
Hemorrhagic Pericardial Effusion
Hemangiosarcoma
Heart base tumors
Other neoplasia
Idiopathic (benign) pericardial effusion
Transudative Pericardial Effusion
Exudative Pericardial Effusion
Cardiac Tamponade
Clinical Presentation
Physical Findings with Tamponade
Diagnosis
Thoracic Radiographs
Echocardiography
Electrocardiography
Central Venous Pressure
Clinicopathologic Findings
Pericardial Fluid Analysis
Management of Cardiac Tamponade
Pericardiocentesis
Preparation and Positioning
Pericardiocentesis Procedure
Complications of Pericardiocentesis
Ancillary Treatment
Idiopathic Pericardial Effusion
Neoplastic Pericardial Effusion
Infectious Pericarditis
Constrictive Pericardial Disease
Clinical Features
Diagnosis
Treatment
Congenital Pericardial Disease
Clinical Features
Diagnosis
Treatment
References
46 Bradyarrhythmias and Conduction Disturbances
Key Points
Definition
Differential Diagnosis
Sinus Bradycardia
Sinus Node Dysfunction
Atrioventricular Block
Atrial Standstill
Treatment
Medical Treatment
Pacemaker Therapy
Transcutaneous pacing
Temporary transvenous pacing
References
47 Supraventricular Tachyarrhythmias
Key Points
Historical Data
Physical Examination Findings
Examining the Electrocardiogram
Distinguishing Supraventricular from Ventricular Tachyarrhythmias
Diagnosing Atrial Versus Atrioventricular Node–Dependent Tachyarrhythmias
Treatment of Supraventricular Tachyarrhythmias
Emergent Therapy
Long-Term Therapy
Medical treatment
Catheter ablation
References
48 Ventricular Tachyarrhythmias
Key Points
Introduction
Electrocardiographic Diagnosis
Approach to the Patient with Ventricular Tachycardia
Noncardiac Causes of Ventricular Tachycardia
Cardiac Causes of Ventricular Tachycardia
Antiarrhythmic Treatment
Decision to Treat
Antiarrhythmic Drugs
Lidocaine
Procainamide
β-Blockers
Sotalol
Amiodarone
Magnesium sulfate
Other Treatments
Anesthesia
Electrical therapies
Postintervention Monitoring
References
49 Myocarditis
Key Points
Infectious Myocarditis
Viral Myocarditis
Protozoal Myocarditis
Chagas’ disease
Bacterial and Other Causes of Myocarditis
Noninfectious Myocarditis
Doxorubicin Toxicity
Diagnosis
Treatment
References
Part V: Electrolyte and Acid-Base Disturbances
50 Sodium Disorders
Key Points
Distribution of Total Body Water
Osmolality and Osmotic Pressure
Regulation of Plasma Osmolality
Antidiuretic hormone
Thirst
Prioritization of Osmolality and Effective Circulating Volume
Total Body Sodium Content Versus Plasma Sodium Concentration
Hypernatremia
Etiology
Free water deficit
Sodium excess
Clinical Signs
Physiologic Adaptation to Hypernatremia
Treatment of the Normovolemic, Hypernatremic Patient
Complications of Therapy for Hypernatremia
Hyponatremia
Etiology
Decreased effective circulating volume
Hypoadrenocorticism
Diuretics
Syndrome of inappropriate antidiuretic hormone secretion
Other causes of hyponatremia
Clinical Signs
Physiologic Adaptation to Hyponatremia
Treatment of the Normovolemic, Hyponatremic Patient
Patients asymptomatic for hyponatremia
Patients symptomatic for hyponatremia
Complications of Therapy for Hyponatremia
Pseudohyponatremia
Volume Expansion in the Hypovolemic, Hyponatremic, or Hypernatremic Patient
References
51 Potassium Disorders
Key Points
Normal Distribution of Potassium in the Body
Hypokalemia
Definition and Causes
Consequences
Management of Hypokalemia
Anticipated Complications
Hyperkalemia
Definition and Causes
Consequences
Pseudohyperkalemia
Treatment of Hyperkalemia
References
52 Calcium Disorders
Key Points
Calcium Homeostasis
Calcium Measurement
Sample Handling Techniques
Ionized Versus Total Calcium
Hypercalcemia
Clinical Signs and Diagnosis
Differential Diagnoses
Treatment of Hypercalcemia
Hypocalcemia
Clinical Signs and Diagnosis
Differential Diagnoses
Treatment
References
53 Magnesium and Phosphate Disorders
Key Points
Magnesium
Hypomagnesemia
Causes
Clinical signs
Diagnosis
Therapy
Hypermagnesemia
Causes
Clinical signs
Diagnosis
Therapy
Phosphate
Hypophosphatemia
Causes
Clinical signs
Diagnosis
Therapy
Hyperphosphatemia
Causes
Clinical signs
Diagnosis
Treatment
References
54 Traditional Acid-Base Analysis
Key Points
Sample Collection and Handling
Traditional Approach
PCO2
Bicarbonate
Base Excess
Total Carbon Dioxide
Anion Gap
Compensation
Acid-Base Analysis
Causes of Acid-Base Abnormalities
Respiratory Acidosis
Respiratory Alkalosis
Metabolic Acidosis
Metabolic Alkalosis
Bicarbonate Therapy
Dose and Administration
References
55 Nontraditional Acid-Base Analysis
Key Points
The Stewart Approach
Strong Ion Difference
Total Weak Acids (ATOT)
Strong Ion Gap
Semi-Quantitative Approach
Free Water Effect
Chloride Effect
Albumin Effect
Phosphate Effect
Lactate Effect
Unmeasured Ions (XA)
Conclusion
Clinical Examples
Case 1
Case 2
References
56 Hyperlactatemia
Key Points
Introduction
Biochemistry
Physiology
Lactate Pharmacokinetics in Health
Lactate Pharmacokinetics in Disease
Etiology of Hyperlactatemia
Type A Hyperlactatemia
Increased oxygen demand
Decreased oxygen delivery
Type B Hyperlactatemia
Type B1
Type B2
Type B3
Hyperlactatemia Without Metabolic Acidosis
d-Lactate
Clinical Use
Prognostic Use
Diagnostic Use
Lactate as a Therapeutic Endpoint
References
Part VI: Fluid Therapy
57 Assessment of Hydration
Key Points
Introduction
Physiologic Definitions
Variability in Assessing Hydration
Distribution and Control of Total Body Water
Measuring Total Body Water
Clinical Assessment of Hydration Status
Interstitial Volume Changes
Intravascular Volume Changes
Intracellular Volume Changes
Hypotonic Fluid Loss
Isotonic Fluid Loss
Special Challenges
Conclusion
References
58 Crystalloids, Colloids, And Hemoglobin-Based Oxygen-Carrying Solutions
Key Points
Crystalloids
Isotonic Fluids
Hypotonic Fluids
Hypertonic Fluids
Acid-Base Effects of Crystalloids
Colloids
Synthetic Starch Colloids
Allogenic Blood Products
Human Albumin
Hemoglobin-Based Oxygen-Carrying Solutions
Conclusion
References
59 Daily Intravenous Fluid Therapy
Key Points
Total Body Water
Movement of Fluids Within the Body
Isotonic Fluid Loss
Hypotonic Fluid Loss
Hypertonic Fluid Loss
Increased Vascular Permeability
Fluid Therapy Plan
Fluid Deficit
Maintenance Fluid Therapy
Ongoing Losses
Route of Administration
Fluid Type
Replacement Fluids
Maintenance Fluids
Free Water Administration
Synthetic Colloids
Monitoring
Discontinuation of Fluid Therapy
References
60 Shock Fluids and Fluid Challenge
Key Points
Administration of Shock Fluids
Resuscitation Endpoints and Monitoring
Shock Fluids
Isotonic Crystalloids
Adverse effects
Synthetic Colloids
Hetastarch
Tetrastarch
Pentastarch
Adverse effects
Hypertonic Solutions
Adverse effects
Albumin
Blood Products
Hypotensive Resuscitation
Fluid Challenge
References
61 Transfusion Therapy
Key Points
Indications for Transfusion Therapy
Red Blood Cell Transfusions
Fresh Frozen Plasma
Other Blood Products
Blood Typing
Canine Blood Types
Feline Blood Types
Blood Crossmatching
Blood Donors and Sources
Blood Collection
Administration of Blood Products
Adverse Transfusion Reactions
Alternatives
References
62 Prevention and Treatment of Transfusion Reactions
Key Points
Complications of Blood Products Transfusions
Monitoring
Severe Transfusion Reactions in the Canine
Severe Transfusion Reactions in Felines
Additional Diagnostics
Storage Lesions
Leukoreduction
Future Directions
References
63 Massive Transfusion
Key Points
Electrolyte Disturbances
Hemostatic Defects
Hypothermia
Metabolic Acidosis
Immunosuppression and Wound Healing
Acute Lung Injury
Other Immunologic Transfusion Reactions
Nonimmunologic Transfusion Reactions
Recommendations for Management
Outcome
References
Part VII: Endocrine Disorders
64 Diabetic Ketoacidosis
Key Points
Pathophysiology
Risk Factors
Clinical Signs and Physical Examination Findings
Clinical Pathology
Differential Diagnosis
Treatment
Outcome
References
65 Hyperglycemic Hyperosmolar Syndrome
Key Points
Pathogenesis
Hormonal Alterations
Reduction of Glomerular Filtration Rate
Influence of Concurrent Disease
History and Clinical Signs
Physical Examination
Diagnostic Criteria
Additional Diagnostic Evaluation
Treatment
Fluids
Insulin
Electrolytes
Treating Concurrent Disease
Monitoring
Postcrisis Therapy
Prognosis
References
66 Hypoglycemia
Key Points
Normal Glucose Homeostasis
Clinical Signs and Consequences of Hypoglycemia
Diagnosis of Hypoglycemia
Causes of Hypoglycemia
Excess Insulin or Insulin Analogs
Exogenous insulin overdose
Insulinoma
Paraneoplastic hypoglycemia
Toxins and medications
Inadequate Glucose Production
Hypoglycemia of neonates and toy breed dogs
Hepatic disease
Hypocortisolism and other counterregulatory hormone deficiencies
Excess Glucose Utilization
Infection
Exercise-induced hypoglycemia
Polycythemia and leukocytosis
Treatment of Hypoglycemic Crisis
References
67 Diabetes Insipidus
Key Points
Urine Concentration Mechanism
Vasopressin Secretion and Sodium Homeostasis
Antidiuretic Effects of Vasopressin
Central Diabetes Insipidus
Nephrogenic Diabetes Insipidus
Diagnosing Diabetes Insipidus
Modified Water Deprivation Test
Problems and risks
Causes of misdiagnoses
Associated risks
Desmopressin Acetate Trial
Imaging After a Diagnosis of CDI
Treatment of Diabetes Insipidus
Emergency Treatment
Prognosis
References
68 Syndrome Of Inappropriate Antidiuretic Hormone
Key Points
Causes
Clinical Signs
Laboratory Findings
Diagnostic Imaging Findings
Diagnosis
Treatment
Prognosis
References
69 Thyroid Storm
Key Points
Pathogenesis
High Levels of Circulating Thyroid Hormones
Rapid, Acute Increases in Circulating Thyroid Hormones
Hyperactivity of the Sympathetic Nervous System
Increased Cellular Response to Thyroid Hormones
Precipitating Events
Clinical Signs
Diagnosis
Laboratory Abnormalities
Treatment
Reduction in Production or Secretion of New Thyroid Hormones
Inhibition of Peripheral Effects of Thyroid Hormone
Systemic Support
Eradication of the Precipitating Factor
Outcome
References
70 Hypothyroid Crisis in the Dog
Key Points
Pathophysiology
Risk Factors
Clinical Signs and Physical Examination Findings
Clinical Pathology
Differential Diagnosis
Treatment
Outcome
References
71 Pheochromocytoma
Key Points
Clinical Signs
Diagnosis
Treatment
Preoperative Treatment
Anesthesia and Monitoring
Surgical Excision
Postoperative Monitoring and Complications
Medical Treatment
Prognosis
References
72 Critical Illness–Related Corticosteroid Insufficiency
Key Points
Background
Suspected Pathophysiology
Clinical Manifestations
Diagnosis of CIRCI
Veterinary Data
Treatment of CIRCI
Veterinary Data
Prognosis
References
73 Hypoadrenocorticism
Key Points
Who is Affected?
Etiology
Clinical Presentation
History
Physical Examination
Clinicopathologic Findings
Electrocardiographic Findings
Diagnostic Imaging
Diagnosis
Treatment
Fluid Therapy
Initial Hormonal Replacement
Supportive Therapies
Timeline for Clinical Improvement
Associated Disorders
Prognosis
References
Part VIII: Therapeutic Drug Overdose
74 Approach to Drug Overdose
Key Points
Obtaining an Appropriate History
Triage
When to Decontaminate
Activated Charcoal (AC)
Multidose Activated Charcoal
Contraindications and Complications of Activated Charcoal Administration
Cathartics
Treatment
Fluid Therapy
Gastrointestinal Support
Neurologic Support
Sedatives and Reversal Agents
Hepatoprotectants
Miscellaneous
Intravenous Lipid Emulsion
Conclusion
References
75 Blood Purification for Intoxications and Drug Overdose
Key Points
Methods
Toxin Overview
Considerations
Ethylene Glycol
Acetaminophen
Nonsteroidal Antiinflammatory Drugs
Mushrooms
Barbiturates
Lily Ingestion
Summary
References
76 Nonsteroidal Antiinflammatory Drugs
Key Points
COX-1, COX-2, and Prostaglandins
Potential Adverse Effects
Gastrointestinal Effects
Renal Effects
Hepatic Effects
Coagulation Effects
Bone and Cartilage Effects
Neurologic Effects
Drug Interactions with NSAIDs
Toxic Dosage
Clinical Signs
Diagnosis of NSAID Toxicity
Treatment
Asymptomatic Patients
Symptomatic Patients
Prognosis
Client Education
References
77 Sedative, Muscle Relaxant, and Narcotic Overdose
Key Points
Sedative Overdose
Mechanism of Action
Pharmacokinetics
Clinical Signs
Treatment
Muscle Relaxant Overdose
Mechanism of Action
Pharmacokinetics
Clinical Signs
Treatment
Prognosis
Narcotic Overdose
Mechanism of Action
Pharmacokinetics
Clinical Signs
Treatment
Prognosis
References
78 Calcium Channel Blocker and β-Blocker Drug Overdose
Key Points
Method of Action
Calcium Channel Blockers
Cardiac effects
Vascular effects
Pancreatic effects
β-Blockers
Cardiac effects
Pulmonary, pancreatic, gastrointestinal, vascular, and renal effects
Pharmacokinetics
Calcium Channel Blockers
β-Blockers
Diagnosis of Overdose
Therapy
Asymptomatic Patients
Decontamination
Symptomatic Patients
Calcium salts
Parasympatholytics and sympathomimetics
Vasopressin
Glucagon
Hyperinsulinemia and euglycemia
Intravenous lipid emulsion
Mechanical support
Supportive Care
Conclusion
References
79 Serotonin Syndrome
Key Points
Definition
Serotonin and Pathophysiology of Serotonin Syndrome
Clinical Signs
Toxicity
Diagnosis and Treatment
Prognosis
References
Part IX: Neurologic Disorders
80 Deteriorating Mental Status
Key Points
States of Consciousness
Normal
Obtunded
Stupor or Semicoma
Coma
Neuroanatomy
Cerebrum
Reticular Activating System
Etiology of Lesions
Evaluation
Level of Consciousness
Motor Activity
Respiratory Patterns
Pupil Size and Reactivity
Oculocephalic Reflex
Diagnostic Approach
Treatment
References
81 Coma Scales
Key Points
Intracranial Pressure After Head Trauma
Neurologic Assessment
Modified Glasgow Coma Scoring System
Levels of Consciousness
Limb Movements, Posture, and Reflexes
Neuroophthalmologic Examination
Pupils
Eye movements
Coma Scales and Long-Term Functional Outcome
The Future of Coma Scales
References
82 Seizures and Status Epilepticus
Key Points
Definitions
Classification
Pathophysiology
Etiology
Diagnostic Plan
History
Age and Breed
Physical Examination
Neurologic Examination
Minimum Database
Diagnostic Tests for Intracranial Disease
Treatment Plan
Status Epilepticus
Pharmacologic Therapy for Status Epilepticus
Benzodiazepines
Barbiturates
Propofol
Chronic Seizure Disorders
References
83 Spinal Cord Injury
Key Points
Pathophysiology
Localization
Spinal Cord Segments S1-S3
Spinal Cord Segments L4-S1
Spinal Cord Segments T3-L3
Spinal Cord Segments C6-T2
Spinal Cord Segments C1-C5
Spinal Shock
Diagnosis
Treatment
Prognosis
Acknowledgment
References
84 Intracranial Hypertension
Key Points
Physiology of Intracranial Pressure
Intracranial Fluid Dynamics
Cerebrospinal Fluid Flow
Brain Water Movement
Cerebral Blood Flow
Intracranial Pressure
Homeostatic Responses of the Brain
Volume buffering
Autoregulatory mechanisms
Pressure autoregulation
Chemical autoregulation
Partial Pressure of Arterial Carbon Dioxide.
Partial Pressure of Arterial Oxygen.
Cerebral Metabolic Rate of Oxygen Consumption.
Cushing Response
Causes of Intracranial Hypertension
Clinical Aspects of Intracranial Hypertension
Level of Consciousness
Brainstem Reflexes
Size and reactivity of pupils
Resting eye position, eye movements, and oculovestibular reflexes
Corneal reflexes
Respiration
Motor Responses
Posture
Diagnosis of Intracranial Hypertension
Treatment of Intracranial Hypertension
General Supportive Care
Prevent hypoxia
Prevent hypotension
Guidelines for Specific Therapy of Intracranial Hypertension
Maintain adequate cerebral perfusion pressure
Decrease cerebral venous blood volume
Control PaCO2
Control PaO2
Reduce cerebral edema with hyperosmolar fluid therapy
Mannitol
Hypertonic Saline
Furosemide
Glucocorticoids
Other Drugs
Cerebral metabolic rate of oxygen consumption
Surgical therapy
Other considerations
Prognosis
References
85 Diseases of the Motor Unit
Key Points
Identifying Neuropathies, Junctionopathies, and Myopathies
Clinical Signs
Clinicopathologic Testing
Electrophysiologic Testing
Nerve and Muscle Biopsy
Imaging
Causes of Acute Neuropathy, Myopathy, or Junctionopathy
Acute Neuropathies
Neuropathies Associated with Specific Cranial Nerves
Trigeminal neuritis
Trigeminal nerve sheath tumor
Facial nerve paralysis
Laryngeal paralysis
Traumatic Neuropathies
Acute Polyneuropathies
Metabolic causes
Neoplasia
Toxoplasmosis and neosporosis
Acute polyradiculoneuritis
Aortic thromboembolism
Intoxications
Myopathies
Inflammatory Myopathies
Generalized polymyositis
Masticatory myositis
Noninflammatory generalized myopathies
Megaesophagus
Junctionopathies
Acquired myasthenia gravis
Botulism
Tick paralysis
Snake bites
Aminoglycoside intoxication
References
86 Tetanus
Key Points
Etiology
Pathogenesis
Clinical Presentation
Diagnosis
Treatment
Neutralization of Unbound Toxin
Removal of Source of Infection
Control of Rigidity and Spasms
Supportive Intensive Care
Prognosis
References
87 Vestibular Disease
Key Points
Neuroanatomy of the Vestibular System
Nerve Pathways to the Extraocular Muscles
Neuron 1
Neuron 2
Nerve Pathways to the Spinal Cord
Nerve Pathways to the Cerebellum
Clinical Signs
Specific Signs of Vestibular Dysfunction
Head tilt
Nystagmus
Ataxia
Signs That May Be Associated with Vestibular Dysfunction
Facial paresis, paralysis, and hemifacial spasm
Horner’s syndrome
Conscious proprioception deficits
Hemiparesis or tetraparesis
Circling, leaning, and falling
Altered mental state
Multiple cranial nerve dysfunction
Decerebellate posturing
Vomiting
Differential Diagnosis of Acute Vestibular Disease
Diagnostic Approach to the Animal with Acute Vestibular Disease
Minimum Database
Otoscopy and Pharyngeal Examination
Radiography
Myringotomy
Brainstem Auditory Evoked Potentials
Cerebrospinal Fluid Analysis
Advanced Imaging
Treatment and Prognosis
References
88 Hepatic Encephalopathy
Key Points
Causes
Pathophysiology
Clinical Signs
Diagnosis
Treatment
References
Part X: Infectious Disorders
89 Nosocomial Infections and Zoonoses
Key Points
Nosocomial Infections in Dogs and Cats
Risk Factors
Multiple Antibiotic–Resistant Nosocomial Pathogens
Zoonoses
Emerging Nosocomial Infections in Dogs and Cats
Nosocomial Infection Prevention and Control
Conclusion
References
90 Febrile Neutropenia
Key Points
Neutrophil Physiology
Neutrophil Function
Neutrophil Production
Pathophysiology of Neutropenia
Increased Utilization
Decreased Egress from the Bone Marrow
Depletion of granulocyte progenitor cells
Infectious diseases
Medications, toxicants, and radiation
Myelophthisis
Cyclic hematopoiesis
Ineffective granulopoiesis despite normal to excessive quantities of progenitor cells
Immune-Mediated Destruction
Clinical Presentation and Diagnostic Tests
Treatment and Supportive Care
References
91 Sepsis and Septic Shock
Key Points
Definitions and Clinical Manifestations
Pathogenesis of the Septic Systemic Inflammatory Response
Microbial Factors
Host Response to Bacterial Infection
Loss of Homeostatic Mechanisms in Sepsis
Loss of vasomotor tone
Dysregulation of inflammation and coagulation
Endothelial, microcirculatory, and mitochondrial abnormalities
Epidemiology
Septic Foci, Diseases, and Pathogens Associated with Sepsis
Resuscitation and Treatment of Sepsis, Severe Sepsis, and Septic Shock
Introduction to the Bundle Concept
Bundle Element: Lactate
Bundle Element: Samples for Culture (Blood, Tissue, or Fluid Cultures)
Bundle Element: Early Source Control and Early Antibiotic Administration (see Chapters 175 to 182)
Bundle Element: Treat Hypotension with Fluids and Possibly Vasopressors
Assessment of volume status and responsiveness
Fluid choice
Hypotension despite volume resuscitation (septic shock)
Bundle Element: Target Central Venous Pressure and Central Venous Pressure and ScvO2
Conclusion
References
92 Mycoplasma, Actinomyces, and Nocardia
Key Points
Nonhemotropic Mycoplasmas
Etiology and Clinical Syndromes
Respiratory Infections
Urogenital Associated Infections
Other Infections
Diagnosis
Treatment
Actinomycosis and Nocardiosis
Etiology and Clinical Syndromes
Clinical Signs
Diagnosis
Treatment
References
93 Gram-Positive Infections
Key Points
Gram-Positive Cell Structure and Pathogenicity
Streptococcal Infections
Enterococcal Infections
Staphylococcal Infections
Empiric Antibiotic Strategies
References
94 Gram-Negative Infections
Key Points
Gram-Negative Cell Structure and Pathogenicity
Identification of Gram-Negative Bacteria of Medical Importance
Enterobacteriaceae
Nonfermenting Gram-Negative Bacteria
Resistance among Gram-Negative Pathogens
Therapy for Gram-Negative Infections
References
95 Fungal Infections
Key Points
Blastomycosis
Clinical Signs
Diagnosis
Prognosis
Histoplasmosis
Clinical Signs
Diagnosis
Prognosis
Coccidioidomycosis
Clinical Signs
Diagnosis
Prognosis
Cryptococcosis
Clinical Signs
Diagnosis
Prognosis
Treatment
Respiratory Supportive Therapy
Gastrointestinal Supportive Therapy
Ocular Supportive Therapy
Other Supportive Therapy
References
96 Viral Infections
Key Points
Canine Distemper Virus Infection
Canine Influenza Virus Infection
Other Emerging Respiratory Viral Infections of Dogs
Feline Panleukopenia
Feline Respiratory Viral Disease
Feline Infectious Peritonitis
References
97 Canine Parvovirus Infection
Key Points
Evolution of Canine Parvovirus 2
Signalment
Pathogenesis
Clinical Signs
Diagnosis
Clinicopathologic Findings
Diagnostic Imaging
Treatment
Fluid Therapy
Antibiotics
Antiemetics
Nutrition
Antiviral Drugs
Gastric Protectants
Controversial Treatments
Vaccination
Prevention of Transmission
Acknowledgement
References
98 Infective Endocarditis
Key Points
Pathophysiology
Microbial Adherence and Endothelial Invasion
Congestive Heart Failure
Immune-Mediated Disease
Thromboembolism
Incidence, Signalment, and Presenting Complaint
Predisposing Factors
Etiologic Agents
Clinical Abnormalities
Clinicopathologic Abnormalities
Diagnosis
Echocardiography
Blood Culture
Modified Duke Criteria for Diagnosis of Infective Endocarditis
Treatment
Prognosis
References
99 Urosepsis
Key Points
Pathogenesis
Causes of Urosepsis
Pyelonephritis
Bladder Rupture
Prostatic Infection
Pyometra
Catheter-Associated Urinary Tract Infection
Conclusion
References
100 Mastitis
Key Points
Anatomy: Brief Overview
Etiology
Clinical Findings
Acute Mastitis
Chronic or Subclinical Mastitis
Diagnosis
Differential Diagnoses
Treatment
References
101 Necrotizing Soft Tissue Infections
Key Points
Diagnosis
Laboratory Findings
Imaging
Definitive Diagnosis
Treatment
Antimicrobial Therapy
Surgical Debridement
Postoperative Care
Hyperbaric Oxygen
Conclusion
References
102 Catheter-Related Bloodstream Infection
Key Points
Definition
Incidence
Diagnosis
Treatment
Prevention
References
103 Multidrug-Resistant Infections
Key Points
Definitions
Risk Factors for Multidrug-Resistant Pathogens
Escalation Versus De-Escalation Therapy
Specific Multidrug-Resistant Pathogens
Methicillin-Resistant Staphylococcus
Enterococcus
Pseudomonas aeruginosa
β-Lactamase–Producing Gram-Negative Bacteria
References
Part XI: Hematologic Disorders
104 Hypercoagulable States
Key Points
Mechanisms of Thrombophilia
Endothelial Disturbances
Increased Procoagulant Elements
Decreased Endogenous Anticoagulants
Perturbations in Fibrinolysis
Diagnostics
Common Conditions in Veterinary Medicine
Systemic Inflammation
Protein-Losing Nephropathy
Immune-Mediated Hemolytic Anemia
Hypercortisolemia
Cardiomyopathies
Neoplasia
Isolated Brain Injury
Management of Hypercoagulable Conditions
Treatment of the Underlying Condition
Recombinant Anticoagulant Therapy
Antithrombotic Therapy
Inflammatory conditions
Protein-losing nephropathy
Immune-mediated hemolytic anemia
Hypercortisolemia
Cardiomyopathies
Neoplasia
Isolated brain injury
Conclusion
References
105 Bleeding Disorders
Key Points
Hemostasis and Fibrinolysis
Hemostatic Testing
Platelet Enumeration and Estimation
Buccal Mucosal Bleeding Time
The Prothrombin Time and Activated Partial Thromboplastin Time
Fibrin Split Products
D-dimers
Fibrinogen Concentration
Thrombin Time
Thromboelastography and Thromboelastometry
Etiology
Hypocoagulability in the Critically Ill or Injured Patient
Dilutional Coagulopathy
Hypothermia
Acidemia
Diagnosis
History
Physical Examination
Hemostatic Testing
Principles of Management
Plasma and Platelet transfusion
Prohemostatic Agents
Desmopressin
Antifibrinolytics
Specific Conditions
Thrombocytopenia
Thrombopathia
Inherited Coagulopathies
Vitamin K Deficiency
Hepatic Failure
Trauma-Induced Coagulopathy
Disseminated Intravascular Coagulation
Delayed Postoperative Bleeding in Greyhound Dogs
References
106 Thrombocytopenia
Key Points
Causes
Thrombocytopenia in the Critically Ill
Diagnostic Techniques for Thrombocytopenia
Mechanisms of Thrombocytopenia
Decreased Production
Consumption
Sequestration
Increased Destruction
Therapeutic Approaches to Thrombocytopenia
Platelet Transfusions
References
107 Platelet Disorders
Key Points
Inherited Disorders
Extrinsic Disorders
Intrinsic Disorders
Acquired Disorders
Drugs
von Willebrand’s Disease
Uremia
Treatment Summary
References
108 Anemia
Key Points
Signalment and History
Clinical Signs
Laboratory Tests
Therapeutic Principles
Summary
References
109 Methemoglobinemia
Key Points
Pathophysiology
Oxidation in the Erythrocyte
Heinz Bodies
Specific Causes of Erythrocyte Oxidation
Acetaminophen
Topical Benzocaine
Skunk Musk
Nitrites and Nitrates
Hydroxycarbamide
Methemoglobin Reductase Deficiency
Diagnosis
Clinical Signs
Determining Methemoglobin Presence and Levels
Treatment
N-Acetylcysteine
Methylene Blue
Adjunctive Treatments
References
110 Acute Hemolytic Disorders
Key Points
Evaluation of the Patient with Hemolysis
Fragmentation Hemolysis
Toxicant-Induced Hemolysis
Heritable Hemolysis
Infection-Related Hemolysis
Infection of Red Blood Cells
Systemic Infections
Immune-Mediated Hemolysis
Findings Suggestive of Immune-Mediated Hemolytic Anemia
Treatment of Immune-Mediated Hemolytic Anemia
Immune suppression
Supportive care
Prevention of complications
Other Causes of Immune-Mediated Hemolytic Anemia
References
111 Rodenticides
Key Points
Anticoagulant Rodenticides
Pathophysiology and Clinical Signs
Case Management
Acute ingestion
Coagulopathies
Outcome
Cholecalciferol
Pathophysiology and Clinical Signs
Case Management
Acute ingestion
Hypercalcemia
Outcome
Bromethalin
Pathophysiology and Clinical Signs
Case Management
Acute ingestion
Neurologic complications
Outcome
Miscellaneous Rodenticides
References
Part XII: Intraabdominal Disorders
112 Acute Abdominal Pain
Key Points
Diagnostic Evaluation
Signalment and History
Physical Examination
Emergency Clinical Pathology
Abdominal Radiographs
Abdominal Fluid Analysis
Surgical Versus Medical Management
References
113 Acute Pancreatitis
Key Points
Pathophysiology
Clinical Presentation
Diagnosis
Laboratory Assessment
Diagnostic Imaging
Cytology and Histopathology
Additional Diagnostic Evaluation
Determining Severity
Treatment
Resuscitation, Fluid Therapy, and Monitoring
Pain Management
Nutrition
Additional and Supportive Therapy
Antibiotic Therapy
Surgery
Outcome
Conclusion
References
114 Acute Cholecystitis
Key Points
Clinical Findings
Common Causes of Cholecystitis in Dogs and Cats
Infectious Agents
Bacteria
Parasites
Obstruction
Gallbladder Mucocele
Gallbladder Infarction
References
115 Hepatitis and Cholangiohepatitis
Key Points
Historical Findings
Physical Examination Findings
Mechanisms of Hepatocellular Injury
Causes of Hepatitis and Cholangiohepatitis in Dogs and Cats
Idiopathic Causes
Feline cholangitis complex
Neutrophilic Cholangitis
Lymphocytic Cholangitis
Canine chronic hepatitis
Role of Copper
Nonspecific reactive hepatitis
Viral Causes
Infectious canine hepatitis
Feline infectious peritonitis
Bacterial Causes
Leptospirosis
Bartonellosis
Septicemia
Drugs and Toxins
References
116 Hepatic Failure
Key Points
Pathophysiology
Hepatic Encephalopathy
Coagulation Disorders
Other
Clinical Signs
Diagnosis
Therapy
Prognosis
Future Therapies
References
117 Gastroenteritis
Key Points
Anatomy and Physiology
History and Clinical Signs
Causes
Infectious Gastroenteritis
Viral enteritis
Bacterial enteritis
Parasitic gastroenteritis
Fungal gastroenteritis
Hemorrhagic Gastroenteritis
Dietary Indiscretion
Protein-Losing Enteropathy
Extraintestinal Diseases
Diagnosis
Treatment
Conclusion
References
118 Motility Disorders
Key Points
Megaesophagus
Etiology and Clinical Signs
Diagnosis and Treatment
Gastric Emptying Disorders
Etiology and Clinical Signs
Diagnosis and Treatment
Small Intestinal Transit Disorders
Etiology and Clinical Signs
Diagnosis and Treatment
Megacolon
Etiology and Clinical Signs
Diagnosis and Treatment
Prokinetic Drugs for Gastrointestinal Motility Disorders
Serotonergic Drugs
Cisapride
Metoclopramide
Ghrelin Mimetics and Motilin Receptor Agonists
Acetylcholinesterase Inhibitors
References
119 Gastrointestinal Hemorrhage
Key Points
Etiology
History and Physical Examination
Diagnostic Tests
Tests to Help Detect Presence of Gastrointestinal Hemorrhage
Tests to Help Identify Underlying Causes
Treatment
Medical Management
Endoscopy, Interventional Radiology, and Surgery
Prognosis
References
120 Regurgitation and Vomiting
Key Points
Differentiation of Vomiting and Regurgitation
Regurgitation
Definition
Clinical Consequences of Regurgitation
Differential Diagnoses
Diagnostic Approach
History
Physical examination
Clinical pathology
Diagnostic imaging
Further diagnostic testing
General Treatment Guidelines
Prognosis
Vomiting
Definition
Physiology of Vomiting
Clinical Consequences of Vomiting
Differential Diagnoses
Diagnostic Approach
History
Physical examination
Clinical pathology
Diagnostic imaging
General Treatment Guidelines
Conclusion
References
121 Diarrhea
Key Points
Pathophysiologic Mechanisms of Diarrhea
Iatrogenic Causes of Diarrhea
Primary Gastrointestinal Causes of Diarrhea
Extragastrointestinal Diseases Causing Diarrhea
Diagnostic Evaluation
Treatment
References
122 Peritonitis
Key Points
Clinical Signs
Diagnostic Tests
Treatment
Medical Stabilization
Surgical Treatment
Postoperative Care
Prognosis
References
123 Gastric Dilatation-Volvulus
Key Points
Pathogenesis
Pathophysiology
History and Clinical Signs
Physical Examination
Diagnosis
Treatment Goals
Surgical Treatment
Postoperative Care
Owner Recommendations
References
Part XIII: Urogenital Disorders
124 Acute Kidney Injury
Key Points
Etiology
Pathophysiology
Clinical Presentation
History
Physical Examination
Diagnosis
Laboratory Tests
Imaging
Other Diagnostic Modalities
Treatment
Fluid Therapy
Diuretics
Acid-Base and Electrolyte Balance
Management of Gastrointestinal Signs
Nutritional Support
Renal replacement therapy
Fluid administration during recovery phase polyuria
Specific Treatments
Prognosis
References
125 Chronic Kidney Disease
Key Points
Etiology
Pathophysiology
Clinical Presentation
Diagnosis
Laboratory Tests
Imaging
Other Diagnostic Modalities
Treatment
Fluid Therapy
Acid-Base and Electrolyte Balance
Management of Gastrointestinal Signs
Nutritional Support
Management of Anemia
Long-Term Management
Dietary Therapy
Fluid Therapy
Additional Considerations
Advanced Therapeutic Modalities
Prognosis
References
126 Pyometra
Key Points
Incidence
Pathogenesis
Diagnosis
Signalment
History and Physical Examination
Diagnostic Imaging
Laboratory Findings
Treatment
Stabilizing the Patient
Surgical Management
Medical Management
Uterine Stump Pyometra
References
Part XIV: Nutrition
127 Nutritional Assessment
Key Points
Impacts of Nutritional Support during Critical Illness
Screening Systems Used for Nutritional Assessments
Body Weight
Body Composition
Adipose Tissue
Body condition score systems
Lean Body Mass
Muscle condition scoring
Diet History
Current intake
Historical intake
Laboratory Data
Conclusion
References
128 Nutritional Modulation of Critical Illness
Key Points
Omega-3 Fatty Acids
Antioxidants
Immune-Modulating Nutrients
Arginine
Glutamine
Nucleotides
Probiotics
Conclusion
References
129 Enteral Nutrition
Key Points
Determining the Route of Nutritional Support
Enteral Versus Parenteral
Oral Intake Versus Enteral Feeding Device
Enteral Feeding Tubes
Nasoesophageal or Nasogastric Tubes
Esophagostomy Tube
Gastrostomy Tube
Jejunal Tubes
Determining the Amount to be Fed
Selecting the Diet
Patient Variables
Nonpatient Variables
Monitoring Therapy
Preventing and Managing Complications
Patient-Related Complications
Non–Patient-Related Complications
References
130 Parenteral Nutrition
Key Points
Technical Requirements
Vascular Access
Monitoring and Nursing Care
Formulating and Compounding Nutrient Admixtures
Nutritional Assessment
Prescription Formulation
Calculation of Energy Requirements
Calculation of Protein Requirements
Calculation of Lipid and Carbohydrate Requirements
Calculation of Micronutrient Requirements
Delivery and Monitoring
Preventing and Managing Complications
Catheter and Parenteral Nutrition Admixture Complications
Metabolic Complications
References
Part XV: Surgical and Postoperative Conditions
131 Perioperative Evaluation of the Critically Ill Patient
Key Points
Preoperative Patient Evaluation
Respiratory Resuscitation
Cardiovascular Resuscitation
Pain
ASA Scoring
Global Assessment
Laboratory Testing
Coagulation
Blood Type and Crossmatch
Kirby’s Rule of Twenty
The Postoperative Period
Airway and Breathing
Ventilation and Oxygenation
Oxygen Delivery
Arrhythmias, Decreased Myocardial Contractility, and Hypotension
Analgesia
Hypothermia
Laboratory Parameters
Coagulation
Acid-Base and Electrolyte Status
Patient Cleanliness, Wound and Catheter Care, and Bandaging
Patient Immobilization and Physical Therapy
Nutrition
Summary
References
132 Portosystemic Shunt Management
Key Points
Preoperative Stabilization
Medical Management
Surgical Options
Postoperative Monitoring
Postoperative Complications
Portal Hypertension
Coagulopathy
Neurologic Complications
Prognosis
References
133 Peritoneal Drainage Techniques
Key Points
Indications for Peritoneal Drainage
Septic Peritonitis
Chemical Peritonitis
Other Indications for Peritoneal Drainage
Techniques for Peritoneal Drainage
Needle or Catheter Paracentesis
Paracentesis with a Fenestrated Catheter per the Mini-Laparotomy Method
Paracentesis with a Fenestrated Catheter Using the Seldinger Technique
Surgical Placement of Closed Suction Drains
Open Peritoneal Drainage Technique
Vacuum-Assisted Drainage
Complications of Peritoneal Drainage
Volume and Albumin Loss
Conclusion
References
134 Postthoracotomy Management
Key Points
Immediate Postthoracotomy Assessment
Analgesia
Postthoracotomy Pain Syndrome in Humans
Ventilation
Hypoxemia
Hypovolemia
Complications and Mortality after Thoracotomy
Hypothermia
Thoracostomy Tube Care
Conclusion
References
135 Kidney Transplantation
Key Points
Indications
Case Selection
Evaluation of the Urinary Tract
Cardiovascular Disease
Infectious Disease
Donor Selection
Preoperative Management
Immunosuppression for the Feline Renal Transplant Recipient
Anesthetic Management
Surgery
Postoperative Management and Perioperative Complications
Long-Term Management and Complications
Canine Transplantation
Conclusion
References
136 Minimally Invasive Procedures
Key Points
Instrumentation
Approaches/Access
Scope-Guided Procedures
Laparoscopic/thoracoscopic procedures
Tracheoscopy/bronchoscopy
Esophagoscopy/gastroscopy/duodenoscopy
Cystourethroscopy
Interventional Radiology Procedures
Urethral stenting
Ureteral stenting
Tracheal stenting
Cavity effusions and percutaneous drainage
Intravascular foreign body removal
Epistaxis
Vascular obstructions
References
Part XVI: Trauma
137 Traumatic Brain Injury
Key Points
Incidence and Prevalence of Head Injury
General Approach to the Patient with a Head Injury
Pathophysiology
Primary Injury
Secondary Injury
Neurologic Assessment
Diagnostic Tests and Monitoring
Treatment
Extracranial Therapy
Intracranial Therapy
Hyperosmotic agents
Corticosteroids
Furosemide
Decreasing cerebral blood volume
Seizure treatment/prophylaxis
Decreasing cerebral metabolic rate
Prognosis
References
138 Thoracic and Abdominal Trauma
Key Points
Trauma Categories
Blunt Trauma
Penetrating Trauma
Diagnostics
Clinical Laboratory Tests
Imaging
Fluid Analysis
Stabilization
Monitoring
Antimicrobial Therapy
Fluid Therapy/Blood Product Administration
External Wound Care
Specific Conditions
Diaphragmatic Rupture
Body Wall Rupture/Abdominal Evisceration
Chylothorax/Chylous Ascites
Pyothorax
Septic Peritonitis
Bile Peritonitis
Hemothorax/Hemoperitoneum/Hemoretroperitoneum
Uroperitoneum/Uroretroperitoneum
Prognosis
References
139 Wound Management
Key Points
Wound Healing Principles
Wound Classification
Phases of Healing
Initial Patient Assessment
Debridement and Lavage
Sugar and Honey
Dressing and Bandaging
Exposed Bone
Wound Closure
Drains
Negative Pressure Wound Therapy
Additional Wound Management Modalities
Antimicrobial Therapy
Patient Care
Complications
Prognosis
References
140 Thermal Burn Injury
Key Points
Definitions
Patient Assessment and Medical Management
Metabolic Derangements
Nutrition
Patient Comfort
Antimicrobial Therapy
Burn Wound Management
Topical Agents
Closure Options and Healing
Complications
References
Part XVII: Anesthesia and Pain Management
141 Pain and Sedation Assessment
Key Points
Definition of Pain
Pain Versus Stress
Pain Assessment
Behavior
Tools
Summary
References
142 Sedation of the Critically Ill Patient
Key Points
Patient Evaluation and Management
Choice of Agent
Opioids
Sedatives and Tranquilizers
Benzodiazepines (see Chapter 164 for further details)
Phenothiazine Tranquilizers
α2 Agonists (see Chapter 165 for further details)
Other Anesthetic Agents
Ketamine
Propofol
Sedation of Animals with Specific Conditions
Cardiovascular Instability
Respiratory Disease
Conclusion
References
143 Anesthesia in The Critically Ill Patient
Key Points
Stabilization
Premedication
Induction
Thiopental and Propofol
Alfaxalone
Etomidate
Ketamine
Opioids
Maintenance
Inhalants
Constant Rate Infusion
Neuromuscular Blocking Agents
Benzylisoquinolinium agents
Monitoring of neuromuscular blocking agents
Reversal Agents for neuromuscular blocking agents
Monitoring
Intraoperative Hypotension
Recovery
Summary
References
144 Analgesia and Constant Rate Infusions
Key Points
Analgesia
Opioids
Nonsteroidal Antiinflammatory Drugs
α2-Adrenergic Agonists
Transdermal Analgesics
N-Methyl-D-Aspartate Receptor Antagonists
Acepromazine
Infiltrative and Local Anesthetics
Epidural Analgesics
Constant Rate Infusions
Morphine-Lidocaine-Ketamine
Conclusion
References
145 Rehabilitation Therapy in the Critical Care Patient
Key Points
Musculoskeletal System
Range-of-Motion Exercise
Passive Range-of-Motion Exercise
Active Assisted and Active Range-of-Motion Exercise
Therapeutic Exercise and the Importance of Early Mobilization
Assisted Standing
Walking (Assisted and Unassisted)
Neuromuscular Electrical Stimulation and Transcutaneous Electrical Stimulation
Neuromuscular electrical stimulation
Transcutaneous electrical stimulation
Massage
Respiratory System
Positioning
Postural Drainage
Percussion (Coupage) and Vibration
Summary
References
146 Complementary and Alternative Medicine
Key Points
Acupuncture
Massage Therapy
Laser Therapy
Music Therapy
Herbs
Aromatherapy
Homeopathy and Flower Essences
Conclusion
References
Part XVIII: Environmental Emergencies
147 Smoke Inhalation
Key Points
Pathophysiology
Carbon Monoxide
Hydrogen Cyanide
Thermal Injury
Irritant Gases and Superheated Particulate Matter
Reduced lung compliance
Airway damage and obstruction
Bacterial pneumonia
Dermal Burn Injury
History
Physical Examination
Clinical Evaluation
Arterial Blood Gas Analysis
Acid-Base Status
Thoracic Radiography
Laryngoscopy, Bronchoscopy, and Transtracheal Aspiration
Diagnosis
Treatment
Oxygen Supplementation
Cyanide Toxicity
Airway Management
Sedation
Mechanical Ventilation
Intravenous Fluid Therapy
Additional Therapies
Prognosis
References
148 Hypothermia
Key Points
Classification
Review of Thermoregulation
Physiologic Effects of Hypothermia
Cardiovascular and Hemodynamic Effects
Respiratory Effects
Neuromuscular Effects
Acid-Base Effects
Coagulation Effects
Renal and Metabolic Effects
Core Body Temperature Measurement
Rewarming
Therapy
Cardiopulmonary Resuscitation
Therapeutic Hypothermia
References
149 Heat Stroke
Key Points
Physiology, Pathogenesis, and Pathophysiology
Physical Examination
Temperature, Pulse, and Respiratory Rate
Cardiovascular System
Respiratory System
Central Nervous System
Renal System
Gastrointestinal System
Coagulation System
Laboratory Evaluation
Treatment and Monitoring
Cooling Procedures
Cardiovascular System
Respiratory System
Central Nervous System
Renal System
Coagulation System
Gastrointestinal System
Prognosis
References
150 Electrical and Lightning Injuries
Key Points
Mechanisms of Electrical Injury
Predisposition to Electrical Injury
Clinical Findings
Secondary Effects of Electrical Injury
Treatment of Electrical Injury
Prognosis
Lightning Injury
References
151 Drowning and Submersion Injury
Key Points
Definitions
Incidence and Epidemiology
Humans
Veterinary Patients
Pathophysiology of Injury
Pulmonary System
Fluids and Electrolytes
Neurologic and Cardiovascular Systems
Effect of Water Temperature
Diagnostic Tests and Monitoring
Treatment
Outcome
References
Part XIX: Miscellaneous Disorders
152 Anaphylaxis
Key Points
Pathophysiology
Differential Diagnosis
Clinical Manifestations
Treatment
Epinephrine
Other Vasopressors
Antihistamines
Glucocorticoids
Potential Therapies
Fluid Therapy
Ancillary Patient Management
Prevention
References
153 Air Embolism
Key Points
Gas Embolization Due to Intravenous Access Mishaps
Gas Embolization during Laparoscopic Procedures
Gas Embolization during Surgery
Gas Embolization From Lung Biopsy
Gas Embolization during Hyperbaric Therapy
Detection of Air Emboli
Management of Air Embolism
References
154 Ocular Disease In The Intensive Care Unit
Key Points
Blepharospasm
Red Eye
Tear Film Abnormalities
Absent Palpebral Reflex
Corneal Changes
Anterior Chamber Abnormalities
Pupil Abnormalities
Anisocoria
Miosis
Mydriasis
Dyscoria
Blindness
References
155 Critically Ill Neonatal and Pediatric Patients
Key Points
Physical Examination Findings
Laboratory Values
Imaging
Intravenous and Intraosseous Catheterization
Fluid Requirements
Temperature Control
Nutrition
Monitoring
Pharmacology
Sepsis
Conclusion
References
156 Critically Ill Geriatric Patients
Key Points
Laboratory Values
Imaging
Fluid Therapy
Nutrition
Pharmacology
Conclusion
References
Part XX: Pharmacology
157 Catecholamines
Key Points
Hypotension
Poor Contractility
Catecholamine Choices
Dopamine
Dobutamine
Ephedrine
Norepinephrine
Phenylephrine
Vasopressin
Angiotensin
Epinephrine
Isoproterenol
Dopexamine
Choosing the Right Catecholamine
Combination Therapies
Vasomotor Tone
Catecholamines and Cortisol
Other Effects of Catecholamines
References
158 Vasopressin
Key Points
Physiology of Vasopressin
Vasopressin Receptors
Physiologic Effects of Vasopressin
Pharmacology
Clinical Uses
Cardiopulmonary Resuscitation
Vasodilatory Shock
Hemorrhagic Shock
Central Diabetes Insipidus
von Willebrand Disease
Gastrointestinal and Pulmonary Disease
Adverse Effects
Vasopressin Antagonists
Conclusion
References
159 Antihypertensives
Key Points
Etiology of Hypertension
Proposed Mechanism of Blood Pressure Elevation
Antihypertensive Drugs
Angiotensin-Converting Enzyme Inhibitors
Mechanism of action
Indications
Adverse effects
Angiotensin II Receptor Blockers
Mechanism of action
Indications
Adverse effects
Adrenergic Receptor Antagonists
Mechanism of action
Indications
Adverse effects
Aldosterone Blockers
Mechanism of action and indications
Adverse effects
Calcium Channel Blockers
Mechanism of action
Indications
Adverse effects
Arteriolar Vasodilators
Hydralazine
Mechanism of action and indications
Adverse effects
Sodium Nitroprusside
Mechanism of action and indications
Adverse effects
Fenoldopam
Mechanism of action
Indications
Adverse effects
Hypertensive Urgency
Treatment of Hypertensive Urgency
Hypertensive Emergency
Treatment of Hypertensive Emergency
References
160 Diuretics
Key Points
Physiology of Diuresis and Antidiuresis
Pharmacology
Osmotic Diuretics
Carbonic Anhydrase Inhibitors
Loop Diuretics
Thiazide Diuretics
Aldosterone Antagonists
Other Potassium-Sparing Distal Diuretics
Aquaretics
Indications for Diuretic Therapy
Urinary Diseases
Congestive Heart Failure
Liver Failure
Electrolyte and Mineral Disorders
Systemic Hypertension
References
161 Gastrointestinal Protectants
Key Points
Histamine-2 Receptor Antagonists
Proton Pump Inhibitors
Sucralfate
Prostaglandin Analogs
Antacids
Future Drug Therapy
Potential Complications of Increased Gastric pH
References
162 Antiemetics and Prokinetics
Key Points
Antiemetics
Neurokinin-1 Receptor Antagonists
5-HT3 Receptor Antagonists
Metoclopramide
Promazine Derivatives
Anticholinergic Agents
Other Drugs
Peripherally Acting Antiemetics
Prokinetic Drugs
5-HT4 Serotonergic Agonists
Cholinomimetic Drugs
Motilin Receptor Agonists
Metoclopramide
Misoprostol
References
163 Narcotic Agonists and Antagonists
Key Points
Terminology and History
Opium
Opiate
Opioid
Narcotic
Structure-Activity Relationship
Mechanism of Action
Opioid Receptors
Physiologic Effects of Opioids
Metabolism and Excretion
Potency and Effectiveness of Opioids
Epidural Opioids
Characteristics of Clinically Useful Opioids
Morphine
Methadone
Hydromorphone and Oxymorphone
Fentanyl and Remifentanil
Butorphanol
Nalbuphine
Buprenorphine
Tramadol
Codeine
Opioid Antagonists: Naloxone, Nalmefene, Naltrexone
Conclusion
References
164 Benzodiazepines
Key Points
Action
Diazepam Versus Midazolam
Benzodiazepine Effects
Benzodiazepines and Cats
Indications
Sedation
Anticonvulsant Therapy
Appetite Stimulation
Hepatic Encephalopathy
References
165 α2 Agonists and Antagonists
Key Points
α2 Adrenoceptors
Effects of α2 Agonists
Central Nervous System
Cardiovascular System
Other Effects
Imidazoline Receptors
Drugs
Clinical Use
α2 Antagonists
Conclusion
References
166 Anticonvulsants
Key Points
Seizures
Phenobarbital
Bromide
Zonisamide
Levetiracetam
Benzodiazepines
Gabapentin and Pregabalin
Felbamate
References
167 Antiplatelet Drugs
Key Points
Platelet Physiology
Antiplatelet Drugs
Adenosine Diphosphate Receptor Antagonists
Thienopyridines
Nucleoside analogs
Cyclooxygenase Inhibitors
Fibrinogen Receptor Antagonists
References
168 Anticoagulants
Key Points
Pathogenesis
Indications for Anticoagulant Use
Anticoagulants
Vitamin K Antagonists
Adverse Effects
Monitoring
Heparins
Unfractionated Heparins
Low-Molecular-Weight Heparins
Heparin Dosage
Direct Thrombin Inhibitors
Factor Xa Inhibitors
Conclusion
References
169 Thrombolytic Agents
Key Points
Specific Thrombolytic Agents
Streptokinase
Urokinase
Tissue Plasminogen Activator
Adverse Effects of Thrombolytic Therapy
Thrombolytic Therapy in Dogs
Streptokinase
Urokinase
Tissue Plasminogen Activator
Thrombolytic Therapy in Cats
Streptokinase
Urokinase
Tissue Plasminogen Activator
Conclusion
References
170 Hemostatic Drugs
Key Points
Antifibrinolytic Drugs
Indications
Contraindications
Use of Antifibrinolytic Drugs in Cats
ε-Aminocaproic acid
Tranexamic Acid
Topical Antifibrinolytic Therapy
Desmopressin
Protamine
Conjugated Estrogens
Recombinant Factor VIIa
Yunnan Paiyao
References
171 Antiarrhythmic Agents
Key Points
Classification Schemes
Class I Antiarrhythmic Agents
Class Ia Antiarrhythmic Agents
Class Ib Antiarrhythmic Agents
Class Ic Antiarrhythmic Agents
Class II Antiarrhythmic Agents
Class III Antiarrhythmic Agents
Class IV Antiarrhythmic Agents
Other Antiarrhythmic Agents
Digoxin
Magnesium Sulfate
Adenosine
Antiarrhythmic Devices and Procedures
References
172 Inhaled Medications
Key Points
Introduction
Principles of Aerosol Deposition in the Lungs
Delivery Systems
Jet Nebulizers
Ultrasonic Nebulizers
Metered Dose Inhalers
Clinical Applications
Feline Bronchopulmonary Disease
Inhaled bronchodilators
Inhaled glucocorticoids
Other inhaled medications
Canine Infectious Tracheobronchitis and Pneumonia
Medications for Use with Bronchoscopy
Conclusion
References
173 Complications of Chemotherapy Agents
Key Points
Principles of Chemotherapy
Testing for Chemotherapy Drug Sensitivity
Chemotherapy Drugs
Toxicities and Treatment of Chemotherapy-Related Emergencies
Acute Tumor Lysis Syndrome
Allergic Reactions
Bone Marrow Toxicity
Anemia
Thrombocytopenia
Neutropenia
Sepsis
Cardiotoxicity
Dermatologic Toxicity
Extravasation
Gastrointestinal Toxicity
Cachexia and anorexia
Vomiting
Diarrhea
Neurologic Toxicity
Urologic Toxicity
References
174 Antitoxins and Antivenoms
Key Points
Tetanus Antitoxin
Tick Antitoxin
Botulism Antitoxin
Black Widow Spider Antivenom
Scorpion Antivenom
Snake Antivenom
Production of Poisonous Snake Antivenom
Pit Viper Antivenom
Coral Snake Antivenom
References
175 Antimicrobial Use in the Critical Care Patient
Key Points
Antimicrobial Resistance
Advent of Resistance
Nosocomial Infections
Reducing Microbial Resistance
Antimicrobial Selection and Treatment
Timely Assessment of Need for and Initiation of Antimicrobial Therapy
Identification of the Target and Its Susceptibility
Design of the Dosing Regimen
Role of the minimum inhibitory concentration in the dosing regimen
Site of Infection
Host Immune Response
Impact of Microbial Factors
Adverse Drug Events
Antimicrobial Deescalation
References
176 β-Lactam Antimicrobials
Key Points
Mechanism of Action
Pharmacology
Resistance
Production of β-Lactamase
Changes in Cell Wall Permeability
Selected Penicillins and Cephalosporins
Penicillin G
Extended-Spectrum Penicillins
Antipseudomonal Penicillins
First-Generation Cephalosporins
Second-Generation Cephalosporins
Third-Generation Cephalosporins
Carbapenems
References
177 Aminoglycosides
Key Points
Mechanism of Action
Spectrum of Activity
Indications
Pharmacology and Dosing
Adverse Effects
References
178 Fluoroquinolones
Key Points
Structure and Physical Properties
Mechanism of Action
Bacterial Spectrum
Pharmacokinetics and Pharmacodynamics
Resistance
Clinical Uses
Administration and Drug Interactions
Adverse Effects
References
179 Macrolides
Key Points
Mechanism of Action
Pharmacology
Resistance
Selected Macrolides
Erythromycin
Azithromycin
References
180 Antifungal Therapy
Key Points
Introduction
Classes of Antifungal Drugs
Polyene Antibiotics
Azole Antifungals
Recommendations for Specific Fungal Infections
Blastomycosis
Histoplasmosis
Coccidioidomycosis
Cryptococcosis
References
181 Miscellaneous Antibiotics
Key Points
Metronidazole
Chloramphenicol
Tetracyclines
Potentiated Sulfonamides
Vancomycin
Polymyxins
Clindamycin
Rifampin
Newer Agents Active Against Multidrug-Resistant Gram-Positive Cocci
Daptomycin
Tigecycline
Quinupristin-Dalfopristin
Linezolid
References
182 Strategies for Treating Infections in Critically Ill Patients
Key Points
Bacterial Susceptibility
How to Proceed with Empirical Treatment
Assessing Initial Response
To Escalate or De-escalate?
What to Do if the Initial Empirical Treatment Fails
Penetration to the Site of Infection
Diffusion into Tissues
Urinary Tract
Intracellular Infections
Local Factors That Affect Antibiotic Effectiveness
Pharmacokinetic-Pharmacodynamic Optimization of Doses
Aminoglycosides
Fluoroquinolones
β-Lactam Antibiotics
Other Time-Dependent Drugs
References
Part XXI: Monitoring
183 Hemodynamic Monitoring
Key Points
Continuous Electrocardiogram Monitoring
Blood Pressure Monitoring
Noninvasive Blood Pressure Monitoring
Photoplethysmography
Invasive Blood Pressure Monitoring
Telemetric Blood Pressure Monitoring
Central Venous Pressure Monitoring
Pulmonary Artery Pressure Monitoring
Mixed Venous and Central Venous Oxygen Saturation
Lactate and Base Deficit
References
184 Cardiac Output Monitoring
Key Points
Indications for Cardiac Output Measurement
Measurement of Cardiac Output
Invasive Methods of Determining Cardiac Output
Fick oxygen consumption method
Carbon dioxide rebreathing methods
Indicator dilution method (including thermodilution)
Noninvasive or Minimally Invasive Methods of Determining Cardiac Output
Normal Values
Potential Causes of Error
Disease States and Cardiac Output Measurement
Potential Complications
References
185 Electrocardiogram Evaluation
Key Points
Indications
Electrocardiographic Principles
Technique
Electrocardiogram Waveforms
Electrocardiogram Interpretation
Effects of Disease States on the Electrocardiogram
Electrolyte Abnormalities
Hyperkalemia
Hypokalemia
Hypercalcemia
Hypocalcemia
Magnesium level
Hypoxemia
Intrathoracic Effusions
Pain
References
186 Blood Gas and Oximetry Monitoring
Key Points
Hydrogen Ions
Buffers
Henderson-Hasselbalch Equation
Regulation of pH
Blood Gas Analysis: Getting Started
Temperature Correction
Step-by-Step Acid-Base Analysis
Number 1: Evaluate the pH
Number 2: Evaluate PCO2 (see also Chapter 16)
Number 3: Evaluate the metabolic indices
Number 4: Determine if there is one problem or many
Anion gap
The Stewart approach (see Chapter 55)
Strong Ion Difference.
Strong Ion Gap.
Base Excess Modification.
Number 5: Determine how well the patient is oxygenating (see also Chapter 15)
Pulse oximetry
Number 6: Look at the whole picture
Venous Blood Gas Values
References
187 Colloid Osmotic Pressure and Osmolality Monitoring
Key Points
Colloid Osmotic Pressure
Starling’s Hypothesis
Calculated versus Measured Values
Normal Colloid Osmotic Pressure Values
Colloid Osmotic Pressure in Critically Ill Patients
How Colloid Osmotic Pressure Is Measured
Indications for Colloid Osmotic Pressure Measurement
Osmolality
Definition
Determination of Osmolality
Osmolal Gap
Effective Osmolality
Urine Osmolality
References
188 Intraabdominal Pressure Monitoring
Key Points
Definitions and Incidence
Risk Factors
Pathophysiology
Methods of Intraabdominal Pressure Measurement
Physiologic Effects of Intraabdominal Hypertension
Hemodynamic Effects
Renal Effects
Pulmonary and Thoracic Effects
Central Nervous System Effects
Visceral Effects
Systemic Effects
General Considerations
Acknowledgment
References
189 AFAST and TFAST in the Intensive Care Unit
Key Points
Terminology
Objective of Focused Assessment with Sonography for Trauma
Abdominal Focused Assessment with Sonography for Trauma
AFAST Technique
Abdominal Fluid Score Technique
AFAST for Blunt Abdominal Trauma
AFAST for Penetrating Abdominal Trauma
AFAST for Determining the Cause of Intraabdominal Injury
Thoracic Focused Assessment with Sonography for Trauma
TFAST Technique
Chest Tube Site Views
Pleural line and the bat sign
A-lines
B-lines
Lung curtain
Sonographic signs of pneumothorax
Absence of glide sign and B-lines
Pericardial Chest Site and Subxiphoid Site Views
Emergency Lung Ultrasound to Detect Interstitial-Alveolar Lung Injury
References
190 Capnography
Key Points
Nondiverting and Diverting Monitors
Technology
Physiology
Capnogram Interpretation
Equipment
Patient
References
191 Intracranial Pressure Monitoring
Key Points
Determination of Intracranial Pressure
Intracranial Pressure
Locations for Monitoring Intracranial Pressure in the Brain
Types of Intracranial Pressure Monitoring Devices
Intracranial Pressure Monitoring Systems
Ventriculostomy catheter with external transducer
Transducer-tipped catheters
Subarachnoid bolt
Fluid-filled catheter
Evaluation of Intracranial Pressure
Normal Intracranial Pressure
Accuracy of Intracranial Pressure Monitoring Systems
Complications of Intracranial Pressure Monitoring
Indications for Intracranial Pressure Monitoring in Dogs and Cats
References
192 Urine Output
Key Points
Urine Output as a Monitoring Tool
Measurement of Urine Output
Determinants of Urine Output
Glomerular Filtration Rate
Tubular Reabsorption of Water and Solutes
Impedance to Flow
Normal Urine Output
Abnormal Urine Output
Oliguria
Prerenal oliguria
Postrenal oliguria
Renal oliguria
Polyuria
Prerenal polyuria
Postrenal polyuria
Renal polyuria
Fluid Balance
Case Example
References
Part XXII: Procedures
193 Peripheral Venous Catheterization
Key Points
Catheter Types
Winged or Butterfly Needle
Over-the-Needle Catheter
Through-the-Needle Catheter
Multilumen Catheter
Advantages of Peripheral Venous Catheterization
Catheter Insertion Site
Cephalic Vein
Saphenous Vein
Pedal Veins
Auricular Vein
Insertion Technique
Percutaneous Placement
Facilitative Incision or Relief Hole
Venous Cutdown
Peripherally Inserted Central Venous Catheters
Complications Associated with Catheterization
Phlebitis
Thrombosis
Catheter Embolism
Subcutaneous Fluid Infiltration
Infection
Catheter Maintenance
References
194 Intraosseous Catheterization
Key Points
Historical Perspectives
Physiology
Indications
Contraindications
Methods
Complications
References
195 Central Venous Catheterization
Key Points
General Concepts
Catheter Types
Through-the-Needle Catheter
Over-the-Needle Catheter
Long Single-Lumen Catheter
Multilumen Catheter
Percutaneous Sheath Catheter Introducer
Catheter Insertion Site
Saphenous Vein
Jugular Vein
Catheter Insertion
Through-the-Needle Catheter Insertion
Seldinger Technique
Rewiring of Seldinger Catheters
Peel-Off Sheathed Needle Technique
Complications and Catheter Maintenance
Heparinized Saline
References
196 Blood Film Evaluation
Key Points
Blood Film Preparation
Blood Film Evaluation
White Blood Cell Responses
Red Blood Cell Responses
Platelet Responses
Leukemia (Myeloid and Lymphoid)
References
197 Endotracheal Intubation and Tracheostomy
Key Points
Endotracheal Intubation
Airway Assessment
Routine Intubation
Dogs
Cats
Difficult Intubation
Preoxygenation
Equipment setup
Approach
Alternative Techniques and Adjuncts
Needle cricothyroidotomy
Cricothyroidotomy
Fiberoptic-assisted intubation
Digital palpation
Nasal intubation
Retrograde intubation
Cricoid pressure
Placement Verification
Complications
Tracheostomy
Tracheostomy Tube Selection
Percutaneous Tracheostomy
Surgical Tracheostomy
Transverse incision
Vertical incision
Securing the tracheostomy tube
Tracheostomy Tube Management
Suctioning
Tube Removal
Complications
Summary
References
198 Thoracocentesis
Key Points
Indications
Materials
Techniques
Needle Insertion Techniques
Thoracocentesis using a butterfly needle
Thoracocentesis using a hypodermic needle with a saline-filled hub
Over-the-Needle Catheter Insertion Technique
Thoracocentesis using an over-the-needle intravenous catheter
Thoracocentesis using a thoracostomy tube
Through-the-Needle Catheter Technique
Seldinger Technique
Diagnostic Evaluation of the Aspirate
Postprocedure Care
Complications
References
199 Thoracostomy Tube Placement and Drainage
Key Points
Indications
Thoracostomy Tube Placement
Materials
Anesthesia
Techniques
Drainage
Passive Drainage Techniques
Active Drainage Techniques
Maintenance and Care
Removal
Complications
References
200 Abdominocentesis and Diagnostic Peritoneal Lavage
Key Points
Indications
Focused Assessment with Sonography for Trauma
Technique
Preparation of the Patient
Closed-Needle Abdominocentesis
Open-Needle Abdominocentesis
Four-Quadrant Abdominocentesis
Alternatives to Abdominocentesis
Abdominal Fluid Analysis
Analysis of Diagnostic Peritoneal Lavage Samples
Conclusion
References
201 Arterial Catheterization
Key Points
Patient Preparation
Percutaneous Arterial Catheter Placement
Dorsal Pedal Artery Catheterization
Femoral Artery Catheterization
Auricular Artery Catheterization
Radial Artery Catheterization
Coccygeal Artery Catheterization
Surgical Cutdown for Arterial Catheter Placement
Maintenance of the Arterial Catheter
Three-Syringe Technique
References
202 Pulmonary Artery Catheterization
Key Points
Types of Catheters and Uses
Cardiac Output
Pulmonary Capillary Wedge Pressure
Right Ventricular End-Diastolic Volume
Selective Pulmonary Angiography
Additional Measurements
Indications
Placement
Flow-Directed Placement
Fluoroscopy
Complications
Alternatives
References
203 Temporary Cardiac Pacing
Key Points
Indications for Temporary Cardiac Pacing
Description of the Temporary Pacemaker Systems
Transvenous Pacing System
Transcutaneous Pacing System
Transesophageal Pacing System
Troubleshooting
Transvenous Pacing System
Transcutaneous Pacing System
Transesophageal Pacing System
Complications
Transvenous Pacing System
Transcutaneous Pacing System
Transesophageal Pacing System
References
204 Cardioversion and Defibrillation
Key Points
Definitions
Mechanism of Cardioversion and Defibrillation
Defibrillator-Cardioverter
Approach to Defibrillation
Indications
Preparation
Therapy
Complications
Approach to Synchronized Cardioversion
Indications
Preparation
Therapy
Complications
References
205 Renal Replacement Therapies
Key Points
Principles of Dialysis
Indications
Contraindications
Components of Dialysis
Catheters for Intermittent Hemodialysis and Continuous Renal Replacement Therapy
Catheters for Peritoneal Dialysis
Dialysate
Dialyzer
Anticoagulation
Dialysis Prescription
Complications and Other Considerations
Outcome and Prognosis
Summary
References
206 Apheresis
Key Points
Equipment
Principles of Apheresis
Indications
Myasthenia Gravis
Immune-Mediated Hemolytic Anemia
Future Applications
References
207 Cerebrospinal Fluid Sampling
Key Points
Cerebrospinal Fluid Formation and Functions
Indications for Cerebrospinal Fluid Collection and Analysis
Contraindications and Risks
Cerebrospinal Fluid Collection Techniques
Preparation
Collection Sites and Techniques
Cisternal puncture
Positioning
Needle insertion
Tips for troubleshooting cerebrospinal fluid puncture
Precaution.
Lumbar puncture
Positioning
Note.
Analysis of Cerebrospinal Fluid
Specimen Handling and Examination
Physical Characteristics
Total Cell Count and Differential
Cytologic Analysis
Protein Concentration
Other Tests
Interpretation of Common Findings
References
208 Urinary Catheterization
Key Points
Indications
Intermittent Catheterization
Indwelling Catheter
Risks and Complications
Infection
Mechanical Difficulties
Catheter Types
Materials
Size
Foley Catheters
Placement Technique
Male Dog
Female Dog
Male Cat
Female Cat
Securing the Catheter
Closed Collection System
Care of an Indwelling Urinary Catheter
References
Part XXIII: ICU Design and Management
209 Intensive Care Unit Facility Design
Key Points
The Design Process
Location in the Hospital
Arrangement and Size
Unit Configuration
Staff Work Areas
Patient Care Areas
Patient modules
Procedure area and storage
Isolation room
Ancillary Services
Utilities
Environmental Aspects
Lighting
Air Conditioning
Acoustic Environment
Floor and Wall Surfaces, Ceiling Finishes
Furnishings
Details and Common Design Elements
Infection Prevention and Control
Safety and Security
Patient- and Owner-Centered Care
Ambiance
Communication
References
210 Management of the Intensive Care Unit*
Key Points
Intensive Care Unit Personnel: Staff Qualifications and Scheduling
Role of the Intensive Care Unit Director
Staffing
Veterinarians
Residents and interns
Nursing staff
Scheduling
Staff/Patient Ratio
Management of Intensive Care Unit Staff
Communication
Delegation of Responsibility
Conflict: Causes, Categories, and Resolution
Categories of conflict
Methods of conflict resolution
Conflict prevention
Recruitment of Intensive Care Unit Nursing Staff
Training intensive care unit nurses
Retention of Staff: Handling Stress and Burnout
References
211 Client Communication and Grief Counseling
Key Points
Client Communication
The Human-Animal Bond
Client Expectations
End-of-Life Decisions
Compassion Fatigue
Support for veterinary staff
Communicating with Difficult Clients
Stages of Grief
Types of Grief
Anticipatory Grief
Multiple Losses and “Trigger Grief”
Grief from Expected Loss
Grief from Unexpected Loss
Disenfranchised Grief
Complicating Factors
Financial Considerations
Mental Health History
Children and Loss
Pet Loss and Older Adults
Veterinary Resources
Support Groups
Individual Grief Support Sessions
Lectures, Seminars, and Workshops
Healing Through Pet Loss
Finding Meaning
Memorializing a Pet
References
Appendices
Appendix 1 Clinical Calculations
Appendix 2 Important Physiologic Formulas
Appendix 3 Ideal Gas Laws
Appendix 4 Surviving Sepsis Campaign 2012 Bundle Recommendations for Humans
Appendix 5 Constant Rate Infusion Calculations
Micrograms per Kilogram per Minute
Milligrams per Kilogram per Hour (Using 250 ml bag of fluids)
Appendix 6 Common Drug Dosages for Constant Rate Infusions
Index
A
B
C
D
E
F
G
H
I
J
K
L
M
N
O
P
Q
R
S
T
U
V
W
X
Y
Z

Citation preview

SMALL ANIMAL

CRITICAL CARE MEDICINE SECOND EDITION

Deborah C. Silverstein, DVM, DACVECC

Associate Professor of Critical Care Department of Clinical Studies Matthew J. Ryan Veterinary Hospital University of Pennsylvania Philadelphia, Pennsylvania Adjunct Professor Temple University School of Pharmacy Philadelphia, Pennsylvania

Kate Hopper, BVSc, PhD, DACVECC

Associate Professor of Small Animal Emergency & Critical Care Department of Veterinary Surgical & Radiological Sciences School of Veterinary Medicine University of California–Davis Davis, California

3251 Riverport Lane St. Louis, Missouri 63043

SMALL ANIMAL CRITICAL CARE MEDICINE, SECOND EDITION

ISBN: 978-1-4557-0306-7

Copyright © 2015, 2009 by Saunders, an imprint of Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. International Standard Book Number: 978-1-4557-0306-7

Senior Vice President, Content: Loren Wilson Content Strategy Director: Penny Rudolph Content Development Specialist: Brandi Graham Publishing Services Manager: Catherine Jackson Senior Project Manager: David Stein Design Direction: Ashley Eberts

Printed in the United States Last digit is the print number:  9  8  7  6  5  4  3  2  1

CONTRIBUTORS Jonathan A. Abbott, DVM, DACVIM (Cardiology)

Anusha Balakrishnan, BVSc, AH

Associate Professor Department of Small Animal Clinical Sciences Virginia Maryland Regional College of Veterinary Medicine Virginia Tech Blacksburg, Virginia Associate Professor Department of Basic Sciences Virginia Tech Carilion School of Medicine Roanoke, Virginia Feline Cardiomyopathy

Resident, Emergency and Critical Care Department of Clinical Studies–Philadelphia School of Veterinary Medicine University of Pennsylvania Philadelphia, Pennsylvania Shock Fluids and Fluid Challenge

Sophie Adamantos, BVSc, CertVA, DACVECC, FHEA, MRCVS Senior Lecturer in Emergency and Critical Care Department of Veterinary Clinical Science Royal Veterinary College Hatfield, Hertfordshire, United Kingdom Pulmonary Edema

Christopher A. Adin, DVM, DACVS Associate Professor Veterinary Clinical Sciences The Ohio State University Columbus, Ohio Postthoracotomy Management

Ashley E. Allen-Durrance, DVM Resident, EMCC College of Veterinary Medicine University of Florida Gainsville, Florida Magnesium and Phosphate Disorders

Robert A. Armentano, DVM, DACVIM Small Animal Internist Veterinary Medical Referral Services Veterinary Specialty Center Buffalo Grove, Illinois Antitoxins and Antivenoms

Lillian R. Aronson, VMD, DACVS Associate Professor of Surgery Clinical Studies University of Pennsylvania, Philadelphia, Pennsylvania Urosepsis Kidney Transplantation

Matthew W. Beal, DVM, DACVECC Associate Professor, Emergency and Critical Care Medicine Small Animal Clinical Sciences Michigan State University East Lansing, Michigan Peritoneal Drainage Techniques

Allyson Berent, DVM, DACVIM (Internal Medicine) Staff Doctor Director of Interventional Endoscopy Services Animal Medical Center New York, New York Hepatic Failure

Amanda K. Boag, MA, VetMB, DACVIM, DACVECC, MRCVS Clinical Director Vets Now Dunfermline, Fife, United Kingdom Aspiration Pneumonitis and Pneumonia Pulmonary Contusions and Hemorrhage

Elise Mittleman Boller, DVM, DACVECC Lecturer, Emergency and Critical Care Faculty of Veterinary Sciences University of Melbourne Melbourne, Victoria, Australia Sepsis and Septic Shock

Manuel Boller, DrMedVet, MTR, DACVECC Senior Lecturer Emergency and Critical Care Faculty of Veterinary Science University of Melbourne Melbourne, Victoria, Australia Cardiopulmonary Resuscitation Post–Cardiac Arrest Care

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Contributors

Dawn Merton Boothe, DVM, PhD, DACVIM (Internal Medicine), DACVCP Professor, Director Clinical Pharmacology Anatomy, Physiology, Pharmacology, and Department of Clinical Sciences Auburn University Montgomery, Alabama Antimicrobial Use in the Critical Care Patient

Angela Borchers, DVM, DACVIM, DACVECC Associate Veterinarian in Small Animal Emergency and Critical Care William R. Pritchard Veterinary Medical Teaching Hospital School of Veterinary Medicine University of California, Davis, Davis, California Hemostatic Drugs

Søren R. Boysen, DVM, DACVECC Associate Professor Veterinary Clinical and Diagnostic Services University of Calgary, Calgary, Alberta, Canada Gastrointestinal Hemorrhage AFAST and TFAST in the Intensive Care Unit

Benjamin M. Brainard, VMD, DACVAA, DACVECC Associate Professor, Critical Care Small Animal Medicine and Surgery College of Veterinary Medicine University of Georgia Athens, Georgia Hypercoagulable States Thrombocytopenia Antiplatelet Drugs Anticoagulants

Andrew J. Brown, MA, VetMB, MRCVS, DACVECC Vets Now Referral Hospital Glasgow, Scotland Cardiogenic Shock Rodenticides Hemodynamic Monitoring

Scott Brown, VMD, PhD, DACVIM Edward H. Gunst Professor of Small Animal Medicine Department of Physiology and Pharmacology College of Veterinary Medicine The University of Georgia Athens, Georgia Hypertensive Crisis

Jamie M. Burkitt Creedon, DVM, DACVECC Critical Consultations Wichita Falls, Texas Sodium Disorders Critical Illness–Related Corticosteroid Insufficiency Hypoadrenocorticism

Margret L. Casal, DrMedVet, PhD, DECAR Associate Professor of Medical Genetics, Pediatrics, and Reproduction Clinical Studies–Philadelphia University of Pennsylvania, Philadelphia, Pennsylvania Mastitis

Ann M. Caulfield, VMD, CCRP, CVA Director Metropolitan Veterinary Associates Rehabilitation Therapy Norristown, Pennsylvania Rehabilitation Therapy in the Critical Care Patient

Daniel L. Chan, DVM, DACVECC, DACVN, FHEA, MRCVS Senior Lecturer in Emergency and Critical Care Veterinary Clinical Sciences The Royal Veterinary College, North Mymms, Hertfordshire, Great Britain Acute Lung Injury and Acute Respiratory Distress Syndrome Nutritional Modulation of Critical Illness

Peter S. Chapman, BVetMed, DECVIM-CA, DACVIM (Internal Medicine), MRCVS Staff Internist Veterinary Specialty and Emergency Center Levittown, Pennsylvania Regurgitation and Vomiting

C.B. Chastain, DVM, MS, DACVIM (Internal Medicine) Director of Undergraduate Biomedical Sciences College of Veterinary Medicine University of Missouri–Columbia Columbia, Missouri Syndrome of Inappropriate Antidiuretic Hormone

Dennis J. Chew, DVM, DACVIM (Internal Medicine) Professor Emeritus Veterinary Clinical Sciences The Hospital for Companion Animals Veterinary Clinical Sciences College of Veterinary Medicine The Ohio State University Columbus, Ohio Calcium Disorders

Dana L. Clarke, VMD, DACVECC Lecturer in Interventional Radiology & Critical Care Department of Small Animal Clinical Sciences University of Pennsylvania Philadelphia, Pennsylvania Upper Airway Disease Minimally Invasive Procedures

Melissa A. Claus, DVM, DACVECC Lecturer School of Veterinary and Biomedical Sciences Murdoch University Murdoch, Western Australia, Australia Febrile Neutropenia

Contributors

Leah A. Cohn, DVM, PhD, DACVIM (SAIM)

Armelle de Laforcade, DVM, DACVECC

Professor Department of Veterinary Medicine and Surgery College of Veterinary Medicine University of Missouri–Columbia Columbia, Missouri Acute Hemolytic Disorders

Associate Professor Clinical Sciences Tufts Cummings School of Veterinary Medicine North Grafton, Massachusetts Shock Systemic Inflammatory Response Syndrome

Edward Cooper, VMD, MS

Teresa DeFrancesco, DVM, DACVIM (CA), DACVECC

Assistant Professor–Clinical Veterinary Clinical Sciences The Ohio State University Columbus, Ohio Hypotension

Etienne Côté, DVM, DACVIM (Cardiology, SAIM) Associate Professor Department of Companion Animals Atlantic Veterinary College University of Prince Edward Island Charlottetown, Prince Edward Island, Canada Pneumonia

M. Bronwyn Crane, DVM, MS, DACT Assistant Professor Health Management Atlantic Veterinary College University of Prince Edward Island Charlottetown, Prince Edward Island, Canada Pyometra

Professor of Cardiology and Critical Care Department of Clinical Sciences College of Veterinary Medicine North Carolina State University Raleigh, North Carolina Temporary Cardiac Pacing

Amy Dixon-Jimenez, DVM Cardiology Resident Small Animal Medicine and Surgery University of Georgia Athens, Georgia Anticoagulants

Suzanne Donahue, VMD, DACVECC Veterinarian Emergency/Critical Care Hope Veterinary Specialists Frazer, Pennsylvania Chest Wall Disease

William T.N. Culp, VMD, DACVS

Patricia M. Dowling, DVM, MSc, DACVIM, DACVP

Assistant Professor Department of Surgical and Radiological Sciences University of California–Davis Davis, California Minimally Invasive Procedures Thoracic and Abdominal Trauma

Professor Veterinary Biomedical Sciences Western College of Veterinary Medicine Saskatoon, Saskatchewan, Canada Motility Disorders Anaphylaxis

Meredith L. Daly, VMD, DACVECC

Kenneth J. Drobatz, DVM, MSCE, DACVIM (Internal Medicine), DACVECC

Director, Critical Care Service Critical Care Bluepearl Veterinary Partners New York, New York Hypoventilation Fluoroquinolones

Emily Davis, DVM Resident, Neurology Department of Neurology and Neurosurgery University of Pennsylvania Philadelphia, Pennsylvania Spinal Cord Injury

Harold Davis, BA, RVT, VTS (ECC) (Anesth) Manager Small Animal Emergency & Critical Care Service William R. Pritchard Veterinary Medical Teaching Hospital University of California–Davis Davis, California Peripheral Venous Catheterization Central Venous Catheterization

Professor and Chief, Section of Critical Care Department of Clinical Studies Director, Emergency Service Matthew J. Ryan Veterinary Hospital School of Veterinary Medicine University of Pennsylvania Philadelphia, Pennsylvania Acute Abdominal Pain Heat Stroke

Adam E. Eatroff, DVM, DACVIM Renal Medicine/Hemodialysis Unit Animal Medical Center New York, New York Acute Kidney Injury Chronic Kidney Disease

Melissa Edwards, DVM, DACVECC Emergency and Critical Care Specialist AVETS Monroeville, Pennsylvania Catheter-Related Bloodstream Infection

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Contributors

Laura Eirmann, DVM, DACVN Nutritionist Oradell Animal Hospital Paramus, New Jersey Veterinary Communications Manager Nestle Purina Pet Care St. Louis, Missouri Enteral Nutrition Parenteral Nutrition

Steven Epstein, DVM, DACVECC Assistant Professor of Clinical Small Animal Emergency and Critical Care Department of Surgical and Radiological Sciences School of Veterinary Medicine University of California–Davis Davis, California Care of the Ventilator Patient Ventilator-Associated Pneumonia Multidrug-Resistant Infections

Daniel J. Fletcher, PhD, DVM, DACVECC Assistant Professor of Emergency and Critical Care Clinical Sciences College of Veterinary Medicine Cornell University Ithaca, New York Cardiopulmonary Resuscitation Post–Cardiac Arrest Care Traumatic Brain Injury

Thierry Francey, DrMedVet, DACVIM Diu Head, Small Animal Internal Medicine Department of Clinical Veterinary Medicine Vetsuisse Faculty University of Bern Bern, Switzerland Diuretics

Mack Fudge, DVM, MPVM, DACVECC Colonel (ret) U.S. Army Veterinary Corps Helotes, Texas Endotracheal Intubation and Tracheostomy

Caroline K. Garzotto, VMD, DACVS, CCRT Owner, Surgeon Veterinary Surgery of South Jersey, LLC Haddonfield, New Jersey Wound Management Thermal Burn Injury

Alison R. Gaynor, DVM, DACVIM, DACVECC Consultant IDEXX Telemedicine Portland, Oregon Adjunct Assistant Professor Department of Clinical Sciences Cummings School of Veterinary Medicine Tufts University North Grafton, Massachusetts Acute Pancreatitis

Urs Giger, PD, DrMedVet, MS, FVH, DACVIM, DECVIM-CA, DECVCP Charlotte Newton Sheppard Professor of Medicine Department of Clinical Studies University of Pennsylvania Philadelphia, Pennsylvania Transfusion Therapy Anemia

Massimo Giunti, DVM, PhD Department of Veterinary Medical Science University of Bologna Bologna, Italy Intraosseous Catheterization

Robert A.N. Goggs, BVSc, DACVECC, PhD, MRCVS Lecturer, Emergency and Critical Care Clinical Sciences College of Veterinary Medicine Cornell University Ithaca, New York Multiple Organ Dysfunction Syndrome Aspiration Pneumonitis and Pneumonia

Richard E. Goldstein, DVM, DACVIM, DECVIM-CA Chief Medical Officer The Animal Medical Center New York, New York Diabetes Insipidus

Todd A. Green, DVM, MS, DACVIM (Internal Medicine) Associate Professor Small Animal Medicine and Surgery Program School of Veterinary Medicine St. George’s University Grenada, West Indies Calcium Disorders

Reid P. Groman, DVM, DACVIM (Internal Medicine), DACVECC Criticalist Veterinary Specialty Center of Delaware Castle, Delaware Gram-Positive Infections Gram-Negative Infections Aminoglycosides Miscellaneous Antibiotics

Julien Guillaumin, DrVet, DACVECC Assistant Professor–Clinical–Emergency and Critical Care Veterinary Clinical Sciences The Ohio State University Columbus, Ohio Postthoracotomy Management

Tim B. Hackett, DVM, MS Professor, Emergency and Critical Care Medicine Clinical Sciences Colorado State University Fort Collins, Colorado Physical Examination and Daily Assessment of the Critically Ill Patient

Contributors

Susan G. Hackner, BVSc, MRCVS, DACVIM, DACVECC Chief Medical Officer & Chief Operating Officer Cornell University Veterinary Specialists Stamford, Connecticut Bleeding Disorders

Sarah Haldane, BVSc, BAnSc, MANZCVSc, DACVECC Veterinary Science University of Melbourne Melbourne, Victoria, Australia Nonsteroidal Antiinflammatory Drugs

Terry C. Hallowell, DVM, DACVECC Critical Care Specialist Critical Care Allegheny Veterinary Emergency Trauma & Specialty Monroeville, Pennsylvania Urine Output

Daniel F. Hogan, DVM, DACVIM (Cardiology) Associate Professor and Chief Comparative Cardiovascular Medicine and Interventional Cardiology Veterinary Clinical Sciences Purdue University West Lafayette, Indiana Thrombolytic Agents

Steven R. Hollingsworth, DVM, DACVO Associate Professor of Clinical Ophthalmology Surgical and Radiological Sciences University of California–Davis Davis, California Ocular Disease in the Intensive Care Unit

Bradford J. Holmberg, DVM, MS, PhD, DACVO Animal Eye Center Little Falls, New Jersey Ocular Disease in the Intensive Care Unit

Ralph C. Harvey, DVM, MS, DACVAA

David Holt, BVSc, DACVS

Associate Professor Small Animal Clinical Sciences College of Veterinary Medicine University of Tennessee Knoxville, Tennessee Narcotic Agonists and Antagonists Benzodiazepines

Professor of Surgery Department of Clinical Studies–Philadelphia School of Veterinary Medicine University of Pennsylvania Philadelphia, Pennsylvania Tracheal Trauma Hepatic Encephalopathy

†

Kate Hopper, BVSc, PhD, DACVECC

Professor Emeritus Department of Surgery and Radiology University of California–Davis Davis, California Hypoxemia Catecholamines

Associate Professor of Small Animal Emergency & Critical Care Department of Veterinary Surgical & Radiological Sciences School of Veterinary Medicine University of California–Davis Davis, California Hypertensive Crisis Basic Mechanical Ventilation Advanced Mechanical Ventilation Discontinuing Mechanical Ventilation Traditional Acid-Base Analysis Nontraditional Acid-Base Analysis

Steve C. Haskins, DVM, MS, DACVAA, DACVECC

Galina Hayes, BVSc, PhD, DACVECC Department of Surgery Valley Central Veterinary Referrals Allentown, Pennsylvania Illness Severity Scores in Veterinary Medicine

Rebecka S. Hess, DVM, DACVIM Professor and Section Chief Internal Medicine University of Pennsylvania Philadelphia, Pennsylvania Diabetic Ketoacidosis Hypothyroid Crisis in the Dog

Guillaume L. Hoareau, DrVet, DACVECC Small Animal Emergency and Critical Care William R. Pritchard Veterinary Medical Teaching Hospital University of California–Davis Davis, California Brachycephalic Syndrome Intraabdominal Pressure Monitoring

†

Deceased.

Dez Hughes, BVSc, MRCVS, DACVECC Associate Professor and Section Head, Emergency and Critical Care Faculty of Veterinary Science Associate Dean, eLearning Faculty of Veterinary Science University of Melbourne Melbourne, Victoria, Australia Pulmonary Edema Hyperlactatemia

Daniel Z. Hume, DVM, DACVIM (Internal Medicine), DACVECC Chief of Emergency and Critical Care WestVet Animal Emergency and Specialty Center Garden City, Idaho Diarrhea

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Contributors

Karen R. Humm, MA, VetMB, CertVA, DACVECC, MRCVS

Lesley G. King, MVB, DACVECC, DACVIM (Internal Medicine)

Lecturer, Emergency and Critical Care Department of Clinical Sciences & Services The Royal Veterinary College, University of London North Mymms, Hatfield, Hertfordshire United Kingdom Canine Parvovirus Infection

Professor, Section of Critical Care Department of Clinical Studies–Philadelphia School of Veterinary Medicine Director, Intensive Care Unit Matthew J. Ryan Veterinary Hospital University of Pennsylvania Philadelphia, Pennsylvania Calcium Channel Blocker and β-Blocker Drug Overdose Management of the Intensive Care Unit

Karl E. Jandrey, DVM, MAS, DACVECC Associate Professor of Clinical Small Animal Emergency and Critical Care Department of Surgical and Radiological Sciences University of California–Davis Davis, California Platelet Disorders Abdominocentesis and Diagnostic Peritoneal Lavage

Shailen Jasani, MA, VetMB, MRCVS, DACVECC Clinical Specialist Vets Now Emergency Ltd. Hertfordshire, United Kingdom Smoke Inhalation

Lynelle R. Johnson, DVM, MS, PhD, DACVIM (SAIM) Associate Professor Medicine & Epidemiology University of California–Davis Davis, California Pulmonary Thromboembolism

L. Ari Jutkowitz, VMD, DACVECC Associate Professor College of Veterinary Medicine Michigan State University East Lansing, Michigan Massive Transfusion

Kayo Kanakubo, DVM Resident, Clinical Nutrition School of Veterinary Medicine University of California–Davis Davis, California Blood Purification for Intoxications and Drug Overdose Renal Replacement Therapies

Marie E. Kerl, DVM, MPH, DACVIM, DACVECC Associate Teaching Professor Department of Veterinary Medicine and Surgery University of Missouri–Columbia Columbia, Missouri Fungal Infections Antifungal Therapy

Marguerite F. Knipe, DVM, DACVIM (Neurology) Health Sciences Assistant Clinical Professor, Neurology/ Neurosurgery Department of Surgical and Radiological Sciences University of California–Davis Davis, California Deteriorating Mental Status

Amie Koenig, DVM, DACVIM (Internal Medicine), DACVECC Associate Professor, Emergency and Critical Care Department of Small Animal Medicine and Surgery College of Veterinary Medicine University of Georgia Athens, Georgia Hyperglycemic Hyperosmolar Syndrome Hypoglycemia Mycoplasma, Actinomyces, and Nocardia

Mary Anna Labato, DVM, DACVIM (Internal Medicine) Clinical Professor, Department of Clinical Sciences Section Head, Small Animal Medicine Clinical Professor Foster Hospital for Small Animals Cummings School of Veterinary Medicine Tufts University North Grafton, Massachusetts Antihypertensives

Catherine E. Langston, DVM, DACVIM (Internal Medicine) Staff Doctor Head of Renal Medicine and Hemodialysis The Animal Medical Center New York, New York Acute Kidney Injury Chronic Kidney Disease

Jennifer A. Larsen, DVM, PhD, DACVN Assistant Professor of Clinical Nutrition VM: Molecular Biosciences University of California–Davis Davis, California Nutritional Assessment

Contributors

Victoria S. Larson, BSc, DVM, MS, DACVIM (Oncology) Adjunct Professor Department of Clinical Sciences University of Calgary Calgary, Alberta, Canada Staff Medical Oncologist Oncology Calgary Animal Referral and Emergency (Care) Centre Calgary, Alberta, Canada Complications of Chemotherapy Agents

Richard A. LeCouteur, BVSc, PhD, DACVIM (Neurology), DECVN Professor of Neurology and Neurosurgery Department of Surgical and Radiological Sciences William R. Pritchard Veterinary Medical Teaching Hospital School of Veterinary Medicine University of California–Davis Davis, California Intracranial Hypertension

Justine A. Lee, DVM, DACVECC, DABT CEO VetGirl, LLC. St. Paul, Minnesota Nonrespiratory Look-Alikes Approach to Drug Overdose Analgesia and Constant Rate Infusions

Daniel Huw Lewis, MA, VetMB, CVA, DACVECC, MRCVS Petmedics Veterinary Hospital Petmedics (CVS) Ltd. Manchester, Greater Manchester, United Kingdom Multiple Organ Dysfunction Syndrome

Ronald Li, BSc, DVM, MVetMed, MRCVS Senior Clinical Training Scholar in Emergency and Critical Care Department of Veterinary Clinical Sciences Queen Mother Hospital for Animals The Royal Veterinary College University of London North Mymms, Hatfield, Hertfordshire, United Kingdom Canine Parvovirus Infection

Debra T. Liu, DVM, DACVECC Criticalist Orange County Veterinary Specialists Tustin, California Veterinary Emergency Service Fresno, California Crystalloids, Colloids, and Hemoglobin-Based Oxygen-Carrying Solutions

Kristin A. MacDonald, DVM, PhD, DACVIM (Cardiology) Veterinary Cardiologist VCA–Animal Care Center of Sonoma Rohnert Park, California Infective Endocarditis

Maggie C. Machen Resident, Cardiology Ryan Hospital School of Veterinary Medicine University of Pennsylvania Philadelphia, Pennsylvania Ventricular Failure and Myocardial Infarction

Valerie Madden, DVM Resident College of Veterinary Medicine Cornell University Ithaca, New York Complications of Chemotherapy Agents

Christina Maglaras, DVM Resident, Small Animal Emergency and Critical Care Department of Small Animal Medicine and Surgery College of Veterinary Medicine The University of Georgia Athens, Georgia Mycoplasma, Actinomyces, and Nocardia

Deborah C. Mandell, VMD, DACVECC Staff Veterinarian, Emergency Service Adjunct Associate Professor, Section of Critical Care Emergency/Critical Care Veterinary Hospital of the University of Pennsylvania Philadelphia, Pennsylvania Cardiogenic Shock Pheochromocytoma Methemoglobinemia Pulmonary Artery Catheterization

F.A. (Tony) Mann, DVM, MS, DACVS, DACVECC Professor Veterinary Medicine and Surgery University of Missouri–Columbia Columbia, Missouri Electrical and Lightning Injuries

Linda G. Martin, DVM, MS Associate Professor, Emergency and Critical Care Medicine Clinical Sciences Auburn University Auburn, Alabama Magnesium and Phosphate Disorders

Christiane Massicotte, DVM, MS, PhD, DACVIM (Neurology) Adjunct Faculty Clinical Studies University of Pennsylvania Philadelphia, Pennsylvania Neurologist Animal Emergency and Referral Associates Philadelphia, Pennsylvania Diseases of the Motor Unit

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x

Contributors

Karol A. Mathews, DVM, DVSc, DACVECC

Carrie J. Miller, DVM, DACVIM (Internal Medicine)

Professor Emerita Clinical Studies Ontario Veterinary College University of Guelph Guelph, Ontario, Canada Illness Severity Scores in Veterinary Medicine

Director of Internal Medicine Virginia Veterinary Specialists Charlottesville, Virginia Allergic Airway Disease in Dogs and Cats and Feline Bronchopulmonary Disease Inhaled Medications

Elisa M. Mazzaferro, MS, DVM, PhD, DACVECC

James B. Miller, DVM, MS, DACVIM

Staff Criticalist Cornell University Veterinary Specialist Stamford, Connecticut Oxygen Therapy Perioperative Evaluation of the Critically Ill Patient Arterial Catheterization

Consultant Antech Diagnostics Stratford, Prince Edward Island, Canada Hyperthermia and Fever

Robin L. McIntyre, DVM Resident in Small Animal Emergency and Critical Care Veterinary Medical Teaching Hospital William R. Pritchard Veterinary Medical Teaching Hospital University of California–Davis Davis, California Patient Suffering in the Intensive Care Unit Cardiac Output Monitoring

Maureen McMichael, DVM, DACVECC Associate Professor, Emergency & Critical Care Service Chief Veterinary Clinical Medicine Veterinary Teaching Hospital University of Illinois Urbana, Illinois Prevention and Treatment of Transfusion Reactions Critically Ill Neonatal and Pediatric Patients Critically Ill Geriatric Patients

Margo Mehl, DVM, DACVS VCA San Francisco Veterinary Specialists Staff Surgeon Surgery San Francisco, California Portosystemic Shunt Management

Matthew S. Mellema, DVM, PhD, DACVECC Assistant Professor, Small Animal Emergency and Critical Care Department of Veterinary Surgical and Radiological Sciences University of California–Davis Davis, California Patient Suffering in the Intensive Care Unit Brachycephalic Syndrome Ventilator Waveforms Cardiac Output Monitoring Electrocardiogram Evaluation Intraabdominal Pressure Monitoring

Kathryn E. Michel, DVM, MS, DACVN Professor of Nutrition Department of Clinical Studies School of Veterinary Medicine University of Pennsylvania Philadelphia, Pennsylvania Enteral Nutrition Parenteral Nutrition

Adam Moeser, DVM, DACVIM (Neurology) Veterinary Neurologist Neurology/Neurosurgery Animal Neurology and MRI Center Commerce, Michigan Anticonvulsants

Cynthia M. Otto, DVM, PhD, DACVECC Associate Professor Clinical Studies–Philadelphia Executive Director Penn Vet Working Dog Center University of Pennsylvania Philadelphia, Pennsylvania Sepsis and Septic Shock Intraosseous Catheterization

Trisha J. Oura, DVM, DACVR Radiologist Diagnostic Imaging Tufts Veterinary Emergency Treatment & Specialties Walpole, Massachusetts Acute Lung Injury and Acute Respiratory Distress Syndrome

Mark A. Oyama, DVM, DACVIM (Cardiology) Professor, Clinical Educator Department of Clinical Studies–Philadelphia University of Pennsylvania Philadelphia, Pennsylvania Mechanisms of Heart Failure

Carrie A. Palm, DVM, DACVIM Assistant Professor of Clinical Small Animal Internal Medicine Department of Medicine and Epidemiology School of Veterinary Medicine University of California–Davis Davis, California Blood Purification for Intoxications and Drug Overdose Renal Replacement Therapies Apheresis

Mark G. Papich, DVM, MS, DACVCP Professor of Clinical Pharmacology Veterinary Teaching Hospital College of Veterinary Medicine North Carolina State University Raleigh, North Carolina Strategies for Treating Infections in Critically Ill Patients

Contributors

Romain Pariaut, DVM, DACVIM (Cardiology), DECVIM-CA (Cardiology) Associate Professor of Cardiology Veterinary Clinical Sciences Louisiana State University Baton Rouge, Louisiana Bradyarrhythmias and Conduction Disturbances Ventricular Tachyarrhythmias Cardioversion and Defibrillation

Sandra Perkowski, VMD, PhD, DACVAA Chief, Anesthesia Service Clinical Studies–Philadelphia School of Veterinary Medicine University of Pennsylvania Philadelphia, Pennsylvania Pain and Sedation Assessment Sedation of the Critically Ill Patient

Michele Pich, MA, MS Veterinary Grief Counselor Social Work School of Veterinary Medicine University of Pennsylvania Philadelphia, Pennsylvania Client Communication and Grief Counseling

Simon R. Platt, BVM&S, MRCVS, DACVIM (Neurology), DECVN Professor of Neurology Small Animal Medicine and Surgery College of Veterinary Medicine University of Georgia Athens, Georgia Coma Scales Tetanus Vestibular Disease

Lisa Leigh Powell, DVM, DACVECC Veterinary Clinical Sciences University of Minnesota St. Paul, Minnesota Drowning and Submersion Injury

Robert Prošek, DVM, MS, DACVIM (Cardiology), DECVIM-CA (Cardiology) Adjunct Professor of Cardiology Department of Small Animal Medicine and Surgery University of Florida Gainesville, Florida President Florida Veterinary Cardiology Miami Beach; South Miami; Ocean Reef; Homestead; Key West, Florida Canine Cardiomyopathy

Bruno H. Pypendop, DrMedVet, DrVetSci, DACVAA Professor Department of Surgical and Radiological Sciences School of Veterinary Medicine University of California–Davis Davis, California Jet Ventilation α2 Agonists and Antagonists Capnography

Jane Quandt, BS, DVM, MS, DACVAA, DACVECC Associate Professor–Comparative Anesthesia Small Animal Medicine and Surgery College of Veterinary Medicine University of Georgia Athens, Georgia Anesthesia in the Critically Ill Patient Analgesia and Constant Rate Infusions

Louisa J. Rahilly, DVM, DACVECC Medical Director Emergency and Critical Care Cape Cod Veterinary Specialists Buzzards Bay, Massachusetts Methemoglobinemia

Alan G. Ralph, DVM, DACVECC Resident in Emergency and Critical Care Medicine Department of Small Animal Clinical Sciences College of Veterinary Medicine Michigan State University East Lansing, Michigan Hypercoagulable States

Shelley C. Rankin, BSc (Hons), PhD Associate Professor Clinician Educator of Microbiology School of Veterinary Medicine University of Pennsylvania Philadelphia, Pennsylvania Nosocomial Infections and Zoonoses

Alan H. Rebar, DVM, PhD, DACVP Senior Associate Vice President for Research Professor of Veterinary Clinical Pathology Department of Comparative Pathology College of Veterinary Medicine Purdue University West Lafayette, Indiana Blood Film Evaluation

Erica L. Reineke, VMD, DACVECC Assistant Professor of Emergency and Critical Care Medicine Clinical Studies–Philadelphia School of Veterinary Medicine University of Pennsylvania Philadelphia, Pennsylvania Evaluation and Triage of the Critically Ill Patient Serotonin Syndrome

Adam J. Reiss, DVM, DACVECC Staff Veterinarian Southern Oregon Veterinary Specialty Center Medford, Oregon Myocardial Contusion

Caryn Reynolds, DVM, DACVIM (Cardiology) Staff Cardiologist Veterinary Emergency and Specialty Center of New Mexico Albuquerque, New Mexico Bradyarrhythmias and Conduction Disturbances

Laura L. Riordan, DVM, DACVIM Florida Veterinary Referral Center Estero, Florida Potassium Disorders

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Contributors

Joris H. Robben, DVM, PhD, DECVIM-CA

Valérie Sauvé, DVM, DACVECC

Associate Professor, Emergency and Intensive Care Medicine Department of Clinical Sciences of Companion Animals Faculty of Veterinary Medicine Utrecht University Utrecht, the Netherlands Intensive Care Unit Facility Design

Head of Critical Care Emergency and Critical Care Centre Vétérinaire DMV Montreal, Quebec, Canada Pleural Space Disease

Narda G. Robinson, DO, DVM, MS, FAAMA Director, CSU Center for Comparative and Integrative Pain Medicine Clinical Sciences Colorado State University Fort Collins, Colorado Complementary and Alternative Medicine

Mark P. Rondeau, DVM, DACVIM (Internal Medicine) Staff Veterinarian Department of Clinical Studies–Philadelphia School of Veterinary Medicine University of Pennsylvania Philadelphia, Pennsylvania Acute Cholecystitis Hepatitis and Cholangiohepatitis

Patricia G. Rosenstein, DVM Emergency Veterinarian Veterinary Hospital The University of Melbourne South Yarra, Victoria, Australia Hyperlactatemia

Alexandre Rousseau, DVM, DACVIM (Internal Medicine), DACVECC Cornell University Veterinary Specialists Stamford, Connecticut Bleeding Disorders

Elizabeth A. Rozanski, DVM, DACVIM, DACVECC Associate Professor Clinical Sciences Tufts Cummings School of Veterinary Medicine North Grafton, Massachusetts Acute Lung Injury and Acute Respiratory Distress Syndrome

Elke Rudloff, DVM, DACVECC Residency Training Supervisor Lakeshore Veterinary Specialists Glendale, Wisconsin Assessment of Hydration Necrotizing Soft Tissue Infections

Kari Santoro-Beer, DVM, DACVECC Lecturer, Critical Care Department of Clinical Studies–Philadelphia Matthew J. Ryan Veterinary Hospital University of Pennsylvania Philadelphia, Pennsylvania Daily Intravenous Fluid Therapy Pheochromocytoma

Emily Savino, CVT, VTS (ECC) ICU Nursing Supervisor Matthew J. Ryan Veterinary Hospital University of Pennsylvania Philadelphia, Pennsylvania Management of the Intensive Care Unit

Michael Schaer, DVM, DACVIM (Internal Medicine), DACVECC Professor Emeritus Small Animal Clinical Sciences; Section of Emergency and Critical Care University of Florida Gainesville, Florida Potassium Disorders Antitoxins and Antivenoms

Sergio Serrano, LV, DVM, DACVECC, MBA Medical Director, Criticalist Connecticut Veterinary Center West Hartford, Connecticut Pulmonary Contusions and Hemorrhage

Claire R. Sharp, BSc, BVMS (Hons), MS, DACVECC Assistant Professor Clinical Sciences Tufts Cummings School of Veterinary Medicine North Grafton, Massachusetts Gastric Dilatation-Volvulus

Scott P. Shaw, DVM, DACVECC Medical Director New England Veterinary Center & Cancer Care Windsor, Massachusetts β-Lactam Antimicrobials Macrolides

Nadja E. Sigrist, DrMedVet, FVH, DACVECC VET ECC CE Affoltern am Albis Zürich, Switzerland Thoracocentesis Thoracostomy Tube Placement and Drainage

Contributors

Deborah C. Silverstein, DVM, DACVECC Associate Professor of Critical Care Department of Clinical Studies Matthew J. Ryan Veterinary Hospital University of Pennsylvania Philadelphia, Pennsylvania Adjunct Professor Temple University School of Pharmacy Philadelphia, Pennsylvania Shock Chest Wall Disease Crystalloids, Colloids, and Hemoglobin-Based Oxygen-Carrying Solutions Daily Intravenous Fluid Therapy Shock Fluids and Fluid Challenge Thoracic and Abdominal Trauma Vasopressin Fluoroquinolones

Meg Sleeper, VMD, DACVIM (Cardiology) Associate Professor of Cardiology Clinical Studies–Philadelphia University of Pennsylvania Veterinary School Philadelphia, Pennsylvania Ventricular Failure and Myocardial Infarction Myocarditis

Sean Smarick, VMD, DACVECC Hospital Director AVETS Monroeville, Pennsylvania Catheter-Related Bloodstream Infection Urine Output Urinary Catheterization

Lisa Smart, BVSc (Hons), DACVECC Senior Lecturer, Veterinary Emergency and Critical Care School of Veterinary and Life Sciences, College of Veterinary Medicine Murdoch University Murdoch, Western Australia, Australia Ventilator-Induced Lung Injury

Laurie Sorrell-Raschi, DVM, DACVAA, RRT Anesthesiologist Anesthesia/Pain Management and Complementary Therapy Veterinary Specialty Center of Delaware New Castle, Delaware Blood Gas and Oximetry Monitoring

Sheldon A. Steinberg, VMD, DMSc, DACVIM (Neurology), DECVN Emeritus Professor of Neurology/Neurosurgery Clinical Studies–Philadelphia School of Veterinary Medicine University of Pennsylvania Philadelphia, Pennsylvania Anticonvulsants

Randolph H. Stewart, DVM, PhD Clinical Associate Professor Veterinary Physiology & Pharmacology Texas A&M University College Station, Texas Interstitial Edema

Beverly K. Sturges, DVM, MS, DACVIM (Neurology) Radiological & Surgical Sciences University of California–Davis Davis, California Intracranial Hypertension Intracranial Pressure Monitoring Cerebrospinal Fluid Sampling

Jane E. Sykes, BVSc (Hons), PhD, DACVIM Professor Medicine and Epidemiology University of California–Davis Davis, California Viral Infections

Rebecca S. Syring, DVM, DACVECC Critical Care Specialist Veterinary Specialty and Emergency Center Levittown, Pennsylvania Traumatic Brain Injury

Jeffrey M. Todd, DVM, DACVECC Assistant Clinical Professor Department of Veterinary Clinical Sciences College of Veterinary Medicine Veterinary Medical Center University of Minnesota St. Paul, Minnesota Hypothermia

Tara K. Trotman, VMD, DACVIM (Internal Medicine) Internal Medicine Consultant Idexx Laboratories Westbrook, Maine Gastroenteritis

Karen M. Vernau, DVM, MAS, DACVIM (Neurology) Associate Clinical Professor of Neurology/Neurosurgery Surgical and Radiological Sciences University of California–Davis Davis, California Seizures and Status Epilepticus

Cecilia Villaverde, BVSc, PhD, DACVN, DECVCN Assistant Professor Ciencia Animal i dels Aliments Universitat Autònoma de Barcelona Bellaterra, Barcelona, Spain Chief of Service Servei de Dietètica i Nutrició Fundació Hospital Clínic Veterinari Universitat Autònoma de Barcelona Bellaterra, Barcelona, Spain Nutritional Assessment

Charles H. Vite, DVM, PhD, DACVIM (Neurology) Associate Professor, Neurology Clinical Studies School of Veterinary Medicine University of Pennsylvania Philadelphia, Pennsylvania Spinal Cord Injury

xiii

xiv

Contributors

Susan W. Volk, VMD, PhD, DACVS

Aaron C. Wey, DVM, DACVIM (Cardiology)

Assistant Professor of Small Animal Surgery Department of Clinical Studies–Philadelphia School of Veterinary Medicine University of Pennsylvania Philadelphia, Pennsylvania Peritonitis

Owner Cardiology Upstate Veterinary Specialties, PLLC Latham, New York Valvular Heart Disease

Lori S. Waddell, DVM, DACVECC Adjunct Assistant Professor, Critical Care Department of Clinical Studies–Philadelphia Matthew J. Ryan Veterinary Hospital School of Veterinary Medicine University of Pennsylvania Philadelphia, Pennsylvania Rodenticides Hemodynamic Monitoring Colloid Osmotic Pressure and Osmolality Monitoring

Andrea Wang, DVM, MA, DACVIM Small Animal Internist, Board Certified Advanced Veterinary Care Salt Lake City, Utah Thrombocytopenia

Cynthia R. Ward, VMD, PhD, DACVIM (Internal Medicine) Professor, Small Animal Internal Medicine Small Animal Medicine and Surgery College of Veterinary Medicine University of Georgia Athens, Georgia Thyroid Storm

Wendy A. Ware, DVM, MS, DACVIM (Cardiology) Professor Departments of Veterinary Clinical Sciences and Biomedical Sciences Iowa State University Ames, Iowa Pericardial Diseases

Michael D. Willard, DVM, MS, DACVIM (Internal Medicine) Professor Department of Small Animal Clinical Sciences Texas A&M University College Station, Texas Gastrointestinal Protectants Antiemetics and Prokinetics

Kevin P. Winkler, DVM, DACVS Surgeon Georgia Veterinary Specialists Atlanta, Georgia Necrotizing Soft Tissue Infections

Annie Malouin Wright, DVM, DACVECC Staff Criticalist Critical Care BluePearl Minnesota Eden Prairie, Minnesota Sedative, Muscle Relaxant, and Narcotic Overdose Calcium Channel Blocker and β-Blocker Drug Overdose

Bonnie Wright, DVM, DACVAA Associate Fort Collins Veterinary Emergency & Rehabilitation Hospital Fort Collins, Colorado Air Embolism

Kathy N. Wright, DVM, DACVIM (Cardiology; Internal Medicine) Lead Cardiologist, Cincinnati and Dayton locations MedVet Medical and Cancer Center for Pets Cincinnati and Dayton, Ohio Supraventricular Tachyarrhythmias Antiarrhythmic Agents

PREFACE The field of critical care is an exciting one and rapidly growing in both human and veterinary medicine. New developments and recommendations are evolving faster than ever, making it especially important for veterinarians to have an up-to-date resource when caring for critically ill dogs and cats. The second edition of Small Animal Critical Care Medicine reflects the current knowledge of experts in the field, with extensive citations to the veterinary and medical literature at the end of each chapter. It builds upon the strong foundation of the first edition, focusing on a comprehensive approach to critical care medicine, from the pathophysiology of disease states to interpretation of diagnostic tests and descriptions of medical techniques that are unique to this specialty. In this edition, there is a greater focus on critical care medicine and fewer chapters devoted to routine care of emergent patients. There are 32 new chapters and all remaining chapters have been updated or completely rewritten. We are delighted to welcome many new contributors; this edition represents the work of over 150 authors from around the world. The scope of topics is broad and clinically oriented, helping practitioners provide the highest standard of care for their critically ill small animal patients. As with the first edition, this textbook is intended to be an essential, state-of-the-art resource for anyone working with critically ill patients in general practice settings, specialty veterinary practices, and university teaching hospitals. An exciting feature of this new edition is its full-color layout, enabling effortless visibility of relevant color photographs throughout each chapter. The organization of this new edition has changed slightly, including a large section dedicated to intensive care unit procedures. All the chapters start with key points to quickly provide the reader with the most important take-home messages for each topic. The appendices provide an outstanding resource of useful information gathered together in one easy-to-access location, including lists of formulas, reference values, and constant rate infusion doses. This text includes 23 major sections with 211 chapters that cover all aspects of critical care medicine. Several chapters of this new edition deserve to be highlighted. The chapter on cardiopulmonary resuscitation was rewritten and a new chapter on post-resuscitation care added, both authored by Daniel J. Fletcher and Manuel Boller, the current leaders of veterinary CPR and the RECOVER project. Another new chapter explores mechanisms of patient suffering in the intensive care unit, an immensely important but poorly recognized subject to date. The respiratory section has been broadened, with a stronger emphasis on the physiology of respiratory failure and new

chapters on tracheobronchial injury and brachycephalic syndrome. In addition, the following chapters deserve special attention: The mechanical ventilation section has been expanded and represents the most thorough and advanced review of mechanical ventilation currently available for veterinary patients The acid-base and hyperlactatemia chapters have been completely rewritten and a new chapter reviewing nontraditional approaches to acid-base analysis has been added. The fluid therapy section has been completely rewritten and includes two new transfusion therapy chapters. There is a new section on therapeutic drug overdose, a wellrecognized issue in the intensive care unit, that includes a new chapter on the role of blood purification in the treatment of toxins and drug overdose. There is a major emphasis on infectious diseases and antimicrobial therapy, including new chapters on approaches to multidrug-resistant infections and advanced antimicrobial strategies for critical patients. The focus on coagulation has been expanded, with outstanding chapters on antiplatelet drugs and hemostatic drugs. A new section focuses on intensive care unit design and management, areas unique to the field of critical care medicine that have not been addressed in previous veterinary publications. There are new chapters on such topics as noninvasive surgery and interventional radiology, AFAST/TFAST in the intensive care unit, and the pharmacology of antitoxins and antivenoms. Critical care medicine poses a unique set of challenges and rewards, and the editors intend for this book to continue to fill the gap that exists between basic medical and surgical references and the available emergency-oriented manuals. Ultimately, we hope that this book will enable veterinarians, who have committed themselves to the knowledgeable and skillful care of their patients, to better deliver on that solemn promise and enhance both quality of life for pets and the ongoing relationship with those who love them.

• • • • • • • •

xv

ACKNOWLEDGMENTS The editors are most appreciative to all of the Elsevier staff, especially Penny Rudolph, Brandi Graham, and David Stein, who made this textbook possible. We would also like to thank all of our contributors; it is their invaluable time and effort that have made this edition such an incredible resource for all veterinarians.

The second edition of this book would not have been possible without the love and support of my husband, Stefan, and precious boys, Maxwell and Henry. Thank you to all of our dedicated contributors, colleagues and mentors, as well as to my amazing co-editor, Kate. Although I am not convinced the second edition was any easier than the first, the “team” that made it possible is truly amazing! I feel honored to have worked with each and every one of you.

—Deb

For all the amazing mentors I have had from day one of my veterinary career. People such as Russell Mitten, Peter Irwin, Glen Edwards, Philip Hartney, Ava Firth, Steve Haskins, Janet Aldrich, Matt Mellema and Deb Silverstein. Each and every one of you showed me what being a clinician and a teacher really means. Thank you.

—Kate

In loving memory of all of our family and colleagues that have left this world prematurely and are missed so dearly every day, especially MaryLee Dombrowski, Sharon Drellich, and Dougie Macintire. You will never be forgotten. And last, but certainly not least, this book is in memory of Steve Haskins, who passed away shortly after contributing to this book. Neither of us would be where we are today if this amazing man had not touched our lives in such a positive and immeasurable way. To Steve and all of our loved ones, this book is for you.

—Deb and Kate

REFERENCE RANGES Most hematologic and biochemical reference ranges were established in-house at the University of Pennsylvania using at least 65 dogs and cats that appeared healthy on physical examination and had normal laboratory values. The Cell Dyn 3500 was used for hematology, the Ortho 350 for chemistries, and the Stago Compact for Coagulation Profiles. All readers are urged to use reference values specific for the laboratory or instrumentation device used when interpreting values for individual patients. Reference intervals depend on the region of the world/country, the type of sample (whole blood vs. plasma or serum), and the type of instrument that is being used.

Hematology Reference Ranges Value

Canine

Feline

Red blood cells × 10 /µl

5.83-8.87

6.56-11.20

Hemoglobin (g/dl)

13.3-20.5

10.6-15.6

Hematocrit (%)

40.3-60.3

31.7-48

–6

Packed cell volume (%)

37-55

25-45

Mean corpuscular volume (fl)

62.7-75.5

36.7-53.7

Mean corpuscular hemoglobin (pg)

22.5-26.9

12.3-17.3

Mean corpuscular hemoglobin concentration (g/dl)

32.3-36.3

30.1-35.6

Red cell distribution width (g/dl)

13.2-17.4

16.7-22.9

177-398

175-500

–3

Platelets (×10 /ml) Mean platelet volume (fl)

7-13

9-18

White blood cells (×10 /ml)

5.3-19.8

4.04-18.70

Segmented neutrophils (×10–3/ml)

3.1-14.4

–3

2.3-14

–3

0.0-0.2

Lymphocytes (×10 /ml)

0.9-5.5

0.8-6.1

Monocytes (×10–3/ml)

0.1-1.4

0.0-0.7

Eosinophils (×10 /ml)

0.0-1.6

0.0-1.5

Basophils (×10–3/ml)

0.0-0.1

0.0-0.1

Value

Canine

Band neutrophils (×10 /ml) –3

–3

0.0

Reference Ranges for Biochemical Parameters Value

Canine

Feline

Albumin/globulin ratio

0.7-1.5

0.6-1.1

Albumin (g/dl)

2.5-3.7

2.4-3.8

Alkaline phosphatase (U/L)

20-155

22-87

Alanine aminotransferase (U/L)

16-91

33-152

Amylase (U/L) Anion gap (mmol/L) Aspartate aminotransferase (U/L) Bilirubin (total) (mg/dl) Blood urea nitrogen/creatinine ratio

339-1536

433-1248

8-21

12-16

23-65

1-37

0.3-0.9 9-33

0.1-0.8 10-24.6

Gamma-glutamyl transpeptidase (U/L) Globulin (g/dl) Glucose (mg/dl)

7-24 2.4-4 65-112

Feline 5-19 3.1-5 67-168

Ionized calcium (mmol/L)

1.25-1.5

1.1-1.4

Ionized magnesium (mmol/L)

0.43-0.6

0.43-0.7

Iron (mcg/dl) Lactate (mmol/L) Lipase (U/L)

94-122 0.5-2 72-1310

68-215 0.5-2 157-1715

Magnesium (mg/dl)

1.6-2.5

1.9-2.6

Calcium (mg/dl)

9.8-11.7

9.1-11.2

Phosphorus (mg/dl)

2.8-6.1

3.0-6.6

Calculated osmolality

264-292

287-307

4.4-276.1

1.2-3.8

Chloride (mEq/L)

109-120

116-126

Pancreatic lipase immunoreactivity (mcg/L)

Cholesterol (mg/dl)

128-317

96-248

Potassium (mEq/L)

3.9-4.9

3.5-4.8

46-467

49-688

Cobalamin (ng/L)

284-836

276-1425

Colloid osmotic pressure (mm Hg)

17.94-21.96 (whole blood) 14.3-20.3 (plasma)

21-28.4 (whole blood) 17.4-22.2 (plasma)

Creatine kinase (U/L)

Creatinine (mg/dl)

0.7-1.8

1-2

Fibrinogen (mg/dl)

200-400

200-400

Folate (mg/dl)

7.5-17.5

7.5-17.5

Protein (g/dl)

5.4-7.1

6.0-8.6

Sodium (mEq/L)

140-150

146-157

Total carbon dioxide (mmol/L) Total iron binding capacity (mcg/dl) Trypsin-like immunoreactivity (mcg/L) Triglyceride (mg/dl) Urea nitrogen (mg/dl) Triglyceride (mg/dl) Urea nitrogen (mg/dl)

17-28

16-25

280-340

170-400

5-35

28-115

29-166

21-155

5-30 29-166 5-30

15-32 21-155 15-32

Thyroid Function Test Reference Values

Liver Function Tests Reference Values

Canine

Feline

T4 (mcg/dl)

1.52-3.60

1.2-3.8

T4 post-SH (mcg/dl)

>3- to 4-fold

>3- to 4-fold

T3 (ng/dl)

48-154

–

T3 post-TSH (ng/dl)

>10 ng increase

–

TSH (mlU/L)

0.14

0.37

Normal Arterial Blood Gas Values and Ranges Dog

Cat

pH

7.40 (7.35-7.45)

7.41 (7.35-7.46)

7.39 (7.31-7.46)

PaCO2 (mm Hg)

40 (35-45)

37 (32-43)

31 (26-36)

Base deficit (mmol/L)

0 (–2 to +2)

–2 (+1 to –5)

–5 (–2 to –8)

Bicarbonate (mmol/L)

24 (22-26)

22 (18-26)

18 (14-22)

PaO2 (mm Hg) (sea level)

95 (80-105)

92 (80-105)

107 (95-115)

Coagulation Test Reference Ranges Feline

6-11

6-12

PTT (sec)

10-25

10-25

FDP (mcg/ml)

α > β2

Positive inotropy Positive chronotropy Vasoconstriction

Injectable: 1 mg/ml

0.01-3.0 mcg/kg/min

Epinephrine

β-Adrenergic agonist, α agonist β 1 = β2 >α

Positive inotropy Positive chronotropy Peripheral vasodilation Vasoconstriction HD

Injectable: 1 mg/ml, 0.1 mg/ml

0.01-0.1 mcg/kg/min

Isoproterenol

β-Adrenergic agonist β 1 > β2

Positive inotropy Positive chronotropy Peripheral vasodilation

Injectable: 0.2mg/mL

Dog: 0.04-0.09 mcg/kg/min IV

Pimobendan*

Phosphodiesterase III inhibitor, Ca sensitizer

Positive inotropy Arteriolar vasodilation

Oral: 1.25, 5 mg chewable tablets

Dog: 0.25 mg/kg PO q12h Cat: 1.25 mg/cat PO q12h

Milrinone

Phosphodiesterase III inhibitor, Ca sensitizer

Positive inotropy Arteriolar vasodilation

Injectable: 1 mg/ml

0.375-0.75 mcg/kg/min

*Commonly used for inotropic support in veterinary medicine. † Consult a pharmacology textbook for complete formulation and administration specifics.

Table 40-1 for specific drug information.) Digoxin (although historically widely used in veterinary medicine as a positive inotrope for chronic therapy) has very weak inotropic properties and has been largely supplanted by pimobendan. The exception is patients in which its negative chronotropic effect is indicated, in which case digoxin can be used in conjunction with pimobendan.

Relieving Signs of Congestion Diuretics become critical should ventricular failure progress to clinical or radiographic signs of congestion, both in the acute stage and for chronic therapy. In many instances, the first knowledge of underlying ventricular failure comes when the patient develops signs of fluid overload and is presented for tachypnea, dyspnea, orthopnea, or coughing. Patients with biventricular or primarily right-sided failure may also develop ascites and abdominal distention. Furosemide is the most commonly used first-line diuretic choice (see Chapters 43 and Chapter 160 for doses). A potent loop diuretic, it works quickly to relieve life-threatening pulmonary edema, and can be given as a bolus (subcutaneously [SC], intramuscularly [IM], or intravenously [IV]) or as a CRI. With pulmonary edema, excess diuresis with overly aggressive preload reduction and relative volume depletion must be avoided.10 If possible, baseline renal values should be obtained before diuretic therapy because patients with underlying renal insufficiency may require more conservative therapy. For animals with pleural or abdominal effusion causing respiratory distress, thoracocentesis or abdominocentesis should be performed at the time of presentation. Furosemide will decrease the rate of future fluid accumulation; however, it has very little effect on existing pleural or abdominal fluid. Secondary diuretics such as spironolactone, hydrochlorothiazide, and torsemide are important in chronic therapy for refractory failure; however, at this time they are only available in an oral formulation and have limited use in the emergency room setting. For information on chronic therapy for congestive heart failure, see Chapters 42 and 43.

Suppressing Arrhythmias Despite variable underlying etiologies, many patients with ventricular failure will develop arrhythmias. All antiarrhythmic drugs can also be proarrhythmic, so it is important to note that prophylactic antiarrhythmic therapy is contraindicated in asymptomatic patients. For example, although it is common for patients to develop intermittent ventricular ectopy, only malignant arrhythmias warrant intervention. For a full discussion of antiarrhythmic therapy, see Chapters 47 and 48.

Treating the Underlying Cause Although primary cardiac disease and myocardial infarctions are generally progressive and irreversible, some causes of heart failure can be treated primarily. For example, tachycardia-induced cardiomyopathy presents a unique situation for possible resolution. Depending on the severity and chronicity, successful rate control can often result in normal systolic function. Moreover, ventricular dysfunction secondary to some extracardiac causes (such as sepsis or nutritional deficiency) may improve or normalize with therapy. However, other causes, such as doxorubicin toxicity, are generally irreversible.

REFERENCES 1. Sisson D, Oyama M: Cardiovascular medicine of companion animals. Course outline for cardiovascular medicine, Champagne-Urbana, IL, 2003, University of Illinois School of Veterinary Medicine. 2. Umana E, Solares CA, Alpert MA: Tachycardia-induced cardiomyopathy, Am J Med 114:51, 2003. 3. Fernandes CJ Jr, de Assuncao MSC: Myocardial dysfunction in sepsis: a large, unsolved puzzle, Critical Care Res Pract 2012:896430, 2012. 4. Merx MW, Weber C: Sepsis and the heart, Circulation 116(7):793-802, 2007. 5. Driehuys S, Van Winkle TJ, Sammarco C, et al: Myocardial infarction in dogs and cats: 37 cases (1985-1994), J Am Vet Med Assoc 213(10):1444, 1998.

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6. Buchanan JW: Vertebral scale system to measure heart size in radiographs, Vet Clin North Am Small Anim Pract 30:379, 2000. 7. Singletary GE, Morris NA, O’Sullivan L, et al: Prospective evaluation of NT-proBNP assay to detect occult dilated cardiomyopathy and predict survival in Doberman pinschers, J Vet Intern Med 26:1330, 2012. 8. Serra M, Papakonstantinou S, Adamcova M, et al: Veterinary and toxicological applications for the detection of cardiac injury using cardiac troponin, Vet J 185:50, 2010.

9. Sleeper MM, Clifford CA, Laster LL: Cardiac troponin I in the normal dog and cat, J Vet Intern Med 501, 2001. 10. Poole-Wilson PA, Opie LH: Acute and chronic heart failure: positive inotropes, vasodilators, and digoxin. In Opie LH, Gersh BJ, editors: Drugs for the heart, ed 7, Philadelphia, 2009, Saunders. 11. Smith FW, Tilley LP, Oyama MA, et al: Common cardiovascular drugs. In Tilley LP, Smith FW, Oyama MA, et al, editors: Manual of canine and feline cardiology, ed 7, St Louis, 2008, Saunders Elsevier.

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PART IV  •  CARDIAC DISORDERS

CHAPTER 41  FELINE CARDIOMYOPATHY Jonathan A. Abbott,

DVM, DACVIM (Cardiology)

KEY POINTS • Myocardial disease accounts for almost all acquired cardiac disorders in the cat. • Cardiomyopathy, defined as a heart muscle disease that is associated with cardiac dysfunction, is an important cause of both morbidity and mortality in the cat. • The most common forms of feline cardiomyopathy result in impaired ventricular filling. • Clinical signs are associated with congestive heart failure (CHF) or systemic thromboembolism. • Diagnostic imaging, through radiography and echocardiography, is vital to the diagnostic approach. • Urgent medical management of CHF secondary to feline cardiomyopathy primarily consists of supportive care and interventions that decrease ventricular filling pressures.

Heart muscle disease is an important cause of morbidity and mortality in the cat. The various forms of myocardial disease account for virtually all acquired cardiac disorders in this species; disease that is primary to valvular structures, the pericardium, or specialized conduction system is uncommon. The nomenclature of myocardial disease is potentially problematic but evolving. Cardiomyopathy has been defined as a heart muscle disease that is associated with cardiac dysfunction.1 Myocardial diseases generally are defined by morphopathologic features or, when it is known, cause. Based on this classification scheme, there are four basic types of cardiomyopathy: (1) dilated cardiomyopathy, (2) hypertrophic cardiomyopathy (HCM), (3) restrictive cardiomyopathy (RCM), and (4) arrhythmogenic right ventricular cardiomyopathy.1 All these forms are observed in the cat.2-6 Heart muscle diseases that are associated with a known causal agent, hemodynamic abnormality, or metabolic derangement are known as specific cardiomyopathies.1 In the cat, the most important disorders in this category are thyrotoxic cardiomyopathy and hypertensive HCM.7 In general, these secondary cardiomyopathies seldom result in clinical signs and are reversible when the underlying disorder resolves.8,9

This chapter addresses the clinical picture and therapy of cardiomyopathy that develop as a result of abnormalities that are primary to the myocardium. HCM is the most common heart disease in the cat and therefore is emphasized.

ETIOPATHOGENESIS HCM is a primary heart muscle disease in which ventricular hypertrophy develops in the absence of a hemodynamic or metabolic cause.10 Although systolic dysfunction and wall thinning occasionally develop in patients with long-standing HCM, the disorder generally is characterized by hypertrophy of a nondilated ventricle.10 It is accepted that HCM in humans is a genetic disease, and this disorder has been associated with hundreds of mutations of genes that encode sarcomeric proteins. The mutations responsible for familial HCM in Maine Coon cats and in Ragdoll cats have been identified.11-13 This finding and the occurrence of HCM in related purebred and mixed breed cats support a genetic basis.14-16 Feline RCM is a disorder in which impaired ventricular filling occurs in the absence of myocardial hypertrophy or pericardial disease. The structural features of RCM are varied and diagnostic criteria are not rigidly defined. The term generally is applied when there is atrial enlargement associated with a ventricle that has a normal or nearly normal appearance.7 The cause of feline RCM is not known. Endomyocardial fibrosis and myocardial functional deficits that impair relaxation are the presumed explanations for diastolic dysfunction and resultant atrial enlargement. It is possible that some examples of RCM represent the sequelae of endomyocardial inflammation.4

PATHOPHYSIOLOGY Diastolic Dysfunction The ability of the ventricle to fill at low diastolic pressures depends on the rate of the active, energy-requiring process known as myocardial relaxation, as well as on mechanical properties that determine chamber compliance.17 Impaired myocardial relaxation and diminished chamber compliance alter the pressure-volume relationship so that diastolic pressures are high when ventricular volume is normal

CHAPTER 41  •  Feline Cardiomyopathy

or small. High diastolic pressures are reflected upstream, potentially resulting in atrial enlargement and venous congestion. In cases in which the end-diastolic volume is diminished, stroke volume may also be reduced. Therefore diastolic dysfunction can explain subnormal cardiac output as well as venous congestion. Diastolic dysfunction is the predominant pathophysiologic mechanism responsible for clinical signs in HCM and RCM.7 With regard to HCM, intrinsic functional deficits of the cardiomyocytes and ischemia related to hypertrophy and abnormalities of the intramural coronary arteries are responsible for impaired myocardial relaxation. Hypertrophy and fibrosis stiffen the ventricle and explain diminished chamber compliance. The basis of cardiac dysfunction in feline RCM has been defined incompletely, although endomyocardial fibrosis likely plays an important role.

Systolic Anterior Motion of the Mitral Valve Systolic anterior motion (SAM) of the mitral valve is echocardiographically detected in approximately 65% of cats with HCM.3 The precise pathogenesis has been the subject of debate, but it is likely that abnormal drag forces are responsible for systolic movement of the valve leaflets toward the septum.18 Abnormal papillary muscle orientation and dynamic systolic ventricular performance provide a structural and functional substrate that predisposes to SAM.19 Movement of the mitral leaflets toward the septum results in dynamic—as opposed to fixed—left ventricular outflow tract obstruction and, usually, concurrent mitral valve regurgitation. SAM is a labile phenomenon; decreases in preload and afterload or increases in contractility may provoke or augment SAM, and this may explain the fact that the intensity of the associated murmur may vary from moment to moment.20 The prognostic relevance of SAM in feline HCM has not been defined. Outflow tract obstruction caused by SAM has been associated with poor prognosis in humans with HCM.21 Interestingly, the results of three retrospective studies of feline HCM suggest that SAM confers a more favorable prognosis than does its absence.3,22,23 Possibly this finding reflects the limitations of retrospective evaluation of a referral population as the finding of SAM is associated with asymptomatic status. SAM is likely the most important cause of cardiac murmurs in cats with HCM.

Feline Arterial Thromboembolism (FATE) Feline patients with myocardial disease are predisposed to the development of intracardiac thrombi. Intraventricular thrombi are occasionally observed, but the left atrium—specifically, its appendage—is more commonly the site of thrombus formation. If a portion of thrombus dislodges, it may embolize, the typical site of embolism being the aortic trifurcation. The causes of and risk factors for intracardiac thrombosis are incompletely defined. Left atrial enlargement, which presumably results in blood stasis, likely predisposes to thrombosis. Indeed, left atria of patients with feline arterial thromboembolism (FATE) are larger than those of patients with subclinical HCM or patients with heart failure caused by HCM.22 However, systematic evaluation of risks and incidence of FATE has not been published and it is relevant that FATE occasionally occurs in patients in whom left atrial size is normal.24 Left atrial enlargement is neither a sufficient nor necessary cause, but it is likely that left atrial enlargement is a risk factor for FATE as might be the echocardiographic findings of spontaneous contrast and systolic myocardial dysfunction. The clinical syndrome of FATE does not result solely from arterial occlusion caused by the thrombus because experimental ligation of the distal feline aorta does not reproduce the clinical syndrome.25 Available evidence suggests that vasoactive mediators, notably prostaglandins and serotonin, released from the thrombus decrease flow

through collateral circulation, contributing importantly to the development of ischemia.26-28

CLINICAL PRESENTATION Patient History and Physical Findings Clinical manifestations of feline cardiomyopathy result from congestive heart failure (CHF) and FATE. When CHF is present, the observation of tachypnea or respiratory distress most commonly prompts the pet owner to seek veterinary evaluation. Cats with heart failure seldom cough. Nonspecific clinical signs such as lethargy, depression, and inappetence often are observed in patients with cardiomyopathy. Although the causative disorder is usually chronic, the onset of clinical signs associated with CHF is typically sudden. Retrospectively evaluated case series have identified an association between the administration of glucocorticoids and the development of CHF in cats.22,29 Some affected cats may have had preexisting but clinically silent HCM, but this has not been established. This association is relevant, because the long-term prognosis for cats with glucocorticoid-associated CHF may be better than for those with CHF from more typical causes.29 Patients with CHF often are depressed, and hypothermia commonly is observed. The heart rates of cats with heart failure differ little from those of healthy cats,30 although bradycardia is occasionally evident. Many cats with HCM have a systolic murmur associated with SAM, but the prevalence of murmurs in cats with subclinical HCM is greater that in cats that have clinical signs of CHF.23 The prevalence of murmurs in cats with other forms of cardiomyopathy is lower.5 A gallop rhythm is a subtle but important auscultatory finding. The third and fourth heart sounds are seldom audible in healthy cats. In general, auscultation of a gallop sound signifies diminished ventricular compliance in association with high atrial pressures. A gallop sound more specifically identifies cats with heart disease than does a murmur. It is important to recognize that the prevalence of murmurs in echocardiographically normal cats is not inconsequential. Because of this, the finding of a cardiac murmur is sometimes incidental to a clinical picture that results from noncardiac disease. Crackles are sometimes heard in feline patients with cardiogenic edema, but it is likely that the auscultation of adventitious pulmonary sounds has low sensitivity and specificity for pulmonary edema. Patients in which pleural effusions are responsible for respiratory distress generally have quiet heart sounds as well as diminished, dorsally displaced bronchial tones. The anatomic site of embolism and time that has elapsed since the embolic event determines the clinical presentation of FATE. The distal aorta is embolized most commonly, but embolism of a brachial arterial, renal artery, mesenteric artery, or arteries of the central nervous system also occurs. Patients in which the clinical presentation is prompted by FATE of the aorta or brachial arteries have weak or absent arterial pulses. The resultant ischemic neuromyopathy causes variable degrees of pain, plegia, and nail bed cyanosis; when the distal aorta is affected, the gastrocnemius muscles often are firm.

Electrocardiography In the absence of arrhythmias, the diagnostic utility of electrocardiography in the assessment of cats with cardiomyopathy generally is low. Electrocardiographic evaluation of cats with clinical signs resulting from feline cardiomyopathy generally reveals sinus rhythm, although pathologic tachyarrhythmias sometimes are observed. The heart rates of cats with heart failure seldom are higher than is normal, and bradycardia resulting from a slow sinus rate or AV conduction disturbances is occasionally evident.

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A

B

FIGURE 41-1  Lateral (A) and ventrodorsal (B) radiographic projections of the thorax of a cat with heart failure caused by hypertrophic cardiomyopathy. The cardiac silhouette is enlarged and there are patchy interstitial and alveolar densities distributed throughout the lung.

Radiography In the cat, radiographic patterns associated with enlargement of specific chambers are relatively indistinct. Because of this, it is often impossible to draw conclusions regarding atrial or ventricular size, but rather, it is apparent only that the silhouette is enlarged. Radiographic cardiomegaly usually is evident when respiratory signs result from feline cardiomyopathy. Cardiogenic pulmonary edema in the cat typically is patchy but distributed diffusely through the lung (Figure 41-1). Fairly often the pulmonary arteries and veins are prominent if not obscured by infiltrates. Pulmonary edema is the most common manifestation of congestion in patients with HCM, but some cats develop large pleural effusions associated with HCM or other types of feline cardiomyopathy. Curiously, cats sometimes develop large pleural effusions as a result of cardiac diseases that affect primarily the left ventricle.

Echocardiography Definitive antemortem diagnosis of feline cardiomyopathy requires echocardiographic evaluation. HCM is characterized echocardiographically by ventricular hypertrophy in the absence of chamber dilation. It is generally accepted that the end-diastolic thickness of the interventricular septum or left ventricular posterior wall is less than 6 mm in healthy cats, and measurements that exceed this figure suggest hypertrophy.3 Left atrial enlargement resulting from diastolic dysfunction and sometimes concomitant mitral valve regurgitation is often present (Figure 41-2). This finding is clinically important because respiratory signs rarely result from cardiomyopathy in patients with normal atrial size.31 It is important to know that echocardiographic pseudohypertrophy can result from hypovolemia.32 When this is the case, atrial dimensions typically are small.

Systemic Blood Pressure Systemic blood pressure is related to both tissue perfusion and vascular resistance. Serial evaluation of blood pressure is potentially useful in the treatment of critically ill patients with feline

cardiomyopathy. Because abnormal ventricular loading conditions associated with systemic hypertension may result in compensatory hypertrophy, feline HCM is a diagnosis of exclusion. Systemic blood pressure can be measured by direct puncture of a peripheral artery but more often is estimated using indirect methods. In the cat, the Doppler technique is likely to be superior to the oscillometric method.33 Accuracy of indirect blood pressure estimation is critically dependent on technique, and results must be interpreted in context of the inherent limitations of the method and the clinical scenario. Repeated measurements of systolic blood pressure in excess of 180 mm Hg are compatible with a diagnosis of hypertension.

Bloodborne Cardiac Biomarkers Biomarkers are objectively determined characteristics that potentially have a role in diagnosis, risk stratification, evaluation of disease progression, and evaluation of response to therapy. Circulating B-type natriuretic peptide (BNP) concentration has a particular role in the diagnostic evaluation of patients suspected to have heart failure. This hormone is released by atrial and ventricular cardiomyocytes in response to increases in ventricular filling pressures; potentially therefore it is a bloodborne diagnostic marker of the heart failure state.34 Two separate studies have evaluated the diagnostic performance of N-terminal–BNP (NT-BNP) in populations of cats with respiratory distress.35,36 Clinical findings including radiographic and echocardiographic data were used to define cardiac and non-cardiac causes of respiratory distress. The results of the two studies generally were concordant; NT-BNP concentration identified respiratory distress caused by feline cardiomyopathy with high sensitivity—near 90%—and a somewhat lower specificity that was in the high 80s.35,36 A BNP assay is commercially available, but because of the time required for transport of samples to a central laboratory, it may be that the diagnostic potential for the evaluation of BNP concentrations will be fully realized only when BNP concentrations can be determined by a point-of-care assay.

CHAPTER 41  •  Feline Cardiomyopathy

B

A

FIGURE 41-2  Echocardiographic images obtained from a cat with heart failure caused by hypertrophic cardiomyopathy. There is moderate left ventricular hypertrophy (A) and left atrial enlargement (B). Static two-dimensional, right parasternal short-axis images and related M-mode echocardiograms are shown for each image plane. Ao, Aorta; IVS, interventricular septum; LA, left atrium; LV, left ventricle; LVPW, left ventricular posterior wall.

Feline respiratory distress Initial evaluation

Patient unable to tolerate diagnostic evaluation

Findings suggest heart failure: • Gallop • Sudden onset • Murmur • Hypothermia

Empiric diuretic therapy ± pleurocentesis

Patient able to tolerate diagnostic evaluation

Findings suggest Abbreviated respiratory disease: echocardiographic • Chronic history examination including cough • Hyperthermia • Cardiac auscultatory abnormalities Atrial enlargement Atrial absent Heart failure likely enlargement absent Heart failure Diuretic therapy unlikely ± pleurocentesis

Radiographic examination

Cardiogenic edema

Pleural effusion

Diuretic therapy

Pleurocentesis ± diuretic therapy

FIGURE 41-3  An algorithm that outlines one approach to the problem of feline respiratory distress; case management is determined by the tolerance of the patient and the availability of diagnostic modalities. When possible, the therapeutic approach is optimally determined by diagnostic data. It should be emphasized that these are only guidelines and that it can be difficult or impossible to distinguish cardiac and noncardiac causes of respiratory distress based on only patient history and physical findings (see text for details).

DIAGNOSTIC APPROACH The therapeutic approach to feline cardiomyopathy is best formulated based on the results of diagnostic evaluation (Figure 41-3). When possible, clinical signs of tachypnea and respiratory distress should be investigated radiographically. The results of radiographic examination direct the therapeutic approach, and it is relevant that tachypnea was identified in 89% of patients with FATE in the absence of CHF.37 When physical and radiographic findings suggest that cardiac disease is responsible for respiratory signs, echocardiographic evaluation is indicated. When the clinical picture is complicated by arrhythmias, the patient also should be evaluated electrocardiographically. However, it is important to recognize that feline patients in respiratory distress are fragile. Sometimes the risks associated with restraint for diagnostic evaluation cannot be justified, and empiric diuretic therapy should be considered. When empirical therapy is

contemplated, it is important that the presumptive diagnosis is plausible based on signalment, history, and physical findings. Furthermore, an understanding of the expected response and a willingness to adapt to changing clinical circumstances is essential. Sometimes it is possible to perform an abbreviated echocardiographic examination while the patient is sternally recumbent, minimally restrained, and receiving supplemental oxygen. In these circumstances, it is not always important to characterize definitively the nature of the myocardial disease. Documentation of left atrial enlargement provides indirect evidence of elevated filling pressures from which it can reasonably be surmised that the clinical signs result from congestion.31 In most circumstances, the absence of left atrial enlargement suggests that respiratory signs are not the result of cardiac disease. It is important to note that patients who have suffered FATE often exhibit tachypnea that presumably is a manifestation of pain. In this patient population, tachypnea is inconsistently

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associated with congestion and it is therefore appropriate to obtain thoracic radiographs before administering diuretics to patients with FATE.

THERAPEUTIC APPROACH Management of FATE Urgent therapy of FATE is challenging and sometimes frustrating. In general, the syndrome is associated with a poor prognosis; mortality, not as a result of euthanasia, associated with FATE is close to 30% during initial hospitalization, and euthanasia is elected for approximately 30% of cases during the same period.24,37,38 Survival is greater for patients in which only a single limb is affected.24,37 Surgical thrombectomy, transcatheter thrombectomy, and the use of fibrinolytic drugs such as streptokinase and tissue plasminogen activator have been brought to bear, but none of these interventions is obviously superior to conservative medical therapy.39-41 Narcotic analgesia is one of the few clear therapeutic indications in this clinical circumstance. Heparin is often administered in the 48 to 72 hours after an embolic event in the hopes that this treatment will prevent enlargement of the thrombus. The use of low-molecular-weight heparin (LMWH) has been suggested, but an advantage of LMWH over unfractionated heparin has not been demonstrated. Optimally, monitoring of the activated clotting time or prothrombin time is used to guide unfractionated heparin therapy. When this is impractical, the use of a relatively low dose of unfractionated heparin (60 to 100 IU/ kg subcutaneously [SC] q8h) can be considered; this dose is seemingly associated with a low incidence of bleeding complications. (Chapter 168, provides further information on this topic.) Supportive care is important because many patients with FATE have concurrent CHF, and even when this is not the case, signs of low cardiac output such as azotemia and hypothermia are commonly observed.24,37 Indeed, during the acute presentation, body temperature is of prognostic importance, with hypothermia being associated with reduced survival. A statistical model developed from retrospectively acquired data predicted 50% short-term survival for patients with a body temperature of 37.2° C.37 For patients that survive the immediate aftermath of embolism, arterial pulses may become palpable within days but a return to normal limb function, if it occurs, may take weeks. As might be expected, some patients suffer the consequences of dermal or even muscular necrosis. Prevention of future embolic events has received considerable attention, and the use of aspirin (acetylsalicylic acid [ASA]) and other antithrombotic medications, including clopidogrel, and LMWH is widespread despite lack of evidence of efficacy (see Chapters 167 and 168). Prophylaxis of FATE presents a particularly difficult problem because the risks for embolism are poorly defined; indeed, embolism is the first indication of cardiac disease in approximately 80% of affected patients.24,37,38 Furthermore, the incidence of FATE in patients known to have cardiac disease is relatively low. Estimates from retrospective data vary, but FATE occurs in fewer than 20% of patients with previously identified cardiomyopathy.24,37 These epidemiologic characteristics—most embolic events occur in patients not known to be at risk, together with the relatively low incidence of FATE in patients with presumed risk factors—present almost insurmountable difficulties. It is also important to consider the magnitude of effect of antithrombotic therapy. In a meta-analysis of trials that compared low-dose aspirin to placebo in human beings with stable cardiovascular disease, the absolute reduction in risk of adverse events—death, stroke, and myocardial infarction—associated with aspirin administration was 3.3%.42 It is necessary to treat 30 human beings with aspirin to prevent a single adverse event. If the magnitude of effect is similar in cats, it is unlikely that an effect of aspirin will be evident in the clinical trials of the size generally performed in

veterinary medicine. There is indirect evidence from retrospective data suggesting that low-dose aspirin is associated with fewer adverse effects than high-dose aspirin.37 The author uses low-dose aspirin in selected cases—most often in those that have already suffered FATE or have a thrombus or spontaneous contrast that is echocardiographically visible in the left atrium.

Management of Acutely Decompensated Heart Failure Heart failure is a syndrome that results from impaired filling or emptying of the heart. Clinical findings may reflect congestion, diminished cardiac output, or both. In veterinary patients it is necessary to use objective rather than subjective markers of disease, and therefore feline heart failure can be defined as pulmonary edema or pleural effusion that is caused by heart disease. General supportive measures are indicated for feline heart failure. Indirect heat sources should be used when hypothermia is present. Supplemental oxygen can be administered by mask, by nasal insufflation, or via an oxygen administration cage. Most patients that respond to medical therapy for cardiogenic edema do so promptly, so mechanical ventilation generally is not required but can be considered for patients with marked respiratory distress. Thoracocentesis should be performed when physical or radiographic findings confirm that a large pleural effusion is responsible for respiratory distress. Intravenous fluids should be administered sparingly to patients with frank congestion and only if required as a vehicle for drug therapy. In animals with congestive failure, infusion of fluid further increases venous pressures but does not improve cardiac performance. When cardiogenic pulmonary edema is present, diuretic therapy is indicated. Furosemide is a high-ceiling loop diuretic that increases urine production and therefore reduces intravascular volume and venous pressures. Furosemide can be administered intravenously, intramuscularly, or orally. During acute decompensation, the intravenous route is preferable, but intramuscular administration is appropriate when resistance to manual restraint or other factors make intravenous administration difficult or impossible. Generally the initial dosage is relatively high, perhaps 2 to 4 mg/kg.43 The patient is then carefully observed for 40 to 60 minutes. If there is a decrease in respiratory rate or effort, a lower dose is administered. The dosage and interval for furosemide should be determined by clinical response. Frequent administration of low doses (0.5 to 1 mg/ kg intravenously [IV] q1h) until respiratory signs resolve may provide a means to prevent excessive diuresis. Constant rate infusion of furosemide may accomplish the same objective, although the utility of furosemide infusion has not been specifically evaluated in the cat. If there is no change or if there is deterioration of clinical status after administration of two or three doses of parenteral furosemide, reevaluation of the presumptive diagnosis and therapeutic approach is indicated. It is noteworthy that the clinical profile of heart failure resulting from feline cardiomyopathy is similar to that of feline endomyocarditis.4 The latter is an idiopathic disorder that is associated with pneumonitis. Patients typically are brought for evaluation of respiratory distress that develops soon after a stressful event, such as surgical sterilization or onychectomy. Because respiratory signs associated with this disorder are apparently not cardiogenic, diuresis is unlikely to improve clinical status. Nitroglycerin (NG) is an organic nitrate that is sometimes used with furosemide as an adjunctive therapy that may further reduce ventricular filling pressures.43 NG causes venodilation as well as dilation of specific arteriolar beds, including those of the coronary circulation. In veterinary medicine, NG is used principally as a venodilator that increases venous capacitance, therefore causing a decrease in ventricular filling pressures. Thus the hemodynamic effect of NG

CHAPTER 41  •  Feline Cardiomyopathy

is similar to that of diuretic therapy; it is primarily a preload-reducing intervention. The efficacy of NG in feline patients has not been established. NG is most commonly administered using a transdermal cream that is applied to the pinnae or inguinal area. In humans, absorption of transdermal NG depends on the surface area of the skin to which it is applied. The dosage in feline patients is based on anecdotal evidence, but 1 8 to 1 4 inch of the transdermal cream has been suggested. Preload reduction is used for heart failure because it may effectively eliminate clinical signs of congestion. However, preload reduction generally does not improve cardiac performance. Indeed, aggressive reduction in filling pressures can decrease stroke volume, potentially resulting in hypotension. This is particularly relevant in the discussion of feline cardiomyopathy because the disorders that most commonly cause heart failure in cats result in diastolic dysfunction. Patients with diastolic dysfunction develop congestion when ventricular volumes are normal or small. This may partly explain the sensitivity of feline patients to diuretic therapy. Patient monitoring is an important aspect of critical care. In the management of feline cardiomyopathy, vital signs are perhaps the most important. It is useful to record body weight, body temperature, heart rate, and respiratory rate at frequent intervals. Other parameters including hematocrit, total serum protein values, blood urea nitrogen concentration, and systemic blood pressure may provide useful ancillary information. Diastolic dysfunction resulting from HCM or RCM is the most common cause of feline heart failure. Other than furosemide, for which efficacy is assumed, no medical interventions have demonstrated efficacy for this syndrome. Based on this, the use of cardio­ active ancillary therapy during acute decompensation is difficult to justify. An exception to this might be the use of antiarrhythmic agents for tachyarrhythmias that contribute to congestive signs. Primarily the management of acutely decompensated feline cardiomyopathy consists of supportive care and judicious lowering of ventricular filling pressures.

Management of Chronic Heart Failure Long-term therapy for feline myocardial disease is best guided by echocardiographic findings. Management of diastolic dysfunction traditionally has been with drugs that slow heart rate or speed myocardial relaxation or both. β-Adrenergic antagonists such as atenolol are believed to indirectly improve ventricular filling by lowering heart rate. It is likely that slowing the heart rate is beneficial when tachycardia contributes to diastolic dysfunction. Furthermore, if diastolic function is markedly impaired, myocardial relaxation may be incomplete, even when the diastolic interval and heart rate are normal. Additionally, slowing the rate may improve coronary perfusion, which presumably is abnormal in cats with HCM. Still, elevated filling pressures resulting in congestion at rest are the most obvious cause of clinical signs in HCM, and it is likely that abnormal ventricular stiffness related to hypertrophy and fibrosis is at least partly responsible. It is therefore unclear whether heart rate reduction in patients in which heart rate initially is normal can decrease venous pressures. Relevant studies are lacking, and the optimal heart rate for patients with heart failure caused by feline HCM is not known. β-Adrenergic antagonists may have a particular role when dynamic left ventricular outflow tract obstruction is caused by SAM and when tachyarrhythmias complicate the clinical picture. Recently there has been interest in antagonists of the “funny” (If ) sodium channel. Drugs such as ivabradine may have value as they slow heart rate but do not exert a negatively inotropic effect.44 Diltiazem is a benzothiazepine calcium channel antagonist. It has only a modest slowing effect on heart rate but is believed to speed myocardial relaxation. The latter effect may serve to reduce

ventricular filling pressures. Additionally, diltiazem may dilate coronary arteries and improve diastolic function by improving coronary perfusion. In general, diltiazem has little effect on outflow tract obstruction caused by SAM. Enalapril and benazepril, angiotensin-converting enzyme (ACE) inhibitors, also have been used in long-term management of feline HCM.45,46 By interrupting the enzymatic conversion of angiotensin I to angiotensin II, these agents have diverse neuroendocrine effects. ACE inhibitors are vasodilators, although this effect is relatively weak. Most patients with HCM have normal or hyperdynamic systolic performance, and arteriolar dilation confers no obvious mechanical advantage. In contrast to patients with systolic dysfunction and chamber dilation, a reduction in afterload is unlikely to increase stroke volume simply because the ventricle empties almost completely in any case. Indeed, vasodilators generally are contraindicated in human HCM primarily because of the concern that vasodilation will provoke or worsen SAM.47 The potential but theoretical benefits of ACE inhibition relate primarily to the neuroendocrine effects of these drugs. The resultant decrease in aldosterone activity might be beneficial by decreasing the renal retention of salt and water. Additionally, aldosterone and angiotensin II have been implicated as trophic factors that might be relevant to the development of hypertrophy and fibrosis.48,49 Although diastolic dysfunction is generally believed to be the dominant pathophysiologic mechanism responsible for clinical signs in HCM, recently published retrospective case series that included patients with HCM have evaluated the effect of pimobendan in feline myocardial disease.50-52 It is possible that a lusitropic effect of pimobendan is beneficial, but studies to date have neither been prospective nor included a control group. Until more data are available, use of pimobendan should probably be reserved for feline patients with echocardiographically demonstrated systolic myocardial dysfunction, recognizing that any use of this drug in the feline species is “off-label.” Unfortunately, little is known of the efficacy of ancillary therapy for feline cardiomyopathy. In a small, open-label clinical trial, the effects of diltiazem, propranolol, and verapamil on cats with pulmonary edema caused by HCM were compared.53 Diltiazem was the most efficacious of the three. However, this trial did not include a placebo group. A multicenter, randomized, placebo-controlled trial that was designed to evaluate the relative efficacy of atenolol, diltiazem, and enalapril in feline patients with CHF caused by HCM or RCM has been completed.54 The results of this study have been presented but are not yet published. The primary endpoint of the trial was recurrence of congestive signs, and none of the agents were superior to placebo in this regard. Patients that received enalapril remained in the trial longer than those receiving the alternatives, although this result did not achieve statistical significance. Interestingly, patients receiving atenolol fared less well than did those in the placebo group. The finding that atenolol may harm cats with pulmonary edema was possibly unexpected but is consistent with the result of the only comparable study in which propranolol administration was associated with decreased survival.31 Studies have not addressed the effect of multivalent therapy; it is possible that β-blockers or other agents are beneficial when used in combination with furosemide and an ACE inhibitor. Regardless, based on these as yet unpublished data, the use of enalapril with furosemide seems a reasonable initial approach to the long-term management of feline patients with CHF resulting from diastolic dysfunction.

REFERENCES 1. Richardson P, McKenna W, Bristow M, et al: Report of the 1995 World Health Organization/International Society and Federation of Cardiology

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PART IV  •  CARDIAC DISORDERS Task Force on the Definition and Classification of cardiomyopathies, Circulation 93:841, 1996. 2. Pion PD, Kittleson MD, Rogers QR, et al: Myocardial failure in cats associated with low plasma taurine: a reversible cardiomyopathy, Science 237:764, 1987. 3. Fox PR, Liu S-K, Maron BJ: Echocardiographic assessment of spontaneously occurring feline hypertrophic cardiomyopathy: an animal model of human disease, Circulation 92:2645, 1995. 4. Stalis IH, Bossbaly MJ, Van Winkle TJ: Feline endomyocarditis and left ventricular endocardial fibrosis, Vet Pathol 32:122, 1995. 5. Ferasin L, Sturgess CP, Cannon MJ, et al: Feline idiopathic cardiomyopathy: a retrospective study of 106 cats (1994-2001), J Fel Med Surg 5:151, 2003. 6. Fox PR, Maron BJ, Basso C, et al: Spontaneously occurring arrhythmogenic right ventricular cardiomyopathy in the domestic cat: a new animal model similar to the human disease, Circulation 102:1863, 2000. 7. Fox P: Feline cardiomyopathies. In Fox PR, Sisson DD, Moise NS, editors: Textbook of canine and feline cardiology: principles and clinical practice, ed 2, Philadelphia, 1999, Saunders, pp 621-678. 8. Nelson L, Reidesel E, Ware WA, et al: Echocardiographic and radiographic changes associated with systemic hypertension in cats, J Vet Intern Med 16:418, 2002. 9. Bond BR, Fox PR, Peterson ME, et al: Echocardiographic findings in 103 cats with hyperthyroidism, J Am Vet Med Assoc 192:1546, 1988. 10. Maron BJ: Hypertrophic cardiomyopathy: a systematic review, JAMA 287:1308,2002. 11. Meurs KM, Sanchez X, David RM, et al: A cardiac myosin binding protein C mutation in the Maine Coon cat with familial hypertrophic cardiomyopathy, Hum Mol Genet 14:3587, 2005. 12. Kittleson MD, Meurs KM, Munro MJ, et al: Familial hypertrophic cardiomyopathy in maine coon cats: an animal model of human disease, Circulation 99:3172, 1999. 13. Meurs KM, Norgard MM, Ederer MM, et al: A substitution mutation in the myosin binding protein C gene in ragdoll hypertrophic cardiomyopathy, Genomics 90:261, 2007. 14. Meurs KM, Kittleson MD, Towbin J, et al: Familial systolic anterior motion of the mitral valve and/or hypertrophic cardiomyopathy is apparently inherited as an autosomal dominant trait in a family of American shorthair cats, J Vet Intern Med 11:138, 1997. 15. Martin L, VandeWoude S, Boon J, et al: Left ventricular hypertrophy in a closed colony of Persian cats [abstract], J Vet Intern Med 8:143, 1994. 16. Kraus MS, Calvert CA, Jacobs GJ: Hypertrophic cardiomyopathy in a litter of five mixed-breed cats, J Am Anim Hosp Assoc 35:293, 1999. 17. Nishimura RA, Tajik J: Evaluation of diastolic filling of left ventricle in health and disease: Doppler echocardiography is the clinician’s Rosetta stone, J Am Coll Cardiol 30:8, 1997. 18. Sherrid MV, Chaudhry FA, Swistel DG: Obstructive hypertrophic cardiomyopathy: echocardiography, pathophysiology, and the continuing evolution of surgery for obstruction, Ann Thorac Surg 75:620, 2003. 19. Levine RA, Vlahakes GJ, Lefebvre X, et al: Papillary muscle displacement causes systolic anterior motion of the mitral valve. Experimental validation and insights into the mechanism of subaortic obstruction, Circulation 91:1189, 1995. 20. Yoerger DM, Weyman AE: Hypertrophic obstructive cardiomyopathy: mechanism of obstruction and response to therapy, Rev Cardiovasc Med 4:199, 2003. 21. Maron MS, Olivotto I, Betocchi S, et al: Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy, N Engl J Med 348:295, 2003. 22. Rush JE, Freeman LM, Fenollosa NK, et al: Population and survival characteristics of cats with hypertrophic cardiomyopathy: 260 cases (1990-1999), J Am Vet Med Assoc 220:202, 2002. 23. Payne J, Luis Fuentes V, Boswood A, et al: Population characteristics and survival in 127 referred cats with hypertrophic cardiomyopathy (1997 to 2005), J Small Anim Pract 51:540, 2010. 24. Laste NJ, Harpster NK: A retrospective study of 100 cases of feline distal aortic thromboembolism: 1977-1993, J Am Anim Hosp Assoc 31:492, 1995.

25. Imhoff RK: Production of aortic occlusion resembling acute aortic embolism syndrome in cats, Nature 192:979, 1961. 26. Butler HC: An investigation into the relationship of an aortic embolus to posterior paralysis in the cat, J Small Anim Pract 12:141, 1971. 27. Olmstead ML, Butler HC: Five-hydroxytryptamine antagonists and feline aortic embolism, J Small Anim Pract 18:247, 1977. 28. Schaub RG, Meyers KM, Sande RD, et al: Inhibition of feline collateral vessel development following experimental thrombolic occlusion, Circ Res 39:736, 1976. 29. Smith SA, Tobias AH, Fine DM, et al: Corticosteroid-associated congestive heart failure in 12 cats, J Appl Res Vet Med 2:159, 2004. 30. Hamlin RL: Heart rate of the cat, J Am Anim Hosp Assoc 25:284, 1989. 31. Smith S, Dukes-McEwan J: Clinical signs and left atrial size in cats with cardiovascular disease in general practice, J Small Anim Pract 53:27, 2012. 32. Campbell FE, Kittleson MD: The effect of hydration status on the echocardiographic measurements of normal cats, J Vet Intern Med 21:1008, 2007. 33. Binns SH, Sisson DD, Buoscio DA, et al: Doppler ultrasonographic, oscillometric sphygmomanometric, and photoplethysmographic techniques for noninvasive blood pressure measurement in anesthetized cats, J Vet Intern Med 9:405, 1995. 34. Sisson DD: Neuroendocrine evaluation of cardiac disease, Vet Clin North Am Small Anim Pract 34:1105, 2004. 35. Fox PR, Oyama MA, Reynolds C, et al: Utility of plasma N-terminal probrain natriuretic peptide (NT-proBNP) to distinguish between congestive heart failure and non-cardiac causes of acute dyspnea in cats, J Vet Cardiol 11:S51, 2009. 36. Connolly DJ, Soares Magalhaes RJ, Fuentes VL, et al: Assessment of the diagnostic accuracy of circulating natriuretic peptide concentrations to distinguish between cats with cardiac and non-cardiac causes of respiratory distress, J Vet Cardiol 11:S41, 2009. 37. Smith SA, Tobias AH, Jacob KA, et al: Arterial thromboembolism in cats: acute crisis in 127 cases (1992-2001) and long-term management with low-dose aspirin in 24 cases, J Vet Intern Med 17:73, 2003. 38. Schoeman JP: Feline distal aortic thromboembolism: a review of 44 cases (1990-1998), J Fel Med Surg 1:221, 1999. 39. Buchanan J, Baker G, Hill J: Aortic embolism in cats: prevalence, surgical treatment and electrocardiography, Vet Rec 79:496, 1966. 40. Reimer SB, Kittleson MD, Kyles AE: Use of rheolytic thrombectomy in the treatment of feline distal aortic thromboembolism, J Vet Intern Med 20:290, 2006. 41. Welch KM, Rozanski EA, Freeman LM, et al: Prospective evaluation of tissue plasminogen activator in 11 cats with arterial thromboembolism, J Fel Med Surg 12:122, 2010. 42. Berger JS, Brown DL, Becker RC: Low-dose aspirin in patients with stable cardiovascular disease: a meta-analysis, Am J Med 121:43, 2008. 43. Sisson DK: Management of heart failure: principles of treatment, therapeutic strategies, and pharmacology. In Fox PR, Sisson DD, Moise NS, editors: Textbook of canine and feline cardiology: principles and clinical practice, ed 2, Philadelphia, 1999, Saunders. 44. Riesen SC, Schober KE, Smith DN, et al: Effects of ivabradine on heart rate and left ventricular function in healthy cats and cats with hypertrophic cardiomyopathy, Am J Vet Res 73:202, 2012. 45. Amberger CN, Glardon O, Glaus T, et al: Effects of benazepril in the treatment of feline hypertrophic cardiomyopathy: results of a prospective, open-label, multicenter clinical trial, J Vet Cardiol 1:19, 1999. 46. Rush JE, Freeman LM, Brown DJ, et al: The use of enalapril in the treatment of feline hypertrophic cardiomyopathy, J Am Anim Hosp Assoc 34:38, 1998. 47. Maron BJ, McKenna WJ, Elliott P, et al: Hypertrophic cardiomyopathy, JAMA 282:2302, 1999. 48. Tsybouleva N, Zhang L, Chen S, et al: Aldosterone, through novel signaling proteins, is a fundamental molecular bridge between the genetic defect and the cardiac phenotype of hypertrophic cardiomyopathy, Circulation 109:1284, 2004. 49. Lim D-S, Lutucuta S, Bachireddy P, et al: Angiotensin II blockade reverses myocardial fibrosis in a transgenic mouse model of human hypertrophic cardiomyopathy, Circulation 103:789, 2001. 50. MacGregor JM, Rush JE, Laste NJ, et al: Use of pimobendan in 170 cats (2006-2010), J Vet Cardiol 13:251, 2011.

51. Gordon SG, Saunders AB, Roland RM, et al: Effect of oral administration of pimobendan in cats with heart failure, J Am Vet Med Assoc 241:89, 2012. 52. Hambrook LE, Bennett PF: Effect of pimobendan on the clinical outcome and survival of cats with non-taurine responsive dilated cardiomyopathy, J Fel Med Surg 14:233, 2012.

53. Bright JM, Golden AL, Gompf RE, et al: Evaluation of the calcium channel-blocking agents diltiazem and verapamil for treatment of feline hypertrophic cardiomyopathy, J Vet Intern Med 5:272, 1991. 54. Fox PR: Prospective, double-blinded, multicenter evaluation of chronic therapies for feline diastolic heart failure: interim analysis [abstract], J Vet Intern Med 17:398, 2003.

CHAPTER 42  •  Canine Cardiomyopathy

CHAPTER 42  CANINE CARDIOMYOPATHY Robert Prošek,

DVM, MS, DACVIM (Cardiology), DECVIM-CA (Cardiology)

KEY POINTS • Primary cardiomyopathies, by definition, are idiopathic diseases that are not the result of an identifiable systemic disorder or any type of congenital or acquired heart disease. • Myocardial diseases resulting from a well-defined disease process are appropriately referred to as secondary myocardial diseases, and these need to be considered before the diagnosis of a primary cardiomyopathy. • Dilated (congestive) cardiomyopathy (DCM) is the most common form of primary myocardial disease in dogs and is characterized by chamber dilation and decreased contractility. • Large and medium sized dogs are typically affected by DCM. • Atrial fibrillation is common and often is one of the first abnormalities detected in giant breeds with DCM such as Great Danes, Irish Wolfhounds, and Newfoundlands. • Breed variations in canine DCM should be considered in Cocker Spaniels, Dalmatians, Boxers, Doberman Pinschers, Portuguese Water Dogs, and the giant breeds. • Boxers with arrhythmogenic right ventricular cardiomyopathy often have syncope and, as the name states, arrhythmias (ventricular). • Myocardial failure that leads to congestion is an emergency that requires a low-stress environment, oxygen, diuretics, vasodilators, and inotropic support.

Primary myocardial diseases, or “true” cardiomyopathies, are those conditions that predominately affect the heart muscle; that are not the result of other congenital or acquired valvular, pericardial, vascular, or systemic diseases; and whose causes are unknown. The most common form of myocardial disease in the dog is dilated cardiomyopathy (DCM), but arrhythmogenic right ventricular cardiomyopathy (ARVC) (in Boxers) and hypertrophic cardiomyopathy (HCM) are also reported. There is increasing breed-specific information about canine DCM, especially in Doberman Pinschers, Dalmatians, Portuguese Water Dogs, Cocker Spaniels, and the giant breeds, which should be considered in diagnosis and treatment. Secondary myocardial diseases resulting from well-defined disease processes are listed in Box 42-1 and should be considered before making the diagnosis of a primary cardiomyopathy. Diagnostic and treatment techniques

BOX 42-1 

Classification of Secondary Myocardial Diseases of Dogs*

Drugs and Toxins

Nutritional

Anthracyclines (doxorubicin*) Catecholamines Ionophores

l-Carnitine deficiency* Taurine deficiency* Vitamin E, selenium deficiency

Canine X-Linked Muscular Dystrophy (Duchenne)*

Inflammatory

Infiltrative

Myocarditis (see Chapter 49)

Glycogen storage diseases Mucopolysaccharidosis

Infectious

Neoplastic Ischemic Metabolic

Viral, bacterial, fungal, protozoal • Parvovirus, distemper • Lyme disease, trypanosomiasis

Acromegaly Diabetes mellitus (see Chapter 64) Hyperthyroidism (see Chapter 70) Systemic hypertension (see Chapter 9) • Idiopathic • Renal disease *Conditions discussed in this chapter.

often are tailored to each patient and breed, with emphasis on control of a stable rhythm, prevention of congestive heart failure (CHF), and improvement in quality and length of life.

DILATED CARDIOMYOPATHY DCM is characterized by chamber dilation and impaired systolic and often diastolic function of one or both ventricles. It is an adult-onset disease, with the exception of the Portuguese Water Dog in which the young are affected (2 to 32 weeks old). Generally, it is a disease of

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large and medium sized dogs with increased incidence in the Doberman Pinscher, Great Dane, Irish Wolfhound, and American Cocker Spaniel in North American surveys, but European studies show an increased incidence in the Airedale Terrier, Newfoundland, English Cocker Spaniel, and Doberman Pinscher.1

Physical Examination Often a soft, grade 1 to 3 of 6 systolic left or right apical murmur is noted and is a result of either mitral or tricuspid valve insufficiency, respectively. Auscultation may also reveal a chaotic rhythm of atrial fibrillation or an irregular rhythm caused by atrial or ventricular premature beats. With right-sided CHF the following may be noted: jugular pulses or distention or both, muffled heart and ventral lung sounds with pleural effusion (pleural fluid line), and hepatomegaly caused by congestion with or without ascites. With left-sided CHF, examination often reveals pulmonary crackles or rales, hypokinetic femoral pulses, pulse deficits with ventricular premature beats, or atrial fibrillation. Peripheral edema is rare. Finally, albeit rare, cardiogenic shock may be present as a result of decreased cardiac output (usually blood pressure is normal as a result of vasoconstriction and neurohormonal activation).

Thoracic Radiography Thoracic radiographs should be examined for generalized cardiomegaly and signs of CHF. Signs of left-sided heart failure include interstitial or alveolar pulmonary edema and moderate to severe left atrial enlargement. Right-sided failure results in pleural effusion, enlarged caudal vena cava, hepatomegaly, and ascites (Figure 42-1).

Electrocardiography The electrocardiogram (ECG) should be examined for sinus tachycardia, possibly with atrial or ventricular premature beats, atrial fibrillation, and ventricular tachycardia, especially in Boxers and Doberman Pinschers. Prolonged or increased voltage QRS complexes suggestive of left ventricular enlargement or low-voltage QRS complexes with pleural effusion may be noted.

Routine Blood Tests Routine bloodwork findings are usually normal unless severe heart disease is present. Prerenal azotemia, high alanine aminotransferase levels, and electrolyte abnormalities may be evident in cases of severe heart disease. Hyponatremia and hypochloremia, if noted with CHF, are associated with a poorer prognosis. Hypokalemia, metabolic alkalosis, and prerenal azotemia may also be the result of diuretic therapy for heart disease.

Effusion Analysis Peritoneal or pleural effusion in dogs with DCM is usually a modified transudate (nucleated cell count 180 beats/min or >10% rise from baseline); maximum infusion rate 15 µg/kg/min. If ventricular ectopy develops, reduce rate. • Other options for positive inotropic support include amrinone, milrinone, and pimobendan. Note: Management should be individually tailored, based on treatment history, clinical picture, complicating arrhythmias, and concurrent diseases. BP, Blood pressure; ECG, electrocardiogram; IM, intramuscularly; IV, intravenously.

Digoxin Digoxin is administered to improve systolic function and to slow ventricular rate in animals with supraventricular tachyarrhythmias (0.003 mg/kg PO q12h, adjusting dosage based on blood levels) (see Chapter 171).

Pimobendan Pimobendan (0.25 mg/kg PO q12h), a benzimidazole-pyridazinone drug, is classified as an inodilator because of its nonsympathomimetic, nonglycoside positive inotropic (through myocardial calcium sensitization) and vasodilator properties. It has become a mainstay in the treatment of patients with dilated cardiomyopathy.

Pimobendan is approved for use in dogs to treat congestive heart failure originating from valvular insufficiency or dilated cardiomyopathy. However, a recent study (The PROTECT Study)2a has shown that administration of pimobendan to Doberman Pinschers with preclinical DCM prolongs the time to onset of clinical signs and extends survival, suggesting that pimobendan should be used earlier (preclinical phase) in Doberman Pinschers.

Novel Therapy Novel therapies may be used after careful consideration of the benefits and risks involved; consultation with a cardiologist may be warranted. β-Blockers may be considered to blunt cardiotoxic effects of the sympathetic nervous system; however, heart failure must be well controlled and the dosage titrated slowly with careful monitoring. Carvedilol (0.5 mg/kg PO q12h; start with 1 4 to 1 2 of a 3.125-mg tablet initially) or metoprolol (0.5 to 1 mg/kg PO q8h)can be used with caution.

Diet It is important to keep patients eating an adequate level of protein, eliminate high salt–containing snacks, and in cats offer a sodiumrestricted commercial diet (not at the expense of anorexia) such as Purina CV, Hills H/D, or Royal Canin Early Cardiac.

Supplements Taurine (500 mg PO q12h) is started while waiting for taurine blood levels, especially in Cocker Spaniels. Omega-3 fatty acids may improve appetite and reduce cachexia (EPA 30 to 40 mg/kg PO q24h; DHA 20 to 25 mg/kg PO q24h). Consider l-carnitine (110 mg/kg PO q12h) in American Cocker Spaniels not responding to taurine and in Boxers.

TREATMENT OF ARRHYTHMIAS Please see Chapters 47 and 48.

BREED VARIATIONS WITH DCM Cocker Spaniels DCM in some Cocker Spaniels is associated with low plasma taurine levels, and supplementation with taurine and l-carnitine (see earlier section for dosing) appears to improve myocardial function.3 Normal

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plasma taurine levels should be more than 50 ng/ml. Additional measures should be used to address complications such as arrhythmias and CHF and might be withdrawn gradually pending response to taurine (usually 3 to 4 months).

Doberman Pinschers Typically considered the poster child for DCM, the Doberman Pinscher does have some unique manifestations that are important for the clinician to recognize. On a molecular level, deficiency in calstabin-2 implicates this cytoskeletal protein abnormality as one of the possible causes of DCM in this breed. From the clinical perspective, 25% to 30% of Doberman Pinschers have ventricular arrhythmias without the classic ventricular dilation seen with DCM and CHF.4 These patients are brought in most commonly for syncope or for arrhythmias noted on routine physical examinations. Sudden death is of great concern in this breed, and successful treatment of ventricular arrhythmias is imperative (see Chapter 48). The author finds the most successful treatment consists of sotalol alone or in combination with mexiletine. A Holter monitor should be used on syncopal Doberman Pinschers to identify the causative arrhythmia (occasionally syncope caused by bradycardia in this breed)5 and to monitor success of treatment. Doberman Pinschers with more than 50 ventricular premature complexes (VPCs) per 24 hours or with couplets or triplets are suspected for development of DCM. The rest of the Doberman Pinschers have left or biventricular failure, or both, and often have atrial fibrillation. Atrial fibrillation and bilateral CHF appear to be poor prognostic signs,6 but outlook is also affected by treatment used and client and patient compliance.

Dalmatians Male dogs appear to be overrepresented in Dalmatians with DCM. All dogs in one study had left-sided heart failure with no evidence of right-sided CHF or atrial fibrillation. Dalmatians fed a low-protein diet for prevention or treatment of urate stones that develop signs consistent with DCM should be switched to a balanced protein diet.7 Otherwise, treatment is the same as for any dog with left-sided heart failure.

Great Danes and Irish Wolfhounds Atrial fibrillation is the most common finding and in some cases develops before any other evidence of underlying myocardial disease.8

Affected dogs commonly are presented for weight loss and loss of full exercise capacity, with occasional cough. Progression of the disease is relatively slow, especially in Irish Wolfhounds.8 An X-linked pattern of inheritance is suspected in some families of Great Danes, with male dogs being overrepresented.9

Portuguese Water Dogs A juvenile form of DCM has been reported in Portuguese Water Dogs. Affected puppies die from CHF at an average age of 13 weeks after rapid disease progression.10

ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY IN BOXERS In Boxer dogs affected with ARVC, approximately one third have predominately left-sided failure, another one third are brought in for syncope or collapse secondary to a rhythm disturbance, and the remaining one third are asymptomatic but have rhythm disturbances (primarily ventricular arrhythmias). Atrial fibrillation occurs less often in Boxers than in other breeds, and cardiomegaly usually is less marked on radiographic evaluation. The pathology of Boxer dog cardiomyopathy closely resembles that seen in humans with ARVC. Similarities between the populations include etiology, clinical picture, and histopathology of fibrous fatty infiltrate of the right ventricular free wall and septum.11 ARVC appears as an autosomal dominant trait with variable penetrance in Boxers.12

Electrocardiography Ventricular premature beats typically have a left bundle branch block morphology in leads I, II, III, and aVF, consistent with right ventricular origin. As in the Doberman Pinschers, a Holter monitor is helpful in quantifying the VPCs and diagnosing the cause of syncope or collapse (Figure 42-3). More than 100 VPCs in a 24-hour period, periods of couplets and triplets, and runs of ventricular tachycardia may be diagnostic in a symptomatic Boxer.

Treatment of Arrhythmogenic Right Ventricular Cardiomyopathy Treatment of arrhythmias is based on clinical signs and generally is considered for animals that experience more than 500 to 1000 VPCs per 24 hours, runs of ventricular tachycardia, or evidence of R-on-T phenomenon. The author prefers sotalol (1.5 to 3 mg/kg PO q12h)

FIGURE 42-3  Sustained ventricular tachycardia in a Boxer dog wearing a Holter monitor (24-hour recorder).

CHAPTER 42  •  Canine Cardiomyopathy

with the combination of mexiletine (5 to 8 mg/kg PO q8h) in lifethreatening ventricular arrhythmias in Boxers13 (see Chapter 48). Another study found that treatment with sotalol or mexiletineatenolol was well tolerated and efficacious in Boxer dogs with ventricular arrhythmias.14 If CHF is present, or echocardiographic ventricular and atrial dilation are noted, treatment is the same as outlined earlier for other breeds. Additionally, supplementation with l-carnitine (110 mg/kg PO q12h) might be considered; a family of Boxers showed improvement in systolic function with this drug.15

HYPERTROPHIC CARDIOMYOPATHY IN DOGS HCM is a condition characterized by idiopathic hypertrophy of the left ventricle. The term is applied appropriately only in circumstances in which a stimulus to hypertrophy cannot be identified. HCM has been recognized in only a small number of dogs and can be assumed to be an uncommon disorder.16,17 A heritable form of hypertrophic obstructive cardiomyopathy has been described in Pointer dogs.16 The cause of HCM in dogs is unknown. A genetic cause has been identified in most human patients,18 but the precise pathogenic mechanism of hypertrophy remains a mystery. As with DCM, there may be more than one form (cause) of HCM.

Pathologic Features The left ventricle is either symmetrically or asymmetrically hypertrophied (concentric hypertrophy), and the left atrium is dilated. Left ventricular mass is increased (heart weight/body weight ratio). When dynamic outflow tract obstruction is present, there is fibrosis of the anterior leaflet of the mitral valve, and a fibrous endocardial plaque on the ventricular septum opposite the mitral valve is noted. Myocardial fiber disarray, which characterizes the human form of this disease,18 does not appear to be consistently present in affected dogs.

Important Differentials for Concentric Hypertrophy of the Left Ventricle HCM and its variant hypertrophic obstructive cardiomyopathy are infrequent in dogs, and patients should be evaluated for other causes of concentric hypertrophy such as subvalvular or valvular aortic stenosis and systemic hypertension.

UNCOMMON MYOCARDIAL DISEASES OF DOGS Duchenne Cardiomyopathy Duchenne muscular dystrophy is an inherited neuromuscular disorder with an X-linked pattern of inheritance. Dystrophin, a cytoskeletal protein of the plasma membrane, is absent or defective in dogs and humans with Duchenne muscular dystrophy.19,20 The disorder has been described best in Golden Retriever dogs.19 Signs of skeletal muscle dysfunction predominate in most affected dogs. Some affected dogs develop deep and narrow Q waves in leads II, III, aVF, CV6LU, and CV6LL and may manifest a variety of ventricular arrhythmias. Echocardiography demonstrates hyperechoic areas (fibrosis and calcification) in the left ventricular myocardium as a sequela to myocardial necrosis.19,20 Some affected dogs develop myocardial failure resembling DCM.

Atrioventricular Myopathy Atrioventricular myopathy (silent atria, persistent atrial standstill) is a progressive idiopathic myocardial disease of dogs that may or may not be associated with a poorly characterized form of shoulder girdle skeletal muscular dystrophy. The unique features of this disorder include the marked degree of myocardial destruction and fibrosis and the characteristic bradyarrhythmias that result. Pathologic studies often reveal dilated, thin, almost transparent atria with little

or no visible muscle. Involvement of the ventricles, especially the right ventricle, occurs somewhat later and is more variable. Histologic findings include variable amounts of mononuclear infiltration, myofiber necrosis and disappearance, and extensive replacement fibrosis. In dogs with muscular dystrophy, changes in skeletal muscle include muscle atrophy, hyalinized degenerated muscle fibers, and mild to moderate steatosis.21,22 A similar cardiac disorder has been observed in human patients with Emery-Dreifuss (scapulohumeral) muscular dystrophy. The most commonly affected dogs are English Springer Spaniels and Old English Sheepdogs. Affected dogs usually are brought in for weakness, collapse, or syncope caused by severe bradycardia. Less commonly, dogs have signs of right ventricular or biventricular CHF. Soft murmurs of atrioventricular valve insufficiency are audible in many cases. The most common ECG abnormality is persistent atrial standstill, but complete heart block and other rhythm and conduction disturbances may occur. Atrial enlargement is often found on thoracic radiographs, and generalized cardiomegaly is present in some dogs. Dilated, immobile atria can be identified by echocardiography or fluoroscopy. The clinical course usually is characterized by declining contractility, progressive ventricular dilation, and eventual heart failure. Management of the bradyarrhythmia by artificial pacemaker implantation usually results in immediate improvement in signs, but most dogs eventually develop refractory myocardial failure.22

Toxic Myocardial Disease Doxorubicin (Adriamycin) and other anthracycline antibiotics can cause myocardial failure, typically after the administration of high cumulative doses (usually more than 200 to 300 mg/m2 doxorubicin). Inasmuch as cardiac toxicity is irreversible, prevention is advised by avoiding high cumulative doses. Dexrazoxane, a cyclic derivative of ethylenediaminetetraacetic acid, protects against cardiomyopathy induced by doxorubicin and other anthracyclines, the main drawback for its use being expense.23

REFERENCES 1. Sisson DD, Thomas WP, Keene BW: Primary myocardial disease in the dog. In Ettinger SJ, Feldman EC, editors: Textbook of veterinary internal medicine, ed 5, St Louis, 2000, Saunders. 2. Bonagura JD, Luis Fuentes V: Echocardiography. In Ettinger SJ, Feldman EC, editors: Textbook of veterinary internal medicine, ed 5, St Louis, 2000, Saunders. 2a.  Summerfield NJ, Boswood A, O’Grady MR, et al: Efficacy of pimobendan in the Prevention of Congestive Heart Failure or Sudden Death in Doberman Pinschers with Preclinical Dilated Cardiomyopathy (The PROTECT Study), J Vet Intern Med 26:1337, 2012. 3. Kittleson MD, Keene B, Pion P: Results of the multicenter spaniel trial (MUST): taurine-responsive and carnitine-responsive dilated cardiomyopathy in American Cocker Spaniels with decreased plasma taurine concentration, J Vet Intern Med 11:204, 1997. 4. Calvert CA, Meurs KM: CVT update: Doberman Pinscher occult cardiomyopathy. In Bonagura JD, editor: Kirk’s current veterinary therapy XIII, St Louis, 2000, Saunders. 5. Calvert CA, Jacobs GJ, Pickus CW: Bradycardia-associated episodic weakness, syncope, and aborted sudden death in cardiomyopathic Doberman Pinschers, J Vet Intern Med 10:88, 1996. 6. Calvert CA, Pickus CW, Jacobs GJ, Brown J: Signalment, survival, and prognostic factors in Doberman Pinschers with end-stage cardiomyopathy, J Vet Intern Med 11:323, 1997. 7. Freeman LM, Michel KE, Brown DJ, et al: Idiopathic dilated cardiomyopathy in Dalmatians: nine cases (1990-1995), J Am Vet Med Assoc 209:1592, 1996. 8. Vollmar AC: The prevalence of cardiomyopathy in the Irish Wolfhound: a clinical study of 500 dogs, J Am Anim Hosp Assoc 36:125, 2000.

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9. Meurs KM, Miller MW, Wright NA: Clinical features of dilated cardiomyopathy in Great Danes and results of a pedigree analysis: 17 cases (19902000), J Am Vet Med Assoc 218:729, 2001. 10. Dambach DM, Lannon A, Sleeper M, et al: Familial dilated cardiomyopathy of young Portugese Water Dogs, J Vet Intern Med 13:65, 1999. 11. Basso C, Fox PR, Meurs KM, et al: Arrhythmogenic right ventricular cardiomyopathy causing sudden cardiac death in Boxer dogs: a new animal model of human disease, Circulation 109:1180, 2004. 12. Meurs KM, Spier AW, Miller MW, et al: Familial ventricular arrhythmias in Boxers, J Vet Intern Med 13:437, 1999. 13. Prosek R, Estrada AH, Adin D: Comparison of sotalol and mexiletine versus stand-alone sotalol in treatment of Boxer dogs with ventricular arrhythmias, Proceedings of the American College of Veterinary Internal Medicine Forum, Louisville, KY, May 2006 (abstract). 14. Meurs KM, Spier AW, Wright NA, et al: Comparison of the effects of four antiarrhythmic treatments for familial ventricular arrhythmias in Boxers, J Am Vet Med Assoc 221:522, 2002. 15. Keene B, Panciera DP, Atkins CE, et al: Myocardial l-carnitine deficiency in a family of dogs with dilated cardiomyopathy, J Am Vet Med Assoc 198:647, 1991.

16. Sisson DD: Heritability of idiopathic myocardial hypertrophy and dynamic subaortic stenosis in Pointer dogs, J Vet Intern Med 9:118, 1995. 17. Thomas WP, Matthewson JW, Suter PF: Hypertrophic obstructive cardiomyopathy in a dog: clinical, hemodynamic, angiographic, and pathologic studies, J Am Anim Hosp Assoc 20:253, 1984. 18. Wynne J: The cardiomyopathies and myocarditis. In Braunwald E, editor: Heart disease, Philadelphia, 1992, Saunders. 19. Moise NS, Valentine BA, Brown CA, et al: Duchenne’s cardiomyopathy in a canine model: electrocardiographic and echocardiographic studies, J Am Coll Cardiol 17:812, 1991. 20. Valentine BA, Winand NJ, Pradhan D, et al: Canine X-linked muscular dystrophy as an animal model of Duchenne muscular dystrophy: a review, Am J Med Genet 42:352, 1992. 21. Jeraj K, Ogburn PN, Edwards WD, Edwards JE: Atrial standstill, myocarditis and destruction of cardiac conduction system: clinicopathologic correlation in a dog, Am Heart J 99:185, 1980. 22. Miller MS, Tilley LP, Atkins CE, et al: Persistent atrial standstill (atrioventricular muscular dystrophy). In Kirk RW, Bonagura JD, editors: Kirk’s current veterinary therapy XI, St Louis, 1992, Saunders. 23. Prošek R, Kitchell BE: Dexrazoxane pharm profile, Compendium 24:220, 2002.

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CHAPTER 43  VALVULAR HEART DISEASE Aaron C. Wey,

DVM, DACVIM (Cardiology)

KEY POINTS • Myxomatous valvular degeneration is the most common acquired cardiovascular disorder encountered in canine patients. • The clinical picture of patients with valvular heart disease in the emergency setting is typically that of cardiogenic pulmonary edema (left-sided congestive heart failure). • Virtually all patients with acquired degenerative valve disease that have congestive heart failure will have an audible cardiac murmur in the left apical position. If the patient does not have a murmur, other diagnoses should be considered. • Radiographic and physical examination findings provide a working diagnosis for the management of most patients with valvular heart disease. Echocardiography is helpful but not essential for empiric emergency management. • Goals of emergency therapy are to relieve signs of congestion, improve forward cardiac output, and improve tissue oxygenation and nutrient delivery.

often referred to as mitral valve disease. This latter designation is technically incorrect, and the condition may affect all four cardiac valves.2 For the purpose of this discussion, myxomatous valvular degeneration is used to describe the condition. MVD most commonly affects canine patients, although it may occur in any mammalian species. Feline patients rarely are affected. In the dog, small breeds are overrepresented. Breeds commonly associated with the disease include the Poodle, Miniature Schnauzer, Chihuahua, Cocker Spaniel, Dachshund, Cavalier King Charles Spaniel, Miniature Pinscher, Lhasa Apso, Shih Tzu, Whippet, and Terrier breeds.2,3 However, the differential should not be excluded in large breed dogs with a heart murmur in the left apical position. The disease typically is seen in elderly patients, but some breeds are known to develop MVD relatively early in life (e.g., Cavalier King Charles Spaniel).4 A male predisposition has been suggested.5

PATHOLOGY Acquired degenerative valvular disease is the most common cardiovascular disorder identified in small animals, accounting for approximately 75% of cases of cardiovascular disease seen in dogs.1 Its incidence (rate of occurrence over time) in older, small breed dogs approaches 100%.2 The condition may also be referred to as myxomatous valvular degeneration (MVD), mitral valve prolapse, acquired atrioventricular valvular degeneration, or valvular endocardiosis. Because the mitral valve is most commonly affected, the condition is

The exact cellular and hormonal mechanisms that result in MVD are unknown. It has been suggested for some time that collagen degeneration and synthesis are imbalanced, supported by the observation that chondrodystrophic breeds with other connective tissue disorders (collapsing trachea, intervertebral disk disease) often develop MVD. Histologic documentation of abnormal collagen distribution in MVD confirms this suspicion, and matrix metalloproteinases (MMPs) may play an important role in the turnover of collagen in the extracellular matrix of diseased valves.6 Numerous

CHAPTER 43  •  Valvular Heart Disease

of circulating volume and atrial pressure, which is ultimately transmitted to the pulmonary or systemic venous system. Capillary hydrostatic pressure eventually overcomes other forces in Starling’s law (interstitial hydrostatic pressure and capillary oncotic pressure) that help to maintain a balance in movement of fluid across the capillary membrane, and fluid transudation results. Initially the pulmonary and systemic lymphatic systems accommodate the extra fluid transudation, but these systems eventually become overwhelmed and overt pulmonary edema or third-space fluid accumulation results (congestive heart failure). Additional complications particular to MVD such as rupture of chordae tendineae may also occur. This may be well tolerated with a minor chord but may result in a large increase in regurgitant orifice area and left atrial pressure with acute pulmonary edema.10 Rarely, left atrial rupture occurs secondary to endothelial tearing at the site of impact of a high-velocity regurgitant jet. This complication may result in an acquired atrial septal defect but more commonly results in acute tamponade (see Chapter 45), collapse, and often death.10,19

neurohormonal factors have been implicated including serotonin, transforming growth factors α and β and I2, insulin-like growth factor 1, angiotensin II, and nitric oxide, but the exact role of these hormonal messengers in the development and progression of the disease is unknown.7-9 A common misconception is that vegetative endocarditis from periodontal disease contributes to MVD, but evidence to support this hypothesis is lacking, and inflammation does not appear to play a role in the development of the disease in dogs.6 Detailed descriptions of the histologic changes that accompany MVD are beyond the scope of this discussion, and readers are referred to other sources for this information.3,10, 11 Grossly the changes are evident as valve thickening and elongation, which subsequently alter the normal coaptation of valve leaflets and may result in valve prolapse. Histologically the valves are distorted and thickened by excessive accumulation of glycosaminoglycans and other extracellular matrix proteins.7,10 The myxomatous changes have been characterized into classes of severity that are useful in a research setting, but these designations rarely are used clinically.10 If the degenerative changes or valve prolapse are significant, they result in a valve regurgitation that increases atrial pressure and decreases forward cardiac output (in the case of atrioventricular valve regurgitation). The degree of valvular insufficiency is dependent on the regurgitant orifice area, the pressure gradient across the valve, and the duration of systole (for the atrioventricular valves) or diastole (for the semilunar valves). In response to the decreased forward cardiac output and increased atrial pressure, several compensatory mechanisms are activated (see Pathophysiology) that result in eccentric hypertrophy (dilation) of the cardiac chambers on either side of the insufficient valve. The valve annulus then enlarges, causing further displacement of the leaflets and more regurgitation. In contrast to diseases with primary myocardial failure (i.e., dilated cardiomyopathy), ventricular function usually is maintained until late in the course of MVD, and patients often are symptomatic before severe myocardial failure develops. Large breed dogs may develop myocardial failure sooner during the course of the disease for reasons that are not completely understood, although increased wall stress as a result of a larger ventricular diameter may be a factor.3 Many patients with MVD have a long asymptomatic phase before the onset of clinical signs. In these patients the murmur of valvular regurgitation often is identified during routine physical examination or when the patient is seen for an unrelated problem. The factors that result in progression from the asymptomatic stage to overt signs of heart failure in some dogs but not others are not completely understood.

Patients with MVD commonly have a history of a cardiac murmur that was identified during a routine physical examination. The murmur is often chronic, although it may be a new finding in the case of chordal rupture. The intensity of the murmur has been correlated with the severity of regurgitation.13 The patient may be brought in for evaluation of a cough, dyspnea, exercise intolerance, syncope, or collapse. Physical examination findings with left-sided heart failure are attributable to pulmonary edema: dyspnea, orthopnea, cyanosis, and abnormal lung sounds. It should be noted that all patients with pulmonary crackles do not have cardiogenic pulmonary edema, and pulmonary edema can be present without crackles clearly evident on auscultation. Tachyarrhythmias (sinus tachycardia, premature contractions, or atrial fibrillation) may also be noted. Right-sided heart failure may result in the accumulation of pleural effusion or ascites, with decreased ventral lung sounds or abdominal distention, respectively. Jugular distention, pulsation, or a positive hepatojugular reflux test should be visible in patients with rightsided heart failure. An S3 gallop sound may be detected with careful auscultation at the left sternal border in a patient with severe mitral regurgitation.13 Femoral pulses usually are strong until late in the course of the disease unless acute chordal or left atrial rupture occurs. With left atrial rupture, patients demonstrate symptoms of cardiac tamponade (see Chapter 45).

PATHOPHYSIOLOGY

LABORATORY EVALUATION

A detailed description of the pathophysiology of heart failure is presented elsewhere in this text (see Chapter 40), but a brief description is presented here. Decreased forward stroke volume and decreased mean arterial pressure result in neurohormonal activation: increased sympathetic tone, activation of the renin-angiotensin-aldosterone system, and a change in the concentration of numerous other neurohormones (endothelin 1, tumor necrosis factor α, nitric oxide).12 The net result of these changes is vasoconstriction, sodium and water retention, and an increased forward cardiac output and blood pressure. This is accomplished through increased contractility (sympathetic stimulation), volume expansion, and eccentric hypertrophy. Other neurohormonal mechanisms may be activated to modulate this response (i.e., natriuretic peptide production secondary to increased atrial pressure and stretch), but these measures often are overwhelmed or downregulated with chronically altered cardiac output. Chronic activation of the renin-angiotensin-aldosterone system and sympathetic nervous system occurs at the expense

Laboratory findings for patients with MVD often are nonspecific. The complete blood cell count may be normal or may demonstrate a normochromic, normocytic nonregenerative anemia. A stress leukogram (neutrophilia, monocytosis, lymphopenia, eosinopenia) often is present in patients with congestive heart failure. The biochemical profile may demonstrate changes secondary to passive congestion of the liver (hepatopathy) or hyponatremia/hypochloridemia in chronic heart failure. Conversely, the biochemical panel may be normal or demonstrate abnormalities consistent with other diseases of aged patients (e.g., chronic renal failure, hepatopathies). Blood gas analysis may reveal varying degrees of hypoxemia with metabolic acidosis secondary to peripheral vasoconstriction and poor perfusion (lactic acidosis). Research has identified several biochemical markers that may aid in the assessment of the patient with heart failure. The concentration of natriuretic peptides (ANP, BNP) is known to increase in congestive heart failure (CHF), although these peptides are difficult to measure

HISTORY AND PHYSICAL EXAMINATION

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in clinical samples because of their short half-life. Logistical difficulties associated with the stability of B-type natriuretic peptide have largely been overcome with the development of assays to evaluate the more stable amino terminal portion of the cleaved pro-hormone (NT-proBNP). These assays have been validated and demonstrate good sensitivity and specificity in differentiating patients with dyspnea secondary to cardiac disease versus primary respiratory disease.14,15 Human “bedside” analyzers for B-type natriuretic peptide and NT-proBNP are available and may eventually be available in the veterinary emergency hospital laboratory. However, numerous other factors may influence NT-proBNP concentration in an emergency patient (e.g., pulmonary hypertension, renal dysfunction) and may confound interpretation of results of this assay.16-18 Cardiac troponins (particularly cardiac troponin I, or cTnI) have also been investigated as blood-based biomarkers for heart disease in dogs and are sensitive but relatively nonspecific.19,20

A

ELECTROCARDIOGRAPHIC FINDINGS The electrocardiogram is not a sensitive or specific diagnostic test for MVD. However, it should be performed in any patient with an arrhythmia or tachycardia. The most common rhythm changes seen in patients with MVD are sinus tachycardia, atrial premature contractions, and atrial fibrillation. Ventricular ectopy is unusual in the typical small breed dog with MVD but may occur with hypoxia, with other organ system failure, or in large breeds. Other abnormalities that may be identified in canine patients include P mitrale (P wave width >40 msec), P pulmonale (P wave height >0.5 mV), or evidence of left ventricular enlargement (R wave amplitude >2.5 mV or duration >60 msec). Severe cardiac disease may be present with normal electrocardiographic findings, and the absence of these electrocardiographic changes should not be interpreted by the clinician as an indicator of normal cardiac chamber size or function.

RADIOGRAPHIC FINDINGS The radiographic findings in canine patients with MVD and congestive heart failure CHF are illustrated in Figure 43-1. Left-sided heart enlargement is apparent as loss of the caudal cardiac waist (left atrial enlargement) and a tall cardiac silhouette (left ventricular enlargement). These changes result in dorsal deviation of the trachea, carina, and mainstem bronchi. Pulmonary venous congestion may be evident in the cranial lobar veins on the lateral projection and the caudal lobar veins on the orthogonal projection. Dorsoventral positioning provides better visualization of the caudal pulmonary vasculature and is less stressful for the dyspneic patient than ventrodorsal positioning. Ventrodorsal positioning should be used in patients with pleural effusion for better visualization of the heart and accessory lung lobe.22 In patients with significant tricuspid regurgitation, the heart may have changes consistent with right-sided heart enlargement (reverse D on dorsoventral films, increased sternal contact on lateral films). Often patients with advanced valvular disease will have global or generalized cardiomegaly. A vertebral scale system (vertebral heart score [VHS]) has been validated as an objective measure of assessing cardiac size in the dog and cat and may help substantiate a clinician’s subjective impression of cardiomegaly.23 Pulmonary edema in the dog initially is identified as a mild, perihilar, or central interstitial infiltrate. As the severity of the infiltrates increases in canine patients, they generally progress in a caudal and dorsal distribution but may be multifocal or asymmetric, particularly right caudal pulmonary interstitial infiltrates.24 In cases with right-sided heart failure or biventricular disease, pleural fissure lines or overt effusion may be visible and there may be a loss of serosal detail in the abdomen.

B FIGURE 43-1  Right lateral (A) and dorsoventral (B) radiographs of a dog with myxomatous valvular degeneration and severe mitral regurgitation. A, Severe left-sided heart enlargement is visible as an increase in overall heart size (vertebral heart score 13.0) with a tall cardiac silhouette (left ventricular enlargement) and loss of the caudal cardiac waist (left atrial enlargement). The pulmonary vascular markings are difficult to evaluate because of a generalized pulmonary interstitial pattern that is more pronounced in the hilar and caudal lung fields. The liver is mildly enlarged. B, Severe generalized cardiomegaly is present with an enlarged left atrium. The pulmonary vasculature is difficult to evaluate. An interstitial pattern is visible in the caudal lung fields.

ECHOCARDIOGRAPHIC FINDINGS Although echocardiography is not essential in generating an emergency medical treatment plan for patients with valvular disease, ultrasound machines commonly are used in the emergency setting. Echocardiography can help gauge disease severity, identify ruptured chordae tendineae, quantify pleural or pericardial effusion, confirm the diagnosis when radiographs are inconclusive, and guide therapy (e.g., thoracocentesis). The classic findings in a patient with MVD affecting the mitral valve include left ventricular and left atrial dilation, hyperdynamic left ventricular wall motion, and thickened mitral valve leaflets. For the emergency veterinarian, evaluation of left atrial size is the easiest assessment and has been reviewed

CHAPTER 43  •  Valvular Heart Disease

A

B FIGURE 43-2  Right parasternal short-axis echocardiographic views of the aorta and left atrium in a normal dog (A) and a dog with myxomatous valve disease (B). The ratio of the cross-sectional dimensions of the left atrium and aorta (LA/Ao) should be less than 1.5 in normal dogs, as depicted in this example. In B, severe left atrial enlargement is present with an LA/Ao 2.0 or greater, suggestive of severe mitral regurgitation and elevated left atrial pressure. In the emergency setting this finding may be used to support a diagnosis of congestive heart failure.

elsewhere.25,26 In general, patients in left-sided heart failure secondary to MVD will have a left atrium/aorta ratio of 2.0 or more (Figure 43-2). If this criterion is not met, other diagnoses should be considered for interstitial pulmonary infiltrates (e.g., pulmonary hypertension or thromboembolism, noncardiogenic edema, primary lung diseases, neoplasia). Other echocardiographic findings that may be identified include valve thickening or prolapse, leaflet flail (protrusion of the leaflet margin into the atrium during systole), and ruptured chordae tendineae. If available, color and spectral Doppler evaluation can confirm valve insufficiencies and offer subjective information regarding the severity of the regurgitant lesion. In patients with left atrial rupture, pericardial effusion and a pericardial thrombus may be identified. Although M-mode and spectral Doppler echocardiography offer many techniques for further evaluating cardiac function in patients with MVD, these techniques are highly dependent on sonographer experience and are beyond the scope of this text. The reader is referred to other sources for descriptions of these techniques.26

EMERGENCY MANAGEMENT As with any cause of heart failure, ideal therapy would be to reverse or correct the underlying disease. Although this is not possible in the emergency setting for a patient with MVD, several hemodynamic

variables can be manipulated to improve cardiovascular function and relieve clinical signs. The goals of emergency therapy for the patient in heart failure secondary to MVD are to relieve signs of congestion, improve forward cardiac output, and improve tissue oxygenation and nutrient delivery. An American College of Veterinary Internal Medicine panel has published a consensus statement outlining diagnostic and therapeutic guidelines for management of congestive heart failure secondary to MVD in dogs.27 The reader is referred to this consensus statement for a more detailed discussion of treatment, but therapeutic recommendations are reviewed briefly here. Congestive signs can be relieved by reducing the hydrostatic pressure in the pulmonary or systemic venous system or by removing third-space effusions. Reducing hydrostatic pressure can be accomplished by decreasing circulating volume or by venodilation. Relief of pulmonary edema usually is accomplished with diuretics to decrease intravascular volume. Furosemide is used most often (2 to 8 mg/kg in dogs or 1 to 4 mg/kg in cats intramuscularly [IM] or intravenously [IV]). A dosage-dependent venodilator effect has been observed with intravenous administration in humans.28 A protocol for constant rate infusion (CRI) of furosemide has been investigated in normal dogs and is more effective than intermittent bolus injection.29 Typical CRI dosing ranges from 0.5 to 1.0 mg/kg/hr after a bolus loading dose. Other loop diuretics (e.g., bumetanide, torsemide) may have greater potency and may be more useful in the future for management of canine patients.30 Oral diuretics are not ideal because of the likelihood of impaired gastrointestinal absorption and a relatively slow onset of action. In patients with refractory edema, moderate restriction of fluid intake may also be helpful in reducing congestive signs. Side effects of diuretic therapy include prerenal azotemia, electrolyte disturbances (hypokalemia, hyponatremia, others), and acid-base derangements (metabolic alkalosis). Overzealous administration of diuretics or restriction of fluids can result in uremia, dangerous reductions in circulating plasma volume, and poor tissue perfusion. Venodilators are not universally effective in veterinary patients, and their use should be considered adjunctive to diuretic therapy and oxygen administration. Topical nitroglycerin ointment ( 1 8 to 1 4 inch q6h on the inner pinnae) is used most commonly. This modality increases venous capacitance in normal dogs,31 but oral nitrates have minimal effect in normal dogs or dogs with CHF.32

Cardiac Output Arterial vasodilators are helpful in reducing regurgitant fraction and increasing forward cardiac output. Hydralazine (0.5 to 2.5 mg/kg PO q12h) has been advocated in this setting for patients with refractory heart failure.3 Side effects of this therapy include emesis and hypotension. Amlodipine (0.2 to 0.4 mg/kg PO q12h) may also be useful and generally has fewer side effects than hydralazine. Enalapril is not a potent vasodilator in dogs and cats and generally is not recommended for emergency management of CHF.27 More aggressive approaches for improving forward cardiac output can be employed using an intravenous vasodilator in conjunction with a positive inotrope. This combination should be used only in settings where invasive blood pressure monitoring is available. Intravenous nitroprusside (1 to 2 mcg/kg/min titrated upward to a target blood pressure) can be administered alone or in conjunction with either dopamine or dobutamine (2.5 to 10 mcg/kg/min [dobutamine for cats: 1 to 5 mcg/kg/min]) to improve forward cardiac output and reduce capillary hydrostatic pressure. Mean arterial pressures should be maintained above 80 mm Hg with this regimen and can be adjusted quickly because of the short half-life of these medications. Potential complications of this therapy include severe hypotension and cyanide toxicity (with expired nitroprusside solutions or ≥3 days after mixing). With universal availability and increased experience with

233

234

PART IV  •  CARDIAC DISORDERS

pimobendan, oral positive inotropic therapy with this agent is now recommended in the emergency setting.27 Pimobendan is a phosphodiesterase inhibitor with both positive inotropic and vasodilatory properties that has significant benefits in the management of CHF.35 This drug is now considered standard therapy in the emergency setting in patients able to tolerate oral administration, with a recommended oral dosage of 0.25 to 0.3 mg/kg PO q12h (see Chapter 40).27 Digoxin and other digitalis glycosides have a long half-life that limits their usefulness for acute therapy. This can be overcome with intravenous administration or oral drug loading, but these approaches may result in toxicity.

Tissue Oxygenation Oxygen therapy should be considered essential for the patient in heart failure from any cause. Increasing the fraction of inspired oxygen will help improve blood oxygen content, but the impaired pulmonary function caused by edema necessitates that oxygen be used in conjunction with the therapies described above. Detailed guidelines for administration of oxygen are given elsewhere in this text (see Chapter 14).

Arrhythmia Management and Adjunctive Therapy Arrhythmias may be present in patients with MVD and complicate medical management. Isolated atrial or ventricular premature contractions rarely require therapy, but atrial fibrillation and ventricular or supraventricular tachycardia should be identified and addressed. These commonly result in a rapid heart rate that decreases diastolic filling and myocardial perfusion and affect forward cardiac output. Tachyarrhythmias may also decrease systolic function and result in myocardial failure if they are chronic (tachycardia-induced cardiomyopathy). Pharmacologic management of these arrhythmias is discussed elsewhere in this text (see Chapters 47 and 48). Direct current cardioversion may be employed for rhythms that are refractory to medical management (see Chapter 204). Sedation is often helpful in managing anxiety associated with dyspnea in congestive heart failure patients, and opioid drugs such as morphine and butorphanol are often recommended for this purpose, although care and monitoring are necessary to minimize the risk of respiratory depression with these agents.27 Control of ambient temperature and humidity should also be a priority, particularly when patients are confined to an oxygen cage.

Monitoring Successful treatment of a patient with CHF from MVD requires monitoring of volume status, renal function, acid-base balance, and blood pressure. When patients are admitted in an emergency setting, a body weight, complete blood cell count, biochemical profile, urine specific gravity, blood pressure, and thoracic radiographs should be obtained before initiation of therapy (condition permitting). Twelve to 24 hours after initiation of therapy, a blood gas analysis, biochemical profile with electrolytes, and thoracic radiographs should be repeated. Frequent (every 12 hours) evaluation of patient weight is often helpful, with a target reduction of 5% to 7% of body weight on admission. If a patient develops significant azotemia (blood urea nitrogen >50 mg/dl, creatinine ≥2.5 mg/dl), dehydration, weight loss greater than 10% of weight on admission, alkalosis, or electrolyte disturbances, diuretic therapy should be modified and alternative modalities employed.

LONG-TERM THERAPY In general, the goals of long-term therapy for MVD mirror those of the emergency setting but with orally administered medications, with additional emphasis on slowing disease progression, prolonging

survival, and maintaining quality of life. The precise timing for initiation of therapy before the onset of CHF is a subject of much debate because clinical trials have demonstrated variable results with the early use of angiotensin-converting enzyme (ACE) inhibitors, and a consensus has still not been reached regarding the use of this drug class before the onset of clinical signs.27,36 β-Blockers have also been evaluated in the preclinical phase of MVD, but recent data suggest that these drugs also do not slow progression of the disease or delay the onset of clinical symptoms.37 Chronic treatment of patients with MVD and CHF should include a diuretic at the lowest effective dosage, pimobendan (0.25 to 0.3 mg/kg PO q12h), and an ACE inhibitor (enalapril, benazepril, or equivalent at 0.25 to 0.5 mg/kg PO q12h).27 A balanced low-sodium diet should also play an integral role in the management of a patient’s congestion and may reduce the dosage of diuretics required to control signs of edema but may be difficult to initiate at the onset of oral therapy because of poor palatability.27,33 Spironolactone has gained recent recognition as an adjunctive agent that may be beneficial as an aldosterone antagonist rather than a diuretic, although a consensus has not been reached to date regarding initiation of therapy before or at the onset of heart failure.27,34 As heart failure progresses or complications such as atrial arrhythmias or systolic dysfunction develop, digoxin is often added to this regimen. Adjunctive therapies (potassium gluconate and cough suppressants) are used on a case-by-case basis. When patients develop edema that is refractory to this therapy, additional diuretics (spironolactone, hydrochlorothiazide), positive inotropic agents (digoxin), vasodilators (amlodipine, hydralazine), cough suppressants (hydrocodone, dextromethorphan, butorphanol, tramadol) and bronchodilators (theophylline/aminophylline) are used in various combinations depending on the patient’s coexisting disease states, ventricular function, and tolerance of therapy.27,36 Sildenafil, a selective phosphodiesterase V inhibitor that causes nitric oxide– mediated vasodilation secondary to increases in cyclic GMP within the vascular endothelium, has been evaluated in the management of pulmonary hypertension secondary to congestive heart failure. This agent may become more important in the management of refractory heart failure as more prospective clinical trials are performed, but cost may also be a limiting factor. For patients whose disease is refractory to medical therapy, surgical intervention is a newer therapeutic modality that is offered at selected teaching institutions.27,38-41

PROGNOSIS In general, MVD carries a more favorable prognosis than many other cardiovascular diseases. The condition has a long (1 to 3 years) preclinical phase when patients have an excellent quality of life with few clinical signs. When CHF signs develop, the prognosis worsens. Medical therapy may offer patients the possibility of approximately 6 to 18 months of good-quality life after the onset of CHF.2 Patients with ruptured major chordae tendineae or a ruptured left atrium have a poor or grave prognosis. When patients decompensate while receiving long-term oral medications, aggressive parenteral therapy can still offer the possibility of temporary recovery and return to life at home with oral medication.

INFECTIOUS ENDOCARDITIS This condition is mentioned here because of the similar hemodynamic changes that develop with valve regurgitation caused by vegetative lesions, but the condition is not typically associated with MVD. With the exception of one case report,42 no published data are available that would suggest that MVD predisposes dogs to bacterial endocarditis. For detailed descriptions of this disease, the reader is referred to Chapter 98.43,44

CHAPTER 43  •  Valvular Heart Disease

REFERENCES 1. Detweiler DK, Patterson DF: The prevalence and types of cardiovascular disease in dogs, Ann N Y Acad Sci 127:481, 1965. 2. Borgarelli M, Buchanan JW: Historical review, epidemiology, and natural history of mitral valve disease, J Vet Card 14:93. 2012. 3. Kittleson MD: Myxomatous atrioventricular valvular degeneration. In Kittleson MD, Kienle RD: Small animal cardiovascular medicine, St Louis, 1998, Mosby. 4. Beardow AW, Buchanan JW: Chronic mitral valve disease in Cavalier King Charles Spaniels: 95 cases (1987-1991), J Am Vet Med Assoc 203:1023, 1993. 5. Swenson L, Häggström J, Kvart C, et al: Relationship between parental cardiac status in Cavalier King Charles Spaniels and prevalence and severity of chronic valvular disease in offspring, J Am Vet Med Assoc 208:2009, 1996. 6. Aupperle H, Disatian S: Pathology, protein expression and signaling in myxomatous mitral valve degeneration: Comparison of dogs and humans, J Vet Card 14:59, 2012. 7. Orton EC, Lacerda CMR, Maclea HB: Signaling pathways in mitral valve degeneration, J Vet Card 14:7, 2012. 8. Pedersen HD, Schutt T, Sondergaard R, et al: Decreased plasma concentration of nitric oxide metabolites in dogs with untreated mitral regurgitation, J Vet Intern Med 17:178, 2003. 9. Parker HG, Kilroy-Glynn P: Myxomatous mitral valve disease in dogs: does size matter? J Vet Card 14:19, 2012. 10. Fox PR: Pathology of myxomatous mitral valve disease in the dog, J Vet Card 14:103, 2012. 11. Sisson DK: Acquired valvular heart disease in dogs and cats. In Fox PR, Sisson DK, Moise NS, editors: Textbook of canine and feline cardiology, ed 2, St Louis, 1999, Saunders. 12. Martin MWS: Treatment of congestive heart failure, a neuroendocrine disorder, J Small Anim Pract 44:154, 2003. 13. Häggström J, Kvart C, Hansson K: Heart sounds and murmurs: changes related to severity of chronic valvular disease in the Cavalier King Charles Spaniel, J Vet Intern Med 9:75, 1995. 14. Prosek R, Sisson DD, Oyama MA, Solter PF: Distinguishing cardiac and non-cardiac dyspnea in 48 dogs using plasma atrial natriuretic factor, B-type natriuretic factor, endothelin, and cardiac troponin-I, J Vet Intern Med 21:238, 2007 15. Oyama MA, Rush JE, Rozanski EA, et al: Assessment of N-terminal proB-type natriuretic peptide concentration for differentiation of congestive heart failure from primary respiratory tract disease as the cause of respiratory signs in dogs, J Am Vet Med Assoc 235:1319, 2009. 16. Lee JA, Herndon WE, Rishniw M: The effect of noncardiac disease on plasma brain natriuretic peptide concentration in dogs, J Vet Emerg Crit Care 21:5, 2011. 17. Kellihan HB, MacKie BA, Stepien RA: NT-proBNP, NT-proANP and cTnI concentrations in dogs with pre-capillary pulmonary hypertension, J Vet Card 13:171, 2011. 18. Raffan E, Loureiro J, Dukes-McEwan J, et al: The cardiac biomarker NT-proBNP is increased in dogs with azotemia, J Vet Intern Med 23:1184, 2009. 19. Oyama MA, Sisson DD: Cardiac troponin-I concentration in dogs with cardiac disease, J Vet Intern Med 18:831, 2004. 20. Spratt DP, Mellanby RJ, Drury N, et al: Cardiac troponin I: evaluation of a biomarker for the diagnosis of heart disease in the dog, J Small Anim Pract 46:139, 2005. 21. Peddle GD, Buchanan JW: Acquired atrial septal defects secondary to rupture of the atrial septum in dogs with degenerative mitral valve disease, J Vet Card 12:129, 2010.

22. Saunders HM, Keith D: Thoracic imaging. In King LG, editor: Textbook of respiratory disease in dogs and cats, St Louis, 2004, Saunders. 23. Buchanan JW, Bucheler J: Vertebral scale system to measure canine heart size in radiographs, J Am Vet Med Assoc 206:194, 1995. 24. Diana A, Guglielmini C, Pivetta M, et al: Radiographic features of cardiogenic pulmonary edema in dogs with mitral regurgitation: 61 cases (19982007), J Am Vet Med Assoc 235:1058, 2009. 25. Rush JE: The use of echocardiography in the ICU and ER, Proceedings of the 23rd American College of Veterinary Internal Medicine Forum, Baltimore, June 2005. 26. Chetboul V, Tissier R: Echocardiographic assessment of canine degenerative mitral valve disease, J Vet Card, 14:127, 2012. 27. Atkins C, Bonagura J, Ettinger S, et al: Guidelines for the diagnosis and treatment of canine chronic valvular heart disease, J Vet Intern Med 23:1142, 2009. 28. Pickkers P, Dormans TP, Russel FG, et al: Direct vascular effects of furosemide in humans, Circulation 96:1847, 1997. 29. Adin DB, Taylor AW, Hill RC, et al: Intermittent bolus injection versus continuous infusion of furosemide in normal adult Greyhounds, J Vet Intern Med 17:632, 2003. 30. Peddle GD, Singletary GE, Reynolds CA, et al: Effect of torsemide and furosemide on clinical, laboratory, radiographic and quality of life variables in dogs with heart failure secondary to mitral valve disease, J Vet Card 14:253, 2012 31. Narayanan P, Hamlin RL, Nakayama T, et al: Increased splenic capacity in response to transdermal application of nitroglycerine in the dog, J Vet Intern Med 13:44, 1999. 32. Adin DB, Kittleson MD, Hornof WJ, et al: Efficacy of a single oral dose of isosorbide 5-mononitrate in normal dogs and in dogs with congestive heart failure, J Vet Intern Med 15:105, 2001. 33. Rush JE, Freeman LM, Brown DJ, et al: Clinical, echocardiographic, and neurohormonal effects of a sodium-restricted diet in dogs with heart failure, J Vet Intern Med 14:513, 2000. 34. Bernay F, Bland JM, Haggstrom J, et al: Efficacy of spironolactone on survival in dogs with naturally occurring mitral regurgitation caused by myxomatous mitral valve disease, J Vet Intern Med 24:331, 2010. 35. Boswood A: Current use of pimobendan in canine patients with heart disease. Vet Clin North Am Small Anim Pract 40:571, 2010. 36. Atkins CE, Haggstrom J: Pharmacologic management of myxomatous mitral valve disease in dogs, J Vet Card 14:165, 2012. 37. Keene BW, Fox PR, Hamlin RL, et al: Efficacy of BAY 41-9202 (bisoprolol oral solution) for the treatment of chronic valvular heart disease (CHVD) in dogs, Proceedings of the 24th American College of Veterinary Internal Medicine Forum, New Orleans, June 2012. 38. Buchanan JW, Sammarco CD: Circumferential suture of the mitral annulus for correction of mitral regurgitation in dogs, Vet Surg 27:182, 1998. 39. Griffiths LG, Orton EC, Boon JA: Evaluation of techniques and outcomes of mitral valve repair in dogs, J Am Vet Med Assoc 224:1941, 2004. 40. Orton EC, Hackett TB, Mama K, et al: Technique and outcome of mitral valve replacement in dogs, J Am Vet Med Assoc 226:1508, 2005. 41. Uechi M: Mitral valve repair in dogs, J Vet Card 14:185, 2012. 42. Tou SP, Adin DB, Castleman WL: Mitral valve endocarditis after dental prophylaxis in a dog, J Vet Intern Med 19:268, 2005. 43. Kittleson MD: Infective endocarditis (and annuloaortic ectasia). In Kittleson MD, Kienle RD: Small animal cardiovascular medicine, ed 1, St Louis, 1998, Mosby. 44. Miller MW, Sisson DK: Infectious endocarditis. In Fox PR, Sisson DK, Moise NS, editors: Textbook of canine and feline cardiology: principles and clinical practice, ed 2, St Louis, 1999, Saunders.

235

CHAPTER 44  MYOCARDIAL CONTUSION Adam J. Reiss,

DVM, DACVECC

KEY POINTS • Myocardial injuries often are overlooked in the trauma patient. • The most common physiologic consequence of myocardial injury in dogs and humans is arrhythmias. • Arrhythmias associated with myocardial injury may be delayed in onset up to 48 hours. • Holter monitoring or continuous electrocardiographic (ECG) monitoring should be considered in high-risk patients. • Troponins, cardiac-specific proteins, are an effective biomarker of myocardial injury in dogs. • Normal ECG findings and cardiac troponin I levels on admission in traumatized human patients are an efficient way to rule out myocardial injuries and arrhythmias associated with trauma. • Management of myocardial injuries is aimed toward maintaining optimal cardiac output and suppressing life-threatening arrhythmias. • The class I antiarrhythmic agents, including lidocaine and procainamide, are used commonly to manage ventricular ectopy associated with myocardial injury.

Traumatic myocarditis is a controversial subject. Much of the controversy in human studies revolves around a lack of consistent evidence that this injury has any effect on patient outcome and the expense associated with diagnostic testing, cardiac monitoring, and prolonged hospital stays.1 Additional controversies associated with this injury revolve around its name, incidence, and how it is diagnosed. What appears to be agreed on consistently in the literature is the basic definition of this injury and that there is lack of an antemortem diagnostic gold standard. Direct visualization of the heart or histologic examination of damaged myocardium are considered the current diagnostic gold standard.2 The term traumatic myocarditis has been used often in veterinary literature to describe an assumed myocardial injury associated with arrhythmias in patients suffering from blunt thoracic trauma.3 This term is used interchangeably with myocardial injury in this chapter.

INCIDENCE Blunt thoracic trauma has been reported to result in myocardial injuries in 8% to 95% of human patients.3-10 Reported variations in the frequency of myocardial injuries of dogs are similar to those described in humans. Several studies (three prospective, two retrospective) have examined the prevalence of traumatic myocarditis in the dog and report a range from 10% to 96%.4,11-14 Variations in study design as well as disagreements regarding terminology, diagnostic modalities, and criteria used to identify myocardial injuries in humans and dogs contribute to the wide range in the reported frequency of this type of injury in both the human and veterinary literature.2,3,7,13-21 The authors of these studies do agree, however, that myocardial injuries are easily overlooked.18 236

ETIOLOGY, MECHANISM OF INJURY, AND PATHOPHYSIOLOGY Thoracic trauma is common in dogs injured by automobiles, animal attacks (bites, kicks), and falls from a height.* Because of the elastic nature of the thoracic cage, blunt trauma may subject the myo­ cardium to compressive and concussive forces.13,14,22-24 The most common mechanism of myocardial injury in the dog is that secondary to lateral chest compression.22,24 In addition to potential concussive injury from forceful contact with the ribs, sternum, and vertebrae when rapid acceleration or deceleration occurs, it has been proposed that distortion of the thoracic cage results in a rise in intrathoracic and intracardiac pressures, causing shearing stresses within the myocardium powerful enough to result in contusions.6 In vivo studies performed in dogs to mimic blunt chest trauma have correlated histopathologic areas of myocardial injury with areas of injury found during echocardiographic examination. Experimental trauma delivered to the left side of the chest resulted in abnormalities that were located primarily in the craniolateral wall of the left ventricle, and right-sided chest trauma produced septal and right ventricular wall damage.6 Gross pathologic findings in the traumatized heart have been characterized by localized edema, ecchymosis, and intramyocardial hematoma formation. Myocardial injuries were often transmural, with the epicardial surface being more severely affected.6 Arrhythmias and conduction defects are the most commonly reported consequences of myocardial injuries in humans and dogs.7,11,22-27 One proposed proarrhythmic mechanism of myocyte trauma is the lowering of the ratio of effective refractory period to action potential duration and an increase in the resting membrane potential (less negative) in damaged myocardial cells. Additionally it is proposed that myocyte injury results in alterations of sodium and calcium currents across cell membranes, increasing the availability of intracellular calcium, resulting in increased sensitivity to depolarization.3 These proposed intracellular derangements secondary to trauma can potentiate arrhythmogenesis.3 Arrhythmias become apparent when the injured myocardium becomes the site of the most rapid impulse formation, overcoming the sinus node as the dominant (overdrive) pacemaker. The injured myocardium becomes the new overdrive pacemaker, propagating the arrhythmia by depolarizing the sinus node before it has a chance to fire and recapture the cardiac rhythm.3 Isolated rabbit hearts have been subjected to injury during highresolution mapping of epicardial excitation to identify the origin of arrhythmias in injured myocardium. The results of this study identified reentry as the mechanism of arrhythmia caused by myocardial contusion. The authors found that the site of impact became electrically silent (temporarily), resulting in a fixed and functional conduction block that caused reentry initiation.28

*References 2, 3, 11-13, 19-21.

CHAPTER 44  •  Myocardial Contusion

Traumatized patients may also develop arrhythmias associated with metabolic acidosis, hypoxia, electrolyte imbalance, intracranial injuries, and catecholamine release.23,25-27,29 These physiologic aberrations all promote alterations in membrane transport and permeability of cations (sodium, potassium, and calcium), which lead to a decrease in resting membrane potential, as described earlier, contributing to aberrant depolarization and arrhythmias.3,23,25 The most commonly reported arrhythmias secondary to canine myocardial injuries include premature ventricular contractions, ventricular tachycardia, and nonspecific ST segment elevation or depression.6,22-27,29 Less commonly reported arrhythmias reported in dogs with chest trauma include atrial fibrillation, sinus arrest with ventricular or junctional escape complexes, and second-degree and third-degree atrioventricular block.7,12,22,27

DIAGNOSIS Although uncommonly performed in the live patient, gross or histologic examination of the heart remains the diagnostic gold standard for myocardial contusions.2,17,30 Because of the impracticality of visualizing the heart or performing myocardial biopsy, an understanding of the mechanism of injury, an awareness of associated injuries, and a high index of suspicion for myocardial injury are essential in making a diagnosis.10 Emergency clinicians should consider myocardial injury in all traumatized dogs that have the following injuries: (1) fractures of extremities, spine, or pelvis, (2) external evidence of thoracic trauma, (3) radiographic evidence of chest trauma such as pulmonary contusions, pneumothorax, hemothorax, diaphragmatic rupture, and rib or scapular fractures, and (4) neurologic injury.* Dogs with any of these injuries should have a lead II electrocardiograph (ECG) performed and, depending on the patient’s condition and the clinician’s index of suspicion, the ECG should be repeated intermittently (i.e., every 2 to 24 hours). ECG abnormalities commonly are delayed in onset for up to 48 hours after blunt chest trauma, so in cases in which there is a high index of suspicion for myocardial injury ECG monitoring should be considered for that time frame.22,23,25 Holter monitoring is the most sensitive and least invasive indicator of arrhythmias in dogs with suspected myocardial injuries. However, the lack of immediate Holter interpretation (rapid turnaround time) may limit the practical application of this modality for veterinarians.12 Other forms of continuous ECG monitoring, such as single patient monitors and telemetry, would likely provide a similar advantage over intermittent ECGs without the delays in interpretation encountered with Holter monitoring.18 An echocardiogram should be considered in severely traumatized dogs with a poor response to resuscitative efforts and evidence of thoracic injuries even if no ECG abnormalities are present. Transthoracic echocardiography in the dog can be used to identify and localize both structural and functional abnormalities of injured myocardium caused by blunt chest trauma. The echocardiographic features of myocardial injuries in the dog include (1) increased end-diastolic wall thickness; (2) impaired contractility, indicated by wall motion abnormalities and decreased fractional shortening; (3) increased echogenicity; and (4) localized areas of echolucency consistent with intramural hematomas.6 Serum myocardial isoenzyme analysis (cardiac troponins T and I [cTnT and cTnI]) has been used to diagnose myocardial injury in dogs and humans. The skeletal isoforms of the troponin proteins expressed are different from those in cardiac muscle.19,31 The troponin structure is highly conserved across many differing species,

*References 2, 12, 22, 25, 29, 30.

allowing for veterinary application of tests currently in use at human care facilities.32 Troponin testing is based on immunologic detection of the cardiac-specific isoforms of troponin T and troponin I.31 In both human and dogs, detectable levels appear in the circulation within 4 to 6 hours of cardiac myocyte injury and serum elevations may be present for up to 7 days.7,19,32 In a comparison of multiple myocardial enzyme and protein markers and ECG to detect myocardial injury in traumatized dogs, cTnI was the most sensitive indicator of this type of injury.2 One of the most important findings of the many human studies investigating the clinical use of cardiac troponins appears to be the negative predictive values for cardiac complications in trauma patients. In human trauma patients a normal cTnI level in combination with a normal ECG tracing on arrival has a negative predictive value of 100% for myocardial injuries, allowing these patients to avoid intensive cardiac monitoring and even be discharged safely in the absence of other significant injuries.33 Because of the controversies and difficulty diagnosing myocardial injuries in dogs, veterinarians should consider using these two tests to rule out this disease in a quick and practical manner. Although there are no studies confirming this hypothesis in dogs, clinicians could consider performing a baseline ECG and cTnI measurement within 4 hours of injury. Extrapolating from human findings, dogs with a combination of normal ECG findings and cTnI levels (normal < 0.03 to 0.07 ng/ml34) would be less likely to develop arrhythmias and therefore would not require intensive cardiac monitoring. A positive finding on either test would suggest the possibility of myocardial injury and would indicate continuous ECG monitoring in those dogs.

TREATMENT Treatment of myocardial injuries typically is aimed at suppressing potentially life-threatening arrhythmias and maintaining adequate tissue perfusion.30 Antiarrhythmic therapy is not recommended if arterial pulse quality is good and synchronous on auscultation, mean arterial pressure is higher than 75 mm Hg, mucous membranes are pink, capillary refill time is 2 seconds or less, and the patient has no clinical signs of weakness or cardiopulmonary distress.30 Antiarrhythmic therapy should be considered when properly stabilized patients (i.e., received adequate fluids, electrolytes, oxygen, pain control) develop arrhythmias such as multiform premature ventricular complexes, ventricular tachycardia, and the R-on-T phenomenon.23,26,27,30 Treatment is imperative when arrhythmias are accompanied by clinical evidence of decreased cardiac output such as hypotension, weakness, pale mucous membranes, delayed capillary refill time, collapse, or syncope.23,26,30 Additionally, treatment is indicated when an arrhythmia has a sustained (>15 to 30 seconds) ventricular rate that exceeds 140 to 180 beats/min in the dog.12,23,26 Lidocaine (2 mg/kg IV bolus) is the agent of choice for traumatized dogs suffering from ventricular ectopy fulfilling the criteria described in the previous paragraph.30 Intravenous boluses of lidocaine may be repeated every 10 to 20 minutes until a cumulative dose of 8 mg/kg is given. A constant rate infusion (CRI) of 40 to 80 mcg/ kg/min may be initiated to maintain a cardiac rate and rhythm that provides appropriate tissue perfusion.23,30 Additional boluses of lidocaine are often required to suppress arrhythmias while steady-state blood levels are achieved by the CRI. The upper end of the recommended dosages of lidocaine may cause vomiting or seizures, so administration should be slowed or temporarily discontinued if these signs develop (see Chapter 48 for more information).23,30,35 If lidocaine does not resolve ventricular ectopy, procainamide may be administered intravenously or intramuscularly (6 to 15 mg/ kg q4-6h).23,30 If repeated boluses of procainamide are required to suppress arrhythmias, a CRI (10 to 40 mcg/kg/min) may be

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started. Oral procainamide (sustained release formulation 20 mg/kg q8h) may be initiated if continued management is required and oral medications can be tolerated. Potential side effects of procainamide administration include hypotension and atrioventricular conduction block.23,35 Additional oral arrhythmia management options include tocainide (10 to 20 mg/kg PO q8-12h) and mexiletine (4 to 8 mg/kg PO q8h).23 The reported side effects of tocainide include nausea, vomiting, and anorexia; although less commonly observed, complications associated with mexiletine include excitement or depression.35 β-Blockers (propranolol, metoprolol, atenolol, sotalol) should be considered cautiously when traumatized dogs with ventricular ectopy are unresponsive to class I antiarrhythmic agents, have been treated appropriately for shock and pain, and are not receiving positive inotropic medications.30,35 An ultrashort-acting intravenous β-blocker, such as esmolol, may be used to test the efficacy of β-blockers in managing ventricular arrhythmias that have not responded to other medications.26 The potential for serious side effects such as atrioventricular block, hypotension, bronchoconstriction, and decreased cardiac contractility must be considered when using β-blockers.23,35 Arrhythmias secondary to myocardial trauma that do not fulfill the stated guidelines for management are likely to be self-limiting and resolve within 3 to 10 days.30 The end point of therapy is not necessarily complete resolution of the arrhythmia; appropriate therapeutic response includes reduction of the heart rate ( 50% of the RR interval) SVT.1 Important identifying characteristics and mechanisms of the more common SVTs are reviewed in Table 47-1 and Figure 47-1. The most commonly occurring SVTs in small animals appear to be atrial fibrillation, intraatrial reentrant tachycardia, orthodromic AV reciprocating

tachycardia (a macroreentrant circuit in which an impulse is carried from the atria to the AV node–His-Purkinje system to the ventricles to a retrograde-conducting accessory pathway to the atria), and automatic atrial tachycardia. Because the retrograde conduction properties of the canine AV node are typically poor and the antegrade fast pathway has a short effective refractory period, AV nodal reentrant tachycardia has not been identified in dogs undergoing electrophysiologic study for clinical tachyarrhythmias.

TREATMENT OF SUPRAVENTRICULAR TACHYARRHYTHMIAS It is essential to identify predisposing factors that are contributing to the initiation or perpetuation of SVT in a given patient. Acid-base abnormalities, electrolyte disturbances, significant anemia, and hypoxemia should be corrected. AV node–dependent tachyarrhythmias are treated in some cases by single-agent therapy aimed at slowing conduction through the AV node. Most AV node–dependent SVTs, however, require that an additional drug be added to suppress another site in the circuit. Atrial tachyarrhythmias are best addressed by dual therapy: one drug to slow AV nodal conduction and a second drug to inhibit the atrial automatic focus or interrupt conduction in an atrial reentrant circuit. Sites of antiarrhythmic drug action in SVT are shown in Figure 47-2.

Emergent Therapy Animals in incessant, rapid SVT require emergent interruption of the tachyarrhythmia. Vagal maneuvers may be tried first and may terminate the SVT if it is AV node dependent. Subjectively, the most effective vagal maneuver in small animals is carotid sinus massage. Sustained, gentle compression is applied for 5 to 10 seconds over the carotid sinus, which is located immediately caudal to the dorsal aspect of the larynx. The ECG needs to be monitored continuously throughout the procedure. Most often, however, the SVT does not terminate with such maneuvers and drug therapy must be initiated. Parenteral negative dromotropic agents can be used to interrupt a tachyarrhythmic circuit that uses the AV node and is causing

Table 47-1  Characteristics of Common Supraventricular Tachyarrhythmias SVT Mechanism

P′ Waves Visible?

P′ Wave Morphology

RP′ vs. RR Interval

Initiation and Termination

Response to AV Block

Atrial Automatic atrial

Yes Yes

Varies with SVT rate, often long Varies with SVT rate, often long

Gradual rate acceleration and deceleration Abrupt onset and offset at SVT rate

SVT continues

Intraatrial reentry Atrial flutter

Flutter (F) waves

Not applicable

No, f waves may be seen

Not applicable

Abrupt onset and offset at SVT rate Abrupt onset and offset at SVT rate, often incessant

SVT continues

Atrial fibrillation

Variable, differs from sinus P Variable, differs from sinus P (may be subtle) Identical saw-toothed F waves No visible P waves; f waves may be seen Retrograde: (–) in II, III, avF Variable

Typically short

Abrupt onset and offset

SVT terminates

Variable

Retrograde: (–) in II, III, avF Retrograde: (–) in II, III, avF

Short

Gradual rate acceleration and deceleration Abrupt onset and offset

SVT continues with AV dissociation SVT terminates

Often incessant. Abrupt onset and offset.

SVT terminates

AV Node–dependent OAVRT Often visible within ST-T segment Automatic Generally yes; AV junctional dissociation common Typical AV nodal Generally no reentry PJRT Typically visible in the T-P segment

Long

SVT continues

SVT continues

AV, Atrioventricular; OAVRT, orthodromic atrioventricular reciprocated tachycardia; PJRT, permanent junctional reciprocating tachycardia; SVT, supraventricular tachycardia.

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AV Node

LAF RBB

Normal ECG

Atrial Reentry

SA Nodal Reentry

Atrial Automaticity

AP

Atrioventricular Reciprocating Tachycardia

Atrial Fibrillation

AV Node or

or

AV Nodal Reentry

Junctional Automaticity

FIGURE 47-1  Representation of the mechanisms and electrocardiographic characteristics of the more common supraventricular tachyarrhythmias. AP, Accessory pathway; AV, atrioventricular; ECG, electrocardiogram; LAF, left anterior fascicle; LBB, left bundle branch; LPF, left posterior fascicle; RBB, right bundle branch; SA, sinoatrial. (From Bonagura JD: Kirk’s current veterinary therapy XIII, ed 13, Philadelphia, 2000, Saunders.)

SA Node -Blockers Calcium channel blockers Digitalis Class III AV Node Digoxin -Blockers Calcium channel blockers Class III Class IC Adenosine

Atrial Myocardium Class IA Class IC Class III Accessory Pathway Class IA Class IC Class III

FIGURE 47-2  Sites of action for various antiarrhythmic drugs, highlighting their utility for specific supraventricular tachyarrhythmias. AV, Atrioventricular; SA, sinoatrial. (From Bonagura JD: Kirk’s current veterinary therapy XIII, ed 13, Philadelphia, 2000, Saunders.)

hemodynamic compromise. In atrial tachyarrhythmias, such agents will not terminate the arrhythmia but will slow conduction to the ventricles. Intravenous calcium channel blockers, β-blockers, or adenosine have been used for this purpose. Blood pressure and ECG should be monitored before and throughout the procedure. A comparison of the electrophysiologic and hemodynamic responses of intravenous diltiazem, esmolol, and adenosine in normal dogs demonstrated the superior efficacy of intravenous diltiazem in slowing AV nodal conduction while maintaining a favorable hemodynamic profile.11 Esmolol was a significantly less effective negative dromotrope than diltiazem and caused a severe drop in left ventricular contractility measurements at dosages that did prolong AV nodal conduction. Adenosine, even at dosages of 2 mg/kg, was ineffective in slowing canine AV nodal conduction. A similar study has not been performed in cats. Diltiazem is administered at dosages of 0.125 to 0.35 mg/kg intravenously (IV) slowly over 2 to 3 minutes in dogs (Box 47-1).1,12 A constant rate infusion (CRI) (0.125 to 0.35 mg/kg/hr) can be used if frequent recurrence of the arrhythmia occurs before the onset of efficacious oral antiarrhythmic therapy. Esmolol is an ultrashort-acting β1-selective blocker that typically is administered at 0.5 mg/kg IV over 1 to 2 minutes.1 Its brief half-life

CHAPTER 47  •  Supraventricular Tachyarrhythmias

BOX 47-1 

Emergency Therapy for Supraventricular Tachycardia in Dogs

Diltiazem • Intermittent Dosing: 0.125 to 0.35 mg/kg slowly IV over 2 to 3 minutes • CRI: 0.125 to 0.35 mg/kg/hr if frequent reoccurrence

compared with that of propranolol makes esmolol the preferred parenteral β-blocker. It should nonetheless be used very cautiously in animals with impaired ventricular systolic function, because it will markedly depress ventricular contractility. The calcium ion is critical for a number of cardiovascular functions. These include impulse formation within the sinoatrial node, conduction through the AV node, and excitation-contraction coupling in cardiac and vascular smooth muscles. Overdosage of calcium channel blockers can therefore result in hypotension, negative chronotropy caused by impaired discharge from the sinus node, negative dromotropy as a result of impaired AV nodal conduction, negative inotropy (decreased contractility), and impaired insulin release. The latter will cause blood glucose concentrations to rise while depleting intracellular calcium stores. The effects on the peripheral vasculature, cardiac muscle, and pancreatic β cells all can lead to hemodynamic collapse with high doses of calcium channel blockers. There are two types of β receptors, β1 and β2. β1 Receptors are located primarily within the heart and adipose tissue. The effects of β1-receptor stimulation occur through coupling of β1 receptors with adenyl cyclase, resulting in enhanced cyclic AMP production. This results in (1) increased heart rate secondary to stimulation of the funny current (If ) and L-type calcium current; (2) enhanced myocardial contractility through L-type calcium current influx stimulating increased sarcoplasmic reticular calcium release; (3) improved myocardial relaxation through phosphorylation of phospholamban; and (4) enhanced automaticity of subsidiary pacemakers.13 β2 receptors are found primarily in bronchial and smooth muscles, where they produce relaxation. Overdosage of β-blocking drugs therefore can produce severe bradyarrhythmias, impaired atrial and ventricular contractility, bronchospasm, and decreased glycogenolysis, lipolysis, and gluconeogenesis. Other agents can prolong the effective refractory period or slow conduction within the myocardium, including an accessory pathway or atrial myocardium. These agents can terminate both atrial and AV node–dependent tachyarrhythmias. Of these, procainamide is the agent most commonly used in veterinary medicine. A sodium and potassium channel blocker, procainamide decreases abnormal automaticity, slows conduction, and prolongs the effective refractory period in atrial (and ventricular), accessory pathway, and retrograde fast AV nodal tissue. In atrial tachyarrhythmias, other agents are used first to slow AV nodal conduction before administration of procainamide. Parenteral procainamide is administered in dosages of 6 to 8 mg/kg IV over 5 to 10 minutes or 6 to 20 mg/kg intramuscularly (IM) in dogs. A CRI of 20 to 40 mcg/kg/min can be used once a therapeutic response is obtained with bolus administration. Parenteral procainamide in cats is used cautiously at dosages of 1 to 2 mg/ kg IV or 3 to 8 mg/kg IM and a CRI of 10 to 20 mcg/kg/min. A precordial thump is a simple, brief procedure that has a low rate of success but has been used to successfully convert an SVT to sinus rhythm.10,14 A sharp, concussive blow is delivered to the left precordium with the animal in right lateral recumbency. This will result in myocardial depolarization that could disrupt a reentrant tachycardia circuit. In addition to being a therapeutic procedure, it can be a diagnostic one in the case of wide complex tachycardias by allowing the clinician to see the morphology of the QRS complex

during sinus rhythm. Unfortunately, often sinus rhythm will only last for a short time, so drug therapy or other intervention must be at the ready. Direct current (DC) cardioversion or overdrive pacing can be used to terminate certain hemodynamically unstable, sustained SVTs.12 DC cardioversion in a proper critical care environment with appropriate hemodynamic and electrocardiographic monitoring offers certain distinct advantages over emergency drug therapy. The need to distinguish between supraventricular and ventricular tachyarrhythmias to design appropriate drug therapy is less important when DC cardioversion is employed. Sinus rhythm may be restored immediately with successful DC cardioversion, avoiding the slower titration and potential side effects seen with parenteral drug administration. The need for general anesthesia (albeit brief) is a risk factor for DC cardioversion but should not preclude its use in patients who would benefit from it. Biphasic cardioversion is more effective than using monophasic waveforms. DC cardioversion and overdrive pacing are effective in terminating SVTs caused by reentry rather than abnormal automaticity. Overdrive pacing can be performed without general anesthesia if the patient is depressed or moribund. The jugular furrow can be locally anesthetized with lidocaine, a catheter introducer placed in the external jugular vein, and a multipolar catheter guided fluoroscopically into the right atrium (for intraatrial reentry) or ventricle (more effective for terminating orthodromic AV reciprocating tachycardia). The distal and second poles of this catheter are then attached to a programmable pacemaker. An electrophysiologic recorder (ideal but not necessary) or multilead surface ECG is used to continuously record cardiac electrical activity. Once the myocardium is captured, the pacing rate is increased to 10 to 20 beats/min faster than the tachyarrhythmia rate. One-to-one capture is ensured for a brief period, and then pacing is stopped once intracardiac electrograms confirm termination of the SVT. If only the surface ECG is recorded, pacing is stopped after a brief period to determine if the tachyarrhythmia terminated. If not, a longer period or slightly faster pacing rate is used. Failure to terminate or rapid resumption of the tachyarrhythmia can indicate either an SVT caused by an automatic mechanism or successful termination but then rapid reinitiation of a reentrant SVT.

Long-Term Therapy Medical treatment Long-term antiarrhythmic drug therapy must be tailored to each patient based on the type of SVT, the presence or absence of congestive heart failure or significant structural heart disease, comorbid conditions (particularly hepatic or renal dysfunction, acid-base disturbances, or endocrine diseases that alter the metabolism of specific antiarrhythmic drugs), and concurrent drug administration. Atrial tachyarrhythmias typically are managed by dual antiarrhythmic therapy, one drug to slow AV nodal conduction and a second to terminate the atrial tachyarrhythmia itself. This general rule is violated when persistent atrial fibrillation is present, when rate control typically becomes the goal. The other option with atrial fibrillation, however, is to cardiovert it to sinus rhythm using a biphasic defibrillator and use antiarrhythmic drug therapy to try to maintain sinus rhythm.15 AV node–dependent tachyarrhythmias occasionally will respond to single- agent therapy aimed at slowing AV nodal conduction. In reality, however, these tachyarrhythmias most often require combination therapy as well. For instance, with orthodromic AV reciprocating tachycardia, one agent is used to slow AV nodal conduction and a second agent is used to block conduction or prolong the effective refractory period within an accessory pathway. Drugs that slow AV nodal conduction include the classes that were discussed under emergent therapy. The three major classes include: digitalis glycosides, calcium channel blockers, and β-blockers.

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Animals with systolic dysfunction classically are placed on digoxin as a first-line negative dromotrope (0.005 to 0.01 mg/kg PO q12h in a normokalemic dog with normal renal function; 0.0312 mg PO q24-48h in a normokalemic cat with normal renal function). The ventricular rate is almost never slowed adequately with digoxin as a single agent, however, and other drugs must be added. The calcium channel blocker diltiazem is effective in prolonging the effective and functional refractory periods of the AV node. This effect is most notable at faster stimulation rates (use dependence) and in depolarized fibers (voltage dependence).16 Diltiazem has gained preference over verapamil because of its more favorable hemodynamic profile (i.e., minimal negative inotropic effect) at effective antiarrhythmic dosages. Standard diltiazem is administered three times a day, which can be difficult from a compliance standpoint. Sustained release preparations appear to have more variable absorption in companion animals, with resultant poorer arrhythmia control. Dilacor XR has been used successfully in dogs at 2 to 5 mg/kg PO q12h. These preparations can have a higher incidence of side effects in cats, including vomiting, inappetence, and hepatopathies.12 A randomized, crossover study in 18 clinical dogs showed that the combination of digoxin and diltiazem produced better ventricular rate control in atrial fibrillation than either agent alone.17 Atenolol is a relatively β1-selective blocker that competitively inhibits the effects of catecholamines on cardiac β receptors. Thus underlying sympathetic tone plays an important role in determining the effectiveness of atenolol in prolonging AV nodal conduction and refractoriness or suppressing abnormal atrial foci.16,18 Because of its negative inotropic effects, the dosages required to significantly affect AV nodal conduction are often not well tolerated by animals with ventricular systolic dysfunction. The beneficial effects of β-adrenergic blockade in the face of impaired ventricular systolic function have been well demonstrated in human patients; therapy must begin at very low dosages and up-titration performed very slowly.16 Patients with rapid SVTs do not have the luxury of this prolonged time for control of their ventricular rate. One must remember that the rapid ventricular rate is either worsening or may be the sole cause for their myocardial dysfunction. Atenolol is particularly useful in cats with hypertrophic cardiomyopathy and SVTs. Because of its renal clearance, the dosage of atenolol should be decreased in the face of concurrent renal failure. Class I antiarrhythmic drugs block fast sodium channels and thus suppress abnormal automaticity and slow myocardial conduction velocity. Oral procainamide typically was used as an extended release preparation. Such preparations are no longer available, however, thus removing them from our armamentarium of effective antiarrhythmic drugs. The need for 2-hour to 6-hour dosing of formulations that are not extended release makes compliance nearly impossible. GI side effects can be prominent, and proarrhythmia is a definite concern with long-term procainamide therapy. Mexiletine, a class IB agent, can be useful as a component of multidrug therapy for some canine SVTs (some accessory pathways are sensitive to class IB agents, as are rare atrial tachyarrhythmias). It is used at 4 to 8 mg/kg PO q8h with food in dogs. Because of its side effect profile, it is not used in cats. Class III antiarrhythmic agents are used to prolong the effective refractory period of atrial myocardium and accessory pathways. Sotalol and amiodarone, the two agents used in small animals, have additional antiarrhythmic actions, including slowing of AV nodal conduction. Sotalol typically is administered at 1 to 3 mg/kg PO q12h on an empty stomach for SVTs, but amiodarone dosing varies and typically includes a loading period.12 The author uses 15 mg/kg q24h for 7 to 10 days, then 10 mg/kg q24h for 7 to 10 days, then 5 to 8 mg/ kg q24h for maintenance. Serum amiodarone levels can be measured but may not correlate with tissue concentrations. The high incidence

of reported extracardiac side effects in dogs receiving long-term amiodarone therapy has limited its widespread use.12,19 Amiodarone has not been used in cats.

Catheter ablation Certain SVTs can be cured, rather than simply controlled, with transvenous radiofrequency catheter ablation.8,20-23 The tachyarrhythmia circuit is first mapped with numerous multielectrode catheters. Once, for example, an accessory pathway is identified, detailed mapping is used to locate precisely the atrial and ventricular insertions of the pathway along the AV groove. The distal electrode (4 mm to 5 mm) of a specialized catheter is positioned at the critical site, and radiofrequency energy is delivered to the tip electrode, causing thermal dessication of a small volume of tissue to permanently interrupt the tachycardia circuit. This technique has successfully been used by this author and others in a large number of canine cases, with long-term follow-up documenting that these dogs are, in fact, cured.

REFERENCES 1. Wright KN: Assessment and treatment of supraventricular tachyarrhythmias. In Bonagura JD, editor: Kirk’s current veterinary therapy XIV, St Louis, 2009, Saunders Elsevier. 2. Wathen MS, Klein GJ, Yee R, et al: Classification and terminology of supraventricular tachycardia, Cardiol Clin 11:109, 1993. 3. Walker NL, Cobbe SM, Birnie DH: Tachycardiomyopathy: a diagnosis not to be missed, Heart 90:e7, 2004. 4. Salemi VM, Arteaga E, Mady C: Recovery of systolic and diastolic function after ablation of incessant supraventricular tachycardia, Eur J Heart Fail 7:1117, 2005. 5. Houmsse M, Tyler J, Kalbfleisch S: Supraventricular tachycardia causing heart failure, Curr Opin Cardiol 26:261, 2011. 6. Lishmanov A, Chockalingam P, Senthilkumar A, et al: Tachycardiainduced cardiomyopathy: evaluation and therapeutic options, Cong Heart Fail 16:122, 2010. 7. Knight BP, Jacobsen JT: Assessing patients for catheter ablation during hospitalization for acute heart failure, Heart Fail Rev 16:467, 2011. 8. Wright KN, Mehdirad AA, Giacobe P, et al: Radiofrequency catheter ablation of atrioventricular accessory pathways in three dogs with subsequent resolution of tachycardia-induced cardiomyopathy, J Vet Intern Med 13:361, 1999. 9. Miller JM, Hsia HH, Das M: Differential diagnosis for wide QRS complex tachycardia. In Zipes DP, Jaliffe J, editors: Cardiac electrophysiology: from cell to bedside, ed 5, Philadelphia, 2009, Saunders Elsevier. 10. Santilli RA, Diana A, Baron Toaldo M: Orthodromic atrioventricular reciprocating tachycardia conducted with intraventricular conduction disturbance mimicking ventricular tachycardia in an English Bulldog, J Vet Cardiol 14:363, 2012. 11. Wright KN, Schwartz DS, Hamlin R: Electrophysiologic and hemodynamic responses to adenosine, diltiazem, and esmolol in dogs, J Vet Intern Med 12:201, 1998. 12. Côté E: Electrocardiography and cardiac arrhythmias. In Ettinger S, Feldman B, editors: Textbook of veterinary medicine, ed 7, St Louis, 2010, Elsevier. 13. Opie LH, Horowitz JD: Beta-blocking agents. In Opie LH, Gersch BJ, editors: Drugs for the heart, ed 7, Philadelphia, 2009, Elsevier. 14. Jan SL, Fu YC, Lin MC, et al: Precordial thump in a newborn with refractory supraventricular tachycardia and cardiovascular collapse after amiodarone administration, Eur J Emerg Med 19:128, 2012. 15. Bright JM, zumBrunnen J: Chronicity of atrial fibrillation affects duration of sinus rhythm after transthoracic cardioversion of atrial fibrillation to sinus rhythm, J Vet Intern Med 22:114, 2008. 16. Miller JM, Zipes DP: Therapy of cardiac arrhythmias. In Braunwald E, Zipes DP, Libby P, Bonow RO, editors: Braunwald’s heart disease: a textbook of cardiovascular medicine, ed 7, Philadelphia, 2005, Saunders. 17. Gelzer AR, Kraus MS, Rishniw M, et al: Combination therapy with digoxin and ditiazem controls ventricular rate in chronic atrial fibrillation in dogs better than digoxin or diltiazem monotherapy: a randomized, crossover study in 18 dogs, J Vet Intern Med 23:499, 2009.

18. Opie LH, Poole-Wilson PA: β-Blocking agents. In Opie LH, Gersch BJ, editors: Drugs for the heart, ed 7, Philadelphia, 2009, Elsevier. 19. Kraus MS, Ridge LG, Gelzer ARM, et al: Toxicity in Doberman Pinscher dogs with ventricular arrhythmias treated with amiodarone, Proceedings of the 23rd American College of Veterinary Internal Medicine Forum, Baltimore, June 2005. 20. Wright KN: Interventional catheterization for tachyarrhythmias, Vet Clin North Am Small Anim Pract 34:1171, 2004.

21. Wright KN, Knilans TK, Irvin HM: When, why, and how to perform radiofrequency catheter ablation, J Vet Cardiol 8:95, 2006. 22. Santilli RA, Spadacini G, Moretti P, et al: Anatomic distribution and electrophysiologic properties of accessory pathways in dogs, J Am Vet Med Assoc 231:393, 2007. 23. Santilli RA, Perego M, Perini A, et al: Electrophysiologic characteristics and topographical distribution of focal atrial tachycardia in dogs, J Vet Intern Med 24:539, 2009.

CHAPTER 48  •  Ventricular Tachyarrhythmias

CHAPTER 48  VENTRICULAR TACHYARRHYTHMIAS Romain Pariaut,

DVM, DACVIM (Cardiology), DECVIM-CA (Cardiology)

KEY POINTS • Wide QRS complex tachycardia with atrioventricular dissociation, fusion beats, and capture beats are electrocardiographic features diagnostic of ventricular tachycardia (VT). • Clinical signs secondary to VT are determined by its rate and duration. • The most common noncardiac causes of VT are hypoxemia, electrolyte imbalances (hypokalemia), acid-base disorders, and drugs. • The most common cardiac diseases associated with clinical VT are arrhythmogenic cardiomyopathy in boxers and dilated cardiomyopathy in Doberman Pinschers. • Antiarrhythmic medications do not prevent sudden death. • Antiarrhythmic therapy is initiated if clinical signs associated with VT are present. • When the origin (supraventricular or ventricular) of a wide QRS tachycardia cannot be determined, it must be managed as if it were VT. • Lidocaine is the first-choice parenteral antiarrhythmic drug for treatment of VT in dogs.

INTRODUCTION Physiologically, specialized ventricular cells known as Purkinje fibers may work as a pacemaker when the sinus and atrioventricular nodes fail to function appropriately, resulting in a ventricular escape rhythm or idioventricular rhythm at a rate of about 30 to 40 beats/min in dogs and 60 to 130 beats/min in cats.1,2 Three arrhythmogenic mechanisms known as enhanced automaticity, triggered activity, and reentry (Box 48-1) may affect Purkinje cells or any excitable ventricular myocyte and result in ventricular tachycardia (VT).3 They result in a ventricular rhythm faster than the physiologic idioventricular rhythm. Most human cardiologists define VT as three or more consecutive ventricular beats occurring at a rate faster than 100 beats/ min, the conventional upper limit for normal sinus rhythm. In our patients, normal sinus rhythm can probably reach 150 to 180 beats/ min in dogs and 220 beats/min in cats. These rates define the lower

BOX 48-1 

Electrophysiologic Mechanisms of Ventricular Tachycardia

Reentry: Requires an impulse to leave a point of departure and return to its starting point with a sufficient delay that the cardiac tissue has recovered its excitability. It usually circles around an area of nonconductive tissue (fibrosis, vessel). Shortening of the refractory period and slow conduction favor this selfperpetuating mechanism. Enhanced automaticity: Any myocardial cell can acquire the property of spontaneous depolarization when its environment is altered. Its membrane potential becomes less negative, which gives it the ability to generate an action potential similar to that of the sinus node. Triggered activity: Results from small membrane depolarizations that appear after and are dependent on the upstroke of the action potential. They trigger an action potential when they reach the threshold potential. When they occur during the process of repolarization they are called early afterdepolarizations (EADs), and when they occur after full repolarization they are called delayed afterdepolarizations (DADs). Hypokalemia and drug-induced prolongation of the QT segment increase the risk of EADs. DADs occur secondary to intracellular calcium overload associated with sustained tachycardia and digoxin toxicity.

limit for VT. If a ventricular rhythm is faster than the physiologic idioventricular rhythm and slower than VT, it is called accelerated idioventricular rhythm (AIVR). The rate of an AIVR is within the range of the underlying sinus rhythm. Therefore both rhythms are seen competing on a surface electrocardiogram (ECG) because the faster pacemaker inhibits the slower one, a property known as overdrive suppression.2 Besides rate, an important feature of VT is duration because both determine the clinical consequences of the arrhythmia. VT is described as nonsustained if it lasts less than 30 seconds and sustained if it lasts longer. Nonsustained VT is usually asymptomatic because of its short duration. The terms

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incessant VT and VT storm are used to describe recurrent episodes of sustained VT during a 24-hour period. VT storm is a life-threatening emergency.

ELECTROCARDIOGRAPHIC DIAGNOSIS In the intensive care unit, VT is first suspected on physical examination or detected on a continuous ECG monitor. Confirmation of VT relies on a good-quality 6-lead surface ECG recording with the patient placed in right lateral recumbency. Ventricular tachycardia is identified as a broad QRS tachycardia with complexes wider than 0.06 second in dogs and 0.04 second in cats. Each QRS complex is followed by a large T wave, directed opposite to the QRS deflection. The challenge of ECG interpretation is to differentiate VT from supraventricular tachycardias (SVTs) with broad QRS complexes because of aberrant conduction of the electrical impulse within the ventricles. Aberrant ventricular conduction results from a structural bundle branch block, a functional or rate-related bundle branch block, or finally an accessory atrioventricular pathway causing preexcitation.4 However, it is important to remember that VT is much more common than broad QRS complex SVT in dogs and cats. The three most reliable diagnostic criteria of VT are atrioventricular dissociation, fusion beats, and capture beats (Figure 48-1). Atrioventricular dissociation is demonstrated when P waves are occasionally seen on the ECG tracing but are not related to ventricular complexes. These P waves reflect atrial activity independently from the ventricle. On occasion apparent atrioventricular association may be seen, or ventricular beats can conduct in a retrograde fashion to the atrium in a 1 : 1 ratio. Therefore signs of atrioventricular association do not rule out VT. Fusion beats and capture beats are seen with paroxysmal VT and AIVR. Fusion beats result from the summation of a ventricular impulse and a simultaneous supraventricular impulse resulting in a QRS complex of intermediate morphology and preceeded by a P wave (unless there is concurrent atrial fibrillation). A capture beat is a supraventricular impulse conducting through the normal conduction pathways to the ventricle during an episode of

F

V

p

VT or AIVR. This complex occurs earlier than expected and is narrow if the conduction system is intact.4 Regularity of the rhythm is a less accurate criterion because VT can be slightly irregular. When the RR interval varies by 100 msec or more, it is suggestive of atrial fibrillation with aberrant ventricular conduction. Other criteria have been suggested by human cardiologists to make the correct diagnosis; for example, QRS complexes are usually wider with VT than with SVT.4 Although rarely effective, vagal maneuvers can be done to slow the atrioventricular conduction, revealing P waves associated to the QRS complexes in case of SVT. It is also important to consider the overall clinical picture. For example, Boxers and Doberman Pinschers usually have VT. Finally, it is accepted that managing SVT as VT is usually less dangerous than the opposite, because drugs used to stop SVT or to slow the ventricular response rate to rapid atrial impulses (i.e., calcium channel blockers and β-blockers) do not interrupt VT and worsen hypotension with their vasodilatory or negative inotropic effects. If doubt persists, a wide complex tachycardia should be treated as if it were VT.

APPROACH TO THE PATIENT WITH VENTRICULAR TACHYCARDIA Once VT is confirmed on a surface ECG, the possible causes for the initiation and maintenance of the arrhythmia must be identified. The knowledge will help in planning an effective treatment protocol and predicting the short-term and long-term prognoses. It is useful to differentiate cardiac from noncardiac causes of VT.

Noncardiac Causes of Ventricular Tachycardia Ventricular cells are sensitive to hypoxemia, electrolyte and acid-base imbalances, sympathetic stimulation, and various drugs. These changes typically affect the passive and energy-dependent ion exchanges across the cellular membrane of the myocyte during the initiation and propagation of the action potential. Hypokalemia is the most commonly reported electrolyte disturbance responsible for or contributing to VT. It increases phase 4

C

S

FIGURE 48-1  Electrocardiographic recording from a dog; paper speed is 25 mm/sec. There is ventricular tachycardia (V) at a rate of 150 beats/min. P waves (p) not related to the wide QRS complexes (V) indicate atrioventricular (AV) dissociation. There are fusion beats (F) with an intermediate morphology and capture beats (C). Note that the PR interval of the capture beat is prolonged compared with a normal sinus beat (S). It results from retrograde depolarization of the AV node by the preceding ventricular impulse and secondary slowing of the propagation of the sinus impulse in a partially refractory node, a phenomenon known as concealed AV conduction.

CHAPTER 48  •  Ventricular Tachyarrhythmias

depolarization, increasing spontaneous automaticity, and prolongs the action potential duration, which promotes arrhythmias from triggered activity.5 Because digoxin competes with potassium on its receptors, hypokalemia increases the risk of digoxin toxicity. Similar arrhythmias result from hypomagnesemia, because magnesium is necessary for proper functioning of the sodium-potassium ATP pump, which maintains normal intracellular potassium concentration. Hypocalcemia and hypercalcemia are also responsible for ventricular arrhythmias. Increased adrenergic tone potentiates arrhythmias through various mechanisms. In the intensive care unit, drugs with sympathetic or sympatholytic activity are used commonly and should be stopped when possible to assess their role in the perpetuation of VT. It is also important to evaluate the potential proarrhythmic effects of all the medications given to a patient with VT. There are many publications on drug-induced prolongation of the QT segment. Prolongation of the QT segment reflects prolongation of the cardiac cell membrane repolarization and indicates a risk of ventricular arrhythmia from triggered activity. Antiarrhythmic drugs such as procainamide and sotalol, but also domperidone, cisapride, chlorpromazine, and erythromycin, are known to prolong the QT segment. Bradycardia and hypokalemia contribute to this effect on repolarization and increase the risk of VT.6 Oxygen therapy, identification and correction of all electrolyte disturbances, and discontinuation of proarrhythmic medications are the initial and necessary first steps in the treatment of all patients with VT.

Cardiac Causes of Ventricular Tachycardia In most patients with VT an echocardiogram is indicated as soon as possible to identify an underlying cardiac disease as the cause for the arrhythmia. In humans the association of sustained VT and heart failure is a marker of increased risk of sudden death from arrhythmia, and this is probably true in our patients as well.7 Identification of cardiac disease may help to elaborate an effective treatment strategy, to know what to expect from the intervention, and to give the most accurate prognosis to the owner. Today there is valuable information on some breed-specific VTs. VT is on occasion observed in patients with cardiac tumors (with or without associated tamponade), myocarditis, endocarditis, and ischemia. VT is an important part of the clinical picture of dilated cardiomyopathy in some breeds. The prevalence of ventricular arrhythmias was 21% in a pool of breeds with dilated cardiomyopathy, 16% in Newfoundlands, and 92% in Doberman Pinschers. The natural history of the disease has been studied extensively in Doberman Pinschers. There is an occult stage of the disease with no clinical signs but with echocardiographic indicators of left ventricular dysfunction and a risk of sudden death of approximately 30%. It can last 2 to 4 years. In the overt stage of the disease, congestive heart failure is present and the risk of sudden death is about 30% to 50%. In Doberman Pinschers, most ventricular ectopies have a right bundle branch block morphology in lead II of the surface ECG, indicating their origin in the left ventricle.8 Cardiomyopathy of Boxers is known as arrhythmogenic right ventricular cardiomyopathy (ARVC). It is an adult-onset disease with a concealed form characterized by occasional ventricular ectopies only, followed by an overt form with VT associated with exercise intolerance and collapse. On occasion myocardial failure is observed. In ARVC, ventricular ectopies typically have a left bundle branch block morphology, indicating their right-sided origin.9 Recently it was shown that the disease not only affects the right ventricle but also the left ventricle and the atria. It is therefore not unusual to observe VT

originating from the left side and supraventricular arrhythmias in these dogs.10,11 An inherited ventricular arrhythmia has been identified in some German Shepherds. In the most severe form of the disease these dogs have a propensity for sudden death until 18 months of age. The form of VT responsible for sudden death is polymorphic, rapid (>300 beats/min), nonsustained, and usually preceded by a pause.12 Dogs with severe subaortic stenosis and pulmonic stenosis are prone to syncope and sudden death. VT progressing to ventricular fibrillation may contribute to some of these episodes. In cats, VT may be seen in association with idiopathic hypertrophic cardiomyopathy and with concentric hypertrophy secondary to hypertension and hyperthyroidism.

ANTIARRHYTHMIC TREATMENT Decision to Treat Antiarrhythmic agents are indicated to treat symptomatic VT and prevent its recurrence. Despite many large-scale randomized studies in humans and a few publications in veterinary medicine, there is no indication that antiarrhythmic agents can prevent sudden death and on some occasions they may precipitate it.7 Hemodynamic compromise usually is associated with rapid (>200 beats/min) and sustained VT in a patient with concurrent cardiac disease. Slower nonsustained VT and AIVR are usually auscultatory or ECG findings in patients with motor vehicle–related trauma, gastric dilation-volvulus, or metabolic imbalances and resolve spontaneously, with no antiarrhythmic medications, within 4 days.13 Some ECG characteristics of VT are viewed as indicators of an increased risk for sudden death and may influence the decision of the clinician toward treatment. Hemodynamic collapse is more likely to result from polymorphic VT, which is characterized by a continuously changing QRS complex pattern, than monomorphic VT. Antiarrhythmic agents are generally considered for sustained VT with rates greater than 180 to 200 beats/min. The presence of polymorphic VT may encourage treatment at the lower rate range. R-on-T phenomenon describes the superimposition of an ectopic beat on the T wave of the preceding beat, also known as the “vulnerable period.” Some observations suggest that it may represent an increased risk for VT and sudden death from ventricular fibrillation. In an experimental study in dogs, ventricular fibrillation could be reliably induced by delivering an electrical impulse on the peak of T wave seen from lead II on the surface ECG.14 However, ECG recordings collected from implantable cardiac defibrillators in human patients showed that ventricular tachycardia was as likely to be initiated by a late-occuring ventricular premature complex because it was from one originating on the T wave.15 In veterinary patients, strong evidence is lacking and this finding by itself cannot justify treatment. Regardless of its cause, rate, duration, or morphology, the decision to treat VT with antiarrhythmic medications must be dictated primarily by the clinical signs related to it.

Antiarrhythmic Drugs A few antiarrhythmic agents will manage most VTs. Because studies in veterinary medicine are lacking and antiarrhythmic medications are complex drugs with many side effects, including proarrhythmic effects, it is important to gain experience with only a few commonly used drugs.

Lidocaine Lidocaine is the first-choice intravenous agent to control VT. It works better on rapid VTs and in normokalemic animals. In dogs, boluses

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of 2 mg/kg can be repeated every 10 to 15 minutes. A maximum dose of 8 mg/kg/hr is recommended to avoid neurotoxic effects. The arrhythmia can be controlled over time with a continuous infusion of lidocaine at a rate between 25 and 80 mcg/kg/min. In cats, the safety margin is smaller and lower dosages of lidocaine can be used but β-blockers usually are preferred. Mexiletine has properties similar to those of lidocaine and is available as an oral medication. Mexiletine, 4 to 8 mg/kg q8h, combined with atenolol, 0.5 to 1 mg/kg q12-24h PO, has been shown to control VT in boxers with ARVC.9,14

Procainamide Procainamide is used intravenously for VTs that do not respond to lidocaine. A bolus of 10 to 15 mg/kg over 1 to 2 minutes can be followed by a constant rate infusion at 25 to 50 mcg/kg/min. Rapid intravenous injection can cause hypotension. Long-term management of VT can be attempted with oral procainamide at 10 to 20 mg/ kg q6h (or q8h if the sustained-release form is used).14

β-Blockers Sympathetic activation has been implicated in the pathogenesis of ventricular arrhythmia. Alternatively, sustained VT causing hemodynamic instability increases circulating cathecolamine concentration. β-Blockers provide adrenergic system blockade and may help control arrhythmias. Esmolol is a short-acting β-blocker that can help control sympathetically driven VTs such as those associated with pheochromocytoma or thyrotoxic disease in cats, but its negative inotropic effects may be too pronounced in some patients and cause cardiovascular collapse. Esmolol should be injected slowly (0.2 to 0.5 mg/kg IV over 1 minute) because its effects dissipate within minutes after administration. Propranolol, a nonselective β-blocker, is the preferred β-blocker for the treatment of VT storm in human patients.16 It is administered intravenously at a dose of 0.02 mg/kg.

Sotalol Sotalol is an oral medication that is very effective at controlling VT. It is the main antiarrhythmic drug for long-term management of VT, especially in Boxers with arrhythmogenic cardiomyopathy.9,17 In addition, the author often administers sotalol at 1 to 2 mg/kg PO to restore sinus rhythm in dogs with VT refractory to lidocaine and procainamide. Many dogs respond successfully within a few hours of oral sotalol administration.

Amiodarone The author has only limited experience with intravenous amiodarone at a slow intravenous bolus of 5 mg/kg over 10 minutes in the setting of ventricular arrhythmias. When administering amiodarone intravenously, it is common that anaphylaxis-like reactions (urticaria, facial edema) occur; careful monitoring is required. These side effects can be treated with antihistamine and steroid injections.18

Magnesium sulfate There are anecdotal accounts of the use of intravenous magnesium sulfate as an adjunct to other antiarrhythmic therapy in dogs with ventricular tachycardia. Although some experimental dog studies have evaluated magnesium therapy in prolonged QT syndrome,19 there are no studies evaluating the efficacy of magnesium therapy in dogs with spontaneously occurring ventricular tachycardia. Currently in human medicine there are reports of magnesium sulfate therapy aiding the treatment of ventricular tachycardia caused by various therapeutic drug overdoses, but it is not considered mainstream antiarrhythmic therapy. The role of magnesium therapy in veterinary clinical patients remains to be defined.

Other Treatments Anesthesia

Sedation and anesthesia may be used to decrease high sympathetic output contributing to VT maintenance. Sedation is recommended for the management of VT storm in human patients. Benzodiazepines and short-acting anesthetics such as propofol have been used.16

Electrical therapies

Rapid pacing is indicated to overdrive suppress some ventricular arrhythmias. In German Shepherds with inherited ventricular arrhythmias, bradycardia and pauses increase the risk of polymorphic VT. Therefore, atrial or ventricular pacing can be used to maintain a regular and faster heart rate, which prevents periods of slower rate and initiation of VT. Finally, when antiarrhythmics fail to control ventricular tachycardia, the arrhythmia can be terminated via synchronized electrical cardioversion or defibrillation. Electrical therapies for the management of ventricular tachyarrhythmias are detailed in Chapter 204 of this book.

POSTINTERVENTION MONITORING Because the response to antiarrhythmic agents cannot be predicted, continuous ECG monitoring is essential after the medication is started and for a minimum of 24 hours. It will give valuable information on the control of the arrhythmia and the possible proarrhythmic effects of the drugs. Twenty-four-hour Holter recording is more adapted to long-term management of the arrhythmia.

REFERENCES 1. Opie LH: Pacemakers, conduction system and electrocardiogram. In Opie LH, editor: The heart physiology, from cell to circulation, ed 3, Philadelphia, 1998, Lippincott-Raven. 2. Kittleson MD: Diagnosis and treatment of arrhythmias (dysrhythmias). In Kittleson MD, Kienle RD: Small animal cardiovascular medicine, ed 1, St Louis, 1998, Mosby. 3. Marriott HJL, Boudreau Conover M: Arrhythmogenic mechanisms and their modulation. In Marriott HJL, Boudreau Conover M, editors: Advanced concepts in arrhythmias, ed 3, St Louis, 1998, Mosby. 4. Brady WJ, Skiles J: Wide QRS complex tachycardia: ECG differential diagnosis, Am J Emerg Med 17:376, 1999. 5. Opie LH: Ventricular arrhythmias. In Opie LH, editor: The heart physiology, from cell to circulation, ed 3, Philadelphia, 1998, Lippincott-Raven. 6. Finley MR, Lillich JD, Gilmour RF Jr et al: Structural and functional basis for the long QT syndrome, J Vet Intern Med 17:473, 2003. 7. Huikuri HV, Castellanos A, Myerburg RJ: Sudden death due to cardiac arrhythmias, N Engl J Med 345:1473, 2001. 8. O’Grady MR, O’Sullivan ML: Dilated cardiomyopathy: an update, Vet Clin North Am Small Anim Pract 34(5):1187-207, 2004. 9. Meurs KM: Boxer dog cardiomyopathy: an update, Vet Clin North Am Small Anim Pract 34(5):1235-1244, 2004. 10. Oxford EM, Danko CG, Kornreich BG, et al: Ultrastructural changes in cardiac myocytes from Boxer dogs with arrhythmogenic right ventricular cardiomyopathy, J Vet Cardiol 13:101, 2011. 11. Vila J, Oxford EM, Saelinger C, et al: Structural and molecular pathology of the atrium of boxer arrhythmogenic cardiomyopathy. Research abstract, J Vet Intern Med 26:714, 2012. 12. Moise NS, Gilmour RF Jr, Riccio ML, et al: Diagnosis of inherited ventricular tachycardia in German Shepherd dogs, J Am Vet Med Assoc 210:403, 1997. 13. Snyder PS, Cooke KL, Murphy ST, et al: Electrocardiographic findings in dogs with motor vehicle-related trauma, J Am Anim Hosp Assoc 37:55, 2001. 14. Pariaut R, Saelinger C, Vila J, et al: Evaluation of shock waveform configuration on the defibrillation capacity of implantable cardioverter defibrillators in dogs, J Vet Cardiol 14:389, 2012.

15. Fries R, Steuer M, Schafers HJ, et al: The R-on-T phenomenon in patients with implantable Cardioverter-defibrillators, Am J Cardiol 91:752, 2003. 16. Eifling M, Razavi M, Massumi A: The evaluation and management of electrical storm, Tex Heart Inst J 38:111, 2011. 17. Moise NS: Diagnosis and management of canine arrhythmias. In Fox PR, Sisson DK, Moise NS, editors: Textbook of canine and feline cardiology: principles and clinical practice, ed 2, St Louis, 1999, WB Saunders.

18. Pedro B, Lopez-Alvarez J, Fonfara S, et al: Retrospective evaluation of the use of amiodarone in dogs with arrhythmias (from 2003 to 2010), J Small Anim Pract 53:19, 2012. 19. Chinushi M, Izumi D, Komura S, et al: Role of autonomic nervous activity in the antiarrhythmic effects of magnesium sulfate in a canine model of polymorphic ventricular tachyarrhythmia associated with prolonged QT interval, J Cardiovasc Pharmacol 48:121, 2006.

CHAPTER 49  •  Myocarditis

CHAPTER 49  MYOCARDITIS Meg Sleeper,

VMD, DACVIM (Cardiology)

KEY POINTS • Myocarditis is an inflammatory process involving the heart. Inflammation may involve the myocytes, interstitium, or vascular tree. • Myocarditis has been associated with a wide variety of diseases. Infectious agents (viral, bacterial, protozoal) may cause myocardial damage by myocardial invasion, production of myocardial toxins, or activation of immune-mediated disease. • Myocarditis can also be associated with physical agents (doxorubicin), underlying metabolic disorders (uremia), toxins (heavy metals), or physical agents (heat stroke).

Myocarditis is a rare cause of heart failure in dogs and cats. Clinical features vary, including those of asymptomatic patients who may have electrocardiographic abnormalities and patients with or without heart enlargement, systolic dysfunction, or even full-blown congestive heart failure (CHF). The patient’s history (i.e., environment and exposure) is often critical in determining likely risk and suggesting appropriate diagnostic tests. Clinical reports of canine myocarditis are most common in immunocompromised or immunonaïve patients.

INFECTIOUS MYOCARDITIS Viral Myocarditis Numerous viruses have been associated with myocarditis in humans. In dogs, viral myocarditis appears most commonly in immunonaïve patients, and the virus most commonly associated with the disease is parvovirus. However, at this time the entity appears to be very rare. In the late 1970s and early 1980s, when the parvovirus pandemic first was recognized, puppies did not receive maternal antibodies and very young puppies developed a fulminant infection with acute death as a result of pulmonary edema when exposed to the virus. Older puppies (2 to 4 months) often died subacutely from CHF, but others developed a milder myocarditis and later developed dilated cardiomyopathy (DCM), usually as young adults. Basophilic

intranuclear inclusion bodies are found in the myocardium of acutely affected younger puppies but may be absent in older puppies.1 Older dogs typically have gross myocardial scarring. Rare cases of parvovirus-induced myocarditis have been reported since the early to mid-1980s. Rarely other viruses have been associated with myocarditis in dogs. In 2001 Maxson and others evaluated myocardial tissue from 18 dogs with an antemortem diagnosis of DCM and 9 dogs with a histopathologic diagnosis of myocarditis based on a polymerase chain reaction analysis to screen for canine parvovirus, adenovirus types 1 and 2, and herpesvirus. Canine adenovirus type 1 was amplified from myocardium of only one dog with DCM and none of the dogs with myocarditis, suggesting these pathogens are not commonly associated with DCM or active myocarditis in the dog.2 Distemper virus–associated cardiomyopathy with a mild inflammatory infiltrate has been produced by experimental infection of immunonaïve puppies.3 Natural infection with West Nile virus was associated with myocarditis in a wolf and a dog in 2002, the third season of the West Nile virus epidemic in the United States.4 Viral genomic deoxyribonucleic acid has also been identified in feline myocardial tissue from patients with hypertrophic cardiomyopathy, DCM, and restrictive cardiomyopathy, suggesting that viral myocarditis may be a factor in these feline-acquired diseases.1

Protozoal Myocarditis Chagas’ disease Chagas’ disease is caused by Trypanosoma cruzi, a protozoal parasite. Chagas’ disease is the leading cause of DCM in humans of Latin America, but it is rare in North America. In North American dogs, Chagas’ disease occurs most commonly in Texas and Louisiana. There have been no reported feline cases in North America. The organism is transmitted by an insect vector (Reduviidae), and reservoir hosts include rodents, raccoons, opossums, dogs, cats, and humans. The trypomastigote is the infective stage, but on entering host cells the organism enters the reproductive stage and becomes an amastigote. Amastigotes multiply until the host cell ruptures.1,5 Dogs with clinical Chagas’ disease have an acute or a chronic syndrome. In the acute stage, circulating trypomastigotes may be seen in a thick blood smear, and most dogs are brought for treatment

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FIGURE 49-1  Electrocardiogram from a mixed breed dog with trichinosis involving the heart. The dog was brought in for collapse caused by complex arrhythmias. Note the ventricular escape beats. An underlying supraventricular tachycardia is likely as well.

because of sudden development of signs of right-sided heart failure (ascites, tachycardia, lethargy). Dogs with chronic Chagas’ disease may enter a quiescent stage free of clinical signs for months or even years. Nervous system damage often causes ataxia and weakness in these patients.1,5

Bacterial and Other Causes of Myocarditis Bacterial myocarditis is possible whenever bacteremia or sepsis is present, with the most common agents being staphylococcal and streptococcal species.1 Myocarditis associated with Citrobacter koseri, an opportunistic pathogen of immunosuppressed human patients, has been described in two 12-week-old sibling Boxer puppies.6 Tyz­ zer’s disease (infection with Bacillus piliformis) was associated with severe necrotizing myocarditis in a wolf-dog hybrid puppy.7 Two cases of feline Streptococcus canis myocarditis have been reported.8,9 Myocarditis has also been recognized secondary to rickettsial organisms such as Rickettsia rickettsii, Ehrlichia canis, and various Bartonella species.1 Myocarditis has been noted in 2 of 12 dogs diagnosed with endocarditis, 11 of which were seroreactive to Bartonella vinsonii subspecies.10 Lymphoplasmacytic myocarditis was observed in 8 cats experimentally infected with Bartonella; however, clinical signs consistent with heart disease were not observed.11 Bartonellae have been implicated as an important cause of endocarditis in humans and dogs. Recently the organism has also been linked to endocarditis in the cat, and a few case reports suggest cats may develop myocarditis associated with Bartonellae as well.12,13 Lyme disease (secondary to infection by the spirochete Borrelia burgdorferi) has been implicated as a cause of myocarditis in dogs, but documented cases are rare. Clinical signs are often vague and nonspecific, and serologic testing is not a reliable method to determine active infection.1 In humans, Lyme myocarditis may be due to direct toxic effects or immunomediated mechanisms, and the disease is usually self-limiting.14 Fungal infections of the myocardium are extremely rare but have occurred in immunocompromised patients.1 A group of cats was described with transient fever and depression that appeared to be infectious in nature. Postmortem examination revealed microscopic lesions consistent with myonecrosis and an inflammatory cell infiltrate. A viral etiology was suspected, but no organism was identified.8 In a retrospective study reviewing 1472 feline necropsies over a 7-year period, 37 cases were diagnosed with endomyocarditis. The cats with endomyocarditis had a mean age at death of 3.4 years, and 62% of them had a history of a stressful event 5 to 10 days before being brought for treatment. Interstitial pneumonia was present in 77% of the cats at postmortem examination. Special stains for bacteria and fungi were negative.15 Parasitic agents can also lead to myocarditis. Toxoplasma gondii bradyzoites can encyst in the myocardium, resulting in chronic infection. Eventually the cysts rupture, leading to myocardial necrosis and hypersensitivity reactions.1 Toxoplasmosis has been reported to be a cause of myocarditis in cats.16 Neospora caninum can infect multiple tissues, including the heart, peripheral muscles, and central nervous system. Clinical signs associated with noncardiac tissues typically predominate; however, collapse and sudden death has been reported in affected dogs.1 Infestation with Trichinella spiralis is a common

BOX 49-1 

Characteristics Suggestive of Myocarditis

• History suggests it is possible (e.g., oncology patient receiving doxorubicin, dog lives in Texas)

• Unusual signalment for heart disease (e.g., Irish Setter, German Shepherd)

• Supportive electrocardiographic findings include conduction abnormalities or arrhythmias

• Supportive echocardiographic findings include myocardial

dysfunction (which may be regional) with or without heart enlargement • Supportive clinical laboratory findings include leukocytosis, eosinophilia, elevated cardiac troponin I levels

cause of mild myocarditis in humans.14 The parasite has been associated with at least one case of canine myocarditis complicated by arrhythmias (Figure 49-1).17

NONINFECTIOUS MYOCARDITIS Doxorubicin Toxicity Doxorubicin cardiotoxicity may be manifested as arrhythmias, myocardial failure, or both. Cardiotoxicity is dosage dependent and irreversible and is more common at cumulative doses exceeding 250 mg/ m2; however, in one study in which only two doses of 30 mg/m2 were administered, 3% of dogs developed cardiomyopathy.1,8 The time to onset of CHF in affected dogs is highly variable. Although pathologic changes have been seen in the feline myocardium after administration, no antemortem echocardiographic or electrocardiographic changes associated with doxorubicin toxicity have been reported. Other causes of noninfectious myocarditis, although rarely recognized in veterinary medicine, include allergic reactions, systemic diseases such as vasculitis, and physical agents such as radiation or heat stroke.14 Numerous chemicals and drugs may lead to cardiac damage and dysfunction. A severe reversible DCM has been observed in humans with pheochromocytoma,14 and similar findings have been observed in experimental animals receiving prolonged infusions of norepinephrine.14 Myocardial coagulative necrosis was found in a dog that died suddenly after an episode of severe aggression, restraint, and sedation for grooming.18 Myocardial lesions were presumed to be caused by catecholamine toxicity. A canine case of immune-mediated polymyositis with cardiac involvement has also been reported.19

DIAGNOSIS Definitive diagnosis, unless the history clearly suggests myocarditis (e.g., doxorubicin toxicity), is elusive (Box 49-1). Supportive clinical laboratory tests include leukocytosis or eosinophilia, particularly in parasitic or allergic myocarditis. Elevated cardiac troponin I levels provide evidence of myocardial cell damage in patients suspected of having myocarditis. If a high suspicion for Chagas’ disease is present,

CHAPTER 49  •  Myocarditis

FIGURE 49-2  Photograph showing a bioptome used for endomyocardial biopsies via intravascular access.

serologic examination for T. cruzi is diagnostic. Demonstration of a rising titer is also helpful to establish the diagnosis of myocarditis associated with T. gondii or N. caninum. Viral and rickettsial testing should be performed if indicated. Blood cultures should be performed if a bacterial cause is suspected. Thoracic radiographs may show normal heart size or heart enlargement with or without evidence of CHF. The electrocardiographic findings may also be varied, and ventricular arrhythmias or conduction disturbances are common. Echocardiography most often demonstrates systolic dysfunction, either global or regional, and cardiac chambers may be normal or increased in size. Endomyocardial biopsy (the gold standard for diagnosis of myocarditis in humans20) may allow definitive antemortem diagnosis (Figure 49-2). However, a focal myocarditis can still be missed because the sample size is small. At postmortem examination, immunohistochemistry or electron microscopy can confirm the diagnosis of N. caninum infection.21 Gross pathology findings may be insignificant, or they may reveal cardiac dilation or ventricular hypertrophy, focal petechiae, and myocardial abscesses.1 Specific findings depend on the underlying etiology. Focal or diffuse myocarditis is definitively diagnosed by histopathology when myocyte necrosis, degeneration, or both are associated with an inflammatory infiltrate.1

TREATMENT Most recommendations for managing myocarditis in dogs and cats are extrapolated from human medicine or research with models of viral myocarditis. Supportive care is the first line of therapy for patients with myocarditis. In those patients with signs of CHF, typical therapy should include preload reduction with diuretics and afterload reduction with angiotensin-converting enzyme inhibitors (see Chapter 40). Digoxin increased expression of proinflammatory cytokines and increased mortality in experimental myocarditis, so it is recommended to be used with caution and at low dosages.20 Intravenous inotropic therapy in the form of dobutamine can be useful if significant systolic dysfunction is present. Alternatively, pimobendan may be beneficial to address systolic dysfunction and reduce afterload. Eliminating unnecessary medications may help reduce the possibility of allergic myocarditis. Results of recent studies suggest that immunosuppression is not routinely helpful in myocarditis patients, but it may have an important role in patients with myocardial dysfunction caused by systemic autoimmune disease.20 Nonsteroidal antiinflammatory agents are contraindicated during the acute phase

of myocarditis in humans (during the first 2 weeks) because they increase myocardial damage. However, they appear to be safe later in the course of disease.14 In a murine model of viral myocarditis, angiotensin-converting enzyme inhibition (with captopril) was beneficial. Similarly, interferon therapy is beneficial in the experimental model of myocarditis and may be useful clinically.14 When diagnosis of acute Chagas’ disease is possible, several agents appear to inhibit T. cruzi; however, by the time a diagnosis is made it is often too late for this approach. Patients with chronic Chagas’ disease are treated symptomatically for CHF. Similarly, successful treatment has been reported using several agents in dogs affected with N. caninum myocarditis, but severely ill dogs often die.1 Clindamycin is the drug of choice for treating clinical toxoplasmosis in dogs and cats; however, significant damage to the heart is irreversible.21 In one report of a cat with presumed toxoplasmosis, signs of heart disease did resolve with clindamycin treatment.22 Dogs with evidence of bacteremia should be treated with antibiotics pending culture and susceptibility results. Empiric treatment should be effective against staphylococcal and streptococcal species (see Chapter 93). Animals with suspected rickettsial disease should be treated with doxycycline (5 to 10 mg/kg PO or IV q12-24h) pending titer results.

REFERENCES 1. Fox PR, Sisson DK, Moise NS, editors: Textbook of canine and feline cardiology: principles and clinical practice, ed 2, St Louis, 1999, WB Saunders. 2. Maxson TR, Meurs KM, Lehmkuhl LB, et al: Polymerase chain reaction analysis for viruses in paraffin-embedded myocardium from dogs with dilated cardiomyopathy or myocarditis, Am J Vet Res 62:130, 2001. 3. Higgins RJ, Krakowka S, Metzler AE, et al: Canine distemper virusassociated cardiac necrosis in the dog, Vet Pathol 18:472, 1981. 4. Lichtensteiger CA, Heinz-Taheny K, Osborne TS, et al: West Nile virus encephalitis and myocarditis in a wolf and dog, Emerg Infect Dis 9:1303, 2003. 5. Kittleson MD: Primary myocardial disease leading to chronic myocardial (dilated cardiomyopathy) and other related diseases. In Kittleson MD, Kienle RD: Small animal cardiovascular medicine, ed 1, St Louis, 1998, Mosby. 6. Cassidey JP, Callanan JJ, McCarthy G, et al: Myocarditis in sibling Boxer puppies associated with Citrobacter koseri infection, Vet Pathol 39:393, 2002. 7. Young JK, Baker DC, Burney DP: Naturally occurring Tyzzer’s disease in a puppy, Vet Pathol 32:63, 1995. 8. Sura R, Hinckley LS, Risatti GR, et al: Fatal necrotizing fasciitis and myositis in cat associated with Streptococcus canis, Vet Rec 162:450, 2008. 9. Matsuu A, Kanda T, Sugiyama A, et al: Mitral stenosis with bacterial myocarditis in a cat, J Vet Med Sci 69:1171, 2007. 10. Breitschwerdt EB, Atkins CE, Brown TT, et al: Bartonella vinsonii subsp berkhoffii and related members of the alpha subdivision of the proteobacteria in dogs with cardiac arrhythmias, endocarditis or myocarditis, J Clin Microbiol 37:3618, 1999. 11. Kordick DL, Brown TT, Shin K, et al: Clinical and pathologic evaluation of chronic Bartonella henselae or Bartonella clarridgeiae infection in cats, J Clin Microbiol 37:1536, 1999. 12. Nakamura RK, Zimmerman SA, Lesser MB: Suspected Bartonellaassociated myocarditis and supraventricular tachycardia in a cat, J Vet Cardiol 13:277, 2011. 13. Varanat M, Broadhurst J, Linder KE, et al: Identification of Bartonella henselae in 2 cats with pyogranulomatous myocarditis and diaphragmatic myositis. Vet Pathology 2012;49:608-61. 14. Wynne JA, Braunwald E: The cardiomyopathies and myocarditides. In Braunwald E, Zipes DP, Libby P, Bonow RO, editors: Braunwald’s heart disease: a textbook of cardiovascular medicine, ed 7, Philadelphia, 2005, Saunders. 15. Stalis IH, Bossbaly MJ, Van Winkle TJ: Feline endomyocarditis and left ventricular endocardial fibrosis, Vet Pathol 32:122, 1999.

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PART IV  •  CARDIAC DISORDERS 16. Dubey JP, Carpenter JL: Histologically confirmed clinical toxoplasmosis in cats: 100 cases (1952-1990), J Am Vet Med Assoc 203:1556, 1993. 17. Sleeper MM, Bissett S, Craig L: Canine trichinosis presenting with high grade second degree AV block, J Vet Intern Med 20:1228, 2006. 18. Pinson DM: Myocardial necrosis and sudden death after an episode of aggressive behavior in a dog, J Am Vet Med Assoc 211:1371, 1997. 19. Warman S, Pearson G, Barret E, et al: Dilation of the right atrium in a dog with polymyositis and myocarditis, J Small Anim Pract 49:302, 2008.

20. Feldman AM, McNamara D: Myocarditis, N Engl J Med 343:1388, 2000. 21. Dubey JP, Lappin MR: Toxoplasmosis and neosporosis. In Green CE, editor: Infectious diseases of the dog and cat, ed 3, St Louis, 2006, WB Saunders. 22. Simpson KE, Devine BC, Funn-Moore D: Suspected toxoplasmosisassociated myocarditis in a cat, J Fel Med Surg 7:203, 2005.

PART V  ELECTROLYTE AND ACID-BASE DISTURBANCES CHAPTER 50  SODIUM DISORDERS Jamie M. Burkitt Creedon,

DVM, DACVECC

KEY POINTS • Most disorders of plasma sodium concentration result from abnormalities in the handling of water rather than sodium. • Plasma sodium concentration is the major determinant of plasma osmolality. • Hypernatremia or hyponatremia can cause central nervous system (CNS) disturbance resulting from changes in neuronal cell volume and function. • Overly rapid correction of hypernatremia or hyponatremia can cause severe CNS dysfunction. • Patients with hypernatremia or hyponatremia that require intravascular volume expansion should be treated with intravenous fluids that contain a similar sodium concentration as the patient’s plasma.

Sodium concentration is important. Alterations in sodium concentration are associated with poor outcome in critically ill people1,2; even sodium concentration changes within the reference interval have been associated with increased mortality risk.1 It is unclear whether small fluctuations in sodium concentration are themselves detrimental to outcome or if they portend a poorer prognosis because they indicate more severe disease. Sodium concentration is expressed as milliequivalents (mEq) or millimoles (mmol) of sodium per liter of serum or plasma. In the vast majority of cases, disorders of sodium concentration in dogs and cats result from abnormalities in water handling rather than an increased or decreased number of sodium molecules. To understand what determines plasma sodium concentration and how changes in plasma sodium concentration alter cellular function, one must understand the distribution of body water and the concept and determinants of osmolality.

Distribution of Total Body Water Water makes up approximately 60% of an adult animal’s body weight; two thirds is intracellular and one third is extracellular. Extracellular water is distributed between the interstitial and intravascular compartments, which contain approximately 75% and 25% of the extracellular water, respectively (see Figure 59-1). The endothelium, which separates the intravascular fluid compartment from the interstitial space, and the cell membrane, which separates the interstitial and intracellular compartments, are freely permeable to water molecules. Therefore, in a closed system (no urinary or gastrointestinal [GI] output), when 1 L of free water (water containing no other molecules) is added to the animal, approximately 666 ml will be

distributed to the intracellular space and 333 ml to the extracellular space. Of the 333 ml added to the extracellular space, approximately 250 ml (75% of 333 ml) will remain in the interstitial fluid space and 83 ml (25% of 333 ml) will be distributed to the intravascular compartment.

Osmolality and Osmotic Pressure An osmole is 1 mole of any fully dissociated substance dissolved in water. Osmolality is the concentration of osmoles in a mass of solvent. In biologic systems, osmolality is expressed as mOsm/kg of water and can be measured using an osmometer. Osmolarity is the concentration of osmoles in a volume of solvent and in biologic systems is expressed as mOsm/L of water. In physiologic systems there is no appreciable difference between osmolality and osmolarity, so the term osmolality will be used for the rest of this discussion for simplicity. Every molecule dissolved in the total body water contributes to osmolality, regardless of size, weight, charge, or composition.3 The most abundant osmoles in the extracellular fluid are sodium (and the accompanying anions chloride and bicarbonate), glucose, and urea. Because they are the most plentiful, these molecules are the main determinants of plasma osmolality in healthy dogs and cats. Plasma osmolality (mOsm/kg) in healthy animals can be calculated by the equation shown in Box 50-1.4,5 As this equation shows, plasma sodium concentration is the major determinant of plasma osmolality. Osmoles that do not cross the cell membrane freely are considered effective osmoles, whereas those that do cross freely are termed ineffective osmoles. The water-permeable cell membrane is functionally impermeable to sodium and potassium. As a result, sodium and potassium molecules are effective osmoles and they exert osmotic pressure across the cell membrane. The net movement of water into or out of cells is dictated by the osmotic pressure gradient. Osmotic pressure causes water molecules from an area of lower osmolality (higher water concentration) to move to an area of higher osmolality (lower water concentration) until the osmolalities of the compartments are equal. When sodium is added to the extracellular space at a concentration greater than that in the extracellular fluid, intracellular volume decreases (the cell shrinks) as water leaves the cell along its osmotic pressure gradient. Conversely, cells swell when free water is added to the interstitial space and water moves intracellularly along its osmotic pressure gradient.

Regulation of Plasma Osmolality Hypothalamic osmoreceptors sense changes in plasma osmolality, and changes of only 2 to 3 mOsm/kg induce compensatory 263

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BOX 50-1 

Calculation of Serum Osmolality

Osmolality (mOsm / kg) = 2([Na + ]) + (BUN [mg / dl] ÷ 2.8) + (glucose [mg / dl] ÷ 18) Where [Na+] = sodium concentration and BUN is the concentration of blood urea nitrogen. The BUN and glucose concentrations are divided by 2.8 and 18, respectively, to convert them from mg/dl to mmol/L.

mechanisms to return the plasma osmolality to its hypothalamic setpoint.6 The two major physiologic mechanisms for controlling plasma osmolality are the antidiuretic hormone (ADH) system and thirst.

Antidiuretic hormone ADH is a small peptide secreted by the posterior pituitary gland. There are two major stimuli for ADH release: elevated plasma osmolality and decreased effective circulating volume. Increased plasma osmolality causes shrinkage of a specialized group of cells in the hypothalamus called osmoreceptors. When their cell volume decreases, these hypothalamic osmoreceptors send impulses via neural afferents to the posterior pituitary, leading to ADH release.7 When effective circulating volume is low, baroreceptor cells in the aortic arch and carotid bodies send neural impulses to the pituitary gland that stimulate ADH release. In the absence of ADH, renal tubular collecting cells are relatively impermeable to water. When ADH activates the V2 receptor on the renal collecting tubular cell, aquaporin-2 molecules are inserted into the cell’s luminal membrane. Aquaporins are channels that allow the movement of water into the renal tubular cell. Water molecules cross through these aquaporins into the hyperosmolar renal medulla down their osmotic gradient. If the kidney is unable to generate a hyperosmolar renal medulla because of disease or diuretic administration, water will not be reabsorbed, even with high concentrations of ADH. Circulating ADH concentration and ADH’s effect on the normal kidney are the primary physiologic determinants of free water retention and excretion.

Total Body Sodium Content Versus Plasma Sodium Concentration Plasma sodium concentration is different than, and independent of, total body sodium content. Total body sodium content refers to the total number of sodium molecules in the body, regardless of the ratio of sodium to water. Sodium content determines the hydration status of the animal. As it is used clinically, hydration is a misnomer, because findings such as skin tenting and moistness of the mucous membranes and conjunctival sac are determined by both the sodium content and the water that those sodium molecules hold in an animal’s interstitial space. When patients have increased total body sodium, an increased quantity of fluid is held within the interstitial space and the animal appears overhydrated, regardless of the plasma sodium concentration. Overhydrated patients may manifest a gelatinous subcutis; peripheral or ventral pitting edema; chemosis; or excessive serous nasal discharge. When patients have decreased total body sodium, a decreased quantity of fluid is held within the interstitial space and the animal appears dehydrated, regardless of the plasma sodium concentration. Once a patient has lost 5% or more of its body weight in isotonic fluid (≥5% “dehydrated”), it may manifest decreased skin turgor, tacky or dry mucous membranes, decreased fluid in the conjunctival sac, or sunken eye position. Patients that are less than 5% dehydrated appear clinically normal. Patients with dehydration can become hypovolemic as fluid shifts from the intravascular space into the interstitial space as a result of decreased interstitial hydrostatic pressure. The sodium/water ratio is independent of the total body sodium content: Patients may be normally hydrated, dehydrated, or overhydrated (normal, decreased, or increased total body sodium content) and have a normal plasma sodium concentration, hypernatremia, or hyponatremia.

HYPERNATREMIA Hypernatremia is defined as plasma or serum sodium concentration above the reference interval. Hypernatremia is common in critically ill dogs and cats.

Thirst

Etiology

Hyperosmolality and decreased effective circulating volume also stimulate thirst. The mechanisms by which hyperosmolality and hypovolemia stimulate thirst are similar to those that stimulate ADH release. Thirst and the resultant water consumption are the main physiologic determinants of free water intake.

Most dogs and cats with hypernatremia have excessive free water loss rather than increased sodium intake or retention.

Prioritization of Osmolality and Effective Circulating Volume Under normal physiologic conditions, the renin-angiotensinaldosterone system monitors and fine tunes effective circulating volume, and the ADH system maintains normal plasma osmolality. However, maintenance of effective circulating volume is always prioritized over maintenance of normal plasma osmolality. Therefore patients with poor effective circulating volume will have increased thirst and ADH release regardless of their osmolality. The resultant increased free water intake (from drinking) and water retention (from ADH action at the level of the kidney) can lead to hyponatremia (and thus hypoosmolality) in patients with poor effective circulating volume. An example of the defense of effective circulating volume at the expense of normal plasma osmolality is seen in patients with chronic congestive heart failure that present with hyponatremia.8

Free water deficit Normal animals can become severely hypernatremic if denied access to water for extended periods. Animals with vomiting, diarrhea, or polyuria of low-sodium urine may also develop hypernatremia. Hypernatremia can occur after administration of activated charcoal suspension containing a cathartic because the hypertonic cathartic draws electrolyte-free water into the GI tract. Osmotic diuresis with mannitol also causes an electrolyte-free water loss and thus can cause hypernatremia. Diabetes insipidus (DI), a syndrome of inadequate release of or response to ADH, can cause hypernatremia (see Chapter 67). Animals with DI become severely hypernatremic when they do not drink water, because they cannot reabsorb free water in the renal collecting duct. Acute or critical illness can unmask previously undiagnosed DI.9 A syndrome of hypodipsic hypernatremia has been reported in Miniature Schnauzers,10-12 one of which was diagnosed with congenital holoprosencephaly.10 This syndrome most likely is due to impaired osmoreceptor or thirst center function. In other dog breeds and cats, hypodipsic hypernatremia has been associated with hypothalamic granulomatous meningoencephalitis, hydrocephalus,

CHAPTER 50  •  Sodium Disorders

and other central nervous system (CNS) deformities and CNS lymphoma.13-17 Diagnostic differentiation between central DI, nephrogenic DI, and hypodipsic hypernatremia can be complex and is outside the scope of this chapter. The reader is referred to more detailed texts for further information.18-20

Sodium excess Severe hypernatremia can also occur with the introduction of large quantities of sodium in the form of hypertonic saline, sodium bicarbonate, sodium phosphate enemas,21 seawater, beef jerky, and saltflour dough mixtures.22

Clinical Signs Hypernatremia causes no specific clinical signs in many cases. If it is severe (usually >180  mEq/L) or occurs rapidly, it may be associated with CNS signs such as obtundation, head pressing, seizures, coma, and death. All cells that have Na+/K+-ATPase pumps shrink as a result of hypernatremia as water moves out of the cell down its osmotic gradient to the relatively hyperosmolar extracellular compartment, but neurons are clinically the least tolerant of this change in cell volume. Thus, neurologic signs are seen most commonly in patients with clinically significant hypernatremia. Patients that develop hypernatremia slowly are often asymptomatic for reasons explained later in Physiologic Adaptation to Hypernatremia. An experimental study found decreased myocardial contractility during injection of hypernatremic or hyperosmolar solutions in dogs.23 Hypernatremia has also been associated with hyperlipidemia, possibly a result of the inhibition of lipoprotein lipase.13 Artifactual hemogram changes in the blood of two hypernatremic cats have been reported with a specific hematology analyzer.24

Physiologic Adaptation to Hypernatremia Hypernatremia causes free water to move out of the relatively hypoosmolar intracellular space into the hyperosmolar extracellular space, leading to decreased cell volume. The brain has multiple ways to protect against and reverse neuronal water loss in cases of hypernatremia. In the early minutes to hours of a hyperosmolal state, as neuronal water is lost to the hypernatremic circulation, lowered interstitial hydraulic pressure draws fluid from the cerebrospinal fluid (CSF) into the brain interstitium.19 As plasma osmolality rises, sodium and chloride also appear to move rapidly from the CSF into cerebral tissue, which helps minimize brain volume loss by increasing neuronal osmolality and thus drawing water back to the intracellular space.25 These early fluid and ionic shifts appear to protect the brain from the magnitude of volume loss that would be expected for a given hyperosmolal state. Additionally, within 24 hours, neurons begin to accumulate organic solutes to increase intracellular osmolality and help shift lost water back to the intracellular space. Accumulated organic solutes are called idiogenic osmoles, or osmolytes, and include molecules such as inositol, glutamine, and glutamate.19 Generation of these idiogenic osmoles begins within a few hours of cell volume loss, but full compensation may take as long as 2 to 7 days.25 Restoration of neuronal cell volume is important for cellular function and is an important consideration during treatment of hypernatremia, as discussed later.

Treatment of the Normovolemic, Hypernatremic Patient Hypernatremia should be treated, even if no clinical signs are apparent. Patients with hypernatremia have a free water deficit, so free water is replaced in the form of fluid with a lower effective osmolality than that of the patient. Treatment must be cautious, and close

BOX 50-2 

Calculation of Free Water Deficit

Free water deficit = ([current [Na + ]p ÷ normal [Na + ]p ] − 1) × (0.6 × body weight in kg) where [current[Na+]p is the patient’s current plasma sodium concentration and normal [Na+]p is the patient’s normal plasma sodium concentration.

monitoring of plasma or serum sodium concentration and CNS signs is imperative. In patients with mild to moderate hypernatremia ([Na+]p < 180 mEq/L), sodium concentration should be decreased no more rapidly than 1 mEq/L/hr. In those with severe hypernatremia ([Na+]p ≥ 180 mEq/L), it should be decreased no more rapidly than 0.5 to 1 mEq/L/hr. This slow decrease in plasma sodium concentration ([Na+]p) is important to prevent cellular swelling. Idiogenic osmoles are broken down slowly, so rapid drops in plasma sodium concentration (and thus plasma osmolality) cause free water to move back into the relatively hyperosmolar intracellular space and can lead to neuronal edema. Free water deficit can be calculated by the free water deficit equation7 listed in Box 50-2. This formula gives the total volume of free water that needs to be replaced. This volume of free water, usually given as 5% dextrose in water, is infused over the number of hours calculated for safe reestablishment of normal plasma sodium concentration. This rate of free water replacement may be inadequate in cases of ongoing free water loss, as seen with diuresis of electrolyte-free water in patients with DI or unregulated diabetes mellitus, but it is a safe starting point in most cases. Plasma sodium concentration should be monitored no less often than every 4 hours to assess the adequacy of treatment, and CNS status should be monitored continuously for signs of obtundation, seizures, or other abnormalities. The rate of free water supplementation should be adjusted as needed to ensure an appropriate drop in plasma sodium concentration, the goal being a drop of no more than 1 mEq/hr and no clinical signs of cerebral edema. Water may be supplemented intravenously (as 5% dextrose in water) or orally on an hourly schedule in animals that are alert, willing to drink, and not vomiting. Free water replacement alone will not correct clinical dehydration or hypovolemia, because free water replacement does not provide the sodium required to correct these problems (see Total Body Sodium Content Versus Plasma Sodium Concentration). Free water replacement in the hypernatremic patient is relatively safe, even in animals with cardiac or renal disease, because two thirds of the volume administered will enter the cells.

Complications of Therapy for Hypernatremia Cerebral edema is the primary complication of therapy for hypernatremia. Clinical signs of cerebral edema include obtundation, head pressing, coma, seizures, and other disorders of behavior or movement. If these signs develop during the treatment of hypernatremia, immediately stop the administration of any fluid that has a lower sodium concentration than the patient and disallow drinking. The patient’s plasma sodium concentration should be measured to confirm that it is lower than it was when treatment was instituted. This is an important step because signs of worsening hypernatremia may be similar to those seen with cerebral edema. If the plasma sodium concentration has decreased, even if it has dropped at less than 1 mEq/L/hr, cerebral edema should be considered. Cerebral edema is treated with a dose of mannitol at 0.5 to 1 g/kg intravenously (IV) over 20 to 30 minutes. Mannitol should be

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administered via a central vein if possible, but it may be diluted 1 : 1 in sterile water and given through a peripheral vein in an emergency situation. If mannitol is not available, or if a single dose does not improve signs, consider a dose of 7.2% sodium chloride at 3 to 5 ml/ kg over 20 minutes. The administration method is similar to that used for mannitol. Hypertonic saline should not be administered as a rapid bolus because it can cause vasodilation.

HYPONATREMIA Hyponatremia is defined as plasma or serum sodium concentration below the reference interval. Clinically detrimental hyponatremia is uncommon in critically ill dogs and cats.

Etiology Dogs and cats with hyponatremia almost always have free water retention in excess of sodium retention; they may have sodium loss as well. Generation of hyponatremia usually requires water intake in addition to decreased water excretion.

Decreased effective circulating volume A common cause of hyponatremia in dogs and cats is decreased effective circulating volume, which causes ADH release and water intake in defense of intravascular volume and thus decreases plasma sodium concentration. Possible causes include congestive heart failure,8 excessive gastrointestinal losses,26,27 excessive urinary losses, body cavity effusions,28,29 and edematous states. Note that in the case of congestive heart failure, the patient has increased total body sodium (is “overhydrated”) because of activation of the reninangiotensin-aldosterone system, yet is hyponatremic because of increased water retention in excess of sodium retention. In the case of excessive salt and water losses from the GI or urinary tract, the patient is total body sodium depleted (is “dehydrated”) and is hyponatremic as a result of compensatory water drinking and retention to maintain effective circulating volume.

Hypoadrenocorticism Hypoadrenocorticism leads to hyponatremia through decreased sodium retention (caused by hypoaldosteronism) combined with increased water drinking and retention in defense of inadequate circulating volume. Animals with atypical hypoadrenocorticism, whose aldosterone production and release are normal, may also develop hyponatremia, because low circulating cortisol concentration leads to increased ADH release and resultant water retention regardless of intravascular volume status.30

Diuretics Thiazide or loop diuretic administration can lead to hyponatremia by induction of hypovolemia, hypokalemia that causes an intracellular shift of sodium in exchange for potassium, and the inability to dilute urine.30 Renal failure can cause hyponatremia by similar mechanisms.

Syndrome of inappropriate antidiuretic hormone secretion Syndrome of inappropriate ADH secretion (SIADH) causes hyponatremia through water retention in response to improperly high circulating concentrations of ADH. The syndrome has been reported in dogs31-34 and a cat35 and has many known causes in humans30 (see Chapter 68).

Other causes of hyponatremia Hyponatremia has been reported in animals with GI parasitism,26 infectious and inflammatory diseases,36-39 psychogenic polydipsia,

and pregnancy.40 It has also been reported in a puppy fed a lowsodium, home-prepared diet.41 A syndrome of cerebral salt wasting (CSW) has been described in humans with CNS disease but has not been reported clinically in dogs or cats. Patients with CSW have increased urinary sodium excretion in the face of intravascular volume depletion, which is inappropriate because a volume-depleted animal’s kidney should avidly conserve sodium. The mechanisms— and even the syndrome’s actual existence—are unclear, but both brain natriuretic peptide (too much) and aldosterone (not enough) have been implicated.30 Cerebral salt wasting is differentiated from SIADH by evaluation of hydration status: patients with CSW are clinically dehydrated because of a decrease in total body sodium content, and those with SIADH are usually adequately hydrated with excessive free water retention.42

Clinical Signs Mild to moderate hyponatremia usually causes no specific clinical signs. If hyponatremia is severe (usually 170) that require intravascular volume expansion should be resuscitated with a fluid that has a sodium concentration that matches that of the patient (±6 mEq/L). Hyponatremic animals may be resuscitated with a balanced electrolyte solution containing 130 mEq/L sodium if appropriate, or with a maintenance solution that has sodium chloride added to bring the sodium concentration of the solution up to that of the patient. Hypernatremic animals should be resuscitated with a balanced electrolyte solution with NaCl added in a quantity sufficient to bring the solution’s sodium concentration up to that of the animal. The simplest way to add sodium to a bag of commercially available fluid is to add 23.4% NaCl to the bag. This product contains 4 mEq NaCl/ml solution, so it adds a significant quantity of sodium in a small volume.

REFERENCES 1. Sakr Y, Rother S, Ferreira AM, et al: Fluctuations in serum sodium level are associated with an increased risk of death in surgical ICU patients, Crit Care Med 41:133, 2013.

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PART V  •  ELECTROLYTE AND ACID-BASE DISTURBANCES 2. Hoorn EJ, Betjes MG, Weigel J, et al: Hypernatraemia in critically ill patients: too little water and too much salt, Nephrol Dial Transplant 23:1562, 2008. 3. Rose BD, Post TW: Introduction to renal function. In Rose BD,Post TW, editors. Clinical physiology of acid-base and electrolyte disorders, ed 5, New York, 2001, McGraw-Hill, pp 3-20. 4. Dugger DT, Mellema MS, Hopper K, et al: Comparitive accuracy of several published formulae for the estimation of serum omolality in cats, J Small Anim Pract 54(4):184, 2013. 5. Dugger DT, Mellema MS, Hopper K, et al: Estimated osmolality of canine serum: A comparison of the clinical ultility of several published formulae, J Vet Emerg Crit Care (In Press). 6. Giebisch G, Windhager E: Integration of salt and water balance. In Boron WF, Boulpaep EL, editors: Medical physiology, Philadelphia, 2003, Saunders, pp 861-876. 7. Rose BD, Post TW: Effects of hormones on renal function. In Rose BD, Post TW, eds. Clinical physiology of acid-base and electrolyte disorders, ed 5, New York, 2001, McGraw-Hill, pp 163-238. 8. Brady CA, Hughes D, Drobatz KJ: Association of hyponatremia and hyperglycemia with outcome in dogs with congestive heart failure, J Vet Emerg Crit Care 14:177, 2004. 9. Edwards DF, Richardson DC, Russell RG: Hypernatremic, hypertonic dehydration in a dog with diabetes insipidus and gastric dilation-volvulus, J Am Vet Med Assoc 182:973, 1983. 10. Sullivan SA, Harmon BG, Purinton PT, et al: Lobar holoprosencephaly in a Miniature Schnauzer with hypodipsic hypernatremia, J Am Vet Med Assoc 223:1783, 1778, 2003. 11. Van Heerden J, Geel J, Moore DJ: Hypodipsic hypernatraemia in a miniature schnauzer, J S Afr Vet Assoc 63:39, 1992. 12. Crawford MA, Kittleson MD, Fink GD: Hypernatremia and adipsia in a dog, J Am Vet Med Assoc 184:818, 1984. 13. Hanselman B, Kruth S, Poma R, et al: Hypernatremia and hyperlipidemia in a dog with central nervous system lymphosarcoma, J Vet Intern Med 20:1029, 2006. 14. Mackay BM, Curtis N. Adipsia and hypernatraemia in a dog with focal hypothalamic granulomatous meningoencephalitis, Aust Vet J 77:14, 1999. 15. DiBartola SP, Johnson SE, Johnson GC, et al: Hypodipsic hypernatremia in a dog with defective osmoregulation of antidiuretic hormone, J Am Vet Med Assoc 204:922, 1994. 16. Morrison JA, Fales-Williams A: Hypernatremia associated with intracranial B-cell lymphoma in a cat, Vet Clin Pathol 35:362, 2006. 17. Dow SW, Fettman MJ, LeCouteur RA, et al: Hypodipsic hypernatremia and associated myopathy in a hydrocephalic cat with transient hypopituitarism, J Am Vet Med Assoc 191:217, 1987. 18. DiBartola SP: Disorders of sodium and water: hypernatremia and hyponatremia. In DiBartola SP, editor: Fluid, electrolyte, and acid-base disorders in small animal practice, ed 3, St Louis, 2006, Saunders Elsevier, pp 47-79. 19. Rose BD, Post TW: Hyperosmolal states—hypernatremia. In Rose BD, Post TW, editors: Clinical physiology of acid-base and electrolyte disorders, New York, 2001, McGraw-Hill, pp 746-793. 20. Feldman EC, Nelson RW: Water metabolism and diabetes insipidus. In Feldman EC, Nelson RW, editors: Canine and feline endocrinology and reproduction, ed 3, St Louis, 2004, Saunders, pp 2-44. 21. Atkins CE, Tyler R, Greenlee P: Clinical, biochemical, acid-base, and electrolyte abnormalities in cats after hypertonic sodium phosphate enema administration, Am J Vet Res 46:980, 1985. 22. Barr JM, Khan SA, McCullough SM, et al: Hypernatremia secondary to homemade play dough ingestion in dogs: a review of 14 cases from 1998 to 2001, J Vet Emerg Crit Care 14:196, 2004. 23. Kozeny GA, Murdock DK, Euler DE, et al: In vivo effects of acute changes in osmolality and sodium concentration on myocardial contractility, Am Heart J 109:290, 1985. 24. Boisvert AM, Tvedten HW, Scott MA: Artifactual effects of hypernatremia and hyponatremia on red cell analytes measured by the Bayer H*1 analyzer, Vet Clin Pathol 28:91, 1999.

25. Verbalis JG: Brain volume regulation in response to changes in osmolality, Neuroscience 168:862, 2010. 26. DiBartola SP, Johnson SE, Davenport DJ, et al: Clinicopathologic findings resembling hypoadrenocorticism in dogs with primary gastrointestinal disease, J Am Vet Med Assoc 187:60, 1985. 27. Boag AK, Coe RJ, Martinez TA, et al: Acid-base and electrolyte abnormalities in dogs with gastrointestinal foreign bodies, J Vet Intern Med 19:816, 2005. 28. Willard MD, Fossum TW, Torrance A, et al: Hyponatremia and hyperkalemia associated with idiopathic or experimentally induced chylothorax in four dogs, J Am Vet Med Assoc 199:353, 1991. 29. Bissett SA, Lamb M, Ward CR: Hyponatremia and hyperkalemia associated with peritoneal effusion in four cats, J Am Vet Med Assoc 218:1580, 1590-1592, 2001. 30. Rose BD, Post TW: Hypoosmolal states—hyponatremia. In Rose BD, Post TW, editors. Clinical physiology of acid-base and electrolyte disorders, ed 5, New York, 2001 McGraw-Hill, pp 696-745. 31. Rijnberk A, Biewenga WJ, Mol JA: Inappropriate vasopressin secretion in two dogs, Acta Endocrinol (Copenh) 117:59, 1988. 32. Breitschwerdt EB, Root CR: Inappropriate secretion of antidiuretic hormone in a dog, J Am Vet Med Assoc 175:181, 1979. 33. Kang MH, Park HM: Syndrome of inappropriate antidiuretic hormone secretion concurrent with liver disease in a dog, J Vet Med Sci 74:645, 2012. 34. Shiel RE, Pinilla M, Mooney CT: Syndrome of inappropriate antidiuretic hormone secretion associated with congenital hydrocephalus in a dog, J Am Anim Hosp Assoc 45:249, 2009. 35. Cameron K, Gallagher A: Syndrome of inappropriate antidiuretic hormone secretion in a cat, J Am Anim Hosp Assoc 46:425, 2010. 36. Lobetti RG, Jacobson LS: Renal involvement in dogs with babesiosis, J S Afr Vet Assoc 72:23, 2001. 37. Keenan KP, Buhles WC, Jr., Huxsoll DL, et al: Studies on the pathogenesis of Rickettsia rickettsii in the dog: clinical and clinicopathologic changes of experimental infection, Am J Vet Res 38:851, 1977. 38. Son TT, Thompson L, Serrano S, et al: Surgical intervention in the management of severe acute pancreatitis in cats: 8 cases (2003-2007), J Vet Emerg Crit Care (San Antonio) 20:426, 2010. 39. Declue AE, Delgado C, Chang CH, et al: Clinical and immunologic assessment of sepsis and the systemic inflammatory response syndrome in cats, J Am Vet Med Assoc 238:890, 2011. 40. Schaer M, Halling KB, Collins KE, et al: Combined hyponatremia and hyperkalemia mimicking acute hypoadrenocorticism in three pregnant dogs, J Am Vet Med Assoc 218:897, 2001. 41. Hutchinson D, Freeman LM, McCarthy R, et al: Seizures and severe nutrient deficiencies in a puppy fed a homemade diet, J Am Vet Med Assoc 241:477, 2012. 42. Palmer BF: Hyponatremia in patients with central nervous system disease: SIADH versus CSW, Trends Endocrinol Metab 14:182-187, 2003. 43. Tyler RD, Qualls CW, Jr., Heald RD, et al: Renal concentrating ability in dehydrated hyponatremic dogs, J Am Vet Med Assoc 191:1095, 1987. 44. Porzio P, Halberthal M, Bohn D, et al: Treatment of acute hyponatremia: ensuring the excretion of a predictable amount of electrolyte-free water, Crit Care Med 28:1905, 2000. 45. MacMillan KL: Neurologic complications following treatment of canine hypoadrenocorticism, Can Vet J 44:490, 2003. 46. Churcher RK, Watson AD, Eaton A: Suspected myelinolysis following rapid correction of hyponatremia in a dog, J Am Anim Hosp Assoc 35:493, 1999. 47. Brady CA, Vite CH, Drobatz KJ: Severe neurologic sequelae in a dog after treatment of hypoadrenal crisis, J Am Vet Med Assoc 215:210, 222-225, 1999. 48. O’Brien DP, Kroll RA, Johnson GC, et al: Myelinolysis after correction of hyponatremia in two dogs, J Vet Intern Med 8:40, 1994.

CHAPTER 51  POTASSIUM DISORDERS Laura L. Riordan,

DVM, DACVIM  •  Michael

Schaer,

KEY POINTS • A normal serum potassium concentration is essential for normal neuromuscular function. • Common predisposing conditions for hypokalemia include diabetes mellitus, chronic renal disease (especially in cats), prolonged anorexia, diarrhea, hyperaldosteronism, and metabolic alkalosis. • The main clinical manifestation in the dog and cat is hypokalemic myopathy. • Rate of potassium infusion rather than total amount infused is of major therapeutic importance. • Mild to moderate hypokalemia (serum potassium 2.5 to 3.5 mEq/L) can be corrected at a rate up to 0.5 mEq/kg/hr. • Decreased renal excretion is the most common cause of hyperkalemia in small animal patients. • Before determination of serum potassium level in any hyperkalemic patient or in any animal with urinary tract obstruction, an electrocardiogram (ECG) should be evaluated to detect bradycardia, atrial standstill, or ventricular arrhythmias. • Renal failure, hypoadrenocorticism, and gastrointestinal disease are the most common causes of sodium/potassium ratios less than 27 : 1. • When serum potassium exceeds 8 mEq/L or severe ECG changes are present, immediate therapy directed toward reducing and antagonizing the effects of serum potassium is warranted (i.e., 10% calcium gluconate, 10% calcium chloride, sodium bicarbonate, dextrose with or without insulin, β2 agonists). • Hemodialysis and hemoperfusion can effectively and rapidly lower serum potassium levels.

Few of the disturbances in fluid and electrolyte metabolism are as commonly encountered or as immediately life threatening as disturbances in potassium balance. Many clinicians are already sensitized to the detrimental effects of potassium disorders, especially hyperkalemia, but sometimes the adverse effects of hypokalemia are nearly as harmful. This chapter discusses the clinical essentials of hypokalemia and hyperkalemia in the critically ill dog and cat and shows why both are important to patient care.

Normal Distribution of Potassium in the Body Potassium is the most abundant intracellular cation, with 98% to 99% located in the intracellular compartment. Most intracellular potassium lies in the skeletal muscle cells. The average potassium concentration in the intracellular space of dogs and cats is 140 mEq/L, and that in the plasma space averages 4 mEq/L.1,2 Serum potassium levels therefore do not reflect whole body content or tissue concentrations.

HYPOKALEMIA Definition and Causes Hypokalemia occurs when the serum potassium concentration is less than 3.5 mEq/L (normal range 3.5 to 5.5 mEq/L). The general causes

DVM, DACVIM, DACVECC

of hypokalemia are (1) disorders of internal balance and (2) disorders of external balance. The clinical conditions most commonly associated with each of these are provided in Box 51-1. Recently there has been a heightened recognition of feline hyperaldosteronism as the cause of marked hypokalemia, usually secondary to either an aldosteronoma or adrenocortical hyperplasia. It has also been associated with an adrenocortical adenoma in ferrets.3

Consequences Abnormalities resulting from hypokalemia are divided into four categories: metabolic, neuromuscular, renal, and cardiovascular. Glucose intolerance is the most notable adverse metabolic effect of hypokalemia. Experiments have shown that release of insulin from the pancreatic β cells is impaired when total body potassium levels are decreased.4 Potassium is necessary for maintenance of normal resting membrane potential. Subsequently the most significant neuromuscular abnormality induced by hypokalemia in dogs and cats is skeletal muscle weakness from hyperpolarized (less excitable) myocyte plasma membranes that may progress to hypopolarized membranes.5-7 Ventroflexion of the head and neck; a stiff, stilted gait; and a plantigrade stance may also be evident. In cats, hypokalemic myopathy typically is associated with chronic renal disease and poorly regulated diabetes mellitus.2,8 It can also result from a potassium-deficient diet or prolonged anorexia.14 More recently feline hyperaldosteronism as a result of aldosteronoma and adrenocortical hyperplasia has been described, although a diagnostic workup for these conditions is only indicated if the more common etiologies are not present. These cats can present with clinical signs

BOX 51-1 

Causes of Hypokalemia3,11,31-34

Disorders of Internal Balance (Redistribution) Metabolic alkalosis Insulin administration Increased levels of catecholamines β-Adrenergic agonist therapy or intoxication Refeeding syndrome

Disorders of External Balance (Depletion) Renal potassium wasting Prolonged inadequate intake Diuretic drugs Osmotic or postobstructive diuresis Chronic liver disease Inadequate parenteral fluid supplementation Aldosterone-secreting tumor or any cause of hyperaldosteronism Prolonged vomiting associated with pyloric outflow obstruction Diabetic ketoacidosis Renal tubular acidosis Severe diarrhea

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FIGURE 51-1  Lead II electrocardiogram at 50 mm/s taken from a dog with a serum potassium measuring 2.1 mEq/L. Note the increased P wave amplitude, the depressed ST segment, and the depressed T waves.

ranging from retinal hemorrhage caused by hypertension to profound muscle weakness with or without rhabdomyolysis.9 Frank paralysis and death as a result of diaphragmatic failure and respiratory muscle failure can occur in severe cases.10 Hypokalemia can also cause rhabdomyolysis, which may have a toxic effect on the renal tubules in some speciaes.5,6Smooth muscle impairment can also occur, leaving the patient with paralytic ileus and gastric atony.11 These neuromuscular signs are seldom present until serum potassium levels fall below 2.5 mEq/L. Cats with chronic renal disease can become markedly potassium depleted, and the resulting hypokalemia may impair renal tubular function.2,8,12 In the myocardial cell, a high intracellular/extracellular potassium concentration ratio induces a state of electrical hyperpolarization leading to prolongation of the action potential. This may predispose the patient to atrial and ventricular tachyarrhythmias, atrioventricular dissociation and ventricular fibrillation. Abnormal electrocardiogram (ECG) findings in animals with hypokalemia are less reliable than in those with hyperkalemia.13 Canine ECG abnormalities include depression of the ST segment and prolongation of the QT interval (Figure 51-1).14 Increased P wave amplitude, prolongation of the PR interval, and widening of the QRS complex may also occur. In addition, hypokalemia predisposes to digitalis-induced cardiac arrhythmias and causes the myocardium to become refractory to the effects of class I antiarrhythmic agents (i.e., lidocaine, quinidine, and procainamide).

Management of Hypokalemia The main management objectives include replacing potassium deficits and correcting the primary disease process. Treatment of moderate (2.5 to 3.4 mEq/L) to severe (7 mEq/L

Depressed P wave amplitude

>8.5 mEq/L

Atrial standstill Sinoventricular rhythm

>10 mEq/L

Biphasic QRS complex Ventricular flutter Ventricular fibrillation Ventricular asystole

PSEUDOHYPERKALEMIA Potassium can be released from increased numbers of circulating blood cells, especially platelets and white blood cells, causing an artifactual increase in potassium termed pseudohyperkalemia. This is seen primarily in animals with severe thrombocytosis or leukocytosis. Pseudohyperkalemia can also be seen in Akita dogs (or other dogs of Japanese origin) secondary to in vitro hemolysis, because their erythrocytes have a functional sodium-potassium adenosine triphosphatase and, as such, have high intracellular potassium concentrations. This potassium is released and causes an artifactual hyperkalemia if hemolysis occurs in the serum blood tube. Confirmation of pseudohyperkalemia can be made by determining the plasma potassium concentration (blood collected in a heparinized tube) because this should not be affected by changes in platelet or white blood cell numbers (unless the patient suffers from leukemia).

Treatment of Hyperkalemia An ECG should be performed in any patient with suspected or confirmed hyperkalemia. In asymptomatic animals with normal urine output, serum potassium concentrations between 5.5 and 6.5 mEq/L rarely warrant immediate therapy; however, the cause of the hyperkalemia should be investigated. In all hyperkalemic patients, exogenous potassium administration should be discontinued. Intravenous potassium-free or potassium-deficient isotonic crystalloids can be administered to promote diuresis, and this alone may be sufficient to correct mild hyperkalemia (≤6 mEq/L). Loop (furosemide 1 to 4 mg/ kg intravenously [IV]) or thiazide (chlorothiazide 20 to 40 mg/kg PO) diuretics can increase urinary potassium excretion; however, their use must follow rehydration. Drugs that promote hyperkalemia, such as ACE inhibitors, β-adrenergic antagonists, and potassiumsparing diuretics, should be discontinued. In patients with chronic renal failure, a potassium-reduced diet should also be considered. Immediate therapy is directed toward reducing and antagonizing serum potassium in patients with severe ECG changes or when the serum potassium concentration exceeds 8 mEq/L. Ten percent calcium gluconate or calcium chloride can be administered to antagonize the cardiotoxic effects of hyperkalemia, but this has no effect on serum potassium concentrations. β-Adrenergic agonists, sodium bicarbonate, and dextrose with or without insulin can be administered to reduce serum potassium concentrations as described in Table 51-3. Peritoneal dialysis, hemodialysis, or continuous renal replacement therapy will effectively treat hyperkalemia that is not responsive to the previously mentioned interventions.

Table 51-3  Treatment of Life-Threatening Hyperkalemia Drug

Dosage

Mechanism of Action

Onset of Action

10% Calcium gluconate

0.5 to 1.5 ml/kg IV slowly over 5 to 10 minutes with ECG monitoring

Increases threshold voltage but will not lower serum potassium

3 to 5 minutes

Sodium bicarbonate

1 to 2 mEq/kg IV slowly over 15 minutes

Increases extracellular pH, allowing for potassium to move intracellularly

15 minutes or longer

25% Dextrose

0.7 to 1 g/kg IV over 3 to 5 minutes

Allows for translocation of potassium into the intracellular space

12 mg/dl in the dog and >11 mg/dl in the cat), an ionized calcium measurement should be performed to confirm the diagnosis.

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A diagnosis of hypercalcemia is confirmed with an ionized calcium measurement greater than 6 mg/dl or 1.5 mmol/L in the dog or greater than 5.7 mg/dl or 1.4 mmol/L in the cat. The increase in ionized calcium typically parallels the increase in total serum calcium except in animals with renal failure, in which the increase in total calcium is caused by calcium binding with citrate, phosphate, or bicarbonate. In cats, hypercalcemia is more commonly discovered when ionized calcium is measured compared with the total calcium measurement in the same cat.6 Once the hypercalcemia is confirmed, a thorough physical examination should be repeated. The clinician should palpate the anal sacs (dogs) and peripheral lymph nodes for any enlargement, perform a fundic examination (e.g., systemic disease, mycoses, neoplasia), and do a thorough evaluation for any masses that may have been missed on initial examination (e.g., mammary tumors). Further diagnostic maneuvers should be tailored to the individual patient based on clinical signs, physical examination findings, initial laboratory testing, and suspected etiology, but may include a complete blood cell count, chemistry panel, urinalysis, imaging (thoracic radiographs, abdominal radiographs, abdominal ultrasonography, parathyroid ultrasonography), fine-needle aspiration with cytologic evaluation of any masses found, PTH measurement, PTH-related protein measurement, calcidiol measurement, calcitriol measurement, bone biopsy, and bone marrow aspiration.

Differential Diagnoses A list of differential diagnoses for hypercalcemia is presented in Box 52-1, with neoplasia-associated hypercalcemia (specifically lymphoma) being the most common cause in dogs, followed by renal failure, hyperparathyroidism, and hypoadrenocorticism.7 In cats, neoplasia is thought to be the third most common cause of hypercalcemia behind idiopathic hypercalcemia and renal failure. Serum phosphorus levels tend to be normal or low in animals with primary hyperparathyroidism or malignancies with an elevated PTH-related protein. Dogs with neoplasia-associated ionized hypercalcemia (specifically lymphoma and anal sac adenocarcinoma) often have higher serum ionized calcium concentrations than those with renal failure, hypoadrenocorticism, and other types of neoplasia.7 However, the magnitude of ionized hypercalcemia alone does not predict specific

disease states.7 A thorough discussion of the pathophysiology of hypercalcemia in various disease processes is beyond the scope of this chapter; however, a thorough understanding of these principles is important because they serve as a guide for diagnosis and treatment.1

Treatment of Hypercalcemia The consequences of hypercalcemia can be severe and affect multiple body systems including the central nervous system (CNS), gastrointestinal tract, heart, and kidneys. Therefore a timely diagnosis and rapid intervention can be vital, especially in animals with acute development of severe hypercalcemia. However, there is no absolute calcium value that should serve as a guide for initiating aggressive treatment. Rather, intervention should be guided by multiple factors, including the magnitude of hypercalcemia, rate of development, stable or progressive disease, clinical signs associated with hypercalcemia, organ dysfunction (renal, cardiac, CNS), clinical condition of the patient, and suspected etiology of the hypercalcemia (Figure 52-1). In addition, evaluation of phosphorus concentrations may help in guiding therapy, because a calciumphosphorus product greater than 60 represents increased risk for soft tissue mineralization. Definitive treatment for hypercalcemia involves removing the underlying cause. However, in many cases the cause is not readily apparent, and sometimes palliative therapy must be instituted before treating the primary disease (Table 52-1). Acute therapy often involves the use of one or more of the following: intravenous fluids, diuretics (furosemide), glucocorticoids, and calcitonin (Figure 52-2). The therapeutic fluid of choice for animals with hypercalcemia is 0.9% sodium chloride because the additional sodium ions provide competition for renal tubular calcium reabsorption, resulting in enhanced calciuria. In addition, 0.9% sodium chloride is calcium free, thus decreasing the calcium load on the body. Intravenous fluid therapy should be used to correct dehydration over 4 to 6 hours (if stable) and then given at rates of at least 1.5 to 2 times maintenance (see Chapter 59). Potassium supplementation is often needed with this fluid protocol (potassium 5 to 40 mEq/L) depending on serum potassium concentrations (see Chapter 51). Judicious fluid therapy should be used in patients with

Cardiac arrhythmias Rapid ↓ renal function

Seizures

Hypercalcemic crisis Rapid ↑ encephalopathy

Muscle twitching High level hypercalcemia With or without clinical signs

7.0 mg/dl 1.75 mmol/L Ionized calcium (cats)

7.5 mg/dl 1.88 mmol/L Ionized calcium (dogs)

FIGURE 52-1  Definition of hypercalcemic crisis.

CHAPTER 52  •  Calcium Disorders

Table 52-1  Treatment of Hypercalcemia1 Treatment

Dosage

Indications

Comments

0.9% NaCl

4-6 ml/kg/hr IV CRI

Moderate to severe hypercalcemia

Contraindicated in congestive heart failure and hypertension

Furosemide

1 to 2 mg/kg IV, SC, PO q6-12h CRI 0.2 to 1 mg/kg/hr

Moderate to severe hypercalcemia

Volume expansion necessary before administration Rapid onset

Dexamethasone

0.1 to 0.22 mg/kg SC, IV q12h

Moderate to severe hypercalcemia

Use before identification of etiology may make definitive diagnosis difficult or impossible

Prednisone

1 to 2.2 mg/kg PO, SC, IV q12h

Moderate to severe hypercalcemia

Use prior to identification of etiology may make definitive diagnosis difficult or impossible

Calcitonin-salmon

4 to 6 IU/kg SC q8-12h

Hypervitaminosis D

Response may be short lived Vomiting may occur after multiple doses Rapid onset

Sodium bicarbonate

1 mEq/kg slowly IV bolus (may give up to 4 mEq/kg total dosage)

Severe, life-threatening hypercalcemia

Requires close monitoring Rapid onset

Pamidronate (Bisphosphonate)

1.3 to 2.0 mg/kg in 150 ml 0.9% NaCl IV over 2 to 4 hr

Moderate to severe hypercalcemia

Expensive Delayed onset

Cinacalcet (Calcimimetic)

No veterinary dosing published

Tertiary hyperparathyroidism Malignant primary hyperparathyroidism

Calcimimetic drug May have future uses in veterinary medicine

CRI, Constant rate infusion; IV, intravenous; NaCl, sodium chloride; PO, per os; SC, subcutaneous.

cardiac disease or hypertension, because volume overload and pulmonary congestion may easily occur. Furosemide enhances urinary calcium loss but should not be used in volume-depleted animals. Suggested dosages of furosemide are 1 to 2 mg/kg intravenously [IV], subcutaneously [SC], or orally [PO] q6-12h. A constant rate infusion (CRI) of 0.2 to 1 mg/kg/hr may occasionally be needed for several hours during a hypercalcemic crisis. Meticulous attention to fluid balance is essential when this method is used to avoid serious volume contraction. It is beneficial to place a urinary catheter in order to match the amount of fluid administered with the amount of urinary losses and ensure adequate volume replacement during aggressive diuresis. Glucocorticoids can cause a reduction in serum calcium concentration in many animals with hypercalcemia. Glucocorticoids lead to reduced bone resorption, decreased intestinal calcium absorption, and increased renal calcium excretion. The magnitude of decline with therapy depends on the cause of the hypercalcemia. Dexamethasone often is given at dosages of 0.1 to 0.22 mg/kg SC or IV q12h, or prednisone at dosages of 1 to 2.2 mg/kg PO, SC, or IV q12h. However, in patients that have no definitive diagnosis for the hypercalcemia, calcitonin therapy should be considered instead of glucocorticosteroids because glucocorticosteroids may interfere with obtaining an accurate cytologic or histopathologic diagnosis as a result of cytolytic effects on lymphoid and plasma cells (e.g., lymphosarcoma, myeloma). Calcitonin acts to decrease serum calcium concentrations mostly by reducing the activity and formation of osteoclasts. Calcitoninsalmon can be used at a dosage of 4 to 6 IU/kg SC q8-12h. Vomiting may occur after several days of administration in dogs. Sodium bicarbonate can also be considered for crisis therapy because it decreases the ionized and total calcium; effects on the bound fractions of calcium have not been examined in this situation.8 Sodium bicarbonate is given at a dosage of 1 mEq/kg IV as a slow bolus (up to 4 mEq/ kg total dose) when patients are at risk for death (see Table 52-1). Acid-base status should be monitored closely to avoid inducing alkalemia or other complications of bicarbonate therapy (i.e., paradoxical cerebral acidosis, hypernatremia, hypokalemia). Peritoneal or

hemodialysis using calcium-free dialysate can be considered in cases refractory to traditional therapy. Fluid therapy should always be considered as the first treatment option and other modalities added based on response to therapy and the status of the patient. Subacute or long-term treatment to decrease calcium levels may be needed in some cases, rather than acute rescue therapy. Glucocorticoids and furosemide can be used for long-term therapy and are usually administered orally. In addition, subcutaneous fluids (0.9% sodium chloride) can be given at dosages of 75 to 100 ml/kg q24h as needed. Bisphosphonates are a class of drugs that have been used in human and veterinary medicine for management of hypercalcemia.9 These drugs decrease osteoclastic activity, thus decreasing bone resorption. Bisphosphonates can take 1 to 3 days to maximally inhibit bone resorption, so they are not considered drugs of choice for acute or crisis therapy.10 Pamidronate has been the most commonly used bisphosphonate in veterinary medicine for management of hypercalcemia; zoledronate is more potent than pamidronate and can be considered for use in selected patients. Pamidronate can be given intravenously at dosages of 1.3 to 2 mg/kg in 150 ml 0.9% saline as a 2-hour to 4-hour infusion.9 This dose can be repeated in 1 week, if needed, but the salutary effect may last for 1 month in some instances. Crisis management for idiopathic hypercalcemia in cats is almost never needed because of the insidious development of hypercalcemia. Oral alendronate starting at 1 to 3 mg/kg/wk has been used for the chronic treatment of idiopathic hypercalcemia in cats.11 This medication may provide more long-term control of idiopathic hypercalcemia in cats compared with other proposed treatments (author’s unpublished observations). However, it should be noted that oral alendronate is not as effective as intravenous bisphosphonate therapy in the acute setting. Oral bisphosphonates can cause esophageal irritation and have been reported to cause abdominal discomfort, nausea, and vomiting in humans,12 so standard precautionary measures should be taken to decrease esophageal transit time in patients receiving these medications. This may include giving several milliliters of water orally after the administration of these pills

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PART V  •  ELECTROLYTE AND ACID-BASE DISTURBANCES ↑ Renal calcium excretion

Dilute calcium in plasma

Mild volume expansion 2-3 times maintenance

Correct dehydration

Calcitoninsalmon 4-6 U/kg SC q8-12h

Short-lived effect

0.9% NaCl  Add KCI

IV fluids

Furosemide bolus IV 1-2 mg/kg

Quick onset of effect

CRI 0.2-1 mg/kg/hr

Monitor urine output

Vomiting and anorexia

Tachyphylaxis

Prednisolone 1-2.2 mg/kg PO, SC, or IV q12h Dexamethasone 0.1-0.22 mg/kg PO, SC, or IV

Avoid if definitive diagnosis unknown

If genesis of hypercalcemia  bone origin

If hypercalcemia expected to be protracted

Subacute onset of effect

Match “ins and outs”

IV bisphosphonates

IV fluids before, during, after

Pamidronate 1.3-2.0 mg/kg IV over 4 hours Expect major ↓ ionized calcium within 72 hours

Repeat every 1-4 weeks if needed

Zolendronate  alternative

FIGURE 52-2  Treatment of critically ill patients with ionized hypercalcemia. CRI, Constant rate infusion; IV, intravenous; PO, per os; SC, subcutaneous.

and also “buttering” of the lips to encourage salivation and to decrease transit time of the pills into the stomach. Splitting of tablets is not recommended because of the potential for more severe corrosive effects. Calcimimetics belong to a new class of drugs that will likely have future use in veterinary medicine to treat some cases of hypercalcemia in which the underlying cause cannot be treated adequately by other means (tertiary hyperparathyroidism, primary hyperparathyroidism caused by carcinoma). These drugs activate the calcium sensing receptor and thus decrease PTH secretion. Cinacalcet has been marketed for use in humans to treat renal secondary hyperparathyroidism and nonsurgical primary hyperparathyroidism.

HYPOCALCEMIA Decreased total serum calcium is a relatively common electrolyte disturbance in critically ill dogs and cats. In two separate previous studies, the prevalence of ionized hypocalcemia was 31% in sick dogs and 27% in cats.5,6

Clinical Signs and Diagnosis A list of clinical signs that occur with hypocalcemia is presented in Box 52-2. Signs of hypocalcemia are often not seen until serum total calcium concentrations are less than 6.5 mg/dl (20 ml/kg over 24 hrs

Inflammatory Variables Leukocytosis Leukopenia Normal WBC count with >10% immature forms Plasma C-reactive protein Plasma procalcitonin >2 SD above the normal value

WBC count >12,000/µl WBC count 10% immature forms >2 SD above the normal value >2 SD above the normal value

Tissue Perfusion Variables Hyperlactatemia Decreased capillary refill or mottling Other Variables ScvO2 Cardiac index

Plasma glucose >120 mg/dl in the absence of diabetes

(>1 mmol/L)

>70% >3.5 L/min

SD, Standard deviation; WBC, white blood cells.

Table 91-3  Diagnostic Criteria for Severe Sepsis in People (Defined as Sepsis with Organ Dysfunction)10 Organ Dysfunction Variables: Arterial hypoxemia Acute oliguria Creatinine Coagulation abnormalities Thrombocytopenia Hyperbilirubinemia

PaO2/FiO2 1.5 or aPTT >60 seconds Platelet count 2 mg/dl or 35 mmol/L

aPTT, Activated partial thromboplastin time; INR, international normalized ratio.

tory failure (in people) is defined as a systolic blood pressure of less than 90 mm Hg, mean arterial pressure of less than 60 mm Hg, or a reduction in systolic blood pressure greater than 40 mm Hg from baseline despite adequate volume.10 In veterinary patients there are no studies to define critical blood pressures, but it is reasonable to consider that similar blood pressure values are appropriate.11 Sepsis is a clinical syndrome characterized by a systemic inflammatory response to a bacterial, viral, protozoal, or fungal infection. Bacteremia, defined by the presence of live organisms in the bloodstream, may be variably present in septic patients. The syndrome of sepsis includes the continuum of severity from uncomplicated (SIRS with an infection) to severe (where organ failure becomes a component) to septic shock (the development of hypotension despite volume resuscitation). The prognosis for survival decreases with

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progression along this continuum and the associated progressive systemic inflammation, organ dysfunction, and ultimately cardio­ vascular collapse. Dysregulation of vasomotor tone, increased vascular permeability, dysfunctional microcirculation, and coagulation abnormalities are hallmarks of sepsis. The clinical manifestations and course of disease in patients with sepsis ultimately depend on the location of infection; virulence of the organism; size of inoculums; host nutritional status, comorbidities, age, immune response, and organ function; and genetic host response, including coding for cytokine genes, immune effector molecules, and receptors. After the 2001 International Sepsis Definitions Conference, a concept called PIRO was adopted to stage sepsis and to describe clinical manifestations of the infection and host response to it.10 In this model, PIRO is an acronym for predisposition, insult or infection, response, and organ dysfunction. This conceptual and clinical framework attempts to incorporate patient factors with the microbial insult in order to stage the disease process and identify factors that may contribute to morbidity and mortality. The PIRO approach may employ advanced diagnostic techniques not yet available in veterinary medicine, but hopefully it can serve as a guideline until similar methods are available and validated.

PATHOGENESIS OF THE SEPTIC SYSTEMIC INFLAMMATORY RESPONSE Microbial Factors Sources for gram-negative sepsis commonly include the gastrointestinal (GI) and genitourinary systems. The gram-negative bacterial cell wall contains a potent molecule, lipopolysaccharide (LPS). This pathogen-associated molecular pattern (PAMP) is recognized as one of the most potent stimuli of the host immune response. Host recognition and reaction involves binding of LPS to lipopolysaccharide binding protein (LBP), followed by the LPS-LBP complex binding to membrane-bound CD14 on macrophages.12,13 This binding activates the macrophage and initiates signaling transduction via the Toll-like receptors to the nucleus to start transcription of inflammatory cytokines,14 most notably tumor necrosis factor-α (TNF-α), interleukin (IL) 1, IL-6, IL-8, and interferon γ. In addition to proinflammatory mediators, the response also generates production of counterinflammatory mediators (IL-4, IL-10, IL-13, transforming growth factor β, and glucocorticoids), also referred to as the compensatory antiinflammatory response syndrome, or CARS.13 Common sources for gram-positive sepsis include skin, injured soft tissue, and intravenous catheters.15 Activation of the inflammatory cascade by gram-positive bacteria occurs in response to cell wall components (lipoteichoic acid, peptidoglycan, peptidoglycan stem peptides) or bacterial DNA or via elaboration of soluble bacterial exotoxins. Gram-positive bacterial exotoxins can act as “superantigens” and induce widespread activation of T cells, leading to uncontrolled release of inflammatory cytokines such as interferon γ and TNF-α.13 In both gram-negative and gram-positive sepsis, interaction with these PAMPS largely drives the host response and clinical manifestations of sepsis.

Host Response to Bacterial Infection Activation of macrophages initiates the sepsis-induced systemic inflammatory response, and TNF-α production is a key factor in the early phase of sepsis.2 LPS is the most potent stimulus for the release of TNF-α, which acts as an early central regulator of interactions among cytokines. Macrophage-derived cytokines, such as TNF-α, activate other inflammatory cells (i.e., neutrophils, monocytes), and chemokines serve to attract other cells to the affected area. Neutrophil responses to cytokine signaling can result in extensive host tissue damage secondary to the release of products such as reactive oxygen

species, proteases, lysozymes, lactoferrin, cathepsins, and defensins. Neutrophils produce relatively small amounts of TNF-α, IL-1, and platelet-activating factor. A controlled inflammatory response is beneficial to the host. Such a response is localized and represents a balance between activation of the inflammatory cascade and host CARS. An excessive inflammatory response results from disproportionate activation of the proinflammatory mediators or lack of regulatory counterparts. On the other extreme, “immune paralysis” results from excessive antiinflammatory activity. Additionally there may be regional and temporal differences in proinflammatory versus antiinflammatory activity.16

LOSS OF HOMEOSTATIC MECHANISMS IN SEPSIS Many of the pathophysiologic derangements and subsequent clinical signs in septic patients are related to derangements of normal homeostatic mechanisms responsible for regulating vasomotor tone, inflammation, coagulation, endothelial permeability, and microvascular perfusion.

Loss of vasomotor tone In patients with severe sepsis and septic shock, loss of the normal homeostatic balance between endogenous vasoconstrictors and vasodilators occurs, resulting in dysregulation of vasomotor tone. Overproduction of nitric oxide (NO) during sepsis is a major contributing factor.17 NO is a powerful vascular smooth muscle relaxant that contributes to the vasodilatory state of patients with septic shock, leading to clinical signs such as hyperemic mucous membranes, short capillary refill time, and tachycardia in dogs and in people.5,17-20 Cats do not typically display the hyperemic, hyperdynamic state.20-22 In response to stimulation with endotoxin, TNF-α, IL-1, or platelet activating factor (PAF), inducible nitric oxide synthase (iNOS) accumulates and generates high levels of nitric oxide (NO), thereby contributing to signs of vasodilatory shock.17,23 In one prospective, observational study in dogs, the NO breakdown products nitrate/ nitrite in plasma were was significantly greater in septic dogs or in dogs with SIRS compared with healthy controls.24

Dysregulation of inflammation and coagulation Bacterial infection and host inflammatory cytokines upregulate tissue factor (TF) levels; TF then combines with factor VIIa to initiate the coagulation cascade.25 The TF-fVIIa complex and its downstream products (i.e., thrombin) can also trigger the elaboration of inflammatory cytokines and platelet activation.25 Normally, initiation of the coagulant pathway causes a counterregulatory activation of fibrinolytic and anticoagulant pathways to maintain hemostasis without excessive thrombosis. In septic patients, however, natural anticoagulant and fibrinolytic processes (as well as other complex processes) are inhibited via downregulation of antithrombin, tissue factor pathway inhibitor, and tissue plasminogen activator (tPA) and increased plasminogen activator inhibitor (PAI-1).25 The protein C/S pathway is also inhibited, leading to a reduction of the normal activated protein C anticoagulant and antiinflammatory effects. Platelets also play a major role in this procoagulant state. Platelets exacerbate expression of procoagulant products such as TF, factor Va, and VIIIa; express the fibrinogen receptor; recruit additional platelets; and serve as part of the support structure of clots.26 The hemostatic balance in septic patients, therefore, favors the procoagulant and antifibrinolytic state initially. Progression over time to a hypocoagulable state depends on host protein synthesis, effectiveness of natural coagulation inhibitors, virulence of the invading organism, and resolution of the inflammatory source.

CHAPTER 91  •  Sepsis and Septic Shock 26,27

Hemostatic dysfunction has been reported in septic dogs. One study showed that septic dogs had significantly lower protein C levels and antithrombin (AT) activities and higher prothrombin time, partial thromboplastin time, d-dimer, and fibrin(ogen) degradation products than did controls.4 In a study of dogs with septic peritonitis, coagulation abnormalities, lower AT activity, lower protein C, higher fibrinogen, and less hypercoagulable thromboelastograms were associated with poor outcomes.28 Dogs with naturally occurring parvoviral enteritis had decreased AT activity and increased maximum amplitude on the thromboelastogram, consistent with hypercoagulability (see Chapter 104).29 Commonly available laboratory testing may elucidate these hematologic and hemostatic changes (see Table 91-2).18,26,30

Endothelial, microcirculatory, and mitochondrial abnormalities Alterations in the endothelium, increased vascular permeability, and microcirculatory derangements can be caused by many different and complicated mechanisms, including endothelial dysfunction,31 alterations and damage to the endothelial glycocalyx layer,32 rheologic changes to red blood cells,33 leukocyte activation, microthrombosis, and loss of vascular smooth muscle autoregulation.34 The overall regulation of vascular permeability is complicated (see Chapter 11). The decreased functional capillary density, increased diffusional distance for oxygen, and heterogenous microvascular blood flow all lead to alterations in tissue oxygen extraction and tissue hypoxia.35-37 Importantly, serious microcirculatory disturbances can occur despite normal macrohemodynamic variables (e.g., blood pressure); this disconnect between systemic hemodynamics and microcirculatory perfusion, also known as cryptic shock, is characteristic of both septic human and canine patients.35,36 One prospective observational study in critically ill dogs evaluated vascular endothelial growth factor (VEGF) levels and edema formation in critically ill dogs. VEGF is a hypoxia-responsive angiogenic factor that is also associated with increasing vascular permeability. Although VEGF levels were not correlated to presence of

edema on physical examination, dogs that had markedly elevated VEGF levels were less likely to survive.37 Increased vascular permeability causes efflux of water, proteins and solutes into the interstitial space, thereby causing an increased distance from the red blood cells within the capillaries to the target cell mitochondria, and consequently impairment of oxygen transport and delivery to the mitochondria.35 One can think of the endothelium itself as an “organ,” subject to dysfunction and failure in sepsis, just as the heart, kidneys and brain (and others) can become dysfunctional. There are likely regional and temporal differences in microcirculatory function and dysfunction. Areas that are very dysfunctional contribute to arteriovenous shunting as a result of functional and mechanical obstruction; the associated tissue suffers from a hypoxic insult. The dysfunctional endothelium has been proposed as the “motor” of MODS. New technology such as sidestream darkfield imaging enables visualization and assessment of microcirculatory derangements during sepsis and in response to therapy. Even if the microcirculation is functional, mitochondrial changes still occur secondary to sepsis.35 Mitochondria themselves can become dysfunctional in septic patients (termed cytopathic hypoxia), which contributes further to heterogenous hypoxic tissue beds.33,38 In addition to their critical role in oxidative phosphorylation, mitochondria are also involved in apoptotic pathways and cell death.

EPIDEMIOLOGY Septic Foci, Diseases, and Pathogens Associated with Sepsis The available epidemiologic information describing the septic foci and common pathogens in small animals can be found in Table 91-4. Although there are numerous possible septic sources (see Table 91-4 and Chapters 23, 97 to 102, 117, 122, and 126), septic peritonitis is a common cause of sepsis, particularly in dogs. Leakage of contents from the GI tract occurs secondary to GI neoplasia, ingestion of foreign bodies (and subsequent perforation), dehiscence of biopsy sites, enterotomies or resected intestine,

Table 91-4  Septic Foci in Cats and Dogs and Pathogens Involved4,19,21,22,40-45,89-92 Site

Disease Examples

Dogs (%)

Cats (%) 2,4,8

10

Pathogens

Peritoneal cavity

GI perforation

35%-36%

47%

Coagulase-negative Staphylococcus spp, Enterococcus spp, B-hemolytic Streptococcus spp, Escherichia coli, Klebsiella spp, Enterobacter spp, Pasteurella spp, Corynebacterium spp4,40,42,43

Pulmonary parenchymal, pleural

Pneumonia

20%4,41

24% (pyothorax) + 14% (pneumonia)21

B-hemolytic Streptococcus spp, E. coli, Bordetella bronchiseptica, Staphylococcus spp, E. coli, Klebsiella spp, Pseudomonas spp, Enterococcus faecalis, Acinetobacter spp, Pasteurella spp4,44

Gastrointestinal

Enteritis, bacterial translocation

4%

5%21

E. coli 21

Reproductive

Pyometra Prostatitis

25%4,6

Urinary tract

Pyelonephritis Bacterial cystitis

4%-10%4

8%,22 7%21

B-hemolytic Streptococcus spp, E. coli, Acinetobacter spp, Enterococcus spp4,22

Soft tissue, bone

Trauma, osteomyelitis, bite wounds

29%

16%,22 3% (osteomyelitis) + 3% (bite wounds21; 3%-50%6,21,22

E. coli, Enterobacter spp4

Cardiovascular

Endocarditis

14%21

Staphylococcus lugdunensis, Bartonella spp, S. aureus, E. faecalis, Granulicatella spp, Streptococcus spp, Brucella spp45

Group G Streptococcus spp, Enterococcus spp, B-hemolytic Streptococcus spp, E. coli, Klebsiella spp4

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nonsteroidal antiinflammatory drug (NSAID)–associated ulcers, perforation of megacolon, and severe colitis. Other reported causes of septic peritonitis include contamination from the urinary bladder, gallbladder, or uterine rupture; GI disease such as salmonellosis or parvoviral enteritis; and hepatic, pancreatic, splenic, and mesenteric lymph node abscess formation.6,22,40 Aside from septic peritonitis, other less common causes of sepsis include pyelonephritis, pneumonia, septic arthritis, deep pyoderma, bacterial endocarditis, tickborne diseases, vasculitis, septic meningitis, pyothorax, trauma, bite wounds, osteomyelitis, septic prostatitis, and immune suppression.* Gram-negative enteric bacteria are the most commonly implicated organisms in sepsis in dogs and cats; however, mixed infections and gram-positive infections are also described.4,22,40,42-45 Culture of infected tissue should be obtained whenever possible (i.e., safe for the patient) because early and appropriate antimicrobial selection is essential for preventing bacterial replication and reducing the host inflammatory response to infection. Knowledge of common isolates and the hospital antibiogram may help guide empiric antimicrobial selection (see Chapter 175).

RESUSCITATION AND TREATMENT OF SEPSIS, SEVERE SEPSIS, AND SEPTIC SHOCK Introduction to the Bundle Concept Major improvements in outcome in septic human patients have been accomplished through use of sepsis treatment “bundles.” A bundle of care refers to a group of therapies that, when instituted together, result in better outcomes than if each individual component were to be implemented alone.46 For sepsis, evidence-based guidelines for sepsis management are published in the Surviving Sepsis campaign international guidelines. Hospitals47 that have implemented the guidelines report decreased mortality rates.48-50 Bundle recommendations and the current guidelines were born out of earlier landmark studies in early goal-directed resuscitation.51 Although there is still controversy regarding the best individual bundle components, numerous studies have since shown that implementation of a sepsis bundle reduces mortality.52 Enthusiasm remains for the bundle approach (even in veterinary medicine), and it stands to reason that the same approach may improve outcomes in veterinary patients.†

Bundle Element: Lactate Lactate production is a result of anaerobic metabolism, most commonly as a result of hypoperfusion. High initial lactate levels are associated with poorer outcomes, particularly if the hyperlactatemia persists and if accompanied by hypotension.55-62 However, lactate clearance as it relates to traditional (e.g., blood pressure) and more recent (e.g., ScvO2) parameters remain unclear. Lactate kinetics in the individual patient probably depends on the phase of sepsis; lactate together with ScvO2 may provide complementary information about the efficacy of resuscitation (see Chapter 183).58,63 The Surviving Sepsis campaign guidelines recommend measuring lactate within the first 6 hours of admission and promptly initiating fluid resuscitation for patients with lactate concentrations 4 mmol/L or greater.38 The available veterinary literature supports this recommendation (see Chapter 56).36,53,55

Bundle Element: Samples for Culture (Blood, Tissue, or Fluid Cultures) In human health care, obtaining blood cultures in patients with sepsis or suspected sepsis is very much the standard of care and blood

*References 4, 6, 21, 22, 29, 41. † References 18, 36, 48, 50, 53, 54.

cultures are positive in 30% to 50% of patients with severe sepsis or septic shock.1,48 In veterinary medicine, blood cultures may be less routinely performed. In one study, however, 49% of critically ill dogs and cats had positive blood cultures.64 Another study reported that 43% of dogs with gastric dilation and volvulus developed positive blood cultures. The importance of obtaining samples for culture to aid in selection (and deescalation) of antimicrobials cannot be overemphasized; however, obtaining the samples should not cause a delay in initiating resuscitation nor put the patient at risk.

Bundle Element: Early Source Control and Early Antibiotic Administration (see Chapters 175 to 182) Of paramount importance in treating the septic patient is the identification and removal of the septic focus (“source control”) and early administration of antimicrobials. In human patients with septic shock, elapsed time from shock recognition and qualification for early goal-directed therapy to appropriate antimicrobial therapy is a primary determinant of mortality; there is no reason to think that the same is not true in veterinary patients.65-67 Early antimicrobial therapy is now conceptually “bundled” with more traditional aspects of sepsis resuscitation such as hemodynamic stabilization.68 Empiric selection of appropriate antimicrobials can be challenging and should consider the location of the infection (and the ability of the antibiotic to penetrate the site), the suspected bacterial flora, community versus nosocomial source, duration of hospitalization, and previous exposure to antimicrobials (see Chapter 175). Bactericidal rather than bacteriostatic antimicrobials are preferred. In both veterinary and human studies, administration of inappropriate antimicrobials is associated with increased mortality.6,67 In patients who have been hospitalized for some time, the chances of infection with multidrug-resistant bacteria increase, so careful consideration of hospital antibiograms should be employed when choosing empiric antimicrobials therapy.69 In some patients, sample collection may be impossible because of cardiopulmonary instability or coagulopathy; however, the inability to gather samples for culture and susceptibility testing should never cause a delay in the administration of antimicrobials to patients with sepsis, severe sepsis, or septic shock. Septic patients require a broad-spectrum bactericidal antimicrobial regimen that is administered via the intravenous route (see Chapters 175 and 182). Following are some examples of four-quadrant therapy (i.e., therapies that are effective against gram-positive and gram-negative aerobes and anaerobes). All dosages are listed for the intravenous route, except when indicated otherwise: Ampicillin (22 mg/kg q8h) and enrofloxacin (10 to 20 mg/kg q24h; 5 mg/kg q24h in cats) Ampicillin (22 mg/kg q8h) and amikacin (15 mg/kg q24h [dog], 10 mg/kg q24h [cat]) Ampicillin (22 mg/kg q8h) and gentamicin (10 mg/kg q24h [dog], 6 mg/kg q24h [cat]) Cefazolin (22 mg/kg q8h) and amikacin (15 mg/kg q24h [dog], 10 mg/kg q24h [cat]) Cefazolin (22 mg/kg q8h) and gentamicin (10 mg/kg q24h [dog], 6 mg/kg q24h [cat]) Ampicillin (22 mg/kg q8h) and cefoxitin (15 to 30 mg/kg q4-6h) Ampicillin (22 mg/kg q8h) and cefotaxime (25 to 50 mg/kg q4-6h) Ampicillin (22 mg/kg q8h) and ceftazidime (30 to 50 mg/kg q6-8h) Clindamycin (8 to 10 mg/kg q8-12h) and enrofloxacin (5 to 20 mg/kg q24h; 5 mg/kg q24h in cats) Clindamycin (8 to 10 mg/kg q8-12h) and amikacin (15 mg/kg q24h [dog], 10 mg/kg q24h [cat]) Clindamycin (8 to 10 mg/kg q8-12h) and gentamicin (10 mg/kg q24h [dog], 6 mg/kg q24h [cat])

• • • • • • • • • • •

CHAPTER 91  •  Sepsis and Septic Shock

Table 91-5  Circulatory Support in Severe Sepsis and Septic Shock20 Fluid Therapy

Indications

Dose

Comments

Isotonic crystalloids

Intravascular volume replacement Interstitial fluid deficits Maintenance

Dog: Up to 60 to 90 ml/kg* Cat: Up to 40 to 60 ml/kg*

May precipitate interstitial edema in patients with capillary leak or a low colloid osmotic pressure

Synthetic colloids (e.g., hydroxyethyl starch)

Volume replacement Colloid osmotic support

Dog: 5 to 20 ml/kg* Cat: 5 to 10 ml/kg*

Dose-related coagulopathies and acute kidney injury (humans) have been documented An arbitrary recommendation is ≤20 ml/kg q24h

Human albumin solution (HSA)

Colloid osmotic pressure support Volume replacement Albumin supplementation

2 ml/kg/hr of 25% HSA for 1 to 2 hours followed by 0.1 to 0.2 ml/kg/hr × 10 hours Or, calculate albumin deficit: Alb deficit (in grams) = 10 × (desired Alb – patient Alb) × wt (kg) × 0.3 and replace over 4 to 6 hours

Doses extrapolated from human literature Monitor closely for reactions

Fresh frozen plasma

Coagulopathies Factor deficiencies Supplemental volume and colloid osmotic support

10 to 15 ml/kg as needed

Not effective at increasing albumin concentration

Packed red blood cells

Anemia

10 to 15 ml/kg will raise PCV by ~10%

—

Fresh whole blood

Anemia Thrombocytopenia Coagulopathies and factor deficiencies Volume replacement

20 ml/kg will raise PCV by ~10%

—

Alb, Albumin; HSA, human albumin serum; PCV, packed cell volume. *Listed intravenous fluid doses are “shock doses.” Generally, a fraction of the listed dose is given (e.g., one fourth to one half) and response is assessed; the dose is repeated as necessary or until fluid tolerance is reached. Cats seem to have a poor pulmonary tolerance to volume resuscitation; therefore smaller doses may be tried first.

• Ticarcillin and clavulanic acid (50 mg/kg q6h) and enrofloxacin (10 to 20 mg/kg q24h; 5 mg/kg q24h in cats) • Imipenem (5 to 10 mg/kg q6-8h) • Meropenem (24 mg/kg q24h or 12 mg/kg SC q8-12h) • Chloramphenicol (25 to 50 mg/kg q8h; 12.5 to 20 mg/kg q12h in cats)

Bundle Element: Treat Hypotension with Fluids and Possibly Vasopressors Assessment of volume status and responsiveness Because septic shock patients are, by definition, in circulatory collapse despite volume resuscitation, cardiovascular support is of key importance. Fluid therapy is essential to maintain adequate tissue oxygen delivery and to prevent the development of MODS and death (see Chapter 60). Assessment of volume status and the potential for volume responsiveness can be difficult. Traditionally, static measures to indirectly measure preload, such as pulmonary artery occlusion pressure (PAOP) and central venous pressure (CVP), have been used. However, they can be cumbersome (PAOP) and not predictive of volume responsiveness (CVP).70 Dynamic measures of fluid responsiveness may include echocardiographic evaluation of cardiac function and arterial waveform variation in ventilated patients. More simple yet still dynamic measures may include administering serial small fluid boluses or (in people) passive leg elevation and evaluation of the hemodynamic response.52,71 Accurate monitoring of body weight and urine output via an indwelling urinary catheter is also helpful in assessing total fluid balance as well as monitoring for oligoanuric renal failure. It should be noted, however, that urinary output is a result of the balance between preglomerular and postglomerular resistance. Thus a marked increase in postglomerular

resistance can induce an increase in urinary output in the presence of renal hypoperfusion.

Fluid choice The first line of resuscitation in septic patients is fluid therapy. Isotonic crystalloids, hypertonic crystalloid solutions, synthetic colloids, and blood component therapy may be used for fluid therapy in the septic patient (Table 91-5). The choice of fluids depends on the overall clinical and clinicopathologic picture (see Chapters 58 and 60). Recent studies in human septic patients have called into question the safety of synthetic colloids, specifically hydroxyethyl starches, which now have a black box warning for this population of human patients.72,73 Synthetic colloids have been a staple of fluid resuscitation in veterinary medicine; however, human studies have shown that resuscitation with these fluids in people is associated with an increased incidence of acute kidney injury and need for renal replacement therapy and, in the case of the Perner et al study, an increased risk of death at day 90. The results of other studies regarding the safety of synthetic colloids were mixed, and no safety studies to date are available in veterinary patients.74-76 The current recommendation in human critical care is to avoid synthetic colloids in septic patients, especially when other fluid therapy options such as albumin, plasma, or crystalloids are available, or until more rigorous data on the safety of synthetic colloids are published.52 Patients with severe sepsis and septic shock are very often hypoalbuminemic.77,78 Unfortunately, large volumes of fresh frozen plasma are required for albumin replacement (i.e., 22 ml/kg of plasma to raise the albumin concentration by 0.5 g/dl).78 Fresh frozen plasma is therefore generally only used to prevent a further decline in albumin in severely hypoalbuminemic patients and for correction of

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Table 91-6  Commonly Used Constant Rate Infusion Vasopressor Therapy Vasopressor

Dose rate

Norepinephrine

0.1-2 mcg/kg/min IV

Vasopressin

0.5-5 mU/kg/min IV

Dopamine

5-15 mcg/kg/min IV

coagulopathies and factor deficiencies. Human serum albumin (5% or 25%) is still in the early stages of clinical use in veterinary medicine and research is ongoing. The 25% human serum albumin solution is hyperoncotic (colloid osmotic pressure = 100 mm Hg) and should be used judiciously in patients with limited fluid tolerance (see Chapter 58 for further details). Although it does seem effective in raising albumin concentration, questions regarding its safety exist.79-81 Coagulopathies, anemia, and thrombocytopenia may prompt the use of blood component therapy (e.g., fresh frozen plasma, packed red blood cells, fresh whole blood, respectively).

Hypotension despite volume resuscitation (septic shock) Hypotension that persists after restoration of intravascular volume is an indication for vasopressors or inotropic agents to support flow to tissues (see Chapters 8, 157, and 158). The decision to use a vasopressor or cardiotonic drug depends on the clinical presentation and objective information obtained from the septic patient (e.g., assessment of cardiac contractility). Vasopressors such as norepinephrine, vasopressin, dopamine, and phenylephrine are most commonly used in patients with peripheral vasodilation (Table 91-6). Norepinephrine is preferred to dopamine in septic human patients, and vasopressin is also considered a reasonable first-line vasopressor.52,82,83 Studies in septic veterinary patients are ongoing. Although vasopressors may maintain arterial blood pressure, they can also result in excessive vasoconstriction, particularly to the splanchnic and renal circulation, thereby causing GI and renal ischemia. Particularly in the dog, splanchnic vasoconstriction may exacerbate the septic state by promoting loss of gut barrier function and bacterial translocation of bacteria to the bloodstream. Positive inotropic agents such as dobutamine are generally used in patients with evidence of impaired myocardial contractility (decreased fractional shortening on M-mode echocardiography, decreased cardiac output per invasive or noninvasive measurements). They might also be combined with more selective vasoconstrictors such as vasopressin or phenylephrine.

Bundle Element: Target Central Venous Pressure and Central Venous Pressure and ScvO2 Venous oxygen saturation is a measure of the saturation of hemoglobin with oxygen in the venous blood; it is reflective of the difference between oxygen delivery (DO2) and oxygen consumption (VO2). Venous oximetry is monitored intermittently via blood sampling or co-oximetry, or continuously using fiberoptics (spectrophotometry).84 Mixed venous oxygen saturation (SvO2) refers to venous blood in the pulmonary artery. Mixed venous blood is pooled blood from the entire body, including blood from the caudal half of the body (i.e., the abdomen and lower extremities) and the coronary circulation. SvO2 can be viewed as the result of the overall difference in oxygen delivery (DO2) and oxygen consumption (VO2) and therefore is a marker of global oxygen debt. Central venous oxygen saturation (ScvO2) generally refers to the saturation of blood in the cranial vena cava, reflective of oxygen delivery and utilization in the head and upper body. In health, ScvO2 is slightly lower than SvO2 by about 2%

to 3%, in part because of the high metabolic rate of the brain and cranial half of the body and also because of the contribution of vascular circuits that use blood for nonoxidative phosphorylation needs in the caudal half of the body (e.g., the renal blood flow).84 In shock states the relationship between central and mixed saturation can reverse; ScvO2 can be much higher than SvO2; this likely is due to redistribution of blood flow from the splanchnic circulation to the coronary and cerebral vascular beds.85-87 Consensus and the international guidelines state that measuring ScvO2 in lieu of SvO2 (because it technically easier) can be used successfully during sepsis resuscitation.48 In health much more oxygen is delivered than is extracted; however, when delivery decreases to a critical threshold, extraction decreases in concert and the patient experiences oxygen debt and lactic acidosis. Monitoring venous oxygen saturation and using it as a therapeutic target is a recommendation in the Surviving Sepsis guidelines.48 The few veterinary studies that have evaluated ScvO2 as a therapeutic goal suggest its potential value in resuscitating septic and critically ill veterinary patients.53,88 In both studies, ScvO2 was associated with prognosis.53,88 These veterinary studies mirror a large body of work in human medicine that resulted in a recommendation in the Surviving Sepsis campaign to resuscitate to an ScvO2 of 70% or greater or an SvO2 65% or greater.48

CONCLUSION Sepsis is an important and very common problem in both veterinary and human health care. Hallmark pathophysiologic changes include widespread endothelial disruption, microcirculatory failure, progressive inflammation or immune paralysis, and activation of the coagulation cascade. Throughout the progression from sepsis to septic shock, there is extensive interplay between the coagulation and immune systems. Ultimately, circulatory collapse (both macro- and micro-) leads to hypoperfusion, tissue ischemia, organ failure, and death. Treatment of septic patients critically depends on early recognition, early antimicrobial therapy, and aggressive hemodynamic support. Bundled care appears to be very effective in human septic patients, and studies in veterinary medicine are starting to suggest the same.

REFERENCES 1. Angus DC, Linde-Zwirble WT, Lidicker J, et al: Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care, Crit Care Med 29(7):1303, 2001. 2. Li J, Carr B, Goyal M, et al. Sepsis: The inflammatory foundation of pathophysiology and therapy, Hosp Pract (Minneap) 39(3):99, 2011. 3. Parsons KJ, Owen LJ, Lee K, et al: A retrospective study of surgically treated cases of septic peritonitis in the cat (2000-2007), J Small Anim Pract 50(10):518, 2009. 4. de Laforcade AM, Freeman LM, Shaw SP, et al: Hemostatic changes in dogs with naturally occurring sepsis, J Vet Intern Med 17(5):674, 2003. 5. Hauptman JG, Walshaw R, Olivier NB: Evaluation of the sensitivity and specificity of diagnostic criteria for sepsis in dogs, Vet Surg 26(5):393, 1997. 6. King LG: Postoperative complications and prognostic indicators in dogs and cats with septic peritonitis: 23 cases (1989-1992), J Am Vet Med Assoc 204(3):407, 1994. 7. Greenfield CL, Walshaw R: Open peritoneal drainage for treatment of contaminated peritoneal cavity and septic peritonitis in dogs and cats: 24 cases (1980-1986), J Am Vet Med Assoc 191(1):100, 1987. 8. Wan L, Bellomo R, May CN: The effect of normal saline resuscitation on vital organ blood flow in septic sheep, Intensive Care Med 32(8):1238, 2006. 9. Martin GS: Sepsis, severe sepsis and septic shock: changes in incidence, pathogens and outcomes, Expert Rev Anti Infect Ther 10(6):701, 2012.

CHAPTER 91  •  Sepsis and Septic Shock 10. Levy MM, Fink MP, Marshall JC, et al: 2001 SCCM/ESICM/ACCP/ATS/ SIS international sepsis definitions conference, Crit Care Med 31(4):1250, 2003. 11. Silverstein DC, Wininger FA, Shofer FS, et al: Relationship between Doppler blood pressure and survival or response to treatment in critically ill cats: 83 cases (2003-2004), J Am Vet Med Assoc 232(6):893, 2008. 12. Dobrovolskaia MA, Vogel SN: Toll receptors, CD14, and macrophage activation and deactivation by LPS, Microbes Infect 4(9):903, 2002. 13. Van Amersfoort ES, Van Berkel TJ, Kuiper J: Receptors, mediators, and mechanisms involved in bacterial sepsis and septic shock, Clin Microbiol Rev 16(3):379, 2003. 14. Jiang Q, Akashi S, Miyake K, et al: Lipopolysaccharide induces physical proximity between CD14 and toll-like receptor 4 (TLR4) prior to nuclear translocation of NF-kappa B, J Immunol 165(7):3541, 2000. 15. Martin GS: Sepsis, severe sepsis and septic shock: changes in incidence, pathogens and outcomes, Expert Rev Anti Infect Ther 10(6):701, 2012. 16. Bone RC, Grodzin CJ, Balk RA: Sepsis: a new hypothesis for pathogenesis of the disease process, Chest 112(1):235, 1997. 17. Fernandes D, Assreuy J: Nitric oxide and vascular reactivity in sepsis, Shock 30(Suppl 1):10, 2008. 18. Aird WC: The hematologic system as a marker of organ dysfunction in sepsis, Mayo Clin Proc 78(7):869, 2003. 19. Reference deleted in pages. 20. Brady CA, Otto CM: Systemic inflammatory response syndrome, sepsis, and multiple organ dysfunction, Vet Clin North Am Small Anim Pract 31(6):1147, v-vi, 2001. 21. Brady CA, Otto CM, Van Winkle TJ, et al: Severe sepsis in cats: 29 cases (1986-1998), J Am Vet Med Assoc 217(4):531, 2000. 22. Costello MF, Drobatz KJ, Aronson LR, et al: Underlying cause, pathophysiologic abnormalities, and response to treatment in cats with septic peritonitis: 51 cases (1990-2001). J Am Vet Med Assoc. 2004;225(6):897-902. 23. De Kock I, Van Daele C, Poelaert J: Sepsis and septic shock: pathophysiological and cardiovascular background as basis for therapy, Acta Clin Belg 65(5):323, 2010. 24. Osterbur K, Whitehead Z, Sharp CR, et al: Plasma nitrate/nitrite concentrations in dogs with naturally developing sepsis and non-infectious forms of the systemic inflammatory response syndrome, Vet Rec 169(21):554, 2011. 25. Levi M, van der Poll T, Schultz M: New insights into pathways that determine the link between infection and thrombosis, Neth J Med 70(3):114, 2012. 26. Brainard BM, Brown AJ: Defects in coagulation encountered in small animal critical care, Vet Clin North Am Small Anim Pract 41(4):783, vii, 2011. 27. de Laforcade A: Diseases associated with thrombosis, Top Companion Anim Med 27(2):59, 2012. 28. Bentley A, Mayhew P, Culp W, et al: Alterations in the hemostatic profiles of dogs with naturally occurring septic peritonitis, J Vet Emerg Crit Care (San Antonio) 2013 (in press). 29. Otto CM, Rieser TM, Brooks MB, Russell MW: Evidence of hypercoagulability in dogs with parvoviral enteritis, J Am Vet Med Assoc 217(10):1500, 2000. 30. Aird WC: Endothelium in health and disease, Pharmacol Rep 60(1):139, 2008. 31. Vallet B, Wiel E: Endothelial cell dysfunction and coagulation, Crit Care Med 29(7 Suppl):S36-S41, 2001. 32. Chappell D, Westphal M, Jacob M: The impact of the glycocalyx on microcirculatory oxygen distribution in critical illness, Curr Opin Anaes 22(2):155-162, 2009. 33. Reggiori G, Occhipinti G, De Gasperi A, et al: Early alterations of red blood cell rheology in critically ill patients, Crit Care Med 37(12):30413046, 2009. 34. De Backer D, Creteur J, Preiser JC, et al: Microvascular blood flow is altered in patients with sepsis, Am J Resp Crit Care Med 166(1):98-104, 2002. 35. De Backer D, Donadello K, Cortes DO: Monitoring the microcirculation, J Clin Monit Comput 26(5):361, 2012. 36. Silverstein D: Tornadoes, sepsis, and goal-directed therapy in dogs, J Vet Emerg Crit Care (San Antonio) 22(4):395, 2012.

37. Silverstein DC, Montealegre C, Shofer FS, et al: The association between vascular endothelial growth factor levels and clinically evident peripheral edema in dogs with systemic inflammatory response syndrome, J Vet Emerg Crit Care (San Antonio), 19(5):459, 2009. 38. Fink MP: Cytopathic hypoxia: mitochondrial dysfunction as mechanism contributing to organ dysfunction in sepsis, Crit Care Clin 17(1):219, 2001. 39. Reference deleted in pages. 40. Bonczynski JJ, Ludwig LL, Barton LJ, et al: Comparison of peritoneal fluid and peripheral blood pH, bicarbonate, glucose, and lactate concentration as a diagnostic tool for septic peritonitis in dogs and cats Vet Surg 32(2):161, 2003. 41. Weiss DJ, Welle M, Mortiz A, et al: Evaluation of leukocyte cell surface markers in dogs with septic and nonseptic inflammatory diseases, Am J Vet Res 65(1):59, 2004. 42. Son TT, Thompson L, Serrano S, et al: Surgical intervention in the management of severe acute pancreatitis in cats: 8 cases (2003-2007), J Vet Emerg Crit Care (San Antonio) 20(4):426, 2010. 43. Parsons KJ, Owen LJ, Lee K, et al: A retrospective study of surgically treated cases of septic peritonitis in the cat (2000-2007), J Small Anim Pract 50(10):518, 2009. 44. Radhakrishnan A, Drobatz KJ, Culp WT, et al: Community-acquired infectious pneumonia in puppies: 65 cases (1993-2002), J Am Vet Med Assoc 230(10):1493, 2007. 45. Meurs KM, Heaney AM, Atkins CE, et al: Comparison of polymerase chain reaction with bacterial 16s primers to blood culture to identify bacteremia in dogs with suspected bacterial endocarditis, J Vet Intern Med 25(4):959, 2011. 46. Cinel I, Dellinger RP: Guidelines for severe infections: are they useful? Curr Opin Crit Care 12(5):483, 2006. 47. Dellinger RP, Levy MM, Rhodes A, et al: Surviving Sepsis campaign: international guidelines for management of severe sepsis and septic shock, 2012, Intensive Care Med 39(2):165, 2013. 48. Dellinger RP, Levy MM, Carlet JM, et al: Surviving sepsis campaign: International guidelines for management of severe sepsis and septic shock: 2008, Crit Care Med 36(1):296, 2008. 49. Nguyen HB, Corbett SW, Steele R, et al: Implementation of a bundle of quality indicators for the early management of severe sepsis and septic shock is associated with decreased mortality, Crit Care Med 35(4):1105, 2007. 50. Levy MM, Dellinger RP, Townsend SR, et al: The surviving sepsis campaign: results of an international guideline-based performance improvement program targeting severe sepsis, Crit Care Med 38(2):367, 2010. 51. Rivers E, Nguyen B, Havstad S, et al: Early goal-directed therapy in the treatment of severe sepsis and septic shock, N Engl J Med 345(19):1368, 2001. 52. Puskarich MA: Emergency management of severe sepsis and septic shock, Curr Opin Crit Care 18(4):295, 2012. 53. Conti-Patara A, de Araujo Caldeira J, de Mattos-Junior E, et al: Changes in tissue perfusion parameters in dogs with severe sepsis/septic shock in response to goal-directed hemodynamic optimization at admission to ICU and the relation to outcome, J Vet Emerg Crit Care (San Antonio) 22(4):409, 2012. 54. Butler AL: Goal-directed therapy in small animal critical illness, Vet Clin North Am Small Anim Pract 41(4):817, vii, 2011. 55. Stevenson CK, Kidney BA, Duke T, et al: Serial blood lactate concentrations in systemically ill dogs, Vet Clin Pathol 36(3):234, 2007. 56. Puskarich MA, Trzeciak S, Shapiro NI, et al: Prognostic value and agreement of achieving lactate clearance or central venous oxygen saturation goals during early sepsis resuscitation. Acad Emerg Med 19(3):252, 2012. 57. Mikkelsen ME, Miltiades AN, Gaieski DF, et al: Serum lactate is associated with mortality in severe sepsis independent of organ failure and shock, Crit Care Med 37(5):1670, 2009. 58. Napoli AM, Seigel TA. The role of lactate clearance in the resuscitation bundle, Crit Care 15(5):199, 2011. 59. Nguyen HB, Loomba M, Yang JJ, et al: Early lactate clearance is associated with biomarkers of inflammation, coagulation, apoptosis, organ dysfunction and mortality in severe sepsis and septic shock, J Inflamm (Lond) 7:6, 2010.

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PART X  •  INFECTIOUS DISORDERS 60. Nguyen HB, Rivers EP, Knoblich BP, et al: Early lactate clearance is associated with improved outcome in severe sepsis and septic shock, Crit Care Med 32(8):1637, 2004. 61. Puskarich MA, Trzeciak S, Shapiro NI, et al: Association between timing of antibiotic administration and mortality from septic shock in patients treated with a quantitative resuscitation protocol, Crit Care Med 39(9): 2066, 2011. 62. Tian HH, Han SS, Lv CJ, et al: The effect of early goal lactate clearance rate on the outcome of septic shock patients with severe pneumonia, Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 24(1):42, 2012. 63. Rivers EP, Elkin R, Cannon CM: Counterpoint: should lactate clearance be substituted for central venous oxygen saturation as goals of early severe sepsis and septic shock therapy? No, Chest 140(6):1408; discussion 1413, 2011. 64. Dow SW, Curtis CR, Jones RL, et al: Bacterial culture of blood from critically ill dogs and cats: 100 cases (1985-1987), J Am Vet Med Assoc 195(1):113, 1989. 65. Gaieski DF, Mikkelsen ME, Band RA, et al: Impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency department, Crit Care Med 38(4):1045, 2010. 66. Kumar A, Roberts D, Wood KE, et al: Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock, Crit Care Med 34(6):1589, 2006. 67. Kumar A, Ellis P, Arabi Y, et al: Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock, Chest 136(5):1237, 2009. 68. Mikkelsen ME, Gaieski DF: Antibiotics in sepsis: timing, appropriateness, and (of course) timely recognition of appropriateness, Crit Care Med 39(9):2184, 2011. 69. Black DM, Rankin SC, King LG: Antimicrobial therapy and aerobic bacteriologic culture patterns in canine intensive care unit patients: 74 dogs (January-June 2006), J Vet Emerg Crit Care (San Antonio) 19(5):489, 2009. 70. Marik PE, Baram M, Vahid B: Does central venous pressure predict fluid responsiveness? A systematic review of the literature and the tale of seven mares, Chest 134(1):172, 2008. 71. Cavallaro F, Sandroni C, Marano C, et al: Diagnostic accuracy of passive leg raising for prediction of fluid responsiveness in adults: Systematic review and meta-analysis of clinical studies, Intensive Care Med 36(9):1475, 2010. 72. Perner A, Haase N, Guttormsen AB, et al: Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis, N Engl J Med 367(2):124, 2012. 73. Bayer O, Reinhart K, Sakr Y, et al: Renal effects of synthetic colloids and crystalloids in patients with severe sepsis: a prospective sequential comparison, Crit Care Med 39(6):1335, 2011. 74. Sakr Y, Payen D, Reinhart K, et al: Effects of hydroxyethyl starch administration on renal function in critically ill patients, Br J Anaesth 98(2):216, 2007. 75. Schortgen F, Lacherade JC, Bruneel F, et al: Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: a multicentre randomised study, Lancet 357(9260):911, 2001.

76. Falco S, Bruno B, Maurella C, et al: In vitro evaluation of canine hemostasis following dilution with hydroxyethyl starch (130/0.4) via thromboelastometry, J Vet Emerg Crit Care (San Antonio) 22(6):640, 2012. 77. Declue AE, Delgado C, Chang CH, et al: Clinical and immunologic assessment of sepsis and the systemic inflammatory response syndrome in cats, J Am Vet Med Assoc 238(7):890, 2011. 78. Sganga G, Siegel JH, Brown G, et al: Reprioritization of hepatic plasma protein release in trauma and sepsis, Arch Surg 120(2):187, 1985. 79. Vigano F, Perissinotto L, Bosco VR: Administration of 5% human serum albumin in critically ill small animal patients with hypoalbuminemia: 418 dogs and 170 cats (1994-2008), J Vet Emerg Crit Care (San Antonio) 20(2):237, 2010. 80. Mathews KA: The therapeutic use of 25% human serum albumin in critically ill dogs and cats, Vet Clin North Am Small Anim Pract 38(3):595, xi, 2008. 81. Trow AV, Rozanski EA, Delaforcade AM, et al: Evaluation of use of human albumin in critically ill dogs: 73 cases (2003-2006), J Am Vet Med Assoc 233(4):607, 2008. 82. De Backer D, Aldecoa C, Njimi H, et al: Dopamine versus norepinephrine in the treatment of septic shock: a meta-analysis*, Crit Care Med 40(3):725, 2012. 83. Vasu TS, Cavallazzi R, Hirani A, et al: Norepinephrine or dopamine for septic shock: systematic review of randomized clinical trials, J Intensive Care Med 27(3):172, 2012. 84. Marx G, Reinhart K: Venous Oximetry, Curr Opin Crit Care 12(3):263, 2006. 85. Scheinman M, Brown M, Rapaport E: Critical assessment of use of central venous oxygen saturation as a mirror of mixed venous oxygen in severely ill cardiac patients, Circulation 40:165, 1969. 86. Lee J, Wright F, Barber R: Central venous oxygen saturation in shock: A study in man. Anesthesiology 36:472, 1972. 87. Reinhart K, Kuhn H, Hartog C, et al: Continuous central venous and pulmonary artery oxygen saturation monitoring in the critically ill, Intensive Care Med 30:1572, 2004. 88. Hayes GM, Mathews K, Boston S, et al: Low central venous oxygen saturation is associated with increased mortality in critically ill dogs, J Small Anim Pract 52(8):433, 2011. 89. Case JB, Fick JL, Rooney MB: Proximal duodenal perforation in three dogs following deracoxib administration, J Am Anim Hosp Assoc 46(4):255, 2010. 90. Hickey MC, Magee A: Gastrointestinal tract perforations caused by ingestion of multiple magnets in a dog, J Vet Emerg Crit Care (San Antonio) 21(4):369, 2011. 91. Rossmeissl EM, Palmer KG, Hoelzler MG, et al: Multiple magnet ingestion as a cause of septic peritonitis in a dog, J Am Anim Hosp Assoc 47(1):56, 2011. 92. Humm KR, Adamantos SE, Benigni L, et al: Uterine rupture and septic peritonitis following dystocia and assisted delivery in a great dane bitch, J Am Anim Hosp Assoc 46(5):353, 2010.

CHAPTER 92  MYCOPLASMA, ACTINOMYCES, AND NOCARDIA Christina Maglaras,

DVM  •  Amie

Koenig,

DVM, DACVIM (Internal Medicine), DACVECC

KEY POINTS • Mycoplasmas should be considered as a differential diagnosis in cats and dogs with disease of the respiratory or urinary tracts. The organism lacks a cell wall, thus cannot be visualized by cytology, and is resistant to β-lactam antimicrobials. • Actinomyces spp. are normal inhabitants on mucous membranes of animals and rely on disruption of the mucosa to cause disease. Prognosis is good with long-term antimicrobial therapy. The empiric drug of choice for treating Actinomyces spp. is penicillin. • Nocardia spp. are found normally in the environment, and opportunistic infection arises after inhalation or direct inoculation. Therapy involves surgical debridement and long-term treatment with antimicrobials; the empiric drug of choice is trimethoprim sulfa. Prognosis is guarded to poor for patients with nocardiosis.

Although Mycoplasma, Actinomyces, and Nocardia spp. belong to different genera, they share the potential to cause life-threatening infection. They also can pose diagnostic dilemmas because of difficulty in isolating the organisms via culture, their presence in mixed infections, and their lack of cell wall (Mycoplasma spp.), which inhibits cytologic identification. This chapter focuses on infections caused by nonhemotropic Mycoplasmas, Actinomyces, and Nocardia spp. that may be encountered in the critical care setting.

NONHEMOTROPIC MYCOPLASMAS Etiology and Clinical Syndromes Mycoplasmas are prokaryotes within the class Mollicutes and are the smallest free-living, self-replicating microorganisms.1,2 All members of the class lack a protective cell wall; thus they are damaged easily when outside of the host and are difficult to identify with most staining techniques. The small genome of mycoplasmas limits their metabolic capacity and requires the organisms to derive nutrients from the mucosal surfaces on which they colonize. Mycoplasmas can be categorized into nonhemotropic and hemotropic forms. Hemotropic forms include Mycoplasma haemocanis and Mycoplasma haemofelis (see Chapter 110). Nonhemotropic forms include Mycoplasma canis, Mycoplasma cynos, Mycoplasma felis, Mycoplasma gateae, and Ureaplasma spp. This section focuses on the nonhemotropic forms, which is referred to generically as “mycoplasmas” for the remainder of the chapter. Canine and feline mycoplasmas encompass a relatively small portion of the veterinary literature when compared with other types of infections.3 The role of mycoplasmas in disease is somewhat controversial, although interest regarding their role as either commensal, primary, or opportunistic pathogens in dogs and cats continues. Mycoplasmas have been implicated in infections of the respiratory, ocular, urogenital, and nervous systems, in addition to systemic infections.

Respiratory Infections Mycoplasmas are found as normal flora in the upper respiratory tract of dogs and cats3; they have been isolated from the lungs of healthy dogs but not healthy cats.1,2,4 Mycoplasmas (including ureaplasmas) were isolated from lungs of ill and healthy dogs at equivalent rates in one study5; M. canis was isolated more frequently from lungs of dogs with respiratory disease (24% versus 13% of healthy dogs) in another.6 Ureaplasmas rarely are isolated from healthy or diseased cat lungs.7 Although it is unclear whether mycoplasmas are primary or opportunistic pathogens, their contribution to upper and lower respiratory disease in veterinary species cannot be overlooked. In the cat, mycoplasma has been implicated as an important contributor to feline upper respiratory disease8 and has been identified in up to 80% of nasal and pharyngeal samples from cats with respiratory disease.9 In shelter cats that were euthanized with signs of upper respiratory disease, feline herpes virus-1 (FHV-1) was identified most commonly; however, M. felis was the next most common isolate (in approximately 30% of the cats).8 M. felis is associated with feline conjunctivitis and has been isolated more commonly from cats with conjunctivitis than clinically normal cats.10,11 In one study of 41 cats with conjunctivitis and upper respiratory disease, 49% had Mycoplasma spp. amplified from PCR testing of conjunctival swabs.11 Of those cats that tested positive for mycoplasma conjunctivitis, 50% had co-infections with Chlamydophila felis and 25% had coinfections with FHV-1 and C. felis.11 Although several Mycoplasma spp. have been isolated from canine conjunctiva, they have not been associated conclusively with canine conjunctivitis.12 Common clinical signs of Mycoplasma infection of the feline upper respiratory tract include serous to purulent oculonasal discharge, conjunctivitis, blepharospasm, chemosis, and hyperemic conjunctiva.11 Mycoplasmas also have been identified in mixed bacterial infections and as the sole pathogen associated with lower airway disease. Mycoplasmas may invade the lower respiratory tract as secondary opportunistic pathogens in patients with impaired mucociliary function secondary to a primary bacterial or viral infection or because of ciliary dyskinesia.1,13 Inflammatory airway disease, concurrent respiratory infections, aspiration of oropharyngeal contents, and/or immunosuppression also can facilitate mycoplasmal infections of the lower airway.3,4 Mycoplasma cynos has been isolated from dogs with naturally occurring respiratory disease, including puppies with lethal neonatal respiratory infections and dogs in kennel settings.14,15 In cats, mycoplasmosis has caused rare cases of bronchopneumonia and was reported in two young cats and one older cat with chronic coughing,16 one cat with bronchopneumonia with associated respiratory failure,17 as well as a pyothorax case in conjunction with Arcanobacterium spp.18 Commonly reported clinical signs of mycoplasma infections of the lower respiratory tract include coughing (spontaneous and on tracheal palpation), labored breathing, tachypnea, dyspnea, and nasal discharge. Secondary signs, such as weakness, anorexia, and fever, may or may not be seen.4 481

482

PART X  •  INFECTIOUS DISORDERS

Urogenital Associated Infections As with the respiratory tract, mycoplasmas are normal inhabitants of the human and canine urinary and urogenital mucosa.1,19 Currently, urogenital mycoplasmas are considered opportunistic bacteria; however, more research is needed to define their role further.1,3 Ureaplasmas require urea for a carbon source and thus are associated more commonly with the urogenital tract epithelium than other locations.20 M. canis has been cultured from dogs with urinary tract infections and from the mucosa of the lower urogenital tract in healthy dogs.21 There are also important species differences regarding urogenital mycoplasmal infections. Ureaplasma spp. can be transmitted from human mothers to their newborns through various routes, and these infections can cause pneumonia in human neonates.19 Thus far, similarly acquired infections have not been documented in the small animal literature. A litter of Golden Retriever puppies infected with M. canis was thought to acquire the infection via oral translocation from the bitch because the pathogen was not isolated from vaginal swabs.15 Mycoplasma infections infrequently are associated with the lower urinary tract but may manifest as pollakiuria, stranguria, hematuria, pyuria, and/or vulvar discharge. Only a small number of mycoplasmas may be needed to induce clinical disease21,22; therefore, in a dog with compatible clinical signs, identifying mycoplasmas in a urine sample obtained by cystocentesis is likely significant. In comparison, traditional canine bacterial urinary tract infections are considered significant if urine cultures obtained via cystocentesis have more than 1000 colony-forming units per milliliter.23 In one study of 100 dogs with signs of lower urinary tract disease, 41% had a positive aerobic culture, but only 4% had Mycoplasma spp. isolated (one with a mixed infection and three with only Mycoplasma spp.).24 All dogs with Mycoplasma spp. infections from this study were azotemic.24 In another study, mycoplasma was cultured from 60 urine samples obtained from 41 dogs with lower urinary tract infections.22 Of the cultures, 68% had mycoplasma grown in pure culture and 32% had mycoplasma mixed with other bacteria. M. canis was the most common mycoplasma species isolated.22 Normal feline urine seems to be relatively impervious to mycoplasmas, and no current evidence suggests that Mycoplasma spp. cause lower urinary tract disease in cats.20,25,26 Because of their lack of a cell wall, mycoplasmas are at high risk for osmotic damage by the normally highly concentrated feline urine.20 During in vitro studies, M. felis and M. gateae seemingly were unable to tolerate the hyperosmotic conditions presented by synthetic feline urine.20

Other Infections Nonhemotropic mycoplasmas also have been associated with other infections, including polyarthritis, bite wound abscesses, and meningoencephalitis.1,27-30 Mycoplasma spp. also have been isolated from blood cultures in one postoperative dog with suspected hyperadrenocorticism-induced immunosuppression that presented 5 days after a bilateral adrenalectomy with fever, vomiting, diarrhea, and shifting leg lameness with associated joint effusion.31 The exact cause of the infection was unclear.31 Identification of such unusual cases associated with mycoplasma suggests that the organism may be more common than recognized.

Diagnosis Cytology of infected tissue or fluids yields neutrophilic inflammation (and possibly presence of coinfecting bacteria)13 (Figure 92-1). Mycoplasmas lack a protective cell wall, preventing cytologic identification with Gram stain and other staining methods that target cell wall components.19 Although the small size and lack of cell wall make

10.0 m

FIGURE 92-1  Suppurative transtracheal wash from a patient with mycoplasmosis. (Photo courtesy Dr. B. Garner, University of Georgia.)

visualization of the organism via light microscopy difficult, negative staining with electron microscopy has been proven highly sensitive.32 Histopathology of Mycoplasma-infected tissues are unlikely useful as the sole diagnostic for this organism. In cats with upper respiratory disease, histopathology of nasal and oropharyngeal tissues commonly showed severe rhinitis and ulceration in cases of a coinfection with FHV-1.8 However, in the cases of solitary M. felis infections, the lesions were nonspecific and showed mild to moderate inflammatory changes.8 Culture with Mycoplasma-specific media still is considered the standard diagnostic test, although PCR is fast becoming the preferred method.11,14,33,34 Appropriate culture and PCR samples should be taken from the affected organ system and may include biopsy samples, conjunctival swabs, exudates, blood, and urine. To prevent contamination of voided samples with normal flora of the distal urogenital tract, urine samples should be obtained via a sterile cystocentesis. Ideal diagnostic specimens depend on the location of the infection (Table 92-1). Contact with a diagnostic lab before sample collection helps ensure appropriate collection, handling, and transport of samples for successful mycoplasma culture.1 Mycoplasmas are osmotically fragile microorganisms, and they require specialized culture media such as Hayflick broth, Amies medium, or modified Stuart bacterial-transport medium.1,19 In the absence of specialized media, samples can be placed in a sterile, red-topped tube.4 Samples should be refrigerated if the culture will not be plated for 2 to 3 days or frozen if plating the culture will take longer.1 Mycoplasmas are slow growing and often are cultured for 1 to 2 weeks before finalizing a “negative” culture. At this time, species identification and antimicrobial sensitivities are not available in all laboratories.4 Because of the fragile state of most mycoplasmas outside of their hosts, the diagnosis of mycoplasma could be missed as a result of improper sample handling, prolonged transport time, or collection errors34,35 Polymerase chain reaction (PCR) methods are used for identification and speciation of mycoplasmal DNA. PCR is valued for its rapidity of test results, improved sensitivity compared with culture, and ability to identify nonviable organisms that may not have survived transport or have been killed by antimicrobial agents.35 However, if only DNA is detected and the organisms are not cultured, then the potential for contamination by commensals must be considered.35 In one study of cats and dogs with respiratory disease, 15.0% of all samples yielded discordant results between culture and PCR; mailed samples were more likely discordant than samples

CHAPTER 92  •  MYCOPLASMA, ACTINOMYCES, AND NOCARDIA

Table 92-1  Diagnostic Options for Mycoplasma1,8,11,14,19,32-35 Diagnostic Test

Utility as a Diagnostic for Mycoplasma Species Tool

Cytology or Gram stain

Low utility

Lack of cell wall precludes identification with standard stains Useful to confirm presence of suppurative inflammation and any co-infections

Transmission electron microscopy (TEM)

Useful

Negative staining is sensitive for identification of mycoplasmas Expensive, not widely available

Histopathology

Low utility

Should identify compatible suppurative inflammatory response

Culture

Extremely useful Current gold standard

Typically slow growing; organism may die before culturing, specialized transport and growth media recommended Contact laboratory before sample collection for protocol

Polymerase chain reaction (PCR)

Extremely useful

Improved sensitivity over culture, able to identify nonviable organisms Faster results than culture

hand-carried to the diagnostic lab immediately after acquisition (31.6% versus 9.3%, respectively).34 Another study demonstrated that PCR and culture were equivalent at detecting Mycoplasma spp. in nasal and pharyngeal swabs in cats with signs of acute upper respiratory tract disease.9 Use of PCR and culture, along with monitoring response to therapy while waiting for test results, may optimize diagnosis. In addition, unresponsive infections that have been treated with antimicrobial drugs targeting cell wall synthesis may be another clinical clue to prompt testing for mycoplasma. Ancillary diagnostic tests, including complete blood count (CBC), serum chemistry, urinalysis, and imaging studies such as thoracic and abdominal radiographs, are important to rule out underlying disease and to assess the severity and extent of the infection. Common CBC abnormalities in dogs and cats with mycoplasma respiratory disease include neutrophilia, leukocytosis, lymphopenia, and eosinophilia; however, CBC and serum chemistry analyses also may be unremarkable.4,16 Thoracic radiographs of patients with mycoplasmal respiratory disease commonly reveal patterns consistent with pneumonia, such as lung lobe consolidation and bronchoalveolar patterns; collapsing trachea and bronchi also were noted in one study.4,16

Treatment Antimicrobials commonly used to treat mycoplasmal infections include tetracyclines, macrolides, lincosamides, fluoroquinolones, and chloramphenicol (Table 92-2).1,36,37 Species of the patient, location of the infection within the body, and presence of any coinfections may influence drug selection. Because the lack of a cell wall renders mycoplasmas resistant to β-lactam antimicrobials, therapy with this drug class should be avoided unless it is used to treat susceptible coinfections. Information regarding prognosis and response to treatment is limited and may vary depending on the type of infection. One study demonstrated that 14.3% of patients with respiratory disease that had mycoplasma as the sole isolate via culture had complete resolution with no recurrence, 42.9% of cases improved but then experienced a recurrence, and the remainder of cases had no response to therapy.4 Treatment is complicated by the bacteriostatic nature of most of the effective drugs, necessitating weeks to months of therapy, and the lack of antimicrobial sensitivity data for isolates.1

ACTINOMYCOSIS AND NOCARDIOSIS Actinomycosis and nocardiosis share similar clinical presentations, but there are some important differences between these organisms and their disease manifestations (Table 92-3).

Additional Information

Etiology and Clinical Syndromes Actinomycosis is an infection caused by organisms belonging to the genus Actinomyces or Arcanobacterium. These anaerobic or microaerophilic, gram-positive organisms are normal inhabitants on the mucous membranes of the oral cavity and gastrointestinal and urogenital tracts in humans and animals.1,38 These organisms are opportunists, have never been cultured from the environment,1 and are dependent upon disruption of the mucosa (i.e., direct inoculation) to cause disease. In dogs, infection seems to occur more commonly in large breed, outdoor, or hunting/working dogs, which have increased exposure to plant material such as migrating grass awns.1,39 Such material likely becomes contaminated with Actinomyces spp. when passing through the oropharynx as it is inhaled or ingested,1,40 then acts as a nidus for infection as it migrates through the body. In cats, exposure seems to stem more commonly from bite wounds.41 Actinomycosis in dogs often manifests as cervicofacial, cutaneous/ subcutaneous, or thoracic forms.1 Cats may have a higher incidence of the thoracic form (i.e., pyothorax) but also may be presented with peritonitis or cellulitis after a bite or puncture wound.1,42 Cervicofacial actinomycosis may result from dental disease, oral foreign bodies, or penetrating wounds to the head or oral cavity. This infection can manifest as an acute to chronic infection of the head and neck, causing swellings, abscesses, or mass effects.1,39 Cutaneous/ subcutaneous infections may present as single or multiple mass lesions with draining tracts and can occur anywhere on the body, including tracking into body cavities.1,39 Thoracic, abdominal, and retroperitoneal actinomycosis can manifest with intracavitary effusions, external draining tracts connecting to the respective body cavity, spinal pain, or palpable abdominal mass or with more vague presenting complaints of weight loss, fever, and weakness.1,39,40 Actinomycosis infections can cause periosteal new bone formation and osteomyelitis if the infection is occurring near or on a bony structure,1 such as when retroperitoneal infections spread to the vertebral bodies. Actinomycosis also has been reported in the central nervous system (CNS).43 Nocardiosis is an opportunistic infection caused by the aerobic gram-positive bacteria of the family Nocardiaceae.1,41,44 Unlike Actinomyces spp., Nocardia spp. are not part of the normal flora of mammals; they are ubiquitous environmental saprophytes found in soil, grasses, and other organic material.1,41 Animals can carry this organism on their claws or skin after environmental exposure,41 and infection may arise from inhalation of the organism or direct inoculation from a penetrating wound. Nocardiosis is reported less commonly than Actinomyces infections.1 Immunosuppression may predispose to infections in humans

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Table 92-2  Common Antimicrobials for Mycoplasmosis, Actinomycosis, Nocardiosis1,36,37 Drug

Organism Targeted

Species

Dose, Route, Frequency

Amikacin

Nocardia

Dog Cat

15 mg/kg IV, SC, IM q24h 10 mg/kg IV, SC, IM q24h

Ampicillin, Ampicillin/sulbactam

Actinomyces,* Nocardia

Dog Cat

20-40 mg/kg IV, SC q8h 20-40 mg/kg IV, SC q8h

Azithromycin

Mycoplasma

Dog Cat

5-10 mg/kg PO, IV q24h 5-10 mg/kg PO, IV q24h

Cefotaxime

Nocardia

Dog Cat

20-80 mg/kg IV, SC, IM q6-8h 20-80 mg/kg IV, SC, IM q6-8h

Chloramphenicol

Mycoplasma, Actinomyces

Dog Cat

40-50 mg/kg PO, IV q6-8h 25-50 mg/kg PO, IV q12h

Clindamycin

Mycoplasma, Actinomyces

Dog Cat

10 mg/kg PO, IV q12h 10 mg/kg PO, IV q12h

Doxycycline

Mycoplasma,† Actinomyces

Dog Cat

5-10 mg/kg PO or IV q12h 5-10 mg/kg PO or IV q12h

Enrofloxacin

Mycoplasma†

Dog Cat

10-15 mg/kg PO, IV, IM q24h 5 mg/kg PO q24h

Erythromycin

Mycoplasma, Actinomyces, Nocardia

Dog Cat

10-20 mg/kg PO, IV q8h 10-20 mg/kg PO, IV q8h

Imipenem

Nocardia

Dog Cat

5-10 mg/kg IV q6-8h 5-10 mg/kg IV q6-8h

Meropenem

Nocardia

Dog Cat

24 mg/kg IV q24h or 12 mg/kg SC q8-12h 24 mg/kg IV q24h or 12 mg/kg SC q8-12h

Penicillin G

Actinomyces*

Dog Cat

100,000 U/kg IV, SC, IM q6-8h or 40 mg/kg PO q8h 100,000 U/kg IV, SC, IM q6-8h or 40 mg/kg PO q8h

Pradofloxacin

Mycoplasma

Dog Cat

5 mg/kg PO q24h 5 mg/kg PO q24h

Trimethoprim-sulfa

Nocardia*

Dog Cat

30 mg/kg PO, IV q12h 30 mg/kg PO, IV q12h

*Indicates drug of choice for that microbe. †Common/preferred drug for Mycoplasma.

Table 92-3  Comparison of Actinomycosis and Nocardiosis1,38-41,44,45,56-59 Actinomycosis

Nocardiosis

Predisposition

Outdoor, male dogs; fight wounds in cats

Immunocompromised patients; fight wounds in cats

Biologic requirements

Facultative or obligate anaerobe

Aerobic

Staining and morphology

Gram positive, rod-shaped, non-acid fast

Gram positive, rod-shaped, partially acid fast

Culture

Challenging to culture; often seen with mixed infections

Typically isolated in pure culture

Preferred empiric antimicrobial

Penicillins

Trimethoprim-sulfamethoxazole

Prognosis

Good, when treated appropriately

Guarded to poor

and veterinary species,41,44 and nocardiosis has been reported in canines with distemper virus–induced immunosuppression.45 In dogs, infections occur more commonly in the young, whereas in cats, there is a strong predisposition (up to 75%) for males to contract the disease, mostly likely through scratches and bites.41 Disease occurs in cats of all ages and infected cats may or may not be immunosuppressed as well (i.e., retroviral infections).41,46 Nocardiosis causes acute to chronic suppurative inflammation and most commonly presents in cutaneous/subcutaneous, pulmonary, and disseminated (involving two or more body systems) forms.1,41,44 When Nocardia spp. initially enter the host through skin

inoculation, the inflammation may resemble a localized pyoderma and often is treated as such.41 The cutaneous form is by far the most common type of infection in feline patients and eventually may manifest as multiple draining tracts or sinuses within the skin that spread outwards from the central lesion.40,41 Pulmonary nocardiosis may manifest as either pneumonia or pyothorax; this form is the most common type of infection in humans, particularly in immunocompromised patients,1,44 and has been reported in more commonly in dogs than in cats.1 Disseminated nocardiosis and systemic disease forms are rare. They may stem from systemic spread of cutaneous/ subcutaneous or pulmonary forms and typically involve abscessation

CHAPTER 92  •  MYCOPLASMA, ACTINOMYCES, AND NOCARDIA

50.0 m

FIGURE 92-2  A focal aggregate of mixed bacteria (arrow), including filamentous beaded rods, is seen against a background of poorly preserved, poorly staining leukocytes admixed with low number of erythrocytes. Individual bacteria (arrowheads) also are observed scattered in the background. Wright’s stain. 1000× magnification. (Photo courtesy Dr. B. Flatland, University of Tennessee.)

50.0 m

FIGURE 92-3  Mixed bacteria of varying morphology, including beaded filamentous rods (arrow), admixed with numerous neutrophils. Neutrophils exhibit nondegenerate and degenerate morphology; rare neutrophils (arrowhead) contain phagocytosed bacteria. Wright’s stain. 1000× magnification. (Photo courtesy Dr. Bente Flatland, University of Tennessee.)

of two or more noncontiguous sites within the body, such as the eyes, bones, joints, spleen, liver, peritoneum, CNS, and lymph nodes.1,43

Clinical Signs Clinical signs of actinomycosis or nocardiosis depend on the location of infection and also may include anorexia, fever, dyspnea, tachypnea, coughing, and depression.1,47 Historical findings may reveal lethargy, weight loss, an outdoor lifestyle (actinomycosis), or a history of bite wounds. Physical examination may reveal decreased heart or lung sounds if pleural effusion is present, draining tracts, abscesses, oral cavity lesions, palpable abdominal mass effect, or spinal pain, depending on the area of the body affected.1,39,40,48

Diagnosis Blood work typically is consistent with an inflammatory response; patients with either disease also may show anemia, hypoalbuminemia, and hyperglobulinemia.1,39 Nocardiosis may manifest with an ionized hypercalcemia secondary to the granulomatous response49 but has not been documented yet in the literature for actinomycosis. Radiographic findings can include cavitary effusions, alveolar or interstitial lung patterns, lymphadenopathy, mass effects in any area of the body (i.e., mediastinum, abdomen), as well as periosteal bone growth or osteomyelitis if lesions are adjacent or affecting bones.39,40,48 Ultrasound findings of the thorax or abdomen may show free fluid accumulation in the chest or abdomen or mass effects within the cavity examined.50 The characteristic cytologic finding of exudates from Actinomyces spp. and Nocardia spp. lesions is suppurative to pyogranulomatous inflammation.1 Both organisms appear as dense mats of grampositive filamentous rods that may be branched; and actinomycosis infections often are accompanied by a population of mixed bacteria (Figures 92-2 and 92-3). In addition, Nocardia spp. are partially acid fast staining, whereas Actinomyces spp. are not.1 Effusions and exudates may contain malodorous, macroscopic sulfur granules, which appear as tan/grey aggregates1 (Figure 92-4). Histopathology of mass lesions and affected lymph nodes with either actinomycosis or nocardiosis infections show pyogranulomatous inflammation and fibrosis and may contain tissue granules of variable diameter. Special stains, such as Brown-Brenn Gram stain, may be needed to visualize further the filamentous structures.1,39

FIGURE 92-4  Sulfur granules present in pleural fluid from a dog with nocardiosis. (Photo courtesy Noah’s Arkive™ at The University of Georgia. Image by Dr. J.A. Ramos-Vara, Purdue University, copyright 1993. University of Georgia Research Foundation, Inc. Noah’s Arkive™ is a trademark of the University of Georgia Research Foundation, Inc.)

Exudates, sulfur granules, needle aspirates of mass-like lesions, airway wash fluid, and cavitary effusions may be submitted for culture, although both organisms are difficult to grow. If either nocardiosis or actinomycosis are suspected, obtaining aerobic and anaerobic cultures optimizes the chance of isolating the organism because some species of actinomycosis are aerotolerant.1 Pure cultures of Nocardia spp. usually are isolated from lesions, although it may take several days to weeks to grow.1 Actinomyces spp. have specific growth requirements (ranging from facultative to obligate anaerobes) and also may require 2 to 4 weeks of incubation.1 Despite their presence, however, Actinomyces spp. may not be isolated, and co-infecting bacteria, such as Escherichia coli, Pasturella multocida, or Streptococcus spp., may be cultured instead.1 Because Actinomyces is a commensal organism of the oropharynx, isolation does not confirm infection; positive culture results are a more reliable indicator of disease if one or more of the following criteria are present: compatible clinical signs, surrounding pyogranulomatous inflammation, and growth of associated co-infectious organisms.

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Species identification can be obtained for both organisms, but it is particularly important to speciate Nocardia spp. because susceptibility to antimicrobial agents varies by species.1,46 Polymerase chain reaction (PCR) methods can be used to speciate Nocardia, although DNA-DNA hybridization is considered the standard method.52 Speciating Actinomyces can be difficult, and sequencing of the 16D rRNA gene may be required.1 PCR has been used to diagnose bacterial endocarditis and also was used to identify an Actinomyces species that did not grow on blood culture.53 Cell wall deficient variants of actinomyces (L-forms) have been identified, albeit infrequently.51

Treatment The mainstay of successful therapy for Actinomyces infections is prolonged high-dose antimicrobials; surgery also may be indicated, depending on the nature of the infection.1 Penicillin is the drug of choice: no Actinomyces spp. have shown resistance to penicillins.1 For patients unable to take penicillins, other antimicrobials have been used successfully (see Table 92-2).1,36,37 Drugs reportedly ineffective for Actinomyces include metronidazole, aztreonam, trimethoprim sulfamethoxazole (TMS), penicillinase-resistant penicillins (e.g., methicillin, nafcillin, oxacillin, cloxacillin), cephalexin, and aminoglycosides, although Arcanobacterium spp. are sensitive to aminoglycosides (except streptomycin).1,54 For all antibiotics, prolonged therapy (6 to 12 months) is necessary, even after resolution of clinical disease, to ensure penetration of the dense mats of bacteria and pyogranulomatous inflammation and reduce the chance of recurrence. In addition to antimicrobials, treatment always should include drainage of any abscessed areas and cavitary effusions; continuous and intermittent suction techniques have proven effective.55,56 Surgery may be indicated for actinomycosis infections that are nonresponsive to appropriate medical management or for isolated lesions such as lung abscesses or solitary body wall masses; even these patients should be followed up with long-term antibiotic therapy. With appropriate management, patients with actinomycosis usually have a good therapeutic response, with reported cure rates of more than 90% in the dog.1,39,55 The prognosis for feline cutaneous and pyothorax Actinomyces infections generally is considered good with appropriate management; however, large clinical or retrospective studies involving feline cases of actinomycosis have not been published.1 Nocardiosis is more difficult to treat and achieve complete resolution of disease. Treatment should include prolonged antibiotic therapy as well as surgical drainage or debulking of lesions to optimize response to treatment.57,58 Sulfonamides (e.g., trimethoprim sulfamethoxazole, or TMS) are the empiric drugs of choice for nocardiosis because most isolates are sensitive to this drug (see Table 92-2).1 However, antimicrobial susceptibility is dependent on the infecting species of Nocardia, so isolates ideally should be speciated,1,46,58 especially if antimicrobial therapy is failing or side effects, such as myelosuppression from the TMS, prohibit its long-term use. Although each Nocardia species has a relatively predictable antibiogram,1 organisms may not be equally susceptible to all drugs within the same class. Combination therapy often is used in patients with severe illness or central nervous system infections, and certain combinations work synergistically.1,59 A combination of TMS and a β-lactam should be effective against most isolates.52,61 For CNS infections, drugs with good penetration include third-generation cephalosporins, imipenem/meropenem, and linezolid, although use of linezolid use has been discouraged to prevent development of resistance to this relatively new antimicrobial.1,52,61 Antimicrobial therapy for nocardiosis is prolonged; durations of therapy range from 1 to 3 months for a simple cutaneous infection or at least 1 year for severe systemic infections or immunocompromised patients.1 Prognosis for patients with nocardiosis is guarded: one study reported a 50% mortality rate from the disease and a 38.5% euthanasia rate resulting

from a lack of clinical response.61 Underlying disease, delayed diagnosis, and inappropriate or inadequate therapy likely contribute to this poor outcome.61 Prognosis appears to be equally as guarded in cats, especially those with disseminated disease.41

REFERENCES 1. Greene CE: Infectious diseases of the dog and cat, ed 4, St Louis, 2012, Elsevier-Saunders. 2. Waites KB, Talkington DF: Mycoplasma pneumonia and its role as a human pathogen, Clin Microbiol Rev 17:697, 2004. 3. Chalker VJ: Canine mycoplasmas, Res Vet Sci 79:1, 2005. 4. Chandler JC, Lappin MR: Mycoplasmal respiratory infections in small animals: 17 cases (1988-1999), J Am Anim Hosp Assoc 38:111, 2002. 5. Randolph JF, Moise NS, Scarlett JM, et al: Prevalence of mycoplasmal and ureaplasmal recovery from tracheobronchial lavages and prevalence of mycoplasmal recovery from pharyngeal swab specimens in dogs with or without pulmonary disease, Am J Vet Res 54:387, 1993. 6. Chalker VJ, Owen WM, Paterson C, et al: Mycoplasmas associated with canine infectious respiratory disease, Microbiology 150:3491, 2004. 7. Randolph JF, Moise NS, Scarlett JM, et al: Prevalence of mycoplasmal and ureaplasmal recovery from tracheobronchial lavages and prevalence of mycoplasmal recovery from tracheobronchial lavages and of mycoplasmal recovery from pharyngeal swab specimens in cats with or without pulmonary disease, Am J Vet Res 54:897, 1993. 8. Burns RE, Wagner DC, Leutenegger CM, et al: Histologic and molecular correlation in shelter cats with acute upper respiratory infection, J Clin Microbiol 49:2454, 2011. 9. Veir JK, Ruch-Gallie R, Spindel ME, et al: Prevalence of selected infectious organisms and comparison of two anatomic sampling sites in shelter cats with upper respiratory tract disease, J Feline Med Surg 10:551, 2008. 10. Low HC, Powell CC, Veir JK, et al: Prevalence of feline herpesvirus 1, Chlamydophila felis, and Mycoplasma spp DNA in conjunctival cells collected from cats with and without conjunctivitis, Am J Vet Res 68:643, 2007. 11. Hartmann AD, Hawley J, Werckenthin C, et al: Detection of bacterial and viral organisms from the conjunctiva of cats with conjunctivitis and upper respiratory tract disease, J Feline Med Surg 12:775, 2010. 12. Campbell LH, Okuda HK: Cultivation of mycoplasma from conjunctiva and production of corneal immune response in guinea pigs, Am J Vet Res 36:893, 1975. 13. Bernis DA: Bordetella and mycoplasma respiratory infections in dogs and cats, Vet Clin North Am Sm Anim Pract 22:1173, 1992. 14. Hong S, Kim O: Molecular identification of Mycoplasma cynos from laboratory beagle dogs with respiratory disease, Lab Anim Res 28:61, 2012. 15. Zeugswetter F, Weissenbock H, Shibly S, et al: Lethal bronchopneumonia caused by Mycoplasma cynos in a litter of golden retriever puppies, Vet Rec 161:626, 2007. 16. Foster SF, Barrs VR, Martin P, et al: Pneumonia associated with Mycoplasma spp. in three cats, Aus Vet J 76:460, 1998. 17. Trow AV, Rozanski EA, Tidwell AS: Primary mycoplasma pneumonia associated with reversible respiratory failure in a cat, J Feline Med Surg 10:398, 2008. 18. Gulbahar M, Gurturk K: Pyothorax associated with a Mycoplasma sp. and Arcanobacterium pyogenes in a kitten, Aus Vet J 80:344, 2002. 19. Waites KB, Katz B, Schelonka RL: Mycoplasmas and ureaplasmas as neonatal pathogens, Clin Microbiol Rev 18:757, 2005. 20. Brown MB, Stoll M, Maxwell J, et al: Survival of feline mycoplasmas in urine, J Clin Microbiol 29:1078, 1991. 21. L’Abee-Lund TM, Heiene R, Friis NF, et al: Mycoplasma canis and urogenital disease in dogs in Norway, Vet Rec 153:231, 2003. 22. Jang SS, Ling GV, Yamamoto R, et al: Mycoplasma as a cause of canine urinary tract infection, J Am Vet Med Assoc 185: 45, 1984. 23. Lulich JP, Osborne CA: Bacterial urinary tract infections. In Ettinger SJ, Feldman EC, editors: Textbook of veterinary internal medicine, ed 4, Philadelphia, 1999, WB Saunders. 24. Ulgen M, Cetin C, Senturk S, et al: Urinary tract infections due to Mycoplasma canis in dogs, J Vet Med A Physiol Pathol Clin Med 53:379, 2006.

CHAPTER 92  •  MYCOPLASMA, ACTINOMYCES, AND NOCARDIA 25. Senior DF, Brown MB: The role of mycoplasma species and ureaplasma species in feline lower urinary tract disease, Vet Clin North Am Sm Anim Pract 26:305, 1996. 26. Abou N, Houwers DJ, van Dongen AM: PCR-based detection reveals no causative role for mycoplasma and ureaplasma in feline lower urinary tract disease, Vet Microbiol 116:246, 2006. 27. Walker RD, Walshaw R, Riggs CM, et al: Recovery of two mycoplasma species from abscesses in a cat following bite wounds from a dog, J Vet Diagn Invest 7:154, 1995. 28. Ilha MRS, Rajeev S, Watson C, et al: Meningoencephalitis caused by Mycoplasma edwardii in a dog, J Vet Diagn Invest 22:805, 2010. 29. Beauchamp DJ, da Costa RC, Premanandan C, et al: Mycoplasma felis– associated meningoencephalitis in a cat, J Feline Med Surg 13:139, 2011. 30. Zeugswetter F, Hittmair KM, de Arespacochaga AG, et al: Erosive polyarthritis associated with Mycoplasma gateae in a cat, J Feline Med Surg 9:226, 2007. 31. Stenske KA, Bernis DA, Hill K, et al: Acute polyarthritis and septicemia from Mycoplasma edwardii after surgical removal of bilateral adrenal tumors in a dog, J Vet Intern Med 19:768, 2005. 32. Barth OM, Majerowica S: Rapid detection by transmission electron microscopy of mycoplasma contamination in sera and cell cultures, Mem Inst Oswaldo Cruz 83:63, 1988. 33. Johnson LR, Drazenovich NL, Foley JE: A comparison of routine culture with polymerase chain reaction technology for the detection of mycoplasma species in feline nasal samples, J Vet Diagn Invest 16:347, 2004. 34. Cruse AM, Sanchez S, Ratterree W, et al: Comparison of culture and polymerase chain reaction assay for the detection of Mycoplasma species in canine and feline respiratory tract samples, Research Abstract Program of the 26th Annual ACVIM Forum, 2008. 35. Reed N, Simpson K, Ayling R, et al: Mycoplasma species in cats with lower airway disease: Improved detection and species identification using a polymerase chain reaction assay, J Feline Med Surg 14:833, 2012. 36. Plumb D: Plumb’s veterinary drug handbook, ed 7, St Paul, 2011, PharmaVet Inc. 37. Papich MG: Saunders handbook of veterinary drugs, ed 3, St Louis, 2011, Elsevier-Saunders. 38. Acevedo F, Baudrand R, Letelier LM, et al: Actinomycosis: a great pretender. Case reports of unusual presentations and review of the literature, Int J Infect Dis 12:358, 2008. 39. Kirpensteijn J, Fingland RB: Cutaneous actinomycosis and nocardiosis in dogs: 48 cases (1980–1990), J Am Vet Med Assoc 201:917, 1992. 40. Edwards DF, Nyland TG, Weigel JP: Thoracic, abdominal and vertebral actinomycosis: diagnosis and long-term therapy in three dogs, J Vet Intern Med 2:184, 1988. 41. Malik R, Krockenberger MB, O’Brien CR, et al: Nocardia infections in cats: a retrospective multi-institutional study of 17 cases, Aust Vet J 84:235, 2006. 42. Love DN, Jones RF, Bailey M, et al: Isolation and characterization of bacteria from pyothorax (empyaemia) in cats, Vet Microbiol 7:455, 1982.

43. Radaelli ST, Platt SR: Bacterial meningoencephalomyelitis in dogs: retrospective study of 23 cases (1990-1999), J Vet Intern Med 16:159, 2002. 44. Ambrosioni J, Lew D, Garbino J: Nocardiosis: updated clinical review and experience at a tertiary center, Infection 38:89, 2010. 45. Ribero MG, Salerno T, Mattos-Guaraldi AL, et al: Nocardiosis: an overview and additional report of 28 cases in cattle and dogs, Rev Inst Med Trop Sao Paulo 50:177, 2008. 46. Hirsh DG, Jang SS: Antimicrobial susceptibility of Nocardia nova isolated from five cats with nocardiosis, J Am Vet Med Assoc 215:815, 1999. 47. Ackerman N, Grain E, Castleman W: Canine nocardiosis, J Am Vet Anim Hosp Assoc 18:147, 1982. 48. Marino DJ, Jaggy A: Nocardiosis, a literature review with selected case reports in two dogs, J Vet Intern Med 7:4, 1993. 49. Mealey KL, Willard MD, Nagode LA, et al: Hypercalcemia associated with granulomatous disease in a cat, J Am Vet Med Assoc 215:959, 1999. 50. Boothe, HW, Howe LM, Boothe DM, et al: Evaluation of outcomes in dogs treated for pyothorax: 46 cases (1983-2001), J Am Vet Med Assoc 236:657, 2010. 51. Buchanan AM, Scott JL: Actinomyces hordeovulneris, a canine pathogen that produces L-phase variants spontaneously with coincident calcium deposition, Am J Vet Res 45:2552, 1984. 52. Brown-Elliott BA, Ward SC, Crest CJ, et al: In vitro activities of linezolid against multiple nocardia species, Antimicrob Agents Chemother 45:1295, 2001. 53. Meurs KM, Heaney AM, Atkins CE, et al: Comparison of polymerase chain reaction with bacterial 16s primers to blood culture to identify bacteremia in dogs with suspected bacterial endocarditis, J Vet Intern Med 25:959, 2011. 54. Guérin-Faublée V, Flandrois JP, Broye E, et al: Actinomyces pyogenes: Susceptibility of 103 clinical animal isolates to 22 antimicrobial agents, Vet Res 24:251, 1993. 55. Turner WD, Breznock EM: Continuous suction drainage for management of canine pyothorax: a retrospective study, J Am Anim Hosp Assoc 24:594, 1988. 56. Frendin J: Pyogranulomatous pleuritis with empyema in hunting dogs, Zentralbl Veterinarmed A 44:167, 1997. 57. Lerner PI: Nocardiosis, Clin Infect Dis 22:891, 1996. 58. McNeil MM, Brown JM: The medically important aerobic actinomycetes: epidemiology and microbiology, Clin Microbiol Rev 7:357, 1994. 59. Gombert ME, Aulicino TM: Synergism of imipenem and amikacin in combinations with other antibiotics against Nocardia asteroides, Antimicrob Agents Chemother 24:810, 1983. 60. Gomez-Flores A, Welsh O, Said-Fernández S, et al: In vitro and in vivo activities of antimicrobials against Nocardia brasiliensis, Antimicrob Agents Chemother 48:832, 2004. 61. Beaman BL, Sugar AM: Nocardia in naturally acquired and experimental infections in animals, J Hygiene 91:393, 1983.

487

CHAPTER 93  GRAM-POSITIVE INFECTIONS Reid P. Groman,

DVM, DACVIM (Internal Medicine), DACVECC

KEY POINTS • Most gram-positive infections are caused by normal resident microflora of the skin, mucous membranes, and gastrointestinal tract. • Critically ill hospitalized patients are at increased risk for infections with opportunistic gram-positive bacteria. • Streptococcus canis is a well-recognized cause of various suppurative infections in animals, including toxic shock syndrome. • Enterococci, traditionally viewed as commensal bacteria in the alimentary tract of animals, are known to be capable of causing life-threatening, multidrug-resistant infections in dogs and cats. • As antibiotic-resistant staphylococci evolve, the ability to treat staphylococcal infections in companion animals with cephalosporins, penicillins, and fluoroquinolones is decreasing.

Since the early 1990s the epidemiology of pathogenic bacteria isolated from critically ill patients has shifted from gram-negative organisms to an increasing number of nosocomial infections caused by gram-positive isolates.1,2 Increasing numbers of pathogenic, multidrug-resistant (MDR) gram-positive organisms now are being isolated from dogs and cats, paralleling the trend in antibioticresistant nosocomial and community-acquired infections in humans.3,6 Awareness of emerging trends of resistance, particularly in Enterococcus faecium and various strains of staphylococci, militates against indiscriminate antimicrobial use and provides a basis for appropriately treating critically ill patients suffering from such infections.7,8

GRAM-POSITIVE CELL STRUCTURE AND PATHOGENICITY Morphologically, gram-positive bacteria are composed of a cell wall, a single cytoplasmic membrane, and cytosol.9-11 The cell wall is a thick, coarse structure that serves as an exoskeleton. Buried within the cell wall are enzymes called transpeptidases, commonly referred to as penicillin-binding proteins (PBPs). PBPs are a group of enzymes responsible for the building and maintenance of the cell wall.9,10 In addition to a thick cell well, most gram-positive bacteria have other protective mechanisms. One of these mechanisms is an outer capsule or biofilm that extends beyond the cell wall and interfaces with the external milieu.9,10 Hydrolase enzymes located within the cytoplasmic membrane, called β-lactamases, serve a protective role for the bacteria.9,10 Once attacked by the hydrolases, the β-lactam antibiotics are no longer capable of binding to PBPs in normally susceptible bacteria. Peptidoglycan is the basic structural component of the cell wall of gram-positive bacteria, accounting for 50% to 80% of the total cell wall content. Like endotoxin, peptidoglycan is released by bacteria during infection, reaches the systemic circulation, and exhibits pro488

inflammatory activity.9,10 Lipoteichoic acids found in the grampositive cell wall have structural and epithelial adherence functions. Lipoteichoic acid induces a proinflammatory cytokine response, the production of nitric oxide, and may lead to cardiovascular compromise. In addition to structural components, gram-positive organisms produce soluble exotoxins that may play a role in the pathogenesis of sepsis. Much attention is focused on the roles of superantigenic exotoxins that promote the massive release of cytokines, potentially leading to shock and multiorgan failure in human and veterinary patients.6,9

STREPTOCOCCAL INFECTIONS The genus Streptococcus consists of gram-positive cocci arranged in chains.11,12 These are fastidious bacteria that require the addition of blood or serum to culture media. They are nonmotile and non–spore forming. Most are facultative anaerobes and may require enriched media to grow.9,12 Streptococci are generally commensal organisms found on the skin and mucous membranes and are ecologically important as part of the normal microflora in pets and humans.11,12 However, several species of streptococci are capable of causing localized or widespread pyogenic infections in companion animals.11 Streptococci may be grouped superficially by how they grow on blood agar plates as either hemolytic or nonhemolytic.9,13 The type of hemolytic reaction displayed on blood agar has been used to classify the bacteria as either α-hemolytic or β-hemolytic. β-Hemolytic species are generally pathogenic, and nonhemolytic or α-hemolytic members of the genera have been viewed traditionally as contaminants or unimportant invaders when isolated. Streptococci also are classified serologically based on speciesspecific carbohydrate cell wall antigens, with groups designated A through L.9,11,12 Group A streptococci (Streptococcus pyogenes) cause pharyngitis, glomerulonephritis, and rheumatic fever in humans.11-13 Although dogs may become colonized transiently with this organism, group A streptococci rarely cause illness in dogs and cats.11 Therapy generally is not indicated, but these organisms are susceptible to most β-lactam agents, macrolides, and chloramphenicol. The group B streptococci, which are all strains of Streptococcus agalactiae, infrequently cause infections in dogs and cats.11 Rare infections with S. agalactiae have been associated with metritis, fading puppy syndrome, and neonatal sepsis in dogs, and septicemia and peritonitis in parturient cats.11 Similarly, group C streptococci are rare causes of illness in immunocompetent pets. Species included in this serologic group include Streptococcus equi ssp. zooepidemicus and Streptococcus dysgalactiae. Sporadic cases of endometritis, wound infections, pyelonephritis, lymphadenitis, and neonatal sepsis resulting from infection with β-hemolytic group C streptococci have been reported in dogs and cats. The number of reports of outbreaks of hemorrhagic pneumonia in dogs caused by S. equi ssp. zooepidemicus is limited but increasing. This acute, highly contagious, and often fatal disease most often is reported in dogs housed in shelters and

CHAPTER 93  •  Gram-Positive Infections

research kennels. Clinical findings include moist cough, sanguinous nasal discharge, fever, and acute respiratory distress.6 Postmortem findings reveal fibrinosuppurative, hemorrhagic, and necrotizing pneumonia. Pleural effusion is also common.6,11 As with most streptococci, isolates frequently were susceptible to ampicillin and amoxicillin. Some isolates were susceptible to doxycycline. Isolates of S. equi ssp. zooepidemicus were found to be susceptible in vitro to enrofloxacin.6 However, many streptococci are intrinsically resistant to secondgeneration fluoroquinolones, and thus single-agent therapy with enrofloxacin is not recommended for any streptococcal infections.14 The combination of penicillin and an aminoglycoside was found to be effective in one study.15 Group G streptococci are common resident microflora and are the cause of most streptococcal infection in dogs and cats.9,11 The most common isolate is Streptococcus canis.9,11 The main source of infection with this pathogen in dogs is the anal mucosa; young cats more commonly acquire infection from the vagina of the queen or via the umbilicus.11 Infection spreads rapidly in neonatal kittens and is often fatal during the first week of life in affected cats. S. canis may be isolated from adult cats with abscesses, pyelonephritis, sinusitis, arthritis, metritis, or mastitis, and from kittens with lymphadenitis, pneumonia, or neonatal septicemia. S. canis is generally an opportunistic pathogen of dogs and is isolated from an array of nonspecific infections, including wounds, mammary tissues, urogenital tract, skin, and ear canal.10,11 S. canis is a cause of canine prostatitis, mastitis, abscesses, infective endocarditis, cholangiohepatitis, pericarditis, pyometra, sepsis, discospondylitis, and meningoencephalomyelitis.11 S. canis has also been implicated in cases of fading puppy syndrome, causing polyarthritis and septicemia in affected pups.11 Despite 50 years of penicillin use in animals, no mechanism of resistance to the drug in β-hemolytic group G streptococci has been documented; penicillin G and ampicillin are therefore effective for most infections.2,10,11 Erythromycin, clindamycin, potentiated sulfonamides (TMP-SMZ), and most cephalosporins are also usually efficacious. Susceptibility to veterinary-approved fluoroquinolones is negligible, and their use generally is discouraged for streptococcal infections.14,16 Streptococcus spp. generally are not considered susceptible to aminoglycosides, owing to poor transport across the cytoplasmic membrane.2 However, combination therapy with a β-lactam agent and an aminoglycoside is an appropriate treatment strategy for critically ill animals with streptococcal bacteremia or endocarditis.2,14 Combination therapy is also recommended for cases of infective necrotizing fasciitis and myositis (NFM) (see Empiric Antibiotic Strategies), endocarditis, or when polymicrobial infections are suspected. Although long-term (at least 6 weeks) therapy is recommended for treating unstable patients with disseminated infection, in most clinical settings aminoglycosides are rarely prescribed for this duration due to concerns for drug-associated nephrotoxicity. Over the past decade, streptococcal toxic shock syndrome (STTS), with or without necrotizing fasciitis and myositis (NFM) resulting from infection with S. canis, has emerged as a recognized syndrome in dogs (see Chapter 101).9,11,17 The most common source for infection in animals with STTS appears to be the lung, with occasional reports of affected dogs suffering from acute or peracute suppurative bronchopneumonia. Some case histories have included failed attempts to treat patients with enrofloxacin and nonsteroidal antiinflammatory agents.11,18 Cases of STTS-associated septicemia are often fatal, whereas most dogs with NFM alone survive with prompt, appropriate medical therapy and aggressive surgical resection (see Chapter 139).11,18 The most likely pathogenesis for STTS and NFM starts with minor trauma. The dog then licks its wounds and seeds S. canis from the oral mucosa into the wound. The bacteria proliferate, typically

resulting in painful, rapidly developing cellulitis, skin discoloration, and often signs of systemic illness.17 Prompt recognition and aggressive surgical debridement are imperative. Clindamycin has proven to be effective therapy in affected animals.11,17 Aminopenicillins, erythromycin, and β-lactam antibiotics also may be effective.11 Culture and susceptibility testing is important because similar toxic shock– like diseases in dogs may be caused by bacteria other than streptococci. Gram staining of tissues or fluids should be helpful in ascertaining the morphology of the infecting agent, particularly in acute infections. A similar syndrome in young cats with suppurative lymphadenopathy and multifocal ulcerative skin lesions caused by group G streptococci has been reported.11

ENTEROCOCCAL INFECTIONS Enterococcus species are facultative anaerobic cocci that demonstrate intrinsic and acquired resistance to multiple antibiotics. Unlike streptococci and staphylococci, most enterococci do not produce reliably a set of proinflammatory toxins, but they are equipped with many genes that mediate adhesion to host tissues.7 Enterococci (previously group D streptococci), as the name implies, are commensal bacteria that inhabit the alimentary tract of animals and humans.9,12 Enterococcal infections previously were considered rare, and not especially virulent, in companion animals. Presently, enterococcal infections are a leading cause of nosocomial disease in human health care, and pathogenic and multidrug resistant (MDR) enterococci are recovered increasingly from hospitalized veterinary patients.1,11 Postoperative wound and urogenital infections are seen most commonly; however, enterococcal cholangiohepatitis, peritonitis, vegetative endocarditis, mastitis, and blood-borne infections have been reported in companion animals.11,19 Many enterococci are intrinsically resistant to numerous antibiotics, and the development of MDR enterococci is thought to result from inappropriate antimicrobial usage and poor infection control measures in hospitalized patients.11,12,19 The majority of clinical isolates belong to the species Enterococcus faecalis, although Enterococcus faecium remains the species that exhibits a disproportionately greater resistance to multiple antibiotics.11,19 E. faecium is increasingly resistant to vancomycin, which was effective for almost all penicillin-resistant enterococci until recently.9,11,19 Strains that remain susceptible to vancomycin may be resistant to a wide range of drugs that are selected empirically for managing bacterial infection in critically ill patients.11,19 E. faecium often possesses inherent and acquired resistance to many drug classes, including the fluoroquinolones, lincosamides, macrolides, and potentiated sulfonamides (TMP-SMZ).7,11,19 Unlike most streptococci, enterococci are often inhibited, but not killed, by penicillins and are generally resistant to cephalosporins.2 Moreover, although enterococci do not often intrinsically produce β-lactamases, production of these enzymes by the bacteria may be induced by exposure to β-lactamase–inhibitor drugs. As such, it is not appropriate to prescribe amoxicillin-clavulanate or ampicillin-sulbactam for an enterococcal isolate that is reported to be susceptible to ampicillin. Until recently, aminopenicillin monotherapy was successful for many enterococcal infections. However, this is no longer predictable. Presently, many isolates are resistant to aminopenicillins and many other antimicrobials that were previously effective in managing grampositive infections.2,11,19 One of the few effective modes of therapy takes advantage of antibiotic synergy. Penicillins alone only arrest bacterial growth, and aminoglycosides are without effect against enterococci, except at very high concentrations, but the combination of both drugs effectively kills the organism.2,14 This high-dosage synergy approach is among the most effective pharmacologic means to clear infection. Unless there is documentation that other

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potentially safer antibiotic regimens are effective in vivo and in vitro, the co-administration of gentamicin (but not amikacin) with a cell wall–active agent (generally ampicillin) is standard of care for serious enterococcal infections in critically ill patients and in those with osteomyelitis, endocarditis, sepsis or joint infections.11,14,17 Unfortunately, some enterococci are resistant to aminoglycosides, even when coadministered with ampicillin, leaving few alternatives for treating these infections.7,11 In some cases, the only effective drugs are glycopeptides, such as vancomycin, but this drug should be viewed as a therapy of absolute last resort.2 Vancomycin has a narrow spectrum and is potentially nephrotoxic (see Chapter 181). Clinical experience with vancomycin is limited in veterinary medicine.

STAPHYLOCOCCAL INFECTIONS The broad distribution of staphylococci as normal flora of domestic animals is perhaps the most important epidemiologic factor in staphylococcal infections.1,5,20,21 These organisms are often not inherently invasive and colonize intact epithelium of healthy animals without causing disease.9,21 Subsequently, isolation of these bacteria may signify the presence of transient or long-term colonization of epithelial surfaces.10,22 Disease pathogenesis and lesion development are not fully understood but likely involve a breach of the host’s mucosal barrier or other means of immunocompromise, in conjunction with numerous bacterial virulence factors such as staphylococcal toxins and enzymes that permit them to withstand phagocytosis by neutrophils.5,11,21,22 Biofilm formation has been demonstrated for many staphylococci, increasing bacterial resistance to stressful environmental conditions and antimicrobial exposure. Biofilm formation may be particularly important for infections associated with implants and invasive devices such as indwelling catheters.2,20,23 For many years, production of coagulase by staphylococci has been associated with virulence and tissue tropism. Almost all infections in humans, dogs, and cats were caused by coagulase-positive species, with coagulase-negative staphylococci viewed invariably as contaminants.5,10,20 More recent studies implicate coagulase-negative staphylococci as a cause of significant morbidity in humans and companion animals.1,2,20 Pathogenic staphylococci may affect any organ system and are responsible for community-acquired and nosocomial infections.5,20,21 Of approximately 35 species of staphylococcal organisms, three are of clinical importance in companion animals: Staphylococcus pseudintermedius, Staphylococcus aureus, and Staphylococcus schleiferi ssp. coagulans.20,22,24 Staphylococcus intermedius previously was considered the most important staphylococcal species in dogs and cats. What was recognized previously as S. intermedius now is known to be the closely related S. pseudintermedius.4,5,20,22 S. pseudintermedius is a common canine commensal, with colonization rates of 31% to 68% in healthy dogs, and is the leading pyogenic bacterium of dogs.4,20,22 Although it is recognized as the most common etiologic agent of bacterial skin and ear infections, it also may cause systemic infections, including arthritis, osteomyelitis, cystitis, mastitis, wound infections, and bacteremia.9,20,22 Sites of infection are similar in cats, although reports of disseminated disease are less numerous.20 Until recently, S. pseudintermedius isolates were generally susceptible to β-lactamase–resistant β-lactam antibiotics.20 Infections with strains of S. pseudintermedius that are resistant to multiple antibiotics are becoming common, and since 2006 methicillin-resistant S. pseudintermedius (MRSP) has emerged as a significant health problem in veterinary medicine.4,20,21,24,25 As with other staphylococci, the methicillin resistance of S. pseudintermedius is mediated by the mecA gene that encodes production of a modified penicillin binding protein (PBP).4,21 Normally, β-lactam antibiotics bind to S. pseudintermedius to prevent cell wall development by the bacterium. The modified PBP

of S. pseudintermedius has a low affinity for β-lactams, and therefore cell wall synthesis is not inhibited by these antimicrobials. The treatment of infections with MRSP is a new challenge in veterinary medicine.4,20,21,25 Determination of methicillin resistance for all staphylococci is based on in vitro resistance to oxacillin. Oxacillin is used as a surrogate for methicillin because it is sensitive and more stable. If staphylococci are resistant to oxacillin, they are inherently resistant to all other β-lactams, including cephalosporins and amoxicillin-clavulanate, regardless of the results of in vitro susceptibility testing.4,24 MRSP isolates are often resistant to many other antimicrobials, including all of those licensed for use in companion animals.3,20,24,25 Most S. pseudintermedius infections are not caused by MRSP, and infections with MRSP are clinically indistinguishable from infections caused by methicillin-susceptible S. pseudintermedius (MSSP).20 Further, there is currently no indication that MRSP is more virulent than MSSP, and most reported MRSP infections have been treated successfully, albeit with fewer options for antimicrobial therapy.3,21,25 Based on in vitro testing, the most useful systemic antibiotics include rifampicin, amikacin, chloramphenicol, and/or minocycline (see Empiric Selection).4,20,25 Similar antibiotic resistance patterns have emerged for pyoderma and systemic infections caused by S. schleiferi. Although this bacterium appears to be a less frequent cause of disseminated infections, results of clinical studies reveal that tissue tropism and antimicrobial susceptibility data are not predictable for this relatively novel species.20 S. aureus is well established as a significant community-acquired and nosocomial pathogen in humans, and infection with methicillinresistant S. aureus (MRSA) is a relatively recent development in veterinary medicine.1,20,21,26 The emergence of MRSA in dogs and cats appears to be a direct reflection of MRSA in the human population.20,21 Unlike S. pseudintermedius, S. aureus is not a true commensal organism in dogs and cats.20,27 Although dogs and cats are not natural reservoirs of S. aureus, they can become colonized, in all likelihood from humans.20,21 Once colonized, pets may clear the organism, go on to develop infection, or remain asymptomatic carriers for an indeterminate period. S. aureus produces a similar range of infections as those caused by S. pseudintermedius.20,21,27 Infected animals should be isolated, and barrier contact precautions should be used when handling patients, food bowls, bandages, and all associated materials. Hand washing between patients is imperative. Such guidelines must be enforced (1) to minimize the risk of patient-to-patient spread of resistant clones and (2) to limit the likelihood of animal-to-human transmission. There is increasing evidence that interspecies transmission of MRSA occurs and that it may emerge as an important zoonotic and veterinary disease.20,21,27 In human hospitals, transmission of MRSA occurs mainly via the transiently colonized hands of health care workers.2,20,26 Colonized veterinary personnel are thought to be the most likely vectors of MRSA in veterinary hospitals.27,28 All personnel in contact with patients should be advised of appropriate precautions once MRSA infection is confirmed. Like other staphylococci, MRSA can survive for long periods on inanimate objects such as bedding and cages, and it is relatively resistant to heat. Thus it may be difficult to eliminate once introduced to the hospital environment. MRSA infections most often remain treatable, albeit by a small number of antibiotics.20 Because MRSA may be transmitted between animals and humans, owners of infected or colonized animals should be informed of this potential. However, veterinarians are discouraged from making any recommendations regarding the diagnosis or treatment of MRSA, or any disease, in humans. Treatment of deep or disseminated staphylococcal infections requires prompt systemic therapy. Drug choices should be based on in vitro susceptibility testing in combination with other factors (e.g., drug penetration, site of infection). Historically, uncomplicated

CHAPTER 93  •  Gram-Positive Infections

methicillin-susceptible staphylococcal infections were predictably susceptible to β-lactam-β-lactamase inhibitor combination drugs (e.g., amoxicillin-clavulanic acid) and first-generation cephalosporins (e.g., cephalexin, cefazolin).20 These agents remain appropriate for treating uncomplicated and/or first-time staphylococcal infections in otherwise stable pets. This level of confidence does not extend to hospitalized patients with risk factors for MDR, such as those with a history of recent antibiotic use, indwelling devices, exposure to nosocomial pathogens, and protracted hospital stays. Clindamycin, potentiated sulfonamides (TMP-SMZ), doxycycline, and aminoglycosides are frequently, although not uniformly, effective for treating staphylococcal infections.5,20,25 The role of fluoroquinolones in critically ill pets with staphylococcal infections is controversial, particularly with methicillin-resistant strains, as emergence of resistance and treatment failures are reported.4,14,20 Inducible resistance to clindamycin is documented and generally is not identified with culture and susceptibility testing. However, S. aureus reported as susceptible to clindamycin but resistant to erythromycin should be inferred to be resistant to clindamycin.4,20 Inducible clindamycin resistance is rare in S. pseudintermedius, but erythromycin-resistant strains similarly should not be managed with clindamycin.20 Commercial veterinary laboratories should test all β-lactam– resistant staphylococci for susceptibility to chloramphenicol, aminoglycosides, tetracyclines, TMP-SMZ, erythromycin, and clindamycin.20,24,25 Duration of therapy depends on the site of infection and comorbid conditions that may impair host defenses or delay healing. When tolerated, therapy generally extends 2 weeks beyond the resolution of clinical signs of infection. Vancomycin, linezolid, tigecycline, and daptomycin remain the only effective antimicrobials for resistant strains of staphylococcus in human health care settings; these drugs should be used only in exceptional circumstances in veterinary medicine.20,25 It is argued that their use should be restricted in dogs and cats because avoidance of antibiotic use is a valid strategy to curtail antibiotic resistance.

EMPIRIC ANTIBIOTIC STRATEGIES In critically ill patients, prompt administration of broad-spectrum injectable antimicrobials is warranted when a polymicrobial infection is suspected or when the causative agent causing an infection is not known (Table 93-1). Wright-Giemsa and Gram-stained cytologic preparations of aspirates or impression smears should be examined to evaluate the morphologic and staining characteristics of bacterial pathogens. Clinicians should be familiar with the gram-positive pathogens associated with severe infections in their hospital and choose therapy based on the prevalence and susceptibility patterns of these bacteria, as well as the site(s) of infection. Once culture and susceptibility data are available, therapy is streamlined to ensure eradication of the pathogen without promoting resistance secondary to inappropriate antimicrobial treatment.14 Although bacterial resistance to previously effective antibiotics is an ever-increasing concern in patients with gram-positive infections, first-choice recommendations for first time and non–life-threatening infections include a first-generation cephalosporin (e.g., cefazolin) or a β-lactam- β-lactamase inhibitor combination (e.g., amoxicillinclavulanic acid, ampicillin-sulbactam). The first-generation cephalosporins have a similar spectrum of activity to ampicillin, with the notable difference that β-lactamase–producing staphylococci often remain susceptible to the cephalosporins.14,20 However, methicillinresistant, coagulase-positive staphylococci are resistant to all cephalosporins.4,22,25 Sulbactam, like clavulanic acid, is an inhibitor of β-lactamases (the latter is more potent). β-Lactamase inhibitors have weak antibacterial activity by themselves, but they show extraordi-

Table 93-1  Antibiotics Used to Treat Gram-Positive Infections Drug

Dosage

Amikacin

15 mg/kg IV q24h (dogs) 10 mg/kg IV q24h (cats)

Ampicillin

22 mg/kg IV q6-8h

Ampicillin-sulbactam

22 mg/kg IV q8h

Azithromycin

5 to 10 mg/kg IV q24h

Cefazolin

22 mg/kg IV q6-8h

Cefotetan

30 mg/kg IV q8h

Cefoxitin

30 mg/kg IV q6-8h

Chloramphenicol

25 to 50 mg/kg IV q8h (dogs) 15 to 20 mg/kg IV q12h (cats)

Clindamycin

10 mg/kg IV q12h

Enrofloxacin

15 to 20 mg/kg IV q24h (dogs) 5 mg/kg IV q24h (cats)

Gentamicin

10 mg/kg IV q24h (dogs) 6 mg/kg IV q24h (cats)

Imipenem-cilastatin

5 to 10 mg/kg IV q6-8h

Meropenem

8 to 12 mg/kg IV q8-12h

Ticarcillin-clavulanate

50 mg/kg IV q6-8h

Trimethoprim-sulfamethoxazole or trimethoprim-sulfadiazine

15 to 30 mg/kg PO/IV q12h

Vancomycin

15 mg/kg IV q8h (dogs) 10 to 15 mg/kg IV q8-12h (cats)

IV, Intravenous.

nary synergism when co-administered with ampicillin, amoxicillin, or ticarcillin owing to the irreversible binding of the β-lactamase enzymes of many resistant bacteria.14 The aminopenicillins and firstgeneration cephalosporins have relatively short half-lives, and in the absence of renal impairment, they may be administered every 6 hours to take advantage of the well-described pharmacodynamic properties of most β-lactam agents. This recommendation is particularly relevant for patients with altered volumes of distribution (i.e., patients receiving intravenous fluids, parenteral nutrition, or blood products, and those with vascular leak or third-spacing syndromes).14 Alterations in drug clearance can occur rapidly. The clinician must consider these and other pharmacokinetic principles when determining dosages of all antibiotics to achieve the desired pharmacodynamic effects. Similarly, individualization of regimens based on prior antibiotic use may reduce the risk of therapeutic failure. An important exception to the above therapeutic recommendations exists when a new infection is documented in a patient currently receiving antibiotics. Similarly, critically ill patients with a history of recent antibiotic use or presumed polymicrobial infection should be managed with broader-spectrum antibiotics, such as a carbapenem, alone or in conjunction with an aminoglycoside or fluoroquinolone, while culture and susceptibility results are pending. For treatment of infections caused by some enterococci or methicillinresistant staphylococci, evaluation of susceptibility data is imperative to avoid treatment failures.2,11,20,29 Fluoroquinolones and aminoglycosides remain effective treatment for some staphylococci. Neither drug class is predictably active against streptococci. However, they are often active against gramnegative pathogens that may be contributing to patient morbidity.

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These agents generally are administered once daily at the upper end of the dosage range. In cats, enrofloxacin should not be prescribed at a dose exceeding 5 mg/kg/day because its administration has been associated with temporary or permanent blindness in domestic felids.14 Among the aminoglycosides, gentamicin is reported to be more effective than amikacin for treatment of staphylococcal infections in humans.25 The clinical relevance of this distinction among veterinary isolates is not clear. Both amikacin and gentamicin are associated with potential renal dysfunction, but both are frequently prescribed without incident for short-term therapy (Mild AI in absence of subaortic stenosis 4. Positive blood culture ≥2 positive blood cultures ≥3 with common skin contaminant

Minor Criteria 1. Fever 2. Medium to large dog (>15 kg) 3. Subaortic stenosis 4. Thromboembolic disease 5. Immune-mediated disease Polyarthritis Glomerulonephritis 6. Positive blood culture not meeting major criteria 7. Bartonella serology ≥ 1 : 1024

Diagnosis Definite Pathology of the valve Two major criteria One major and two minor criteria

Possible One major and one minor criterion Three minor criteria

Unlikely Other diagnosis made Resolved in 6-8 wk; may add azithromycin 5 mg/kg PO q24h × 7 days then EOD if lack of response

Culture negative

Unknown

Acute: amikacin and timentin IV × 1-2 wk Chronic: amoxicillin with clavulanic acid PO ≥ 6-8 wk and enrofloxacin PO ≥ 6-8 wk

Specific drug doses should be based on the high end of the recommended range with consideration of patient factors such as renal disease. Typical MIC profiles derived from UC Davis VMTH microbial service database of antimicrobial sensitivity of cultured microorganisms. Recommended antibiotics for particular bacteria were chosen based on ≥ 90% of the cultured isolates sensitive to the particular antibiotic. d, Day; EOD, every other day; MBC, minimum bactericidal concentration; MIC, minimum inhibitory concentration; wk, week.

Nitroprusside may be necessary in patients with acute fulminant heart failure resulting from severe mitral or aortic IE.

PROGNOSIS Dogs with aortic IE have a grave prognosis, and median survival in one study was only 3 days compared with a median survival of 476 days for dogs with mitral valve IE.4 Likewise, dogs with Bartonella IE have short survival times because the aortic valve is affected almost exclusively. Another case series of dogs with aortic IE reported similar outcomes, including 33% mortality in the first week and 92% mortality within 5 months of diagnosis.9 Other risk factors for early cardiovascular death include glucocorticoid administration before treatment, presence of thrombocytopenia, high serum creatinine concentration, renal complications, and thromboembolic disease.5,8 Death occurring soon after diagnosis most often is due to CHF or sudden cardiac death from a lethal arrhythmia. Other causes of death within the first week of treatment in dogs with IE include renal failure, pulmonary hemorrhage, and severe neurologic disease.

REFERENCES 1. Que YA, Moreillon P: Infective endocarditis, Nat Rev Cardiol 8:322-336, 2011. 2. Guyton AC, Lindsay AW: Effect of elevated left atrial pressure and decreased plasma protein concentration on the development of pulmonary edema, Circ Res 7:649-657, 1959. 3. Baddour LM, Wilson WR, Bayer AS, et al: Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever,

Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America, Circulation 111:e394-e434, 2005. 4. MacDonald KA, Chomel BB, Kittleson M, et al: A prospective study of canine infective endocarditis in northern California (1999-2001): emergence of Bartonella as a prevalent etiologic agent, J Vet Intern Med 18:5664, 2004. 5. Sykes JE, Kittleson MD, Chomel BB, et al: Clinicopathologic findings and outcome in dogs with infective endocarditis: 71 cases (1992-2005), J Am Vet Med Assoc 228:1735-1747, 2006. 6. Mugge A, Daniel WG, Frank G, Lichtlen PR: Echocardiography in infective endocarditis: reassessment of prognostic implications of vegetation size determined by the transthoracic and the transesophageal approach, J Am Coll Cardiol 14:631-638, 1989. 7. Macarie C, Iliuta L, Savulescu C, et al: Echocardiographic predictors of embolic events in infective endocarditis, Kardiol Pol 60:535-540, 2004. 8. Calvert CA: Valvular bacterial endocarditis in the dog, J Am Vet Med Assoc 180:1080-1084, 1982. 9. Sisson D, Thomas WP: Endocarditis of the aortic valve in the dog, J Am Vet Med Assoc 184:570-577, 1984. 10. Peddle GD, Drobatz KJ, Harvey CE, et al: Association of periodontal disease, oral procedures, and other clinical findings with bacterial endocarditis in dogs, J Am Vet Med Assoc 234:100-107, 2009. 11. Sykes JE, Kittleson MD, Pesavento PA, et al: Evaluation of the relationship between causative organisms and clinical characteristics of infective endocarditis in dogs: 71 cases (1992-2005), J Am Vet Med Assoc 228:1723-1734, 2006. 12. Schmiedt C, Kellum H, Legendre AM, et al: Cardiovascular involvement in 8 dogs with blastomyces dermatitidis infection, J Vet Intern Med 20:1351-1354, 2006.

13. Breitschwerdt EB, Hegarty BC, Hancock SI: Sequential evaluation of dogs naturally infected with Ehrlichia canis, Ehrlichia chaffeensis, Ehrlichia equi, Ehrlichia ewingii, or Bartonella vinsonii, J Clin Microbiol 36:2645-2651, 1998. 14. Breitschwerdt EB, Atkins CE, Brown TT, et al: Bartonella vinsonii subsp. berkhoffii and related members of the alpha subdivision of the Proteobacteria in dogs with cardiac arrhythmias, endocarditis, or myocarditis, J Clin Microbiol 37:3618-3626, 1999. 15. Chomel BB, Kasten RW, Williams C, et al: Bartonella endocarditis: a pathology shared by animal reservoirsand patients, Ann N Y Acad Sci 1166:120-126, 2009. 16. Ohad DG, Morick D, Avidor B, et al: Molecular detection of Bartonella henselae and Bartonella koehlerae from aortic valves of Boxer dogs with infective endocarditis, Vet Microbiol 141:182-185, 2010. 17. Pesavento PA, Chomel BB, Kasten RW, et al: Pathology of bartonella endocarditis in six dogs, Vet Pathol 42:370-373, 2005. 18. Peddle G, Sleeper MM: Canine bacterial endocarditis: a review, J Am Anim Hosp Assoc 43:258-263, 2007. 19. Meurs KM, Heaney AM, Atkins CE, et al: Comparison of polymerase chain reaction with bacterial 16s primers to blood culture to identify bacteremia in dogs with suspected bacterial endocarditis, J Vet Intern Med 25:959-962, 2011. 20. Perez C, Maggi RG, Diniz PP, et al: Molecular and serological diagnosis of Bartonella infection in 61 dogs from the United States, J Vet Intern Med 25:805-810, 2011.

21. Arai S, Wright BD, Miyake Y, et al: Heterotopic implantation of a porcine bioprosthetic heart valve in a dog with aortic valve endocarditis, J Am Vet Med Assoc 231:727-730, 2007. 22. Barker CW, Zhang W, Sanchez S, et al: Pharmacokinetics of imipenem in dogs, Am J Vet Res 64:694-699, 2003. 23. Breitschwerdt EB, Blann KR, Stebbins ME, et al: Clinicopathological abnormalities and treatment response in 24 dogs seroreactive to Bartonella vinsonii (berkhoffii) antigens, J Am Anim Hosp Assoc 40:92-101, 2004. 24. Rolain JM, Maurin M, Raoult D: Bactericidal effect of antibiotics on Bartonella and Brucella spp.: clinical implications, J Antimicrob Chemother 46:811-814, 2000. 25. Biswas S, Maggi RG, Papich MG, et al: Molecular mechanisms of Bartonella henselae resistance to azithromycin, pradofloxacin and enrofloxacin, J Antimicrob Chemother 65:581-582, 2010. 26. Raoult D, Fournier PE, Vandenesch F, et al: Outcome and treatment of Bartonella endocarditis, Arch Intern Med 163:226-230, 2003. 27. Tornos P, Gonzalez-Alujas T, Thuny F, et al: Infective endocarditis: the European viewpoint, Curr Probl Cardiol 36:175-222, 2011. 28. Vanassche T, Peetermans WE, Herregods MC, et al: Anti-thrombotic therapy in infective endocarditis, Expert Rev Cardiovasc Ther 9:12031219, 2011. 29. From MacDonald KA: Infective endocarditis. In Bonagura J, editor: Current Veterinary Therapy XIV, St. Louis, 2005, Saunders.

CHAPTER 99  •  Urosepsis

CHAPTER 99  UROSEPSIS Lillian R. Aronson,

VMD, DACVS

KEY POINTS • Urosepsis is an uncommonly diagnosed condition in the small animal patient. • E. coli is the most frequently diagnosed uropathogen in patients with urosepsis. • In most animals with urosepsis, bacteria from the rectum, genital, and perineal areas serve as the principle source of infection. • Patients with a urinary tract infection and risk factors, including the presence of an anatomic abnormality, a urinary tract obstruction, nephrolithiasis, prior urinary tract disease, renal failure, neurologic disease, diabetes mellitus, hyperadrenocorticism, and immunosuppression, are more prone to the development of urosepsis. • Causes of urosepsis that have been identified in the veterinary patient include pyelonephritis, bladder rupture, prostatic infection, testicular and vaginal abscessation, pyometra, and catheterassociated urinary tract infections. • Treatment should be instituted as soon as possible and often includes a combination of intravenous fluid and broad-spectrum antimicrobial therapy, correction of the underlying condition, as well as attempting to correct any predisposing or complicating factors.

Urosepsis, an uncommonly reported condition in veterinary medicine, refers to sepsis associated with a complicated urinary tract infection (UTI). In humans, the source of the infection can be the kidney, bladder, prostate, or genital tract.1 More specifically, urosepsis in humans has been associated with acute bacterial pyelonephritis, emphysematous pyelonephritis, pyonephrosis, renal abscessation, fungal infections, bladder perforation, and prostatic and testicular infections.2-5 In addition in human patients, urinary catheterassociated infections also have resulted in sepsis.6-8 Although many of these conditions often are diagnosed in the veterinary patient, little information currently exists in the veterinary literature regarding the incidence of urosepsis as a complication of these conditions. In one retrospective study looking at sepsis in small animal surgical patients, the urogenital tract was identified as the source of infection in approximately 50% of the cases.9 Of 61 dogs included in the study, sources of urosepsis included a pyometra (14), prostatic abscessation or suppuration (12), testicular abscessation (3), renal abscessation (3; see Figure 99-1) and vaginal abscessation (1). Of four cats included in the study, one cat had a pyometra and a second cat had a ruptured uterus. This chapter discusses pathogenesis and reviews the current veterinary literature to determine what conditions in veterinary medicine have been associated with urosepsis. Accurate recognition

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A

B FIGURE 99-1  A, Renal and ureteral abscessation in a dog that presented with urosepsis. B, The kidney was not salvageable and a nephrectomy was performed. Purulent fluid was aspirated from the kidney.

of these complicated UTIs and appropriate treatment are necessary to prevent morbidity and mortality.

PATHOGENESIS Urosepsis is a clinical condition that occurs secondary to a systemic bacterial infection originating from the urogenital tract and the associated inflammatory response. In most cases of urosepsis, bacteria isolated from the rectum, genital, and perineal area are the principle source of infection.10 These bacteria then can migrate from the genital tract to the lower and then upper urinary tract.10 Similar to human patients, E. coli is the most common uropathogen affecting dogs and cats and accounts for up to 50% of the urine isolates.10-16 Gram-positive cocci, including staphylococci, streptococci, and enterococci account for up to one third of bacteria isolated and, although uncommonly diagnosed, Pseudomonas, Klebsiella, Pasteurella, Corynebacterium, and Mycoplasma spp. account for the remaining isolates.12,17-19 In humans, gram-negative sepsis frequently is caused by infections originating from the urinary tract.6,13 E. coli is the most common pathogen affecting the urinary tract of human and veterinary patients and consequently the most commonly isolated pathogen in patients with urosepsis; therefore its virulence has been investigated extensively. Most E. coli UTIs are caused

by pathogenic E. coli from the phylogenetic group B2, and to a lesser extent, group D.20 Although several hundred serotypes of E. coli are known, fewer than 20 account for most bacterial UTIs.21 In dogs and humans, the majority of strains associated with urovirulence belong to a small number of serogroups (O, K, and H; see Chapter 94).13 Certain properties that may enhance the bacterial virulence include the presence of a particular pilus that mediates attachment to the uroepithelium; the presence of hemolysin and aerobactin; resistance to the bactericidal action of serum; and the rapid replication time in urine.10-13 In mouse models of human disease, uropathogenic E. coli have been shown to possess multiple adaptations, allowing them to survive and persist in the urinary tract.22-26 In patients with structural or functional abnormalities of the urinary tract or those with altered defenses, infections can be caused by gram-negative aerobic bacilli other than E. coli, gram-positive cocci including staphylococci and enterococci, and by bacterial strains that normally lack uropathogenic properties.5,14 In patients that have a septic peritonitis associated with a urinary tract disorder, the visceral and parietal peritoneum provide a large surface area for absorption of bacteria and endotoxins, resulting in septic shock (see Chapter 91).27 The development of a UTI and subsequent urosepsis in human and veterinary patients often represents a balance between the quantity and pathogenicity of the infectious agents and host defenses. The following local host defense mechanisms typically prevent ascending UTIs: normal micturition, extensive renal blood supply, normal urinary tract anatomy (i.e., urethral length and high pressure zones within the urethra), urethral and ureteral peristalsis, mucosal defense barriers, antimicrobial properties of the urine, and systemic immunocompetence.10,12 Systemic defenses are most important for the prevention of hematogenous spread from the urinary tract.10 Patients with a UTI and risk factors including the presence of an anatomic abnormality, a urinary tract obstruction, nephrolithiasis, prior urinary tract disease, renal failure, neurologic disease, diabetes mellitus, hyperadrenocorticism, and/or immunosuppression should be considered to have a complicated UTI and are more prone to the development of urosepsis.2,5,10,28-30 In addition, a UTI diagnosed in pregnant or intact dogs and cats also should be considered complicated. Clinical and laboratory findings in patients with urosepsis are often similar to patients whose sepsis originated from another source; these may include lethargy, fever, hypothermia, hyperemic mucous membranes, tachycardia, tachypnea, bounding pulses, a positive blood culture, and a leukogram that reveals a leukocytosis or leukopenia with or without a left shift (see Chapter 91).31 However, patients with urosepsis may display early laboratory changes that identify abnormalities specifically related to the urinary tract, including azotemia, an active urine sediment, and a positive urine bacterial culture. A positive urine culture is extremely important in these patients to confirm the results of the blood culture by isolation of the same organism(s) with identical antimicrobial profiles.6 In cases of severe sepsis, multiple organ dysfunction can be present along with pale mucous membranes, weak pulses, and a prolonged capillary refill time (see Chapter 7). In addition, in cats, diffuse abdominal pain, bradycardia, anemia, and icterus may be identified.31 Aggressive treatment is necessary and typically includes a combination of intravenous fluids and broad-spectrum antimicrobial therapy. However, specific treatment protocols vary depending on the source of the infection and the complications resulting from sepsis. Once the culture and susceptibility testing results are available, antimicrobial coverage should be modified to treat the isolated organism(s). Veterinary professionals have continued concerns regarding the increasing resistance of canine urinary tract isolates to common antimicrobials, including fluoroquinolones, clavulanic acid–potentiated β-lactams, and third-generation cephalosporins.32-35

CHAPTER 99  •  Urosepsis

Similar to humans, canine E. coli isolates resistant to fluoroquinolones have a lower prevalence for many of the virulence genes and are more likely to be from phylogenetic groups A and B1 and less likely from phylogenetic group B2.36 Prudent use of antimicrobials is critical to reduce the incidence of antimicrobial resistance. In addition, the clinician should address the underlying condition and attempt to correct any complicating factors.14 Although different causes of urosepsis in the veterinary patient somewhat overlap, some clinical findings, laboratory results, and treatments are unique to each condition. The rest of this chapter discusses the different causes of urosepsis that have been identified in small animals.

CAUSES OF UROSEPSIS Pyelonephritis The kidneys and ureters are affected most commonly by ascending bacteria rather than via hematogenous infections. Renal trauma or the presence of a urinary tract obstruction may increase the incidence of hematogenous spread of infection to the urinary tract because of interference with the renal microcirculation.37,38 In human patients, hematogenous pyelonephritis occurs most commonly in patients debilitated from either chronic illness or those receiving immunosuppressive therapy.13 Urosepsis resulting from pyelonephritis has been reported uncommonly in the veterinary literature. In a retrospective study evaluating 61 dogs with severe sepsis, a renal abscess in conjunction with pyelonephritis was the source of the infection in only three dogs.9 In a second retrospective study evaluating 29 cats with sepsis, pyelonephritis was the cause in only two cats.31 The author has identified seven cats with obstructive calcium oxalate urolithiasis that also were diagnosed with a pyelonephritis based upon a positive bacteriologic culture result from urine collected by pyelocentesis. None of the cats identified were clinically septicemic, but this can be difficult to diagnose definitively in feline patients. Human patients with infected stones or renal pelvic urine were found to be at a greater risk for the development of urosepsis than those with a lower UTI.39 Dogs and cats with pyelonephritis and urosepsis may be febrile, anorexic, lethargic, and dehydrated and have a history of recent weight loss. If the disease is acute, one or both kidneys may be enlarged and painful, and the animal may have signs of polyuria, polydipsia, and vomiting. Azotemia secondary to acute kidney injury may be present, and blood work often reveals a neutrophilic leukocytosis with a left shift and a metabolic acidosis. In acute and chronic cases, abdominal ultrasound and/or intravenous pyelography may reveal mild to moderate pelvic dilation and ureteral dilation. The renal cortex as well as the surrounding retroperitoneal space may appear hyperechoic. Renal enlargement often is identified in cases of acute pyelonephritis; poor corticomedullary definition, distortion of the renal collecting system, irregular renal shape, and reduced kidney size may be seen with chronic cases. The urinalysis may reveal impaired urine concentrating ability, bacteriuria, pyuria, proteinuria, hematuria, and/or granular casts.10,40 As previously mentioned, treatment includes the removal of predisposing factors, intravenous fluid therapy, and broad-spectrum antimicrobial administration until a specific organism is identified. Antimicrobial therapy targeted against the isolated organism should continue for 4 to 8 weeks. A urinalysis and bacterial culture should be performed after 1 week of treatment and before discontinuation of antimicrobial therapy to determine whether the infection has resolved. In addition, a urine culture should be performed 2 to 3 days after therapy has been discontinued. In cases of unilateral advanced pyelonephritis, pyonephrosis, or the presence of a renal abscess, a total nephrectomy in addition to antimicrobial therapy is often the preferred treatment.41 Cases of pyonephrosis have been treated

successfully at the author’s institution with the temporary placement of a ureteral stent to allow for continued drainage of the kidney. This is done in conjunction with antimicrobial therapy based on culture and susceptibility.

Bladder Rupture Although rare, urosepsis may result from a bladder and/or a proximal urethral rupture in a patient with a lower UTI.42 Urosepsis is not identified typically in patients with an intact lower urinary tract.10 Rupture of the urinary tract in dogs and cats most commonly occurs after blunt trauma resulting from being hit by a car. Other causes include penetrating injuries, aggressive catheterization, rupture secondary to prolonged urethral obstruction, or excessive force during bladder expression. Physical examination may reveal dehydration, lack of a bladder on palpation, fluid accumulation within the peritoneal cavity, and ventral abdominal bruising. Clinical signs are often vague initially but can worsen as the uremia and inflammation/sepsis progress. Signs may include vomiting, anorexia, depression, abdominal pain, and systemic inflammation (see Chapter 6). Abdominocentesis and abdominal fluid to peripheral blood creatinine and/or potassium ratios are often diagnostic of uroperitoneum,43,44 and the presence of bacteria on cytology confirms a septic peritonitis (for further details, see Chapter 122).45 Urosepsis after bladder rupture is reported uncommonly in the veterinary literature. In a retrospective study evaluating 23 dogs and cats with septic peritonitis, only one cat had septic peritonitis associated with intestinal herniation and bladder rupture.46 In a second study evaluating 26 cases of uroperitoneum in cats, five patients had aerobic bacterial cultures performed from the peritoneum or bladder, and of those, three were positive. Organisms isolated included Enterococcus spp., Staphylococcus spp., and alpha-streptococcus.43 If septic peritonitis is confirmed, early repair and/or urinary diversion is recommended to halt continued accumulation of septic urine in the abdominal cavity. The bladder defect is debrided of any devitalized tissue and then closed using a single-layer appositional suture pattern. If the viability of the bladder wall is a concern, a closed indwelling urinary catheter system can be used to maintain bladder decompression postoperatively. Treatment options for patients with urethral trauma include primary urethral repair, placement of a urethral catheter to stent the urethra, placement of a cystostomy tube for urinary diversion until the urethra heals, or the combination of a cystostomy tube and a urethral catheter.

Prostatic Infection In addition to normal host defense mechanisms previously mentioned, prostatic fluid contains a zinc-associated antibacterial factor, which serves as an important natural defense mechanism. Despite these defense mechanisms, bacterial colonization of the prostate can occur through ascension of urethral flora or by the hematogenous route.47 Suppurative prostatitis and prostatic abscessation are some of the most common causes of urosepsis in canine surgical patients, with 12 out of 61 cases diagnosed in one study.9 Dogs with suppurative prostatitis usually have a history of an acute onset of illness. Patients often are presented with signs of anorexia, vomiting, tenesmus, lethargy, fever, dehydration, injected mucous membranes, weight loss, pain upon rectal examination, caudal abdominal discomfort and/or pain in the pelvic and lumbar region, a stiff or stilted gait, and an unwillingness to breed.48-50 In addition, hematuria, pyuria, stranguria, hemorrhagic preputial discharge, urinary incontinence, or the inability to urinate also may be identified. If the infection is not treated, microabscesses can form and eventually coalesce into a large abscess. A complete blood count often reveals a mature neutrophilia and evidence of a left shift. Septicemia and endotoxemia quickly develop, particularly if the abscess has ruptured into the

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abdominal cavity.51 After rupture of a prostatic abscess, the peritoneal surface provides a large surface area for absorption of bacteria and bacterial by-products, thus leading to the development of septic shock. Hindlimb edema also has been identified in these patients and can result from altered vascular permeability that commonly occurs with sepsis as well as the presence of an abscess interfering with normal lymphatic and venous drainage from the peripheral lymph nodes. A definitive diagnosis is confirmed after identification of a septic exudate from an ejaculated sample, prostatic wash, traumatic catheterization, urethral discharge, or fine-needle aspirate (although this can be dangerous). Inflammatory changes identified in prostatic fluid are associated with histologic inflammation in more than 80% of the cases.52 Because of the potential of inducing septicemia during prostatic palpation or rupturing an abscess on fine-needle aspiration, it can be difficult and even clinically dangerous to collect prostatic fluid using some of the above-mentioned techniques from dogs with acute prostatitis.49 In dogs, similar to humans with acute bacterial prostatitis, bacteremia may result from manipulation of the inflamed gland.13,49 Because the infectious agent often can be identified on a Gram stain of the urine and bacterial culture collected via cystocentesis, vigorous prostatic palpation generally is avoided.13 Abdominal radiographs often reveal prostatomegaly; the area near the bladder neck may have poor detail resulting from localized peritonitis. Abdominal ultrasound may reveal varying echogenicity with symmetric or asymmetric enlargement of the gland. Cyst like structures as well as hypoechoic areas also may be present and could represent abscess formation. Rectal examination may reveal fluctuant areas when the abscess is near the dorsal periphery of the gland. Dogs with prostatitis may have a normal ultrasound examination, underscoring the need to make a definitive diagnosis using the previously mentioned techniques. Suppurative prostatitis and prostatic abscessation are serious lifethreatening disorders. In patients with acute suppurative prostatitis, treatment involves fluid therapy to correct dehydration and treat cardiovascular shock and antimicrobial therapy based on culture and susceptibility of urine or prostatic fluid. Because of the risks of obtaining prostatic fluid in this patient population, a urine sample for a urinalysis as well as culture and susceptibility testing should be obtained first to determine if a diagnosis can be made. Antimicrobials should be administered for a minimum of 4 to 6 weeks, then the urine or prostatic fluid should be cultured after discontinuation of antimicrobial therapy and again in 2 to 4 weeks to determine if the infection is eliminated completely.47-49 If the infection is not eliminated, resistant bacterial infections of the prostate and urinary tract can develop. Castration also is recommended once the infection is controlled and appears to be beneficial in the resolution of chronic bacterial prostatitis in an experimental model.49,52,53 In addition to the above-mentioned treatments, surgical drainage or excision is often the treatment of choice in a patient with a prostatic abscess. Antimicrobial therapy in conjunction with castration alone has been ineffective at resolving abscesses.50 Before surgery, ultrasonography is used to determine the location(s) of the abscess(es). Surgical techniques that have been described to treat prostatic abscessation include prostatic omentalization, placement of Penrose drains, marsupialization of the abscess, ultrasound-guided percutaneous drainage, and subtotal or excisional prostatectomy.42,54,55 In one study, of the three dogs that were presented with prostatic abscessation, two already had signs of sepsis.54 In a second study, 15 out of 92 dogs died in the postoperative period because of sepsis. E. coli was the most common bacteria isolated.51 Sepsis and shock were common postoperative complications developing in 33% of the dogs surviving surgery. Absorption of bacteria and toxins from an infected prostate gland and inflamed peritoneal surface contributed to the

development of septic shock.51 Approximately half of the dogs that died had rupture of the abscess and secondary septic peritonitis and shock before surgery.

Pyometra Pyometra is a serious condition affecting older dogs in the luteal stage of the estrus cycle. It has been associated with neutrophilia and impaired immune function, including a decrease in lymphocyte activity.56 Urosepsis can occur in dogs and cats diagnosed with pyometra with or without uterine rupture. In the largest retrospective study to date evaluating sepsis in the small animal surgical patient, pyometra was the most common source of urosepsis, with 14 out of 61 dogs reported. Of four cats included in the study, urosepsis occurred secondary to a pyometra in one cat and a ruptured uterus in a second cat.9 In a review of 80 cases of pyometra, 3 out of 73 dogs developed complications from generalized septicemia and thromboembolic disease in the immediate postoperative period, and one dog died from endotoxic shock resulting from a ruptured uterus.57 In a second retrospective study evaluating 183 cats diagnosed with pyometra, uterine rupture was present in seven cats. Four of seven cats died of septic peritonitis after uterine rupture.58 Many aerobic and some anaerobic bacteria have been identified in dogs and cats with pyometra, including Staphylococcus, Streptococcus, Pasteurella, Klebsiella, Proteus, Pseudomonas, Aerobacter, Haemophilus, and Moraxella spp. and Serratia marcescens. However, E. coli is the most common bacteria isolated. Strains of E. coli in cases of canine pyometra display a strong similarity to isolates obtained from UTIs, likely because of the similar pathogenesis (i.e., ascending from the host’s intestinal or vaginal flora).59 UTIs are common complications of pyometra. Although culture results are rarely negative in the dog, aerobic culture results are negative in 15% to 31% of affected cats.58,60 Dogs diagnosed with a pyometra often are presented systemically sick with signs of anorexia, lethargy, depression, polydipsia, vomiting, diarrhea, and, if the cervix is patent, vaginal discharge. When abdominal pain is present, septic peritonitis is likely.58 E. coli pyometra has been associated commonly with renal dysfunction in dogs, albeit typically transient.61-65 A recent study evaluating urinary biomarkers in these patients has identified the glomerulus and proximal tubules of the nephron as the main sites of injury.66 Body temperature may be normal, elevated, or subnormal. Clinical signs in cats are similar but often more subtle. Clinicopathologic abnormalities in both species can occur to varying degrees and may include anemia, leukocytosis, or leukopenia with a left shift, azotemia, hypoalbuminemia, hypoglycemia or hyperglycemia, hyperglobulinemia, increased alkaline phosphatase, and metabolic acidosis.58,67-69 Before surgery, medical therapy should be instituted and include intravenous fluid and antimicrobial therapy to correct deficits and concurrent metabolic derangements (see Chapters 60 and 91). Surgery is not postponed in the very sick animals for more than a few hours because of worsening septicemia. Treatment for pyometra is ovariohysterectomy. If the uterus ruptures at surgery, the abdomen is lavaged and the patient treated for septic peritonitis (see Chapter 122).

Catheter-Associated Urinary Tract Infection In human patients, bacteriuria occurs in up to 20% of hospitalized patients with indwelling urinary catheters and, of these patients, 1% to 2% develop gram-negative bacteremia.13 The catheterized urinary tract has been demonstrated repeatedly to be the most common source of gram-negative sepsis in human patients13 and, although rare, the mortality rate in these patients can reach 30%.13 In human patients, bacteremia can occur immediately as a result of mucosal trauma associated with catheter placement and removal or secondary to mucosal ulceration.13 Many infecting strains, including E. coli and

CHAPTER 99  •  Urosepsis

Proteus, Pseudomonas, Klebsiella, and Serratia spp., show marked antimicrobial resistance compared with organisms identified in uncomplicated UTIs. Although nosocomial UTIs after the use of an indwelling urinary catheter in dogs and cats is reported to be a common complication by some authors, the subsequent development of urosepsis is uncommon. Bacterial UTIs developed in 20% of healthy adult female dogs after intermittent catheterization; in 33% of male dogs during repeated catheterization and in 65% of healthy male cats within 3 to 5 days of open indwelling catheterization.10,70 A few studies in the veterinary literature have looked at the incidence of UTIs in dogs and cats when a closed catheter system was used. In one study, 11 out of 21 (52%) animals and in a second study, 9 out of 28 animals (32%) developed catheter-associated infections.71,72 Both of these studies suggested that the risk of infection increased with duration of catheterization and that antimicrobial therapy was associated with increasingly resistant gram-negative organisms. Although the incidence of catheter-associated infections was high in both studies, urosepsis was not identified. In the most recent study looking at the incidence of catheter-associated UTIs in 39 dogs in a small animal intensive care unit, only 4 of 39 dogs (10.3%) developed a UTI.72 The lower incidence reported in this study was attributed to a shorter duration of catheterization, stricter definition of infection, different indications for catheterization, urine sample collection technique, and the protocol for catheter placement and maintenance. Urosepsis was not a reported complication. In veterinary and in human hospitals, pathogens can be introduced from the hands of hospital staff, via instrumentation or contaminated disinfectants. The most common location for bacteria to enter the system can occur at the catheter-collecting tube junction or at the drainage bag portal. Intestinal flora also can migrate along the catheter into the bladder from the perineal area of the patient.13 In a study evaluating multidrug-resistant (MDR) E. coli isolates from urine collected from dogs with an indwelling urinary catheter, the electrophoresis pattern of the MDR isolate from one dog was similar to the rectal isolate from the same dog.73 To prevent or minimize the incidence of catheter-associated infections, clinicians should avoid indiscriminate use of catheters. In addition, catheters should be used cautiously in patients with preexisting urinary tract disease, cats or female dogs with voluminous diarrhea, or those whose immune system is compromised. Appropriate antimicrobial therapy should be instituted rapidly should an infection occur. Many veterinary hospitals use used intravenous fluid bags as part of their urine collection system, resulting in an open system. In a recent study, 95 properly stored (at least 7 days), used intravenous bags were cultured to see if they were a potential source of contamination for the patient. No aerobic bacterial contamination or growth was identified in the system.74 Recently, the use of an open versus closed collection system for a short duration of catheterization (at least 7 days) was evaluated with regard to the development of nosocomial bacteriuria. The study included 51 dogs and found an overall incidence of bacteriuria of 9.8%; the type of collection system (open vs. closed) was not associated with the development of bacteriuria. The authors concluded that the low incidence of bacteriuria likely was associated with a strict standard protocol of catheter placement and maintenance as well as the short duration of indwelling catheterization.75 Another study found that the risk of infection increased by 27% for each 1-day increase in catheterization.76 Because a longer duration of catheterization has been associated with antimicrobial resistant bacteria and the duration of catheterization is unpredictable, prophylactic use of antimicrobials is not recommended.72 In addition, diagnostic and therapeutic procedures that may result in the introduction of bacteria into the urinary system also should be minimized.10,13

CONCLUSION Urosepsis is an uncommonly diagnosed but serious problem that can affect dogs and cats. Conditions in veterinary medicine that have been associated with urosepsis include bacterial pyelonephritis and renal abscessation, bladder rupture in patients with a UTI, prostatic suppuration and abscessation, testicular and vaginal abscessation, pyometra, and catheter-associated UTIs. Risk factors that may cause patients to be more prone to the development of urosepsis or complicate treatment include the presence of an anatomic abnormality, a urinary tract obstruction, nephrolithiasis, prior urinary tract disease, acute kidney injury, neurologic disease, diabetes, Cushing’s disease, and immunosuppression. Accurate recognition and aggressive therapy addressing the underlying condition, complicating risk factors, and the associated inflammatory response are necessary to prevent significant morbidity and mortality.

REFERENCES 1. Kunin CM: Definition of acute pyelonephritis vs the urosepsis syndrome, Arch Intern Med 163:2393-2394, 2003. 2. O’Donnell MA: Urological sepsis. In Zinner SR, editor: Sepsis and multiorgan failure, Baltimore, 1997, Williams & Wilkins, pp 441-449. 3. Stamm WE: Urinary tract infections and pyelonephritis. In Harrison’s principles of internal medicine, ed 15, New York, 2001, McGraw-Hill, pp 1620-1626. 4. Opal SM: Urinary tract infections. In Irwin RS, Cerra FB, Rippe JM: Intensive care medicine, Philadelphia, 1999, Lippincott-Raven, pp 1117-1126. 5. Melekos MD, Naber KG: Complicated urinary tract infections, Int J Antimicrob Agents 15:247-256, 2000. 6. Paradisi F, Corti G, Mangani V: Urosepsis in the critical care unit, Crit Care Clin 14:166-181, 1998. 7. Rosser CJ, Bare RL, Meredith JW: Urinary tract infections in the critically ill patient with a urinary catheter, Am J Surg 177:287-290, 1999. 8. Reed RL: Contemporary issues with bacterial infection in the intensive care unit, Surg Clin North Am 80:1-12, 2000. 9. Hardie EM, Rawlings CA, Calvert CA: Severe sepsis in selected small animal surgical patients, J Small Anim Pract 44:13-16, 2003. 10. Bartges JW: Urinary tract infections. In Ettinger SC, Feldman EC: Textbook of veterinary internal medicine, ed 6, St Louis, 2005, Elsevier, pp 1800-1808. 11. Senior DF: Management of difficult urinary tract infections. In Bonagura JD: Kirk’s current veterinary therapy XIII: small animal practice, Philadelphia, 1999, WB Saunders, pp 883-888. 12. Bartges JW, Barsanti JE: Bacterial urinary tract infections in cats. In Bonagura JD: Kirk’s current veterinary therapy XIII: small animal practice, Philadelphia, 1999, WB Saunders, pp 880-886. 13. Stamm WE, Turck M: Urinary tract infections and pyelonephritis. In Harrison JR, Wilson JD, Isselbacher KJ, et al, editors: Harrison’s Principles of internal medicine, ed 12, New York, 1991, McGraw-Hill, pp 538-544. 14. Wagenlehner FME, Naber KG: Hospital-acquired urinary tract infections, J Hosp Infect 46:171-181, 2000. 15. Feldman EC: Urinary tract infections. In Nelson RW, Couto CG, editors: Small animal internal medicine, ed 4, St Louis, 2009, Mosby, pp 624-630. 16. Olszyna DP, Prins JM, Dekkers PEP: Sequential measurements of chemokines in urosepsis and experimental endotoxemia, J Clin Immunol 19:399-405, 1999. 17. Lees GE: Epidemiology of naturally occurring feline bacterial urinary tract infections, Vet Clin North Am Small Anim Pract 14:471-479, 1984. 18. Ling GV, Norris CR, Franti CE, et al: Interrelations of organism prevalence, specimen collection method, and host age, sex, and breed among 8,354 canine urinary tract infections (1969-1995), J Vet Intern Med 15:341-347, 2001. 19. Wooley RE, Blue JL: Quantitative and bacteriological studies of urine specimens from canine and feline urinary tract infections, J Clin Microbiol 4:326-329, 1976.

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PART X  • INFECTIOUS DISORDERS 20. Thompson MF, Litster AL, Platell JL, et al: Canine bacterial urinary tract infections: new developments in old pathogens, Vet J 190:22-27, 2011. 21. Oluoch AO, Kim CH, Weisiger RM, et al: Nonenteric Escherichia coli isolates from dogs: 674 cases (1990-1998), J Am Vet Med Assoc 218:381384, 2001. 22. Kau AL, Hunstad DA, Hultgren SJ: Interaction of uropathogenic Escherichia coli with host uroepithelium, Curr Opin Microbiol 8:54-59, 2005. 23. Garofalo CK, Hooton TM, Martin SM, et al: Escherichia coli from the urine of female patients with urinary tract infections is competent for intracellular bacterial community formation, Infect Immun 75:52-60, 2007. 24. Mulvey MA, Schilling JD, Hultgren SJ: Establishment of a persistent Escherichia coli reservoir during the acute phase of a bladder infection, Infect Immun 69:4572-4579, 2001. 25. Justice SS, Hung C, Theriot JA, et al: Differentiation and development pathways of uropathogenic Escherichia coli in urinary tract pathogenesis, Proc Natl Acad Sci USA 101:1333-1338, 2004. 26. Bower JM, Eto DS, Mulvey MA: Covert operations of uropathogenic Escherichia coli within the urinary tract, Traffic 6:18-31, 2005. 27. Matthiessen DT, Marretta SM: Complications associated with the surgical treatment of prostatic abscessation, Probl Vet Med 1:63-73, 1989. 28. Stewart C: Urinary tract infections. In Howell JM: Emergency medicine, Philadelphia, 1998, WB Saunders, pp 859-868. 29. Karunajeewa H, Mcgechie D, Stuccio G, et al: Asymptomatic bacteriuria as a predictor of subsequent hospitalization with urinary tract infection in diabetic adults: The Fremantle Diabetic Study, Diabetologia 48:12881291, 2005. 30. Farley MM: Group B Streptococcal disease in nonpregnant adults, Emerg Infect 33:556-561, 2001. 31. Brady CA, Otto CM, Van Winkle TJ, et al: Severe sepsis in cats: 29 cases (1986-1998), J Am Vet Med Assoc 217:531-535, 2000. 32. Gibson JS, Morton JM, Cobbold RN, et al: Multidrug resistant E. coli and Enterobacter extraintestinal infection in 37 dogs, J Vet Intern Med 22:844850, 2008. 33. Cooke CL, Singer RS, Jang SS, et al: Enrofloxacin resistance in Escherichia coli isolated from dogs with urinary tract infections, J Am Vet Med Assoc 220:190-192, 2002. 34. Cohn LA, Gary AT, Fales WH, et al: Trends in fluoroquinolone resistance of bacteria isolated from canine urinary tracts, J Vet Diag Invest 15:338343, 2003. 35. Prescott JF, Hanna WJB, Reid-Smith R, et al: Antimicrobial drug use and resistance in dogs, Can Vet J 43:107-116, 2002. 36. Johnson JR, Kuskowski MA, Owens K, et al: Virulence genotypes and phylogenetic background of fluoroquinolone-resistance and susceptible Escherichia coli urine isolates from dogs with urinary tract infections, Vet Microbiol 136:108-114, 2009. 37. Bartges JW, Finco DR, Polzin DJ, et al: Pathophysiology of urethral obstruction, Vet Clin North Am Small Anim Pract 26:255-264, 1996. 38. Finco DR, Barsanti JA: Bacterial pyelonephritis, Vet Clin North Am 9:645, 1979. 39. Mariappan P, Smith G, Bariol SV, et al: Stone and pelvic urine culture and sensitivity are better than bladder urine as predictors of urosepsis following percutaneous nephrolithotomy: a prospective clinical study, J Urol 173:1610-1614, 2005. 40. Dibartola SP, Rutgers HC: Diseases of the kidney. In Sherding RG: The cat: diseases and clinical management, St Louis, 1994, Saunders, pp 1353-1395. 41. Rawlings CA, Bjorling DE, Christie BA: Kidneys. In Slatter D, editor: Textbook of small animal surgery, ed 3, Philadelphia, 2003, Saunders, pp 1606-1619. 42. McGrotty Y, Doust R: Management of peritonitis in dogs and cats, Companion Anim Pract Jul/Aug, pp 360-367, 2004. 43. Aumann M, Worth LT, Drobatz KJ: Uroperitoneum in cats: 26 cases (1986-1995), J Am Anim Hosp Assoc 34:315-324, 1998. 44. Schmiedt C, Tobias KM, Otto CM: Evaluation of abdominal fluid: peripheral blood creatinine and potassium ratios for diagnosis of uroperitoneum in dogs, J Vet Emerg Crit Care 11:275-280, 2001. 45. Kirby BM: Peritoneum and peritoneal cavity. In Slatter D: Textbook of small animal surgery, ed 3, Philadelphia, 2003, Saunders, pp 414-445.

46. King LG: Postoperative complications and prognostic indicators in dogs and cats with septic peritonitis: 23 cases (1989-1992), J Am Vet Med Assoc 204:407-413, 1994. 47. Johnson C: Reproductive system disorders. In Nelson RW, Couto CG, editors: Small animal internal medicine, St Louis, 2003, Mosby, pp 930-932. 48. Basinger RR, Robineete CL, Spaulding KA: Prostate. In Slatter D, editor: Textbook of small animal surgery, ed 3, Philadelphia, 2003, Saunders, pp 1542-1557. 49. Krawiec DR: Canine prostate disease, J Am Vet Med Assoc 204:1561-1563, 1994. 50. Kutzler MA, Yeager A: Prostatic diseases. In Ettinger SG, Feldman EC, editor: Textbook of veterinary internal medicine, St Louis, 2005, Elsevier, pp 1809-1819. 51. Mullen HS, Matthiesses DT, Scavelli TD: Results of surgery and postoperative complications in 92 dogs treated for prostatic abscessation by a multiple Penrose drain technique, J Am Anim Hosp Assoc 26:370-379, 1990. 52. Barsanti JA, Finco DR: Canine prostatic disease, Vet Clin North Am 16:587-599, 1986. 53. Cowan LA, Barsanti JA, Crowell W, et al: Effects of castration on chronic bacterial prostatitis in dogs, J Am Vet Med Assoc 199:346-350, 1991. 54. Apparicio M, Vicenti WRR, Pires EA, et al: Omentalisation as a treatment for prostatic cysts and abscesses, Aust Vet Pract 34:157-159, 2004. 55. Boland LE, Hardie RJ, Gregory SP, et al: Ultrasound-guided percutaneous drainage as the primary treatment for prostatic abscesses and cysts in dogs, J Am Anim Hosp Assoc 39:151-159, 2003. 56. Faldyna M, Laznicka A, Toman M: Immunosuppression in bitches with pyometra, J Small Anim Pract 42:5-10, 2001. 57. Wheaton LG, Johnson AL, Parker AJ, et al: Results and complications of surgical treatment of pyometra: a review of 80 cases, J Am Anim Hosp Assoc 25:563-568, 1989. 58. Kenney KJ, Matthiessen DT, Brown NO, et al: Pyometra in cats: 183 cases (1979-1984), J Am Vet Med Assoc 191:1130-1131, 1987. 59. Hagman R, Kuhn I: E. coli strains isolated from the uterus and urinary bladder of bitches suffering from pyometra: comparison by restriction enzyme digestion and pulsed filed gel electrophoresis, Vet Microbiol 84:143-153, 2002. 60. Dow C: The cystic hyperplasia-pyometra complex in the cat, Vet Rec 74:141, 1962. 61. Asheim A: Pathogenesis of renal damage and polydipsia in dogs with pyometra, J Am Vet Med Assoc 147:736-745, 1965. 62. Heiene R, Kristiansen V, Teige J, et al: Renal histomorphology in dogs with pyometra and control dogs, and long term clinical outcome with respect to signs of kidney disease, Acta Vet Scand 49:13-22, 2007. 63. Heiene R, Moe L, Molmen G: Calculation of urinary enzyme excretion, with renal structure and function in dogs with pyometra, Res Vet Sci 70:129-137, 2001. 64. Obel AL, Nicander L, Asheim A: Light and electron microscopic studies of the renal lesions in dogs with pyometra, Acta Vet Scand 5:93-125, 1964. 65. Stone EA, Littman MP, Robertson JL, et al: Renal dysfunction in dogs with pyometra, J Am Vet Med Assoc 193:457-464, 1988. 66. Maddens B, Daminet S, Smets P, et al: Escherichia coli pyometra induces transient glomerular and tubular dysfunction in dogs, J Vet Intern Med 24:1263-1270, 2010. 67. Marretta SM, Matthiessen DT, Nichols R: Pyometra and its complications, Probl Vet Med 1:50-61, 1989. 68. Hardy RM, Osborne CA: Canine pyometra: a polysystemic disorder. J Am Anim Hosp Assoc 10:245-268, 1974. 69. Stone EA, Littman MP, Robertson JL, et al: Renal dysfunction in dogs with pyometra, J Am Vet Med Assoc 193:457-464, 1988. 70. Smarick SD, Haskins SC, Aldrich J, et al: Incidence of catheter-associated urinary tract infection among dogs in a small animal intensive care unit, J Am Vet Med Assoc 224: 1936-1940, 2004. 71. Lippert AC, Fulton RB, Parr AM: Nosocomial infection surveillance in a small animal intensive care unit. J Am Anim Hosp Assoc 24:627-636, 1988. 72. Barsanti JA, Blue J, Edmunds J: Urinary tract infection due to indwelling bladder catheters in dogs and cats, J Am Vet Med Assoc 187:384-387, 1985.

73. Ogeer-Gyles J, Mathews K, Weeses S, et al: Evaluation of catheterassociated urinary tract infections and multi-drug resistant Escherichia coli isolates from the urine of dogs with indwelling urinary catheters, J Am Vet Med Assoc 229:1584-1590, 2006. 74. Barrett M, Campbell VL: Aerobic bacterial culture of used intravenous fluid bags intended for use as urine collection reservoirs, J Am Anim Hosp Assoc 44:1-6, 2008.

75. Sullivan LA, Campbell VL, Onuma SC: Evaluation of open versus closed urine collection systems and development of nosocomial bacteriuria in dogs, J Am Vet Med Assoc 237:187-190, 2010. 76. Bubenik LJ, Hosgood GL, Waldron DR, et al: Frequency of urinary tract infection in catheterized dogs and comparison of bacterial culture and susceptibility testing results for catheterized and non-catheterized dogs with urinary tract infections, J Am Vet Med Assoc 231:893-899, 2007.

CHAPTER 100  •  Mastitis

CHAPTER 100  MASTITIS Margret L. Casal,

DrMedVet, PhD, DECAR

KEY POINTS • After parturition, the mammaries should be evaluated twice daily for signs of mastitis until the puppies or kittens are weaned. • Clinical signs of acute mastitis are painful, erythematous, edematous, and swollen mammaries that may turn dark red to purple, abscess, and become gangrenous. • Causes are trauma to the nipples by nursing puppies or kittens, poor environmental conditions, and concurrent disease. • The most common bacteria found are E. coli, Streptococcus spp., and Staphylococcus spp.; in the absence of culture and susceptibility, antibiotics should be chosen to treat these infectious agents. • Despite immediate treatment, abscesses and gangrene often develop, which spontaneously rupture or should be drained and usually heal on secondary intention.

Mastitis (mammary inflammation or mammitis) is defined as inflammation of the mammary gland tissue that generally occurs during lactation during either the postpartum period or pseudopregnancy.1-4 Infections are common but need not be present.5 Mastitis may be localized within a single gland, or diffuse inflammation may be present in one or more mammary glands.2-4 Acute inflammation is characterized by local clinical signs, which may be accompanied by systemic signs. The frequency of subclinical or chronic mastitis is not known, and clinical signs are generally not present in this form. The diagnosis is made by physical examination, culture and susceptibility of the affected tissue and/or milk from the affected gland, blood work, and potentially ultrasound. Treatment includes appropriate antibiotics, debridement of the affected tissue, or removal of the affected gland if necessary.2-4

ANATOMY: BRIEF OVERVIEW In dogs and cats, one pair of mammary glands refers to a left gland and its corresponding right gland. Neither blood nor lymphatic vessels communicate between the two. Most dogs have five pair of mammary glands, although four pair are more common in smaller

breed dogs, but six pair also have been described in mid-size to larger dogs. In dogs, the glands are named according to their location: two pairs of thoracic glands, two pairs of abdominal glands, and one pair of inguinal glands. In cats, each pair of glands is numbered 1 to 4 from cranial to caudal (older texts refer to the feline glands as axial, thoracic, abdominal, and inguinal). The parenchyma is prominent only during the second half of pregnancy, lactation, and pseudopregnancy (in the dog), and regresses by 50 days after weaning. Milk is produced in the parenchyma and collected in sinuses from which the milk exits via the teat through 4 to 8 ducts in cats and 7 to 16 in dogs. Arterial blood is supplied to the cranial glands from the cranial superficial epigastric artery that branches off of the internal thoracic artery. The caudal glands receive their blood supply from the caudal superficial epigastric artery that branches off of the external pudendal artery. In the dog, the two cranial (thoracic) mammary glands on each side drain into the respective axillary lymph nodes and also may drain into the cranial sternal lymph node along with the middle (cranial abdominal) gland. The two pairs of caudal (caudal abdominal and inguinal) glands drain into their respective superficial inguinal lymph nodes, and the middle gland on each side can drain into either the axillary or superficial inguinal lymph node.6

ETIOLOGY The primary cause of mastitis is an ascending infection after trauma to the nipples by nursing puppies or kittens. Hematogenous infections may occur in bitches with concurrent disease such as endometritis, but this is less common. Predisposing factors include skin disease, contamination of the mammaries with lochia, poor environmental conditions, overcrowding, and galactostasis shortly before birth, after weaning, or after the loss of a litter.1-4, 7 Various pathogens that have been isolated from infected mammaries include Klebsiella spp., Proteus spp., Pasteurella spp., Pseudomonas spp., and others.8,9 However, Staphylococcus spp., Streptococcus spp., and in particular E. coli are the most common offenders.5,8-11 If culture and susceptibility are not available for diagnosis, as a rule of thumb staphylococcal infections lead to abscesses and gangrene, streptococcal infections are generally diffuse and spread into other glands, and E. coli lead to abscessation and septic mastitis.

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PART X  • INFECTIOUS DISORDERS

B

A

C FIGURE 100-1  A, Acute mastitis with areas of distinct demarcation (arrowheads). B, Formation of abscesses with development of necrotic tissue resulting in tearing of the skin (arrows). C, Acute mastitis with ruptured abscesses and gangrene (arrows). (A, Courtesy Dr. Lauren Jones, Country Companion Animal Hospital, Morgantown, Penn. B, Courtesy Dr. Kit Kampschmidt, Brittmoore Animal Hospital, Inc., Houston, Tex. C, Courtesy Dr. B. J. Parsons, Kanuga Animal Clinic, Hendersonville, NC.)

CLINICAL FINDINGS Acute Mastitis Acute mastitis is characterized by extremely painful, hot, swollen, erythematous, and edematous mammary tissue. The skin over the affected area generally is discolored and has a dark red to purple appearance with distinct areas of demarcation (Figure 100-1, A). The caudalmost mammaries are most likely to be affected during the acute phase. Systemic signs such as lethargy, fever, vomiting, dehydration, and inappetence are common and, if left untreated, bitches may become septic.1-4,6,11,12 Bitches or queens with mastitis may neglect their puppies or kittens, which may fade and die. Secretions from the affected gland can look almost normal but are more commonly purulent, brownish, bloody, or malodorous. As the disease progresses, abscesses may form (Figure 100-1, B), and the gland may rupture, exposing the necrotic tissue underneath the skin (Figure 100-1, C). The gangrenous gland(s) must be treated immediately to avoid severe sepsis in the bitch or queen.

Chronic or Subclinical Mastitis Chronic or subclinical mastitis is a poorly defined condition. Bitches and queens with subclinical mastitis do not present with systemic signs other than perhaps fading offspring. The affected glands and the expressed milk generally appear macroscopically normal, but the parenchyma of the affected gland may palpate thickened and hardened. Bitches and queens may have offspring that fail to gain weight, that lose weight, or that die.5,8

Neonatal death is not necessarily linked to the type of bacteria found in the mother’s infected mammary, regardless of acute or subclinical mastitis.5,8 Studies have shown that bacteria are present in 10% to 50% of milk from normal bitches or older queens.8,13 In one study, cultures were obtained from 25 puppies that died of sepsis within the first week of life and from their seven dams that were affected with acute mastitis.5 Only one of these deceased puppies had the same bacteria as its mother with mastitis.

DIAGNOSIS The case history and the typical clinical signs provide the basis for a diagnosis. Milk samples should be obtained for cytology and microbial culture and susceptibility before antibiotic therapy is initiated. To avoid contamination by the surrounding skin, vaginal discharge, and other environmental contaminants, the affected gland should be cleaned gently with a dilute chlorhexidine solution before expressing milk for diagnostics. Gloves should be worn and the first drop of expressed milk discarded before collecting the milk for analysis. In one study, cytology of milk from the affected gland during the early stages of acute mastitis revealed macrophages and large numbers of neutrophils with engulfed bacteria. Three days after onset of disease, the neutrophils became degenerate, and by day 6 lymphocytes began to invade the affected gland and were present in the corresponding milk. As the disease progressed, lymphocytes increased in number and by 2 weeks after onset, they made up the majority of cells on cytologic evaluation of the milk.11 Cell counts can be highly variable

CHAPTER 100  •  Mastitis

between the individual glands in a single bitch and between bitches with and without disease.11,13 High cell counts have been observed in normal bitches at weaning or at the end of pseudopregnancy when the mammaries begin to involute.11,13 Typically, some neutrophils are present, and a large number of macrophages with vacuolated cytoplasm predominate. A diagnosis of mastitis should not be made by cytology alone. Complete blood cell counts may reveal neutrophilia with a left shift in acute mastitis. One dog with gangrenous mastitis resulting from S. aureus presented with leukocytosis and thrombocytopenia.14 Alternatively, neutropenia may be present in advanced stages of the disease. Ultrasound is a useful adjunct in determining the extent of the mastitis. Normal inactive and active glands are characterized by layers that are different from each other. In active glands, the parenchyma is mildly coarse grained and echogenic, whereas distinctive layering was absent in inflamed tissues, which also demonstrated a loss in echogenicity.15 Using a Doppler to assess vascularity of the inflamed tissue may allow for prognosis: dogs with decreased vessel density in the inflamed tissue appeared to have a poorer outcome as opposed to those with increased vascularity.15 This can be explained by having increased vascularity during the beginning stages of inflammation, and as the disease progresses necrosis sets in, thereby decreasing vascularity.

DIFFERENTIAL DIAGNOSES Any dog or cat that is presented with a swollen, painful, and inflamed mammary gland after having given birth most likely has mastitis. However, mammary cancers may mimic the clinical signs, and thus every attempt should be made to confirm the diagnosis. Other differentials include trauma (overzealous neonatal nursers), galactostasis, severe pyoderma, or fibroadenomatous mammary hyperplasia, a benign condition of young cats. Other clinical signs and unusual pathogens such as blastomycosis in three dogs16 and toxoplasmosis in a cat17 also have been reported as causes of mastitis.

TREATMENT Therapy depends on the severity of disease. In dogs or cats with acute mastitis and sepsis, hospitalization and treatment for sepsis/ shock are required. The puppies or kittens must be removed from their mothers and fostered to another or hand-raised. Antibiotics are required and initially have to be administered intravenously. In dogs or cats with septic mastitis, a combination of antibiotics such as ampicillin/enrofloxacin (see below) provides excellent coverage. For any mastitis being treated, a course of 3 to 4 weeks of antibiotics is recommended. Antibiotics that are weak bases get trapped in the slightly acidic milk.2,3,9,12,18 However, the blood milk barrier breaks down in the face of severe inflammation. Thus the pH of the milk approaches that of the plasma. In the absence of microbial culture results, antibiotics should be chosen according to the cytology results. If predominantly cocci are noted in the milk sample, cephalosporins or amoxicillin– clavulonic acid are preferred antibiotics. On the other hand, if rods are primarily present, enrofloxacin and marbofloxacin are generally better. In dogs or cats with subclinical mastitis, the blood milk barrier is generally intact. Treatment is based on culture and susceptibility results and long-term therapy is required. The choice of drugs has to be based on pH, lipid solubility, and the amount of drug bound to proteins. The more drug that is protein bound, the less is transferred into the milk. Finally, treatment also depends on the presence or absence of nursing offspring.

If the bitch or queen with acute mastitis is not septic, antibiotic therapy can be initiated without removing the puppies or kittens. The choice of antibiotics has to take into consideration that they will be present in the milk and therefore will be passed to the offspring. All of the penicillins, cephalosporins, and macrolides are safe to use in bitches and queens that are still nursing offspring. Most other drugs have side effects in the neonates and should be avoided. These include chloramphenicol, tetracyclines, and aminoglycosides. Fluoroquinolones are debatable because most of the damage to cartilage occurs in puppies when they are ambulatory. Thus, if a fluoroquinolone is required, any ambulatory puppies should be removed. If the puppies are younger than 2 weeks of age, they need not be removed if their dam is being treated with a fluoroquinolone. Side effects seen in puppies receiving fluoroquinolones do not appear to occur in kittens.19,20 The most common side effect in any of the offspring of a mother with mastitis receiving antibiotics is diarrhea.12 In addition to antibiotic therapy, the affected gland should be treated with hot compresses several times daily to encourage drainage. The offspring may be allowed to nurse if the mother is not septic or in shock; often the bitch or queen does not allow them to nurse from the affected gland.12 However, once the dam is being treated, there does not appear to be a detriment to the offspring that are nursing from an affected mammary gland.5 Demarcation in a mammary gland with mastitis indicates imminent abscessation and/or gangrene and drainage will likely be necessary.2,12 The affected gland should be cleaned carefully and prepared as if for sterile surgery. A scalpel blade can be used to lance the abscess, which is then left to drain. Necrotic tissue should be debrided and the cavity irrigated with sterile saline until the fluid runs clear. Anesthesia is generally not required because the tissue is already dead and necrotic. The wound should be cleaned at least two to three times daily and is left to heal by secondary intention. In severe cases, the affected gland should be removed surgically in its entirety. Non-steroidal antiinflammatory drugs such as meloxicam or carprofen for 3 to 4 days have been recommended. However, these drugs will be present in the milk and may result in side effects in the offspring. In the author’s experience, opiates, including tramadol, are a safer choice. Dopamine agonists decrease prolactin resulting in decreased milk production and thus prevent galactostasis in the other mammary glands. If offspring are present, dopamine agonists may be given for 2 to 3 days, and for 8 or more days if the offspring have been weaned. Cabergoline is the drug of choice and is given at 5 mcg/kg once daily.9

REFERENCES 1. Feldman EC, Nelson RW: Periparturient diseases. In Feldman EC, Nelson RW, editors: Canine and feline endocrinology and reproduction, Philadelphia, 1996, Saunders. 2. Kitchell BE, Loar AS: Diseases of the mammary glands. In Morgan RV, editor: Handbook of small animal practice, Philadelphia, 1997, Saunders. 3. Olson PN: Periparturient diseases of the bitch. In Proceedings, Annual Meeting of the Society for Theriogenology, Orlando, 1988. 4. Wheeler SL, Magne ML, Kaufman PW, et al: Postpartum disorders in the bitch, Comp Cont Educ Pract 6:493-500, 1984. 5. Schäfer-Somi S, Spergser J, Breitenfellner J, et al: Bacteriological status of canine milk and septicaemia in neonatal puppies—a retrospective study, J Vet Med B 50:343-6, 2003. 6. Johnston SD, Root Kustritz MV, Olson PNS: In Canine and feline theriogenology, Philadelphia, 2001, Saunders. 7. Walser K, Henschelchen O: [Contribution to the etiology of acute mastitis in the bitch], Berliner und Münchener tierarztliche Wochenschrift 96:195197, 1983. 8. Sager M, Remmers C: [Perinatal mortality in dogs. Clinical, bacteriological and pathological studies], Tierarztliche Praxis 18:415-419, 1990.

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9. Wiebe VJ, Howard JP: Pharmacologic advances in canine and feline reproduction, Top Companion Anim Med 24:71-99, 2009. 10. Kuhn G, Pohl S, Hingst V: [Elevation of the bacteriological content of milk of clinically unaffected lactating bitches of a canine research stock]. Berliner und Münchener tierarztliche Wochenschrift 104:130-133, 1991. 11. Ververidis HN, Mavrogianni VS, Fragkou IA, et al: Experimental staphylococcal mastitis in bitches: clinical, bacteriological, cytological, haematological and pathological features, Vet Microbiol 124:95-106, 2007. 12. Biddle D, Macintire DK: Obstetrical emergencies, Clin Tech Small Anim Pract 15:88-93, 2000. 13. Olson PN, Olson AL: Cytologic evaluation of canine milk, Vet Med Small Anim Clin 79:641-646, 1984. 14. Hasegawa T, Fujii M, Fukada T, et al: Platelet abnormalities in a dog suffering from gangrenous mastitis by Staphylococcus aureus infection, J Vet Med Sci 55:169-71, 1993.

15. Trasch K, Wehrend A, Bostedt H: Ultrasonographic description of canine mastitis, Vet Radiol Ultrasound 48:580-584, 2007. 16. Ditmyer H, Craig L: Mycotic mastitis in three dogs due to Blastomyces dermatitidis, J Am Anim Hosp Assoc 47:356-358, 2011. 17. Park CH, Ikadai H, Yoshida E, et al: Cutaneous toxoplasmosis in a female Japanese cat, Vet Pathol 44:683-687, 2007. 18. Greene CE, Schultz RD: Immunoprophylaxis. In Greene CE, editors: Infectious diseases of the dog and cat, Philadelphia, 2006, WB Saunders. 19. Altreuther P: Safety and tolerance of enrofloxacin in dogs and cats. In 1st International Symposium on Baytril, Bonn, Germany, 1992. 20. Brown SA: Fluoroquinolones in animal health, J Vet Pharmacol Ther 19:1-14, 1996.

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CHAPTER 101  NECROTIZING SOFT TISSUE INFECTIONS Elke Rudloff,

DVM, DACVECC  •  Kevin

P. Winkler,

KEY POINTS • Necrotizing soft tissue infections (NSTI) and toxic shock syndrome can be rapidly fatal if not identified and treated aggressively. • Signs of circulatory shock must be treated rapidly using fluid resuscitation and analgesia. • Because of the lack of obvious skin changes in many cases of necrotizing soft tissue infections, a high index of suspicion is necessary for diagnosis. • Broad-spectrum intravenous antimicrobial therapy should be instituted early. • Surgery is the cornerstone of treatment in necrotizing soft tissue infections, and radical debridement including amputation may be necessary to eliminate the infection. • Antibiotic therapy should be broad spectrum until directed by culture and susceptibility results.

Necrotizing soft tissue infection (NSTI) is the term used to describe a subset of soft tissue infections involving skin, subcutaneous tissue, muscle, and fascia that cause vascular occlusion, ischemia, and necrosis. NSTIs are associated with virulent bacterial and fungal organisms and encompass syndromes including Fournier’s gangrene, Ludwig’s angina, flesh-eating disease, hemolytic streptococcal gangrene, necrotizing fasciitis (NF), and myonecrosis.1,2 In contrast to uncomplicated soft tissue infections, NSTIs are progressive and rapidly spread along tissue planes. Uncontrolled NSTIs are lethal. The term severe soft tissue infection (SSTI) also has been used to describe lesions with or without necrosis.3 Toxic shock syndrome (TSS) is an acute, severe, systemic inflammatory response initiated by a microbial infection at a normally

DVM, DACVS

sterile site, usually exotoxin-releasing Staphylococcus or Streptococcus spp. Unlike other invasive infections, TSS manifests as an acute, early occurrence of circulatory shock and multiorgan dysfunction that can include renal and/or hepatic dysfunction, coagulopathy, acute respiratory distress syndrome, and/or an erythematous rash.4 In people, TSS commonly is associated with NF and pleuropulmonary infection.5 NSTI and STTI have been described in dogs and cats and are associated with virulent Streptococcus spp. and other bacterial organisms.3,6-18 Human mortality rates for NSTI are reported to be between 12% and 41.6%.19,20 An increased awareness and knowledge of the importance of early debridement has resulted in a trend toward an improved outcome. The mortality rate for TSS in people is reported to be more than 35%.21 A report of 47 dogs with NSTI found a 53% mortality rate, but the majority of deaths were due to euthanasia, so this result is difficult to interpret.3 Risk factors identified in human medicine include age more than 50 years, atherosclerosis or peripheral vascular disease, obesity, trauma, hypoalbuminemia, diabetes mellitus, and glucocorticoid usage.1,22,23 NSTI can be stratified into four categories based on type of infection (Box 101-1). Type I NSTI is polymicrobial, Type II NSTI is monomicrobial, Type III NSTI is associated with gram-negative, often marine-related organisms, and Type IV NSTI is associated with fungal infection.23,24 Most of the veterinary cases reported could be categorized as Type II NF3 associated with a history of minor trauma and inoculation with virulent bacteria. Infection can spread rapidly, and seemingly limited infections can cause limb-threatening and life-threatening systemic sequelae. Fibrous attachments between the subcutaneous and fascial tissue can form a boundary to limit spread of organisms; however, such boundaries do not exist in the extremities or truncal regions, making these areas more susceptible to widespread infection and NF.26,27

CHAPTER 101  •  Necrotizing Soft Tissue Infections

Despite their severity and rapid progression, relatively little actually is known about the pathophysiology of TSS and NSTI. Enhanced toxicity of virulent streptococci through the release of exotoxin superantigens, cell envelope proteinases, hyaluronidase, complement inhibitor, M protein, protein F, and streptolysins amplifies cytokine release and induction of a systemic inflammatory response and septic shock. Clostridial toxins can cause hemolysis, platelet aggregation, leukocyte destruction, and histamine release, in addition to damage vascular endothelium, collagen, and hyaluron. Angiothrombotic microbial invasion with liquefactive necrosis of the superficial fascia and soft tissue is a key pathologic process of NSTI. Occlusion of nutrient vessels can lead to extensive undermining of apparently normal-appearing skin, followed by gangrene of the subcutaneous fat, dermis, and epidermis, evolving into ischemic necrosis.1 Preliminary diagnosis is based initially on clinical suspicion, because definitive diagnosis requires tissue sampling and time for test results to return.

DIAGNOSIS The clinical signs of NSTI and TSS can be nonspecific. Skin changes, fever, respiratory signs, increased urination frequency, or signs of malaise may be described by the pet owner. Surgery or a recent traumatic event may be included in the history. TSS and NSTI are associated with circulatory shock. NSTI may be associated with signs of bruising, edema, cellulitis, or crepitus from subcutaneous emphysema (Figure 101-1). Cutaneous bullae are considered an important indicator of impending dermal necrosis in humans; however, this has not been a frequent finding in veterinary

BOX 101-1 

Categories of Necrotizing Soft Tissue Infections24,25

Type I Infections: Polymicrobial

• Mixed anaerobes and aerobes • Usually isolate four or more organisms Type II Infections: Monomicrobial

• β-hemolytic Streptococcus commonly Type III Infections: Gram-Negative Monomicrobials

• Such as Clostridia infections • Includes marine organisms Type IV Infections: Fungal

• Such as Candida infections

8

patients. Although a skin wound or discoloration is obvious, the epidermis can appear unscathed with deep tissue necrosis. When skin lesions are seen, they should be outlined with a marker so that progression of the discoloration can be followed. Rapid progression (extension within a few hours) and disproportionate localized pain are hallmark signs of NSTI; however, NSTI associated with postoperative, gut flora-associated infection may progress more slowly (hours to days).24 Protective gloves should be worn during examination of the lesions and patient handling to prevent inadvertent contamination of a cut on the examiner’s hand or another patient with potentially virulent pathogens.

Laboratory Findings Laboratory findings cannot be used to diagnose NSTI or TSS, but they may reflect changes associated with infection and a systemic inflammatory response syndrome. These may include hemoconcentration, anemia, hypoalbuminemia, neutrophilia or neutropenia, left shift (often severe), hyperlactatemia, coagulation alterations consistent with DIC, hypoglycemia, elevated creatinine phosphokinase levels, and organ dysfunction (elevated serum alanine transaminase, alkaline phosphatase, bilirubin, creatinine levels). Hypocalcemia can occur when extensive fat necrosis has developed with NF.22 TSS is associated with bacterial toxins invading the circulatory system through the skin barrier or via organ infections, such as pneumonia or urinary tract infections. Urinalysis may show evidence of infection confirmed with culture analysis. When thoracic radiographs suggest pneumonia, transtracheal wash samples may indicate infection. Blood cultures may yield positive growth. Fine-needle aspirate from an affected tissue site or organ may reveal a discharge, and cytology and Gram stain may identify chains of gram-positive cocci. A diagnostic scoring system called the laboratory risk indicator for necrotizing fasciitis (LRINEC) score, based on measurement of C-reactive protein, white blood cell count, hemoglobin, sodium, creatinine, and glucose has been used in human patients, although it has been reported to fail to detect some cases and its role is currently under debate.28,29

Imaging Imaging studies are suggestive but not specific for NSTI. On plain film radiographs, subcutaneous air is rare but characteristic of necrotizing lesions with gas-producing organisms (Figure 101-2). Computed tomography features suggestive of NSTI include asymmetric fascial thickening, hypodermal fat inflammation, and gas in the soft tissue planes.30,31 Magnetic resonance imaging (MRI) may prove helpful in determining the extent of deep tissue infections not readily identified from the skin surface because of its soft tissue and multiplanar imaging capabilities. Thickened fascia with high signal intensity in T2 images is seen commonly on MRI.31 Absence of deep fascial involvement can exclude NF. However, MRI cannot differentiate necrotizing infections from nonnecrotizing problems, and the time involved in obtaining test results may delay surgery.32 Diagnostic imaging should never delay time to surgical intervention.

Definitive Diagnosis

FIGURE 101-1  Necrotizing soft tissue infection of the medial aspect of the elbow of a dog.

Definitive diagnosis of TSS requires positive streptococcal or staphylococcal culture findings and evidence of septic shock. Definitive diagnosis of NSTI is based on the histopathologic findings, including fascial necrosis and myonecrosis. Pathologic descriptions also include deep angiothrombotic microbial invasion and liquefactive necrosis.33,34 Frozen section biopsy can provide a rapid diagnosis at the time of surgical exposure.35 Because of the rapid progression of disease and the time in obtaining results, rapid treatment and immediate surgical evaluation is necessary when there is a clinical suspicion of a NSTI.

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collected and immediately evaluated. Samples for aerobic, anaerobic, and fungal culture and susceptibility testing of the affected area are submitted before injectable broad-spectrum antibiotic coverage is instituted. A second set of culture and susceptibility samples always should be acquired during the debridement procedure. Penicillin G, aminopenicillins (ampicillin, amoxicillin), and cephalosporins target gram-positive and many gram-negative organisms and should be part of the initial antimicrobial therapy plan. However, high tissue concentrations of Group A streptococcal organisms can put them in a stationary phase, causing penicillins to become ineffective.38 Clindamycin remains effective during the stationary phase and turns off exotoxin synthesis, inhibits streptococcal M-protein synthesis (which facilitate mononuclear phagocytosis), and suppresses lipopolysaccharide-induced monocyte synthesis of tumor necrosis factor.39 It also provides coverage for anaerobic organisms. Aminoglycosides and third-generation cephalosporins may increase gramnegative organism coverage. Gentamicin has a synergistic effect with penicillin against streptococci. For broad-spectrum coverage in the compromised patient, the authors would recommend clindamycin in combination with an aminoglycoside or third-generation cephalosporin. Fluoroquinolone administration, specifically enrofloxacin, is not recommended, because it may have limited activity against streptococcal infection and may cause bacteriophage-induced lysis of S. canis, enhancing its pathogenicity.39 In the severely immunocompromised patient, antifungal therapy also may be considered pending fungal culture results. FIGURE 101-2  Radiographs of necrotizing fasciitis may demonstrate soft tissue swelling and occasionally subcutaneous emphysema. The extent of the necrosis may not be reflected by the size of the skin lesion.

TREATMENT Successful management of TSS and NSTI is based on treatment of the entire patient, not just the infected site, although cardiovascular stabilization may be difficult without surgical intervention. Patients in circulatory shock are resuscitated rapidly using large-volume resuscitation techniques with a combination of balanced isotonic crystalloid fluids and synthetic colloids (e.g., hydroxyethyl starch).36 Recent reports have identified an increased risk of acute kidney injury in people with severe sepsis who have received hydroxyethyl starch; however, this problem has yet to be recognized in small animals.37 Fluids are titrated to perfusion end points, namely, normal heart rate, arterial blood pressure, mucous membrane color, and capillary refill time (see Chapter 60). Heart rate may not return to normal until analgesics are administered. Because there may be a high degree of pain associated with NSTI, strong analgesic intervention is necessary (see Chapter 144). Injectable opioid agonists (e.g., hydromorphone, oxymorphone) in combination with regional or local anesthesia may be adequate. Opioids can be continued as a constant rate infusion in combination with low-dose ketamine and lidocaine to provide continuous analgesia. Nonsteroidal antiinflammatory analgesic medications are not recommended until signs of circulatory shock have been alleviated and debridement has been successful. Circulatory shock unresponsive to fluid infusion may require vasopressor therapy (see Chapter 8). If hypoglycemia occurs, glucose is administered as a bolus followed by a constant rate infusion (see Chapter 66). Calcium is administered when plasma ionized calcium levels are decreased significantly (see Chapter 52).

Antimicrobial Therapy Rapid administration of appropriate antimicrobial therapy is an essential part of treatment. Samples for cytology and Gram stain are

Surgical Debridement Necrosis and underlying loss of blood supply limit tissue penetration of systemic antibiotics. Necrotic tissue serves as a culture medium, creating an anaerobic environment that impairs polymorphonuclear cell activity. Therefore the most important part of treatment of NSTI is surgical debridement. Inadequate debridement promotes continuing spread of infection and may result in an inoperable condition or death. Surgical intervention should occur within 4 to 6 hours of presentation, once the cardiovascular system is stabilized as best as possible. Higher amputation and mortality rates have been documented in humans when surgery was delayed more than 12 hours.40,41 Surgical preparation should include a generous area surrounding the affected tissue because significant undermining of the tissue planes may not be evident until surgical exposure. Because of the lack of purulent discharge, typical drainage techniques are ineffective. With no large pockets of purulent material for drainage, appropriate debridement frequently requires removal of large amounts of tissue, including skin and open wound management. Successful debridement may require multiple procedures, not just a single surgery. Removal of nonviable tissue may involve resection of muscle and tendons. Muscle viability can be tested by its response to stimulation from an electrocautery device. When contraction is absent, the muscle may not be viable and should be debrided. If the wound is on the limb, debridement can result in loss of limb function. Therefore amputation may be the best option for limiting morbidity and mortality in addition to minimizing postoperative cost of treatment. This is a difficult emotional decision for the owner. Often the pet has deteriorated in such a rapid fashion that the owner may not understand the necessity for an amputation. Because a delay can result in loss of the pet, appropriate client communication to emphasize the severity and rapid progression of an NSTI is essential.

Postoperative Care Postoperative monitoring should follow Kirby’s Rule of 20.42 Crystalloid and colloid fluids are continued to maintain intravascular volume and replace ongoing fluid losses. The cardiovascular system is monitored closely for decompensation, and frequent evaluation of

CHAPTER 101  •  Necrotizing Soft Tissue Infections

glucose, albumin, and electrolyte levels uncover any abnormalities that require intervention. Bandage removal for evaluation of the wound edges is done frequently (initially every 30 to 60 minutes) to determine if necrosis is continuing to spread despite surgery, indicating the need for repeat debridement. Antimicrobial therapy is adjusted once culture and susceptibility results are available. Special attention is paid to providing adequate nutrition and analgesia. Nutritional support is an important consideration, because these patients have increased protein loss in the exudates and increased demands of healing (see Chapter 127). There also may be a decrease in voluntary food intake associated with pain or fever. Partial parenteral nutrition and/or enteral feeding via nasogastric or esophagostomy tube facilitates protein metabolism and limits protein catabolism during recovery. Caloric requirements should be calculated and then nutritional supplementation started immediately postoperatively, with full caloric supplementation reached within 48 hours. High-dose intravenous immunoglobulin G therapy has shown some benefit in clinical improvement and reduction in mortality in treated versus control human patients.43 It also may reduce the need for radical debridement in cases of NSTI by augmenting immune clearance of streptococcal organisms, neutralizing superantigens, as well as providing an immunomodulating effect.44-45 Positive benefits have been recognized with group A streptococcal NF but not gramnegative infection. Its use in veterinary medicine for TSS or NSTI has not been established.

Hyperbaric Oxygen Hyperbaric oxygen therapy is the delivery of oxygen at higher than atmospheric pressure to compromised tissue. Hyperbaric oxygen therapy may enhance host antimicrobial activity and the action of various antibiotic agents by facilitating their transport across the bacterial cell wall.46 Unfortunately, most reports are either anecdotal or have yielded conflicting results.8,47-49 There are no prospective, controlled veterinary studies demonstrating efficacy of hyperbaric oxygen in NSTI, but it has been described in a single canine case of limb NF.8

CONCLUSION NSTI and TSS can be treated successfully if medical and surgical therapy is provided rapidly. A delay in therapy worsens the prognosis. Circulatory shock and laboratory abnormalities must be corrected immediately and aggressive analgesia provided. Broad-spectrum intravenous antimicrobial therapy should be administered as soon as possible. Prompt surgery with radical debridement and appropriate antimicrobial therapy is required for successful treatment of NSTI. The extent of the lesion may not be appreciated fully until surgery is performed. Amputation or multiple surgical procedures may be necessary to remove diseased tissue. Major reconstructive procedures may be required once diseased tissue has been removed successfully.

REFERENCES 1. Wong CH, Chang HC, Pasupathy S, et al: Necrotizing fasciitis: clinical presentation, microbiology, and determinants of mortality, J Bone Joint Surg Am 85:1454, 2003. 2. Phan HH, Cocanour CS: Necrotizing soft tissue infections in the intensive care unit, Crit Care Med 38:S460, 2010. 3. Buriko Y, Van Winkle TJ, Drobatz KJ, et al: Severe soft tissue infections in dogs: 47 cases (1996-2006), J Vet Emerg Crit Care 18:608, 2008. 4. Defining the group A streptococcal toxic shock syndrome. Rationale and consensus definition. The Working Group on Severe Streptococcal Infections, J Am Med Assoc 269:390, 1993.

5. Plainvert C, Doloy A, Loubinoux J, et al: CNR-Strep network. Invasive group A streptococcal infections in adults, France (2006-2010), Clin Microbiol Infect 18:702, 2012. 6. Prescott JF, Miller CW, Mathews KA, et al: Update on canine streptococcal toxic shock syndrome and necrotizing fasciitis, Can Vet J 38:241, 1997. 7. Miller CW, Prescott, JF, Mathews KA, et al: Streptococcal toxic shock syndrome in dogs, J Am Vet Med Assoc 209:1421, 1996. 8. Jenkins CM, Winkler K, Rudloff E, et al: Necrotizing fasciitis in a dog, J Vet Emerg Crit Care 11:299, 2001. 9. DeWinter LM, Low DE, Prescott JF: Virulence of Streptococcus canis from canine streptococcal toxic shock syndrome and necrotizing fasciitis, Vet Microbiol 70:95, 1999. 10. Declercq, J: Suspected toxic shock-like syndrome in a dog with closedcervix pyometra, Vet Dermatol 18:41, 2007. 11. Sura R, Hinckley LS, Risatti GR, et al: Fatal necrotising fasciitis and myositis in a cat associated with Streptococcus canis, Vet Record 162:450, 2008. 12. Crosse PA, Soares K, Wheeler JI, et al: Chromobacterium violaceum infection in two dogs, J Am Anim Hosp Assoc 42:154, 2006. 13. Slovak J, Parker VJ, Deitz KL: Toxic shock syndrome in two dogs, J Am Anim Hosp Assoc 48:434–438, 2012. 14. Taillefer M, Dunn M: Group G streptococcal toxic shock-like syndrome in three cats, J Am Anim Hosp Assoc 40:418, 2004. 15. Worth AJ, Marshal N, Thompson KG: Necrotising fasciitis associated with Escherichia coli in a dog, N Z Vet J 53:257, 2005. 16. Kulendra E, Corr S: Necrotising fasciitis with sub-periosteal Streptococcus canis infection in two puppies, Vet Comp Orthop Traumatol 21:474, 2008. 17. Weese JS, Poma Rr, James F, et al: Staphylococcus pseudintermedius necrotizing fasciitis in a dog, Can Vet J 50:655, 2009. 18. Csiszer AB, Towle HA, Daly CM: Successful treatment of necrotizing fasciitis in the hind limb of a Great Dane, J Am Anim Hosp Assoc 46:433, 2012. 19. Mills MK, Faraklas I, Davis C, et al: Outcomes from treatment of necrotizing soft tissue infections: results from the National Surgical Quality Improvement Program database, Am J Surg 200:790, 2010. 20. George SMC, Harrison DA, Welch CA, et al: Dermatological conditions in intensive care: a secondary analysis of the Intensive Care National Audit & Research Centre (ICNArc) Case Mix Programme Database, Crit Care 12:S1, 2008. 21. Group A streptococcal disease. Centers for Disease Control and Prevention. Update April 3 2008. http://www.cdc.gov/ncidod/dbmd/diseaseinfo/ groupastreptococcal_t.htm. 22. McHenry CR, Piotrowski JJ, Petrinic D, et al: Determinants of mortality for necrotizing soft tissue infections, Ann Surg 221:558, 1995. 23. Sarani B, Strong M, Pascual J, et al: Necrotizing fasciitis: Current concepts and review of the literature, J Am Coll Surg 208:279, 2009. 24. Morgan MS: Diagnosis and management of necrotising fasciitis: a multiparametric approach, J Hosp Infect 5:249, 2010. 25. Ustin JS, Sevransky JE: Necrotizing soft tissue infection, Crit Care Med 39:2156, 2011. 26. Hill MK, Sanders CV: Necrotizing and gangrenous soft tissue infections. In Nesbitt LT Jr, Saunders CV, editors: The skin and infection: a color atlas and text, Baltimore, 1995, Williams & Wilkins. 27. Bosshardt TL, Henderson VJ, Organ CH Jr: Necrotizing soft tissue infections, Arch Surg 131:846, 1996. 28. Wall DB, Klein SR, Black S, et al: A simple model to help distinguish necrotizing fasciitis from nonnecrotizing soft tissue infection, J Am Coll Surg 191:227, 2000. 29. Wilson MP, Schneir AB: A case of necrotizing fasciitis with a LRINEC score of zero: clinical suspicion should trump scoring systems, J Emerg Med 44(5):928, 2013. 30. Wysoki MG, Santora TA, Shah RM, et al: Necrotizing fasciitis: CT characteristics, Radiology 203:859, 1997. 31. Malghem J, Lecouvet FE, Omoumi P, et al: Necrotizing fasciitis: contribution and limitations of diagnostic imaging, Joint Bone Spine 80(2):146, 2013. 32. Loh NN, Ch’en IY, Cheung LP, et al: Deep fascial hyperintensity in softtissue abnormalities as revealed by T2-weighted MR imaging, AJR Am J Roentgenol 168:1301, 1997. 33. Wong CH, Wang YS: The diagnosis of necrotizing fasciitis, Curr Opin Infect Dis 18:101, 2005.

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34. Umbert IJ, Winkelmann RK, Oliver GF, et al: Necrotizing fasciitis: a clinical, microbiological, and histopathological study of 14 patients, J Am Acad Dermatol 20:774, 1989. 35. Stamenkovic I, Lew PD: Early recognition of potentially fatal necrotizing fasciitis. The use of frozen-section biopsy, N Engl J Med 310:1689, 1984. 36. Kirby R, Rudloff E: Crystalloid and colloid fluid therapy. In Ettinger SJ, Feldman EC, editors: Textbook of veterinary internal medicine, ed 6, St Louis, 2005, Saunders. 37. Perner A, Haase N, Guttormsen AB, et al: Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis, N Engl J Med 367:124-134, 2012. 38. Theis JC, Rietweld J, Danesh-Clough T: Severe necrotising soft tissue infections in orthopaedics surgery, J Orthop Surg 10:108, 2012. 39. Ingrey KT, Ren J, Prescott JF: A fluoroquinolone induces a novel mitogenencoding bacteriophage in Streptococcus canis, Infect Immun 71:3028, 2003. 40. Sudarsky LA, Laschinger JC, Coppa GF, Spencer FC: Improved results from standardized approach in treating patients with necrotizing fasciitis, Ann Surg 206:661, 1987. 41. Kaiser RE, Cerra FB: Progressive necrotizing surgical infections: a unified approach, J Trauma 21:349, 1981.

42. Purvis D, Kirby R: Systemic inflammatory response syndrome: septic shock, Vet Clin North Am Small Anim Pract 24:1225, 1994. 43. Darenberg J, Ihendyane N, Sjolin J, et al: Intravenous immunoglobulin G therapy in streptococcal toxic shock syndrome: a European randomized, double-blind, placebo-controlled trial, Clin Infect Dis 37:333, 2003. 44. BarryW: Intravenous immunoglobulin therapy for toxic shock syndrome, J Am Med Assoc 267:3315, 1992. 45. Norrby-Teglund A, Haul R, Low DE, et al: Evidence for the presence of streptococcal-superantigen neutralising antibodies in normal polyspecific immunoglobulin, Infect Immun 64:5395, 1996. 46. Hosgood G, Kerwin SC, Lewis DD, et al: Clinical review of the mechanism and applications of hyperbaric oxygen therapy in small animal surgery, Vet Comp Orthop Traumatol 5:31, 1992. 47. Kerwin SC, Hosgood G, Strain GM, et al: The effect of hyperbaric oxygen treatment on a compromised axial pattern flap in the cat, Vet Surg 22:31, 1993. 48. Cooper NA, Unsworth IP, Turner DM, et al: Hyperbaric oxygen used in the treatment of gas gangrene in a dog, J Small Anim Pract 17:759, 1976. 49. George ME, Rueth NM, Skarda DE, et al: Hyperbaric oxygen does not improve outcome in patients with necrotizing soft tissue infection, Surg Infect (Larchmt) 10:21, 2009.

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CHAPTER 102  CATHETER-RELATED BLOODSTREAM INFECTION Sean Smarick,

VMD, DACVECC  •  Melissa

Edwards,

KEY POINTS • Intravenous catheters may become contaminated and can lead to local and distal infectious complications. Septicemia caused by a colonized catheter is referred to as a catheter-related bloodstream infection (CRBSI). • The diagnosis of a catheter-related bloodstream infection includes culturing the catheter and blood, but any fever of unknown origin, bacteremia, or infection at the insertion site should prompt the clinician to consider this type of infection. • Treatment of known catheter-related bloodstream infection includes removing the catheter and administering systemic antibiotics. • Frequency of catheter-related bloodstream infection may be reduced by aseptically placing and maintaining catheters and educating caretakers involved in catheter placement and maintenance.

DEFINITION Intravenous catheters often are used in critically ill patients, but they can become contaminated with microorganisms. Skin contaminants may be introduced during placement or may migrate along the external surface of the catheter. In addition, contamination of the catheter hub or infusate may lead to colonizing of the internal surface. Some bacteria and fungi produce biofilm, a matrix of microorganisms and

DVM, DACVECC

their produced glycocalyces along with host salts and proteins that provide protection from the host’s defenses. Catheter contamination may lead to local signs of phlebitis; when catheter colonization leads to septicemia, the resultant infection is referred to as a catheterrelated bloodstream infection (CRBSI).1,2 The majority of CRBSIs are bacterial; however, fungal causes play an important role in people but are not well documented in veterinary medicine.3

INCIDENCE CRBSI has been reported in dogs and cats. In small animal intensive care units, CRBSIs have been implicated as a cause of morbidity and mortality.4-8 In veterinary medicine the incidence of catheter contamination has been reported as 10.4% to 24% in peripheral catheters3,4,8-10 and from 0 to 26% in jugular catheters, which is consistent with human reports.7,8,10,11 CRBSI is well studied in humans, and the incidence is approximately 1.5% with central venous catheters.12 In a few studies in dogs and cats looking at catheter contamination rates, 4 in 304 cases were identifiable as CRBSI in a combination of peripherally and centrally placed venous catheters.4,7,8,11 This suggests a combined rate of 1.3% (1.3 bloodstream infections per 100 catheters). This rate likely underestimates the current and future incidence of CRBSI because peripheral venous catheters have a lower rate of CRBSI, and the use of central venous and arterial catheters is increasing in veterinary medicine. Indwelling catheters that are tunneled through the subcutaneous tissues have been described for long-term

CHAPTER 102  •  Catheter-Related Bloodstream Infection

use (weeks to months) in veterinary patients. Some of these catheters have access ports also placed subcutaneously. The combined reported rate of CRBSI for these types of catheters of 6 in 244 is consistent with rates reported in people for similar catheter types, despite a decreased duration of catheterization in the veterinary patients. The veterinary population was overrepresented by patients undergoing radiation therapy or chemotherapy for neoplasia, and that group included all of the patients that developed CRBSI.12-17

DIAGNOSIS CRBSI should be considered in febrile patients that have an intravascular catheter in place when no other source of infection is obvious. Phlebitis and especially purulent discharge at the catheter site may indicate that catheter colonization has resulted in a localized infection that may lead to a CRBSI; however, the lack of localized reaction does not rule out a CRBSI; close to 50% of humans show no local signs. Because clinical signs are not reliable, cultures are required for the diagnosis of a CRBSI.1,10,18 A CRBSI differs from a catheterassociated bloodstream infection. In a CRBSI, the catheter is the primary source of the bloodstream infection as determined by cultures of the catheter and blood, whereas in a catheter-associated bloodstream infection, a catheter is present in the face of a bloodstream infection but is unable to be cultured, and no other source of infection can be identified. The lack of another identifiable or suspected source of infection and critical interpretation of cultures are needed to diagnose a CRBSI.19 Considering the relatively low incidence of CRBSI, routine screening of qualitative (i.e., positive versus negative) catheter tip or segment cultures is not recommended because of the number of false-positive results.18-20 Numerous culturing methods of diagnosing a CRBSI have been reported, and the source (intraluminal versus extraluminal) of the infection, number of lumens of the catheter, availability of culturing methods, ability to aspirate the catheter, and need to keep the present catheter in place may dictate which method is to be used in individual patients. Because infections identified soon after catheter placement tend to originate on the external surface, and infections of long-term catheters tend to originate on the internal lumen, culturing blood from the lumen may be a source of falsenegative cultures in short-term catheterization.18 Multilumen catheters pose a challenge in that one or multiple lumens may be colonized, leading to false-negative results if only one lumen is cultured. In humans, sampling only one lumen of a triple-lumen catheter correctly identified less than two thirds of the CRBSIs.21,22 Catheters do not necessarily have to be removed to diagnose a CRBSI. Considering the low number of true CRBSIs in febrile patients, catheters in such patients may remain unless they are no longer needed, they have a purulent discharge, or the patient is decompensating.1,18,23 Ideally, quantitative cultures of blood obtained percutaneously and through the catheter are submitted. A positive result is one in which the catheter-obtained culture(s) has three to five times more bacterial concentration than the culture obtained percutaneously. Alternatively, qualitative cultures in which positive blood culture results from the catheter precede results from the percutaneous culture by more than 2 hours can be used if the quantitative methods are unavailable. If neither method is available or if the catheter is removed, a semiquantitative culture obtained by rolling a 5-cm section of the catheter four times over a blood agar plate and finding more than 15 colony-forming units (CFU) is also a method with good sensitivity and specificity in humans. Qualitative or quantitative (more than 100 CFU/ml) blood cultures drawn from the catheter and quantitative cultures (more than 1000 CFU/ml) of broth that

was flushed through or sonicated with the catheter also have been described for diagnosing CRBSI. Staining lysed cells from catheterobtained blood samples with acridine orange to look for organisms and performing cultures of endoluminal brushing of the catheter are additional methods of diagnosis.1,18,20 For obtaining blood cultures, the catheter and percutaneous site should undergo aseptic preparation, equal volumes for each sample site should be collected, and the samples should be obtained within 10 minutes of each other. Ideally, cultures are obtained before instituting empiric antibiotic therapy.1,18,20

TREATMENT Treatment of known CRBSI consists of removal of the catheter and appropriate antimicrobial therapy; however, in febrile patients with a catheter in place without local signs of infection, “watchful waiting” is an effective strategy. In humans, leaving the catheter in place awaiting culture results led to a 60% reduction in the number of catheters removed with no significant change in outcome. The risks of catheter replacement versus having a potential nidus of infection must be weighed in each patient; deteriorating patients should be treated more aggressively. When a suspected infected catheter is left in place, an antibiotic lock consisting of concentrated amounts of antibiotics, ethanol, or other substances occupying the lumen dead space has been shown in humans to effectively eliminate many bacterial infections and spares the patient the catheter removal. The concentrated amount of antibiotic allows biofilm penetration unattainable with systemic administration. If replacement of a catheter suspected to be infected is necessary, it should not be replaced with an over-the-wire technique; a separate insertion site should be used. Systemic antibiotics guided by culture and susceptibility should be continued for 10 to 14 days after catheter removal. As with many infections, the best treatment of CRBSI is prevention.1,20,23

PREVENTION Recommendations for the prevention of CRBSI have been published in the veterinary literature and include caregiver hand washing, placement of catheters by trained personnel, aseptic catheter placement, use of the most bioinert catheter material (i.e., polyurethane versus Teflon), and monitoring for CRBSI. Scheduled catheter replacement is no longer recommended. These recommendations were based on limited veterinary observational studies and guidelines for human patients.2,7,8 In the absence of well-controlled and well-powered veterinary studies, it is reasonable to adopt human recommendations to prevent CRBSI formulated on evidence-based guidelines. In 2011 the Centers for Disease Control and Prevention (CDC) published (and made available online) the “Guidelines for the Prevention of Intravascular Catheter-Related Infections.”19 A checklist adapted to veterinary patients to decrease the incidence of CRBSI is presented in Box 102-1. Educating caregivers about the indications, proper catheter selection and placement, maintenance, and nosocomial surveillance of vascular catheters is considered paramount in preventing CRBSI. As with all nosocomial infections, hand washing is crucial for prevention; wearing gloves augments the preventive effect of but does not replace hand washing. Other recommendations from the CDC include not to administer prophylactic antibiotics and not to replace catheters routinely for infection control. However, catheters that were placed under less-than-ideal emergency conditions should be replaced within 48 hours, and peripheral catheters may be replaced every 72 to 96 hours to prevent phlebitis.19

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BOX 102-1 

Checklist for Placement and Maintenance of Intravascular Catheters to Prevent Catheter-Related Bloodstream Infections

• Wash hands with soap and water or alcohol-based hand rub. • Wear clean gloves. • Provide aseptic insertion and care of catheter. • Use a 2% chlorhexidine skin preparation. • For peripheral intravenous catheters, use three to seven cycles of

scrub, then wipe with alcohol, and do not touch the insertion site after preparation. • Use sterile gloves for arterial and central venous catheters and maximum barrier protection (sterile gown and drape, mask) when placing central venous catheters. Change gloves for the new catheter when rewiring. • Minimize cut down approaches for catheter placement. • Dress the catheter with a sterile gauze (or Band-Aid) and bandage or sterile, transparent, semipermeable dressing. • Avoid ointments at the catheter site. • Monitor regularly: visualize when dressing changed, palpate through dressing, look for discomfort, phlebitis, or fever without another source.

Catheter Dressings Inspect dressing daily. • Change gauze dressings every 48 hours or if moist or soiled and transparent dressings every 7 days, sooner if loose or concerns arise. • Wipe injection ports with alcohol before using; stopcocks should be capped. • Change administration sets (aseptically) every 4 to 7 days. • Change arterial line administration sets and transducers (aseptically) every 96 hours. • Change administration sets (aseptically) every 6 to 12 hours if propofol infused. • Change administration sets (aseptically) every 24 hours if lipid-containing TPN solutions or blood products are infused. • Evaluate the need for the catheter; remove it when it is no longer needed. TPN, Total parenteral nutrition.

The CDC also recognizes infusates and intravenous admixtures as a source for CRBSI. Blood products and lipid-containing parenteral nutrition solutions should not be infused for longer than 4 hours and 24 hours, respectively.24 The administration sets through which blood products and lipid-containing emulsions are given should also be changed within 24 hours.19 In addition, the sterility of administered drugs and intravenous admixtures should be maintained by using single-dose vials, swabbing multidose vials with alcohol before aspiration, and discarding any suspected compromised solution.19,25 In the war against device-associated nosocomial infections, catheters impregnated with antiseptics and antibiotics have been introduced. In humans, studies support a reduction in the incidence of CRBSI with the use of these catheters; however, the debate over their use continues. Current recommendations are for using these catheters only in areas in which comprehensive strategies (e.g., education, hand washing) have been unsuccessful in decreasing CRBSI rates and not for routine use because of reported allergic reactions, potential for the development of resistant organisms, and the additional expense.1,19 The current trend is toward the use of needleless intravascular catheter systems in the prevention of needlestick injuries. These

systems come in several forms, such as stopcocks, split septum connectors, and mechanical valve systems, and can contribute to catheter contamination and CRBSI. Stopcocks should be capped at all times when not in use and their use avoided if possible. Some evidence suggests that mechanical valve needleless connector systems also may increase risk over split septum connector designs in some cases.19,26,27

REFERENCES 1. Slaughter SE: Intravascular catheter-related infections. Strategies for combating this common foe, Postgrad Med 116:59, 2004. 2. Tan RH, Dart AJ, Dowling BA: Catheters: a review of the selection, utilisation and complications of catheters for peripheral venous access, Aust Vet J 81:136, 2003. 3. Seguela J, Pages JP: Bacterial and fungal colonisation of peripheral intravenous catheters in dogs and cats, J Small Anim Pract 52:531, 2011. 4. Burrows CF: Inadequate skin preparation as a cause of intravenous catheter-related infection in the dog, J Am Vet Med Assoc 180:747, 1982. 5. Francey T, Gaschen F, Nicolet J, et al: The role of Acinetobacter baumannii as a nosocomial pathogen for dogs and cats in an intensive care unit, J Vet Intern Med 14:177, 2000. 6. Glickman LT: Veterinary nosocomial (hospital-acquired) Klebsiella infections, J Am Vet Med Assoc 179:1389, 1981. 7. Lippert AC, Fulton RB, Parr AM: Nosocomial infection surveillance in a small animal intensive care unit, J Am Anim Hosp Assoc 24:627, 1988. 8. Mathews KA, Brooks MJ, Valliant AE: A prospective study of intravenous catheter contamination, J Vet Emerg Crit Care 6:33, 1996. 9. Lobetti RG, Joubert KE, Picard J, et al: Bacterial colonization of intravenous catheters in young dogs suspected to have parvoviral enteritis, J Am Vet Med Assoc 220:1321, 2002. 10. Marsh-Ng ML, Burney DP, Garcia J: Surveillance of infections associated with intravenous catheters in dogs and cats in an intensive care unit, J Am Anim Hosp Assoc 43:13, 2007. 11. Martin GJ, Rand JS: Evaluation of a polyurethane jugular catheter in cats placed using a modified Seldinger technique, Aust Vet J 77:250, 1999. 12. Dudeck MA, Horan TC, Peterson KD, et al: National Healthcare Safety Network (NHSN) Report, data summary for 2010, device-associated module, Am J Infect Control 39:798, 2011. 13. Abrams-Ogg AC, Kruth SA, Carter RF, et al: The use of an implantable central venous (Hickman) catheter for long-term venous access in dogs undergoing bone marrow transplantation, Can J Vet Res 56:382, 1992. 14. Evans KL, Smeak DD, Couto CG, et al: Comparison of two indwelling central venous access catheters in dogs undergoing fractionated radiotherapy, Vet Surg 23:135, 1994. 15. Blaiset MA, Couto CG, Evans KL, et al: Complications of indwelling, silastic central venous access catheters in dogs and cats, J Am Anim Hosp Assoc 31:379, 1995. 16. Culp WT, Mayhew PD, Reese MS, et al: Complications associated with use of subcutaneous vascular access ports in cats and dogs undergoing fractionated radiotherapy: 172 cases (1996-2007), J Am Vet Med Assoc 236:1322, 2010. 17. Valentini F, Fassone F, Pozzebon A, et al: Use of totally implantable vascular access port with mini-invasive Seldinger technique in 12 dogs undergoing chemotherapy, Res Vet Sci 94:152, 2013. 18. Safdar N, Fine JP, Maki DG: Meta-analysis: methods for diagnosing intravascular device-related bloodstream infection, Ann Intern Med 142:451, 2005. 19. O’Grady NP, Alexander M, Burns LA, et al: Guidelines for the prevention of intravascular catheter-related infections, Clin Infect Dis 52:e162, 2011. 20. Mermel LA, Allon M, Bouza E, et al: Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 Update by the Infectious Diseases Society of America, Clin Infect Dis 49:1, 2009. 21. Dobbins BM, Catton JA, Kite P, et al: Each lumen is a potential source of central venous catheter-related bloodstream infection, Crit Care Med 31:1688, 2003. 22. Guembe M, Rodriguez-Creixems M, Sanchez-Carrillo C, et al: How many lumens should be cultured in the conservative diagnosis of catheterrelated bloodstream infections? Clin Infect Dis 50:1575, 2010.

23. Sherertz RJ: Update on vascular catheter infections, Curr Opin Infect Dis 17:303, 2004. 24. O’Grady NP, Alexander M, Dellinger EP, et al: Guidelines for the prevention of intravascular catheter-related infections, Infect Control Hosp Epidemiol 23:759, 2002. 25. Macias AE, Huertas M, de Leon SP, et al: Contamination of intravenous fluids: a continuing cause of hospital bacteremia, Am J Infect Control 38:217, 2010.

26. Rupp ME, Sholtz LA, Jourdan DR, et al: Outbreak of bloodstream infection temporally associated with the use of an intravascular needleless valve, Clin Infect Dis 44:1408, 2007. 27. Jarvis WR, Murphy C, Hall KK, et al: Health care-associated bloodstream infections associated with negative- or positive-pressure or displacement mechanical valve needleless connectors, Clin Infect Dis 49:1821, 2009.

CHAPTER 103  •  Multidrug-Resistant Infections

CHAPTER 103  MULTIDRUG-RESISTANT INFECTIONS Steven Epstein,

DVM, DACVECC

KEY POINTS • Multidrug-resistant pathogens are increasingly common in veterinary medicine, and early culture and susceptibility testing is crucial to their diagnosis. • Regional knowledge of likely pathogens and their susceptibility patterns is helpful in guiding empiric therapy. • Consultation with an infectious disease specialist can be helpful in optimizing success for multidrug- resistant infections.

Multidrug-resistant (MDR) pathogens are an increasing concern in veterinary medicine in the hospitalized and outpatient populations. In human hospitalized patients, the intensive care unit (ICU) has the highest rate of antimicrobial resistance.1,2 These pathogens also are identified frequently in the veterinary ICU.3-5 Within veterinary teaching hospitals, MDR pathogens are also commonly found on multiple other surfaces.6-8 The possibility of MDR pathogens in the ICU is a major factor in the empiric selection of antimicrobials for these patients, creating numerous challenges. ICU clinicians are more commonly faced with treating infections caused by organisms with limited (MDR or extensively drug resistant [XDR]) or no viable treatment options (pandrug-resistant [PDR]).

DEFINITIONS Antimicrobial resistance is a measure of an antimicrobial agent’s decreased ability to kill or inhibit the growth of a microorganism. This is determined practically by testing a bacterial isolate in an in vitro system against various antimicrobials. From this testing a minimum inhibitory concentration (MIC) can be determined. A MIC is the lowest concentration of an antimicrobial that inhibits growth of a microorganism. An organism is said to be susceptible to that antimicrobial if the MIC is below the breakpoint for that antimicrobial. The Clinical and Laboratory Standards Institute has established many breakpoints based on large numbers of isolates that determine resistance or susceptibility. A breakpoint is the highest MIC achievable (usually a serum concentration of antimicrobial

given at routine doses) that still inhibits growth of that microorganism. These are based on achievable serum concentrations, not necessarily the concentration of the antimicrobial of the infected tissue, which are typically slightly less than the serum. Bacteria may exhibit three different types of resistance. Intrinsic resistance is an inherent feature of a microorganism that results in lack of activity of an antimicrobial drug or class of drugs. One example of this is Pseudomonas aeruginosa, which shows resistance to the majority of β-lactam antimicrobials, except for the few specifically designed as anti-Pseudomonas drugs. Another example is that all gram-negative organisms are resistant to vancomycin, which cannot penetrate their cell membrane. Circumstantial resistance is when an in vitro test predicts susceptibility, but in vivo the antimicrobial lacks clinical efficacy. This may be due to lack of the drug to penetrate the site of infection (CNS, prostate, bone) or inability to work because of local pH (inactivation in acidic urine). Acquired resistance is a change in the phenotypic characteristics of a microorganism, compared with the wild type, which confers decreased effectiveness of an antimicrobial against that microorganism. Acquired resistance can occur via many different mechanisms, and a full review of this topic is beyond the scope of this chapter. One of the most important mechanisms is exposure to prior antimicrobials; this is a known risk factor in veterinary medicine.9 This acquired resistance is what leads to the development of many MDR microorganisms. The European Centre for Disease Prevention and Control and the U.S. Centers for Disease Control and Prevention published standardized terminology for grading antimicrobial resistance.10 MDR organisms are defined as those not susceptible to at least one agent in three or more classes of antimicrobials to which they are usually susceptible. XDR organisms are susceptible to only one or two classes of antimicrobials. PDR organisms are not susceptible to all known or licensed antimicrobials currently available.

RISK FACTORS FOR MULTIDRUG-RESISTANT PATHOGENS The identification of patients at risk for having a MDR infection is paramount for the selection and treatment of empiric antimicrobials

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in critical care. In human medicine some of the major risk factors associated with either MDR gram-negative or gram-positive infections are previous antimicrobial use, admission to an ICU, infection control lapses, prolonged length of hospital stay, recent surgery or invasive procedures, mechanical ventilation, or colonization or exposure to a patient with colonization of a MDR pathogen.11-13 Minimal information is available on this topic in veterinary medicine, but the risk factors are likely the same as in human medicine. In dogs, predisposing diseases, prior antimicrobial use, duration of hospitalization, duration of ICU hospitalization, surgical procedure, and mechanical ventilation have been associated with increased MDR pathogen identification.4,14-16 Evaluating a patient for these risk factors helps the clinician to decide whether an escalation or de-escalation approach to antimicrobial therapy is appropriate for the patient.

ESCALATION VERSUS DE-ESCALATION THERAPY Escalation therapy involves selecting an antimicrobial with a narrow spectrum of activity that likely covers the pathogen causing the suspected infection. When culture and susceptibility results are available, the antimicrobial agent may be continued if susceptibility is predicted or switched if resistance is documented. De-escalation therapy consists of the empiric administration of broad-spectrum antimicrobials aimed to cover all pathogens most frequently related to the infection, including MDR and XDR pathogens. The coverage selected usually is limited to bacterial infections, unless lifethreatening fungal infections are suspected. When culture and susceptibility results are available, the spectrum of activity of the antimicrobials is then narrowed if possible. The rationale for using de-escalation therapy is to lower mortality by early achievement of appropriate empiric antimicrobial coverage in addition to prevention of the development of MDR pathogens. Human patients in which a de-escalation approach is recommended include patients with pneumonia at risk for MDR pathogens17 and patients with severe sepsis or septic shock.18 This recommendation is based on results of a study that found that, for every 1 hour that appropriate antimicrobial therapy is not given after the first 6 hours a patient is diagnosed with septic shock, mortality increased by 7.6%. This means that 24 hours of ineffective antimicrobials would reduce the chance of survival to approximately 20%.19 De-escalation therapy has been demonstrated to be feasible in human ICUs with de-escalation rates of 32% to 51%.20-22 In addition, de-escalation has not been shown to increase the level of MDR carriage.21,22 The majority of patients in veterinary medicine should have an escalation approach to antimicrobial therapy taken. In veterinary critical care, a de-escalation approach usually is reserved for patients who have severe sepsis/septic shock or for patients that have acquired an infection in hospital while on antimicrobials. Practically speaking, for a critically ill patient the clinician must consider, “Does this patient appear sick enough, that if I choose the wrong antimicrobial, it might die of its infection/sepsis in the next 24 hours?” When the answer is yes, then a de-escalation approach should be instituted. If a de-escalation approach is used, then obtaining a culture from the infected tissue should be considered mandatory, if it can be accomplished without compromising patient safety. This allows for Gram stain and cytology, which help guide empiric therapy.

SPECIFIC MULTIDRUG-RESISTANT PATHOGENS Methicillin-Resistant Staphylococcus Staphylococcal infections in small animals are most likely to be Staphylococcus pseudintermedius (SP), whereas Staphylococcus aureus

(SA) is rare. Various coagulase-negative Staphylococcus species are clinically important. The primary mechanism of resistance is the acquisition of the mecA gene, which confers methicillin resistance. This encodes an altered penicillin-binding protein, making it resistant to all members of the β-lactam family regardless of susceptibility testing. Laboratory testing may be to oxacillin instead of methicillin; however, they are equivalent in determining resistance to all members of the β-lactams group. If a methicillin-resistant Staphylococcus (MRS) is suspected, culture and susceptibility testing is imperative because more than 90% of canine isolates of MRSP were resistant to representatives of at least four additional antimicrobial drug classes.23 Along with resistance to the β-lactam group of antimicrobials, MRS is frequently resistant to clindamycin, fluoroquinolones, macrolides, and trimethoprim-sulfonamides. Given the high rates of co-resistance in MRS, if a de-escalation approach is to be taken, the antimicrobial typically used empirically would be vancomycin (see Chapter 181). Vancomycin is the drug of choice for MRSA in human medicine, although the frequency of vancomycin-intermediate and vancomycinresistant S. aureus is increasing. In the author’s ICU, if empiric vancomycin therapy is used, culture and susceptibility testing as well as therapeutic drug monitor typically are initiated to help prevent resistance from developing. Serum levels of vancomycin when steady state has been reached, typically just before the fourth dose, are recommended and dosing altered to maintain trough concentrations higher than 10 mg/L to avoid development of resistance.24 An alternative to vancomycin for MRS in veterinary medicine are the aminoglycosides (amikacin and gentamicin, primarily). Aminoglycosides have efficacy against many MRS. Potential disadvantages to aminoglycoside therapy are that with extended use or concurrent hypotension, the risk of acute kidney injury increases; they must be administered parentally; and they have decreased activity in purulent material or cellular debris. Despite these disadvantages, they are an acceptable alternative to vancomycin for empiric therapy for suspected MRS. Other antimicrobials that may have efficacy against MRS are bacteriostatic and may be useful with an escalation approach (e.g., healthy patient with superficial infection). These antimicrobials include the tetracyclines (doxycycline and minocycline), chloramphenicol, and rifampin. Prior knowledge of the common resistance patterns of MRS in the practice location helps clinicians decide which of these is most likely to be efficacious (e.g., at the author’s institution, the majority of MRS are resistant to doxycycline). If a MRS is identified that is also a vancomycin-resistant Staphylococcus sp., human medicine offers multiple alternatives for antimicrobials, but few have been used in veterinary medicine. These antimicrobials include daptomycin, linezolid, quinupristin/ dalfopristin, tigecycline, and a fifth-generation cephalosporin ceftaroline fosamil. Consultation with an infectious disease specialist is recommended before starting therapy with any of these medications.

Enterococcus Enterococci are gram-positive cocci found normally in the gastrointestinal tract. The two species most commonly identified are Enterococcus faecalis and Enterococcus faecium. They are an important source of nosocomial infection and have been isolated frequently from surfaces in one veterinary study.6 E. faecalis is isolated more commonly; however, E. faecium is more often MDR. Enterococci have a high level of intrinsic resistance to many antimicrobials, including all cephalosporins, clindamycin, and aminoglycosides at serum concentrations achievable without toxicity. Fluoroquinolones also exhibit poor activity against Enterococcus spp. Third-generation cephalosporin use and fluoroquinolone use have

CHAPTER 103  •  Multidrug-Resistant Infections

been associated with the development of vancomycin-resistant Enterococcus spp. in humans.25,26 Acquired resistance in enterococci is related primarily to acquisition of aminoglycoside-modifying enzymes (AME) or alterations in penicillin-binding protein (PBP5), which confer resistance to high levels of aminoglycosides (HLAR) and all penicillins and carbapenems, respectively. Because enterococci are not highly pathogenic organisms, isolation from a culture does not always necessitate treatment of the organism. In cases in which colonization, not infection, is suspected (e.g., superficial wound or asymptomatic bacteriuria), the patient may be monitored and not treated. When MDR Enterococcus spp. co-exist with other pathogens, clinical resolution of disease is possible without treating the Enterococcus spp. and directing therapy at the other microorganisms. This has been shown in humans with intraabdominal sepsis treated with surgery but no enterococcal antimicrobial, although no veterinary studies evaluate this.27 Treatment of MDR Enterococcus spp. typically involves one of two options: (1) the combination of ampicillin and gentamicin or (2) vancomycin.28 The combination of ampicillin and gentamicin rely on the synergistic activity of these two drugs. This combination of agents allows for bacterial killing with differing mechanisms with ampicillin disturbing the cell wall, which then facilitates the entry of gentamicin into the cytoplasmic space affecting protein synthesis. This synergistic combination can be achieved even if routine susceptibility testing predicts resistance to both drugs. Specialized testing for high-level resistance is needed to determine if this combination would be effective in vivo. If MICs are 64 mg/L or less for ampicillin and at least 500 mg/L for gentamicin, this combination can be used. Amikacin or tobramycin should not be used for the treatment of Enterococcus spp. because no synergy with ampicillin exists. If this combination is not possible, then treatment of MDR Enterococcus spp. with vancomycin is recommended. As with MRS, if a vancomycin-resistant Enterococcus sp. is encountered, treatment may involve linezolid, daptomycin, quinupristin/dalfopristin, or ceftaroline (for E. faecalis not E. faecium).

Pseudomonas aeruginosa P. aeruginosa is a nonfermenting gram-negative pathogen found widely in the health care environment, and outbreaks of clonal infections have been seen in ICUs.29 P. aeruginosa is a pathogen that has a very high level of intrinsic resistance. It is resistant to the majority of β-lactam antimicrobial with the exception of ticarcillin, piperacillin, ceftazidime, and the carbapenems. Other classes of antimicrobials with known efficacy are aminoglycosides and the fluoroquinolones. Acquired resistance to P. aeruginosa occurs frequently. The three main mechanisms behind acquired resistance include a decrease in intracellular drug entry from efflux pumps or altered membrane structure, enzymes that modify or destroy antimicrobials, or modification of the target of the antimicrobials (DNA gyrase mutation). These mechanisms frequently lead to resistance against aminoglycosides, fluoroquinolones, and the β-lactams. Production of carbapenemases is uncommon unless previous use in that patient exists. Treatment of MDR P. aeruginosa often involves the use of amikacin or a carbapenem. In a large-scale human study the highest susceptibility rates for P. aeruginosa were to amikacin (90%), whereas only 83% to meropenem.30 As such amikacin or a carbapenem can be used empirically when P. aeruginosa is suspected. The ideal carbapenem for use is not clear; meropenem31 and imipenem32 have been associated with the development of resistance to carbapenems. The role for combination therapy for MDR or XDR P. aeruginosa is not clear because some studies show synergistic effects, whereas others show antagonistic effects; therefore combination therapy is not recommended routinely.

For XDR P. aeruginosa, the use of colistin, an old antimicrobial previously known as polymyxin E, is more frequently being administered in human medicine. It is used primarily as a rescue treatment with inconsistent results; however, 92% of MDR P. aeruginosa were susceptible to colistin.33 The ideal dosing is not known and nephrotoxicity is a possibility, potentially limiting its use in veterinary medicine.

β-Lactamase–Producing Gram-Negative Bacteria Acquisition of a β-lactamase is one the most frequent mechanisms of acquired resistance in gram-negative organisms. β-Lactamase is an enzyme that hydrolyzes and disrupts the β-lactam ring in the β-lactam group of antimicrobials (see Chapter 176). This confers resistance to penicillins, aminopenicillins, carboxypenicillins and narrow-spectrum cephalosporins. β-Lactams combined with a β-lactamase inhibitor (sulbactam, clavulanic acid) retain efficacy against these pathogens. Many third-generation cephalosporins and the carbapenems are also stable in the presence of this enzyme. Multiple other forms of this resistance mechanism have developed in recent decades. Extended-spectrum β-lactamases (ESBLs) occur in more than 300 different varieties and now are being seen in veterinary patients. In addition to hydrolyzing the above antimicrobials, the ESBLs hydrolyze third-generation cephalosporins. However, carbapenems are stable in the presence of this enzyme. ESBLs primarily have been identified from E. coli, Klebsiella pneumoniae, and Enterobacter spp. Their isolation has been shown to be as much as twice as frequent in an ICU versus a non-ICU population.2 There are no data from a randomized controlled trial for the treatment of ESBL-producing bacteria; however, carbapenems are considered the preferred treatment. Alternatively, fluoroquinolones or aminoglycosides can be used if shown to be susceptible from culture results. Enterobacteriaceae also have evolved carbapenemases as a form of acquired resistance. These bacteria are considered XDR and are resistant to the entire class of β-lactam antimicrobials. There are no reports of carbapenemase producing bacteria in dogs and cats. Treatment options are often limited because co-resistance to fluoroquinolones (90% to 100% of isolates), aminoglycosides (45% to 90% of isolates), and trimethoprim-sulfamethoxazole are frequent.34,35 Polymyxins such as colistin with or without rifampin are often the only option to treat these infections. Consultation with an infectious disease specialist is recommended if one of these pathogens is encountered.

REFERENCES 1. Archibald L, Phillips L, Monnet D, et al: Antimicrobial resistance in isolates from in-patients nd outpatients in the United States: increasing importance of the intensive care unit, Clin Infect Dis 24:211, 1997. 2. Badal RE, Bouchillon SK, Lob SH, et al: Etiology, extended-spectrum β-lactamase rates and antimicrobial susceptibility of gram-negative bacilli causing intra-abdominal infections in patients in general pediatric and pediatric intensive care units-global data from the study for monitoring antimicrobial resistance trends from 2008 to 2010, Pediatr Infect Dis J 32:636, 2013. 3. Black DM, Rankin SC, King LG: Antimicrobial therapy and aerobic bacteriologic culture patterns in canine intensive care unit patients: 74 dogs (January-June 2006), J Vet Emerg Crit Care 19:489, 2009. 4. Ogeer-Gyles J, Mathews K, Sears W, et al: Development of antimicrobial drug resistance in rectal Escherichia coli isolates from dogs hospitalized in an intensive care unit, J Am Vet Med Assoc 229:694, 2006. 5. Ghosh A, Dowd SE, Zurek L: Dogs leaving the ICU carry a very large multi-drug resistant enterococcal population with the capacity for biofilm formation and horizontal gene transfer, PLoS ONE 6:e22451, 2011. 6. Hamilton E, Kaneene JB, May KJ, et al: Prevalence and antimicrobial resistance of Enterococcus spp and Staphylococcus spp isolated from

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PART X  • INFECTIOUS DISORDERS surfaces in a veterinary teaching hospital, J Am Vet Med Assoc 240:1463, 2012. 7. Kukanich KS, Ghosh A, Skarbek JV, et al: Surveillance of bacterial contamination in small animal veterinary hospitals with special focus on antimicrobial resistance and virulence traits of enterococci, J Am Vet Med Assoc 240:437, 2012. 8. Julian T, Singh A, Rousseau J, et al: Methicillin-resistant staphylococcal contamination of cellular phones of personnel in a veterinary teaching hospital, BMC Res Notes 5:193, 2012. 9. Baker SA, Ban-Balen J, Lu B, et al: Antimicrobial drug use in dogs prior to admission to a veterinary teaching hospital, J Am Vet Med Assoc 241:210, 2012. 10. Magiorakos AP, Srinivasan A, Carey RB, et al: Multi-drug resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance, Clin Microbiol Infect 18:268, 2012. 11. Maragakis LL: Recognition and prevention of multidrug-resistant gramnegative bacteria in the intensive care unit, Crit Care Med 38:s345, 2010. 12. Lin MY, Hayden MK: Methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus: recognition and prevention in intensive care units, Crit Care Med 38:s335, 2010. 13. Ogeer-Gyles JS, Mathews KA, Boerlin P: Nosocomial infections and antimicrobial resistance in critical care medicine, J Vet Emerg Crit Care 16:1, 2006. 14. Epstein SE, Mellema MS, Hopper K: Airway microbial culture and susceptibility patterns in dogs and cats with respiratory disease of varying severity, J Vet Emerg Crit Care 20:587, 2010. 15. Gibson JS, Morton JM, Cobbold RN, et al: Multi-drug resistant E. coli and Enterobacter extraintestinal infection in 37 dogs, J Vet Int Med 22:844, 2008. 16. Gibson JS, Morton HM, Cobbold RN, et al: Risk factors for multidrugresistant Escherichia coli rectal colonization of dogs on admission to a veterinary hospital, Epidemiol Infect 139:197, 2011. 17. American Thoracic Society: Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia, Am J Resp Crit Care Med 171:388, 2005. 18. Dellinger RP, Levy MM, Rhodes A, et al: Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock, Intens Care Med 39:165, 2013. 19. Kumar A, Roberts D, Wood KE, et al: Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock, Crit Care Med 34:1589, 2006. 20. Joung MK, Lee J, Moon S, et al: Impact of de-escalation therapy on clinical outcomes for intensive care unit-acquired pneumonia, Crit Care 15:R79, 2011. 21. Gonzalez L, Cravoisy A, Barraud D, et al: Factors influencing the implementation of antibiotic de-escalation and impact of this strategy in critically ill patients, Crit Care 17:R140, 2013.

22. Morel J, Casoetto J, Jospe R, et al: De-escalation as part of a global strategy of empiric antibiotherapy management. A retrospective study in a medico-surgical intensive care unit, Crit Care 14:R225, 2010. 23. Bemis DA, Jones RD, Frank LA, et al: Evaluation of susceptibility rest breakpoints used to predict mecA-mediated resistance in Staphylococcus pseudintermedius isolated from dogs, J Vet Diagn Invest 21:53, 2009. 24. Rybak MJ, Lomaestro BM, Rotscahfer JC, et al: Vancomycin therapeutic guidelines: a summary of consensus recommendations from the infectious diseases society of America, the American society of health-system pharmacists, and the society of infectious diseases pharmacists, Clin Infect Dis 49:325, 2009. 25. Hayakawa K, Marchaim D, Palla M, et al: Epidemiology of vancomycinresistant Enterococcus faecalis: a case-case-control study, Antimicrob Agents Chemother 57:49, 2013. 26. Fridkin SK, Edwards JR, Courval JM, et al: The effect of vancomycin and third-generation cephalosporin’s on prevalence of vancomycin-resistant enterococci in 126 U.S. adult intensive care units, Ann Intern Med 135:175, 2001. 27. Chatterjee I, Iredell JR, Woods M, et al: The implications of enterococci for the intensive care unit, Crit Care Resusc 9:69, 2007. 28. Arias CA, Contreras GA, Murray BE: Management of multidrug-resistant enterococcal infections, Clin Microbial Infect 16:555, 2010. 29. Koutsogiannou M, Drougka E, Liakopoulos A, et al: Spread of multidrugresistant Pseudomonas aeruginosa clones in a university hospital, J Clin Microbiol 51:665, 2013. 30. Zhanel GG, Adam JH, Baxter MR, et al: Antimicrobial susceptibility of 22746 pathogens from Canadian hospitals: results of the CANWARD 2007-2011 study, J Antimicrob Chemother 68(suppl):i7, 2013. 31. Ong DS, Jongerden IP, Buiting AG, et al: Antibiotic exposure and resistance development in Pseudomonas aeruginosa and Enterobacter species in intensive care units, Crit Care Med 39:2458, 2011. 32. Carmeli Y, Troillet N, Eliopoulos GM, et al: Emergence of antibioticresistant Pseudomonas aeruginosa: comparison of risks associated with different antipseudomonal agents, Antimicrob Agents Chemother 43:1279, 1999. 33. Walkty A, DeCorby M, Nichol K, et al: In vitro activity of colistin (polymyxin E) against 3,480 isolates of gram-negative bacilli obtained from patients in Canadian hospitals of the CANWARD study, 2007-2008, Antimicrob Agents Chemother 53:4924, 2009. 34. Bratu S, Tolany P, Karumudi U, et al: Carbapenemase-producing Klebsiella pneumoniae in Brooklyn, NY: molecular epidemiology and in vitro activity of polymyxin B and other agents, J Antimicrob Chemother 53:5046, 2005. 35. Endimiani A, Huger AM, Perez F, et al: Characterization of blaKPCcontaining Klebsiella pneumoniae: isolates detected in different institutions in the eastern USA, J Antimicrob Chemother 63:427, 2009.

PART XI  HEMATOLOGIC DISORDERS CHAPTER 104  HYPERCOAGULABLE STATES Alan G. Ralph,

DVM, DACVECC  •  Benjamin

M. Brainard,

KEY POINTS • Thrombophilia is a propensity for pathologic thrombus formation. • Thrombophilia may be inherited (congenital causes) or acquired. • Many acquired thrombophilias exist in veterinary medicine. • Causes may include increases in procoagulant elements, altered blood flow, endothelial barrier disruption, or decreases in endogenous anticoagulants or fibrinolysis.

Hypercoagulability, or thrombophilia, describes a propensity for inappropriate thrombus formation. In vivo, coagulation is kept in check by a delicate balance of endogenous factors that either promote or decrease blood clot formation. Many of the factors that reduce clot formation are activated by the products of procoagulant factors.1 Hypercoagulability indicates that the balance has been tipped in favor of coagulation, which may arise because of a variety of perturbations in the coagulation system (increased procoagulant elements, decreased anticoagulant elements, or diminished fibrinolysis), ultimately culminating in an increased risk of thrombosis or thromboembolism (TE). Thrombotic disease can increase morbidity, duration of hospital stay, cost of hospitalization, and potentially mortality. Thrombophilia is a result of inherited or acquired causes. Inherited conditions reported in people include the factor V Leiden mutation or protein C deficiency, among others. No inherited forms of thrombophilia have been described in veterinary medicine. Three major areas of predisposition to thrombotic disease are described as “Virchow’s triad” and include endothelial dysfunction, hypercoagulability of blood, and blood stasis or altered blood flow. In most clinical scenarios, these contributors overlap. For instance, endothelial dysfunction leads to numerous alterations (e.g., loss of thrombomodulin function [TM], release of von Willebrand [vWF] multimers) that ultimately affect the coagulability of blood. Nonetheless, this model provides a meaningful template for understanding prothrombotic conditions. Activation of coagulation is a central theme throughout many inflammatory disease states, such as sepsis. Likewise, widespread coagulation perpetuates the inflammatory response by direct activation of inflammatory mediators (e.g., thrombin, which can induce directly inflammatory cytokine production, and microthrombosis, which leads to tissue hypoxia and possible reperfusion injury).2 Inflammation and coagulation are intertwined inextricably, and both processes proceed in a bidirectional fashion.

VMD, DACVECC, DACVAA

MECHANISMS OF THROMBOPHILIA Endothelial Disturbances In health, the endothelium exhibits an anticoagulant phenotype, maintaining normal blood flow and organ perfusion. Upon activation or injury, the endothelium transitions to a prothrombotic phenotype. The endothelial barrier is comprised of vascular endothelial cells (EC) and a thin, carbohydrate-rich luminal glycocalyx that localizes many key anticoagulant elements. The glycocalyx comprises a large network of negatively charged glycosaminoglycans (GAGs), proteoglycans, and glycoproteins. Hepa­ ran sulfate accounts for 50% to 90% of the proteoglycans and facilitates the binding of antithrombin (AT),3,4 which increases the efficiency of AT-mediated inhibition of thrombin.5 Other important anticoagulants bind the glycocalyx, including heparin cofactor II and TM. Tissue factor pathway inhibitor (TFPI) localizes to the glycocalyx, although the exact binding mechanism is debatable, occurring either via heparan sulfate6,7 or via a glycosylphosphatidylinositollipid anchor.8 The glycocalyx also serves as a mechanoreceptor, sensing altered blood flow and releasing nitric oxide during conditions of increased shear stress to maintain appropriate organ perfusion. Nitric oxide (NO) has important effects on the inflammatory response, leukocyte adhesion to the endothelium, and inhibition of platelet aggregation.10-12 With inflammation, synthesis of the GAGs is decreased: these comprise the glycocalyx, decreasing the function of key anticoagulants that rely on the glycocalyx (e.g., TM and protein C, TFPI).9 The glycocalyx also buffers EC by preventing the binding of inflammatory cytokines to cell surface receptors.13,14-16 EC can be activated by tumor necrosis factor-α (TNF-α), bradykinin, thrombin, histamine, and vascular endothelial growth factor (VEGF).17-20 Once activated or injured, EC release ultralarge multimers of vWF (UL-vWF) from the Weibel-Palade bodies (which also contain P-selectin, IL-8, tissue plasminogen activator [tPA], and factor VIII [fVIII]).21 UL-vWF can bind platelet GP Ibα receptors, initiate platelet tethering and activation, and are more active for platelet adhesion and activation than smaller vWF multimers.22 In health, UL-vWF quickly are cleaved into smaller multimers by a disintegrin-like and metalloproteinase with thrombospondin type 1 repeats (ADAMTS13).23 These smaller vWF molecules circulate freely in association with fVIII and have considerably less platelet aggregatory activity than the UL-vWF molecules. The UL-vWFs usually remain tethered at sites of endothelial activation or injury, bound to the cell surface or to exposed collagen. A decrease or absence of ADAMTS13 may result in high concentrations of UL-vWF, which then can cause systemic platelet aggregation, thrombosis, and 541

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a subsequent consumptive thrombocytopenia (thrombotic thrombocytopenic purpura [TTP], reported in people). Acquired TTP has been reported in human patients who have developed antibodies against ADAMTS13 and in patients exposed to certain drugs such as clopidogrel or cyclosporine. Patients with certain malignancies and systemic lupus erythematosus are also at risk. Lower ADAMTS13 levels resulting from inflammatory disease may contribute to pathologies seen with other coagulopathies (e.g., disseminated intravascular coagulation [DIC]).24,25

Increased Procoagulant Elements Endothelial disruption exposes procoagulant substances such as tissue factor (TF) to the circulating blood. Our current understanding suggests that virtually all coagulation in vivo is initiated through the interaction of TF with activated factor VII (fVIIa).26,27 TF may be expressed on monocytes/macrophages that have been activated by inflammation28 and also has been identified on the surface of various neoplastic cells.29 Like many procoagulant elements, TF perpetuates inflammation through the activation of nuclear factor κB, leading to the production of TNF-α.30 Platelets also may serve as a source of procoagulant membrane. Upon activation, platelets undergo shape change and shuffle negatively charged phospholipids (phosphatidylserine and phosphatidylethanolamine) to the surface. These provide the catalytic surface essential for the tenase and prothrombinase complexes for the propagation phase of clot formation.1 With activation, platelets activate and greatly increase the number of copies of the active fibrinogen receptor (glycoprotein IIbIIIa [GP IIbIIIa], also known as integrin αIIbβ3) on their surface. The contents of alpha and dense granules also are secreted, releasing procoagulant elements such as calcium, factor Va, serotonin, fibrinogen, P-selectin, and ADP. Feline alpha granules also release vWF.31 Microparticles (MPs) are circulating small vesicles (membrane blebs) released from activated or apoptotic cells. MPs may be derived from platelets, ECs, leukocytes, erythrocytes, and neoplastic cells.32,33 Like platelets, MPs also can provide an asymmetric phospholipid membrane for thrombin generation. MPs can express TF on their surface, and those expressing phosphatidylserine and TF are characterized as procoagulant MPs.34 TF-bearing MPs originating from granulocytes and platelets have been identified in people with sepsis.35 Moreover, TF-bearing MPs have been shown to induce coagulation in vitro through the VIIa-TF pathway.36 Some evidence suggests the presence of increased circulating TF activity in dogs with IMHA, which may be a result of TF-bearing MPs.37 Other procoagulant MPs may display vWF-binding sites and UL-vWF multimers, which can tether and activate circulating platelets.38,39

Decreased Endogenous Anticoagulants Endogenous (natural) anticoagulants are essential to restricting coagulation to the site of vascular insult. The nearly simultaneous activation of anticoagulant factors, even while clot propagation is still occurring, helps to prevent a procoagulant state or the systemic dissemination of coagulation. The three primary anticoagulant proteins are AT, protein C, and TFPI. Many other anticoagulant factors exist, with an anticoagulant described for nearly every procoagulant element. The endothelium is where all three major systems are most active, underscoring the importance of an intact endothelial barrier. AT, TFPI, and the protein C system are directly or indirectly antiinflammatory. Antithrombin acts primarily to inhibit thrombin and factor Xa and has lesser inhibitory effects on factors IXa and the fVIIa-TF complex. AT is most effective when bound to heparin-like GAGs of the glycocalyx (e.g., heparan sulfate), or when exposed to exogenous

heparins, increasing the inhibition of thrombin greater than 1000fold from non-bound AT.40 In the absence of heparins, AT’s inhibition of thrombin can be enhanced (nearly eightfold) by the binding of AT to TM in the presence of thrombin.41 Antithrombin typically is decreased in systemic inflammation or critical illness by one of three mechanisms: consumption (because of thrombin generation), decreased production (negative acute phase protein), or degradation by neutrophil elastase.42-44 Urinary loss of AT also may occur in animals with glomerulonephritis.45 The protein C system is an important inhibitor of factors Va and VIIIa. Protein C is activated (to activated protein C, APC) when trace amounts of thrombin bind TM located on the endothelium, predominantly in the microcirculation.46 This reaction is accelerated in the presence of the endothelial protein C receptor (EPCR). In the presence of the cofactor protein S, APC’s inhibition of Va and VIIIa is accelerated nearly twentyfold.47,48 By binding thrombin, TM helps generate APC and prevents thrombin from acting on fibrinogen and platelets. This reaction also generates thrombin activatable fibrinolysis inhibitor (TAFI), which inhibits fibrinolysis. The protein C system is less functional during systemic inflammation resulting from decreased hepatic synthesis of protein C and S. The activation of protein C also is hindered by the effects of inflammatory cytokines on the endothelium and TM. TNF-α can downregulate the expression of TM,49 whereas elastase from endotoxin-activated neutrophils can cleave TM from the endothelium.50,51 Circulating or soluble TM is less effective than when it is complexed with the EPCR on the endothelium. Soluble TM is increased in people with sepsis and independently predicts the presence of DIC, multiorgan dysfunction syndrome (MODS), and mortality.52 TFPI is released primarily from ECs and acts to inhibit fVIIa-TF complexes and factor Xa (fXa); in essence, all components of the TF- or extrinsic pathway.53 Other sources of TFPI include platelets,54 mononuclear cells,55 vascular smooth muscle and cardiac myocytes,56 fibroblasts,56 and megakaryocytes.57 Protein S serves as a cofactor for the inhibition of fXa by TFPI, and a decrease in TFPI activation contributes to the thrombophilia associated with protein S deficiency in people.58,59

Perturbations in Fibrinolysis Fibrinolysis is the final protective step to prevent vascular occlusion. Thrombi that remain in the macro- or microvasculature can impair organ perfusion and oxygen delivery and may be an important contributor to secondary injury that leads to MODS. Circulating plasminogen is incorporated into forming clots and is converted to plasmin by fibrinolytic activators, including tissue-type (tPA) and urinary-type plasminogen activator (urokinase). Plasmin breaks down the fibrin meshwork of the formed clot and allows for recannulation of blood vessels. tPA and urokinase are derived largely from the endothelium and released upon activation or injury. The effects of plasminogen are decreased by endogenous plasminogen activator inhibitor (PAI-1). In the presence of TNF-α and IL-1β, there is a delayed but more sustained increase in PAI-1 than tPA, decreasing fibrinolysis and resulting in the persistence of thrombi.61

DIAGNOSTICS The identification of a hypercoagulable state before the development of a consumptive coagulopathy or thrombotic complications can be challenging. Often in clinical veterinary medicine, a hypercoagulable state is not identified until a thrombotic event occurs or the patient develops DIC, limiting the opportunity to intervene with specific therapies. In fact, detecting the presence of a thrombus or

CHAPTER 104  •  Hypercoagulable States

thromboembolus is one of the only means for a clinician to learn definitively that pathologic coagulation is occurring. Traditional coagulation tests, such as platelet count, activated partial thromboplastin time (aPTT), and prothrombin time (PT), are most accurate for the demonstration of hypocoagulability and do not reliably identify a predisposition towards hypercoagulability. Prolongations of aPTT/PT and decreased platelet count may appear in patients with hypercoagulability, although this usually is due to consumption of platelets and coagulation factors after unregulated thrombin generation. In practice, a drop in circulating platelet count accompanied by a prolongation of at least 20% in baseline aPTT in an at-risk patient should raise concern of consumptive coagulopathy and prompt further investigation.62 Documentation of a hypercoagulable state relies on identifying a rise in procoagulant elements (e.g., MPs, fV, or VIII activities, or fibrinogen), a decrease in endogenous anticoagulants (e.g., AT, protein S and C, or TFPI), or a decrease in fibrinolysis (decreased tPA; increased α2-antiplasmin, PAI-1, TAFI). Testing that assesses more than one aspect (e.g., viscoelastic coagulation [thromboelastography] or calibrated automated thrombography [CAT]) also may be useful. In addition, markers of ongoing thrombin generation (e.g., thrombin-AT complex [TAT], prothrombin activation fragment [F1+2], or fibrinopeptides A and B) or lysis of fibrin clots (fibrin [-ogen] degradation product [FDP] or D-dimer) may be used (Box 104-1). Procoagulant factor (fV and fVIII) activities and many anticoagulant and fibrinolytic components can be evaluated at specialty reference laboratories, such as the Comparative Coagulation Laboratory at Cornell University. Many sensitive assays are available for documenting activation of specific coagulation components in people (e.g., activation of the contact pathway by factor XIIa or factor XII-C1 inhibitor complex); however, these have not been validated for veterinary species.63 Other markers of thrombin generation, such as fibrinopeptide A and F1+2, have been evaluated in dogs, although poor cross-reactivity to the reagents in the human-based assay was noted.64 Tests to assess coagulation globally are becoming more widely available in veterinary medicine and are unique in the information they provide. Commonly available tests include viscoelastic coagulation devices (thromboelastography [TEG] or rotational thromboelastometry [ROTEM]) or CAT. Viscoelastic testing evaluates the time to initial fibrin cross-linking, rate of clot formation, and the viscoelastic characteristics of the clot formed,65 whereas CAT focuses on the thrombin generation potential (endogenous thrombin potential, ETP) in a sample. These tests may help to suggest a hypercoagulable state. Hypercoagulable samples clot more quickly, with a faster rate of clot formation, and greater clot strength (viscoelastic tests); or exhibit a greater ETP for CAT. Platelet contributions to a hypercoagulable state may be inferred by assessing markers of platelet activation (e.g., P-selectin expression, platelet-neutrophil aggregates) (Box 104-2) or documentation of hyperfunctional platelets in response to standard stimuli (see Chapter 107). Although whole blood viscoelastic testing does integrate platelet function, detection of specific proteins on platelets or other circulating cells requires advanced techniques such as flow cytometry. Flow cytometric techniques also can be used to document the presence of procoagulant MPs, although standardization of techniques is necessary because of the small size of the MPs (less than 1.5 microns). The Advia 120 hemostasis analyzer (Bayer Healthcare, Shawnee Mission, KS) reports a parameter called mean platelet component (MPC), which is related to the granularity of the circulating platelets. After activation, the granularity of platelets decreases, and thus a decreased MPC may represent circulating activated platelets, although

BOX 104-1 

Laboratory Markers of a Hypercoagulable State

Ongoing Thrombin Generation Thrombin-antithrombin complex (TAT)141 Prothrombin fragment (F1+2)226 Fibrinopeptides A + B227,228 D-dimer (lysis of cross-linked fibrin by plasmin)

Supportive of Hypercoagulable State Hyperfibrinogenemia Elevated factor V or VIII activities Activation of specific factors (e.g., factor IX activation peptide)229 Elevated tissue factor (TF) expression (e.g., fX-dependent chromogenic assay)230 Elevated von Willebrand multimers (particularly ultralarge multimers) Deficiency of disintegrin and metalloproteinase with thrombospondin type-1 repeats, member 13 (ADAMTS-13) Elevated fibrin(ogen) degradation products (fibrin or fibrinogen lysis by plasmin) Whole blood coagulation assessed viscoelastic coagulation tests (e.g., TEG) Enhanced thrombin generation (calibrated automated thrombography)231 Presence of lupus anticoagulants or anticardiolipin antibodies Presence of procoagulant microparticles (e.g., Bearing TF or phosphatidylserine) Decreased endogenous anticoagulants Antithrombin Protein C, S, or Z Decreased activation of protein C Activated protein C232 Protein C peptide233 Protein C-inhibitor complex234 Activated protein C-α2-macroglobulin complex235 Activated protein C-α1-antitrypsin complex235 Tissue factor pathway inhibitor Suppressed fibrinolysis Hypoplasminogenemia236 Decreased tissue-type plasminogen activator236 Increased thrombin activatable fibrinolysis inhibitor (carboxypeptidase-B2)237 Increased plasminogen activator inhibitor-1238 Increased α-2 antiplasmin239 Decreased Bβ1-42 or Bβ15-42 fragment (cleaved from amino terminus of Bβ chain of fibrin I or fibrin II, respectively, by plasmin)240,241 Prolonged euglobulin lysis time (estimate of overall fibrinolysis using the euglobulin fraction of plasma) Fibrinolysis assessed by viscoelastic coagulation testing

further study is necessary to apply this technology to veterinary medicine.

COMMON CONDITIONS IN VETERINARY MEDICINE Systemic Inflammation Our current understanding of the coagulopathy associated with systemic inflammation describes a complex process involving increased expression of TF, activation of ECs and disruption of the glycocalyx, impairment of anticoagulant systems, and abatement of fibrinolysis.66-68

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BOX 104-2 

Markers of Platelet Activation

Platelet Membrane Expression Conformational changes in the GPIIb/IIIa Complex (also termed αIIbβ3) Monoclonal antibody (mAb) PAC1 (binds only to the exposed fibrinogen-binding site of GPIIb/IIIa after activation [conformational change])242 mAb targeting ligand-induced binding sites (LIBS) of GPIIb/IIIa (e.g. LIBSa, LIBS6)243-245 mAb against receptor-induced binding sites (RIBS): changes induced by receptor-ligand (fibrinogen) binding (e.g., 2G5, F26, canine activated platelet 1 [CAP1])244-246

Granule membrane protein exposure P-selectin from alpha granules247 GMP-33 (α granule membrane protein)248 Lectin-like oxidized LDL receptor-1 (LOX-1)249 Lysosomal-associated membrane proteins (e.g., LAMP-1)250 CD63 (lysosomal glycoprotein)251

Platelet-leukocyte aggregates Binding of platelets (via P-selectin) to leukocytes via the P-selectin glycoprotein Ligand-1 counter-receptor on leukocytes252

Surface binding of secreted proteins CD40L (transmembrane protein of the tumor necrosis family)253 Multimerin (large alpha granule glycoprotein involved in factor V/Va binding)254 Thrombospondin (alpha granule protein involved in platelet aggregation)255

Procoagulant platelet surface Factor Va binding256 Factor VIIIa binding257 Factor Xa binding258

Platelet-Derived Microparticles Flow cytometry evaluated259 Procoagulant assays260

Soluble Markers Soluble P-selectin261 Platelet factor 4262 β-Thromboglobulin262 Soluble GP V263 Plasma and urine thromboxane A2 metabolites264 Soluble CD40L265,266

Many of the processes by which inflammation affects coagulation are interrelated: glycocalyx shedding and EC activation leads to compromised production of local regulators (e.g., NO) and increased expression of procoagulant molecules (e.g., UL-vWF or TF) and adhesion molecules (e.g., P-selectin),69,70 with derangement of anticoagulant defenses. TM may be damaged by multiple mechanisms (leading to decreased activation of protein C), and AT is less effective because of decreased concentrations and impaired interactions with an endothelium that has been denuded of GAGs.9 TFPI similarly may have impaired EC localization. In addition, an exuberant release of PAI-1 resulting from inflammatory cytokine release can slow fibrinolysis and further impede coagulation defenses.61 Patients with sepsis develop an initial hypercoagulable phase, followed by a much longer hypocoagulable phase resulting from consumption. The majority of patients described in the veterinary literature display a hypocoagulable phenotype with evidence of prior clot formation. In dogs with septic peritonitis, the presence of coagulopathy (defined by prolongations of PT or aPTT, or a platelet count

of 100,000/µl or less) is associated independently with increased odds of death.71 Although less is known about coagulopathy in cats, inflammatory conditions (pancreatitis and sepsis) are recognized as two of the top three identified causes of DIC in cats.72 Dogs with sepsis have significantly prolonged aPTT and/or PT, along with higher FDP and D-dimer concentrations than control dogs. Septic dogs also have lower protein C and AT activities, further supporting a consumptive coagulopathy.73 Septic dogs with continually decreasing levels of protein C and AT proteins had a worse outcome.74 TAFI is increased in dogs with bacterial sepsis and other inflammatory conditions (e.g., neoplasia), resulting in downregulation of fibrinolysis.75 Studies in dogs with induced endotoxemia have demonstrated a decrease in fibrinogen concentration and platelet count, as well as a prolongation in PT, aPTT, and a rise in D-dimer concentration, consistent with a consumptive coagulopathy. TEG testing in this cohort showed progressively hypocoagulable tracings after endotoxemia. A dramatic decrease in protein C and S also were noted in these dogs, consistent with a tendency towards hypercoagulability, although this was more likely a response to the widespread activation of coagulation.76 Other studies of canine platelet activity during endotoxemia (using the PFA-100 [see Chapter 107]) showed increased activity within 30 minutes of lipopolysaccharide (LPS) administration, which then decreased to activity values less than baseline.77 The initial shortening of the PFA closure time may indicate platelet hyperactivity in response to the LPS and may provide a plausible origin for the consumptive coagulopathy seen at later time points.

Protein-Losing Nephropathy Dogs with glomerular disease and significant proteinuria with or without nephrotic syndrome (NS) are at a heightened risk of thrombotic complications and are represented in nearly every study describing pathologic thrombus formation or TE.78-82 One case series reported the rate of thrombosis or TE to be 22.2%,83 and nearly half of the protein-losing nephropathy (PLN) patients in a recent study were diagnosed with thrombi ante- or postmortem.45 In people, the thrombophilia associated with PLN appears to be multifactorial. Platelets are hyperaggregable and exhibit increased markers of activation (e.g., P-selectin).84,85 Soluble factors show increases in fVIII activity and fibrinogen concentration, whereas vWF levels and fV are elevated variably.86-88 The loss of endogenous anticoagulant potential centers on low AT activity, which occurs in people and dogs.87,89 Despite this consistent finding, AT activity fails to uniformly predict thrombotic risk across studies in people.90,91 Protein C levels are variable in patients with PLN,92,93 and several studies have documented elevated levels of TFPI, suggesting that this anticoagulant is not likely a significant component of the thrombophilia.94 In people, levels of TAFI can be increased,95 along with PAI-1, suggesting a decreased fibrinolytic state.96 People have a propensity toward development of renal vein thrombosis, and increased markers of endothelial activation have been documented.95,97 These suggest some involvement of a local mechanism (e.g., endothelial activation or abnormal renal blood flow) contributing to the overall thrombophilia. Coagulation abnormalities have been investigated thoroughly in a group of seven dogs with marked proteinuria compared with dogs with nonproteinuric renal failure and dogs presenting for other systemic illness. TEG tracings were more hypercoagulable in PLN and renal failure compared with systemically ill and healthy dogs, and fibrinogen activity was elevated in PLN dogs. AT activity was lower in PLN than systemically ill dogs, and higher α2-antiplasmin and protein C activities were identified.45 Hyperfibrinogenemia and low AT activity were described in a previous study of three dogs, which also identified elevated fVIII activity.98 All of these factors could contribute to increased procoagulant potential.

CHAPTER 104  •  Hypercoagulable States

Immune-Mediated Hemolytic Anemia

activities of factors II, V, VII, IX, X, and XII, in addition to decreased AT and elevated TAT complexes were noted. There were no differences in plasminogen or PAI-1 compared with healthy control dogs.129 An earlier study found increased activities of factors V, XI, AT, and elevated plasminogen in 12 dogs.130 A more recent study evaluated platelet count, mean platelet volume, AT, PT, aPTT, fibrinogen, and TEG. No differences were noted between age-matched controls and 28 dogs with naturally occurring HAC.131 TEG and thrombin generation have been used to assay for a procoagulant state in six healthy beagles given 1 or 4 mg/kg/day oral prednisone for 2-week periods. TEG revealed changes consistent with a procoagulant state in both prednisone groups, whereas the CAT measure of thrombin generation was increased only in the 1 mg/kg/day treatment group.132

Thrombi have been identified in up to 46% to 80% of nonsurvivors99,100 and DIC in 45% of dogs suffering from immune-mediated hemolytic anemia (IMHA).101 The majority of deaths in dogs with IMHA occur within the first 2 weeks, primarily because of anemia and/or thrombotic complications.99,100 A postmortem evaluation of dogs suffering from IMHA found lesions consistent with coagulopathy (macro- and microthrombi, widespread fibrin deposition, and hemorrhage) in 73.5% of dogs.102 Coagulation abnormalities consistent with a hypercoagulable state (low AT activity, elevated FDPs and D-dimer, and markedly elevated fibrinogen concentration) are commonly reported in this population.101 TEG studies also have documented hypercoagulability, primarily on the basis of an increased clot strength (maximal amplitude or MA).103-105 The cause of an increased MA is difficult to tease apart in this population; fibrinogen, platelet count and function, and hematocrit are key contributors to the MA. Nonetheless, the hypercoagulable changes reflected in these dogs are often striking (see Chapter 110). Circulating TF is also a likely contributor to the procoagulant state of IMHA, with upregulation of TF gene expression in whole blood, although the source of the TF has not been determined.37 Increased TF could come from numerous sources (e.g., platelet, MPs, mononuclear cells); or from stimulation of EC TF expression by cellfree heme.106 Free heme can also decrease the bioavailability of NO and upregulate EC adhesion molecules (e.g., E-selectin).107-110 Hemolyzed erythrocytes augment thrombin generation in vitro, an effect attributed to erythrocyte-derived MPs or procoagulant erythrocyte membrane.111 Platelet activation in canine IMHA has been evaluated in two studies, reaching disparate conclusions. In one study, increased platelet P-selectin expression was identified,112 whereas another found no significant changes in P-selectin expression, fibrinogen binding (representing GP IIb/IIIa expression), or platelet-leukocyte aggregates when dogs with IMHA were compared with healthy controls.113 An increase in MPs was also reported, although no further characterizations (e.g., cellular origin) were made.113 A survival benefit was observed in dogs with IMHA who were receiving aspirin as part of their therapy in one retrospective study.114 Antiphospholipid syndrome (APS) refers to the thrombophilia associated with a broad family of autoantibodies that are detected by lupus anticoagulant tests (LA), or by ELISA for anticardiolipin antibodies (aCL) or antibodies directed against other phospholipids or phospholipid-binding proteins.115,116 Currently available studies suggest that APS does not likely play a significant role in dogs with IMHA.117,101 There have been healthy Bernese Mountain Dogs detected with aCLs and LAs in Europe,118 and LAs were found in a dog suffering from hemolysis and thrombosis.119

Arterial thromboembolism (ATE) in cats is associated most commonly with cardiac disease; many cats are asymptomatic before experiencing an ATE.133,134 Thrombosis secondary to cardiac disease is reported infrequently in dogs but has been associated with dilated cardiomyopathies and atrial fibrillation (AF).135 Left atrial (LA) and LA appendage enlargement is associated with numerous structural changes, culminating in a procoagulant phenotype, such as increased TF and vWF on areas of denuded or damaged endothelium.136 Growth hormones (e.g., VEGF), which are increased in people with AF, may promote the upregulation of TF.137 Through atrial enlargement, shear stress is decreased (stasis), reducing the release of NO.138 There is a direct link between inflammation and AF development in humans and experimental dogs.139,140 A systemic hypercoagulable state occurs in 50% of cardiomyopathic cats with spontaneous echocardiographic contrast (or “smoke”) with or without a LA thrombus, and in 56% of cats with ATE and LA enlargement.141 vWF : Ag concentrations were elevated in only the cats with ATE, and the presence of hypercoagulability was not related to LA size or the presence of congestive heart failure.141 These results are echoed by an earlier study that revealed changes consistent with a hypercoagulable state in 45% of cats with hypertrophic cardiomyopathy (HCM).142 Platelets from cats with cardiomyopathy required significantly lower doses of ADP to result in irreversible aggregation compared with control cats.143 In a small group of cats with predominantly thyrotoxic cardiomyopathy, platelets were less responsive to ADP and more responsive to collagen for aggregation.144 Many of these cats were receiving medications to treat hyperthyroidism or heart disease, and it is unclear if these may have interfered with aggregation responses. A more recent study evaluated platelet function in cats with HCM compared with healthy control cats and did not show significant differences in platelet activity.145 Many of the cats in this study had less severe disease, and cats with ATE were excluded.

Hypercortisolemia

Neoplasia

Hyperadrenocorticism (HAC) in people is associated with a significantly increased risk of thrombotic complications, with rates comparable to those following major orthopedic surgery (rates of venous TE up to 5%).120 Changes identified in people with HAC include elevated activities of fVIII and vWF,121,122 heightened levels of PAI1,123 and elevated activities of factors IX, XI, and XII.120,124-127 In contrast to veterinary patients, many people with HAC suffer from comorbidities (e.g., obesity, diabetes mellitus, and hypertriglyceridemia) that are also prothrombotic conditions. Dogs with HAC are represented in most case series describing thrombotic conditions (e.g., aortic thrombosis, pulmonary TE [PTE], splenic or portal vein thrombosis).78-81,128 Despite these observations, a consistent cause or definable procoagulant state has not been identified. In an early study of 56 dogs with HAC, increased

Coagulopathic complications are common in many dogs and cats with neoplasia.146-155 DIC has been described in 9.6% of dogs with malignancies; the highest rates occur in dogs with hemangiosarcoma, mammary carcinoma, and adenocarcinoma of the lung.156 The criteria of DIC were fulfilled in 50% of dogs with hemangiosarcoma,157 and malignancies were among the top three most common reasons for DIC in cats.72 Coagulation components are both contributors to thrombosis and important in cancer behavior: in particular, tumor growth, angiogenesis, and metastasis. TF has been identified on malignant cells and in tumor vasculature,158,159 and tumor cells have the ability to shed TF-bearing MPs.159 TF supports thrombophilia and also plays a key role in regulation of integrin function responsible for tumor angiogenesis. In mice, TF blockade results in decreased angiogenesis

Cardiomyopathies

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and tumor growth, through modulation of VEGF.160,161 Moreover, TF expression on histopathology samples is an independent predictor of poor overall or relapse-free survival for many tumor types in people.162-165 TF expression has been evaluated in canine cell lines of mammary tumors, pancreatic carcinoma, pulmonary adenocarcinoma, prostatic carcinoma, and sarcomas (osteosarcoma and fibrosarcoma). TF was highly expressed in all but osteosarcoma; tumors of epithelial origin (mammary carcinoma and pulmonary adenocarcinoma) expressed the highest levels. These tumors also shed TF-bearing microparticles into tissue culture supernatants.29 A recent investigation in dogs with various neoplasms showed a hypercoagulable TEG tracing in 70.4%, with 4.2% having a hypocoagulable tracing. All three dogs with hypocoagulable tracings were suffering from disseminated neoplasia, a finding also noted in another TEG study of 49 dogs with cancer.166 Patients with distant metastasis commonly have a higher fibrinogen and D-dimer compared with locally invasive or noninvasive disease.167 In canine patients with carcinomas, thrombocytosis and hyperfibrinogenemia were found more commonly (compared with healthy controls). TEG-derived thrombus generation (TEGTG), revealed a faster TEGTG in dogs with carcinoma (46% of these dogs being hypercoagulable on other testing). PAI-1 activity was decreased in this population.168 The most common hemostatic abnormalities in dogs with untreated mammary carcinoma included hyperfibrinogenemia, elevated fV, and decreased fVIII activities; these hemostatic abnormalities are more common with increasing tumor stage.169 Platelet and fibrinogen survival in dogs with metastatic disease are decreased, further supporting ongoing consumption.170 In a broad evaluation of AT activities in dogs, a low AT was frequently present in dogs with neoplasia and was associated with a greater risk of mortality.171 Platelet aggregometry was assessed in dogs with untreated multicentric lymphoma; affected dogs had a greater maximum aggregation than controls.172 Another study of dogs with various malignancies showed that platelets from affected dogs had shorter delays in aggregation response, higher maximum aggregation, greater ATP secretion, and a tendency to aggregate in response to lower concentrations of weak agonists (e.g., ADP).173

Isolated Brain Injury A state of intravascular coagulation resembling DIC has been recognized in people suffering traumatic brain injury (TBI), with significant impacts on outcome in adults and children.174-176 For TBI patients who are coagulopathic on presentation, there is an approximately doubled rate (85% vs. 31%) of hemorrhagic progression of neuronal lesion(s) or development of new ischemic lesions.177 Coagulopathy upon hospital presentation is associated with higher rates of craniotomy, single and multiple organ failures, less intubation-free days, and longer ICU and hospital stays, compared with noncoagulopathic TBI patients. The overall mortality for TBI patients with coagulopathy was 50.4%, compared with 17.3% in patients without coagulopathy.178 The coagulopathy can develop up to 4.5 days posttrauma (mean of 68 ± 7.4 hours), with a faster onset with worsening injury severity.179 The brain is rich in TF, suggesting TF is likely the initiator of coagulation in TBI patients.180 TBI patients have elevated monocyte TF expression for the first 24 hours, which then quickly returns to normal.181 Enhanced thrombin generation has been documented as blood passes the vasculature of the brain. In a study of people with severe isolated TBI, patients had prolonged aPTT and PT; elevated D-dimer, TAT, and F1+2; and low AT, platelets, and fibrinogen upon presentation. Complement C5b-9 and IL-6 also were elevated, with IL-6 levels at least 100-fold greater than controls. A transcranial gradient (arterial vs. jugular venous blood) of TAT, F1+2, and IL-6

was present, representing brain vasculature-initiated thrombin generation.182 Similar results were found in another study comparing internal jugular, peripheral venous, and arterial samples of coagulation markers.183 Procoagulant MPs after TBI are increased significantly in CSF and blood. These MPs were primarily of EC and platelet origin, adding evidence to the likely contribution of cerebrovascular endothelial activation or injury.184 Although local procoagulant factors initiate coagulation, inflammatory cytokines and procoagulant MPs provide a means for dissemination of the condition, leading to a systemic response. Studies have suggested a state of platelet hypofunction in brain injured patients.182,185 This is opposed to non–brain-injured trauma patients who generally have increased platelet reactivity.186 A subset of TBI patients in this study also showed an increase in flowcytometric markers of platelet activation (e.g., P-selectin expression, activated conformation of GPIIb/IIIa), despite exhibiting decreased aggregation responses. The cause of the platelet dysfunction in TBI patients has not been identified; however, this pattern would be most consistent with platelets that are partially activated in vivo (e.g., acted on by thrombin). Eight experimental cats with TBI-induced coagulopathy secondary to bullet-inflicted brain injury showed a decreased platelet count and decreased platelet clumping, possibly suggesting a decreased reactivity of the cats’ platelets. A decreasing fibrinogen was also present throughout the experiment.187

MANAGEMENT OF HYPERCOAGULABLE CONDITIONS Treatment of the Underlying Condition The management of hypercoagulable states should be focused on eliminating the underlying condition or trigger. This can include appropriate antimicrobials, source control (including surgery if necessary), and aggressive supportive care. Maintenance of oxygen delivery to tissues is paramount to avoid ischemia and tissue acidosis, which may worsen inflammation.

Recombinant Anticoagulant Therapy Endogenous anticoagulant replacement therapy has long been investigated as a means to address complex coagulopathies while simultaneously decreasing inflammation. These therapies, although logical given the decrease in endogenous anticoagulants in many disease states (e.g., decreased protein C or AT), have failed thus far to improve survival in large clinical trials. AT supplementation has been effective at reversing apparent heparin resistance in cardiopulmonary patients with low AT activities.188 In a study of people with severe sepsis, AT supplementation did not improve survival, but subgroup analysis of patients who were not administered concomitant heparin showed an improvement in survival at 90 days for those receiving AT.189 A study of AT without heparin for severe sepsis found an improved survival in human patients with DIC but no difference (compared to placebo) for patients that did not display DIC.190 Recombinant APC (rAPC) has been shown to have numerous benefits in sepsis and inflammatory conditions. It has been documented to prevent TNF-α-mediated hypotension in rats with septic shock,191 improve microvascular perfusion in people with sepsis,192 and result in dramatic improvements in survival in baboons with Escherichia coli septicemia.193 Recent large trials have failed to confirm a survival benefit in people with sepsis, and the patented product (Xigris) was removed from the market in October of 2011.194 Recombinant TFPI (rTFPI) has been proven an effective antithrombotic agent in experimental models of sepsis and DIC,195-197

CHAPTER 104  •  Hypercoagulable States

coronary artery disease, and thrombosis in animal models, and it was shown to reduce the mortality rate in sepsis-induced DIC.197 More extensive human trials have failed to prove a survival benefit to date.198-200 Recombinant soluble TM recently has garnered considerable attention and has shown promise for attenuating DIC,201-203 with a survival benefit seen in septic patients requiring mechanical ventilation.204

Antithrombotic Therapy Exogenous antithrombotic therapy can consist of drugs that inhibit platelet function (e.g., aspirin or clopidogrel) or drugs that facilitate the inhibition of thrombin (e.g., unfractionated [UFH] or low molecular weight heparins [LMWH]). Exogenous antithrombotics should be used when a patient has an identified risk for thrombotic complications, and the risks of thrombosis outweigh possible adverse effects of the therapy. Much of the decision on therapy depends on the underlying condition, perceived length of therapy, and underlying hemostatic status of the patient. Although oral platelet inhibitors are typically easier for long-term administration by owners, heparin may be more advantageous for in-hospital use because many conditions (e.g., sepsis) may be accompanied by thrombocytopenia. Although commonly prescribed for people with thrombophilia, warfarin therapy can prove challenging for the clinician not experienced in its behavior in small animals. It has the added disadvantage of being dosed orally, a hindrance in some critically ill patients (see Chapters 167 and Chapter 168).

Inflammatory conditions Although dogs and cats with inflammatory conditions have a known risk for thrombotic complications, no veterinary studies are currently available to help identify specific populations in which thromboprophylaxis may prove most advantageous. Coagulation testing should be evaluated frequently in these patients, with particular attention paid to those exhibiting more than one significant predisposition (e.g., a patient with cancer that develops a source of sepsis or hypoxemia). A drop in circulating platelet count or at least 20% prolongation in aPTT should raise concerns for the early stages of a consumptive coagulopathy. In a study of thromboplastin-induced DIC in dogs, high doses of LMWH (0.9 ± 0.07 anti-FXa U/ml) were required to decrease further consumptive coagulopathy when administered 2 hours after initiation.205 This highlights the difficulty in slowing the consumption of coagulation components once DIC is initiated. Unfortunately, highdose heparin therapy after initiation of a consumptive coagulopathy may worsen the clinical picture, and the identification of the hypercoagulable phase when heparin therapy may be most useful remains difficult.

Protein-losing nephropathy Despite the long-standing association of thrombosis with PLN, no studies have assessed antithrombotic interventions. Any patient with PLN or NS, and likely those with significant proteinuria, may benefit from some form of thromboprophylaxis (unless contraindicated). Given the broad nature of this thrombophilia and lack of utility for AT as a sole indicator, this should not be the only measure of a patient’s risk for thrombotic complications. Historically, these patients have been treated with platelet inhibitors such as aspirin206; however, more aggressive therapy may be warranted. In cases of markedly decreased AT activity, heparins may have less efficacy and other anticoagulants (e.g., warfarin) may be needed for more substantial anticoagulation. Larger studies are needed to better define the risk of thrombotic complications in the face of antithrombotics.

Immune-mediated hemolytic anemia Various thromboprophylactics have been reported for use in IMHA, including aspirin,114,207 clopidogrel,207 and heparin.208 In one retrospective study, aspirin was associated with a survival benefit in IMHA dogs. Heparin was also evaluated in this study, but a lower dose was used compared with current recommendations.114 UFH was given at 300 IU/kg SC q6h to 18 dogs with IMHA. Half (three of six) of necropsied nonsurvivors had thrombi identified. One of these dogs was 2 months postdiagnosis and no longer receiving any antithrombotics. Only 8 out of 18 dogs attained target anti-Xa at this dosing protocol.208 Adjusted-dose heparin therapy (targeting an anti-Xa activity of 0.35 to 0.7 U/ml) may improve survival from IMHA by limiting thrombotic complications.209 Clopidogrel recently was evaluated alone and with aspirin in dogs with primary IMHA.206 There was one dog in each group receiving aspirin or clopidogrel (monotherapy) with thrombotic complications. None of the patients on the combination therapy developed apparent thrombotic disease.

Hypercortisolemia Given the conflicting evidence regarding hypercortisolemiaassociated thrombophilia, testing for markers to support a prothrombotic state seems prudent before anticoagulation. Clinicians should be vigilant when other procoagulant insults (e.g., surgery or systemic infection) occur in patients with hypercortisolemia because it is more likely that multiple contributors are involved with thrombosis in these patients.

Cardiomyopathies Long-term thromboprophylaxis in cats with cardiomyopathies traditionally has been with an oral platelet inhibitor. There was no difference in survival times for cats with ATE treated with high-dose (at least 40 mg per cat q24-72h) or low-dose aspirin (5 mg per cat q72h) therapy, although there were fewer side effects in the low-dose group, and cats in both groups suffered a second ATE.134 The most effective dose of aspirin for inhibition of platelet aggregation in cats remains unclear,210 but clopidogrel does result in decreased platelet aggregation and platelet serotonin release in cats.211,212 Clopidogrel is also effective in dogs when administered at 1 mg/kg PO q24h.213 LMWH (dalteparin or enoxaparin) have been administered to cats with cardiomyopathy, but the effective doses, dosing interval, and anti-Xa ranges for these drugs have yet to be determined definitively.214-216 Thrombolysis may be considered for any recent onset ATE with signs of ischemia. Studies of cats undergoing thrombolysis suggest a similar survival compared with conservative management, with a heightened risk of complications.134,217-219 More recently, tPA administration resulted in pulse restoration for 53% of affected limbs within 24 hours.217

Neoplasia The risk of thrombotic complications in veterinary patients with neoplasia is similar to that for people. Despite the known risk, prediction of thrombotic complications in animals with particular tumor types remains challenging. Tumors of epithelial cell origin and hemic neoplasms (e.g., lymphoma, leukemia, histiocytic sarcoma, hemangiosarcoma) are among the most commonly implicated; however, any cancer may promote thrombus formation resulting from alterations in vascular flow, endothelial damage, inflammation, or a combination of all three. Various antithrombotics (e.g., warfarin220 and aspirin221) have been implicated in decreasing the rate of metastasis with cancer, presumably by preventing metastasis on thrombi, activated platelets,

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or possibly MPs. The role of antithrombotics in veterinary species requires further study to determine whether a benefit or detriment in tumor behavior may exist. Coagulation testing is advised in patients with known predilections (e.g., hemic neoplasms or carcinoma), especially in those with greater tumor burdens (e.g., disseminated or metastatic disease). Antithrombotics should be considered when testing suggests a risk for (or ongoing) thrombin generation (e.g., elevated D-dimer or TAT) in concert with a clinical suspicion.

Isolated brain injury Hypertonic saline (HTS)/dextran administration decreases leukocyte cell-surface adhesion molecules, degranulation markers on neutrophils and monocytes, vascular and intercellular adhesion molecules, TNF-α, TF, and D-dimer in severely brain injured patients given HTS/dextran before hospital presentation.222 Many of these benefits are attributed to the immunomodulatory effects of HTS and from earlier restoration of normal cerebral perfusion pressure. Recombinant factor VIIa (rVIIa) has been shown to attenuate the hemorrhagic phenotype of the TBI-induced coagulopathy in people. Patients receiving rFVIIa used less plasma, required fewer days of mechanical ventilation, and had a decreased cost of hospitalization.223 rFVIIa use also may allow shorter times to neurosurgical intervention224 and lower mortality rates when patients need transfer to another hospital for definitive care.225 The TBI-induced coagulopathy described in humans has not been described in clinical veterinary cases. Given the nature of this disorder, clinicians should be diligent in assessing the hemostatic status of TBI patients, particularly those with more severe injury. Most people exhibit significant coagulopathy at the time of hospital presentation, suggesting that the management in veterinary patients would be aimed largely at directed therapy for consumptive coagulopathy.

CONCLUSION Hypercoagulability or thrombophilia describes a tendency for pathologic thrombus formation. Acquired thrombophilias exist in veterinary medicine and can be caused by commonly recognized conditions (e.g., proteinuria). Any perturbation in the delicate balance of coagulation may beget a thrombophilia. Early recognition of risk relies on an index of clinical suspicion and laboratory testing, although a thrombophilia is noted in many patients after exhibiting thrombotic complications or a consumptive coagulopathy. Despite the prevalence of these conditions, large prospective studies to guide intervention are lacking.

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PART XI  •  HEMATOLOGIC DISORDERS 73. de Laforcade AM, Freeman LM, Shaw SP, et al: Hemostatic changes in dogs with naturally occurring sepsis, J Vet Intern Med 17(5):674-679, 2003. 74. de Laforcade AM, Rozanski EA, Freeman LM, et al: Serial evaluation of protein C and antithrombin in dogs with sepsis, J Vet Intern Med 22(1):26-30, 2008. 75. Jesser LR, Wiinberg B, Kjelgaard-Hansen M, et al: Thrombin-activatable fibrinolysis inhibitor activity in healthy and diseased dogs, Vet Clin Pathol 39(3):296-301, 2010. 76. Eralp O, Yilmaz Z, Failing K, et al: Effect of experimental endotoxemia on thrombelastography parameters, secondary and tertiary hemostasis in dogs, J Vet Intern Med 25(3):524-531, 2011. 77. Yilmaz Z, Ilcoi YO, Ulus IH: Investigation of diagnostic importance of platelet closure times measured by Platelet Function Analyzer—PFA 100 in dogs with endotoxemia, Berl Munch Tierztl Wochenschr 118(7-8):341-348, 2005. 78. Winter RL, Sedacca CD, Adams A, et al: Aortic thrombosis in dogs: presentation, therapy, and outcome in 26 cases, J Vet Cardiol 14(2):333342, 2012. 79. Laurenson MP, Hopper K, Herrera MA, et al: Concurrent diseases and conditions in dogs with splenic vein thrombosis, J Vet Intern Med 24(6):1298-1304, 2010. 80. Respess M, O’Toole TE, Taeymans O, et al: Portal vein thrombosis in 33 dogs: 1998-2011, J Vet Intern Med 26(2):230-237, 2012. 81. Lake-Bakaar GA, Johnson EG, Griffiths LG: Aortic thrombosis in dogs: 31 cases (2000-2010), J Am Vet Med Assoc 241(7):910-915, 2012. 82. Johnson LR, Lappin MR, Baker DC: Pulmonary thromboembolism in 29 dogs: 1985-1995, J Vet Intern Med 1913(4):338-345, 1999. 83. Cook AK, Cowgill LD: Clinical and pathological features of proteinlosing glomerular disease in the dog: a review of 137 cases (1985-1992), J Am Anim Hosp Assoc 32(4):313-322, 1996. 84. Remuzzi G, Mecca G, Marchesi D, et al: Platelet hyperaggregability and the nephrotic syndrome, Thromb Res 16(3-4):345-354, 1979. 85. Sirolli V, Ballone E, Garofalo D, et al: Platelet activation markers in patients with nephrotic syndrome. A comparative study of different platelet function tests, Nephron 91(3):424-430, 2002. 86. Thomson C, Forbes CD, Prentice CR, et al: Changes in blood coagulation and fibrinolysis in the nephrotic syndrome, Q J Med 43(171):399407, 1974. 87. Vaziri ND, Branson HE, Ness R: Changes in coagulation factors IX, VIII, VII, X, and V in nephrotic syndrome, Am J Med Sci 280(3):167-171, 1980. 88. Kanfer A: Coagulation factors in nephrotic syndrome, Am J Nephrol 10(suppl 1):63-68, 1990. 89. Kauffman RH, Veltkamp JJ, Van Tilburg NH, et al: Acquired antithrombin III deficiency and thrombosis in the nephrotic syndrome, Am J Med 65(4):607-613, 1978. 90. Robert A, Olmer M, Sampol J, et al: Clinical correlation between hypercoagulability and thrombo-embolic phenomena, Kidney Int 31(3):830835, 1987. 91. Mehls O, Andrassy K, Koderisch J, et al: Hemostasis and thromboembolism in children with nephrotic syndrome: differences from adults, J Pediatr 110(6):862-867, 1987. 92. Cosio FG, Harker C, Batard MA, et al: Plasma concentration of the natural anticoagulants protein C and protein S in patients with proteinuria, J Lab Clin Med 106(2):218-222, 1985. 93. Mannucci PM, Valsecchi C, Bottasso B, et al: High plasma levels of protein C activity and antigen in the nephrotic syndrome, Thromb Haemost 55(1):31-33, 1986. 94. Ariens RA, Moia M, Rivolta E, et al: High levels of tissue factor pathway inhibitor in patients with nephrotic proteinuria, Thromb Haemost 82(3):1020-1023, 1999. 95. Malyszko J, Malyszko JS, Mysliwiec M: Markers of endothelial cell injury and thrombin activatable fibrinolysis inhibitor in nephrotic syndrome, Blood Coagul Fibrinolysis 13(7):615-621, 2002. 96. Yoshida Y, Shiiki H, Iwano M, et al: Enhanced expression of plasminogen activator inhibitor 1 in patients with nephrotic syndrome, Nephron 88(1):24-29, 2001.

97. Zhang Q, Zeng C, Fu Y, et al: Biomarkers of endothelial dysfunction in patients with primary focal segmental glomerulosclerosis, Nephrology 17(4):338-345, 2012. 98. Green RA, Kabel AL: Hypercoagulable state in three dogs with nephrotic syndrome: role of acquired antithrombin III deficiency, J Am Vet Med Assoc 181(9):914-917, 1982. 99. Thompson MF, Scott-Moncrieff JC, Brooks MB: Effect of a single plasma transfusion on thromboembolism in 13 dogs with primary immunemediated hemolytic anemia, J Am Anim Hosp Assoc 40(6):446-454, 2004. 100. Carr AP, Panciera DL, Kidd L: Prognostic factors for mortality and thromboembolism in canine immune-mediated hemolytic anemia: a retrospective study of 72 dogs, J Vet Intern Med 16(5):504-509, 2002. 101. Scott-Moncrieff MA, McCullough SM, Brooks MB: Hemostatic abnormalities in dogs with primary immune-mediated hemolytic anemia, J Am Anim Hosp Assoc 37(3):220-227, 2001. 102. McManus PM, Craig LE: Correlation between leukocytosis and necropsy findings in dogs with immune-mediated hemolytic anemia: 34 cases (1994-1999), J Am Vet Med Assoc 218(8):1308-1313, 2001. 103. Sinnott VB, Otto CM: Use of thromboelastography in dogs with immune-mediated hemolytic anemia: 39 cases (2000-2008), J Vet Emerg Crit Care 19(5):484-488, 2009. 104. Goggs R, Wiinberg B, Kjelgaard-Hansen M, et al: Serial assessment of the coagulation status of dogs with immune-mediated haemolytic anaemia using thromboelastography, Vet J 191(3):347-353, 2012. 105. Fenty RK, de Laforcade AM, Shaw SP, et al: Identification of hypercoagulability in dogs with primary immune-mediated hemolytic anemia by means of thromboelastography, J Am Vet Med Assoc 238(4):463-467, 2011. 106. Setty BN, Betal SG, Zhang J, et al: Heme induces endothelial tissue factor expression: potential role in hemostatic activation in patients with hemolytic anemia, J Thromb Haemost 6(12):2202-2209, 2008. 107. Reiter CD, Wang X, Tanus-Santos JE, et al: Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease, Nat Med 8(12):13831389, 2002. 108. Minneci PC, Deans KJ, Zhi H, et al: Hemolysis-associated endothelial dysfunction mediated by accelerated NO inactivation by decompartmentalized oxyhemoglobin, J Clin Invest 115(12):3409-3417, 2005. 109. Kato GJ, McGowan V, Machado RF, et al: Lactate dehydrogenase as a biomarker of hemolysis-associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension and death in patients with sickle cell disease, Blood 107(6):2279-2285, 2006. 110. Wagener FA, Feldman E, deWitte T, et al: Heme induces the expression of adhesion molecules ICAM-1, VCAM-1, and E-selectin in vascular endothelial cells, Proc Soc Exp Biol Med 216(3):456-463, 1997. 111. Horne MK III, Cullinane AM, Merryman PK, et al: The effect of red blood cells on thrombin generation, Br J Haematol 133(4):403-408, 2006. 112. Weiss DJ, Brazzell JL: Detection of activated platelets in dogs with primary immune-mediated hemolytic anemia, J Vet Intern Med 20(3):682-686, 2006. 113. Ridyard AE, Shaw DJ, Milne EM: Evaluation of platelet activation in canine immune-mediated haemolytic anaemia, J Small Anim Pract 51(6):296-304, 2010. 114. Weinkle TK, Cener SA, Randolph JF, et al: Evaluation of prognostic factors, survival rates, and treatment protocols for immune-mediated hemolytic anemia in dogs: 151 cases (1993-2002), J Am Vet Med Assoc 226(11):1869-1880, 2005. 115. Rand JH, Senzel L: Antiphospholipid antibodies and the antiphospholipid syndrome. In Hemostasis and thrombosis: basic principles and clinical practice, ed 5, Philadelphia, 2006, Lippincott, Williams & Wilkins, pp 1621-1636. 116. Levin JS, Branch DW, Rauch J: The antiphospholipid syndrome, New Engl J Med 346(10):752-763, 2002. 117. Miller AG, Dow S, Long L, et al: Antiphospholipid antibodies in dogs with immune mediated hemolytic anemia, spontaneous thrombosis, and hyperadrenocorticism, J Vet Intern Med 26(3):614-623, 2012. 118. Nielson LN, Wiinberg B, Kjelgaard-Hansen M, et al: The presence of antiphospholipid antibodies in healthy Bernese Mountain Dogs, J Vet Intern Med 25(6):1258-1263, 2011.

CHAPTER 104  •  Hypercoagulable States 119. Stone MS, Johnstone IB, Brooks M, et al: Lupus-type “anticoagulant” in a dog with hemolysis and thrombosis, J Vet Intern Med 8(1):57-61, 1994. 120. Van Zaane B, Nur E, Squizzato A, et al: Hypercoagulable state in Cushing’s syndrome: a systematic review, J Clin Endocrinol Metab 94(8):2743-2750, 2009. 121. Dal Bo Zanon R, Fornasiero L, Boscaro M, et al: Increased factor VIII associated activities in Cushing’s syndrome: a probable hypercoagulable state, Thromb Haemost 47(2):116-117, 1982. 122. Casonato A, Pontara E, Boscaro M, et al: Abnormalities of von Willebrand factor are also part of the prothrombotic state of Cushing’s syndrome, Blood Coagul Fibrinol 10(3):145-151, 1999. 123. Erem C, Nuhoglu I, Yilmaz M, et al: Blood coagulation and fibrinolysis in patients with Cushing’s syndrome: increased plasminogen activator inhibitor-1 and unchanged thrombin-activatable fibrinolysis inhibitor levels, J Endocrinol Invest 32(2):169-174, 2009. 124. Brotman DJ, Girod JP, Posch A, et al: Effects of short-term glucocorticoids on hemostatic factors in healthy volunteers, Thromb Res 118(2):247-252, 2006. 125. Fatti LM, Bottasso B, Invitti C, et al: Markers of activation of coagulation and fibrinolysis in patients with Cushing’s syndrome, J Endocrinol Invest 23(3):145-150, 2000. 126. Franchini M, Lippi G, Manzato F, et al: Hemostatic abnormalities in endocrine and metabolic disorders, Eur J Endocrinol 162(3):439-451, 2010. 127. Sjoberg HE, Blomback M, Granberg PO: Thromboembolic complications, heparin treatment and increase in coagulation factors in Cushing’s syndrome, Acta Med Scand 199(1-2):95-98, 1976. 128. Boswood A, Lamb CR, White RN: Aortic and iliac thrombosis in six dogs, J Small Anim Pract 41(3):109-114, 2000. 129. Jacoby RC, Owings JT, Ortega T, et al: Biochemical basis for the hypercoagulable state seen in Cushing syndrome, Arch Surg 136(9):10031006, 2001. 130. Feldman BF, Rasedee A, Feldman EC: Haemostatic abnormalities in canine Cushing’s syndrome, Res Vet Sci 41(2):228-230, 1986. 131. Klose TC, Creevy KE, Brainard BM: Evaluation of coagulation status in dogs with naturally occurring canine hyperadrenocorticism, J Vet Emerg Crit Care 21(6):625-632, 2011. 132. Rose LJ, Dunn ME, Allegret V, et al: Effects of prednisone administration on coagulation variables in healthy Beagle dogs, Vet Clin Pathol 40(4):426-434, 2011. 133. Schoeman JP: Feline distal aortic thromboembolism: a review of 44 cases (1990-1998), J Feline Med Surg 1(4):221-231, 1999. 134. Smith SA, Tobias AH, Jacob KA, et al: Arterial thromboembolism in cats: acute crisis in 127 cases (1992-2001) and long-term management with low-dose aspirin in 24 cases, J Vet Intern Med 17(1):73-83, 2003. 135. Usechak PJ, Bright JM, Day TK: Thrombotic complications associated with atrial fibrillation in three dogs, J Vet Cardiol 14(3):453-458, 2012. 136. Nakamura Y, Nakamura K, Fukushima-Kusano K, et al: Tissue factor expression in atrial endothelia associated with nonvalvular atrial fibrillation: possible involvement in intracardiac thrombogenesis, Thromb Res 111(3):137-142, 2003. 137. Armesilla AL, Lorenzo E, Gomez del Arco P, et al: Vascular endothelial growth factor activates nuclear factor of activated T cells in human endothelial cells: a role for tissue factor gene expression, Mol Cell Biol 19(3):2032-2043, 1999. 138. Davis ME, Cai H, Drummond GR, et al: Shear stress regulates endothelial nitric oxide synthase expression through c-Src by divergent signaling pathways, Circ Res 89(11):1073-1080, 2001. 139. Conway DS, Buggins P, Hughes E, et al: Prognostic significance of raised plasma levels of interleukin-6 and C-reactive protein in atrial fibrillation, Am Heart J 148(3):462-466, 2004. 140. Zhang Z, Zhang C, Wang H, et al: N-3 polyunsaturated fatty acids prevents atrial fibrillation by inhibiting inflammation in a canine sterile pericarditis model, Int J Cardiol 153(1):14-20, 2011. 141. Stokol T, Brooks M, Rush JE, et al: Hypercoagulability in cats with cardiomyopathy, J Vet Intern Med 22(3):546-552, 2008. 142. Bedard C, Lanevschi-Pietersma A, Dunn M: Evaluation of coagulation markers in the plasma of healthy cats and cats with asymptomatic hypertrophic cardiomyopathy, Vet Clin Pathol 36(2):167-172, 2007.

143. Helenski CA, Ross JN: Platelet aggregation in feline cardiomyopathy, J Vet Intern Med 1(1):24-28, 1987. 144. Welles EG, Boudreaux MK, Crager CS, et al: Platelet function and antithrombin, plasminogen, and fibrinolytic activities in cats with heart disease, Am J Vet Res 55(5):619-627, 1994. 145. Jandrey KE, Norris JW, MacDonald KA, et al: Platelet function in clinically healthy cats and cats with hypertrophic cardiomyopathy: analysis using the platelet function analyzer-100, J Vet Clin Pathol 37(4):385-388, 2008. 146. Wray JD, Bestbier M, Miller J, et al: Aortic and iliac thrombosis associated with angiosarcoma of skeletal muscle in a dog, J Small Anim Pract 47(5):272-277, 2006. 147. Ledieu D, Palazzi X, Marchal T, et al: Acute megakaryoblastic leukemia with erythrophagocytosis and thrombosis in a dog, Vet Clin Pathol 34(1):52-56, 2005. 148. Saridomichelakis MN, Koutinas CK, Souftas V, et al: Extensive caudal vena cava thrombosis secondary to unilateral renal tubular cell carcinoma in a dog, J Small Anim Pract 45(2):108-112, 2004. 149. Santamarina G, Espino L, Vila M, et al: Aortic thromboembolism and retroperitoneal hemorrhage associated with a pheochromocytoma in a dog, J Vet Intern Med 17(6):917-922, 2003. 150. LaRue MJ, Murtaugh RJ: Pulmonary thromboembolism in dogs: 47 cases (1986-1987), J Am Vet Med Assoc 197(10):1368-1372, 1990. 151. Schermerhorn T, Pembleton-Corbett JR, Kornreich B: Pulmonary thromboembolism in cats, J Vet Intern Med 18(4):533-535, 2004. 152. Currao RL, Buote NJ, Flory AB, et al: Mesenteric vascular thrombosis associated with disseminated abdominal visceral hemangiosarcoma in a cat, J Am Anim Hosp Assoc 47(6):168-172, 2011. 153. Rogers CL, O’Toole TE, Keating JH, et al: Portal vein thrombosis in cats: 6 cases (2001-2006), J Vet Intern Med 22(2):282-287, 2008. 154. Norris CR, Griffey SM, Samii VF: Pulmonary thromboembolism in cats: 29 cases (1987-1997), J Am Vet Med Assoc 215(11):1650-1654, 1999. 155. Sottiaux J, Franck M: Cranial vena caval thrombosis secondary to invasive mediastinal lymphosarcoma in a cat, J Small Anim Pract 39(7):352355, 1998. 156. Maruyama H, Miura T, Sakai M, et al: The incidence of disseminated intravascular coagulation in dogs with malignant tumor, J Vet Med Sci 66(5):573-575, 2004. 157. Hammer AS, Couto CG, Swardson C, et al: Hemostatic abnormalities in dogs with hemangiosarcoma, J Vet Intern Med 5(1):11-14, 1991. 158. Contrino J, Hair G, Kreutzer DL, et al: In situ detection of tissue factor in vascular endothelial cells: correlation with the malignant phenotype of human breast disease, Nat Med 2(2):209-225, 1996. 159. Rak J: Microparticles in cancer, Semin Thromb Hemost 36(8):888-906, 2010. 160. Zhang Y, Deng Y, Luther T, et al: Tissue factor controls the balance of angiogenic and antiangiogenic properties of tumor cells in mice, J Clin Invest 94(3):1320-1327, 1994. 161. Hembrough TA, Swartz GM, Papathanassiu A, et al: Tissue factor/factor VIIa inhibitors block angiogenesis and tumor growth through a nonhemostatic mechanism, Cancer Res 63(11):2997-3000, 2003. 162. Regina S, Valentin JB, Lachot S, et al: Increased tissue factor expression is associated with reduced survival in non-small cell lung cancer and with mutations of TP53 and PTEN, Clin Chem 55(10):1834-1842, 2009. 163. Ryden L, Grabau D, Schaffner F, et al: Evidence for tissue factor phosphorylation and its correlation with protease-activated receptor expression and the prognosis of primary breast cancer, Int J Cancer 126(10):2330-2340, 2010. 164. Yamashita H, Kitayama J, Ishikawa M, et al: Tissue factor expression is a clinical indicator of lymphatic metastasis and poor prognosis in gastric cancer with intestinal phenotype, J Surg Oncol 95(4):423-431, 2007. 165. Poon RT, Lau CP, Ho JW, et al: Tissue factor expression correlates with tumor angiogenesis and invasiveness in human hepatocellular carcinoma, Clin Cancer Res 9(14):5339-5345, 2003. 166. Kristensen AT, Wiinberg B, Jessen LR, et al: Evaluation of human recombinant tissue factor-activated thrombelastography in 49 dogs with neoplasia, J Vet Intern Med 22(1):140-147, 2008. 167. Andreasen EB, Tranholm M, Wiinberg B, et al: Haemostatic alterations in a group of canine cancer patients are associated with cancer type and disease progression, Acta Veterinaria Scandinavica 54:3, 2012.

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PART XI  •  HEMATOLOGIC DISORDERS 168. Saavedra PV, Garcia AL, Lopez SZ, et al:Hemostatic abnormalities in dogs with carcinoma: a thromboelastographic characterization of hypercoagulability, Vet J 190(2):e78-83, 2011. 169. Stockhaus C, Kohn B, Rudolph R, et al: Correlation of haemostatic abnormalities with tumour stage and characteristics in dogs with mammary carcinoma, J Small Anim Pract 40(7):326-331, 1999. 170. O’Donnell MR, Slichter SJ, Weiden PL, et al: Platelet and fibrinogen kinetics in canine tumors, Cancer Res 41(4):1379-1383, 1981. 171. Kuzi S, Segev G, Haruvi E, et al: Plasma antithrombin activity as a diagnostic and prognostic indicator in dogs: a retrospective study of 149 dogs, J Vet Intern Med 24(3):587-596, 2010. 172. Thomas JS, Rogers KS: Platelet aggregation and adenosine triphosphate secretion in dogs with untreated multicentric lymphoma, J Vet Intern Med 13(4):319-322, 1999. 173. McNiel EA, Ogilvie GK, Fettman MJ, et al: Platelet function in dogs with malignancies, J Vet Intern Med 11(3):178-182, 1997. 174. Laroche M, Kutcher ME, Huang MC, et al: Coagulopathy after traumatic brain injury, Neurosurgery 70(6):1334-1345, 2012. 175. Stein SC, Chen XH, Sinson GP, et al: Intravascular coagulation: a major second insult in nonfatal traumatic brain injury, J Neurosurg 97(6): 1373-1377, 2002. 176. Chiaretti A, Piastra M, Pulitano S, et al: Prognostic factors and outcome of children with severe head injury: an 8-year experience, Child’s Nerv Syst 18(3-4):129-136, 2002. 177. Stein SC, Young GS, Talucci RC, et al: Delayed brain injury after head trauma: significance of coagulopathy, Neurosurgery 30(2):160-165, 1992. 178. Wafaisade A, Lefering R, Tjardes T, et al: Acute coagulopathy in isolated blunt traumatic brain injury, Neurocrit Care 12(2):211-219, 2010. 179. Lustenberger T, Talving P, Kobayashi L, et al: Time course of coagulopathy in isolated severe traumatic brain injury, Injury 41(9):924-928, 2010. 180. Eddleston M, de la Torre JC, Oldstone MB, et al: Astrocytes are the primary source of tissue factor in the murine central nervous system: a role for astrocytes in cerebral hemostasis, J Clin Invest 92(1):349-358, 1993. 181. Utter GH, Owings JT, Jacoby RC, et al: Injury induces increased monocyte expression of tissue factor: factors associated with head injury attenuate the injury-related monocyte expression of tissue factor, J Trauma 52(6):1071-1077, 2002. 182. Nekludov M, Bellander BM, Blomback M, et al: Platelet dysfunction in patients with severe traumatic brain injury, J Neurotrauma 24(11): 1699-1706, 2007. 183. Murshid WR, Gader AG: The coagulopathy in acute head injury: comparison of cerebral versus peripheral measurements of haemostatic activation markers, Br J Neurosurg 16(4):362-369, 2002. 184. Morel N, Morel O, Petit L, et al: Generation of procoagulant microparticles in cerebrospinal fluid and peripheral blood after traumatic brain injury, J Trauma 64(3):698-704, 2008. 185. Davis KP, Musunuru H, Walsh M, et al: Platelet dysfunction is an early marker for traumatic brain injury-induced coagulopathy, Neurocrit Care 18(2):201-208, 2013. 186. Jacoby RC, Owings JT, Holmes J, et al: Platelet activation and function after trauma, J Trauma 51(4):639-647, 2001. 187. Awasthi D, Rock WA, Carey ME, et al: Coagulation changes after an experimental missile wound to the brain in the cat, Surg Neurol 36(6):441-446, 1991. 188. Avidan MS, Levy JH, Scholz J, et al: A phase III, double-blinded, placebo-controlled, multicenter study on the efficacy of recombinant human antithrombin in heparin-resistant patients scheduled to undergo cardiac surgery necessitating cardiopulmonary bypass, Anesthesiology 102(2):276-284, 2005. 189. Warren BL, Eid A, Singer P, et al: Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial, J Am Med Assoc 286(15):1869-1878, 2001. 190. Kienast J, Juers M, Wiedermann CJ, et al: Treatment effects of high-dose antithrombin without concomitant heparin in patients with severe sepsis with or without disseminated intravascular coagulation, J Thromb Haemost 4(1):90-97, 2006.

191. Isobe H, Okajima K, Uchiba M, et al: Activated protein C prevents endotoxin-induced hypotension in rats by inhibiting excessive production of nitric oxide, Circulation 104(10):1171-1175, 2001. 192. De Backer D, Verdant C, Chierego M, et al: Effects of drotrecogin alfa activated on microcirculatory alterations in patients with severe sepsis, Crit Care Med 34(7):1918-1924, 2006. 193. Taylor FBJ, Chang A, Esmon CT, et al: Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon, J Clin Invest 79(3):918-925, 1987. 194. Ranieri VM, Thompson BT, Barie PS, et al: Drotrecogin alfa (activated) in adults with septic shock, N Eng J Med 366(22):2055-2064, 2012. 195. Holst J, Lindblad B, Bergqvist D, et al: Antithrombotic effect of recombinant truncated tissue factor pathway inhibitor (TFPI1-161) in experimental venous thrombosis- a comparison with low molecular weight heparin, Thromb Haemost 71(2):214-219, 1994. 196. Abendschein DR, Meng Y, Torr-Brown S, et al: Maintenance of coronary patency after fibrinolysis with tissue factor pathway inhibitor, Circulation 92(4):944-949, 1995. 197. Camerota AJ, Creasey AA, Patla V, et al: Delayed treatment with recombinant human tissue factor pathway inhibitor improves survival in rabbits with gram-negative peritonitis, J Infect Dis 177(3):668-676, 1998. 198. Abraham E, Reinkart K, Opal S, et al: Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial, J Am Med Assoc 290(2):238-247, 2003. 199. Abraham E, Reinkart K, Svoboda P, et al: Assessment of the safety of recombinant tissue factor pathway inhibitor in patients with severe sepsis: a multicenter, randomized, placebo-controlled, single-blind, dose escalating study, Crit Care Med 29(11):2081-2089, 2001. 200. Wunderink RG, Laterre PF, Francois B, et al: Recombinant tissue factor pathway inhibitor in severe community-acquired pneumonia: a randomized trial, Am J Respir Crit Care Med 183(11):1561-1568, 2011. 201. Yagasaki H, Kato M, Shimozawa K, et al: Treatment responses for disseminated intravascular coagulation in 25 children treated with recombinant thrombomodulin: a single institutional experience, Thromb Res 130(6):e289-293, 2012. 202. Ikezoe T, Takeuchi A, Isaka M, et al: Recombinant human soluble thrombomodulin safely and effectively rescues acute promyelocytic leukemia patients from disseminated intravascular coagulation, Leuk Res 36(11):1398-1402, 2012. 203. Saito H, Maruyama I, Shimazaki S, et al: Efficacy and safety of recombinant human soluble thrombomodulin (ART-123) in disseminated intravascular coagulation: results of a phase III, randomized, doubleblinded clinical trial, J Thromb Haemost 5(1):31-41, 2007. 204. Ogawa Y, Yamakawa K, Ogura H, et al: Recombinant human soluble thrombomodulin improves mortality and respiratory dysfunction in patients with severe sepsis, J Trauma Acute Care Surg 72(5):1150-1157, 2012. 205. Mischke R, Fehr M, Nolte I: Efficacy of low molecular weight heparin in a canine model of thromboplastin-induced acute disseminated intravascular coagulation, Res Vet Sci 79(1):69-76, 2005. 206. Grauer GF, Greco DS, Getzy DM, et al: Effects of enalapril versus placebo as a treatment for canine idiopathic glomerulonephritis, J Vet Intern Med 14(5):526-533, 2000. 207. Mellett AM, Nakamura RK, Bianco D: A prospective study of clopidogrel therapy in dogs with primary immune-mediated hemolytic anemia, J Vet Intern Med 25(1):71-75, 2011. 208. Breuhl EL, Moore G, Brooks MB, et al: A prospective study of unfractionated heparin therapy in dogs with primary immune-mediated hemolytic anemia, J Am Anim Hosp Assoc 45(3):125-133, 2009. 209. Helmond SE, Polzin DJ, Armstrong PJ, et al: Treatment of immunemediated hemolytic anemia with individually adjusted heparin dosing in dogs, J Vet Intern Med 24(3):597-605, 2010. 210. Cathcart CJ, Brainard BM, Reynolds LR, et al: Lack of inhibitory effect of acetylsalicylic acid and meloxicam on whole blood platelet aggregation in cats, J Vet Emerg Crit Care 22(1):99-106, 2012. 211. Hogan DF, Andrews DA, Green HW, et al: Antiplatelet effects and pharmacodynamics of clopidogrel in cats, J Am Vet Med Assoc 225(9):14061411, 2004.

CHAPTER 104  •  Hypercoagulable States 212. Hamel-Jolette A, Dunn M, Bedard C: Plateletworks: a screening assay for clopidogrel therapy monitoring in healthy cats, Can J Vet Res 73(1):73-76, 2009. 213. Brainard BM, Kleine SA, Papich MG, et al: Pharmacodynamic and pharmacokinetic evaluation of clopidogrel and the carboxylic acid metabolite SR 26334 in healthy dogs, Am J Vet Res 71(7):822-830, 2010. 214. Smith CE, Rozanski EA, Freeman LM, et al: Use of low molecular weight heparin in cats: 57 cases (1999-2003), J Am Vet Med Assoc 225(8):12371241, 2004. 215. Vargo CL, Taylor SM, Carr A, et al: The effect of a low molecular weight heparin on coagulation parameters in healthy cats, Can J Vet Res 73(2):132-136, 2009. 216. Alwood AJ, Downend AB, Brooks MB, et al: Anticoagulant effects of low-molecular-weight heparins in healthy cats, J Vet Int Med 21(3):378387, 2007. 217. Welch KM, Rozanski EA, Freeman LM, et al: Prospective evaluation of tissue plasminogen activator in 11 cats with arterial thromboembolism, J Feline Med Surg 12(2):122-128, 2010. 218. Moore KE, Morris N, Dhupa N, et al: Retrospective study of streptokinase administration in 46 cats with arterial thromboembolism, J Vet Emerg Crit Care 10(4):245-257, 2000. 219. Laste NJ, Harpster NK: A retrospective study of 100 cases of feline distal aortic thromboembolism 1977-1993, J Am Anim Hosp Assoc 31(6):492-500, 1995. 220. Maat B, Hilgard P: Anticoagulants and experimental metastasesevaluation of antimetastatic effects in different model systems, J Cancer Res Clin Oncol 101(3):275-283, 1981. 221. Gastpar H: Platelet-cancer cell interaction in metastasis formation: a possible therapeutic approach to metastasis prophylaxis, J Med 8(2): 103-114, 1977. 222. Rhind SG, Crnko NT, Baker AJ, et al: Prehospital resuscitation with hypertonic saline-dextran modulates inflammatory, coagulation and endothelial activation marker profiles in severe traumatic brain injured patients, J Neuroinflammation 7:5, 2010. 223. Stein DM, Dutton RP, Kramer ME, et al: Reversal of coagulopathy in critically ill patients with traumatic brain injury: recombinant factor VIIa is more cost-effective than plasma, J Trauma 66(1):63-72, 2009. 224. Stein DM, Dutton RP, Kramer ME, et al: Recombinant factor VIIa: decreasing time to intervention in coagulopathic patients with severe traumatic brain injury, J Trauma 64(3):620-627, 2008. 225. Brown CV, Sowery L, Curry E, et al: Recombinant factor VIIa to correct coagulopathy in patients with traumatic brain injury presenting to outlying facilities before transfer to the regional trauma center, Am Surg 78(1):57-60, 2012. 226. Teitel JM, Bauer KA, Lau HK, et al: Studies of the prothrombin activation pathway utilizing radioimmunoassays for the F2/F1+2 fragment and thrombin-antithrombin complex, Blood 59(5):1086-1097, 1982. 227. Nossel HL, Yudelman I, Canfield RE, et al: Measurement of fibrinopeptide A in human blood, J Clin Invest 54(1):43-53, 1974. 228. Bilezikian SB, Nossel LH, Butler BP Jr, et al: Radioimmunoassay of human fibrinopeptide B and kinetics of cleavage by different enzymes, J Clin Invest 56(2):438-445, 1975. 229. Bauer KA, Kass BL, ten Cate H, et al: Factor IX is activated in vivo by the tissue factor mechanism, Blood 764(4):731-736, 1990. 230. Stokol T, Daddona JL, Choi B: Evaluation of tissue factor procoagulant activity on the surface of feline leukocytes in response to treatment with lipopolysaccharide and heat-inactivated fetal bovine serum, Am J Vet Res 71(6):623-629, 2010. 231. Cate H: Thrombin generation in clinical conditions, Thromb Res 129(3):367-370, 2012. 232. Gruber A, Griffin JH: Direct detection of activated protein C in blood from human subjects, Blood 79(9):2340-2348, 1992. 233. Bauer KA, Kass BL, Beeler DL, et al: Detection of protein C activation in humans, J Clin Invest 74(6):2033-2041, 1984. 234. Espana F, Griffin JH: Determination of functional and antigenic protein C inhibitor and its complexes with activated protein C in plasma by ELISAs, Thromb Res 55(6):671-682, 1989.

235. Scully MF, Toh CH, Hoogendoorn H, et al: Activation of protein C and its distribution between its inhibitors, protein-C inhibitor, alpha 1-antitrypsin and alpha 2-macroglobulin, in patients with disseminated intravascular coagulation, Thromb Haemost 69(5):448-453, 1993. 236. Brandt JT: Plasminogen and tissue-type plasminogen activator deficiency as risk factors for thromboembolic disease, Arch Pathol Lab Med 126(11):1376-1381, 2002. 237. Heylen E, Miljic P, Willemse J, et al: Procarboxypeptidase U (TAFI) contributes to the risk of thrombosis in patients with hereditary thrombophilia, Thromb Res 124(4):427-432, 2009. 238. Lau HK, Teitel JM, Cheung T, et al: Hypofibrinolysis in patients with hypercoagulability: the roles of urokinase and of plasminogen activator inhibitor, Am J Hematol 44(4):260-265, 1993. 239. Levi M, Roem D, Kamp AM, et al: Assessment of the relative contribution of different protease inhibitors to the inhibition of plasmin in vivo, Thromb Haemost 69(2):141-146, 1993. 240. Weitz JI, Koehn JA, Canfield RW, et al: Development of a radioimmunoassay for the fibrinogen-derived peptide Bβ1-42, Blood 67(4):10141022, 1986. 241. Kudryk B, Rohoza A, Ahadi M, et al: Specificity of a monoclonal antibody for the NH2-terminal region of fibrin, Mol Immunol 21(1):89-94, 1984. 242. Shattil SJ, Hoxie JA, Cunningham M, et al: Changes in the platelet membrane glycoprotein IIb/IIIa complex during platelet activation, J Biol Chem 260(20):11107-11114, 1985. 243. Frelinger AL, Lam SC, Plow EF, et al: Selective inhibition of integrin function by antibodies specific for ligand-occupied receptor conformers, J Biol Chem 265(11):6346-6352, 1990. 244. Michelson AD: Laboratory markers of platelet activation. In Colman RW, Marder VJ, Clowes AW, et al, editors: Hemostasis and thrombosis: basic principles and clinical practice, ed 5, Philadelphia, 2006, Lippincott Williams & Wilkins, pp 825-834. 245. Gralnick HR, Williams SB, McKeown L, et al: Endogenous platelet fibrinogen: its modulation after surface expression is related to sizeselective access to and conformational changes in the bound fibrinogen, Br J Haematol 80(3):347-357, 1992. 246. Boudreaux MK, Panangala VS, Bourne C: A platelet activation-specific monoclonal antibody that recognizes a receptor-induced binding site on canine fibrinogen, Vet Pathol 33(4):419-427, 1996. 247. Sharp KS, Center S, Randolph JF, et al: Influence of treatment with ultralow-dose aspirin on platelet aggregation as measured by whole blood impedance aggregometry and platelet P-selectin expression in clinically normal dogs, Am J Vet Res 71(11):1294-1304, 2010. 248. Metzelaar MJ, Heijnen HF, Sixma JJ, et al: Identification of a 33-kD protein associated with the alpha-granule membrane (GMP-33) that is expressed on the surface of activated platelets, Blood 79(2):372-379, 1992. 249. Chen M, Kakutani M, Naruko T, et al: Activation-dependent surface expression of LOX-1 in human platelets, Biochem Biophys Res Commun 282(1):153-158, 2001. 250. Febbraio M, Silverstein RL: Identification and characterization of LAMP-1 as an activation-dependent platelet surface glycoprotein, J Biol Chem 265(30):18531-18537, 1990. 251. Nieuwenhuis HK, van Oosterhout JJ, Rozemuller E, et al: Studies with a monoclonal antibody against activated platelets: evidence that a secreted 53,000-molecular weight lysome-like granule protein is exposed on the surface of activated platelets in the circulation, Blood 70(3):838-845, 1987. 252. McEver RP: P-selectin/PSGL-1 and other interactions between platelets, leukocytes, and endothelium. In Michelson AD, editor: Platelets, New York, 2002, Academic Press/Elsevier Science. 253. Andre P, Nannizzi-Alaimo L, Prasad SK, et al: Platelet-derived CD40L, the switch hitting player of cardiovascular disease, Circulation 106(8):896-899, 2002. 254. Hayward CP, Bainton DF, Smith JW, et al: Multimerin is found in the alpha-granules of resting platelets and is synthesized by a megakaryocytic cell line, J Clin Invest 91(6):2630-2639, 1993. 255. Aiken ML, Ginsberg MH, Plow EF: Mechanisms for expression of thrombospondin on the platelet cell surface, Semin Thromb Hemost 13(3):307-316, 1987.

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256. Sims PJ, Faioni EM, Wiedmer T, et al: Complement proteins C5b-9 cause release of membrane vesicles from the platelet surface that are enriched in the membrane receptor for coagulation factor Va and express prothrombinase activity, J Biol Chem 263(34):18205-18212, 1988. 257. Gilbert GE, Sims PJ, Wiedmer T, et al: Platelet-derived microparticles express high affinity receptors for factor VIII, J Biol Chem 266(26):1726117268, 1991. 258. Holme PA,Brosstad F, Solum NO: Platelet-derived microvesicles and activated platelets express factor Xa activity, Blood Coagul Fibrinolysis 6(4):302-310, 1995. 259. Michelson AD, Rajasekhar D, Bednarek FJ, et al: Platelet and plateletderived microparticle surface factor V/Va binding in whole blood: differences between neonates and adults, Thromb Haemost 84(4):689-694, 2000. 260. McMichael M, Smith SA, Herring JM, et al: Quantification of procoagulant phospholipid in erythrocyte concentrates stored with and without leukoreduction [abstract], J Vet Emerg Crit Care 21(suppl 1): S8, 2011.

261. Chong BH, Murray B, Berndt MC, et al: Plasma P-selectin is increased in thrombotic consumptive platelet disorders, Blood 83(6):1535-1541, 1994. 262. Levine SP: Secreted platelet proteins as markers for pathological disorders. In Phillips DR, Shuman MA, editors: Biochemistry of platelets, Orlando, 1986, Academic Press, pp 378-415. 263. Blann AD, Lanza F, Galajda P, et al: Increased platelet glycoprotein V levels in patients with coronary and peripheral atherosclerosis—the influence of aspirin and cigarette smoking, Thromb Haemost 86(3):777783, 2001. 264. Oates JA, FitzGerald GA, Branch RA, et al: Clinical implications of prostaglandin and thromboxane A2 formation, N Engl J Med 319(11):689-698, 1988. 265. Henn V, Steinbach S, Buchner K, et al: The inflammatory action of CD40 ligand (CD154) expressed on activated human platelets is temporally limited by coexpressed CD40, Blood 98(4):1047-1054, 2001. 266. Prasad KS, Andre P, Yan Y, et al: The platelet CD40L/GPIIb/IIIa axis in atherothrombotic disease, Curr Opin Hematol 10(5):356-361, 2003.

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PART XI  •  HEMATOLOGIC DISORDERS

CHAPTER 105  BLEEDING DISORDERS Susan G. Hackner, BVSc, MRCVS, DACVIM, DACVECC  •  Alexandre Rousseau, DVM, DACVIM (Internal Medicine), DACVECC

KEY POINTS • Patients with subclinical hemostatic defects may not demonstrate evidence of bleeding until an invasive procedure or contributory event occurs. The clinician should be suspicious of bleeding disorders in certain patient populations to identify the patient at risk. • Bleeding disorders occur as a result of disorders of primary hemostasis, disorders of secondary hemostasis, hyperfibrinolysis, or combinations of these. • Diagnosis begins with determining if the bleeding is due to local factors or to a systemic bleeding disorder and, in case of the latter, characterization of the hemostatic defect(s). • Characterization of the disorder is achieved via careful history taking, a thorough physical examination, and routine coagulation testing. • Massive trauma or surgery can cause an acute coagulopathy. This is exacerbated by shock, hypothermia, acidemia, and aggressive fluid therapy, which can result in profound coagulopathy and exacerbation of bleeding. • Management relies on early recognition and reversal of lifethreatening events and contributing factors, the provision of plasma or platelet products and, when possible, therapy targeted at the inciting cause. The use of prohemostatic agents is indicated in certain conditions.

Bleeding disorders are conditions that result in inappropriate hemostasis, causing or predisposing to bleeding. Some coagulopathies result in spontaneous bleeding, but many are subclinical and hemorrhage occurs only after an invasive procedure. This is particularly true in cats, in whom subclinical hemostatic defects are relatively

common with underlying disease, such as hepatopathy, viral disease, or neoplasia.1 Bleeding disorders always should be considered life threatening. Even the stable patient can decompensate rapidly from massive hemorrhage, or hemorrhage into a vital organ. Therefore, rapid diagnosis is paramount. Recognizing patients at risk, identifying the hemostatic disorder, and initiating rational therapy are necessary steps for successful outcomes.

HEMOSTASIS AND FIBRINOLYSIS Hemostasis and fibrinolysis maintain the integrity of a closed, highpressure circulatory system after vascular damage.2 Vascular injury provokes a complex response in the endothelium and the blood that culminates in the formation of a thrombus to seal the breach. Hemostasis can be divided into two distinct but overlapping phases: primary hemostasis, involving the interaction between platelets and endothelium resulting in the formation of a platelet plug, and secondary hemostasis, a system of proteolytic reactions involving coagulation factors and resulting in the generation of fibrin polymers, which stabilize the platelet plug to form a mature thrombus. These phases occur concomitantly and, under normal physiologic conditions, intrinsic regulatory mechanisms contain thrombus formation temporally and spatially. Fibrinolysis is the dissolution of the fibrin clot to restore vascular patency. The delicate balance between proteolytic and inhibitory reactions in hemostasis and fibrinolysis can be disrupted, by inherent or acquired defects, to result in abnormal bleeding. Primary hemostasis immediately follows vascular damage. Platelets adhere to subendothelial collagen via the platelet glycoprotein VI

CHAPTER 105  •  Bleeding Disorders Initiation

Intrinsic pathway fXII kallikrein fXI

PL, Ca2+ fVIIa

fIXa*

fX

fXa fVa PL, Ca2+ Prothrombin Thrombin

VIII/vWF VIIIa

V

Va

XI

XIa

TF VIIa IX PT

IXa

X IXa

Fibrinogen

IIa

Xa Va

TF-bearing cell

fVII

Common pathway aPTT

II

TF VIIa

Tissue factor

fVIIIa PL, Ca2+

fIX

X

Extrinsic pathway

fXIa

Amplification

Fibrin

FIGURE 105-1  The cascade model of coagulation. The intrinsic pathway was considered to be initiated through contact activation of factor XII, and the extrinsic system by exposure to extravascular tissue factor (TF). Either pathway results in the activation of factor X in the common pathway, leading to thrombin production. The aPTT tests the intrinsic and common pathways; the PT tests the extrinsic and common pathways. aPTT, Activated partial thromboplastin time; PL, platelet phospholipid; PT, prothrombin time. (From Hackner SG, White CR: Bleeding and hemostasis. In Tobias KM, Johnston SA, editors: Veterinary surgery small animal, St Louis, 2012, Elsevier, p 95.)

receptor, or to collagen-bound von Willebrand factor (vWF) via the glycoprotein Ib receptor.2 Adherence triggers a cascade of cytosolic signaling that stimulates platelet arachidonic acid metabolism and the release of granular contents (activation). Thrombin, generated by secondary hemostasis, is also a powerful platelet agonist. Activated platelets release secondary agonists, notably thromboxane A2 (TxA2), adenosine diphosphate (ADP), and serotonin, which recruit and activate additional platelets, thus amplifying and sustaining the initial response.2,3 The final common pathway for all agonists is the activation of the platelet integrin αIIbβ3 receptor (formerly known as glycoprotein IIbIIIa receptor).2,3 Agonist binding induces a conformational change in the receptor, exposing binding domains for fibrinogen. Binding results in interplatelet cohesion and aggregation. Aggregated platelets constitute the primary hemostatic plug and provide a stimulus and framework for secondary hemostasis. Secondary hemostasis culminates in the formation of fibrin. The traditional model of coagulation consisted of a cascade of enzymatic reactions, in which enzymes cleaved substrates to generate the next enzyme in the cascade (Figure 105-1).4 This model was divided into two pathways: the “extrinsic” pathway, initiated by tissue factor (TF), and the “intrinsic” pathway, initiated through contact activation of fXII. These two pathways converge into a final common pathway of thrombin generation and fibrin formation. Although this model is valid for interpretation of traditional in vitro coagulation testing, it does not adequately explain coagulation in vivo.2,5 For example, although deficiencies of fXII cause marked coagulation test prolongation, they do not result in a bleeding tendency. In contrast, isolated deficiencies of the intrinsic pathway, such as hemophilia, result in profound bleeding in spite of an intact extrinsic pathway. A cell-based model of coagulation more accurately reflects coagulation in vivo.2,5,6 This model includes two fundamental paradigm shifts: that TF is the primary physiologic initiator of coagulation (contact activation playing no role in vivo); and that coagulation is localized to, and controlled by, cellular surfaces.2,5 Coagulation occurs in three overlapping phases: initiation (on TF-bearing cells), amplification, and propagation (on platelets) (Figure 105-2).5,6 The initiation phase is the TF-initiated (“extrinsic”) pathway that generates

VIIIa

Platelet

II

IIa Xa

XIa

Va

XI Activated platelet Propagation FIGURE 105-2  A cell-based model of coagulation. Coagulation is initiated through tissue factor (TF) on the surface of TF-bearing cells, leading to the generation of small amounts of thrombin (IIa) from prothrombin (II) (initiation phase). Thrombin amplifies the initial signal by activating platelets and cofactors (fVa, fVIIIa) on the platelet surfaces (amplification phase). Large-scale thrombin generation occurs on the surface of the activated platelet (propagation phase). (From Hackner SG, White CR: Bleeding and hemostasis. In Tobias KM, Johnston SA, editors: Veterinary surgery small animal, St Louis, 2012, Elsevier, p 96.)

small amounts of thrombin. TF is a membrane protein, expressed on endothelial cells, fibroblasts, and other extravascular cells under physiologic conditions. Coagulation is initiated when vascular damage or inflammation enables contact between plasma and TF-bearing cells. Plasma fVII binds to TF and is activated, generating small amounts of thrombin, which, in turn, activate platelets that are adhered at the site of vascular damage. During the activation phase, platelets are activated and have activated cofactors V and VIII bound to their surfaces. In this manner, thrombin amplifies the initial signal, acting on the platelet to “set the stage” for procoagulant complex assembly. During the propagation phase, complexes are assembled on the surface of the activated platelet, and large-scale thrombin generation occurs (similar to the previously-named “intrinsic” pathway). This provides the burst of thrombin necessary to produce large quantities of fibrin. Fibrin monomers are then complexed to form fibrin polymers and a stable thrombus. Fibrinolysis is the enzymatic dissolution of fibrin. Plasminogen activators, most notably tissue-type plasminogen activator (tPA) proteolytically convert plasminogen to plasmin, which, in turn, degrades fibrin into soluble degradation products (fibrin split products, FSPs).

HEMOSTATIC TESTING Hemostatic testing is essential for the identification and characterization of hemostatic defects. However, in vitro tests do not accurately reflect in vivo hemostasis. Moreover, hemostatic testing makes high demands on sampling procedure; improper technique leads to artifactual results.7 Tests should always be performed and interpreted carefully, along with the clinical findings, and with their limitations in mind. Normal values are presented in Table 105-1.

Platelet Enumeration and Estimation Platelet counts detect quantitative platelet disorders (thrombocytopenia). Enumeration is performed via automated cell counter or

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PART XI  •  HEMATOLOGIC DISORDERS

Table 105-1  Normal Values for Common Coagulation Tests

The Prothrombin Time and Activated Partial Thromboplastin Time

Diagnostic Test

The prothrombin time (PT) and the activated partial thromboplastin time (aPTT) assess secondary hemostasis via reagents that activate the extrinsic or the intrinsic pathway, respectively (see Figure 105-1).15 The PT evaluates the extrinsic and common pathways, specifically factors VII, X, V, II and fibrinogen. Because of the short half-life of factor VII, the PT is sensitive to vitamin K deficiency or antagonism. The APTT evaluates the intrinsic and common pathways; only factors VII and XIII are not evaluated. It is more sensitive to heparin than is the PT. A point-of-care (POC) coagulometer (e.g., CoagDx, Idexx, ME) is invaluable for patient-side coagulation testing. However, it is not equivalent to conventional laboratory testing. In canine patients, sensitivities of the aPTT and PT were 100% and 86%, respectively; specificities were 83% and 96%, respectively.16 In the authors’ experience, clinically significant defects are reliably identified; marked prolongations are generally accurate, whereas mild prolongations should be interpreted with caution. Results that do not correlate with clinical findings should be verified via conventional testing. Although the PT and aPTT are invaluable in the diagnosis of disorders of secondary hemostasis, they are in vitro plasma-based tests, represented by the cascade model of coagulation, and do not accurately represent in vivo hemostasis. As such, they are not predictive of bleeding.

Platelet count (× 103/µl) Buccal mucosal bleeding time (min) Prothrombin time (sec) Activated partial thromboplastin time (sec) Fibrin split products (mcg/ml) D-dimer (ng/dl) Fibrinogen (mg/dl)

Dog

Cat

200-500

200-600

1.7-4.2

1.4-2.4

6-11

6-12

10-25

10-25

1.5 cm with normal wall layering

Not reported but should aggressively investigate for intestinal obstruction

Not reported but luminal diameter not dilated then intestinal obstruction not likely

Fluid to blood potassium ratio for diagnosis of uroabdomen

Dogs: ratio of 1.4 : 1 Cats: ratio 1.9 : 1

Dogs: 100% Cats: unknown

Not reported but considered diagnostic for uroabdomen

Fluid to blood creatinine ratio for diagnosis of uroabdomen

Dogs: ratio 2 : 1 Cats: ratio 2 : 1

Dogs: 86% Cats: unknown

Dogs: 100% Cats: unknown

Fluid to blood bilirubin ratio for diagnosis of bile peritonitis (also may see bile pigment/crystals in abdominal fluid)

>2 : 1

Dogs: 100% Cats: unknown

Not reported

Dogs: ratio of maximal small intestinal diameter to the narrowest width of L5 on lateral radiograph

Ratio > 1.6

Not reported but suggestive of small intestinal obstruction.

Not reported but suggestive of small intestinal obstruction

Cats: ratio of maximal small intestinal diameter to the height of cranial endplate of L2

Ratio > 2.0

Not reported but suggestive of small intestinal obstruction.

Not reported but suggestive of small intestinal obstruction

Specific cPLI (serum) for diagnosis of pancreatitis

400 mcg/L: pancreatitis likely

82% with severe pancreatitis, 63.6% with less severe pancreatitis

96.8%

Specific fPLI (serum) for diagnosis of pancreatitis

5.3 mcg/L: pancreatitis likely

67% in all cats with pancreatitis and 100% in cats with moderate to severe pancreatitis

100%

SNAP cPLI (serum) for diagnosis of pancreatitis

Spot intensity test

92%-94%

71%-78%

SNAP fPLI (serum) for diagnosis of pancreatitis

Spot intensity test

79%

80%

*Confidence intervals for the diagnostic characteristics (sensitivity and specificity) have not been reported. Therefore the numbers are point estimates and should be considered to have some degree of variation.

REFERENCES 1. Boag AK, Coe RJ, Martinez TA, et al: Acid-base and electrolyte abnormalities in dogs with gastrointestinal foreign bodies, J Vet Intern Med 19:816, 2005. 2. Owens JM, Biery DN: Radiographic interpretation for the small animal clinician, ed 2, Media, Penn, 1999, Williams & Wilkins. 3. Sharma A, Thompson S, Scrivani PV, et al: Comparison of radiography and ultrasonography for diagnosing small-intestinal mechanical obstruction in vomiting dogs, Vet Radiol Ultras 52(3):248-255, 2011. 4. Schmiedt C, Tobias KM, Otto CM: Evaluation of abdominal fluid: peripheral blood creatinine and potassium ratios for diagnosis of uroperitoneum in dogs, J Vet Emerg Crit Care 11:4, 275, 2001.

5. Aumann M, Worth LT, Drobatz KJ: Uroperitoneum in cats: 26 cases (19861995), J Am Anim Hosp Assoc 34:315, 1998. 6. Bonczynski JJ, Ludwig LL, Barton BJ, et al: Comparison of peritoneal fluid and peripheral blood pH, bicarbonate, glucose, and lactate concentration as a diagnostic tool for septic peritonitis in dogs and cats, Vet Surg 32:161, 2003. 7. Ludwig LL, McLoughlin MA, Graves TK, et al: Surgical treatment of bile peritonitis in 24 dogs and 2 cats: a retrospective study (1987-1994), Vet Surg 26:90, 1997.

CHAPTER 113  ACUTE PANCREATITIS Alison R. Gaynor,

DVM, DACVIM, DACVECC

KEY POINTS • Acute pancreatitis is a dynamic inflammatory disease, with episodes ranging in severity from mild and self-limiting to severe fulminant disease with extensive necrosis, systemic inflammation, and multiorgan failure. • Clinical signs, physical examination findings, and results of diagnostic evaluation are variable and often nonspecific in dogs and cats with acute pancreatitis. • Suggested risk factors associated with increased morbidity and mortality include older age, obesity, gastrointestinal disease, and concurrent endocrinopathies in dogs, and ionized hypocalcemia in cats. Hepatic lipidosis and other concurrent diseases also are associated with more severe disease in cats. • Evaluation of serum amylase and lipase concentrations is not useful for diagnosis of acute pancreatitis in dogs and cats. • Early, aggressive intravascular volume resuscitation and intensive monitoring are crucial for patients with severe acute pancreatitis. • Early enteral nutrition and aggressive pain control are important aspects of therapy, whereas prophylactic antibiotic therapy and surgical intervention are infrequently indicated. • Development of clinical and histopathologic consensus definitions, prognostic scoring systems, and other objective means of determining and stratifying severity of acute pancreatitis in veterinary patients is greatly needed.

Pancreatitis, broadly classified as acute, recurrent, or chronic, is a fairly common disease in dogs and has become more widely recognized in cats.1,2 Acute and recurrent acute pancreatitis (AP) are characterized by episodes of pancreatic inflammation with a sudden onset and variable course. Episodes may range in severity from mild and self-limiting to severe fulminant disease with extensive necrosis, systemic inflammation and/or sepsis, multiorgan failure, and death. In addition to these systemic complications, moderately severe acute pancreatitis (MSAP) and severe acute pancreatitis (SAP) may include local complications (acute peripancreatic fluid collection, acute necrotic collection, pancreatic pseudocyst, or walled-off necrosis), which may be sterile or infected.3 In veterinary medicine there is no universally accepted classification scheme for pancreatitis, with most current schemes based on variable terminology and histopathologic descriptions. However, these usually are not available at the time of diagnosis and do not necessarily correlate well with clinical severity and disease progression.1,4-7 Therefore a clinically based classification system, simplified and adapted from consensus definitions in human medicine,8 recently revised,3 and used by other authors,1,4,9-11 may be more appropriate to our patient population and is used in this chapter.

however, are considered to be idiopathic, because a direct causal relationship is infrequently demonstrated.* Regardless of the underlying etiology, AP involves intrapancreatic activation of digestive enzymes with resultant pancreatic autodigestion. Studies of animal models suggest that initial events occur within the acinar cell by abnormal fusion of normally segregated lysosomes with zymogen granules (catalytically inactive forms of pancreatic enzymes), resulting in premature activation of trypsinogen to trypsin, and may involve changes in signal transduction, intracellular pH, and increases in intracellular ionized calcium (iCa) concentrations.14 Trypsin in turn activates other proenzymes, setting in motion a cascade of local and systemic effects that are responsible for the clinical manifestations of AP.† Local ischemia, phospholipase A2, and reactive oxygen species (ROS) (produced in part from activation of xanthine oxidase by chymotrypsin) disrupt cell membranes, leading to pancreatic hemorrhage and necrosis, increased capillary permeability, and initiation of the arachidonic acid cascade. Elastase can cause increased vascular permeability secondary to degradation of elastin in vessel walls. Phospholipase A2 degrades surfactant, promoting development of pulmonary edema, acute lung injury (ALI), and acute respiratory distress syndrome (ARDS) (see Chapter 24). Trypsin may activate the complement cascade, leading to an influx of inflammatory cells and production of multiple cytokines and more ROS. Trypsin also can activate the kallikrein-kinin system, resulting in vasodilation, hypotension, and possibly acute renal failure, and the coagulation and fibrinolytic pathways, resulting in microvascular thromboses and disseminated intravascular coagulation (DIC). Local inflammation and increases in pancreatic and peripancreatic microvascular per­ meability may cause massive fluid losses, further compromising perfusion and stimulating additional recruitment of inflammatory cells and mediators, leading to a vicious cycle culminating in the systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS) (see Chapters 6 and 7).

CLINICAL PRESENTATION Clinical signs and presentation associated with AP are variable and often nonspecific, particularly in cats, and may be difficult to distinguish from those of other acute abdominal disorders. Dogs with AP are usually presented because of anorexia, vomiting, weakness, depression, and sometimes diarrhea.1,4,17,18 They may be febrile, dehydrated, and icteric, and often exhibit signs of abdominal discomfort, sometimes with abdominal distention and absent bowel sounds from associated peritonitis and intestinal ileus. Dogs that are middleaged and older, those that are overweight, those that have a history of prior or recurrent gastrointestinal (GI) disturbances, and those

PATHOPHYSIOLOGY A number of factors have been implicated as potential etiologic factors of pancreatitis. In humans, most cases of AP are caused by biliary calculi or alcohol exposure. Most cases in dogs and cats,

*For more in-depth reviews of etiologies see references 1, 2, and 4 (veterinary patients) and 12 and 13 (humans). † See references 1, 2, and 13 through 16 for more in-depth reviews of pathophysiology.

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with concurrent endocrinopathies (diabetes mellitus [DM], hypothyroidism, or hyperadrenocorticism) have been suggested to be at increased risk for development of fatal SAP.9,18,19 Yorkshire Terriers, Miniature Schnauzers, and other terrier breeds also may be at increased risk.18,19 Common clinical findings in cats with AP include lethargy, anorexia, dehydration, and hypothermia; vomiting and abdominal pain appear to be reported less frequently.20-22 Icterus and pallor often are noted as well.5,22 Concurrent conditions such as hepatic lipidosis, inflammatory bowel disease (IBD), interstitial nephritis or other kidney disease, DM, and cholangitischolangiohepatitis occur frequently, and signs of these conditions may predominate.5,6,20-23 In either species, patients with MSAP or SAP may present with signs of systemic complications including dyspnea, bleeding disorders, cardiac arrhythmias, oliguria, shock, and collapse.

Although it is neither sensitive nor specific, evaluation of TLI may have some clinical utility in cats in combination with diagnostic imaging,26 but is not considered useful in dogs.1 Elevations in pancreatic elastase-1 (cPE-1) also have been demonstrated in dogs with AP. A recent study suggested that evaluation of serum cPE-1 may be useful for diagnosis of SAP in dogs, but not for mild AP28; however, further evaluation is needed. Species-specific pancreatic lipase immunoreactivity (fPLI, cPLI) assays have been validated for use in cats and dogs, respectively; data suggest that PLI is sensitive and specific for AP in experimental and spontaneous cases of AP in both species, and does not appear to be affected by renal disease or glucocorticoid administration.1,27,29 PLI is currently the most useful serum marker available for the diagnosis of AP in cats and dogs.29,30

DIAGNOSIS

Abdominal radiographs are neither sensitive nor specific for AP but may provide supportive evidence, and are especially valuable in helping to rule out other causes of acute abdominal disease such as intestinal obstruction or perforation. In dogs radiographic signs may include increased density and loss of detail in the right cranial abdomen, displacement of the descending duodenum to the right with widening of the angle between the proximal duodenum and the pylorus, and caudal displacement of the transverse colon. Gastric distention and static gas patterns suggestive of ileus may be noted in the descending duodenum and transverse colon.1,17 Abdominal radiographs in cats typically are nonspecific, with decreased peritoneal detail most commonly reported; hepatomegaly, a mass effect in the cranial abdomen, and small intestinal dilation also have been reported.5,20,21,31 Abdominal ultrasonography (US) is particularly helpful as a diagnostic tool, for monitoring progression of the disease, and for evaluating the extent of associated complications and concurrent disorders. The pancreas may appear enlarged and hypoechoic, suggesting edema or necrosis, with hyperechoic peripancreatic tissue. More subtle changes such as pancreatic duct dilation, thromboses, and organ infarcts also may be detected.17,22,27,31,32 US is also valuable for identifying and guiding sampling of masses, localized inflammation, and focal or regional fluid accumulations.* US-guided fine-needle aspiration (FNA) of pancreatic necrosis is used routinely in humans with AP to identify infected pancreatic necrosis3,12,34,35 and has been described in dogs32 and cats.25 Contrast-enhanced computed tomography (CECT) is considered the gold standard in human patients with AP for identifying pancreatic/peripancreatic necrosis and other local complications, and is used frequently as a guide for FNA.3,12,34-36 Preliminary studies in veterinary patients suggested that CT was not particularly sensitive for diagnosis of AP in cats,26,27 although a more recent study showed promising results.37 CECT has been used to identify pancreatic necrosis in two dogs with AP.32

Diagnosis of AP requires careful integration of historical, physical examination, laboratory, and diagnostic imaging findings combined with a high degree of suspicion. Because many of these findings may be nonspecific and disease severity varies widely, diagnosis can be challenging. It is important to note that the absence of specific findings in any one diagnostic test does not rule out the possibility of AP.

Laboratory Assessment Initial hemogram and serum chemistry profile abnormalities are variable and nonspecific, and may reflect concurrent extrapancreatic disease. Neutrophilic leukocytosis with a left shift is reported most commonly,1,17,20 although neutropenia also has been reported in dogs17 and may be more common in cats.2 Thrombocytopenia also appears to be common.17 The hematocrit and red blood cell counts may be normal, but anemia also may be seen, especially in cats.5,20,21 An elevated hematocrit reflecting hemoconcentration and dehydration may be present; in human patients with AP this is associated with more severe disease. Elevations in hepatic enzyme activities and total bilirubin are often noted,5,6,17,20,21 which may reflect ischemic and/or toxic hepatocellular injury or concurrent hepatobiliary disease. Patients are frequently azotemic, usually from prerenal causes, although acute renal failure also may be present.17,19,20 Hyperglycemia is common17,20 and is thought to be secondary to stressrelated increases in endogenous cortisol and catecholamine levels, to hyperglucagonemia, or to overt DM. However, hypoglycemia may be seen if concurrent hepatic dysfunction, severe SIRS, or sepsis is present. Hypercalcemia has been reported in some dogs with SAP.17 Mild to moderate hypocalcemia and hypomagnesemia are not uncommon, possibly as a result of pancreatic and peripancreatic fat saponification, although multiple mechanisms have been proposed.22 Ionized hypocalcemia appears to be common in cats with AP and is associated with a poorer outcome.22 Other common findings include hypokalemia, hypercholesterolemia, hypertriglyceridemia, and hypoalbuminemia, which may be secondary to GI losses, sequestration, and shifting of protein production to acute phase proteins. Hyperlipemia may be grossly apparent and may interfere with determination of other serum chemistry values.17,19 Increased activities of serum lipase and amylase historically have been used as markers of pancreatitis, but are of limited diagnostic value because elevations also may occur from extrapancreatic sources such as azotemia and glucocorticoid administration.1,17 Furthermore, lipase and amylase activities are often within normal limits in animals with confirmed pancreatitis, particularly cats.1,17,20,24,25 Elevations in trypsin-like immunoreactivity (TLI) may suggest a diagnosis of pancreatitis, but also occurs with azotemia, and with GI disease in cats6; TLI may be normal in some patients with AP.6,26,27

Diagnostic Imaging

Cytology and Histopathology FNA of the pancreas is minimally invasive, relatively safe, and can be used as a diagnostic aid, although this may be unnecessary in many clinical cases, and as mentioned below, focal lesions can be missed.1,7 However, as discussed elsewhere in this chapter, cytology may be more valuable for evaluating local complications, infected necrosis, and for monitoring disease progression than for diagnosis of AP per se. Although histopathology is the gold standard for diagnosis of AP in veterinary patients, this is infrequently obtained antemortem, may be too invasive for critically ill patients, and may be unnecessary for *References 6, 17, 21, 22, 32, 33.

CHAPTER 113  •  Acute Pancreatitis 1,30

most clinical cases. Determining the significance of histopathologic findings may be challenging because these may not correlate with clinical severity.1,4-7 Inflammatory lesions are often focal or multifocal and easily can be missed, necessitating multiple biopsies, and it appears that histopathologic evidence of pancreatic inflammation is common in both species, even in patients with no corresponding clinical signs.1,7,29 Histopathology has been described elsewhere.1,2,7,20

Additional Diagnostic Evaluation Additional diagnostic evaluation not specific for AP but to help determine patient status and provide baseline information for subsequent monitoring may include urinalysis, urine culture and susceptibility, thoracic radiographs, evaluation of venous and arterial blood gases, lactate and iCa concentrations, and a complete coagulation profile. Coagulation abnormalities reflecting DIC and thromboses appear to be common in dogs and cats with SAP.* If focal or regional fluid accumulations (including pleural effusions) are detected, these should be sampled, with fluid analysis, cytology, and cultures evaluated as indicated. Serial cytologic and imaging evaluation may be helpful in monitoring disease progression. A recent preliminary investigation suggested that elevated cPLI concentration and lipase activity in peritoneal fluid may support a diagnosis of AP in dogs.38

DETERMINING SEVERITY Because of the variability in presentation, early determination of disease severity and identification of those patients at risk for more severe disease would help guide earlier, more aggressive goal-oriented monitoring and therapy. In human medicine, various clinical and radiologic scoring systems and biochemical markers have been evaluated as objective methods for early determination of severity. In addition to selecting patients for earlier admission to an intensive care unit, these allow objective stratification of patients for prognostic purposes, for evaluating disease progression, and for clinical research including evaluation and comparison of various treatment protocols. Clinical scoring systems include generalized predictors of severity such as the Acute Physiology and Chronic Health Evaluation (APACHE) II score, and pancreatitis-specific scoring systems including Ranson’s Criteria, the Glasgow (Imrie) score, and Balthazar’s CT index, as well as newer, more simplified systems such as the Bedside Index for Severity in AP (BISAP) and Harmless AP Score (HAPS).† The updated clinical classification system mentioned previously3 incorporates the modified Marshall (MODS) scoring system,41 and also defines local and systemic complications. Of the many biochemical markers evaluated, pancreas-specific ones such as trypsinogen activation peptides (TAP) and carboxypeptidase, and more global markers of systemic inflammation such as C-reactive protein (CRP), interleukin-6, interleukin-8, and neutrophil elastase seem most promising. CRP is currently the best established and most widely available biochemical marker for predicting severity.‡ In veterinary medicine, in addition to the potential risk factors previously described, a simplified scoring system based on organ involvement43 and a clinical severity index10 have been proposed for dogs with AP; a survival prediction index has been developed for critically ill dogs (see Chapter 13). Increases in CRP10,44 and urinary *References 9, 17, 20-22, 25, 32. † See references 11, 12, 35, 36, 39, and 40 for more in-depth reviews of clinical scoring systems. ‡ See references 11, 12, 39, and 42 for more in-depth reviews of biochemical markers.

9

TAP-to-creatinine ratios have been demonstrated in dogs with spontaneous AP, although further evaluation is needed to determine their clinical utility.

TREATMENT Therapy for patients with AP involves elimination of any identifiable underlying cause, if possible, symptomatic and supportive therapy, and anticipation of and early aggressive intervention against systemic complications. Although severity scoring systems and prognostic indicators are valuable, these do not replace the need for intensive monitoring and therapy on an individual basis. Patients that initially appear stable can decompensate rapidly; therefore close monitoring and frequent reassessment are critical. Throughout this section the reader is referred to related chapters in this book for more specific details on various therapies and monitoring.

Resuscitation, Fluid Therapy, and Monitoring Patients with severe disease may be hemodynamically unstable and in need of rapid resuscitation with shock-rate replacement fluids. A recent preliminary study in human AP patients suggested that resuscitation with lactated Ringer’s solution reduced systemic inflammation at 24 hours when compared with normal saline; however, there were no significant differences between treatment groups for other outcomes.45 Resuscitation fluid types and rates of administration have not been evaluated in veterinary patients with AP. Maintenance fluid requirements also may be substantial, to combat massive ongoing fluid losses from the vascular space due to vomiting and third spacing into the peritoneal cavity, GI tract, and the interstitium. Balanced electrolyte solutions are appropriate for maintenance needs, but should be modified based on frequent evaluation of electrolyte and acid-base status. Potassium supplementation is usually necessary. Calcium should not be supplemented unless clinical signs of tetany are observed, because of the potential for exacerbation of free radical production and cellular injury. Concurrent use of a synthetic colloid is often necessary for patients with severe disease. This will reduce the volume of crystalloids needed, and may help maintain intravascular volume and improve micro­ circulatory perfusion and oxygen delivery. Frequent monitoring of vital signs, arterial blood pressure, central venous pressure, and urine output may help guide rates and types of intravenous fluids while avoiding overhydration. Other parameters that require frequent monitoring include hematocrit and total plasma solids; venous blood gas and electrolytes; blood glucose, albumin, and lactate; oxygenation and ventilation; an electrocardiogram; coagulation status; renal function; and mentation. Patients that are hypotensive despite adequate volume replacement will need pressor therapy; dopamine may be used, although in some instances other agents may be necessary. In experimental feline models of AP, low-dose dopamine (5 mcg/kg/min) has been shown to reduce the degree of pancreatic inflammation by decreasing microvascular permeability,46 although there have been no controlled studies in cats or dogs with spontaneous disease. Supplemental oxygen is indicated for patients with evidence of hypovolemic shock and/or respiratory abnormalities. Patients that present with or develop tachypnea or dyspnea should be evaluated for ALI and ARDS, as well as aspiration pneumonia, pleural effusion, pulmonary thromboembolism, overhydration, and preexisting cardiopulmonary disease, and appropriate therapy instituted. Systemic causes of tachypnea such as metabolic acidosis, pain, and hyperthermia should also be considered. Patients with significant anemia may require packed red blood cell transfusions; this may be more of a problem in cats and small dogs, in part as a result of repeated blood sampling.

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Use of fresh frozen plasma (FFP) often is advocated for patients with SAP to provide a source of α2-macroglobulins, important protease inhibitors that help to clear activated circulating proteases. However, studies in human patients with SAP have not shown any improvement in morbidity or outcome with use of plasma.47 A recent retrospective study in dogs with AP also suggested no benefit,48 but there have been no prospective controlled studies in veterinary patients. FFP administration may be indicated for treatment of coagulopathies, including DIC.

Pain Management Aggressive analgesic therapy is indicated for all patients with AP, including those that may not exhibit overt signs of pain. Adequate analgesic therapy is critical for maintaining patient comfort and will help decrease levels of stress hormones, will improve ventilation, and may improve GI motility if ileus is due in part to pain. Systemic opioids are the mainstay of therapy, and may be supplemented with low-dose ketamine or lidocaine, or both, in patients with more severe pain. Low-dose lidocaine has promotility effects and may be particularly beneficial for patients with severe ileus. Epidural and intraperitoneal analgesia also may be effective in select patients. Nonsteroidal antiinflammatory agents are not recommended unless patients are hemodynamically stable, not azotemic, and are well perfused.

Nutrition

monitoring for complications associated with refeeding is critical, and overfeeding should be avoided. Considering the benefits of early enteral nutrition in patients with more severe disease as well as the fact that patient status at presentation can change rapidly, early enteral nutrition (within 24 hours) is also recommended for patients with mild AP.1,49 This can be accomplished by oral feeding (if the patient is able and willing to eat), or by tube feeding, with vomiting controlled as needed.

Additional and Supportive Therapy Other therapies that do not necessarily influence the outcome of AP but do provide patient comfort include the use of GI protectants, thermal support, and physical therapy. Antiemetics and promotility agents are useful for patients that are vomiting and for those with GI ileus. It has been suggested that dopaminergic antagonists such as metoclopramide may be less effective or should be avoided.1,2,4 Intermittent nasogastric decompression also may be helpful for patients with severe ileus; this will improve patient comfort, decrease nausea, and may decrease the risk of aspiration. Treatment of concurrent diseases and of any inciting factors that may be identified is also important. Patients with overt DM, diabetic ketoacidosis (DKA), and those with persistent hyperglycemia should receive regular insulin, because strict glycemic control is important in the treatment of any critically ill patient. Cats with concurrent IBD may require glucocorticoid therapy.

The traditional recommendation to withhold food and water for patients with AP is no longer recommended; the current standard of care is to initiate enteral nutrition early, ideally within 24 hours of hospitalization.1,34,49,50 Although there is no agreement about the timing of feeding for patients with mild AP, patients with MSAP and SAP are in a hypercatabolic state and for these patients early enteral nutrition is definitely indicated.* Potential benefits of early enteral nutrition in patients with MSAP and SAP include improved gut mucosal structure and function and decreased bacterial translocation, thus attenuating stimuli for propagation of SIRS.34,36,49-51 Compared with parenteral nutrition, early enteral feeding is associated with fewer complications including fewer infections, decreased risk of MODS, decreased mortality rates, less expense, and shorter duration of hospitalization.12,34,49,52 Use of a jejunostomy tube to deliver nutrients to the jejunum is thought to minimally stimulate exocrine pancreatic secretion; however, it is not clear how exocrine pancreatic function is altered during AP, or whether stimulation of these secretions is actually detrimental. Because jejunostomy tube placement can be technically difficult and usually requires general anesthesia and special equipment, many veterinary clinicians have used other routes of enteral feeding including nasogastric and esophagostomy tubes, particularly in cats with AP because of the risk for hepatic lipidosis.1,2 Preliminary studies suggest that early nasogastric tube feeding in cats23 and human patients53 and esophagostomy tube feeding in dogs50 with SAP is well tolerated and feasible. Although additional studies are needed, thus far no differences in outcome compared with nasojejunal feeding have been noted in human patients.49 Patients with severe ileus or intractable vomiting may tolerate low-volume enteral nutrition (trickle feeding or microenteral nutrition); however, supplemental total or partial parenteral nutrition should be considered when nutritional requirements cannot be met with enteral nutrition alone. Elemental or partial-elemental diets usually are recommended; although the ideal composition is unknown, supplementation with glutamine currently is recommended.4,34 Cats, particularly those with concurrent GI tract disease, may require parenteral cobalamin supplementation.1 Close

Indications for surgery in patients with SAP are not always clear, and in the veterinary literature usually include those patients with infected pancreatic necrosis, those with extrahepatic biliary obstruction (EHBO), and those who continue to deteriorate despite aggressive medical therapy.1,4,11,25,55 However, these patients are also very poor anesthetic risks, so the decision for surgical intervention should be made on an individual basis. In human medicine the trend in

*References 1, 12, 34, 35, 49, 50.

*References 1, 4, 10, 11, 33, 55.

Antibiotic Therapy Routine use of prophylactic antibiotic therapy is controversial and is not recommended in most cases of AP because of the risk of inducing resistant bacterial strains and fungal infections.1,12,34-36 For patients with documented infections, broad-spectrum antibiotics with activity against gram-negative species can be started while awaiting results of culture and susceptibility testing. In human patients with SAP, there is an increased risk for pancreatic/peripancreatic infection with greater than 30% necrosis, and infected pancreatic necrosis is a major risk factor for MODS and death; the incidence of infection appears to peak later during the course of the disease and is rare in the first week.3,12,34,36 Despite numerous studies, however, it has not been shown convincingly that prophylactic antibiotic therapy improves outcome and, although conflicting, most of the recent consensus statements and meta-analyses recommend against routine antibiotic prophylaxis.12,34-36,54 In the veterinary literature antibiotic therapy is frequently recommended despite a lack of supporting evidence, but in fact the incidence of infection is thought to be low.* The actual incidence is unknown. Empiric antibiotic therapy may be reasonable for those patients that do not respond to other therapy and for those that initially respond but later deteriorate. However, every attempt to document infection in these patients should be made, including serial US or CECT-guided FNA of areas of pancreatic and peripancreatic necrosis. Development of infection in extrapancreatic sites such as the urinary tract or respiratory tract also may occur.

Surgery

CHAPTER 113  •  Acute Pancreatitis

recent years has been away from early aggressive surgical intervention to more conservative treatment strategies, and it is generally agreed that surgery is not indicated for most cases involving sterile pancreatic necrosis.12,34,35,56 Debridement and/or drainage is indicated for patients with infected necrosis, although whenever possible delayed and/or staged therapy is recommended to allow time for better demarcation of necrotic from viable tissue. This may also allow for use of less invasive interventions, including percutaneous, endoscopic, and laparoscopic techniques. Successful US-guided percutaneous drainage of pancreatic pseudocysts33 and US-guided percutaneous cholecystocentesis57 have been described in veterinary patients with AP.

OUTCOME Patients that survive an episode of pancreatitis may be normal, or may continue to have episodic flare-ups. Those that improve but again become ill several weeks to months after the initial presentation should be evaluated closely for development of local complications such as pancreatic pseudocyst or walled-off necrosis, as well as for EHBO. Some patients may develop DM, chronic pancreatitis, and/or exocrine pancreatic insufficiency. Development of pancreatic exocrine and/or endocrine dysfunction is not uncommon in human patients.12

CONCLUSION Specific therapies using direct inhibitors of pancreatic secretion (atropine, somatostatin, glucagon, calcitonin) or using protease and other pancreatic enzyme inhibitors generally have proved unsuccessful; despite decades of research, therapy for AP remains primarily supportive. With the increasing recognition of the importance of inflammatory mediators in the progression to systemic organ dysfunction, much ongoing research is focused on the use of free radical scavengers, cytokine antagonists, and other forms of immunomodulation. Continued advances in biochemical and diagnostic imaging modalities will help improve our ability to more rapidly and definitively diagnose AP in our patients, and may provide improved and objective means for determining and monitoring severity of disease. Decreases in morbidity and mortality in human patients with AP in the recent past have been attributed in part to development of consensus definitions, scoring systems, and other predictors of severity, as previously discussed. In order to have meaningful evaluation of different therapies and to better understand the pathophysiologic mechanisms involved in canine and feline patients with AP, development of consensus definitions for clinical and histopathologic classification of AP and validation of severity scoring systems should be encouraged.

REFERENCES 1. Xenoulis PG, Steiner JM: Pancreas-diagnostic evaluation; necrosis and inflammation: canine. In Washabau RJ, Day MJ, editors: Canine and feline gastroenterology, St Louis, 2013, Elsevier. 2. Washabau RJ: Pancreas-necrosis and inflammation: feline. In Washabau RJ, Day MJ, editors: Canine and feline gastroenterology, St Louis, 2013, Elsevier. 3. Banks PA, Bollen TL, Dervenis C, et al: Classification of acute pancreatitis—2012: revision of the Atlanta classification and definitions by international consensus, Gut 62:102-111, 2013. Originally published online October 25, 2012: doi:10.1136/gutjnl-2012-302779. 4. Mansfield C: Acute pancreatitis in dogs: advances in understanding, diagnostics, and treatment, Topics Companion Anim Med 27:123-132, 2012.

5. Ferreri J, Hardam E, Kimmel SE, et al: Clinical differentiation of acute necrotizing from chronic nonsuppurative pancreatitis in cats: 63 cases (1996-2001), J Am Vet Med Assoc 223:469-474, 2003. 6. Swift NC, Marks SL, MacLachan NJ, et al: Evaluation of serum feline trypsin-like immunoreactivity for the diagnosis of pancreatitis in cats, J Am Vet Med Assoc 217:37-42, 2000. 7. Newman S, Steiner J, Woosley K, et al: Localization of pancreatic inflammation and necrosis in dogs, J Vet Intern Med 18:488-493, 2004. 8. Bradley EL: A clinically based classification system for acute pancreatitis. Summary of the International Symposium on Acute Pancreatitis, Atlanta, GA, September 11 through 13, 1992, Arch Surg 128:586-590, 1993. 9. Mansfield CS, Jones BR, Spillman T: Assessing the severity of canine pancreatitis, Res Vet Sci 74:137-144, 2003. 10. Mansfield CS, James FE, Robertson ID: Development of a clinical severity index for dogs with acute pancreatitis, J Am Vet Med Assoc 233:936-944, 2008. 11. Holm JL, Chan DL, Rozanski EA: Acute pancreatitis in dogs, J Vet Emerg Crit Care 13:201-213, 2003. 12. Lipsett PA: Acute pancreatitis. In Vincent JL, Abraham E, Moore FA, et al, editors: Textbook of critical care, ed 6, Philadelphia, 2011, Elsevier. 13. Elfar M, Gaber LW, Sabek O, et al: The inflammatory cascade in acute pancreatitis: relevance to clinical disease, Surg Clin N Am 87:1325-1340, 2007. 14. Halangk W, Lerch MM: Early events in acute pancreatitis, Gastroenterol Clin N Am 33:717-731, 2004. 15. Mansfield C: Pathophysiology of acute pancreatitis: potential application from experimental models and human medicine to dogs, J Vet Intern Med 26:875-887, 2012. 16. Isenmann R, Henne-Bruns D, Adler G: Shock and acute pancreatitis, Best Pract Res Clin Gastroenterol 17:345-355, 2003. 17. Hess RS, Saunders HM, Van Winkle TJ, et al: Clinical, clinicopathologic, radiographic, and ultrasonographic abnormalities in dogs with fatal acute pancreatitis: 70 cases (1986-1995), J Am Vet Med Assoc 213:665-670, 1998. 18. Hess RS, Kass PH, Shofer FS, et al: Evaluation of risk factors for fatal acute pancreatitis in dogs, J Am Vet Med Assoc 214:46-51, 1999. 19. Cook AK, Breitschwerdt EB, Levine JF, et al: Risk factors associated with acute pancreatitis in dogs: 101 cases (1985-1990), J Am Vet Med Assoc 203:673-679, 1993. 20. Hill RC, Van Winkle TJ: Acute necrotizing pancreatitis and acute suppurative pancreatitis in the cat. A retrospective study of 40 cases (1976-1989), J Vet Intern Med 7:25-33, 1993. 21. Akol KG, Washabau RJ, Saunders HM, et al: Acute pancreatitis in cats with hepatic lipidosis, J Vet Intern Med 7:205-209, 1993. 22. Kimmel SE, Washabau RJ, Drobatz KJ, et al: Incidence and prognostic value of low plasma ionized calcium concentration in cats with acute pancreatitis: 46 cases (1996-1998), J Am Vet Med Assoc 219:1105-1109, 2001. 23. Klaus JA, Rudloff E, Kirby R: Nasogastic tube feeding in cats with suspected acute pancreatitis: 55 cases (2001-2006), J Vet Emerg Crit Care 19:337-346, 2009. 24. Parent C, Washabau RJ, Williams DA, et al: Serum trypsin-like immunoreactivity, amylase and lipase in the diagnosis of feline acute pancreatitis (abstract), J Vet Intern Med 9:194, 1995. 25. Son TT, Thompson L, Serrano S, et al: Surgical intervention in the management of severe acute pancreatitis in cats: 8 cases (2003-2007), J Vet Emerg Crit Care 20:426-435, 2010. 26. Gerhardt A, Steiner JM, Williams DA, et al: Comparison of the sensitivity of different diagnostic tests for pancreatitis in cats, J Vet Intern Med 15:329-333, 2001. 27. Forman MA, Marks SL, De Cock HEV, et al: Evaluation of serum feline pancreatic lipase immunoreactivity and helical computed tomography versus conventional testing for the diagnosis of feline pancreatitis, J Vet Intern Med 18:807-815, 2004. 28. Mansfield C, Watson PD, Jones BR: Specificity and sensitivity of serum canine pancreatic elastase-1 concentration in the diagnosis of pancreatitis, J Vet Diag Invest 23:691-697, 2011. 29. Xenoulis PG, Steiner JM: Canine and feline pancreatic lipase immunoreactivity, Vet Clin Pathol 41:312-324, 2012. 30. McCord K, Morley PS, Armstrong J, et al: A multi-institutional study evaluating the diagnostic utility of the Spec cPLTM and SNAP

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cPLTM in clinical acute pancreatitis in 84 dogs, J Vet Intern Med 26:888-896, 2012. 31. Saunders HM, Van Winkle TJ, Drobatz K, et al: Ultrasonographic findings in cats with clinical, gross pathologic, and histologic evidence of acute pancreatic necrosis: 20 cases (1994-2001), J Am Vet Med Assoc 221:17241730, 2002. 32. Jaeger JQ, Mattoon JS, Bateman SW, et al: Combined use of ultrasonography and contrast enhanced computed tomography to evaluate acute necrotizing pancreatitis in two dogs, Vet Radiol Ultrasound 44:72-79, 2003. 33. Van Enkevort BA, O’Brien RT, Young KM: Pancreatic pseudocysts in 4 dogs and 2 cats: ultrasonographic and clinicopathologic findings, J Vet Intern Med 13:309-313, 1999. 34. Nathens AB, Curtis JRC, Beale RJ, et al: Management of the critically ill patient with severe acute pancreatitis, Crit Care Med 32:2524-2536, 2004. 35. Hasibeder WR, Torgersen C, Rieger M, et al: Critical care of the patient with acute pancreatitis, Anaesth Intensive Care 37:190-206, 2009. 36. Banks PA, Freeman ML, Practice Parameters Committee of the American College of Gastroenterology: Practice guidelines in acute pancreatitis, Am J Gastroenterol 101:2379-2400, 2006. 37. Head LL, Daniel GB, Becker TJ, et al: Use of computed tomography and radiolabeled leukocytes in a cat with pancreatitis, Vet Radiol Ultrasound 46:263-266, 2005. 38. Chartier M, Hill S, Sunico S, et al: Evaluation of canine pancreas-specific lipase (Spec cPL) concentration and, amylase and lipase activities in peritoneal fluid as complementary diagnostic tools for acute pancreatitis in dogs (abstract), J Vet Intern Med 27:696, 2013. 39. Mofidi R, Patil PV, Suttie SA, et al: Risk assessment in acute pancreatitis, Br J Surg 96:137-150, 2009. 40. Mounzer R, Langmead CJ, Wu BU, et al: Comparison of existing clinical scoring systems to predict persistent organ failure in patients with acute pancreatitis, Gastroenterology 142:1476-1482, 2012. 41. Marshall JC, Cook DJ, Christou NV, et al: Multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome, Crit Care Med 23:1638-1652, 1995. 42. Papachristou GI, Clermont G, Sharma A, et al: Risk and markers of severe acute pancreatitis, Gastroenterol Clin N Am 36:277-296, 2007. 43. Ruaux CG, Atwell RB: A severity score for spontaneous canine acute pancreatitis, Aust Vet J 76: 804-808, 1998.

44. Holm JL, Rozanski EA, Freeman LM, et al: C-reactive protein concentrations in canine acute pancreatitis, J Vet Emerg Crit Care 14:183-286, 2004. 45. Wu BU, Hwang JQ, Gardner TL, et al: Lactated ringer’s solution reduces systemic inflammation compared with saline in patients with acute pancreatitis, Clin Gastroenterol Hepatol 9:710-717, 2011. 46. Karanjia ND, Lutrin FJ, Chang YB, et al: Low dose dopamine protects against hemorrhagic pancreatitis in cats, J Surg Res 48:440-443, 1990. 47. Lees T, Holliday M, Watkins M, et al: A multicentre controlled clinical trial of high-volume fresh frozen plasma therapy in prognostically severe acute pancreatitis, Ann R Coll Surg Engl 73:207-214, 1991. 48. Weatherton LK, Streeter EM: Evaluation of fresh frozen plasma administration in dogs with pancreatitis: 77 cases (1995-2005), J Vet Emerg Crit Care 19:617-622, 2009. 49. Olah A, Romics L: Evidence-based use of enteral nutrition in acute pancreatitis, Langenbecks Arch Surg 395:309-316, 2010. 50. Mansfield CS, James FE, Steiner JM, et al: A pilot study to assess tolerability of early enteral nutrition via esophagostomy tube feeding in dogs with severe acute pancreatitis, J Vet Intern Med 25:419-425, 2011. 51. Qin HL, Su ZD, Hu LG: Effect of early intrajejunal nutrition on pancreatic pathological features and gut barrier function in dogs with acute pancreatitis, Clin Nutr 21:469-473, 2002. 52. Al-Omran M, AlBalawi ZH, Tashkandi MF, et al: Enteral versus parenteral nutrition for acute pancreatitis (Review), Cochrane Database Syst Rev 1:CD002837, 2010. 53. Eatock FC, Chong P, Menezes N, et al: A randomized study of early nasogastric versus nasojejunal feeding in severe acute pancreatitis, Am J Gastroenterol 100:432-439, 2005. 54. Wittau M, Mayer B, Scheele J, et al: Systematic review and meta-analysis of antibiotic prophylaxis in severe acute pancreatitis, Scand J Gastroenterol 46:261-270, 2011. 55. Thompson LJ, Seshadri R, Raffe MR: Characteristics and outcomes in surgical management of severe acute pancreatitis: 37 dogs (2001-2007), J Vet Emerg Crit Care 19:165-173, 2009. 56. Freeman ML, Werner J, van Santvoort HC, et al: Interventions for necrotizing pancreatitis: summary of a multidisciplinary consensus conference, Pancreas 41:1176-1194, 2012. 57. Herman BA, Brawer RS, Murtaugh RJ, et al: Therapeutic percutaneous ultrasound-guided cholecystocentesis in three dogs with extrahepatic biliary obstruction and pancreatitis, J Am Vet Med Assoc 227:1782-1786, 2005.

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PART XII  •  INTRAABDOMINAL DISORDERS

CHAPTER 114  ACUTE CHOLECYSTITIS Mark P. Rondeau,

DVM, DACVIM (Internal Medicine)

KEY POINTS • Although clinical findings in dogs and cats with cholecystitis are often nonspecific, clinical pathologic and abdominal ultrasound findings are often essential for localizing the gallbladder as the source of disease. • Gallbladder mucocele is the most common disease of the gallbladder in dogs. However, the presence of cholecystitis is variable and depends on the degree of injury or vascular compromise to the gallbladder wall.

• Ultrasonographic appearance of echogenic fluid within the gallbladder fossa or generalized throughout the abdomen, echogenic reaction in the pericholecystic region, and radiographic evidence of decreased peritoneal detail are each sensitive indicators of gallbladder rupture and warrant surgical intervention regardless of the underlying cause of gallbladder disease.

CHAPTER 114  •  Acute Cholecystitis

Cholecystitis implies inflammation of the gallbladder; however, the term has been used to describe gallbladder-related symptoms in humans without confirmation of inflammation.1 In dogs and cats, two main histologic types of cholecystitis have been described: neutrophilic cholecystitis and lymphoplasmacytic, follicular cholecystitis.2 Most clinical descriptions in the veterinary literature involve neutrophilic cholecystitis. Cholecystitis may be caused by infectious agents, duct obstruction, blunt trauma, or systemic disease.3 Some common and significant gallbladder disease is not always associated with inflammation. In dogs, gallbladder mucocele is a major cause of clinical disease, and the presence of inflammation is variable depending on the degree of injury or vascular compromise to the gallbladder wall.2 Gallbladder infarction in dogs is thought to be a vascular disease that is not associated with inflammation of the gallbladder.4 Because these diseases may mimic cholecystitis clinically they are discussed in this chapter.

CLINICAL FINDINGS In general, patient signalment, history, and physical examination findings are nonspecific in dogs and cats with cholecystitis. Affected patients can be of any age, breed, or sex. Shetland Sheepdogs are predisposed to gallbladder disorders in general, and gallbladder mucocele in particular.5 Cocker spaniels also are overrepresented in surveys of dogs with gallbladder mucocele.6-8 Common historical findings include anorexia, lethargy, vomiting, and diarrhea. Some physical examination findings are similarly nonspecific (i.e., fever). However, many patients have abdominal pain, which helps to localize the disease to the abdominal cavity. Some patients are visibly icteric, which suggests that the hepatobiliary system may be the source of the problem. However, in most cases clinical pathologic data raise the suspicion of a hepatobiliary disorder and imaging (particularly abdominal ultrasound) is most useful for identifying the gallbladder as the source of the problem. Clinical pathologic findings consistent with hepatobiliary disease are common in dogs and cats with gallbladder disease. Serum biochemical analysis commonly reveals increased activity of hepatocellular and biliary epithelial enzymes, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and γ-glutamyltransferase (GGT). In cases with significant cholestasis or biliary obstruction, elevation in serum total bilirubin and cholesterol may be present. Hematologic analysis often reveals an inflammatory leukogram characterized by leukocytosis and neutrophilia. Once a suspicion of hepatobiliary disease is raised by the clinical findings, abdominal ultrasound is recommended to characterize the disease further. Specific imaging findings are discussed in the following sections.

COMMON CAUSES OF CHOLECYSTITIS IN DOGS AND CATS Infectious Agents Bacteria Bacterial infection is the most commonly reported infectious cause of cholecystitis in dogs and cats. Bacterial cholecystitis may be a component of neutrophilic cholangitis in cats (see Chapter 115). Bacterial species isolated from dogs and cats with cholecystitis are typically of enteric origin, most commonly Escherichia coli, Enterococcus spp., Bacteroides spp. and Clostridium spp.9-11 The underlying cause of bacterial infection in the bile often is unknown. Although the biliary tracts of dogs and cats are normally sterile, transient presence of low numbers of bacteria has been reported.12 Bacterial colonization of bile may occur via reflux of duodenal bacteria or by hematogenous spread through the portal vasculature. The presence

of bacteria within the bile, combined with increased biliary pressure as a result of an obstructive process, leads to infection of the bile and cholecystitis.12 The limited clinical descriptions of cholecystitis in the veterinary literature focus mainly on the canine disease.10,11 Clinical findings are nonspecific as described above but often include vomiting, lethargy, and anorexia. Abdominal ultrasound findings in dogs with cholecystitis may include hyper- or hypoechoic thickening of the gallbladder wall, distention of the gallbladder, and/or cystic duct and echogenic bile.10,11 The presence of gas within the lumen or wall of the gallbladder implies emphysematous cholecystitis, which is associated with infection by gas producing bacteria such as Escherichia coli and Clostridium spp.3 Necrotizing cholecystitis has been described to occur in three types: type I involves areas of necrosis without gallbladder rupture; type II involves acute inflammation with rupture; type III involves chronic inflammation with adhesions and/or fistulae to adjacent organs.10 The majority of dogs reported with necrotizing cholecystitis have had bacterial infection,10 although it can occur in the absence of infection secondary to gallbladder mucocele (see below). Recognition of existing or impending gallbladder rupture is critical because prompt surgical intervention is required. The ultrasonographic presence of echogenic fluid within the gallbladder fossa or generalized throughout the abdomen, echogenic reaction in the pericholecystic region, and radiographic evidence of decreased peritoneal detail are sensitive indicators of gallbladder rupture.13 In cases with peritoneal effusion, an effusion bilirubin concentration greater than twice the serum bilirubin confirms bile peritonitis (see Chapter 122).14 If gallbladder rupture is considered unlikely, cholecystitis may be treated medically.11 Ideally, this would involve antimicrobial selection based on culture and susceptibility testing results from bile obtained via ultrasound-guided cholecystocentesis. Empiric antimicrobial therapy should be directed at aerobic and anaerobic enteric flora. Although little information exists regarding the outcome of medically managed patients with cholecystitis, the prognosis for surgical intervention is guarded. High perioperative mortality is reported, with overall long-term survival ranging from 61% to 82% for dogs with bacterial cholecystitis undergoing surgery.10,13

Parasites Trematode parasites may inhabit the gallbladder and bile ducts of cats and rarely dogs, leading to cholecystitis and/or cholangitis.15,16 The most commonly identified organisms are the feline parasites Platynosomum concinnum and Amphimerus pseudofelineus. Both organisms have a similar life cycle, with their eggs ingested by a land snail, then entering a second intermediate host (fish or arthropod). Cats acquire infection by ingesting the second intermediate host. Adult worms develop in the gallbladder or bile ducts, causing varying degrees of illness ranging from nonspecific signs (anorexia, lethargy) to complete bile duct obstruction. Praziquantel appears to be the most effective treatment. Patients with severe infestations have a grave prognosis, with long-term survival rarely reported.

Obstruction Any obstruction to bile flow from the gallbladder leads to cholecystitis. Complete extrahepatic bile duct obstruction (EHBDO) results in dilation of the gallbladder and cystic duct within 24 hours, and dilation of intrahepatic bile ducts within 5 to 7 days.3 With more chronic obstruction, hepatic changes can occur, including hepatocyte necrosis, cholangitis, and periportal fibrosis.3 Potential causes of EHBDO are listed in Box 114-1. Cholelithiasis uncommonly is associated with cholecystitis in dogs and cats. Most choleliths are incidental findings. However, choleliths can cause cholecystitis by mechanical trauma or duct obstruction. Choleliths also may develop secondary to cholecystitis; increased

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PART XII  •  INTRAABDOMINAL DISORDERS

BOX 114-1 

Causes of Extrahepatic Bile Duct Obstruction in Dogs and Cats

Hepatobiliary Disorders

Duodenal Disorders

Cholangitis/cholecystitis/ choledochitis Gallbladder mucocele Cholelithiasis Neoplasia Cysts Biliary trematode infestation Inspissated bile

Neoplasia Intraluminal foreign body

Pancreatic Disorders

GALLBLADDER

0

1

2

Miscellaneous Disorders

2

Regional mass or lymphadenopathy Local peritonitis Iatrogenic (surgical ligation) Trauma (stricture/fibrosis)

4

6

Pancreatitis, acute or chronic Neoplasia 1 L 55.69 mm 2 L 58.87 mm

gallbladder mucin production and decreased gallbladder motility associated with inflammation may promote cholelith formation.17,18 Choleliths in dogs and cats are composed most commonly of calcium carbonate and bilirubin pigments (bilirubin or calcium bilirubinate), as opposed to the cholesterol stones that predominate in humans.3 Clinical signs may be absent in many cases. However, in cases with concurrent cholecystitis or bile duct obstruction, the clinical signs associated with those conditions are present. Abdominal ultrasound is the preferred imaging modality for identification of choleliths because radiopaque choleliths are reported in only 48% of dogs and 83% of cats with symptomatic cholelithiasis.17,18 Radiopaque stones may be less prevalent in asymptomatic patients. Although identification of choleliths during abdominal ultrasound may represent an incidental finding, the concurrent presence of bile duct distention and/or clinical signs and clinicopathologic evidence of cholecystitis warrants suspicion of gallbladder disease. In such cases, abdominal exploratory surgery is indicated and cholecystectomy may be the treatment of choice. Samples of liver, gallbladder, and bile should be obtained for biopsy and aerobic and anaerobic culture and susceptibility testing. Prognosis likely depends on the presence or absence of concurrent disease, bacterial infection, and/or gallbladder rupture. Reported long-term survival rates after surgery are 78% for cats and 41% for dogs.17,18

Gallbladder Mucocele Gallbladder mucocele is a condition exclusive to dogs that has been recognized at an increasing rate as the use of diagnostic abdominal ultrasound has become more common. The condition involves the accumulation of thick, mucin-laden bile within the gallbladder and bile ducts leading to varying degrees of obstruction to bile flow. Progressive distention of the gallbladder can lead to ischemic necrosis of the wall and resultant gallbladder rupture. Development of gallbladder mucocele is thought to result from a combination of increased mucin production and decreased gallbladder motility,3 although the cause of these changes is unknown. A genetic susceptibility to gallbladder mucocele must be considered because Shetland Sheepdogs, Cocker Spaniels, and Miniature Schnauzers appear to be at increased risk.5-8 An insertion mutation on the ABCB4 gene, which encodes for a protein that translocates phosphatidylcholine from the hepatocyte to the biliary canalicular lumen, has been associated with gallbladder mucocele formation in Shetland Sheepdogs and other breeds.19 The condition also has been associated with dsylipidemias and glucocorticoid excess. Dogs with hyperadrenocorticism have a significantly increased risk of developing gallbladder mucocele.20 Histopathologic examination of the gallbladder in affected dogs routinely reveals cystic mucinous hyperplasia (in addition to secondary

FIGURE 114-1  Ultrasonographic appearance of gallbladder mucocele in a dog.

changes such as necrotizing cholecystitis),6-8 which may be an incidental finding in older dogs and has been induced by administration of progestational compounds in the study that first described gallbladder mucoceles in dogs.21 Because the development of a gallbladder mucocele likely occurs gradually and the time of progression to necrotizing cholecystitis and/or gallbladder rupture is unknown, affected dogs may be identified incidentally. Increased activity of liver enzymes, hypercholesterolemia, and/or hyperbilirubinemia may be identified on routine screening serum biochemical analysis. Alternatively, the mucocele may be identified during abdominal ultrasound examination to evaluate another problem. Affected dogs are typically middle age to older, with a median age of 9 to 11 years, but dogs as young as 3 years of age have been reported.6-8 When clinical signs do occur as a result of gallbladder mucocele, they are often nonspecific, as described above for other forms of gallbladder disease. Vomiting, lethargy, and decreased appetite are seen most commonly. When present, these clinical signs are usually present for 1 week or less.6-8 Gallbladder mucocele usually is suspected on the basis of its hallmark ultrasonographic appearance (Figure 114-1). Echogenic, nonmobile material fills the distended gallbladder in either a stellate (resembling the cut surface of a kiwi fruit) or finely striated pattern, often with a hypoechoic rim along the wall.6 In contrast to nonpathologic bile sludge, the echogenic contents of the gallbladder mucocele do not move as the patient’s position is changed. As discussed previously, concurrent identification of echogenic fluid within the gallbladder fossa or generalized throughout the abdomen, or an echogenic reaction in the pericholecystic region suggests possible gallbladder rupture. Bacterial infection of the gallbladder or bile appears to be uncommon in dogs with gallbladder mucocele; it was reported in fewer than 10% of cases in most studies,7,8,13 with the exception of positive aerobic bile cultures in six of nine cases in one study.6 The optimal treatment plan for gallbladder mucocele in dogs is unknown. Most would agree that surgical intervention clearly is indicated in cases with ultrasonographic suspicion of gallbladder rupture.3,8 Surgical intervention also may be appropriate in dogs with clinicopathologic evidence of biliary obstruction (hyperbilirubinemia, hypercholesterolemia) and/or clinical signs consistent with cholecystitis and no other apparent cause aside from the mucocele. Some clinicians recommend surgical intervention as a preventive measure in any dog having an ultrasonographically identified gallbladder mucocele, even if the dog is asymptomatic.3 When surgical inter­ vention is pursued, cholecystectomy is the preferred treatment.

CHAPTER 114  •  Acute Cholecystitis

Cholecystotomy to remove gallbladder contents is contraindicated because the underlying cause of mucocele formation is not being addressed (resulting in recurrence of mucocele), and there may be areas of gallbladder necrosis, even in the absence of gross rupture (resulting in postoperative leakage). Biliary diversion techniques have been associated with a worse prognosis and also should be avoided.22 At the time of cholecystectomy, the common bile duct must be catheterized and thoroughly flushed to ensure patency. The excised gallbladder should be submitted for histopathologic examination as well as aerobic and anaerobic bacterial culture. Concurrent liver biopsy is recommended to evaluate for underlying disease. Medical management and strict patient surveillance may be considered in lieu of surgery for asymptomatic dogs. Nonsurgical resolution of gallbladder mucocele within 3 months has been reported in two dogs.23 Both of these dogs had hypothyroidism and were treated with ursodeoxycholic acid (UDCA) and levothyroxine after the mucocele was identified. One of the two also was treated with S-adenosylmethionine (SAMe), amoxicillin, and omega fatty acid supplementation. Although these two cases do not provide enough information to make recommendations regarding medical management, the use of UDCA has several potential benefits: it causes choleresis, has immunomodulatory properties, may decrease mucin secretion, and may improve gallbladder motility.3 UDCA is dosed at 10 to 15 mg/kg orally once to twice daily. SAMe also has hepatoprotective effects as a glutathione precursor and antioxidant and may have choleretic effects (shown at higher doses in cats).3 SAMe is given on an empty stomach for optimal absorption at a dose of 20 to 40 mg/kg daily. Antimicrobial therapy aimed at enteric flora also may be considered to treat potential bacterial cholangitis associated with the mucocele, although bacterial infection is uncommon, as discussed above. Ultimately, it should be stressed that gallbladder mucocele is a surgical disease, and attempting medical resolution assumes a risk of necrotizing cholecystitis and gallbladder rupture. Medical management should be undertaken only with intensive follow-up patient monitoring and client communication. The prognosis for dogs with gallbladder mucocele is guarded. The progression with medical management is unknown. Surgery carries a high perioperative mortality of 20% to 40%.6-8,23 However, dogs surviving the immediate postoperative period appear to have good long-term survival. Although the presence of gallbladder rupture may not be associated with a worse prognosis,7,8,13 septic bile peritonitis does carry a worse prognosis than sterile bile peritonitis.14

Gallbladder Infarction Gallbladder infarction is another condition of dogs that does not result in gallbladder inflammation but can present with clinical signs that mimic cholecystitis. This disease has been described in a small group of 12 dogs.4 Affected dogs ranged in age from 4 to 14 years. Clinical signs of fewer than 2 weeks’ duration include vomiting, anorexia, and diarrhea. Clinicopathologic findings also mimic cholecystitis with increased activity of liver enzymes, hyperbilirubinemia, and leukocytosis in more than 50% of cases. The diagnosis is confirmed by histopathology, and no hallmark diagnostic findings allow for a presurgical diagnosis. All 12 of the described dogs were treated by cholecystectomy. Gallbladder rupture was present at the time of surgery in 50% of the cases. Bacterial infection was documented in 25% of the cases, with isolation of enteric organisms (Escherichia coli, Clostridium spp.). Postoperative survival rate was 67%. Histologic findings in affected gallbladders include transmural coagulative necrosis with minimal to absent inflammation. Thrombi were identified in an artery supplying the gallbladder in 2 of 12 cases. An additional case had atherosclerotic changes in arterioles adjacent to the gallbladder. Another two dogs had evidence of distant

thrombosis of the spleen. Therefore the authors suggest that the gallbladder necrosis in affected dogs is a result of infarction that may be a sign of a more generalized hypercoagulable state. Three of the 12 dogs described were receiving treatment for hypothyroidism and another for hyperadrenocorticism. The role of these concurrent diseases in the pathogenesis of gallbladder infarction is unknown. Gallbladder infarction represents an uncommon condition in dogs that can mimic cholecystitis and can result in gallbladder rupture.

REFERENCES 1. Aguirre A: Diseases of the gallbladder and extrahepatic biliary system. In Ettinger SJ, Feldman EC, editors: Textbook of veterinary internal medicine, St Louis, 2010, Saunders Elsevier. 2. Cullen JM: Hepatobiliary histopathology. In Washabau RJ, Day MJ, editors: Canine and feline gastroenterology, St Louis, 2013, Elsevier Saunders. 3. Center SA: Diseases of the gallbladder and biliary tree, Vet Clin North Am Small Anim Pract 39:543-598, 2009. 4. Holt DE, Mehler SE, Mayhew PD, et al: Canine gallbladder infarction: 12 cases (1990-2003), Vet Pathol 41:416-418, 2004. 5. Aguirre AL, Center SA, Randolph JF, et al: Gallbladder disease in Shetland Sheepdogs: 38 cases (1995-2005), J Am Vet Med Assoc 231:79-88, 2007. 6. Besso JG, Wrigley RH, Gliatto JM, et al: Ultrasonographic appearance and clinical findings in 14 dogs with gallbladder mucocele, Vet Radiol Ultrasound 41:261-271, 2000. 7. Worley DR, Hottinger HA, Lawrence HJ: Surgical management of gallbladder mucoceles in dogs: 22 cases (1999-2003), J Am Vet Med Assoc 225:1418-1422, 2004. 8. Pike FS, Berg J, King NW, et al: Gallbladder mucocele in dogs: 30 cases (2000-2002), J Am Vet Med Assoc 224:1615-1622, 2004. 9. Wagner KA, Hartmann FA, Trepanier LA: Bacterial culture results from liver, gallbladder or bile in 248 cats and dogs evaluated for hepatobiliary disease: 1998-2003, J Vet Intern Med 21:417-424, 2007. 10. Church EM, Matthiesen DT: Surgical treatment of 23 dogs with necrotizing cholecystitis, J Am Anim Hosp Assoc 24:305-310, 1988. 11. Rivers BJ, Walter PA, Johnston GR, et al: Acalculous cholecystitis in four canine cases: ultrasonographic findings and use of ultrasonographicguided, percutaneous cholecystocentesis in diagnosis, J Am Anim Hosp Assoc 33:207-214, 1997. 12. Neel JA, Tarigo J, Grindem CB: Gallbladder aspirate from a dog, Vet Clin Pathol 35:467-470, 2006. 13. Crews LJ, Feeney DA, Jessen CR, et al: Clinical, ultrasonographic and laboratory findings associated with gallbladder disease and rupture in dogs: 45 cases (1997-2007), J Am Vet Med Assoc 234:359-366, 2009. 14. Ludwig LL, McLoughlin MA, Graves TK, et al: Surgical treatment of bile peritonitis in 24 dogs and 2 cats: a retrospective study (1987-1994), Vet Surg 26:90-98, 1997. 15. Bowman DD, Hendrix CM, Lindsay DS, et al: Feline clinical parasitology, Ames, Iowa, 2002, Iowa State University Press. 16. Foley RH: Platynosomum concinnum infection in cats, Compend Contin Educ Pract Vet 16:1271-1274, 1994. 17. Kirpensteijn J, Fingland RB, Ulrich T, et al: Cholelithiasis in dogs: 29 cases (1980-1990), J Am Vet Med Assoc 202:1137-1142, 1993. 18. Eich CS, Ludwig LL: The surgical treatment of cholelithiasis in cats: a study of 9 cases, J Am Anim Hosp Assoc 38:290-296, 2002. 19. Mealey KL, Minch JD, White SN, et al: An insertion mutation in ABCB4 is associated with gallbladder mucocele formation in dogs, Comp Hepatol 9:6, 2010. 20. Mesich MLL, Mayhew PD, Paek M, et al: Gallbladder mucoceles and their association with endocrinopathies in dogs: a retrospective case-control study, J Small Anim Pract 50:630-635, 2009. 21. Kovatch RM, Hildebrandt PK, Marcus LC: Cystic mucinous hypertrophy of the mucosa of the gallbladder in the dog, Pathol 2:574-584, 1965. 22. Amsellem PM, Seim HB, MacPhail CM, et al: Long-term survival and risk factors associated with biliary surgery in dogs: 34 cases (1994-2004), J Am Vet Med Assoc 229:1451-1457, 2006. 23. Walter R, Dunn ME, d’Anjou M, et al: Nonsurgical resolution of gallbladder mucocele in two dogs, J Am Vet Med Assoc 232:1688-1693, 2008.

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CHAPTER 115  HEPATITIS AND CHOLANGIOHEPATITIS Mark P. Rondeau,

DVM, DACVIM (Internal Medicine)

KEY POINTS • Hepatitis is defined as any inflammatory cell infiltrate within the hepatic parenchyma; the term cholangiohepatitis describes the extension of that inflammation to include the intrahepatic bile ducts. • Although many causes of hepatitis and cholangiohepatitis have been described in dogs and cats, the cause in many cases remains unknown. • A suspicion of hepatitis or cholangiohepatitis may be based on supportive historical, physical examination, and clinicopathologic findings that are similar for most causes of hepatic disease. A diagnosis of hepatitis or cholangiohepatitis is made ultimately via histopathologic evaluation of hepatic tissue. • The mechanisms of hepatocellular injury in animals with hepatitis and cholangiohepatitis are poorly understood. Elucidation of these mechanisms may provide the basis for future therapeutic options. • Successful treatment of the patient with hepatitis or cholangiohepatitis involves addressing the underlying disease or inciting cause and providing aggressive symptomatic therapy and supportive care.

Hepatitis is defined as any inflammatory cell infiltrate within the hepatic parenchyma, and the term cholangiohepatitis describes extension of that inflammation to include the intrahepatic bile ducts.1 A diagnosis of these conditions is based on histopathologic examination of hepatic biopsy specimens. The histopathologic appearance gives clues regarding the duration of the inflammation. Acute hepatitis is characterized by a combination of inflammation, hepatocellular apoptosis, necrosis, and possibly regeneration, but a lack of fibrosis. The relationship between the development of hepatitis and necrosis is complex, and it can be difficult to determine which abnormality was the initial lesion.1 Chronic hepatitis, on the other hand, is identified by the presence of fibrosis, proliferation of ductular structures, and regenerative nodules in addition to an inflammatory infiltrate, apoptosis, and/or necrosis.2 The type of inflammatory cellular infiltrate may give the clinician some clues regarding the cause. Occasionally, causative agents are identified within biopsy specimens. However, the cause remains unknown for many cases of hepatitis and cholangiohepatitis in dogs and cats. This chapter discusses the clinical presentation of animals with hepatitis and cholangiohepatitis and outlines the most commonly recognized clinical syndromes with respect to diagnosis and treatment of the specific disease. Effective treatment of patients with hepatitis or cholangiohepatitis includes specific therapy of any identified inciting cause and aggressive symptomatic and supportive therapy. A discussion of symptomatic treatment and supportive therapy for the sequelae of hepatitis and cholangiohepatitis can be found in Chapter 116.

HISTORICAL FINDINGS In general, the historical findings associated with hepatitis are nonspecific, as with most types of liver disease. Exposure to certain 610

etiologic agents or toxins may be ascertained from the client history and thus raise the suspicion for hepatic involvement. Because of the large reserve capacity of the liver, a short duration of clinical signs does not necessarily indicate acute disease. Animals with cholangiohepatitis (CH) may not show outward clinical signs until a significant portion of hepatic function is affected. Presenting owner complaints for animals with hepatitis may include vomiting, diarrhea, anorexia, lethargy, polyuria, polydipsia, abdominal distention, dysuria, neurologic abnormalities associated with hepatic encephalopathy or vascular accidents, and icterus.

PHYSICAL EXAMINATION FINDINGS Similar to historical findings, the physical examination findings in animals with hepatitis are often nonspecific. Icterus, when present in the absence of hemolytic anemia, suggests disease of the hepatic parenchyma or extrahepatic biliary system. Animals with acute hepatitis are more likely to have fever and abdominal pain, and those with CH are more likely to have ascites. Hepatomegaly may be present in some patients, especially those with acute hepatitis. Many animals with hepatitis do not have any of these physical abnormalities present on the initial examination, and serum biochemical changes in those cases are likely to direct the clinician toward the liver as the site of disease.

MECHANISMS OF HEPATOCELLULAR INJURY The pathogenesis by which hepatitis and cholangiohepatitis lead to hepatocellular necrosis and apoptosis is not understood completely. Experimental studies have suggested many mechanisms of hepatocellular injury, but their specific evaluation in dogs and cats with hepatitis is lacking. Mechanisms of hepatocellular injury that are not specific to hepatitis include tissue hypoxia, lipid peroxidation, intracellular cofactor depletion, intracellular toxin production, cholestatic injury, endotoxic insults, and hepatocyte plasma membrane injury.3 Hepatocytes are especially susceptible to anoxia because the liver receives a mixture of venous and arterial blood. Hypoxic damage quickly leads to plasma membrane and cytosolic organelle injury secondary to adenosine triphosphate (ATP) depletion. Free radicals may cause oxidative cellular injury that can result in lipid peroxidation and subsequent plasma membrane damage. Cellular toxins may bind to nucleic acids and inhibit protein synthesis. Cholestasis causes retention of bile acids that directly damage cellular organelles. Endotoxins work via various mechanisms, most of which involve stimulation of inflammatory cells to produce inflammatory mediators (cytokines such as prostaglandins and leukotrienes) that perpetuate inflammation within the liver parenchyma. Experimental work in mouse models suggests an important role for tumor necrosis factor-α (TNF-α) in the initiation and perpetuation of hepatitis. TNF-α, produced secondary to the interaction of the costimulatory molecules CD154 on T cells and

CHAPTER 115  •  Hepatitis and Cholangiohepatitis

CD40 on hepatocytes and Kupffer cells, stimulates hepatocyte apoptosis through the Fas-Fas ligand pathway.4 A better understanding of the complex mechanisms of hepatocellular injury in animals with hepatitis may encourage the development of novel therapeutic modalities for affected patients.

Protothecosis

Hepatotoxins

Lymphocytic Cholangitis

Acetaminophen Aflatoxin Amiodarone Aspirin Azathioprine Azole antifungals Carprofen Cycads (e.g., Sago palm) Diazepam (oral) Halothane Lomustine Methimazole Phenobarbital Phenytoin Primidone Tetracyclines Trimethoprim/sulfadiazine or sulfamethoxazole Xylitol Zonisamide

Lymphocytic cholangitis (LC) is a chronic form of disease that is characterized histologically by a mixed inflammatory infiltrate (typically small lymphocytes, or lymphocytes and plasma cells) within portal areas and is associated with varying degrees of fibrosis and bile duct hyperplasia.7 Inflammation within the walls or lumens of intrahepatic bile ducts may be present but is not a specific hallmark of the disease. LC likely includes a wide spectrum of clinical diseases with varying severity and clinical significance.14 LC likely includes syndromes that have been referred to previously as chronic cholangiohepatitis, nonsuppurative cholangitis-cholangiohepatitis, and lymphocytic portal hepatitis.5,8,9,12 The clinical picture of cats with LC varies widely and has significant overlap with other forms of hepatobiliary disease in cats, including NC.10,11 Nonspecific clinical signs, including anorexia, lethargy, vomiting, and weight loss, may be chronic and intermittent.8 Physical examination findings may include icterus, hepatomegaly, or ascites, but none are consistent findings. Signs of hepatic encephalopathy (dullness, ptyalism, seizures) may develop in severely affected cats. Definitive diagnosis is made by liver biopsy. As discussed for NC, ancillary diagnostics

Box 115-1 lists the reported causes of hepatitis and cholangiohepatitis in dogs and cats. A complete discussion of all disease entities is beyond the scope of this chapter. A discussion of the most common clinical syndromes follows.

Idiopathic Causes Feline cholangitis complex The feline cholangitis complex is one of the most common hepatobiliary disorders in cats.5 This syndrome has been reported in dogs6 but is primarily a feline disease. Several classification schemes have been proposed to define the various elements of this syndrome. The World Small Animal Veterinary Association (WSAVA) Liver Standardization Group has proposed a classification system that divides

Causes of Hepatitis and Cholangiohepatitis in Dogs and Cats

Idiopathic

Parasitic

Canine chronic hepatitis Feline cholangitis complex Nonspecific reactive hepatitis Lobular dissecting hepatitis

Visceral larval migrans Dirofilariasis (caudal vena caval syndrome) Liver fluke migration Schistosomiasis Echinococcus cysts

Viral Infectious canine hepatitis (adenovirus type I) Acidophil cell hepatitis Herpesvirus (neonates) Feline infectious peritonitis

Bacterial Feline cholangitis complex Leptospirosis Bartonellosis Tyzzer’s disease (Clostridium piliforme) Salmonellosis Listeriosis Tularemia Brucellosis Yersiniosis Helicobacter spp. Mycobacteria Septicemia

Rickettsial Ehrlichiosis Rocky Mountain spotted fever

Protozoal Toxoplasmosis Neosporosis Leishmaniasis Cytauxzoonosis Hepatozoonosis Coccidiosis

Neutrophilic Cholangitis Histologically, neutrophilic cholangitis (NC) is characterized by infiltration of neutrophils within the wall or lumen of intrahepatic bile ducts. This disease can be seen in acute and chronic stages. In acute neutrophilic cholangitis (ANC), edema and neutrophilic inflammation may extend into the portal areas. In chronic neutrophilic cholangitis (CNC), a mixed inflammatory infiltrate may be noted in portal areas, along with varying degrees of fibrosis and bile duct hyperplasia.7 This syndrome was referred to previously as acute cholangiohepatitis or suppurative cholangitis-cholangiohepatitis.8,9 NC can occur in cats of any age, breed, or sex. Clinical signs are nonspecific and include anorexia, lethargy, vomiting, and weight loss. The duration of these clinical signs ranges from a few days to a few months and may be shorter in cats with ANC than in those with CNC,8 but this is not a consistent finding.10,11 Physical examination findings commonly include dehydration and icterus. Fever is present in 19% to 37.5% of cases.10,12 Some reports suggest that fever is associated more commonly with ANC than CNC,12 whereas others recognize no difference.10,11 Hepatomegaly is seen in fewer than half of the cases and abdominal pain is noted occasionally.8,10,11 Biochemical analysis commonly reveals increased activity of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and γ-glutamyltransferase (GGT) ranging in severity from mild to severe. However, increased liver enzyme activity may be absent in some cases.13 Cholangitis in cats has been associated with inflammatory bowel disease (IBD) and pancreatitis,12 and many investigators believe that NC is the result of an ascending bacterial infection from the gastrointestinal (GI) tract. However, rates of bacterial isolation using traditional methods have varied greatly, from less than 20% to more than 60% in affected cats.8,10 When isolated, common bacterial species include Escherichia coli, Enterococcus spp., Clostridium spp., and Staphylococcus spp. Samples for aerobic and anaerobic bacterial cultures should be obtained in any cat suspected of having cholangitis; gallbladder bile is preferred to liver tissue as the culture source.14 Treatment with a broad-spectrum antimicrobial therapy, focusing on enteric flora, is recommended pending results of culture and susceptibility testing. Prognosis for cats with NC is typically good with aggressive treatment, although sequelae may include bile duct obstruction, acute necrotizing pancreatitis, sepsis, and multiple organ dysfunction.

CAUSES OF HEPATITIS AND CHOLANGIOHEPATITIS IN DOGS AND CATS

BOX 115-1 

feline cholangitis into two main categories: neutrophilic cholangitis and lymphocytic cholangitis.7

Fungal Histoplasmosis Blastomycosis Coccidioidomycosis Aspergillosis (disseminated) Phycomycosis

Algal

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provide information to support hepatobiliary disease but are not specific for LC. Activity of serum liver enzymes is increased in many but not all cases and varies in severity. Abdominal radiographic and ultrasonographic findings are nonspecific but may aid in the recognition of concurrent disease. The cause of LC is unknown, although a chronic response to an ascending bacterial infection from GI flora and an association with IBD and pancreatitis (as seen with NC) has been suggested.8,9 Immunohistochemical analysis of hepatic biopsy specimens from cats with LC has shown a predominance of CD3+ T cells infiltrating the bile duct epithelium and periportal areas, a smaller proportion of B cells forming discrete aggregates in the portal regions, and expression of major histocompatibility complex class II on the biliary epithelium.15,16 These findings, combined with anecdotal response to glucocorticoid therapy and the fact that active infection has been documented rarely in cats with LC, have led to the suspicion that LC is an immune-mediated disease. Treatment typically involves immunosuppressive glucocorticoid therapy in animals with no evidence of infection. Treatment with ursodeoxycholic acid (10 to 15 mg/kg PO q24h) has anecdotal and theoretic benefits, although no clinical studies examining its efficacy in cats have been published. Prognosis is typically good with appropriate management, although concurrent disease is common and may affect prognosis.

Canine chronic hepatitis Although many causes of chronic hepatic inflammation in dogs have been identified, the term canine chronic hepatitis (CCH) describes an idiopathic, progressive necroinflammatory disease of unknown cause that is common in the canine population.1 Evidence supports an immune-mediated process as the perpetuating factor,1,17,18 although it is unclear whether the disease is a primary or secondary immune response. Because of the chronic nature of the disease and the large reserve capacity of the liver, many affected animals are not identified until the onset of fulminant hepatic failure. However, increasing numbers of cases are now being identified at an earlier asymptomatic stage as a result of increased hepatic enzyme activity that is noted on routine serum biochemical screening. Animals of any age and sex are affected, although middle-age female dogs may be overrepresented. CCH is seen with increased frequency in certain breeds (Box 115-2), suggesting a familial predisposition. No specific diagnostic findings separate CCH from other causes of hepatitis. Ultimately, the diagnosis is based on histopathologic examination of liver tissue revealing inflammation (usually lymphocytic and plasmacytic, occasionally neutrophilic), necrosis and/or apoptosis, evidence of regeneration, fibrosis and/or

BOX 115-2 

Breeds Predisposed to Chronic Hepatitis

American Cocker Spaniel Bedlington Terrier* Dalmatian* Doberman Pinscher* English Cocker Spaniel English Springer Spaniel Labrador Retriever* Skye Terrier* Standard Poodle West Highland White Terrier* *Proven or suspected copper-associated hepatopathy.

hyperplasia of ductular structures and the absence of an identifiable underlying cause.1 The optimal treatment protocol for animals with CCH has not been well studied, but immunosuppressive therapy is the mainstay of treatment. Corticosteroids are the only class of drug shown potentially to provide benefit19 and their use is indicated in patients with signs of hepatic failure. Other immunomodulatory drugs that may be used include ursodeoxycholic acid, metronidazole, azathioprine, and cyclosporine. Colchicine may delay progression of hepatic fibrosis. Copper chelation may be beneficial when copper retention is a significant contributing factor. The overall prognosis is difficult to ascertain because asymptomatic animals may have a slowly progressive course and excellent prognosis. However, once hepatic failure and/or cirrhosis develops, the prognosis is poor.

Role of Copper The role of copper in the pathogenesis of CCH is unclear. Elevated hepatic copper levels have been identified in many dogs with CCH, but because biliary excretion is the major mechanism of maintaining copper homeostasis, any cause of cholestasis would be expected to increase hepatic copper levels.18 However, it has been shown in the Bedlington Terrier that elevated copper levels (caused by an inherited defect in excretion) lead to chronic hepatitis and cirrhosis.1 However, it may be difficult to determine which came first, the copper accumulation or the hepatitis. A propensity for increased hepatic copper levels in association with CCH has been described for many breeds in addition to the Bedlington Terrier, and these are listed in Box 115-2. A suspected primary hepatic copper storage disorder also has been reported in one cat.20 Whether the copper accumulation is a primary or secondary event, the excessive copper is damaging to hepatocytes. Copper chelation treatment has improved or resolved the hepatic pathologic findings in a group of Doberman Pinschers with elevated hepatic copper levels and subclinical CCH.21 Hepatic tissue should be harbored for copper quantification in any dog undergoing liver biopsy. If elevated levels are identified, a reduction of dietary copper and chelation with d-penicillamine (10 to 15 mg/ kg q12h, given 1 to 2 hours before feeding) or trientine (10 to 15 mg/ kg q12h, given 1 to 2 hours before feeding) are likely to be beneficial.

Nonspecific reactive hepatitis Nonspecific reactive hepatitis is a histologic diagnosis that describes the liver’s response to a variety of extrahepatic disease processes. The lesion is characterized by widespread inflammatory infiltrates (usually lymphocytes and plasma cells) in the portal areas and parenchyma in the absence of hepatocellular necrosis.2 Identification of this lesion should alert the clinician that a liver-specific problem is unlikely and that further investigation into the underlying disease process is necessary.

Viral Causes Viral hepatitis is uncommon in dogs and cats. Most viral infections carry a poor prognosis. Specific therapy is not available or has not been evaluated. Symptomatic therapy and supportive care are therefore the primary therapeutic options.

Infectious canine hepatitis Infectious canine hepatitis is caused by canine adenovirus type I. This disease has become rare because of extensive vaccination protocols using the cross-reacting adenovirus type II vaccine. As such, the disease is seen only in young, unvaccinated dogs. The degree of antibody response determines the severity of disease, with a poor

CHAPTER 115  •  Hepatitis and Cholangiohepatitis

response resulting in an acutely fatal syndrome. Animals that mount an appropriate response may recover or develop CH. Corneal edema and anterior uveitis may develop in animals that recover from acute illness. The diagnosis is made by histopathologic identification of large basophilic to amphophilic intranuclear inclusion bodies within hepatocytes and Kupffer cells that are identified during the first week of infection.15 Histopathology also reveals multifocal coagulative necrosis and a neutrophilic inflammatory infiltrate that may not be present in animals with severe acute infection.

Feline infectious peritonitis Feline infectious peritonitis (FIP) is caused by the feline enteric coronavirus. FIP can affect any organ in the body. Cats with hepatic involvement often have increased activities of ALT and AST and develop hyperbilirubinemia as the disease progresses. Histologic lesions include multifocal necrosis (often around blood vessels) with associated infiltration with neutrophils and macrophages. Pyogranulomatous lesions may be noted on the liver capsule.17 Immunohistochemistry can be performed on liver biopsy specimens to confirm the presence of virus.22 When hepatic involvement occurs, the disease is uniformly fatal. Because there is no definitive treatment, supportive care is the mainstay of therapy.

Bacterial Causes Leptospirosis Leptospirosis is caused by any one of several serovars of spiral bacteria belonging to the species Leptospira interrogans sensu lato. The commonly isolated serovars in small animals include Leptospira icterohaemorrhagiae, Leptospira canicola, Leptospira pomona, Leptospira hardjo, Leptospira grippotyphosa, and Leptospira bratislava. Infection in dogs most commonly results in acute renal failure, although hepatic involvement may occur in 20% to 35% of cases.3,23 Other clinical manifestations of infection include pulmonary hemorrhage, uveitis, and acute fever.24 Infection in young animals and infection with serovars L. icterohaemorrhagiae and L. pomona are more likely to result in hepatic involvement.25 Affected dogs may show acute hepatitis or develop chronic hepatitis with subclinical acute infection. Although cats are generally resistant to leptospirosis, experimental infection with L. pomona has caused hepatic lesions in this species.3 Patients with hepatic involvement show increased activity of hepatic enzymes (ALT, AST, ALP), although ALP often is affected most severely. Hyperbilirubinemia and signs of hepatic failure may occur. Diagnosis of leptospirosis usually is based on clinical suspicion because of renal and hepatic involvement combined with serologic evidence of infection. However, antibody titers may be negative during the first week of infection, and antibody production may persist for only 2 to 6 weeks.3 Suspected patients with negative antibody titers and a short duration of illness should be treated as though they have leptospirosis, and antibody titers should be repeated in 2 weeks. Histopathologic changes in the liver of affected animals may include coagulative necrosis and infiltration of lymphocytes and plasma cells with lesser numbers of neutrophils and macrophages. Organisms may be identified in biopsy specimens with silver staining, but this is an insensitive diagnostic test. Polymerase chain reaction (PCR) techniques to detect organisms in blood and urine samples are available. These techniques have not been well studied in dogs with clinical disease, but they are likely to make this diagnosis less challenging in the future. Historically, treatment recommendations have included penicillin to eliminate the leptospiremic stage, followed by doxycycline to eliminate the carrier state. However, treatment with doxycycline alone is effective for the leptospiremic stage and carrier state (5 mg/kg PO/IV q12h).24 Penicillins may be used in animals that do not tolerate doxycycline. Alternative antibiotic

24

choices include azithromycin, ceftriaxone, and cefotaxime. Prognosis is typically good, but patients often require intensive supportive care, including hemodialysis in animals with oliguric or anuric renal failure. Pulmonary involvement worsens prognosis.

Bartonellosis Bartonella species are arthropod-transmitted bacteria that have been associated with multiple clinical syndromes in veterinary medicine.26 Bartonella henselae and Bartonella clarridgeiae have been identified as causes of hepatic disease in dogs.27 Clinical findings are similar to those of dogs with other causes of hepatitis. Histologic examination of hepatic tissue from dogs with B. henselae infection has revealed peliosis hepatis28 and granulomatous hepatitis,27 both of which have been described in infected humans. Diagnosis was made via identification of Bartonella DNA using PCR techniques on hepatic biopsy specimens. This is the preferred method of diagnosis because serologic assays impart information only regarding exposure, and granulomatous hepatitis may be caused by other agents. The cause of granulomatous hepatitis in dogs frequently is unknown, although reported causes include fungal infection, mycobacterial infection, dirofilariasis, lymphoma, histiocytosis, and intestinal lymphangiectasia.29 Azithromycin is the antibiotic of choice for treatment of bartonellosis, although its use in dogs with hepatic disease caused by Bartonella spp. has not been evaluated thoroughly. Other antibiotics that may be effective include doxycycline (high dose, 10 to 15 mg/kg q12h), enrofloxacin, and rifampin (in combination with doxycycline or enrofloxacin).26

Septicemia An important cause of hepatitis in critically ill dogs and cats is bacterial seeding of the liver secondary to bacteremia or via translocation from the GI tract. Commonly isolated aerobic bacteria include Staphylococcus spp., Streptococcus spp., and enteric gramnegative organisms. Commonly identified anaerobes include Bacteroides spp., Clostridium spp., and Fusobacterium spp.3 The diagnosis of bacteremia can be difficult in veterinary patients (see Chapter 91). Septicemia-induced hepatitis should be suspected in critically ill animals that develop clinicopathologic evidence of hepatic disease while hospitalized, especially those in which bacterial infection or severe GI disease have been documented. Treatment with broad-spectrum antimicrobials (pending sensitivity testing), along with aggressive supportive care, are vital to a successful outcome.

Drugs and Toxins The liver is particularly susceptible to toxic injury because it receives blood from the portal circulation. Histologic changes in the liver secondary to toxic injury vary and may include no changes, hepatocellular swelling, steatosis, necrosis, cholestasis, inflammation, and/ or fibrosis.2 Several substances reported to cause hepatotoxicity are noted in Box 115-1, but this is by no means an exhaustive list. Because of the varying and nonspecific nature of histologic changes, diagnosis of hepatotoxicity often is made on the basis of clinical suspicion (biochemical alterations, such as marked increases in liver enzyme activity) with or without a history of known exposure. Treatment involves removal of the offending agent and aggressive supportive care. S-Adenosylmethionine (SAMe) (20 mg/kg PO q24h) has been effective in treating acetaminophen toxicity.30,31 Although its effectiveness against other forms of hepatotoxicity has not been evaluated, it is a logical choice for supportive care in animals suffering any hepatotoxic insult, mainly because of its ability to increase hepatic glutathione levels, which may increase antioxidant and repair abilities.

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REFERENCES 1. Johnson SE: Parenchymal disorders. In Washabau RJ, Day MJ, editors: Canine and feline gastroenterology, St Louis, 2013, Elsevier Saunders. 2. van den Ingh TSGAM, Van Winkle T, Cullen JM, et al: Morphological classification of the parenchymal disorders of the canine and feline liver. In Rothuizen J, Bunch SE, Charles JA, et al, editors: WSAVA standards for clinical and histological diagnosis of canine and feline liver disease, Edinburgh, 2006, Saunders Elsevier. 3. Center SA: Acute hepatic injury: hepatic necrosis and fulminant hepatic failure. In Guilford WG, et al, editors: Strombeck’s small animal gastroenterology, ed 3, Philadelphia, 1996, WB Saunders Company. 4. Zhou F, Ajuebor MN, Beck PL, et al: CD154-CD40 interactions drive hepatocyte apoptosis in murine fulminant hepatitis, Hepatology 42:372380, 2005. 5. Gagne JM, Weiss DJ, Armstrong PJ: Histopathologic evaluation of feline inflammatory liver disease, Vet Pathol 33:521-526, 1996. 6. Forrester SD, Rogers KS, Relford RL: Cholangiohepatitis in a dog, J Am Vet Med Assoc 200:1704-1706, 1992. 7. van den Ingh TSGAM, Cullen JM, Twedt DC, et al: Morphological classification of biliary disorders of the canine and feline liver. In Rothuizen J, Bunch SE, Charles JA, et al, editors: WSAVA standards for clinical and histological diagnosis of canine and feline liver disease, Edinburgh, 2006, Saunders Elsevier. 8. Center SA: The cholangitis/cholangiohepatitis complex in the cat. In Proceedings, 12th Am Coll Vet Intern Med, 766-771, 1994. 9. Weiss DJ, Gagne JM, Armstrong PJ: Relationship between inflammatory hepatic disease and inflammatory bowel disease, pancreatitis, and nephritis in cats, J Am Vet Med Assoc 209:1114-1116, 1996. 10. Rondeau MP: WSAVA classification and role of bacteria in feline inflammatory hepatobiliary disease. In Proceedings, Forum Am Coll Vet Intern Med, 590-591, 2009. 11. Morgan M, Rondeau M, Rankin S, et al: A survey of feline inflammatory hepatobiliary disease using the WSAVA classification, J Vet Intern Med 22:860A, 2008. 12. Gagne JM, Armstrong PJ, Weiss DJ, et al: Clinical features of inflammatory liver disease in cats: 41 cases (1983-1993), J Am Vet Med Assoc 214:513516, 1999. 13. Callahan Clark JE, Haddad J, Brown DC, et al: Feline cholangitis: a necropsy study of 44 cats (1986-2008), J Feline Med Surg 13:570-576, 2011. 14. Rondeau MP: Intrahepatic biliary disorders. In Washabau RJ, Day MJ, editors: Canine and feline gastroenterology, St Louis, 2013, Elsevier Saunders. 15. Day MJ: Immunohistochemical characterization of the lesions of feline progressive lymphocytic cholangitis/cholangiohepatitis, J Comp Pathol 119:135-147, 1998.

16. Warren A, Center S, McDonough S, et al: Histopathologic features, immunophenotyping, clonality, and eubacterial fluorescence in situ hybridization in cats with lymphocytic cholangitis/cholangiohepatitis, Vet Pathol 48:627-641, 2011. 17. Center SA: Chronic hepatitis, cirrhosis, breed-specific hepatopathies, copper storage hepatopathy, suppurative hepatitis, granulomatous hepatitis, and idiopathic hepatic fibrosis. In Guilford WG, et al, editors: Strombeck’s small animal gastroenterology, ed 3, Philadelphia, 1996, WB Saunders Company. 18. Boisclair J, Doré M, Beauchamp G, et al: Characterization of the inflammatory infiltrate in canine chronic hepatitis, Vet Pathol 38:628-635, 2001. 19. Strombeck DR, Miller LM, Harrold D: Effects of corticosteroid treatment on survival time in dogs with chronic hepatitis: 151 cases (1977-1985), J Am Vet Med Assoc 193:1109-1113, 1988. 20. Meertens NM, Bokhove CA, van den Ingh TSGAM: Copper-associated chronic hepatitis and cirrhosis in a European Shorthair cat, Vet Pathol 42:97-100, 2005. 21. Mandigers PJ, van den Ingh TSGAM, Bode P, et al: Improvement in liver pathology after 4 months of D-penicillamine in 5 Doberman Pinschers with subclinical hepatitis, J Vet Int Med 19:40-43, 2005. 22. Giori L, Giordano A, Giudice C, et al: Performances of different diagnostic tests for feline infectious peritonitis in challenging clinical cases, J Small Anim Pract 52:152-157, 2011. 23. Adin CA, Cowgill LD: Treatment and outcome of dogs with leptospirosis: 36 cases (1990-1998), J Am Vet Med Assoc 216:371-375, 2000. 24. Sykes JE, Hartmann K, Lunn KF, et al: 2010 ACVIM small animal consensus statement on leptospirosis: diagnosis, epidemiology, treatment and prevention, J Vet Intern Med 25:1-13, 2011 25. Greene CE, Sykes LE, Moore GE, et al: Leptospirosis. In Greene CE, editor: Infectious diseases of the dog and cat, ed 4, St Louis, 2012, Elsevier Saunders. 26. Breitschwerdt EB, Chomel BB: Canine bartonellosis. In Greene CE, editor: Infectious diseases of the dog and cat, ed 4, St Louis, 2012, Elsevier Saunders. 27. Gillespie TN, Washabau RJ, Goldschmidt MH, et al: Detection of Bartonella henselae and Bartonella clarridgeiae DNA in hepatic specimens from two dogs with hepatic disease, J Am Vet Med Assoc 222:47-51, 2003. 28. Kitchell BE, Fan TM, Kordick D, et al: Peliosis hepatic in a dog infected with Bartonella henselae, J Am Vet Med Assoc 216:519-523, 2000. 29. Chapman BL, Hendrick MJ, Washabau RJ: Granulomatous hepatitis in dogs: nine cases (1987-1990), J Am Vet Med Assoc 203:680-684, 1993. 30. Wallace KP, Center SA, Hickford FH, et al: S-adenosylmethionine (SAMe) for the treatment of acetaminophen toxicity in a dog, J Am Anim Hosp Assoc 38:246-254, 2002. 31. Song Z, McClain CJ, Chen T: S-Adenosylmethionine protects against acetaminophen-induced hepatotoxicity in mice, Pharmacology 71:199208, 2004.

CHAPTER 116  HEPATIC FAILURE Allyson Berent,

DVM, DACVIM (Internal Medicine)

KEY POINTS • Hepatic failure typically holds a poor prognosis; a prompt diagnosis, search for an underlying cause, and rapid and appropriate treatment are critical for survival. • Hepatic encephalopathy and coagulopathy are typically the main clinical consequences of hepatic failure and should be treated accordingly. • Therapy should be aimed at minimizing signs of encephalopathy and treating the underlying pathology, thereby allowing the liver to regenerate. • Researchers currently are exploring adipose-derived mesenchymal stem cell therapy and liver replacement therapy. This has potential promise for veterinary medicine.

Liver failure occurs as a result of severe hepatocyte injury or dysfunction, regardless of the cause,1-3 manifesting as an acute or chronic process. The loss of hepatic function leads to a spectrum of metabolic derangements, which results in devastating clinical consequences and most commonly the clinical onset of hepatic encephalopathy and coagulopathy. Other complications associated with this state include gastrointestinal ulceration, bacterial sepsis, cardiopulmonary dysfunction, and ascites. Before the development of hepatic transplantation, liver failure had a mortality rate greater than 90% in people.1,2 Early detection, treatment, and aggressive supportive care is critical to embracing the regenerative capacity of the liver because it is capable of regenerating 75% of its functional capacity in only a few weeks. Common causes of liver disease that can result in failure in dogs and cats are listed in Table 116-1.4-6

PATHOPHYSIOLOGY The histologic changes seen in the liver of patients with acute or chronic liver failure are variable and depend on the underlying cause. Acute liver diseases are likely to display hepatocellular necrosis as the prominent lesion. Fat accumulation or hepatocellular drop-out also may be noted. A chronically diseased liver also may demonstrate hepatocellular necrosis, but fibrosis, inflammation, and hyperplasia of ductular structures are often present as well. Patients with hepatic failure display common physiologic clinical features, regardless of the cause. These include hypotension, lactic acidosis resulting from the poor oxygen uptake by muscles and peripheral tissues combined with decreased hepatic lactate metabolism, electrolyte alterations, hepatic encephalopathy, and coagulopathy. Over time, dysfunction of multiple organ systems can occur. In people, acute kidney injury is a common sequela to liver failure (hepatorenal syndrome),7 although this is described rarely in veterinary patients.5

Hepatic Encephalopathy Hepatic encephalopathy (HE), the hallmark feature of hepatic failure, is a neuropsychiatric syndrome involving many neurologic abnor-

malities. The pathogenesis of HE is understood incompletely in veterinary and human medicine and typically occurs when more than 70% of hepatic function is lost.2,4,8-11 This results in the central nervous system (CNS) entering an encephalopathic state. More than 20 different compounds have been found in excess in the circulation when liver function is impaired, including ammonia, aromatic amino acids, endogenous benzodiazepines, γ-aminobutyric acid (GABA), glutamine, short-chain fatty acids, tryptophan, and others (Table 116-2).4,8,9,11,12 These substances may impede neuronal and astrocyte function, causing cell swelling, inhibition of membrane pumps or ion channels, an elevation in intracellular calcium concentrations, depression of electrical activity, and interference with oxidative metabolism.8-10 Ammonia often is considered the most important neurotoxic substance. Increased concentrations trigger a sequence of metabolic events that have been implicated in HE in rats, humans, and dogs.8,9,11,13,14 Ammonia is produced by the gastrointestinal flora and then converted in the normal liver to urea and glutamine via the urea cycle. Ammonia is excitotoxic and associated with an increased release of glutamate, the major excitatory neurotransmitter of the brain. Overactivation of the glutamate receptors, mainly N-methylD-aspartate (NMDA) receptors, has been implicated as one of the causes of HE-induced seizures. With chronicity, inhibitory factors such as GABA and endogenous benzodiazepines surpass the excitatory stimulus, causing signs more suggestive of coma or CNS depression.8,9,13 Long-standing metabolic dysfunction, as seen in patients with chronic liver failure, also results in alterations in neuronal responsiveness and energy requirements.9,14 Acute liver failure may result in a form of HE that leads to cerebral edema, increased intracranial pressure, and possible herniation of the brain.8,9 Edema is described in up to 80% of humans with hepatic failure, and 33% can develop fatal herniation.3,8,9 Clinical signs associated with HE are variable, with most being suggestive of neuroinhibition. Excitatory activity such as seizures, aggression, and hyperexcitability also occur. A combination of complex metabolic derangements that occur in patients with hepatic insufficiency (e.g., hypoglycemia, dehydration, hypokalemia, azotemia, alkalemia) and systemic toxins (see Table 116-2) are responsible for a variety of signs that can be exacerbated by exogenous substances such as nonsteroidal antiinflammatory drugs (NSAIDs), high-protein meals, gastrointestinal ulcerations, constipation, stored blood transfusions (because of ammonia levels), and drugs (sedatives, analgesics, benzodiazepines, antihistamines). Recently inflammation and elevated manganese levels also have been proven to be associated with HE in people and dogs.15,16 These factors, in addition to an altered permeability of the blood brain barrier, impair cerebral function in various ways.4,8,9,15,16 Treatments that decrease ammonia concentrations, which are measured easily in animals, seem to reduce the signs of HE. In humans, the degree of encephalopathy is not well correlated with the blood ammonia levels,17 suggesting that other suspected neurotoxins are also important in pathophysiology of HE. Ammonia 615

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Table 116-1  Causes of Hepatic Failure4-6 Dog

Cat

Infectious agents

Canine adenovirus-1 Acidophil cell hepatitis virus Canine herpes virus Clostridiosis Bartonellosis Leptospirosis Liver abscess Tularemia Hepatozoonosis Rickettsia rickettsii Histoplasmosis Coccidiomycosis/blastomycosis Leishmaniasis Toxoplasmosis Dirofilaria immitis Ehrlichia canis

Feline infectious peritonitis Clostridiosis Liver abscesses Histoplasmosis Cryptococcosis Toxoplasmosis

Drugs

Acetaminophen Aspirin Phenobarbital Phenytoin Carprofen Tetracycline Macrolides Trimethoprim-sulfa Griseofulvin Thiacetarsemide Ketoconazole/itraconazole Halothane

Acetaminophen Aspirin Diazepam Halothane Griseofulvin Ketoconazole/itraconazole Methimazole Methotrexate Phenobarbital Phenytoin

Chemical agents/toxins

Industrial solvents Plants: sago palm Envenomation Heavy metals (Cu, Fe, P) Mushrooms (Amanita phalloides) Aflatoxins Blue-green algae Cycad seeds Carbon tetrachloride Dimethylnitrosamine Zinc phosphide Xylitol (dogs only)

Same as for dogs

Miscellaneous

Chronic hepatitis/cirrhosis-idiopathic, copper storage disease, leptospirosis induced,idiosyncratic drug reaction, lobular dissecting hepatitis Granulomatous hepatitis Hepatic amyloidosis (Chinese Shar-Pei) Hepatic neoplasia (primary or metastatic disease) Portosystemic shunting Portal venous hypoplasia/microvascular dysplasia (Yorkshire and Cairn Terrier)

Feline hepatic lipidosis Inflammatory bowel disease Pancreatitis Cholangitis/cholangiohepatitis Septicemia/endotoxemia Hemolytic anemia Neoplasia: lymphoma, mastocytosis Metastasis Amyloidosis (Abyssinian, Oriental, and Siamese cats)

Traumatic/thermal/hypoxic

Diaphragmatic hernia Shock Liver torsion Heat stroke Massive ischemia

concentrations do not correlate always with signs of HE in veterinary patients either, and on rare occasions, dogs with normal ammonia concentrations have obvious HE signs. In addition, many dogs with high ammonia levels appear neurologically normal.

Coagulation Disorders Coagulation abnormalities that develop in patients with liver failure are multifactorial, depending on the interactions of the coagulation, anticoagulation, and fibrinolytic systems. Spontaneous hemorrhage

is uncommon. Hemorrhagic complications usually are induced with associated factors such as gastrointestinal ulceration, invasive procedures (aspiration, biopsy, surgery), or other concurrent medical problems. Suggested causes of coagulopathy in liver failure patients include decreased factor synthesis, increased factor utilization, decreased factor turnover, increased fibrinolysis and tissue thromboplastin release, synthesis of abnormal coagulants (dysfibrinogenemia), decreased platelet function and numbers, vitamin K deficiency (particularly in patients with bile duct obstruction), and increased production of anticoagulants.4,18

CHAPTER 116  •  Hepatic Failure

Table 116-2  Toxins Implicated in Hepatic Encephalopathy4,6,8-12,15,16 Toxins

Mechanisms Suggested in the Literature

Ammonia

Increased brain tryptophan and glutamine; decreased ATP availability; increased excitability; increased glycolysis; brain edema; decreased microsomal Na+/K+-ATPase in brain

Aromatic amino acids

Decreased DOPA (dihydroxyphenylalanine) neurotransmitter synthesis; altered neuroreceptors; increased production of false neurotransmitters

Bile acids

Membranocytolytic effects alter cell/membrane permeability; blood-brain barrier more permeable to other HE toxins; impaired cellular metabolism because of cytotoxicity

Decreased alpha-ketoglutaramate

Diversion from Krebs cycle for ammonia detoxification; decreased ATP availability

Endogenous benzodiazepines

Neural inhibition: hyperpolarize neuronal membrane

False Neurotransmitters Tyrosine→ Octapamine Phenylalanine → Phenylethylamine Methionine → Mercaptans

Impairs norepinephrine action Impairs norepinephrine action Synergistic with ammonia and SCFA Decreases ammonia detoxification in brain urea cycle; GIT derived (fetor hepaticus-breath odor in HE); decreased microsomal Na+/K+-ATPase

GABA

Neural inhibition: hyperpolarize neuronal membrane; increase blood-brain barrier permeability to GABA

Glutamine

Alters blood-brain barrier amino acid transport

Manganese

Elevated manganese levels seen with hepatic failure and HE and results in neurotoxicity. Its toxicity is associated with disruption of the glutamine (Gln)/glutamate (Glu)-γ-aminobutyric acid (GABA) cycle (GGC) between astrocytes and neurons, thus leading to changes in Glu-ergic and/or GABAergic transmission and Gln metabolism

Phenol (from phenylalanine and tyrosine)

Synergistic with other toxins; decreases cellular enzymes; neurotoxic and hepatotoxic

Short chain fatty acids (SCFA)

Decreased microsomal Na+/K+-ATPase in brain; uncouple oxidative phosphorylation, impairs oxygen use, displaces tryptophan from albumin, increasing free tryptophan

Tryptophan

Directly neurotoxic; increases serotonin: neuroinhibition

ATP, Adenosine triphosphate DOPA, dihydroxyphenylalanine, GABA, γ-aminobutyric acid.

Other In addition to altered mentation and coagulation disorders, hepatic failure has been associated with an increased susceptibility to infection, systemic hypotension, pulmonary abnormalities, acid-base disturbances, renal dysfunction, and portal hypertension. Bacterial infection occurs in 80% of human patients, and this may be due to various mechanisms.1,3,4,18 Inhibition of the metabolic activity of granulocytic cells, cell adhesion, and chemotaxis, as well as decreased hepatic synthesis of plasma complement, has been described.1,3,4,18 Kupffer cells also have shown reduced phagocytic ability, allowing pathogens to translocate from the portal circulation into the systemic circulation. Hypotension is seen in most people with hepatic failure and may be due to systemic vasodilation. This is likely a centrally mediated phenomenon and may be linked to systemic infection, inflammation, cytokine release, cerebral edema, or circulating toxins. Approximately 33% of humans with hepatic failure develop pulmonary edema. Altered permeability of pulmonary capillaries leading to vascular leak, as well as decreased albumin/colloid osmotic pressure and vasodilation, has been implicated in the development of edema. This may be associated with endotoxemia as well.1,3 Tissue oxygen extraction decreases in patients with hepatic failure, resulting in tissue hypoxia and the development of lactic acidosis. Hypoxemia (which can occur with pulmonary edema) further exacerbates cerebral dysfunction in patients with HE, accelerating cerebral hypotension and additional cerebral edema. Ventilatory support may be needed if respiratory distress or arrest occurs. This may be of central origin or secondary to muscle weakness.1,18 The development of acute kidney injury has been well described in humans and rarely suggested in dogs.5 Hypovolemia and hypotension, secondary to vasodilation, can diminish renal blood flow and glomerular filtration rate.1-3 Some hepatotoxins (nonsteroidal drugs) and infectious

agents (leptospirosis, feline infectious peritonitis) also cause acute and chronic kidney injury. Portal hypertension, typically secondary to cirrhosis, is a common sequela of chronic liver failure. It has been seen in some acute patients and typically holds a poor prognosis. Massive sinusoidal collapse can block intrahepatic flow, causing portal pressure elevations. In addition, portal vein thrombosis can be seen.19 This may lead to severe congestion of the splanchnic vasculature, exacerbating gastrointestinal bleeding and diarrhea.3-5

CLINICAL SIGNS Most of the clinical signs seen in dogs and cats with hepatic failure are nonspecific and include anorexia, vomiting, diarrhea, weight loss, and dehydration. Icteric mucous membranes, sclera, hard palate, and skin, are seen commonly in patients with liver failure associated with intrahepatic cholestasis. If icterus is documented, prehepatic (hemolysis), hepatic (intrinsic hepatic injury/failure), and/or posthepatic (functional or mechanical bile duct obstruction) causes should be discerned. Dogs and cats with liver failure secondary to congenital portosystemic shunting should not be icteric. Polyuria and polydipsia are common findings, which may be due to failure of the liver to produce urea, resulting in defective renal medullary concentrating ability, and a decreased release and/or responsiveness of the renal collecting ducts to antidiuretic hormone (ADH). Primary polydipsia, resulting from the central effects of hepatotoxins, also has been hypothesized. Other theories include increased renal blood flow and increased adrenocorticotropic hormone (ACTH) secretion with associated hypercortisolism.20,21 Clinical signs associated with HE include behavioral changes, ataxia, blindness, circling, head pressing, panting, pacing, seizures,

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coma, and ptyalism (especially cats). The clinical manifestations of HE range from minimal behavior and motor activity changes, to overt deterioration of mental function, decreased consciousness, coma, and/or seizure activity. Bleeding diathesis, melena (resulting from gastroduodenal ulceration), and ascites (resulting from portal hypertension and/or hypoalbuminemia) are also common findings.

DIAGNOSIS Fulminant hepatic failure is diagnosed when a patient shows signs of HE, changes in the liver function parameters on blood chemistry, possible evidence of coagulopathy, and associated historical and physical examination findings. Hematologic abnormalities may include the presence of target cells, acanthocytes, and anisocytosis. A nonregenerative anemia may be noted in association with chronic disease, chronic GI bleeding, or portosystemic/microvascular shunting. A regenerative anemia may be noted in association with blood loss from gastroduodenal ulceration. A leukocytosis or leukopenia may be seen with infectious causes or bacterial translocation, depending on the agent and severity of infection. A consumptive thrombocytopenia may occur in animals that develop disseminated intravascular coagulation and an immune-mediated thrombocytopenia can be associated with infectious or immune causes of liver failure. Serum biochemical analysis reveals elevated activities of hepatic enzymes in most cases. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are found in the cytosol of hepatocytes and leak from the cell after disruption of the cell membrane. ALT is the more liver specific of these enzymes and has a short half-life (24 to 60 hours).4,6,22,23 AST is present in many tissues (liver, muscle, red blood cells) and has a shorter half-life than ALT. Alkaline phosphatase (ALP) has many clinically significant isoenzymes (bone, liver, and steroid induced [in the dog only]). The hepatic isoenzyme is located on the membranes of hepatocyte canalicular cells and biliary epithelial cells. Its activity increases in association with cholestatic disease. ALP has a short half-life in cats, making any elevation suggestive of active liver disease. γ-Glutamyltransferase (GGT) also is found in many tissues, although most of the biochemically measured enzyme is located on membranes of hepatocyte canalicular cells and biliary epithelial cells. GGT is useful in the diagnosis of cholestatic disease and is more specific and less sensitive than ALP (particularly in feline patients). The presence of normal or only mildly elevated liver enzyme activity does not eliminate hepatic failure as a possible diagnosis because animals with end-stage hepatic failure or portalsystemic vascular anomalies may have normal, or near normal, enzyme activities. Serum biochemical analysis also may reveal hyperbilirubinemia in animals with hepatic failure. Bilirubin is one of the breakdown metabolites of hemoglobin, myoglobin, and cytochromes. With significant cholestasis, bile duct obstruction, or canalicular membrane disruption, bilirubin escapes into the systemic circulation, resulting in hyperbilirubinemia and the typical icteric appearance to the skin, mucous membranes, and organs (visible when values are at least 2.3 to 3.3 mg/dl).6,22,23 The liver functional parameters that are noted classically when hepatic failure is present include hypoalbuminemia with normal to increased globulins, hypocholesterolemia, hypoglycemia, and decreased blood urea nitrogen (BUN). Albumin is produced only in the liver, representing approximately 25% of all proteins synthesized by the liver. Altered albumin synthesis is not detected until more than 66% to 80% of liver function is lost.23 Because of its long half-life (8 days in dogs and cats) hypoalbuminemia is a hallmark of chronic liver dysfunction (although concomitant disease processes also may contribute to its loss, including protein-losing nephropathy (PLN),

protein-losing enteropathy (PLE), and third-spacing protein loss). Cholesterol is synthesized in many tissues, although up to 50% of its synthesis occurs in the liver. In patients with hepatic failure, hypocholesterolemia is observed commonly. With extrahepatic bile duct obstruction or pancreatitis, cholesterol elimination is altered and hypercholesterolemia can develop. Because the liver helps to maintain glucose homeostasis via gluconeogenesis and glycogenolysis, hypoglycemia may develop when less than 30% of normal hepatic function is present.4,6 Urine sediment examination may show ammonium biurate or urate crystals, particularly in animals with portal-systemic vascular anomalies. Dogs have the ability to produce and conjugate bilirubin in their renal tubules, accounting for a small amount of bilirubinuria in a healthy state (males more than females). Cats, on the other hand, do not have this ability and have a higher threshold (9 times higher) than dogs to reabsorb bilirubin rather than eliminate it in the urine.4,22 Therefore bilirubinuria in the cat is always inappropriate and indicative of abnormal bilirubin metabolism. Additional testing may be performed to assess hepatic function. Coagulopathies are seen classically in animals with hepatic failure. Prolongation of the activated partial thromboplastin time (aPTT), prothrombin time (PT), activated clotting time (ACT), and buccal mucosal bleeding time (BMBT) may be observed. Increased fasting and postprandial serum bile acids are indicative of hepatic dysfunction and classically seen in animals with hepatic failure. They also may play a role in inciting inflammatory liver disease.4,6 Plasma fasting ammonia, 6-hour postprandial ammonia, or ammonia tolerance testing are sensitive tests of liver function. The ammonia tolerance test is contraindicated in animals with encephalopathy and may precipitate seizure activity.4-6,22 Electrolyte abnormalities also may be seen in patients with hepatic failure. Hypokalemia may develop because of inadequate intake, vomiting, or the use of potassium-wasting diuretics for treatment of ascites. Centrally induced hyperventilation and respiratory alkalosis may encourage renal potassium excretion, worsening the hypokalemia, and a decrease in potassium levels may exacerbate HE. In addition, hypocapnia results in a shift of intracellular carbon dioxide into the extracellular space, raising intracellular pH and accelerating the use of phosphate to phosphorylate glucose. This may result in hypophosphatemia, which ultimately can cause hemolysis of red blood cells. Diagnostic imaging is often useful to determine the underlying cause of hepatic failure. Abdominal radiographs are useful for determining liver size and contour, identifying mass lesions and evaluating abdominal detail, which may be decreased in the presence of ascites. Abdominal ultrasonography is valuable for the evaluation of hepatic parenchymal architecture, the biliary tract, and vascular structures. It also can help to guide diagnostic sampling procedures, when indicated. Computed tomography with angiography is a great tool to diagnose portosystemic shunting but requires general anesthesia, which carries considerable risk in patients with clinical HE. Ultimately cytologic or histologic evaluation is necessary to determine the underlying cause of hepatic failure if a congenital PSS is not found. Fine-needle aspiration cytology is useful for diagnosing infiltrative neoplasia such as lymphoma but gives little information about the hepatic parenchymal changes needed for a definitive diagnosis of the inflammatory/infectious, necrotic, fibrosing, and microvascular diseases. Aspiration has been proven insensitive in making a definitive diagnosis.24 Histopathologic evaluation of liver tissue is more useful and should be obtained whenever possible. Liver biopsies can be performed with ultrasound guidance, laparoscopy, or surgery. In humans, a transjugular approach, under fluoroscopic guidance, is used commonly, particularly in coagulopathic patients, to avoid penetrating the hepatic capsule and cause third space

CHAPTER 116  •  Hepatic Failure 1

bleeding. This currently is not recommended in veterinary patients. A blood type and coagulation profile should be obtained before liver biopsy in all animals. A small amount of liver tissue should be stored so that further testing can be performed, if indicated, after histopathology is complete, such as aerobic and anaerobic culture, copper analysis (dogs), or PCR testing for certain infectious agents.

THERAPY Successful management of patients with hepatic failure requires treatment of the underlying liver disease, therapy aimed at the complications of hepatic failure (HE and coagulopathy), and routine supportive care. Fortunately, hepatocytes have an immense ability to regenerate if given appropriate support and time. Treatment of the primary disease process, if possible, is critical. However, a discussion of the treatment recommendations for each specific liver disease is beyond the scope of this chapter. Supportive care is required to maintain the normal physiologic functions of the patient while the liver recovers from the insult (Table 116-3). Animals that are presented with, or develop, focal or generalized seizure activity require immediate anticonvulsant therapy (see Table 116-3 and Chapters 82, 88, and 166). Propofol (0.5 to 1 mg/kg IV bolus, then 0.05 to 0.1 mg/kg/min constant rate infusion) generally is recommended for rapid control of seizures resulting from

hepatoencephalopathy. More recently the use of levetiracetam has been shown to prevent postanesthetic seizures in dogs with portosystemic shunts, so prophylactic loading and maintenance therapy now is performed commonly.25 Endotracheal intubation should be performed in patients that are hypoventilating because hypercapnia further increases intracranial pressure. Animals that lose their gag reflex also should be intubated to protect the airway from aspiration. Mannitol therapy also may prove beneficial if cerebral edema is present (0.5 to 1 g/kg IV over 20 to 30 minutes), especially because cerebral edema is associated with herniation in people (see Chapter 84).1-3 The use of diazepam for the treatment of HE-associated seizures in animals is controversial. GABA and its receptors are implicated in the pathogenesis of HE, and the use of a benzodiazepine antagonist, such as flumazenil, has been proven beneficial in humans with HE-induced comas.8,9 Flumazenil therapy for HE has not been evaluated yet in veterinary patients, however. Symptomatic therapy for patients with HE may include withholding food, cleansing enemas with warm water and/or lactulose, oral lactulose therapy, and antimicrobial therapy.4-6,10 Antimicrobials such as metronidazole, neomycin, or ampicillin decrease GI bacterial numbers, thus reducing ammonia production. Metronidazole and ampicillin also help decrease the risk of bacterial translocation and systemic bacterial infections. However, neurotoxicity from

Table 116-3  Therapies for Hepatic Failure Symptom

Therapy

Bacterial translocation

Cleansing enemas with warm water or 30% lactulose solution at 5-10 ml/kg (see Chapter 88 for further details) Antibiotics: Metronidazole: 7.5 mg/kg IV or PO q12h Ampicillin: 22 mg/kg IV q8h Neomycin: 22 mg/kg PO q12h (avoid if any evidence of intestinal bleeding, ulcerations, or renal failure)

Gastrointestinal ulceration

Antacid20: Famotidine: 0.5-1.0 mg/kg/day IV or PO q12-24h Omeprazole: 0.5-1.0 mg/kg/day q12h PO Esomeprazole: 0.5-1 mg/kg IV q24h Misoprostol: 2-5 mcg/kg PO q6-12h Protectant: Sucralfate: 0.25-1 g PO q6-12h Correct coagulopathy

Coagulopathy

Fresh frozen plasma (10-15 ml/kg over 2-3 hours) Vitamin K1: 1.0-2.0 mg/kg SC q12h for three doses, then once daily

Control seizures

Avoid benzodiazepines: consider propofol 0.5-1 mg/kg IV bolus + IV CRI at 0.05-0.4 mg/kg/min OR IV phenobarbital (16 mg/kg IV, divided into 4 doses over 12-24 hours), or potassium bromide/sodium bromide loading (see Chapter 166) OR IV levetiracetam: 30-60 mg/kg once, then 20 mg/kg q8h

Decrease cerebral edema

Mannitol (0.5-1.0 g/kg IV over 20-30 min)

Hepatoprotective therapy

SAMe (Denosyl): 17-22 mg/kg PO q24h Ursodeoxycholic acid (Actigall): 10-15 mg/kg/day Vitamin E: 15 IU/kg/day Milk thistle: 8-20 mg/kg divided q8h L-Carnitine: 250-500 mg/cat q24h Vitamin B complex: 1 ml/L of IV fluids

Antifibrotic therapy

D-Penicillamine: 10-15 mg/kg PO q12h Colchicine: 0.03 mg/kg/day Prednis(ol)one: 1 mg/kg/day

Nutritional support

Moderate protein restriction: 18% to 22% dogs and 30% to 35% cats; dairy or vegetable proteins; vitamin B supplementation; multivitamin supplementation

619

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PART XII  •  INTRAABDOMINAL DISORDERS

metronidazole therapy may occur more commonly in animals with hepatic disease. Symptomatic therapy is necessary for bleeding patients. Those with gastric ulceration should be treated with acid receptor blockade (H2 blocker, proton pump inhibitor, prostaglandin analog) and sucralfate (see Chapter 161). Recent evidence suggests that ranitidine may not be as effective as famotidine in reducing gastric acid in dogs.26 Coagulopathic patients with signs of active bleeding should be treated with fresh frozen plasma or fresh whole blood and subcutaneous vitamin K1 (especially if the coagulopathy is thought to be due to cholestasis and fat malabsorption).4-6 Patients that are significantly anemic benefit from packed red blood cell or whole blood transfusions. If HE is evident, fresh whole blood is preferred because stored blood has increased levels of ammonia (see Chapter 61). Ascites and hepatic fibrosis may be seen in patients with chronic, severe liver disease. If ascites is due to low oncotic pressure, then synthetic colloidal therapy should be considered (see Chapters 58 and 59). If the ascites is due to portal hypertension, the use of diuretics and a low-sodium diet should be considered. Spironolactone is the initial diuretic of choice for its aldosterone antagonism and subsequent potassium-sparing effects. Furosemide may be necessary as well but should be used with caution because it may potentiate hypokalemia. A number of drugs theoretically decrease connective tissue formation and may be helpful in patients with hepatic fibrosis (i.e., prednisone, D-penicillamine, and colchicines; see Table 116-3).4-6,23 Fluid therapy and nutritional support are the cornerstones of supportive therapy. Fluid therapy is indicated to maintain hydration and provide cardiovascular (and occasionally oncotic) support. Lactated Ringer’s solution often is avoided because of the need for hepatic conversion of lactate to bicarbonate. Supplementation with potassium and glucose often are required. Nutritional management is important in patients with acute and chronic liver failure, particularly cats with hepatic lipidosis. The diet should be readily digestible, contain a protein source of high biologic value (enough to meet the animal’s need, but not worsen HE), supply enough essential fatty acids, maintain palatability, and meet the minimum requirements for vitamins and minerals. Low-protein diets should be avoided unless HE is noted. Milk and vegetable proteins are lower in aromatic amino acids and higher in branched chain amino acids (valine, leucine, isoleucine) than animal proteins and are considered less likely to potentiate HE.4,6,23 In the patient with hepatic failure, total parenteral or partial parenteral nutrition should be considered if enteral intake cannot be tolerated (see Chapter 130). If the animal is not vomiting or regurgitating and temperature and systemic blood pressure are stable but the patient will not eat voluntarily, a feeding tube should be considered to allow for localized enterocyte nutrition (see Chapter 129). Supportive nutraceutical therapy has been recommended for a variety of liver diseases. Drugs in this class include S-adenosylmethionine (SAMe), vitamin E, and milk thistle.26 SAMe has hepatoprotective, antioxidant, and antiinflammatory properties. It also serves as a precursor to the production of glutathione, which plays a critical role in detoxification of the hepatocyte. Vitamin E is another antioxidant and should be considered to prevent and minimize lipid peroxidation within the hepatocytes. Silymarin is the active extract in milk thistle. An abundance of in vivo animal and in vitro experimental data show the antioxidant and free radical scavenging properties of silymarin.27 Specifically, it inhibits lipid peroxidation of hepatocyte and microsomal membranes. Silymarin increases hepatic glutathione content and appears to retard hepatic collagen formation.26 Ursodeoxycholic acid, another hepatoprotective medication, is recommended for most types of inflammatory, oxidative, and chole-

static liver disease. It has antiinflammatory, immunomodulatory, and antifibrotic properties, as well as promoting choleresis and decreasing the toxic effects of hydrophobic bile acids on hepatocytes. This medication is contraindicated in patients with biliary duct outflow obstruction until after the obstruction is relieved. Zinc is an essential trace mineral involved in many metabolic and enzymatic functions of the body and is an important intermediary involved in enhanced ureagenesis, glutathione metabolism, copper chelation, and immune function. Zinc appears to have antifibrotic activities as well. Zinc deficiency occurs in many humans with liver disease, and this decrease seems to correlate with hepatic encephalopathy, demonstrating its importance in ureagenesis. Please refer to Chapter 88 and other sources for further explanation.26-29

PROGNOSIS The prognosis for animals with hepatic failure is generally poor. Few published guidelines are established to predict outcome. Some factors suggested to be poor prognostic indicators include PT of greater than 100 seconds, very young or very old animals, viral or idiosyncratic drug reaction as the underlying cause, and a markedly increased bilirubin.4 When a known hepatotoxin is involved, the use of an appropriate antidote can improve survival markedly, although most do not have an antidote. Better survival rates likely are attained in a hospital where aggressive and intensive supportive therapy is available. The prognosis for hepatic failure associated with congenital portosystemic shunting is considered good if the patient is medically managed appropriately and the shunt ultimately can be occluded.

FUTURE THERAPIES People with severe HE are placed immediately on a liver transplant list, which may be an option for veterinary patients in the future. Substitution of hepatocytes with various forms of artificial liver support has been promoted over the past 10 years in human medicine. A multicenter randomized trial using a bio-artificial liver showed no benefit over traditional therapy while awaiting transplantation in overall outcome, although more advanced equipment is showing great promise. More recently research has shown the benefit of this modality, especially in acute-on-chronic liver failure.* This may be something for the future in veterinary medicine. Over the past 5 years great advances have been made in the area of stem cell therapy for the treatment of liver failure in various animal models. Mesenchymal stem cells (MSC) have been used in veterinary medicine for osteoarthritis and kidney disease,31-33 with the goal of autogenous multipotent stem cells acting in a paracrine manner to improve the regenerative environment of an organ undergoing inflammation, fibrosis, and necrosis. More recently the use of MSC for chronic and acute inflammatory liver disease in dogs is being investigated. Studies in mice have shown that undifferentiated MSC have the ability to improve hepatic function in mice with acute liver injury.34 In a rabbit model35 of acute-on-chronic liver failure, those who received adipose-derived MSC had improved biochemical parameters, histomorphologic scoring, and survival rates when compared with those that did not. This holds great promise for the future of veterinary medicine. Overall, hepatic failure is a severe life-threatening disease that holds a poor prognosis. With aggressive intensive care, avid supportive therapy, and early diagnosis, the regenerative capacity will improve, as will the outcome.

*References 1-3, 8, 9, 28, 30.

CHAPTER 116  •  Hepatic Failure

REFERENCES 1. Gill RQ, Sterling RK: Acute liver failure, J Clin Gastroenterol 33:191-198, 2001. 2. Atillasoy E, Berk PD: Fulminant hepatic failure: pathophysiology, treatment and survival, Ann Rev Med 46:181-191, 1995. 3. D’Agata ID, Balistreri WFF: Pediatric aspects of acute liver failure. In Lee WM, Williams R, editors: Acute liver failure, Cambridge, 1997, Cambridge University Press. 4. Center SA: Acute hepatic injury: hepatic necrosis and fulminant hepatic failure. In Guilford WG, et al, editors: Strombeck’s small animal gastroenterology, ed 3, Philadelphia, 1996, WB Saunders. 5. Walton RS: Severe liver disease. In Wingfield WE, Raffe MR, editors: The Veterinary ICU book, Jackson Wyo, 2002, Teton NewMedia. 6. Webster CR: History, clinical signs, and physical findings in hepatobiliary disease. In Ettinger SJ, Feldman EC, editors: Textbook of veterinary internal medicine, ed 6, St Louis, 2005, Elsevier Saunders. 7. Sandhu BS, Sanyal AJ: Hepatorenal syndrome, Curr Treat Options Gastroenterol 8:443-450, 2005. 8. Jalan R, Shawcross D, Davies N: The molecular pathogenesis of hepatic encephalopathy, Intern J Biochem Cell Biol 35:1175-1181, 2003. 9. Jalan R: Pathophysiological basis of therapy of raised intracranial pressure in acute liver failure, Neurochem Intern 47:78-83, 2005. 10. Shawcross D, Jalan R: Dispelling myths in the treatment of hepatic encephalopathy, Lancet 365:431-433, 2005. 11. Holt DE, Washabau RJ, et al: Cerebrospinal fluid glutamine, tryptophan, and trypophan metabolite concentrations in dogs with portosystemic shunts, Am J Vet Res 63:1167-1171, 2002. 12. Albrecht J, Jones EA: Hepatic encephalopathy: molecular mechanisms underlying the clinical syndrome, J Neurol Sci 170:138-146, 1999. 13. Berent AC, Rondeau M: Hepatic failure. In Silverstein DC, Hopper K, editor: Small animal critical care medicine, St Louis, 2009, Saunders Elsevier. 14. Center SA: Hepatic vascular diseases. In Guilford WG, editor: Strombeck’s small animal gastroenterology, ed 3, Philadelphia, 1996, WB Saunders, 1996, p 802. 15. Gow AG, Marques AI, Yool DA, et al: Dogs with congenital porto-systemic shunting (cPSS) and hepatic encephalopathy have higher serum concentrations of C-reactive protein than asymptomatic dogs with cPSS, Metab Brain Dis 27(2):227-229, 2012. 16. Gow AG, Marques AI, Yool DA, et al: Whole blood manganese concentrations in dogs with congenital portosystemic shunts, J Vet Intern Med 24(1):90-96, 2010. 17. Fischer J: On the occurrence of false neurochemical transmitters. In Williams R, Murray-Lyons I, editors: Artificial liver support, Tunbridge Wells, UK, 1975, Pitman Medical. 18. Fingerote RJ, Bain VG: Fulminant hepatic failure, Am J Gastroenterol 88(7):1000-1010, 1993.

19. Respess M, O’Toole TE, Taeymans O, et al: Portal vein thrombosis in 33 dogs: 1998-2011, J Vet Intern Med 26(2):230-237, 2012. 20. Center SA: Serum bile acids in companion animal medicine, Vet Clin North Am Small Anim Pract 23:625, 1993. 21. Berent A, Weisse C: Hepatic vascular Anomalies. In Ettinger SJ, Feldman ED, editor: Textbook of veterinary internal medicine: diseases of the dog and cats, ed 7, St Louis, 2010, Elsevier Saunders. 22. Willard MD, Twedt DC: Gastrointestinal, pancreatic, hepatic disorders. In Willard MD, Tvedten H, Turnwald G, editors: Small animal clinical diagnosis by laboratory methods, ed 3, Philadelphia, 1999, WB Saunders. 23. Taboada J: Hepatic pathophysiology. In Proceedings: International Veterinary Emergency and Critical Care Symposium, 2003. 24. Wang KY, Panciera DL, Al-Rukibat RK, et al: Accuracy of ultrasoundguided fine needle aspiration of the liver and cytologic findings in dogs and cats: 97 cases (1990-2000), J Am Vet Med Assoc 224(1):75-78, 2004. 25. Fryer KJ, Levine JM, Peycke LE, et al: Incidence of postoperative seizures with and without levetiracetam pretreatment in dogs undergoing portosystemic shunt attenuation, J Vet Intern Med 25(6):1379-1384, 2011. 26. Flatland B: Botanicals, vitamins, and minerals and the liver: therapeutic applications and potential toxicities, Comp Cont Ed 25(7):514-524, 2003. 27. Flora K, Hahn M, Rosen H, et al: Milk thistle (Silybum marianum) for the therapy of liver disease, Am J Gastroenterol 93(2):139, 1998. 28. Williams R, Gimson AE: Intensive liver care and management of acute hepatic failure, Digest Dis Sci 36(6):820-826, 1991. 29. Bersenas, AM, Mathews, KA, Allen DG, et al: Effects of ranitidine, famotidine, pantoprazole, and omeprazole on intragastric pH in dogs, Am J Vet Res 66:425-431, 2005. 30. Bañares R, Catalina MV, Vaquero J: Liver support Systems: will they ever reach prime time? Curr Gastroenterol Rep 15(3):312, 2013. 31. Black LL, Gaynor J, Adams C, et al: Effect of intraarticular injection of autologous adipose-derived mesenchymal stem and regenerative cells on clinical signs of chronic osteoarthritis of the elbow joint in dogs, Vet Ther 9(3):192-200, 2008. 32. Quimby J, Webb TL, Gibbons DS, et al: Evaluation of intrarenal MSC injection for treatment of chronic kidney disease in cats: a pilot study, J Fel Med Surg 13:418-426, 2011. 33. Berent A, Weisse C, Langston C, et al: Selective renal intra-arterial and nonselective IV Delivery of autologous mesenchymal-derived stem cells for kidney disease in dogs and cats: pilot study. Abstract, ACVS 2012, Washington, DC. 34. Kim SJ, Park KC, Lee JU, et al: Therapeutic potential of adipose tissuederived stem cells for liver failure according to the transplantation routes, J Korean Surg Soc 81(3):176-186, 2011. 35. Zhu W, Shi XL, Xiao JQ, et al: Effects of xenogeneic adipose-derived stem cell transplantation on acute-on-chronic liver failure, Hepatobiliary Pancreat Dis Int 12(1):60-67, 2013.

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CHAPTER 117  GASTROENTERITIS Tara K. Trotman,

VMD, DACVIM (Internal Medicine)

KEY POINTS • Clinical signs of acute gastroenteritis typically involve vomiting, diarrhea, and partial or complete anorexia. • Physical examination findings are often nonspecific but may include abdominal discomfort, dehydration, and hypovolemia. • Gastroenteritis has a variety of causes, and determination of an underlying cause is often not possible. Fecal samples should be evaluated for parasitic and bacterial infections in most animals. Systemic diseases are often diagnosed based on the results of a complete blood cell count, biochemical profile, and urinalysis. • Supportive care is the mainstay of therapy if an underlying cause is not found. Prognosis for most dogs and cats with gastroenteritis is excellent.

Gastroenteritis is a broad term used to indicate inflammation of the stomach and the intestinal tract. It is a common cause for acute-onset vomiting, anorexia, and diarrhea in dogs and cats but should be differentiated from other problems that may cause similar clinical signs, such as pancreatitis, azotemia, hepatitis, and intestinal obstruction (see additional chapters in Intraabdominal Disorders section).1 Inflammation of the alimentary tract may occur in dogs and cats and can be due to a wide variety of underlying causes, including dietary indiscretion, infectious organisms, toxins, immune dysregulation, and metabolic disorders (see Chapters 120 and 121). A thorough history and physical examination may aid in uncovering an underlying cause, but often a specific cause is not identified. In most cases, supportive therapy, including appropriate fluid support, dietary modification, antiemetics, and gastric protectant agents, are sufficient for resolution of clinical signs. However, acute decompensation can occur in severe cases. This is usually secondary to volume depletion, fluid losses, electrolyte imbalances and acid-base disturbances that occur because the intestinal tract cannot perform its normal hemostatic functions.

ANATOMY AND PHYSIOLOGY The stomach is the compartment between the esophagus and small intestine that functions as a storage reservoir for food and a vessel for mixing and grinding food into smaller components that then enter the small intestine.2 The stomach is made up of muscular layers, glandular portions, and a mucosal barrier. The muscular layers grind food into smaller particles and move it forward into the small intestine through the pyloric sphincter. Of equal importance are the glandular portions of the stomach, which include parietal cells (for secretion of hydrochloric acid), chief cells (for secretion of pepsinogen), and mucus-producing cells (which also secrete bicarbonate). Normally, the gastric mucosal barrier keeps hydrochloric acid and digestive enzymes within the lumen and prevents loss of plasma constituents into the stomach.2 Once the food particles are ground into small enough components, they pass through the pyloric sphincter into the beginning of the small intestine, known as the duodenum. 622

The small intestine of cats and dogs functions in digestion and absorption of food and its nutrients and is divided arbitrarily into the duodenum, jejunum, and ileum.3 The mucosa of the small intestine is involved in secretory and absorptive functions and contains a single layer of epithelial cells called enterocytes. The mucosa along the length of the small intestine is formed into villi, which are fingerlike projections into the intestinal lumen that enlarge the surface of the small intestine. Microvilli then form the “brush border” to further increase the surface area available for digestion and absorption of nutrients. Enzymes within the brush border aid in digestion of larger food molecules into smaller, more readily absorbable particles. Absorption may occur via specific transport mechanisms or by pinocytosis. The epithelial cells also are involved with absorption and secretion of electrolytes and water.3 Enterocytes are connected to each other by tight junctions, limiting absorption between cells, as well as preventing backflow of nutrients from the interstitium into the intestinal lumen. The enterocytes start at the crypt (base of the villus) and migrate toward the intestinal lumen where they are shed, with a lifespan of approximately 2 to 5 days. A healthy, intact mucosal lining is important for the integrity of the intestine. Any type of inflammation that disrupts this layer can lead to significant intestinal disease.4 The gastrointestinal (GI) tract absorbs approximately 99% of the fluid presented to it; therefore any damage can cause significant alterations in acid-base and fluid balances.5,5a

HISTORY AND CLINICAL SIGNS A thorough history is critical to identifying an underlying cause for gastroenteritis. Questions may be related to the patient’s current diet, recent change in diet, and exposure to unusual food, foreign materials, garbage, or toxins. It is also important to find out about the patient’s environment, including exposure to other animals, and if other exposed animals have similar signs or a history of similar signs. Vaccination status, deworming history, and medication use are also important. Clinical signs of gastroenteritis are often similar regardless of the underlying cause. Vomiting, diarrhea, and anorexia are most common, and certain combinations of these signs may make one cause more or less likely than another. Severe inflammation or ulceration, depending on the cause, can lead to hematemesis or melena. Physical examination is often unrewarding towards finding an underlying cause. Patients may have varying degrees of dehydration, as well as abdominal pain. In severe cases, such as those animals with hemorrhagic gastroenteritis (HGE) or parvoviral enteritis, patients may have signs of hypovolemia and shock because of the severe fluid losses and acid-base disturbances.

CAUSES Infectious Gastroenteritis A variety of infectious agents can affect the GI tract. Viruses, bacteria, parasites, protozoa, and fungi have been shown to cause

CHAPTER 117  •  Gastroenteritis 8-9,12

BOX 117-1 

Infectious Causes of Gastroenteritis in Dogs and Cats

Bacterial Campylobacter spp. Clostridium spp. Escherichia coli Salmonella spp. Helicobacter spp.

Viral Parvovirus Rotavirus Enteric coronavirus Feline infectious peritonitis Canine distemper virus Feline leukemia virus Feline immunodeficiency virus

Fungal, Algal, and Oomycoses Histoplasmosis Protothecosis Pythiosis

Parasitic Ascarids (Toxocara canis, Toxocara cati, Toxascaris leonina) Hookworms (Ancylostoma spp., Uncinaria stenocephala) Strongyloides stercoralis Whipworms (Trichuris vulpis) Coccidiosis (Isospora canis or felis, Toxoplasma gondii, Cryptosporidium parvum) Giardia Tritrichomonas Balantidium coli

Rickettsial Neorickettsia helminthoeca (salmon poisoning)

gastroenteritis of varying severity. The descriptions in the text are limited to the most common. Please see Box 117-1 for a more complete list of potential infectious causes of gastroenteritis.

Viral enteritis Canine parvovirus-2 (CPV-2) is one of the most common infectious diseases in dogs and may be characterized by severe enteritis, vomiting, hemorrhagic diarrhea, and shock.4 The pathophysiology and treatment of CPV-2 are discussed in Chapter 97. Other viral diseases that can lead to severe GI inflammation include coronavirus and rotavirus infection, although clinical manifestations of these viral diseases are typically milder than those of CPV-2, possibly because they affect the tips of the villi, whereas CPV-2 affects the crypts.6 Feline panleukopenia, also caused by a parvovirus, can cause similar signs of severe gastroenteritis in cats.

Bacterial enteritis The bacterial organisms most commonly associated with acute gastroenteritis in dogs and cats include Clostridium perfringens and Clostridium difficile, Campylobacter jejuni and Campylobacter upsaliensis, Salmonella spp., Helicobacter spp., and enterotoxigenic E. coli.7-10 Controversy continues regarding whether some of these organisms truly cause clinical disease because some of them can be found in nondiarrheic patients as well as animals with diarrhea. With emerging and improved diagnostic techniques such as ELISA and PCR testing, newer recommendations for definitive diagnosis rely on a multimodal evaluation for some of these organisms.11 Evidence does

support the role of Clostridium spp. in gastroenteritis. However, because many dogs have C. perfringens and its CPE toxin in their GI tracts without developing clinical signs, evaluation of the roles of these organisms, as well as those of Campylobacter and Helicobacter spp. in GI disease of companion animals, is ongoing.13 Although the majority of Salmonella infections in dogs are selflimiting and resolved by the host’s local immune response, bacterial translocation and septicemia can occur, leading to systemic inflammatory response and multi-organ dysfunction in some patients (see Chapters 6 and 7). Those most at risk are the young or immunocompromised, those that have concurrent infections, or those that have received prior antibiotic or glucocorticoid therapy. As is the case with many bacterial organisms, Salmonella can be found in a population of healthy, nonclinical patients, so its documentation in the GI tract should be correlated with clinical signs.13 In addition to the aforementioned more commonly diagnosed bacterial infections, evidence is beginning to suggest that histiocytic ulcerative colitis in Boxer dogs may be due to invasive E. coli organisms within the colonic mucosa of affected dogs.14,15 Fluoroquinolones have become the standard treatment for these patients, with the use of fluorescent in situ hybridization (FISH) to confirm the presence of these organisms.14,15 Culture and susceptibility testing of colonic tissue can be used to isolate and guide therapy because antimicrobial resistance has become of increasing concern.14,15

Parasitic gastroenteritis Although most dogs and cats with GI parasites have mild clinical signs, ascarids (Toxocara spp., Toxascaris leonina, Ollulanus tricuspis, and Physaloptera spp.), hookworms (Ancylostoma spp., Uncinaria stenocephala), and whipworms (Trichuris spp.) can cause significant GI tract inflammation, vomiting, and diarrhea. GI blood loss is also common with severe hookworm infestations. Protozoans that cause canine and feline gastroenteritis include Giardia spp., coccidia, and Cryptosporidia spp. Tritrichomonas foetus infection is another protozoal cause of diarrhea in cats (primarily large bowel) with waxing and waning signs. Although patients may appear unthrifty, it is rarely the cause of critical illness.6

Fungal gastroenteritis Fungal disease can affect the GI tract of dogs and cats, although the likelihood greatly depends on the animal’s geographic location or recent travel destinations. Histoplasmosis is the fungal pathogen that most commonly affects the GI tract, causing a severe protein-losing enteropathy (PLE). Pythium spp., an oomycete, also can cause similar disease.

Hemorrhagic Gastroenteritis Hemorrhagic gastroenteritis (HGE) is a disease of unknown cause. It typically affects young to middle-age, small breed dogs, and its clinical course usually includes a peracute onset of clinical signs that can progress rapidly to death without appropriate therapy.7,16 Affected animals are often previously healthy dogs with no pertinent historical information. The syndrome is characterized by acute onset of bloody diarrhea, often explosive, along with an elevated packed cell volume (PCV) (at least 60%).7,16 Although the cause remains unknown, it has been suggested that abnormal immune responses to bacteria, bacterial endotoxin, or dietary ingredients may play a role.17 C. perfringens has been isolated from cultures of GI contents in dogs with HGE; however, its exact role in the syndrome has not been determined. Fatal acute HGE was reported in a dog with large numbers of enterotoxin-positive A C. perfringens isolated from the intestinal tract.12 Clinical signs of vomiting and depression, progressing to explosive, bloody diarrhea and anorexia are classic, and the diarrhea often

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PART XII  •  INTRAABDOMINAL DISORDERS

is described as having the appearance of raspberry jam.7 Thorough investigation to rule out other causes of hemorrhagic diarrhea such as parvovirus, bacterial infections, or GI parasites should be undertaken before arriving at a diagnosis of HGE. Along with hemoconcentration, the total protein concentration typically increases little or not at all (it may actually decrease). The elevated PCV occurs because of hemoconcentration and/or splenic contraction, whereas GI loss of serum proteins or redistribution of body water into the vascular space explains the lack of rise in total protein levels.7 Aggressive therapy is warranted in these animals because rapid decompensation may occur. Adequate replacement of fluid volume is essential; more specific fluid management strategies can be found in Chapters 59 and 60. General goals are to replace quickly the fluid deficits from the acute diarrhea and vomiting then adjust fluid rates to maintain proper hydration. The GI tract is a “shock organ” in the dog, and lack of proper perfusion to the GI tract can lead to worsening GI inflammation, bacterial translocation, sepsis, and disseminated intravascular coagulation (see Chapter 91).18,19 Because serum proteins are lost through the intestinal tract, close attention should be paid to the patient’s colloid osmotic pressure and colloidal support given when necessary. Fluid therapy is the mainstay of treatment for patients with HGE. Antiemetic and gastric protectant drugs should be used as indicated. Although antimicrobials may be warranted in patients with suspected bacterial translocation, caution is advised because inappropriate use of these drugs may promote antimicrobial resistance or other unwanted side effects. In some dogs with HGE but no signs of sepsis, antimicrobial therapy may not be indicated.20 With rapid and appropriate therapy, the prognosis for full recovery from HGE is excellent.

Dietary Indiscretion Gastroenteritis caused by ingestion of toxins (i.e., organophosphates), foreign materials, or garbage is common in dogs, and less so in cats. Some toxins lead directly to inflammation of the GI tract, although ingestion of other foreign materials may lead to direct GI trauma or an osmotic diarrhea secondary to nondigestible substances within the intestinal tract. Ingestion of excessive fatty products also may cause pancreatitis in these animals. Many drugs are associated with vomiting and diarrhea (antimicrobials, antineoplastics, anthelminthics), and garbage ingestion can lead to exposure of the intestinal tract to preformed bacterial toxins. Most commonly, dietary indiscretion leads to acute onset of vomiting, diarrhea, and anorexia. The patient’s history is useful because the owner may be aware of exposure to a specific toxicant or garbage. The diagnosis is usually presumptive, and treatment involves supportive care such as fluid therapy to maintain hydration, antiemetic drugs, and gastric protectants as needed. The prognosis is excellent, and most animals recover within 24 to 72 hours.

Protein-Losing Enteropathy Protein-losing enteropathy (PLE) is a broad diagnosis that includes any cause of GI disease that results in excessive loss of plasma proteins. The diseases most commonly associated with PLE are severe lymphocytic-plasmacytic, eosinophilic, or granulomatous inflammatory bowel diseases, lymphangiectasia, diffuse GI fungal disease, and diffuse neoplasia such as lymphosarcoma. Some of the aforementioned GI diseases can cause PLE if the inflammation and damage to the intestinal mucosa are severe enough. The mechanism of protein loss may be related to inflammation or loss of the GI barrier.21 Protein loss likely arises because of disruption to the normal enterocyte function, as well as deranged permeability through the tight junctions.21 Clinical signs of PLE usually are associated with chronic wasting because of lack of nutrient integra-

tion into the body. However, the proteins lost into the intestinal tract can include large proteins such as albumin and antithrombin, both of which have important roles in homeostasis. Albumin, with a molecular weight of 69,000 daltons, contributes significantly to oncotic pressure. Loss of albumin through the GI tract can lead to a reduced colloid osmotic pressure and subsequent loss of fluid from the intravascular space. Although this is typically a gradual process, it can cause significant changes in the compartmentalization of fluids in some patients. If third spacing has occurred, it may be necessary to use colloidal fluids such as hydroxyethyl starch or human albumin, in addition to crystalloids, to prevent further intravascular fluid losses (see Chapter 58).22Albumin also has additional beneficial effects, such as its antioxidant and antiinflammatory properties.23 Antithrombin plays a critical role in the coagulation and fibrinolytic cascade by inactivating thrombin and other clotting factors. Even a small reduction in antithrombin levels can cause a large propensity toward thrombosis and thromboembolism. This becomes important in patients with PLE that lose large amounts of protein and are predisposed to developing thromboemboli in various parts of the body, including the pulmonary vessels, portal vein, or coronary or cerebral vessels. Therapy for PLE often involves glucocorticoids, which also increase the risk of thromboembolic disease. Therefore anticoagulant or antiplatelet therapy, or both, may be warranted in these cases. Therapy for PLE is aimed at treating the underlying cause. Animals with diffuse neoplasia such as lymphosarcoma should be treated with chemotherapy, and those with severe inflammatory bowel disease may benefit from antiinflammatory drugs and a hypoallergenic diet. Lymphangiectasia may be primary or secondary, and administration of a diet low in fat may be more important than feeding a hypoallergenic diet, depending on the degree of inflammation.

Extraintestinal Diseases Hypoadrenocorticism, liver or kidney disease, acute pancreatitis, and peritonitis are common extraintestinal causes of gastroenteritis in small animals.

DIAGNOSIS The extent of diagnostic testing in a dog that is presented with signs of acute gastroenteritis depends on factors such as historical information, prior occurrence of similar clinical signs, and stability of the patient. Fecal samples should be evaluated for parasitic diseases and bacterial infections in most animals with clinical signs of acute gastroenteritis. A culture and Gram stain evaluation also should be performed. Feces should be tested at least three times before a negative result is confirmed. Testing for clostridial enterotoxins may include use of a C. perfringens enterotoxin enzyme-linked immunosorbent assay (ELISA), or an ELISA that detects C. difficile toxins A and B. Recent developments with real PCR testing have provided another diagnostic method for detection of many organisms that are seen commonly in small animals. A Giardia antigen test also exists. If parvovirus is suspected, a fecal antigen test (ELISA) should be performed. Systemic evaluation should include a complete blood count, chemistry screen, and urinalysis. Typically results of these tests are normal and do not aid in determining an underlying cause for the gastroenteritis. However, in certain circumstances such as HGE (in which the PCV is elevated with a normal to decreased total protein concentration), PLE (which may cause a decrease in total protein, globulin, albumin, and cholesterol levels), these tests can aid in making a diagnosis. Electrolytes should be checked regularly to confirm adequate fluid management.

CHAPTER 117  •  Gastroenteritis

Abdominal radiographs may be unrewarding or may show signs of fluid-filled bowel loops. Radiographs are indicated if a GI obstruction (i.e., foreign body, neoplasia) is suspected. Abdominal ultrasonography is an excellent tool to evaluate all abdominal organs, including the thickness and layering of the stomach and small intestine. These findings may be insensitive and nonspecific, however, and always should be used in conjunction with other diagnostic tests. If PLE is suspected and biopsies of the stomach and intestine are required, there are two main ways of achieving this. Endoscopy is a noninvasive method for visualizing the esophageal, gastric, and duodenal mucosa, as well as for obtaining small (1.8- to 2.4-mm) biopsy samples. Disadvantages of this method are that the samples are small and biopsies cannot be obtained distal to the duodenum. Ileal samples can be obtained if colonoscopy is performed, but this requires patient preparation (i.e., administration of cleansing enemas), which can cause decompensation in unstable animals resulting from fluid and electrolyte shifts. Another method for obtaining samples is via exploratory laparotomy. This is an excellent method for acquiring full-thickness biopsy samples of multiple areas of the GI tract (and other organs if they are found to be abnormal). The disadvantages are that it is much more invasive, and poor wound healing may be a concern in patients with reduced albumin levels. This has been reported in human surgical patients as well as canine surgical patients.24-26 In addition, diseased gastric and intestinal walls may heal poorly. Laparoscopy is another technique that can be used to obtain excellent visualization of the abdominal cavity along with full-thickness biopsies of the GI tract (and other organs as needed). Laparoscopy is less invasive than exploratory laparotomy and may be associated with less morbidity because of smaller incisions; however, healing of gastric and intestinal biopsy sites would remain a concern in patients with low albumin levels or diseased walls. The most common clinical signs of gastroenteritis are vomiting, diarrhea, and anorexia. These are common to a variety of diseases; therefore gastroenteritis is often a diagnosis of exclusion. Differential diagnosis may include systemic diseases such as kidney disease, liver disease, hypoadrenocorticism, complicated diabetes mellitus (diabetic ketoacidosis), vestibular disease or other neurologic abnormalities, pancreatitis, pyometra, prostatitis, and peritonitis. Additional primary GI diseases to consider include intussusception, foreign body or mass obstruction, infiltrative disease (neoplasia, infectious), or ischemia. It is important to rule out these other disorders, as indicated, before making a diagnosis of gastroenteritis.

TREATMENT Most cases of gastroenteritis respond well to supportive care. Aggressiveness of treatment depends on the severity of clinical signs and the underlying cause. Because the most common clinical signs of gastroenteritis, regardless of underlying cause, are vomiting, diarrhea, and anorexia, dehydration is a common occurrence, and initial therapy should be aimed at addressing the patient’s hydration status and perfusion parameters (see Chapters 57, 59, and 60). Other treatments can be divided into specific or symptomatic therapies. Specific drugs can be used to treat some of the underlying causes of disease. For the most part, drugs used to eradicate many of the infectious causes for gastroenteritis are available. GI parasites may be treated with fenbendazole or other antihelminthic drugs. Campylobacter spp. have responded well to such drugs as erythromycin, enrofloxacin, and cefoxitin,27 and Clostridium spp. may respond to metronidazole or ampicillin.28 The choice of drug depends on many factors, including patient age and ability to take oral medications. Few antiviral drugs are effective in veterinary medicine; therefore diseases such as parvoviral enteritis are treated supportively. As stated

before, the aims of therapy for animals with PLE are to treat the underlying cause, commonly with diet change and antiinflammatory agents. Many of the drugs used to treat gastroenteritis are nonspecific. In addition to fluids, most animals respond well to resting the GI tract by withholding food for 24 to 48 hours. When food is offered, a wet, easily digestible diet is recommended. Addition of GI protectants (see Chapter 161) or antiemetics (see Chapter 162), or both, may hasten recovery of the enterocyte damage, give the GI tract time to heal, and decrease nausea. In animals with severe GI damage, in which bacterial translocation is a concern (especially in puppies with parvoviral enteritis), antimicrobials may be indicated and should aim at treating the common organisms expected in the intestinal tract. This usually consists of drugs with good gram-negative and anaerobic coverage. More recently, use of probiotics has been evaluated in veterinary medicine for treatment of acute and chronic GI disease. Two recent prospective studies have shown that the use of probiotics in acute gastroenteritis may hasten recovery and reduce the severity of diarrhea in affected patients. Although specific mechanisms for their benefit still are poorly understood, probiotics may compete with pathogenic organisms for nutrition, they may produce antimicrobial substances, and they may stimulate the immune system.29,30

CONCLUSION Prognosis for animals with mild to moderate gastroenteritis is typically excellent. However, early diagnosis and timely therapy are important to prevent multiple organ involvement and maximize outcome.

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12. Schlegel BJ, Van Dreumel T, Slavic D, et al: Clostridium perfringens type A fatal acute gastroenteritis in a dog, Can Vet J 53(5):555-557, 2012. 13. Lappin MR: Infection (small intestine). In Washabau RJ, Day MJ: Canine and feline gastroenterology, St Louis, 2013, Elsevier Saunders. 14. Simpson KW, Dogan B, Rishniw M, et al: Adherent and invasive Escherichia coli is associated with granulomatous colitis in boxer dogs, Infect Immun 74(8):4778-4792, 2006. 15. Mansfield CS, James FE, Craven M, et al: Remission of histiocytic ulcerative colitis in boxer dogs correlates with eradication of invasive intramucosal Escherichia coli, J Vet Intern Med 23:964-969, 2009. 16. Guilford WG, Strombeck DS: Acute hemorrhagic enteropathy (hemorrhagic gastroenteritis: HGE). In Guilford WG, Center SA, Strombeck DR, et al, editors: Strombeck’s small animal gastroenterology, ed 3, Philadelphia, 1996, Saunders. 17. Spielman BL, Garvey MS: Hemorrhagic gastroenteritis in 15 dogs, J Am Anim Hosp Assoc 29:341, 1993. 18. Guilford WG, Strombeck DS: Classification, pathophysiology, and symptomatic treatment of diarrheal disease. In Guilford WG, Center SA, Strombeck DR, et al, editors: Strombeck’s small animal gastroenterology, ed 3, Philadelphia, 1996, Saunders. 19. Hackett T: Acute hemorrhagic diarrhea. In Wingfield WE, Raffe MR, editors: The veterinary ICU book, Jackson Hole, Wyo, 2002, Teton NewMedia. 20. Unterer S, Strohmeyer K, Kruse BD, et al: Treatment of aseptic dogs with hemorrhagic gastroenteritis with amoxicillin/clavulanic acid: a prospective blinded study, J Vet Intern Med 25(5):973-9, 2011. 21. Williams DA: Malabsorption, small intestinal bacterial overgrowth, and protein losing enteropathy. In Guilford WG, Center SA, Strombeck DR

et al, editors: Strombeck’s small animal gastroenterology, ed 3, Philadelphia, 1996, Saunders. 22. Vigano F, Perissinotto L, Bosco VRF: Administration of 5% human serum albumin in critically ill small animal patients with hypoalbuminemia: 418 dogs and 170 cats (1994-2008), J Vet Emerg Crit Care April 20(2):237-243, 2010. 23. Powers KA, Kapus A, Khadaroo RG, et al: Twenty-five percent albumin prevents lung injury following shock/resuscitation, Crit Care Med 31:2355, 2003. 24. Gibbs J, Cull W, Henderson W, et al: Preoperative serum albumin level as a predictor of operative mortality and morbidity, Arch Surg 134:36, 1999. 25. Ralphs SC, Jessen CR, Lipowitz AJ: Risk factors for leakage following intestinal anastomosis in dogs and cats: 115 cases (1991-2000), J Am Vet Med Assoc 223:73, 2003. 26. Grimes JA, Schmiedt CW, Cornell KK, et al: Identification of risk factors for septic peritonitis and failure to survive following gastrointestinal surgery in dogs, J Am Vet Med Assoc 238(4):486-494, 2011. 27. Fox JG: Campylobacter infections. In Greene CE, editor: Infectious diseases of the dog and cat, ed 4, St Louis, 2012, Elsevier Saunders. 28. Marks SL: Clostridium perfringens- and Clostridium difficile-associated diarrhea. In Greene CE, editor: Infectious diseases of the dog and cat, ed 4, St Louis, 2012, Elsevier Saunders. 29. Herstad HK, Nesheim BB, L’Abée-Lund T, et al: Effects of a probiotic intervention in acute canine gastroenteritis—a controlled clinical trial, J Small Anim Pract 51(1):34-38, 2010. 30. Bybee SN, Scorza AV, Lappin MR: Effect of the probiotic Enterococcus faecium SF68 on presence of diarrhea in cats and dogs housed in an animal shelter, J Vet Intern Med 25(4):856-860, 2011.

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CHAPTER 118  MOTILITY DISORDERS Patricia M. Dowling,

DVM, MSc, DACVIM, DACVP

KEY POINTS • Treatment of canine congenital and acquired megaesophagus is symptomatic, with protectants and histamine-2 blockers or serotonergic drugs for esophageal reflux and esophagitis. • Gastric emptying disorders can be treated with metoclopramide, serotonergic drugs, ghrelin mimetics, motilin receptor agonists, and acetylcholinesterase inhibitors. • Intestinal transit disorders can be treated with serotonergic drugs, ghrelin mimetics, motilin receptor agonists, and acetylcholinesterase inhibitors. • Megacolon in cats can be treated with serotonergic drugs.

Gastrointestinal (GI) motility disorders are common yet challenging to diagnose and treat in humans and animals. Therapy is directed at correcting predisposing factors and using prokinetic drugs to promote normal GI motility.

MEGAESOPHAGUS Etiology and Clinical Signs Congenital megaesophagus is seen in a number of breeds of dogs, including Wire-haired Fox Terriers, Miniature Schnauzers, German Shepherd Dogs, Great Danes, Irish Setters, Labrador Retrievers, Newfoundlands, and Chinese Shar Peis. It is rare in cats, but Siamese cats may be predisposed. Congenital megaesophagus in dogs is due to organ specific sensory dysfunction, in which the distention sensitive vagal afferent system innervating the esophagus is defective, whereas other contiguous and physiologically similar distention sensitive vagal afferent systems are unaffected.1 Acquired megaesophagus can develop in association with a number of primary diseases in dogs and cats, but most adult-onset cases are idiopathic.2 Myasthenia gravis accounts for the majority of cases with a known cause. Other causes of acquired megaesophagus include hypoadrenocorticism, lead and thallium poisoning, lupus, esophageal neoplasia, and severe esophagitis. Inflammatory myopathies associated with megaesophagus in dogs include immune-mediated polymyositis infectious and preneoplastic myositis and dermatomyositis. Dogs with peripheral

CHAPTER 118  •  Motility Disorders

neuropathies, laryngeal paralysis, myasthenia gravis, esophagitis, and chronic or recurrent gastric dilatation with or without volvulus are at an increased risk of developing megaesophagus. German Shepherd Dogs, Golden Retrievers, and Irish Setters and Abyssinians and Somali cats are predisposed to acquired megaesophagus.2,3 Esophageal dysmotility without overt megaesophagus occurs in young terriers and is thought to be a syndrome of delayed esophageal maturation.4 Affected dogs can be symptomatic or asymptomatic, and normal esophageal motility develops with time in some dogs. Although often blamed as a cause, a clear link between hypothyroidism and megaesophagus cannot be demonstrated. Regurgitation is the predominant clinical sign associated with megaesophagus and a careful history can help distinguish between passive regurgitation and active vomition. The frequency of episodes and relation to time of feeding vary considerably. Puppies with congenital megaesophagus typically begin regurgitating when started on solid foods. Emaciation from malnutrition and aspiration pneumonia are the most common complications of megaesophagus.

Diagnosis and Treatment Plain survey radiographs are often diagnostic, but contrast radiography may be useful to confirm the diagnosis and evaluate motility. Endoscopy also confirms the diagnosis and can identify esophagitis, which often occurs in dogs with megaesophagus. Routine hematology, serum biochemistries, and urinalysis should be performed to investigate primary disorders that can result in secondary megaesophagus. Additional diagnostic tests for acquired megaesophagus include serology for nicotinic ACH receptor antibody and antinuclear antibody, adrenocorticotropic hormone stimulation, serum creatine phosphokinase activity, electromyography and nerve conduction velocity, and nerve and muscle biopsies. Treatment of congenital megaesophagus is symptomatic; traditional prokinetic drugs such as metoclopramide or cisapride have not proven beneficial. Because of the high incidence of esophagitis, affected animals should be treated with sucralfate (1 g q8h for large dogs, 0.5 g q8h for smaller dogs and 0.25 g q8-12h for cats), a histamine-2 blocker (cimetidine, 5 to 10 mg/kg q8-12h PO; ranitidine, 1 to 2 mg/kg q12h PO; famotidine, 0.5 to 1 mg/kg q12h PO), or a proton pump inhibitor (omeprazole, 1 to 2 mg/kg q24h PO). Animals with secondary megaesophagus should be treated appropriately for the primary disease. Myasthenia gravis in dogs is treated with pyridostigmine (1 to 3 mg/kg q12h PO), prednisone (1 to 2 mg/ kg q12h PO), or azathioprine (2 mg/kg q24h PO initially). Mycophenolate mofetil, a new immunosuppressant drug, does not improve clinical outcome when added to pyridostigmine therapy in dogs with acquired myasthenia gravis.5 Affected animals should be fed small amounts of high-calorie diet at frequent intervals from an elevated position to allow gravity to assist passage into the stomach. The “Bailey Chair” is an example of a positioning device that may be helpful for affected dogs; images and directions on how to build the chair are available on the Internet. If dogs are unable to maintain adequate nutritional intake with positioning, a temporary or permanent gastrostomy tube can be placed. Without a definitive diagnosis, most cases of megaesophagus typically do not do well long term, and affected patients should be given a poor prognosis because of recurrent complications.

GASTRIC EMPTYING DISORDERS Etiology and Clinical Signs Gastric emptying disorders from mechanical obstruction or defective propulsion frequently occur in dogs and cats.6 Defective propulsion is caused by abnormalities in myenteric neuronal or gastric smooth muscle function or antropyloroduodenal coordination. In cats, hair

balls can be caused by and be the cause of gastric obstruction or disturbed motility.7 Primary problems known to cause defective propulsion include infectious or inflammatory diseases, ulcers, and postsurgical gastroparesis. Delayed gastric emptying also occurs secondarily to electrolyte imbalances, metabolic derangements, drugs (cholinergic antagonists, adrenergic and opioid agonists), and peritonitis. In critically ill animals, delayed gastric emptying limits enteral nutrition, and the effects of severe disease further deplete caloric reserves, impairing wound healing, decreasing immune function, and increasing morbidity and mortality.8

Diagnosis and Treatment The most common presenting complaint is chronic, intermittent vomiting that occurs more than 8 hours after eating. Gastric distention may be discernible after eating and is relieved by vomiting. In addition, some patients are presented with weight loss. Although diagnosis and management of mechanical obstruction is straightforward, disorders of propulsion are more challenging. Imaging studies are used to confirm delayed gastric emptying, the most common gastric motility disorder. Survey films, barium contrast studies, and fluoroscopy may be used to document abnormal gastric emptying. Barium impregnated polyspheres (BIPS) can be administered to evaluate the passage of different size beads. Endoscopy is used to rule out gastritis or obstructive disease. If no underlying cause is determined, a functional disorder of gastric emptying is diagnosed presumptively. Treatment consists of dietary management and gastric prokinetic agents.6 Animals should be fed frequent small meals that are low in fat and protein and high in carbohydrate (e.g., cottage cheese, rice, pasta).

SMALL INTESTINAL TRANSIT DISORDERS Etiology and Clinical Signs Causes of small intestinal transit disorders include enteritis, postsurgical ileus, nematode impaction, intestinal sclerosis, and radiation enteritis.9 Pseudo-obstructions are functional obstructions caused by hypomotility and ileus; most are idiopathic. Intestinal stasis can result in bacterial overgrowth, and the absorption of endotoxin and bacteria can lead to endotoxemia and septicemia. Clinical signs depend on the location and cause of the disorder but typically include vomiting, diarrhea, and weight loss. Abdominal pain and distention may be noted.

Diagnosis and Treatment With pseudo-obstruction, survey radiographs show dilated bowel loops without evidence of a physical obstruction. Contrast studies or BIPS demonstrate delayed transit through the small intestine. The hemogram is typically normal, but changes in the serum biochemical profile may be seen with protracted vomiting and/or diarrhea. Mechanical obstructions always should be ruled out before treatment with prokinetic drugs. Additional therapy is based on the primary cause of the transit disorder and may include corticosteroids and/or antimicrobials.

MEGACOLON Etiology and Clinical Signs Idiopathic megacolon with constipation or obstipation is a common clinical condition in middle-age cats.10,11 Less common causes of constipation in cats are pelvic canal stenosis, dysautonomia, nerve injury, and Manx sacral spinal cord deformities. The underlying cause of megacolon in cats appears to be a generalized dysfunction of colonic smooth muscle.12 Cats with megacolon typically are presented for reduced, absent, or painful defecation. The owner usually notices the cat making

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PART XII  •  INTRAABDOMINAL DISORDERS

numerous unproductive attempts to eliminate in the litter box. When passed, feces are often dry and hard, and hematochezia may be present. Prolonged constipation may also cause anorexia, vomiting, and weight loss.

Diagnosis and Treatment Colonic impaction is usually obvious on physical examination. Depending on the severity and duration of the condition, other clinical signs can include weight loss, abdominal pain, dehydration, and mesenteric lymphadenopathy. Results of complete blood counts and serum chemistries are typically normal, but metabolic causes of constipation, such as dehydration, hypokalemia, or hypocalcemia, occasionally can be detected. Abdominal radiography can document the extent of fecal impaction and identify exacerbating factors including foreign material (e.g., bones), intraabdominal masses, pelvic fractures, and spinal column abnormalities. Digital rectal examination should be performed carefully but may be helpful in identifying pelvic fractures, rectal diverticula, or neoplasia. Therapy of constipation depends on the severity and the underlying cause. Mild to moderate cases typically are managed with dietary modification, laxatives, and colonic prokinetic agents. Subtotal colectomy with preservation of the ileocolic junction should be considered in cats that are refractory to medical therapy.13 Cats have a generally favorable prognosis for recovery after colectomy, although mild to moderate diarrhea may persist for weeks to months post­ operatively in some cases.

PROKINETIC DRUGS FOR GASTROINTESTINAL MOTILITY DISORDERS Serotonergic Drugs The enteric nervous system (ENS) of the GI tract can function independently of the central nervous system (CNS) to control bowel function.14 Because no nerve fibers actually penetrate the intestinal epithelium, the ENS uses enteroendocrine cells such as the enterochromaffin cells as sensory transducers. More than 95% of the body’s serotonin (also known as 5-hydroxytryptamine, 5-HT) is located in the GI tract, and more than 90% of that store is in the enterochromaffin cells that are scattered in the enteric epithelium from the stomach to the colon. The remaining serotonin is located in the ENS, where 5-HT acts a as a neurotransmitter. From the enterochromaffin cells, serotonin is secreted into the lamina propria in high concentrations, with overflow into the portal circulation and intestinal lumen. The effect of serotonin on intestinal activity is coordinated by 5-HT receptor subtypes. The 5-HT1P receptor initiates peristaltic and secretory reflexes, and so far no drugs have been developed to target this specific receptor. The 5-HT3 receptor activates extrinsic sensory nerves and is responsible for the sensation of nausea and induction of vomiting from visceral hypersensitivity. Therefore specific 5-HT3 antagonists such as ondansetron and granisetron are used to treat the nausea and vomiting seen with chemotherapy. Stimulation of the 5-HT4 receptor increases the presynaptic release of acetylcholine (ACH) and calcitonin gene-related peptide, thereby enhancing neurotransmission. This enhancement promotes propulsive peristaltic and secretory reflexes. Specific 5-HT4 agonists such as cisapride enhance neurotransmission and depend on natural stimuli to evoke peristaltic and secretory reflexes. This makes these drugs safe because they do not induce perpetual or excessive motility. It is also the reason for the limitations of these drugs because they will not be effective if enteric nerves have degenerated or become nonfunctional.

Cisapride Cisapride was introduced in 1993 and was the most efficacious prokinetic drug in the treatment of human GI motility disorders. It also

became popular for treating motility disorders in dogs and cats. Cisapride is related chemically to metoclopramide, but unlike metoclopramide, it does not cross the blood-brain barrier or have antidopaminergic effects. Therefore it does not have antiemetic action and it does not cause the extrapyrimidal effects seen with metoclopramide. Cisapride is more potent and has broader prokinetic activity than metoclopramide, increasing the motility of the colon, as well as that of the esophagus, stomach, and small intestine. Cisapride is useful in managing gastric stasis, idiopathic constipation, gastroesophageal reflux, and postoperative ileus in dogs and cats. Cisapride is useful in managing cats with megacolon; in many cases, it alleviates or delays the need for subtotal colectomy.15 Initially, the only adverse side effects reported in humans were increased defecation, headache, abdominal pain, cramping, and flatulence, and cisapride appeared to be well tolerated by dogs and cats. As cisapride became widely used in the management of gastroesophageal reflux in humans, cases of heart rhythm disorders and deaths were reported. These cardiac problems in humans were associated highly with concurrent drug therapy or specific underlying conditions. Cisapride is metabolized by the liver by the cytochrome P450 enzyme system. Cardiac abnormalities in humans were associated with concomitant administration of other drugs that inhibit cisapride’s metabolism, thereby increasing cisapride blood concentrations. Drugs known to inhibit the metabolism of cisapride include clarithromycin, erythromycin, troleandomycin, nefazodone, fluconazole, itraconazole, indinavir, and ritonavir. Because of the human cardiovascular adverse effects, the manufacturer of cisapride withdrew the product from sale in North America. Currently, cisapride can be obtained only from compounding pharmacies in the United States and Canada and is formulated from active pharmaceutical ingredient. Because of the lack of standardized products, efficacy may vary, but a suggested dose is 2.5 to 5 mg/cat q8-12h PO. Oral absorption increases with food, so cisapride should be administered 15 minutes before feeding. Because of the adverse effects of cisapride, alternative 5-HT4 receptor agonists have been developed. The most promising is mosapride, which has shown prokinetic and anti-ulcerogenic properties in dogs.16-18 However, mosapride is currently not available in North America.

METOCLOPRAMIDE Metoclopramide (Reglan, Schwarz Pharma) is a central dopaminergic antagonist and peripheral 5-HT3 receptor antagonist and 5-HT4 receptor agonist with GI and CNS effects. Metoclopramide stimulates and coordinates esophageal, gastric, pyloric, and duodenal motor activity. It increases lower esophageal sphincter tone and stimulates gastric contractions, while relaxing the pylorus and duodenum. Metoclopramide is administered to control nausea and vomiting associated with chemotherapy and as an antiemetic for dogs with parvoviral enteritis. Metoclopramide is effective in treating postoperative ileus in dogs, which is characterized by decreased GI myoelectric activity and motility.19 Metoclopramide has little or no effect on colonic motility, so it is not useful in cats with megacolon. Metoclopramide readily crosses the blood-brain barrier, where dopamine antagonism at the chemoreceptor trigger zone produces an antiemetic effect. However, dopamine antagonism in the striatum causes adverse effects known collectively as extrapyramidal signs, which include involuntary muscle spasms, motor restlessness, and inappropriate aggression. Many practitioners can relate stories of frenzied dogs and cats with resulting human injuries after metoclopramide administration. If recognized in time, the extrapyramidal signs can be reversed by restoring an appropriate dopamine to ACH balance with the anticholinergic action of diphenhydramine

CHAPTER 118  •  Motility Disorders

hydrochloride (Benadryl, Johnson & Johnson, Inc.) administered at a dose of 1.0 mg/kg IV. Metoclopramide is available in 5- and 10-mg tablets, as 1 mg/ml oral solution, and as a 5 mg/ml injectable formulation. In dogs and cats, it is dosed at 0.2 to 0.5 mg/kg q8h, PO or SC, at least 30 minutes before a meal and at bedtime. It also can be given by continuous IV infusion at 0.01 to 0.02 mg/kg/hr.

Ghrelin Mimetics and Motilin Receptor Agonists Ghrelin and motilin participate in initiating the migrating motor complex in the stomach and stimulate gastrointestinal motility, accelerate gastric emptying, and induce “gastric hunger.” Ghrelin mimetics and motilin agonists currently are being developed to reverse gastrointestinal hypomotility disorders. Rikkunshito is a kampo herbal medicine that is used widely in Japan for the treatment of the upper gastrointestinal disorders by potentiating ghrelin. In dogs, intragastric administration of rikkunshito stimulated gastrointestinal contractions in the interdigestive state through cholinergic neurons and 5-HT type 3 receptors and increased plasma ghrelin levels.20 Macrolide antibiotics, including erythromycin and clarithromycin, are motilin receptor agonists. At microbially ineffective doses, they stimulate migrating motility complexes and antegrade peristalsis in the proximal GI tract. They also appear to stimulate cholinergic and noncholinergic neuronal pathways that increase motility. Erythromycin increases gastroesophageal sphincter pressure in dogs and cats, so it should be useful in treating gastroesophageal reflux and reflux esophagitis.21 Erythromycin increases gastric emptying rate in normal dogs; however, large food chunks may enter the small intestine and be digested inadequately.6 Erythromycin accelerates colonic transit in the dog and stimulates canine but not feline colonic smooth muscle in vitro.21 Human pharmacokinetic studies indicate that erythromycin suspension is the ideal dosage form for administration of erythromycin as a prokinetic agent. The suggested prokinetic dose is 0.5 to 1.0 mg/ kg q8h. Nonantibiotic derivatives of erythromycin are being developed as prokinetic agents. Mitemcinal is a motilin agonist derived from erythromycin that accelerated gastric emptying in dogs with normal and delayed gastric emptying better than cisapride.22 In a dose-dependent manner, mitemcinal also stimulated antroduodenal motility in the interdigestive and digestive states. Oral administration of mitemcinal (0.3 to 3 mg/kg) stimulated colonic motility and accelerated bowel movement after feeding without inducing diarrhea in dogs.23 Mitemcinal is currently in development as a treatment for diabetic gastroparesis in humans.

Acetylcholinesterase Inhibitors Ranitidine (Zantac, Boehringer Ingelheim) and nizatidine (Axid, Braintree Laboratories) are histamine H2 receptor antagonists that are prokinetics in addition to inhibiting gastric acid secretion.24,25 Their prokinetic activity is due to acetylcholinesterase inhibition, with the greatest activity seen in the proximal GI tract. Cimetidine and famotidine are not acetylcholinesterase inhibitors and do not have prokinetic effects. Ranitidine and nizatidine stimulate GI motility by increasing the amount of acetylcholinesterase available to bind smooth muscle muscarinic cholinergic receptors. However, oral ranitidine had no detectable effect on gastrointestinal transit times in normal dogs using a wireless motility capsule system,26 and it does not reduce the incidence of gastroesophageal reflux when given before anesthesia in dogs.27 Ranitidine is available as 75-mg (available over the counter in the United States and Canada), 150-mg and 300-mg tablets, a 15 mg/ml syrup, and a 25 mg/ml injectable solution. An oral dose of 1 to 2 mg/ kg every 12 hours inhibits gastric acid secretion as well as stimulating

gastric emptying. Nizatidine is available as 75-mg (available over the counter in the United States only), 150-mg, and 300-mg capsules. Like ranitidine, at gastric antisecretory doses of 2.5 to 5 mg/kg, nizatidine also has prokinetic effects. Ranitidine causes less interference with cytochrome P450 metabolism of other drugs than cimetidine and nizatidine does not affect hepatic microsomal enzyme activity, so both drugs have a wide margin of safety. Acotiamide is a novel selective acetylcholinesterase inhibitor that has gastroprokinetic action in the dog via cholinergic pathways.28 It currently is undergoing clinical trials for the treatment of functional dyspepsia in people.

REFERENCES 1. Holland CT, Satchell PM, Farrow BR: Selective vagal afferent dysfunction in dogs with congenital idiopathic megaoesophagus, Auton Neurosci 99:18-23, 2002. 2. Gaynor AR, Shofer FS, Washabau RJ: Risk factors for acquired megaesophagus in dogs, J Am Vet Med Assoc 211:1406-1412, 1997. 3. Shelton GD, Ho M, Kass PH: Risk factors for acquired myasthenia gravis in cats: 105 cases (1986-1998), J Am Vet Med Assoc 216:55-57, 2000. 4. Bexfield NH, Watson PJ, Herrtage ME: Esophageal dysmotility in young dogs, J Vet Intern Med 20:1314-1318, 2006. 5. Dewey CW, Cerda-Gonzalez S, Fletcher DJ, et al: Mycophenolate mofetil treatment in dogs with serologically diagnosed acquired myasthenia gravis: 27 cases (1999-2008), J Am Vet Med Assoc 236:664-668, 2010. 6. Hall JA, Washabau RJ: Diagnosis and treatment of gastric motility disorders, Vet Clin North Am Small Anim Pract 29:377-395, 1999. 7. Cannon M: Hair balls in cats: a normal nuisance or a sign that something is wrong? J Feline Med Surg 15:21-29, 2013. 8. Woosley KP: The problem of gastric atony, Clin Tech Small Anim Pract 19:43-48, 2004. 9. MacPhail C: Gastrointestinal obstruction, Clin Tech Small Anim Pract 17:178-183, 2002. 10. Bertoy RW: Megacolon in the cat, Vet Clin North Am Small Anim Pract 32:901-915, 2002. 11. Washabau RJ, Holt D: Pathogenesis, diagnosis, and therapy of feline idiopathic megacolon, Vet Clin North Am Small Anim Pract 29:589-603, 1999. 12. Washabau RJ, Stalis IH: Alterations in colonic smooth muscle function in cats with idiopathic megacolon, Am J Vet Res 57:580-587, 1996. 13. White RN: Surgical management of constipation, J Feline Med Surg 4:129138, 2002. 14. Gershon MD: Review article: serotonin receptors and transporters—roles in normal and abnormal gastrointestinal motility, Aliment Pharmacol Ther 20(suppl)7:3-14, 2004. 15. Hasler AH, Washabau RJ: Cisapride stimulates contraction of idiopathic megacolonic smooth muscle in cats, J Vet Intern Med 11:313-318, 1997. 16. Matsunaga Y, Tanaka T, Yoshinaga K, et al: Acotiamide hydrochloride (Z-338), a new selective acetylcholinesterase inhibitor, enhances gastric motility without prolonging QT interval in dogs: comparison with cisapride, itopride, and mosapride, J Pharmacol Exp Ther 336:791-800, 2011. 17. Tsukamoto A, Ohno K, Maeda S, et al: Prokinetic effect of the 5-HT4R agonist mosapride on canine gastric motility, J Vet Med Sci 73:1635-1637, 2011. 18. Tsukamoto A, Ohno K, Tsukagoshi T, et al: Ultrasonographic evaluation of vincristine-induced gastric hypomotility and the prokinetic effect of mosapride in dogs, J Vet Intern Med 25:1461-1464, 2011. 19. Graves GM, Becht JL, Rawlings CA: Metoclopramide reversal of decreased gastrointestinal myoelectric and contractile activity in a model of canine postoperative ileus, Vet Surg 18:27-33, 1989. 20. Yanai M, Mochiki E, Ogawa A, et al: Intragastric administration of rikkunshito stimulates upper gastrointestinal motility and gastric emptying in conscious dogs, J Gastroenterol, 2012. 21. Washabau RJ: Gastrointestinal motility disorders and gastrointestinal prokinetic therapy, Vet Clin North Am Small Anim Pract 33:1007-1028, vi, 2003. 22. Onoma M, Yogo K, Ozaki K, et al: Oral mitemcinal (GM-611), an erythromycin-derived prokinetic, accelerates normal and experimentally

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delayed gastric emptying in conscious dogs, Clin Exp Pharmacol Physiol 35:35-42, 2008. 23. Ozaki K, Sudo H, Muramatsu H, et al: Mitemcinal (GM-611), an orally active motilin receptor agonist, accelerates colonic motility and bowel movement in conscious dogs, Inflammopharmacology 15:36-42, 2007. 24. Bertaccini G, Coruzzi G, Poli E: Histamine H2 receptor antagonists may modify dog intestinal motility independently of their primary action on the H2 receptors, Pharmacol Res Commun 17:241-254, 1985. 25. Ueki S, Matsunaga Y, Yoneta T, et al: Gastroprokinetic activity of nizatidine during the digestive state in the dog and rat, Arzneimittelforschung 49:618-625, 1999.

26. Lidbury JA, Suchodolski JS, Ivanek R, et al: Assessment of the variation associated with repeated measurement of gastrointestinal transit times and assessment of the effect of oral ranitidine on gastrointestinal transit times using a wireless motility capsule system in dogs, Vet Med Int 2012:938417, 2012. 27. Favarato ES, Souza MV, Costa PR, et al: Evaluation of metoclopramide and ranitidine on the prevention of gastroesophageal reflux episodes in anesthetized dogs, Res Vet Sci 93:466-467, 2012. 28. Nagahama K, Matsunaga Y, Kawachi M, et al: Acotiamide, a new orally active acetylcholinesterase inhibitor, stimulates gastrointestinal motor activity in conscious dogs, Neurogastroenterol Motil 24:566-574, e256, 2012.

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CHAPTER 119  GASTROINTESTINAL HEMORRHAGE Søren R. Boysen,

DVM, DACVECC

KEY POINTS • Gastrointestinal hemorrhage is an important cause of blood loss anemia. • In dogs and cats gastrointestinal ulceration is the most commonly reported cause of gastrointestinal hemorrhage. • Nonsteroidal antiinflammatory drugs and hepatic disease are frequent causes of gastrointestinal ulceration in dogs. • Neoplasia is a common cause of gastrointestinal ulceration in cats. • Severe thrombocytopenia should not be overlooked as a cause of gastrointestinal hemorrhage in dogs. • Hematemesis and melena suggest gastrointestinal hemorrhage but are not always noted. • With acute severe gastrointestinal hemorrhage, the primary objective is to assess rapidly the patient’s cardiovascular status and institute resuscitative efforts if shock is present. • It is reasonable to administer gastrointestinal protectants before confirming the cause of gastrointestinal hemorrhage. • Most cases of gastrointestinal hemorrhage respond well to medical treatment, although surgery may be indicated in others.

Gastrointestinal (GI) hemorrhage is an important cause of blood loss anemia and a potentially life-threatening condition in dogs.1 It is reported less frequently in cats. It may be acute or chronic, occult (no visible blood) or overt (grossly visible blood), and can vary from mild, self-limiting states to severe life-threatening conditions. Significant GI hemorrhage often can be detected during history and physical examination. However, on occasion even acute severe GI hemorrhage may be overlooked if signs localizing blood loss to the GI tract are not present or if concurrent disease obscures the diagnosis.2,3 In addition, because even mild cases may progress to life-threatening events, it is important to identify rapidly patients with GI hemorrhage and institute therapies to prevent their deterioration.

ETIOLOGY GI hemorrhage in dogs and cats can be the result of a primary insult to the GI tract or may be secondary to a systemic disease process. It may originate in the esophagus, stomach, small intestine, or large intestine. As such, a number of pathologic processes have been associated with GI hemorrhage. In general, these can be divided into three broad categories: diseases causing ulcers, diseases causing coagulopathies, and diseases associated with vascular anomalies. Some diseases are difficult to classify into one of the above categories, and animals may have single or multiple predisposing causes.1,4 Diseases associated with GI ulceration and/or GI hemorrhage in dogs and cats are listed in Box 119-1. The most common cause of GI hemorrhage in dogs and cats is GI ulceration.3-6 The severity of GI hemorrhage associated with ulcers varies with the degree and extent of mucosal erosion. With erosion into an underlying artery, the magnitude of bleeding is related to the size of the arterial defect and the diameter of the artery.7 Nonsteroidal antiinflammatory drugs (NSAIDs) and hepatic disease are the most commonly reported risk factors for ulcers in dogs (Figure 119-1).4 Neoplasia is a common risk factor for ulcers in cats; systemic mastocytosis, gastrinoma, intestinal lymphosarcoma, and adenocarcinoma are the most commonly reported tumors.3 Inflammatory bowel disease also may be an important nonneoplastic cause of GI ulceration in cats and dogs.3,8 Stress ulcers are a frequent cause of GI hemorrhage in critically ill human patients and have been reported in dogs and cats after hypovolemia and surgery.3,9 The true incidence and significance of stress ulcers in critically ill cats and dogs has not been determined but should be considered in patients that develop GI hemorrhage while in the hospital. Coagulation disorders associated with GI hemorrhage include rodenticide toxicity, disseminated intravascular coagulation, coagulation factor deficiencies (factor XII and prekallikrein deficiency), and thrombocytopenia.1,5 Thrombocytopenia is the most common coagulation disorder resulting in GI hemorrhage in dogs and should

CHAPTER 119  •  Gastrointestinal Hemorrhage

literature, and it appears to be an infrequent cause of GI hemorrhage in dogs and cats.10 It should be considered when more common causes of GI hemorrhage have been ruled out.

HISTORY AND PHYSICAL EXAMINATION

FIGURE 119-1  Severe hematemesis in a dog subsequent to ingestion of naproxen, a nonselective nonsteroidal anti-inflammatory drug used in humans. Although this case involved accidental ingestion, gastrointestinal hemorrhage has been reported in animals after administration of nonsteroidal antiinflammatory drugs at recommended therapeutic dosages.

BOX 119-1 

Diseases Associated with Gastrointestinal Ulceration and Hemorrhage in Dogs and Cats

Drug Administration

Parasitic Infections

NSAIDs Glucocorticoids

Hookworms Whipworms Coccidia Roundworms

Systemic and Metabolic Diseases Hepatic disease Uremia Pancreatitis Hypoadrenocorticism

Ischemic Events GDV Mesenteric volvulus Mesenteric thrombosis Intussusception

Viral Infections Parvovirus Coronavirus

Algal Infections Protothecosis

Systemic neoplasia Mastocytosis Gastrinoma

Neurologic Disease

Gastrointestinal Neoplasia

Head trauma IVDD Mucosal trauma Foreign bodies

Lymphoma Adenocarcinoma Leiomyoma Leiomyosarcoma Hemangioma

Fungal Infections Pythium Histoplasma

Bacterial Infections Salmonella Clostridium spp. Campylobacter Helicobacter (controversial)

Stress of Critical Illness Major surgery Hypovolemia Sepsis

Miscellaneous IBD Polyps Idiopathic eosinophilic masses HGE

GDV, Gastric dilatation-volvulus; GI, gastrointestinal; HGE, hemorrhagic gastroenteritis; IBD, inflammatory bowel disease; IVDD, intervertebral disk disease; NSAIDs, nonsteroidal antiinflammatory drugs.

not be overlooked.1 Coagulation disorders resulting in GI hemorrhage appear to be less common in cats. Vascular anomalies, because of the high incidence of varices, are a common cause of GI hemorrhage in humans. In contrast, only a few cases of vascular anomaly have been reported in the veterinary

With extensive hemorrhage, vomiting, diarrhea, or ulcer perforation, patients with GI hemorrhage may be presented in a state of shock resulting from blood loss, hypovolemia, endotoxemia, or sepsis. Examination findings consistent with shock include tachycardia, diminished or thready arterial pulses (particularly peripheral), cool extremities, prolonged capillary refill time, and pale mucous membranes. Immediate resuscitative therapies to reverse the state of shock take precedence (see Chapters 5 and 60), and localization of the site of hemorrhage and tailored therapies may have to be delayed until the cardiovascular system is stable. Once resuscitative efforts have commenced, a complete history and physical examination should be performed. Hematemesis (vomitus with the appearance of coffee grounds or frank blood), hematochezia (passage of bright red or frank blood with or without stool), or melena (black, tarry stool) suggests the GI tract as a source of hemorrhage. However, these signs are not always evident clinically and may not appear until significant GI hemorrhage has occurred.3,4,11 With duodenal hemorrhage, if reflux of duodenal contents into the stomach is insufficient, blood may not be visible in the vomitus.12 However, when it is present, hematemesis suggests ongoing blood loss.13 Diseases of the nasal cavity and oropharynx occasionally can cause hematemesis and melena from swallowing blood of epistaxis or hemoptysis (coughing of blood). In addition, activated charcoal, metronidazole, bismuth (Pepto-Bismol), and diets high in iron (liver, unsweetened baking chocolate) can result in dark stools and should not be confused with melena.14 A history of aspirin or other NSAID administration is not uncommon.4,11,15 Case reports exist of GI ulceration, hemorrhage, and GI perforation occurring in veterinary patients that have received selective cyclooxygenase inhibitors at recommended therapeutic dosages.11 Decrease or loss of appetite with or without other signs of GI disease should prompt consideration of GI side effects in any patients receiving NSAIDs. The medication should be discontinued and the patient should be examined. In cases of thrombocytopenia or coagulation disorders, there may be a history of bleeding from other sites of the body, including the nasal cavities or urinary tract. Thorough examination of the mucosal surfaces may reveal petechiae in severely thrombocytopenic patients. A search for subcutaneous nodules or masses may detect underlying mast cell tumors. Because GI hemorrhage may be insidious in onset, especially when chronic, the abdomen should be examined carefully. Abdominal palpation may localize areas of pain (tenderness, voluntary or involuntary guarding) or induce nausea, identify masses or foreign objects, or detect abdominal distention or a fluid wave. Splenomegaly or hepatomegaly may be identified in patients with mastocytosis, other neoplasia, or hepatic diseases. A careful rectal examination should be performed to detect frank blood or melena and to look for masses or foreign bodies. Localizing the site of GI hemorrhage is important because the cause, diagnostic tests, and therapies for upper and lower GI hemorrhage may vary.5,14 Although hemorrhage from any site in the GI tract can be serious, upper GI hemorrhage tends to be more severe.13,14 Hematemesis or melena suggests upper GI hemorrhage.14 However, it is the amount of time the blood remains in the GI tract and not necessarily the site of bleeding that determines its color.14,15 Delayed GI transit time and retention of blood in the colon could result in melena associated with a lower GI tract lesion.14,16 Hematochezia is usually reflective of large intestinal, rectal, or anal hemorrhage;

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however, severe acute intestinal hemorrhage can act as a cathartic, significantly decreasing GI transit time.13-15 This may result in the passage of frank blood in the stool after significant blood loss into the upper GI tract.13,15

DIAGNOSTIC TESTS GI hemorrhage is confirmed when a source of bleeding is localized to the GI tract. Patients with signs of shock should have emergency minimum blood tests performed (hematocrit, total protein, blood urea nitrogen [BUN], glucose and, if available, pH, lactate, and electrolytes) while resuscitative efforts and a search for the underlying cause are undertaken. In cases suspected to have hemoabdomen or septic peritonitis, abdominocentesis, emergency abdominal sonography, and possibly diagnostic peritoneal lavage are warranted and may be performed during initial resuscitation of the patient. Once resuscitative efforts have commenced or the patient’s condition has stabilized, other diagnostic modalities should be considered.

Tests to Help Detect Presence of Gastrointestinal Hemorrhage Certain hematologic and biochemical abnormalities are suggestive of GI hemorrhage. Anemia of undetermined origin should prompt consideration of GI hemorrhage. The finding of microcytic, hypochromic anemia (iron deficiency anemia) is reported with chronic GI hemorrhage.4 However, because iron deficiency anemia takes time to develop, normocytic normochromic anemia is more common in cases of recent GI hemorrhage.1,4 A high BUN-to-creatinine ratio (greater than 20) has been reported with GI hemorrhage.16 This phenomenon has been explained by volume depletion and intestinal absorption of proteins, including digested blood, into the circulatory system.16 However, diseases resulting in increased protein metabolism (fever, burns, infections, starvation, and administration of glucocorticoids) also may result in an increased BUN-to-creatinine ratio.1,16 Large bowel hemorrhage reportedly has little effect on BUN levels, and many dogs with GI hemorrhage do not have an elevation in the BUN concentration.1,16,17 In equivocal cases of GI hemorrhage a fecal occult blood test (most of which rely on the peroxidase activity of hemoglobin) may be performed. Although helpful for detecting occult GI hemorrhage, diets containing red meat or having high peroxidase activity, such as fish, fruits, or vegetables, can cause false-positive results.18 Animals should be fed a meat-free diet for at least 72 hours before a fecal occult blood test.19 The presence of peroxidase-producing bacteria within the GI tract also may cause false-positive results.18 Despite false-positive results a negative fecal occult blood test result does rule out significant GI hemorrhage.2 When significant gastric hemorrhage is suspected, passage of a nasogastric tube and aspiration of the stomach contents may confirm and help localize the site of GI hemorrhage. However, this procedure may cause discomfort, and falsenegative results have been reported.12,17

Tests to Help Identify Underlying Causes A coagulation profile, complete blood count, routine biochemistry profile, electrolytes, adrenocorticotropic hormone stimulation testing, imaging, and endoscopy often are indicated to try to identify the underlying cause of GI hemorrhage. The coagulation profile may identify coagulopathies such as rodenticide intoxication or clotting factor deficiencies. It also may detect prolonged bleeding times that are not the direct cause of GI hemorrhage. The platelet count is important, because immunemediated thrombocytopenia is a common cause of moderate to

severe GI hemorrhage in dogs.1 An elevated hematocrit in a patient with acute hemorrhagic diarrhea and a relatively normal plasma protein concentration is suggestive of hemorrhagic gastroenteritis.19 Biochemical markers reflective of hepatic and renal disease may be evident (alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, and bilirubin in cases of hepatic disease; and urea, creatinine, and phosphorus in cases of renal disease). Because hypoadrenocorticism has been reported as a cause of severe GI hemorrhage in the dog, electrolyte levels should be evaluated and an adrenocorticotropic hormone (ACTH) stimulation test performed if another cause for GI hemorrhage cannot be found.20 Fecal smears, cultures, and parvovirus testing may be indicated if infectious disease is suspected. Measurement of gastrin levels is recommended in cases of recurrent GI ulceration and in cases that fail to respond to medical therapy.4 Radiographs may detect foreign bodies, masses, or free air in the peritoneal cavity. Pneumoperitoneum is suggestive of GI perforation in a patient that has not undergone recent abdominal surgery. Although contrast radiographs may identify gastrointestinal mucosal defects, they generally have been replaced by ultrasonography and endoscopy.4,17 Ultrasonography may identify foreign bodies and masses and may help to identify concurrent GI perforation when present.21,22 The use of ultrasonography to identify ulcers in dogs has been described. It allows evaluation of the intestinal wall structure and thickness and can detect the presence of a defect or crater.22 When used serially, it may help determine changes in response to therapy and has suggested the need for surgery in some instances.22 Ultrasonography also has been reported in the assessment of cats with GI ulceration.3 Endoscopy is considered the most sensitive test to evaluate upper GI tract hemorrhage and ulcers, although patients must be resuscitated optimally before the procedure.7,17 It often provides a diagnosis, helps assess prognosis, and may have therapeutic benefits (i.e., foreign body retrieval). In addition to allowing direct visualization of the mucosa, it permits biopsies for histology and culture, which may be required to identify lesions and infectious diseases (i.e., neoplasia, inflammatory bowel disease, protothecosis). The disadvantages of endoscopy include the need for anesthesia, its limitation to the proximal GI tract and colon, the potential to exacerbate GI hemorrhage, and the possibility of causing iatrogenic ulcer perforation.15 If the above diagnostic procedures fail to identify the cause of significant ongoing GI hemorrhage, abdominal exploratory surgery, scintigraphy using technetium-labeled red blood cells, and arteriography should be considered.2,17,19 Scintigraphy has been demonstrated to aid in localization of GI hemorrhage in dogs, and arteriography may help identity GI vascular anomalies.2,10,19

TREATMENT The treatment priority in patients with GI hemorrhage is to stabilize the cardiovascular system, control ongoing hemorrhage, treat existing ulcers, prevent bacterial translocation, and to identify and address the underlying cause. Because of the large number of disease conditions that can result in GI hemorrhage, therapy directed toward correcting the underlying cause is variable (i.e., surgery for foreign bodies or tumors, steroids for hypoadrenocorticism, immunosuppressives for immune-mediated thrombocytopenia, discontinuation of NSAIDs). In considering the underlying cause, it is important to consider related or unrelated coagulation abnormalities (i.e., liver disease causing ulceration and a clotting factor deficiency) and to address concurrent diseases that may exacerbate GI hemorrhage (i.e., uremia in a patient on NSAIDs).

CHAPTER 119  •  Gastrointestinal Hemorrhage

Medical Management The initial priority is to identify rapidly and reverse any signs of shock (see Chapters 5 and 60). Depending on the duration and extent of blood loss, administration of packed red blood cells, whole blood, or hemoglobin-based oxygen-carrying solution may be indicated. In the patient with severe acute GI hemorrhage, this often is implemented as part of the initial resuscitation protocol. Guidelines regarding when to transfuse patients with GI hemorrhage that are anemic but cardiovascularly stable are not well established in veterinary medicine and are controversial in human medicine.23 The hematocrit at which a patient requires a transfusion varies depending on the degree and rate of blood loss, hemodynamic status, initial and subsequent hematocrits, presence of concurrent illness, and severity of clinical signs.24 If the patient displays clinical signs attributable to a decrease in oxygen delivery (i.e., tachycardia, hyperlactatemia, tachypnea) or if serial measurements reveal a decreasing hematocrit after initiating therapy, a blood transfusion is indicated.24 The need for general anesthesia and surgery also may influence the decision of when to transfuse. If GI hemorrhage is the result of a primary coagulopathy or is exacerbated by a secondary coagulopathy (i.e., disseminated intravascular coagulation, hepatic failure, shock, or dilution with aggressive fluid therapy), fresh frozen plasma should be considered. In patients with persistent GI hemorrhage as a result of thrombocytopenia, vincristine may increase the release of platelets from the bone marrow, although the function of these platelets has been questioned.25 The use of iced saline gastric lavage to decrease GI hemorrhage is no longer recommended5,6; it has not been proven to slow hemorrhage, is known to cause discomfort and rapidly can lower core body temperature, which prolongs bleeding in experimental canine studies.6,15 Animals with hematemesis and melena should be treated for GI ulcers until proven otherwise. Medications known to cause ulcers should be discontinued (i.e., NSAIDs). Given the association between GI hemorrhage and steroids in dogs, unless they are considered essential to therapy (i.e., hypoadrenocorticism, immune-mediated diseases), they also should be discontinued. It is reasonable to administer GI protectants before confirming the cause of GI hemorrhage, given that ulcers are the most common cause of GI hemorrhage in dogs and cats, and GI protectants have a wide safety margin. In addition, intraluminal gastric acid neutralization may slow GI hemorrhage by promoting mucosal homeostasis.7,26 Commonly used GI protectants include acid suppressants such as histamine-2 receptor antagonists (cimetidine, ranitidine, famotidine) and proton pump inhibitors (omeprazole, pantoprazole), mucosal binding agents such as sucralfate, and synthetic prostaglandins such as misoprostol. There are no veterinary studies to conclude which gastroprotectants or combination of gastroprotectants is most efficacious in the management of GI ulcers. However, a study demonstrated that famotidine (0.5 mg/kg IV q12h), omeprazole (1 mg/ kg PO q24h), and pantoprazole (1 mg/kg IV q24h) significantly suppressed gastric acid secretion in dogs, but ranitidine (2 mg/kg IV q24h) failed to show significant gastric acid suppression at the dosage evaluated.26 In cases of NSAID toxicity, misoprostol may provide additional benefit (see Chapters 76 and 161). In deciding which medications to use, clinicians should give consideration to the route of drug administration because absorption of medications administered orally in critically ill patients has been questioned, particularly if GI hypoperfusion is present. Many dogs with GI hemorrhage are also vomiting, which may further limit the utility of oral medications. In patients that have persistent vomiting,

antiemetics can be used. Metoclopramide, given as a constant intravenous infusion (1 to 2 mg/kg q24h), often is tried initially. Cases refractory to metoclopramide may benefit from additional antiemetics such as ondansetron. Because many causes of GI hemorrhage are associated with discomfort and pain, analgesics such as an opioid should be considered. Although controversial, in cases with significant GI hemorrhage and suspected GI mucosal barrier compromise, broad-spectrum antibiotics (i.e., a penicillin and an aminoglycoside or fluoroquinolone, or a combination of a cephalosporin, metronidazole, and an aminoglycoside or fluoroquinolone) are warranted because of the risk of bacterial translocation. Broad-spectrum antibiotics also are recommended in patients that are septic. Ideally, samples for culture and susceptibility (i.e., urine and blood) should be collected before starting antibiotic therapy. In cases in which GI mucosal barrier compromise is not believed to be a factor (i.e., idiopathic immune mediated thrombocytopenia) and there is no evidence of sepsis, supportive therapy and addressing the underlying cause supersedes the administration of broad-spectrum antibiotics. A recent study evaluating the efficacy of amoxicillin/clavulanic acid in dogs with aseptic idiopathic acute hemorrhagic gastroenteritis found no difference in morbidity or mortality in patients treated with antibiotics compared with those given a placebo.27

Endoscopy, Interventional Radiology, and Surgery Most cases of GI hemorrhage can be managed medically. In cases of severe GI ulceration and hemorrhage refractory to medical treatment, endoscopic hemostasis may be beneficial. Upper GI endoscopy is recommended for the diagnosis and treatment of upper GI bleeding in people: the source of bleeding can be identified in up to 95% of cases and endoscopic therapy is reported to be effective in 80% to 90% of patients.28 Ulcer hemostasis has been described by injecting epinephrine or 98% alcohol through an endoscope sclerotomy needle into the base of an ulcer.7,29 The combination of epinephrine injection and use of either endoclips, endoscopic cautery (thermal, electric, or laser), or fibrin/thrombin injections currently is recommended in people to control GI hemorrhage unresponsive to medical management.7,12,30 In people, endoscopic therapy also is indicated for active arterial bleeding as well as visualization of a nonbleeding vessel or an adherent blood clot because both findings are associated with high risk of rebleeding (50% and 25% to 30%, respectively).30 Surgery can be avoided in most cases but is indicated for preexisting surgical disease (foreign body, tumor, septic abdomen) in patients at risk of exsanguination or perforation (based on endoscopy or serial sonographic evaluation), or if the patient fails to respond to medical therapy. An equally efficacious alternative to surgery with lower morbidity in human studies is percutaneous angiography and embolization, which may be applicable to veterinary patients.30,31

PROGNOSIS Many cases of GI hemorrhage are self-limiting and the prognosis varies with the underlying cause. In cases of moderate to severe GI hemorrhage requiring a blood transfusion, the prognosis is reportedly fair to poor, with a mortality rate of 29% to 45%.1

REFERENCES 1. Waldrop JE, Rozanski EA, Freeman LM, et al: Packed red blood cell transfusions in dogs with gastrointestinal hemorrhage: 55 cases (1999-2001), J Am Anim Hosp Assoc 39:523, 2003. 2. Washabau RJ: Acute gastrointestinal hemorrhage. Part I. Approach to patients, Comp Cont Educ Pract Vet 1:1317, 1996.

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3. Liptak JM, Hunt GB, Barrs VRD, et al: Gastroduodenal ulceration in cats: eight cases and a review of the literature, J Feline Med Surg 4:27, 2002. 4. Stanton ME, Ronald BM: Gastroduodenal ulceration in dogs: retrospective study of 43 cases and literature review, J Vet Intern Med 3:238, 1989. 5. Washabau RJ: Acute gastrointestinal hemorrhage. Part II. Causes and therapy, Comp Cont Educ Pract Vet 1:1327, 1996. 6. Kirk RW, Bonagura JD, editors: Kirk’s current veterinary therapy XI, St Louis, 1992, Saunders. 7. Palmer K: Management of haematemesis and melaena, Postgrad Med J 80:399, 2004. 8. Lyles SE, Panciera GK, Saunders GK, et al: Idiopathic eosinophilic masses of the gastrointestinal tract in dogs, J Vet Intern Med 23:818-823, 2009. 9. Hinton LE, McLoughlin MA, Johnson SE, et al: Spontaneous gastroduodenal perforation 16 dogs and 7 cats (1982-1999), J Am Anim Hosp Assoc 38:176, 2002. 10. Gelens HCJ, Moreau RE, Stalis IH, et al: Arteriovenous fistula of the jejunum associated with gastrointestinal hemorrhage in a dog, J Am Vet Med Assoc 202:1867, 1993. 11. Enberg TB, Braun LD, Kuzma AB: Gastrointestinal perforation in five dogs associated with the administration of meloxicam, J Vet Emerg Crit Care 16:34, 2006. 12. Kupfer Y, Cappell MS, Tessler S: Acute gastrointestinal bleeding in the intensive care unit, Gastroenterol Clin North Am 29:275, 2000. 13. Zuckerman GR: Acute gastrointestinal bleeding: clinical essentials for the initial evaluation and risk assessment by the primary care clinician, J Am Osteopath Assoc 100:S4, 2000. 14. Case VL: Melena and hematochezia. In Ettinger SJ, Feldman EC, editors: Textbook of veterinary internal medicine, ed 7, St Louis, 2010, Saunders. 15. Shaw N, Burrows CF, King RR: Massive gastric hemorrhage induced by buffered aspirin in a Greyhound, J Am Anim Hosp Assoc 33:215, 1997. 16. Prause LC, Grauer GF: Association of gastrointestinal hemorrhage with increased blood urea nitrogen and BUN/creatinine ratio in dogs: a literature review and retrospective study, Vet Clin Pathol 27:107, 1998. 17. Steiner J, editor: Small animal gastroenterology, Hannover, 2008, Schluetersche (distributed by Manson publishing).

18. Tuffli SP, Gaschen F, Neiger R: Effect of dietary factors on the detection of fecal occult blood in cats, J Vet Diagn Invest 13:177, 2001. 19. Hall EJ, German AJ: Diseases of the small intestine. In Ettinger SJ, Feldman EC, editors: Textbook of veterinary internal medicine, ed 7, St Louis, 2010, Saunders. 20. Medinger TL, Williams DA, Bruyette DS: Severe gastrointestinal tract hemorrhage in three dogs with hypoadrenocorticism, J Am Vet Med Assoc 202:1869, 1993. 21. Boysen SR, Tidwell AS, Penninck DG: Ultrasonographic findings in dogs and cats with gastrointestinal perforation, Vet Radiol Ultrasound 44:556, 2003. 22. Penninck DG, Matz M, Tidwell AS: Ultrasonographic detection of gastric ulceration, Vet Radiol Ultrasound 38:308, 1997. 23. Villanueva C, Colomo A, Bosch A, et al: Transfusion strategies for acute upper gastrointestinal bleeding, N Eng J Med 368(1):11-21, 2013. 24. Maltz GS, Siegel JE, Carson JL: Hematologic management of gastrointestinal bleedings, Gastroenterol Clin North Am 29:169, 2000. 25. Rozanski EA, Callan MB, Hughes DH, et al: Comparison of platelet count recovery with use of vincristine and prednisone or prednisone alone for treatment of severe immune-mediated thrombocytopenia in dogs, J Am Vet Med Assoc 220:477, 2002. 26. Bersenas AM, Mathews KA, Allen DG, et al: Effects of ranitidine, famotidine, pantoprazole, and omeprazole on intragastric pH in dogs, Am J Vet Res 66:425, 2005. 27. Unterer S, Strohmeyer BD, Kruse C, et al: Treatment of aseptic dogs with hemorrhagic gastroenteritis with amoxicillin/clavulanic acid: a prospective blinded study, J Vet Intern Med 25:973-979, 2011. 28. Millward S: ACR appropriateness criteria on treatment of acute nonvariceal gastrointestinal tract bleeding, J Am Coll Radiol 5:550-554, 2008. 29. Matz ME: Endoscopy. In Wingfield WE, Raffe MR, editors: The veterinary ICU book, Jackson Hole, Wyo, 2002, Teton NewMedia. 30. Dineson L, Benson M: Managing acute upper gastrointestinal bleeding in the acute assessment unit, Clin Med 12(6):589-593, 2012. 31. Ripoll C, Banares R, Baceiro I, et al: Comparison of transcatheter arterial embolization and surgery for treatment of bleeding peptic ulcer after endoscopic treatment failure, J Vasc Radiol 15:447-550, 2004.

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CHAPTER 120  REGURGITATION AND VOMITING Peter S. Chapman,

BVetMed, DECVIM-CA, DACVIM (Internal Medicine), MRCVS

KEY POINTS • Differentiation between vomiting and regurgitation is important before proceeding with further diagnostic testing or therapy. • Idiopathic megaesophagus is the most common cause of persistent regurgitation in the adult dog. Myasthenia gravis is the most common cause of secondary megaesophagus, accounting for 20% to 30% of all cases. Aspiration pneumonia is the most important cause of morbidity in the regurgitating patient. • The multitude of differential diagnoses for vomiting can be subdivided into primary gastrointestinal and other causes. • Abdominal imaging is critical in the evaluation of the patient with persistent vomiting. Radiographs have reasonable sensitivity for the identification of obstruction, but ultrasonography may be preferred, if available, given its higher sensitivity.

DIFFERENTIATION OF VOMITING AND REGURGITATION Before formulating a diagnostic and therapeutic plan, clinicians must define the patient’s clinical problem. Most importantly, vomiting and regurgitation must be distinguished. Pet owners may not differentiate between the two problems, but the diagnostic investigation and treatment options differ significantly. It also may be necessary to differentiate respiratory signs from gastrointestinal (GI) signs because some pet owners mistake the harsh coughing and retching of from diseases such as canine infectious tracheobronchitis for attempts at vomiting. In most cases the problem can be defined accurately after taking a thorough history. Historic findings likely to assist in the differentiation between vomiting and regurgitation are presented in

CHAPTER 120  •  Regurgitation and Vomiting

Table 120-1  Comparison of the Key Features of Vomiting and Regurgitation

BOX 120-1 

Vomiting

Regurgitation

Pharyngeal Disease

Premonitory signs (nausea) often seen (hypersalivation, depression, discomfort)

No premonitory signs

Active abdominal contractions

Passive ejection of food

Cricopharyngeal achalasia Focal or generalized neuromuscular disease Foreign body Neoplasia

May occur at any time

Typically occurs shortly after ingestion of food

Esophageal Disease Hypomotility: megaesophagus

Digested food

Undigested food, may conform to the cylindric shape of the esophagus

Bile may be present

No bile

Congenital Idiopathic (primary) Secondary • Myasthenia gravis (20% to 30% of cases) • Generalized neuromuscular disease • Hypoadrenocorticism • Lead toxicity • Hypothyroidism • Dysautonomia

Table 120-1. Premonitory signs, active abdominal contractions, and the presence of bile in the vomitus are the characteristics that are most useful for distinguishing vomiting because they are seen uncommonly in regurgitating patients. However, regurgitating animals may stretch and arch their necks, mimicking abdominal contractions, and the response to pain from an inflamed or ulcerated esophagus may resemble the classic signs of nausea. Ptyalism is commonly seen secondary to nausea in vomiting patients or as a result of pooling and/or inability to swallow saliva effectively in animals with regurgitation. True bile must be distinguished from the froth and saliva that animals with esophageal disease may regurgitate. Frequency of the episodes also can help define the problem; animals with esophageal disease may regurgitate saliva frequently (e.g., hourly) yet remain bright and systemically healthy. A vomiting animal is unlikely to sustain this frequency of vomiting without developing further systemic signs of illness, such as dehydration and lethargy.

Important Differential Diagnoses for Regurgitation

Inflammation: esophagitis Drug: chemical-induced Gastroesophageal reflux • General anesthesia • Hiatal hernia • Idiopathic Lupus myositis Spirocerca lupi infection

Mechanical obstruction Esophageal stricture Foreign body Neoplasia Vascular ring anomalies Extraluminal compression (e.g., mediastinal mass) Hiatal hernia Gastroesophageal intussusception

REGURGITATION Definition Regurgitation is the passive ejection of food, water, or saliva associated with esophageal or, less commonly, pharyngeal disease.

Clinical Consequences of Regurgitation The most significant clinical complication of regurgitation is aspiration pneumonia, which has been proven to be a significant negative prognostic indicator in patients with megaesophagus.1 Regardless of the underlying disease, any patient with persistent regurgitation is at risk of aspiration pneumonia, and measures to reduce its occurrence such as appropriate feeding strategies, amended anesthetic protocols, and elevation of the head in recumbent patients should be instigated. Aspiration pneumonia is the most likely indication for hospitalization and intensive treatment of regurgitating patients. In the absence of aspiration pneumonia or other disease, most patients are able to maintain good hydration, although persistent regurgitation of undigested food may lead to marked weight loss.

Differential Diagnoses Regurgitation is associated with esophageal or pharyngeal disease. It is more common in dogs than in cats. In most cases the problem is localized to the esophagus or pharynx, but it is sometimes a manifestation of systemic disease. Common differential diagnoses are provided in Box 120-1. Idiopathic megaesophagus is the most common cause of regurgitation in the adult dog, and most middleage to older patients with uncomplicated regurgitation have this

disease.2 However, a significant subset of dogs with megaesophagus have focal myasthenia gravis in the absence of other neurologic signs.3 Many other concurrent diseases, such as hypothyroidism, have been reported to cause megaesophagus, but epidemiologic evidence supporting an association is lacking.3 It is reasonable to exclude these diseases from the differential diagnosis if other clinical and clinicopathologic changes are lacking and the problem list is limited to regurgitation.

Diagnostic Approach History Important historic information includes access to drugs or caustic substances and recent drug therapy or anesthesia that may have precipitated esophagitis. Most cases of drug-induced esophagitis are a result of doxycycline administration, but many drugs have the potential to cause this side effect. Animals with esophagitis also may show signs of apparent esophageal discomfort, such as pain on swallowing (odynophagia), repeated swallowing attempts, lip smacking, and arching of the neck. These signs are seen less often in patients with megaesophagus, most of which regurgitate without premonitory signs and show no odynophagia. Most animals that do not have odynophagia maintain a good appetite and often attempt to eat the regurgitated ingesta. Other systemic signs such as lethargy, anorexia, vomiting, and diarrhea are not seen in patients with uncomplicated esophageal disease and

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suggest a concurrent disease process or an underlying cause for the esophageal disease. Coughing or a sudden deterioration in the patient’s clinical status should alert the clinician to the possibility of aspiration pneumonia.

Physical examination The physical examination should include a thorough oral examination and palpation of the neck. Abnormalities in the neck may include masses, palpable esophageal dilation, or pain. In some cases, palpation of the esophagus may elicit regurgitation or discomfort. Any crackles ausculted over the lung fields should be noted, but these should be differentiated from sounds of fluid in the esophagus.

Clinical pathology Routine hematology and biochemistry may show evidence of an underlying cause of megaesophagus. Results are unremarkable in most patients with uncomplicated idiopathic megaesophagus.

Diagnostic imaging Thoracic radiography is the most important and useful imaging modality for evaluating patients with regurgitation. Plain radiographs are diagnostic in most cases of megaesophagus resulting from a foreign body obstruction. Plain radiographs also may show evidence of secondary aspiration pneumonia, mediastinal masses, or congenital abnormalities (e.g., vascular ring anomaly). Two lateral radiographs and an orthogonal view should be obtained to evaluate all lung fields. If plain radiographs do not show any abnormalities, contrast studies or endoscopy may be indicated. Abdominal ultrasonography rarely provides useful information in animals with regurgitation.

Further diagnostic testing Serum should be submitted for acetylcholine receptor antibody assay on all patients with megaesophagus. Additional tests to consider based on clinical suspicion include an adrenocorticotropic hormone stimulation test, serology for antinuclear antibody, serum creatine phosphokinase activity, lead levels in the blood, electromyography and nerve conduction velocity, and muscle and nerve biopsy. Evidence for an association with hypothyroidism is lacking, but thyroid function (thyroid stimulating hormone assay, thyroid stimulating hormone stimulation, free and total thyroid hormone levels) testing may be warranted in individual patients with other suspicious signs.3 Most patients with megaesophagus secondary to hypoadrenocorticism have electrolyte changes and other systemic signs.

General Treatment Guidelines Most animals with regurgitation are stable and well hydrated and do not require emergent therapy before a definitive diagnosis is made. In the absence of concurrent disease, these patients can be treated on an outpatient basis and do not require hospitalization. Empiric treatment with a histamine-2 receptor antagonist or proton pump inhibitor is indicated to reduce the risk of secondary esophagitis (see Chapter 161). The addition of sucralfate may be warranted in patients with suspected active esophageal ulceration. The canine esophagus is comprised almost exclusively of striated muscle, so smooth muscle prokinetic agents such as metoclopramide and cisapride have no beneficial effect. Moreover, these agents could decrease the transit of ingesta to the stomach by increasing lower esophageal sphincter tone. Anecdotal reports show that the parasympathomimetic agent, bethanechol, is a useful prokinetic agent in dogs with megaesophagus, but data are lacking. The caudal third of the feline esophagus comprises smooth muscle. However, although prokinetics such as cisapride theoretically may be more useful in this species, primary esophageal dysmotility is uncommon in the cat.

Animals with secondary aspiration pneumonia require more intensive therapy and monitoring. These patients should be treated with broad-spectrum antimicrobials (see Chapter 23) and may require supplemental oxygen (see Chapter 14). Prolonged or repeated courses of antimicrobial agents may be required and, when possible, airway samples should be collected for cytology and culture before initiating antimicrobial therapy. If regurgitating animals require hospitalization, the priority should be to prevent aspiration pneumonia by feeding a high-calorie diet in small, frequent meals from an elevated or upright position, and dietary consistency should be tailored to the animal. Although intuitively a firm diet would appear to reduce the risk of aspiration, many patients have less frequent regurgitation when fed a more liquid ration. Animals that cannot maintain adequate nutritional balance with oral intake should be fed using a temporary or permanent gastrostomy tube (see Chapter 129). Esophagostomy and nasoesophageal tube placement is contraindicated.

Prognosis Animals with congenital idiopathic megaesophagus have a fair prognosis. With adequate attention to caloric needs and prevention of aspiration pneumonia, many animals develop improved esophageal motility over several months. Pet owners must be committed to a prolonged period of physical therapy and nutritional support. The morbidity and mortality associated with acquired idiopathic megaesophagus continues to be unacceptably high. Patients with megaesophagus or other causes of regurgitation where a specific underlying disease can be identified and treated may have a better prognosis.

VOMITING Definition Vomiting is the forceful ejection of upper GI tract contents and may occur as a result of gastric, intestinal, or systemic disease.

Physiology of Vomiting The vomiting reflex is mediated by the vomiting center in the medulla.4 Vagal and sympathetic afferent pathways from the GI tract transmit impulses to the vomiting center when stimulated by inflammation or overdistention. The vomiting center also receives stimulation from within the brain: the vestibular system, cerebrum, and chemoreceptor trigger zone provide input to the vomiting center. The latter is a specialized region (area postrema) that is located on the floor of the fourth ventricle and lacks an intact blood-brain barrier. The chemoreceptor trigger zone is sensitive to several common drugs and toxins. The pathways involved in vomiting and the receptors involved are shown schematically in Figure 120-1. Sufficient stimulation of the vomiting center results in the initiation of vomiting. A period of intestinal antiperistalsis is followed by a highly coordinated sequence of events, beginning with a deep inspiration and ending with a strong simultaneous contraction of the diaphragm and abdominal wall musculature and relaxation of the lower esophageal sphincter.

Clinical Consequences of Vomiting The principal deleterious consequence of vomiting is dehydration as a result of fluid loss in the vomitus and a reduced fluid intake. The loss of GI contents compounded by dehydration may lead to electrolyte and acid-base disturbances. A hypochloremic metabolic alkalosis, primarily resulting from the loss of gastric contents rich in hydrogen and chloride ions, with or without a contraction alkalosis, is the most common finding in dogs with GI foreign bodies, regardless of their location.5 Patients with more chronic vomiting may be more prone to developing metabolic acidosis as a result of dehydration, and mixed acid-base disorders may be seen. Hypokalemia is the

CHAPTER 120  •  Regurgitation and Vomiting Apomorphine Uremic toxins Hepatotoxins Endotoxins Cardiac glycosides

Anxiety Anticipation

2

ENK

Cerebral cortex

D2

H1

2

5-HT3

Motion

M1

NK1

ENK,

1

H1

Chemoreceptor trigger zone

5-HT1A

2

M1

NMDA

Vestibular system

2

Vomiting center

Afferent neuron

Efferent neuron 5-HT3

5-HT4

M2

D2

MOT

GUT

FIGURE 120-1  Schematic representation of the receptors and pathways involved in vomiting. 1, Pathway more important in dogs; 2, pathway more important in cats. Receptors: D, dopaminergic; H, histaminergic; M, acetylcholine (muscarinic); NK, neurokinin; 5-HT, serotonin; α, α-adrenergic; ω, benzodiazepine; ENK, enkephalinergic opioid; MOT, motilin; NMDA, N-methyl-D-aspartate (glutamate receptor).

most common electrolyte disturbance in vomiting patients. Aspiration pneumonia is a less common complication of vomiting than it is of regurgitation because reflex closure of the glottis occurs during emesis. It is a greater risk in animals with impaired laryngeal function, typically a result of primary laryngeal disease or a decreased level of consciousness.

Differential Diagnoses Many differential diagnoses for vomiting exist; therefore subdividing the causes is useful to assist in the diagnostic investigation and treatment plan. One commonly used subdivision is between those diseases in which the primary pathology is in the GI tract and those in which the primary pathology is outside the GI tract. Other systemic signs such as polydipsia or weight loss are often present in patients with extra-GI causes, but vomiting (and/or diarrhea) is likely to be the major presenting complaint in patients with primary GI disease. Thus an animal that is vomiting but lacks other signs is more likely to have primary GI disease, and an animal that vomits only occasionally but has marked systemic signs is more likely to have an extra-GI problem. It also can be useful to distinguish between those diseases that are more likely to cause acute vomiting and those that are more likely to cause chronic vomiting. The most common and important differential diagnoses for vomiting are shown in Box 120-2.

Diagnostic Approach History A description of the character of the vomiting should be obtained and, as described above, should be distinguished from regurgitation. The approximate frequency and duration of vomiting should be determined because the chronicity and severity of signs help the clinician formulate a diagnostic and therapeutic plan. Fresh blood or digested blood (“coffee grounds”) is suggestive of gastric ulceration, but bleeding also may be present in animals with acute infectious conditions (see Chapter 119). Other important information from the patient’s history includes vaccination status, travel history, medica-

BOX 120-2 

Important Differential Diagnoses for Vomiting

Gastrointestinal Obstruction Foreign body* Intussusception* Neoplasia Torsion or volvulus

Dietary Allergy† Intolerance† Indiscretion*

Infectious Viral (parvovirus)* Parasitic† Bacterial (salmonellosis)*

Other Neoplasia† Inflammatory bowel disease† Gastrointestinal ulceration

Drug-induced (e.g., chemotherapy, NSAIDs, antibiotics) Uremic gastritis Liver disease

Extragastrointestinal Uremia Pancreatitis* Diabetic ketoacidosis* Liver disease Peritonitis* Pyometra* Prostatitis Drug or toxin induced* Hypoadrenocorticism† Hyperthyroidism Vestibular disease Heartworm disease (cats)

*More commonly acute. † More commonly chronic. NSAID, Nonsteroidal antiinflammatory drug.

tion history, dietary indiscretion or recent diet changes, drug or toxin exposure, and any possibility of foreign body ingestion. As noted above, systemic signs should raise the possibility of an extra-GI cause for the vomiting.

Physical examination Vital signs and a thorough physical examination are important in the vomiting patient. The most important part of the physical

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examination is a thorough palpation of the abdomen. Attention should be paid to any abdominal pain or discomfort and the presence of any palpable effusion, organ distention, masses, or foreign bodies. The mouth should be examined for evidence of systemic disease (uremic or ketotic odor, ulcers) or a linear foreign body. In cats, the thyroid gland should be palpated to check for a goiter. A rectal examination should be performed for additional information (hematochezia, worms, prostatomegaly with or without pain), and an examination of the central nervous system may be indicated in difficult cases. Assessment of hydration and hemodynamic status helps the clinician formulate an appropriate treatment plan.

Clinical pathology A full hematology and biochemistry panel should be performed in any persistently vomiting patient. In most animals with an extra-GI cause, the biochemistry panel results have notable abnormalities. Normal biochemical and hematologic parameters are more strongly suggestive of primary GI disease. The hematology and biochemistry panels also allow evaluation of abnormalities in electrolytes and acid-base status, which may be complications of protracted vomiting. A sample for urinalysis should be obtained at the earliest opportunity to aid in differentiating prerenal from renal azotemia. A fecal sample should be submitted for zinc sulfate flotation in all cases, and also for selective bacterial culture or analyses in patients with acute vomiting. Further testing should be performed based on clinical suspicions.

Diagnostic imaging Abdominal imaging is vital in the investigation of persistent vomiting. The choice of abdominal radiographs or ultrasound depends on the nature of the complaint. In the acutely vomiting patient, the priority is to establish whether medical or surgical management is indicated (i.e., rule out a GI obstruction). Abdominal radiographs have reasonable specificity in identifying the presence of obstruction and the wide availability of abdominal radiography makes them an acceptable first line test.6 However, in the hands of an experienced operator, abdominal ultrasonography has been shown to have greater accuracy for identifying small intestinal obstruction than radiographs and is indicated in patients with equivocal radiographs or persistent vomiting.6 Abdominal ultrasound also may assist in the identification of neoplastic obstructions and allows evaluation of the other abdominal organs to help exclude extra-GI cause of the vomiting. If ultrasonography is not available, administration of barium and sequential abdominal radiographs may be helpful. Patients with chronic vomiting are less likely to suffer from intestinal obstruction than those that are vomiting acutely, and abdominal radiography therefore has a lower diagnostic yield. Abdominal ultrasonography generally is preferred in these patients. It allows an evaluation of the intestinal wall thickness and layering along with a thorough evaluation of the extraintestinal structures. It therefore proves useful in helping to decide whether medical management, endoscopy, or surgery would be the most appropriate management strategy. Thoracic radiographs should also be obtained in vomiting patients. Their role is multifold. They may show evidence of

esophageal disease if the history has led to an incorrect identification of the primary problem; they aid in the detection of neoplastic involvement in the thorax and allow for assessment of the heart and pulmonary vasculature; and they may show evidence of pulmonary disease such as aspiration pneumonia.

General Treatment Guidelines The important factors to consider when treating a vomiting patient are (1) treatment of the underlying cause, (2) treatment and prevention of electrolyte and acid-base disturbances, and (3) symptomatic control of further vomiting, when appropriate. Fluid therapy and supportive care for the vomiting patient are discussed in Chapters 57, 59, 161, and 162. The general recommendation for stable animals with recent onset of vomiting is to withhold food for 24 to 48 hours.7 The rationale behind this recommendation is to avoid stimulating further vomiting and let the GI tract rest, to prevent the development of food aversions in nauseated patients, and to reduce the risk of aspiration pneumonia. Food always should be withheld from patients with suspected GI obstruction or any patient whose signs worsen after feeding. However, some vomiting patients may have a significantly quicker recovery when early enteral nutrition is instigated, and dogmatic enforcement of starvation may be unnecessary for some canine and feline patients.8 Animals with persistent vomiting may not be good candidates for feeding tubes, and parenteral nutrition may be necessary (see Chapter 130).

CONCLUSION A wide variety of underlying diseases may cause regurgitation or vomiting. Successful management of these patients requires an accurate definition of the clinical problem and determination of whether the disease is primarily gastrointestinal or systemic in origin. An appropriate treatment plan then may be initiated.

REFERENCES 1. McBrearty AR, Ramsey IK, Courcier EA, et al: Clinical factors associated with death before discharge and overall survival time in dogs with generalized megaesophagus, J Am Vet Med Assoc 238:1622, 2011. 2. Washabau RJ: Gastrointestinal motility disorders and gastrointestinal prokinetic therapy, Vet Clin North Am Small Anim Pract 33:1007, 2003. 3. Gaynor AR, Shofer FS, Washabau RJ: Risk factors for acquired megaesophagus in dogs, J Am Vet Med Assoc 211:1406, 1997. 4. Guyton AC, Hall JE: Vomiting. In Guyton AC, Hall JE, editors: The textbook of medical physiology, ed 12, Philadelphia, 2010, Saunders/Elsevier. 5. Boag AK, Coe RJ, Martinez TA, et al: Acid-base and electrolyte abnormalities in dogs with gastrointestinal foreign bodies, J Vet Intern Med 19:816, 2005. 6. Sharma A, Thompson MS, Scrivani PV, et al: Comparison of radiography and ultrasonography for diagnosing small-intestinal mechanical obstruction in vomiting dogs, Vet Radiol Ultrasound 52:248, 2011. 7. Webb C, Twedt DC: Canine gastritis, Vet Clin North Am Small Anim Pract 33:969, 2003. 8. Mohr AJ, Leisewitz AL, Jacobson LS, et al: Effect of early enteral nutrition on intestinal permeability, intestinal protein loss, and outcome in dogs with severe parvoviral enteritis, J Vet Intern Med 17:791, 2003.

CHAPTER 121  DIARRHEA Daniel Z. Hume,

DVM, DACVIM (Internal Medicine), DACVECC

KEY POINTS • Diarrhea is a common clinical finding in critically ill animals. • Diarrhea can lead to abnormalities in nutrient, acid-base, and electrolyte balance. • Diarrhea may result from iatrogenic causes, primary gastrointestinal diseases, or other disease processes.

Diarrhea is a common clinical sign observed in critically ill canine and feline patients. Diarrhea is defined as an increase in fecal mass caused by an increase in fecal water or solid content. This usually is associated with an increase in frequency, fluidity, or volume of feces. In a 20-kg dog, approximately 2.5 L of fluid enters the duodenum each day, and about 98% of the fluid entering the intestine is absorbed.1 Diarrhea in the critical care setting often is overlooked and overshadowed by the primary disease process. However, diarrhea can lead to severe aberrations in nutrient, acid-base, fluid, and electrolyte balance. Without proper attention it can lead to deterioration of the patient’s condition. Diarrhea may be associated with patient discomfort, local dermatitis, catheter or catheter site infections, and potentially bacterial translocation if the integrity of the intestinal mucosa is altered. Consideration of the most likely cause is important because it allows the clinician to decide which diagnostic modalities are indicated for proper workup of the diarrhea. Three broad etiologic categories may be used when considering the potential cause of diarrhea in a given patient: iatrogenic causes, primary gastrointestinal (GI) causes, and other diseases secondarily causing diarrhea.

PATHOPHYSIOLOGIC MECHANISMS OF DIARRHEA The several categorization schemes for diarrhea have great overlap among the classifications. One of the most commonly used classification schemes arranges the pathophysiologic mechanisms underlying diarrhea as follows: osmotic diarrhea, secretory diarrhea, diarrhea resulting from altered permeability, and diarrhea resulting from deranged motility. Osmotic diarrhea is caused by the presence of excess luminal osmoles, drawing fluid into the intestinal lumen. Most causes of a diarrhea have an osmotic component. Secretory diarrhea is caused by a net increase in intestinal fluid secretion. This results from either an absolute increase in intestinal secretion or a relative increase caused by a decrease in intestinal absorption. Normal intestinal physiology and systemic health depend on the semipermeable nature of the intestinal mucosa. Nutrients, electrolytes, and fluid are absorbed and secreted, and the mucosa and immune system of the intestine inhibit translocation of bacteria and bacterial toxins. However, microscopic and macroscopic damage to either the epithelial cells or epithelial cell junctions can lead to altered

intestinal permeability. Vital substances are lost into the intestinal lumen, and the altered permeability leaves the intestine vulnerable to translocation of potentially fatal bacteria and their products. Alterations in intestinal motility are probably the least understood of the causes of diarrhea. Motility alterations leading to diarrhea include either increased peristaltic contractions or decreased segmental contractions.1 Even within this classification scheme, significant overlap occurs among the groups. In animals with primary GI causes of diarrhea, historical questions may provide evidence that allows anatomic localization of the disease to either the small or large bowel. This differentiation allows a more accurate formation of differential diagnoses and subsequent diagnostic testing. Historical and clinical differences usually noted between small and large bowel diarrhea are illustrated in Table 121-1.

IATROGENIC CAUSES OF DIARRHEA Iatrogenic causes of diarrhea are likely more common than is realized and should be ruled out to facilitate clinical improvement. Diarrhea is a common side effect of several classes of drugs used in critically ill patients (Box 121-1). Antimicrobial agents may cause diarrhea as a direct result of drug formulation or properties, or as a result of alterations in intestinal microbacterial flora. Most of the chemotherapeutic agents have direct toxic effects against the rapidly dividing cells of the intestinal crypts, leading to villous blunting and altered absorption. Other classes of drugs, such as antiarrhythmic agents, lactulose, and proton pump inhibitors, also may be associated with diarrhea. Acute or abrupt changes in the diet are not uncommon in hospitalized or critically ill patients. Anorexic animals often are coaxed to eat with canned diets and other potentially novel foods. Enteral tube feeding also is employed commonly in critically ill patients. The osmotic and caloric properties of these diets may exceed the digestive and absorptive capacities of the intestine and lead to osmotic

Table 121-1  Differentiation of Diarrhea Based on Anatomic Location Characteristic

Small Bowel

Large Bowel

Mucus

Uncommon

Common

Hematochezia

Uncommon

May be present

Stool volume

Increased to normal

Normal to decreased

Melena

May be present

Absent

Frequency

May be increased to normal

Increased

Urgency

Uncommon

Common

Tenesmus

Uncommon

Common

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BOX 121-1 

Medications Commonly Associated with Diarrhea20,21

Antimicrobial Agents Gastrointestinal medications Histamine-2 antagonists Misoprostol Proton pump inhibitors Oral antacids

Chemotherapeutic Agents Cardiac medications Quinidine Procainamide Digoxin

Antihypertensive Agents β-adrenergic antagonists ACE inhibitors

Endocrine Medications Mitotane Trilostane Methimazole Acarbose

NSAIDs Miscellaneous agents Amitriptyline Parasiticides Bethanechol Clomipramine Colchicine Acetazolamide

Immunomodulatory Agents Azathioprine Cyclophosphamide Cyclosporine ACE, Angiotensin-converting enzyme; NSAIDs, nonsteroidal antiinflammatory drugs.

diarrhea. Furthermore, prolonged quiescence of the intestine from either anorexia or parenteral nutrition can lead to villous atrophy and decreased absorptive function when enteral feeding is initiated (see Chapter 129).

PRIMARY GASTROINTESTINAL CAUSES OF DIARRHEA Adverse reactions to foods can result from immunologic reactions (food allergy) or nonimmunologic reactions (food intolerance) to a dietary substance.2 Although true food allergies are rare, food intolerance is probably one of the more common causes of acute diarrhea in the small animal patient. Intolerance can result from dietary indiscretion or gluttony, but often the exact cause is unknown. The resultant diarrhea is short term and self-limiting. Infectious disease is a common cause of diarrhea in canine and feline patients. Gastrointestinal parasitism (e.g., Ancylostoma spp., Toxocara spp., Toxascaris spp., Trichuris spp.) is another common cause of diarrhea but rarely is associated with debilitation except in young or small patients. The exact role of various infectious bacterial organisms as the cause of diarrhea is controversial. Gastrointestinal disease and diarrhea may be associated with a variety of bacteria, including Salmonella spp., Campylobacter spp., enteropathogenic Escherichia coli, Clostridium difficile, and Clostridium perfringens.3-8 Although diarrhea has been associated with clostridial organisms in the dog and cat,3-8 the direct role remains unclear given that C. difficile toxin and C. perfringens enterotoxin can be found in the feces of animals with normal stool quality and no clinical GI signs.6-8 Systemic viral infections such as canine parvovirus and feline panleukopenia commonly are associated with diarrhea. Feline panleukopenia and canine parvovirus are caused by similar, but not identical, nonenveloped DNA parvoviruses.9,10 Transmission occurs via oronasal exposure and the organism subsequently spreads to the bone marrow, lymphoid organs, and intestinal crypts, leading to a peripheral leukopenia and intestinal villus blunting and collapse.9,10

Fungal (Histoplasma, Pythium, and Cryptococcus spp.), algal (Prototheca spp.), protozoal (Tritrichomonas foetus, Giardia, Cryptosporidium, Isospora spp.), and rickettsial (Neorickettsia spp.) induced gastroenteritis may be seen depending on the geographic location and husbandry of the patient. Intussusceptions may occur secondary to infectious or idiopathic causes and may lead to severe diarrhea. The role of small intestinal bacterial overgrowth (SIBO) or antibiotic-responsive diarrhea (ARD) is a controversial subject in small animal gastroenterology. Debate exists regarding whether the disease occurs as a primary condition, how it should be defined, and how it is diagnosed best. Some authors have divided the disease into either secondary SIBO (in cases in which an accompanying or primary intestinal disease can be identified) or idiopathic ARD in cases, in which no underlying disease can be found.11 Examples of secondary SIBO can be seen with exocrine pancreatic insufficiency and inflammatory bowel disease (IBD). The exact cause of ARD has yet to be identified, but local intestinal immunodeficiency may play a role in the pathogenesis.12 Neoplastic disease also may lead to diarrhea in small animal patients; GI adenocarcinoma, alimentary lymphosarcoma, mast cell tumor, and GI stromal tumors are examples. These tumors may cause significant intestinal leakage and loss of protein and blood. IBD is one of the more common causes of chronic diarrhea in cats and dogs. Loss of local immune tolerance to normal dietary and bacterial components leads to up-regulation of immune and inflammatory responses and establishment of an inflammatory focus within the intestine. Infiltration with inflammatory cells leads to thickening of the intestinal absorptive surface and decreased absorptive capacity. Different types of IBD are found in the dog and cat, and classification is based on the primary type of inflammatory cell infiltrate. Lymphocytic-plasmacytic is the most common form of IBD, but eosinophilic and granulomatous forms also are reported. Prolonged or extensive bowel disease can lead to severe metabolic derangements, including panhypoproteinemia and hypocholesterolemia. The diagnosis of IBD is based on histopathologic evidence of moderate to severe GI inflammation coupled with the exclusion of an underlying cause of the inflammation. Lymphangiectasia can occur as a primary disease (Yorkshire Terrier, Norwegian Lundehund, and Maltese Terrier) or secondary to other infiltrative processes such as IBD. Alterations of intestinal lymphatic permeability lead to leakage of protein-rich and fat-rich chyle into the intestinal lumen and loss of these dietary components into the feces. Resultant clinical signs include chronic diarrhea and severe weight loss.

EXTRAGASTROINTESTINAL DISEASES CAUSING DIARRHEA Extragastrointestinal causes of diarrhea include hepatobiliary disease, pancreatic disease, endocrine disease, or other miscellaneous abnormalities. Diarrhea may occur in dogs and cats with hepatobiliary disease for several reasons. Concurrent inflammatory GI disease may be seen in the dog and is common in the cat.13-15 End-stage cirrhosis may be associated with elevated portal hydrostatic pressures, and functional hepatic failure may lead to hypoalbuminemia and GI wall edema. Both of these conditions often lead to altered absorptive properties of the GI tract. Diseases affecting the biliary tree also may hinder delivery of bile salts to the intestine, leading to fat maldigestion. Diarrhea is seen commonly as a sequela of pancreatic disease. Exocrine pancreatic insufficiency may result from pancreatic acinar atrophy (primarily dogs) or chronic pancreatitis (primarily cats). Lack of exocrine pancreatic function leads to maldigestion and malabsorption of dietary substrates and culminates in diarrhea and

CHAPTER 121  •  Diarrhea

weight loss. Acute and chronic pancreatitis also may lead to diarrhea. Pancreatic inflammation may cause local inflammation of the duodenum and colon, interfere with pancreatic acinar secretion, and result in decreased bile salt delivery to the small intestine via obstruction of biliary flow. Congestive heart failure, particularly right-sided failure, can lead to intestinal and hepatic venous congestion and ascites. Congestion of the splanchnic vasculature may cause alteration in the absorptive capacities of the intestine. Several endocrine disorders may be associated with diarrhea. Diarrhea is noted in some cats with hyperthyroidism. The diarrhea in these cases may be a result of increased food intake as well as intestinal hypermotility. Waxing and waning GI signs are seen frequently in dogs and less commonly in cats with hypoadrenocorticism. Cortisol is vital for maintenance of normal GI function, motility, and integrity, as well as vascular tone and subsequent perfusion. The lack of mineralocorticoids may be associated with alterations in electrolyte balance, leading to altered GI motility and absorption. Diarrhea is an uncommonly reported clinical sign associated with hypothyroidism. Various other diseases may be associated with diarrhea. Idiopathic noncirrhotic portal hypertension may interfere with absorption within the intestinal tract. The role of hypoalbuminemia as a direct cause of diarrhea is debated. The decreased oncotic draw resulting from hypoalbuminemia leads to alterations in Starling forces and decreased absorption of fluid across the intestinal lumen. Hemorrhagic diarrhea is seen commonly in critically ill patients suffering from, or after resuscitation from, various causes of cardiovascular shock (e.g., heat-induced illness). GI complications are common in animals with acute and chronic renal disease, but diarrhea is not reported commonly. Systemic infections (including sepsis) may affect secondarily the GI tract and cause diarrhea. Experimental canine studies have shown that bacterial endotoxin impairs colonic water and sodium absorption and increases small and large intestinal motility, at least partially explaining the diarrhea noted in septic patients.16,17

DIAGNOSTIC EVALUATION The diagnostic evaluation of patients with diarrhea is guided best by the historical, clinicopathologic, and physical examination findings. The physical condition of the patient and the duration and clinical course of the diarrhea help determine how aggressive the clinician should be in attempting to find a cause. Results of a complete blood count, serum chemistry profile, and urinalysis are indicated in all critically ill patients and often help to differentiate between GI and non-GI causes of diarrhea. Based on these findings, additional tests may be needed to screen for hyperthyroidism, hypoadrenocorticism, or occult liver disease. Fecal flotation (including zinc sulfate for Giardia spp.) and direct cytologic examination of the feces is recommended in most cases. Although cytologic examination of the feces may help indirectly to point toward a particular pathogen, isolation or amplification of toxin or enterotoxin may provide a more specific diagnosis in the case of clostridial infection. Bacterial culture (Salmonella spp., Campylobacter spp., enteropathogenic E. coli), enterotoxin screening (Clostridium spp.), and enzyme-linked immunosorbent assay (ELISA) (parvovirus) of the feces may be indicated when an infectious cause is suspected. Specific tests for other infectious agents also may prove helpful depending on the geographic location and husbandry of the patient. Exfoliative rectal cytology may be useful in diagnosing fungal, algal, inflammatory, and neoplastic diseases. Trypsin-like immunoreactivity testing is indicated in any patient with suspected exocrine pancreatic insufficiency. Folate and cobalamin testing may

be helpful in animals with suspected SIBO. Although abdominal radiographs are of limited value in animals affected primarily with diarrhea, abdominal ultrasound often is indicated and useful for assessing integrity, architecture, and thickness of the GI system and other abdominal organs. Last, GI endoscopy or exploratory laparotomy often is needed for direct visualization of the intestinal tract and procurement of diagnostic samples.

TREATMENT Iatrogenic causes of diarrhea should be considered in all patients, especially those in which diarrhea was not part of the presenting complaint. If the diarrhea is severe, current medications may have to be discontinued or modified. Although diarrhea is associated commonly with enteral feeding, the diet formulation may require alteration if the diarrhea is severe or adversely affecting the patient’s quality of life. Treatment of diarrhea associated with primary GI diseases or diseases secondarily causing diarrhea is achieved best after careful diagnostic evaluation of the underlying cause. Once a definitive diagnosis has been achieved, direct treatment can be initiated. Rarely, medications directed toward symptomatic treatment of the diarrhea are used (see Chapter 161). Intestinal transit time is effectively a result of the balance between propulsive peristalsis and segmental contractions.1 Contrary to historical belief, diarrhea rarely results from increased peristalsis but more commonly is the result of decreased segmental contractions.1 Anticholinergic agents generally are contraindicated because they decrease propulsive peristalsis and segmental contractions and predispose the patient to ileus. Conversely, opioid-containing medications such as loperamide, diphenoxylate, and opium tincture can decrease propulsive contractions and increase segmental contractions; water and fluid absorption also is augmented.1 These medications may be indicated in some cases of diarrhea in which infectious causes have been excluded. Kaolin, pectin, and bismuth subsalicylate are used occasionally for symptomatic treatment.1 However, this rarely is indicated because treatment of the primary disease process provides the best means for eliminating diarrhea. Indications for symptomatic therapy include diarrhea that adversely affects the patient’s quality of life, causes severe fecal scalding of the skin, or predisposes to secondary infection (e.g., urinary or intravenous catheter infections in recumbent animals). In animals with IBD, treatment often is tailored to the individual patient based on the severity of the clinical signs and histopathologic lesions. Dogs and cats with intermittent clinical signs, good body condition, and mild histologic lesions may respond to dietary therapy alone. This may be due to a loss of immunologic tolerance to normal dietary proteins and subsequent GI inflammation in patients with IBD. Dietary therapy for pets with IBD usually relies on either a novel protein diet or a diet with a hydrolyzed protein source. Animals with some degree of lymphangiectasia may benefit from a low-fat diet. However, most animals with moderate to severe disease need some degree of immunomodulation to obtain clinical remission. Glucocorticoids (prednisone, prednisolone, and dexamethasone) are the mainstay of immunomodulatory therapy. The locally active steroid, budesonide, undergoes significant first-pass metabolism, thereby limiting systemic absorption and potentially lessening the side effects compared with glucocorticoids. Azathioprine, chlorambucil, or other immunomodulating agents may be necessary for dogs with refractory disease or those unable to tolerate glucocorticoid therapy. Aminosalicylates (sulfasalazine, mesalamine) can be prescribed for dogs with primarily large bowel disease. Metronidazole often is used for its antimicrobial and antiinflammatory effects. Antimicrobial therapy may be useful in many other diarrheal diseases of dogs and cats (Table 121-2). Primary (idiopathic) or

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Table 121-2  Formulary of Commonly Used Drugs for the Treatment of Diarrhea in Small Animals Drug

Canine

Feline

Prednisone

1 to 2 mg/kg PO q12h

1 to 4 mg/kg PO q12h

Budesonide

15 kg: 3 mg PO q24h

1 mg PO q24h

Azathioprine

2 mg/kg PO q24h

Not routinely used

Chlorambucil

Not routinely used

2 mg/m2 PO q48h

Sulfasalazine

10 to 15 mg/kg PO q8-12h

10 to 20 mg/kg PO q24h

Metronidazole

10 to 15 mg/kg PO q12h

10 to 15 mg/kg PO q12h

Oxytetracycline

22 mg/kg PO q8h

10 to 15 mg/kg PO q8h

Tylosin

10 to 20 mg/kg PO q8-12h

10 to 20 mg/kg PO q8-12h

Erythromycin

10 to 20 mg/kg PO q8h

10 to 20 mg/kg PO q8h

Enrofloxacin

10 to 20 mg/kg PO q24h

5 mg/kg PO q24h

PO, Per os.

secondary ARD often respond well to antimicrobial agents. Those most often prescribed include metronidazole, oxytetracycline, and tylosin.4 The drug of choice for treatment of Campylobacter spp. is the macrolide erythromycin. However, its use is associated with GI side effects (typically vomiting and/or diarrhea). Other antimicrobial drugs that may be considered include azithromycin, enrofloxacin, tetracyclines, chloramphenicol, cefoxitin, and tylosin. Animals with diarrhea of suspected clostridial origin may be treated with metronidazole, ampicillin, macrolides, or tetracyclines.4 In stable, immunocompetent animals, the routine empiric use of antimicrobials may not be beneficial. A recent study showed no significant difference in outcome parameters in a group of aseptic dogs with hemorrhagic gastroenteritis treated with a broad-spectrum antimicrobial.18 Probiotic supplementation is becoming increasingly more popular in human and veterinary medicine. Specific indications for probiotic use include antibiotic-associated diarrhea and diarrhea resulting from alterations of the normal GI flora. Numerous mechanisms have been proposed, but they likely exert their effects through modulation of the immune system and direct competition for, or antagonism of, pathogenic bacteria. In at least one veterinary report, probiotic therapy has been shown to shorten the duration of clinical signs in dogs with acute gastroenteritis.19

REFERENCES 1. Guilford WG, Strombeck DR: Classification, pathophysiology, and symptomatic treatment of diarrheal diseases. In Strombeck’s small animal gastroenterology, Philadelphia, 1996, WB Saunders. 2. Guilford WG: Adverse reactions to food. In Strombeck’s small animal gastroenterology, Philadelphia, 1996, WB Saunders. 3. Cave NJ, Marks SL, Kass PH, et al: Evaluation of a routine diagnostic fecal panel for dogs with diarrhea, J Am Vet Med Assoc 221:52, 2002. 4. Fox JG, Greene CE, Marks SL: Enteric bacterial infections. In Greene CL, editor: Infectious diseases of the dog and cat, ed 4, St Louis, 2012, Elsevier Saunders. 5. Weese JS, Wesse HE, Bourdeau TL, et al: Suspected Clostridium difficileassociated diarrhea in two cats, J Am Vet Med Assoc 218:1436, 2001. 6. Marks SL, Kather EJ, Kass PH, et al: Genotypic and phenotypic characterization of Clostridium perfringens and Clostridium difficile in diarrheic and healthy dogs, J Vet Intern Med 16:533, 2002. 7. Weese JS, Staempfli HR, Prescott JF, et al: The roles of Clostridium difficile and enterotoxigenic Clostridium perfringens in diarrhea in dogs, J Vet Intern Med 15:374, 2001. 8. Marks SL, Rankin SC, Byrne BA, et al: Enteropathogenic bacteria in dogs and cats: Diagnosis, epidemiology, treatment, and control: ACVIM Consensus Statement, J Vet Intern Med 25:1195, 2011. 9. Green CL: Canine viral enteritis. In Greene CL, editor: Infectious diseases of the dog and cat, ed 4, St Louis, 2012, Elsevier Saunders. 10. Greene CE: Feline panleukopenia. In Greene CL, editor: Infectious diseases of the dog and cat, ed 4, St Louis, 2012, Elsevier Saunders. 11. Hall EJ: Small intestine. In Washabau RJ, Day MJ, editors: Canine and feline gastroenterology, St Louis, 2013, Elsevier Saunders. 12. German AJ, Hall EJ, Day MJ: Chronic intestinal inflammation and intestinal disease in dogs, J Vet Intern Med 17:8, 2003. 13. Weiss DJ, Gagne JM, Armstrong PJ: Relationship between inflammatory hepatic disease and inflammatory bowel disease, pancreatitis, and nephritis in cats, J Am Vet Med Assoc 209:1114, 1996. 14. Baez JL, Hendrick MJ, Walker LM, et al: Radiographic, ultrasonographic, and endoscopic findings in cats with inflammatory bowel disease of the stomach and small intestine: 33 cases (1990-1997), J Am Vet Med Assoc 215:349, 1999. 15. Ferreri JA, Hardam E, Kimmel SE, et al: Clinical differentiation of acute necrotizing from chronic nonsuppurative pancreatitis in cats: 63 cases (1996-2001), J Am Vet Med Assoc. 223:469, 2003. 16. Spates ST, Cullen JJ, Ephgrave KS, et al: Effect of endotoxin on canine colonic motility and transit, J Gastrointest Surg 2:391, 1998. 17. Cullen JJ, Spates ST, Ephgrave KS, et al: Endotoxin temporarily impairs canine colonic absorption of water and sodium, J Surg Res 74:34, 1998. 18. Unterer S, Strohmeyer K, Kruse, et al: Treatment of aseptic dogs with hemorrhagic gastroenteritis with amoxicillin/clavulanic acid: a prospective blinded study, J Vet Intern Med 25, 973, 2011. 19. Herstad, HK, Nesheim BB, et al: Effects of a probiotic intervention in acute canine gastroenteritis- a controlled clinical trial, J Small Anim Pract 51:34, 2012. 20. Ringel AF, Jameson GJ, Foster ES: Diarrhea in the intensive care patient, Crit Care Clin 11:465, 1995. 21. Plumb DC: Plumb’s veterinary handbook, ed 7, Ames, Iowa, 2011, Wiley-Blackwell.

CHAPTER 122  PERITONITIS Susan W. Volk,

VMD, PhD, DACVS

KEY POINTS • Peritonitis is inflammation of the peritoneal cavity and is most commonly the result of gastrointestinal rupture, perforation, or dehiscence in small animals. • Clinical signs in patients with peritonitis may be mild to severe and are often nonspecific. • Abdominocentesis is the preferred diagnostic method for confirming peritonitis. • When abdominal fluid cytology reveals degenerative neutrophils and intracellular bacteria, confirming a diagnosis of septic peritonitis, emergency surgical exploration of the abdomen is indicated. • Open peritoneal drainage or closed suction drainage should be considered for management of septic peritonitis in which the source of contamination cannot be controlled completely, or if significant contamination or inflammation remains after surgical debridement and lavage. • Prognosis is guarded for patients with peritonitis. Reported survival rates are highly variable and depend on the cause, presence of infection, and development of systemic inflammatory response syndrome and/or organ dysfunction.

Peritonitis is defined as inflammation of the peritoneal cavity and may be classified according to the underlying cause (primary or secondary), extent (localized or generalized), or the presence of infectious agents (septic or nonseptic). Primary peritonitis refers to a spontaneous inflammatory condition in the absence of underlying intraabdominal pathology or known history of penetrating peritoneal injury. Secondary peritonitis occurs more commonly in the dog and cat and is the consequence of a preexisting aseptic or septic pathologic intraabdominal condition. Because of the multitude of conditions that may lead to peritonitis the types of clinical signs and their severity vary. Hematogenous dissemination of infectious agents has been postulated as the mechanism of development of primary peritonitis and likely is facilitated by impaired host immune defenses. The most common form of primary peritonitis is the effusive form of feline infectious peritonitis, caused by feline coronavirus, which should be included on any differential diagnosis list for cats with peritoneal effusion. Other infectious agents reported to cause primary peritonitis in dogs and cats include Salmonella typhimurium, Chlamydia psittaci, Clostridium limosum, Mesocestoides spp., Bacteroides spp., Actinomyces spp., Blastomyces spp., and Candida spp. Given the common occurrence of isolated Bacteroides and Fusobacterium spp. from cats with primary septic peritonitis, these bacteria may be translocating from the oral cavity through either unrecognized direct penetration (bites) or a hematogenous route.1 Inflammation of the abdominal cavity in the absence of infectious pathogens (aseptic peritonitis) most commonly occurs in response to exposure of the peritoneum to sterile fluids (i.e., gastric, biliary, or urine), pancreatic enzymes, or foreign material. Aseptic bile and

urine cause minimal peritoneal inflammation, whereas gastric fluid and pancreatic enzyme leakage lead to a more intense peritoneal reaction. Microscopic and macroscopic foreign material, including surgical glove powder, surgical materials (suture, cotton swabs, surgical sponges), hair, and impaled objects (sticks, plant material, metal) may elicit a granulomatous response. To minimize iatrogenic causes of aseptic peritonitis, surgeons should rinse surgical gloves preoperatively with sterile saline or use powder-free gloves, perform a surgical sponge count before opening and closing a celiotomy, and use surgical sponges with radiopaque markers. More commonly, secondary peritonitis is identified as a septic process, most commonly secondary to contamination from the gastrointestinal (GI) tract. Leakage of GI contents may occur through stomach and intestinal walls that have been compromised by ulceration, foreign body obstruction, neoplasia, trauma, ischemic damage, or dehiscence of a previous surgical incision. Spontaneous gastroduodenal perforation may be associated with nonsteroidal antiinflammatory drug administration but also may be seen with corticosteroid administration, neoplastic and nonneoplastic GI infiltrative disease, gastrinoma, and hepatic disease.2,3 Neoplasia was found to be the underlying pathology in 25% of cats with septic peritonitis secondary to GI leakage in one study, with adenocarcinoma and lymphosarcoma the most common types.4 Septic peritonitis secondary to surgical site dehiscence occurs in 6% to 16% of postoperative patients requiring intestinal enterotomy or resection and anastomosis.5-8 GI linear foreign bodies in dogs have been reported as the inciting cause of peritonitis in 41% of cases, higher than that previously reported for cats.9 One canine study found that two or more of the following conditions increased the risk for leakage after intestinal anastomosis: preoperative peritonitis, intestinal foreign body, and a serum albumin concentration of 2.5 g/dl or less.8 In addition, a recent study suggests that intraoperative hypotension is also a risk factor for the development of septic peritonitis after gastrointestinal surgery.5 Interestingly, this retrospective of 225 surgeries found the presence of a foreign body to be a protective factor. Other causes of septic peritonitis can be found in Box 122-1.

CLINICAL SIGNS Historical information may provide clues regarding the underlying cause of peritonitis. Previous and current maladies and surgical procedures (including neutering), current medications (particularly those that may predispose to GI ulceration), and duration of current clinical signs should be investigated. Owners should be questioned specifically regarding the potential for trauma exposure and foreign body ingestion. A history of recent abdominal surgery should raise suspicion for septic peritonitis, particularly if gastrointestinal surgery was performed. Clinical signs of dogs and cats with peritonitis vary in type and intensity and may reflect the underlying disease process. Peritoneal effusion is a consistent finding but may be difficult to appreciate on physical examination if only a small volume of fluid is present; it also 643

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BOX 122-1 

Differential Diagnoses of Septic Peritonitis in Dogs and Cats

Primary Feline coronavirus (feline infectious peritonitis) Salmonella typhimurium Chlamydia psittaci Clostridium limosum Mesocestoides spp. Blastomyces spp. Candidiasis spp.

Secondary Penetrating abdominal wounds Surgical peritoneal contamination Peritoneal dialysis Gastrointestinal conditions Gastric rupture secondary to GDV, neoplasia, perforating ulcer Intestinal leakage Perforating foreign body, ulcer, or neoplasia Bacterial translocation secondary to obstruction (foreign body, neoplasia, intussusception, or bowel incarceration) Dehiscence of intestinal surgical wound Ischemic intestinal injury Hepatobiliary condition Liver abscess Liver lobe torsion with abscess formation Ruptured biliary tract with bacterobilia Pancreatitis or pancreatic abscess Hemolymphatic conditions Splenic abscess Splenic torsion with anaerobic bacterial colonization Mesenteric lymph node abscess formation Urogenital conditions Renal abscess Septic uroabdomen Pyometra (ruptured or with mural bacterial translocation) Uterine torsion Prostatic abscess formation GDV, Gastric dilatation-volvulus.

may be difficult to detect sonographically in animals that are dehydrated. Abdominal pain may be appreciated on palpation, with a small number of dogs exhibiting the “prayer position” in an attempt to relieve their abdominal discomfort. Abdominal pain is a less consistent finding in feline peritonitis patients (38% to 62%).4,10 Most animals with septic peritonitis are systemically ill and exhibit nonspecific clinical signs such as anorexia, vomiting, mental depression, and lethargy. These patients may arrive in progressive states of hypovolemic and cardiovascular shock, with either injected or pale mucous membranes, prolonged capillary refill time, tachycardia with weak pulses, and with either hyperthermia or hypothermia reflecting poor peripheral perfusion. A significant number of cats (16%) with septic peritonitis exhibited bradycardia (see Chapters 6 and 91).4 In fact, the combination of bradycardia and hypothermia in cats with primary septic peritonitis has been established as a negative prognostic indicator.1 Animals with uroperitoneum may continue to urinate with concurrent leakage into the peritoneal cavity.

DIAGNOSTIC TESTS Although the preoperative diagnosis of peritonitis is confirmed by identification of a septic or aseptic inflammatory process in peritoneal fluid obtained by abdominocentesis, patients with suspected or

FIGURE 122-1  Lateral abdominal radiograph showing free peritoneal gas and possibly ingesta free within the abdomen. Pneumoperitoneum, without a history of recent surgery or open-needle abdominocentesis, indicates the need for abdominal exploratory surgery. This cat was diagnosed with a ruptured gastric mass at surgery.

confirmed peritonitis should have routine hematologic, biochemical, and coagulation analyses performed. A marked neutrophilia with a left shift is the predominant hematologic finding, although a normal or low neutrophil count may be present. Animals recovering without incident from GI surgery also may have a transient inflammatory leukogram; however, the overall peripheral white blood cell counts typically fall within normal limits.11 An increasingly left-shifted neutrophilia (or neutropenia) paired with clinical signs of peritonitis may raise the clinician’s index of suspicion for postoperative intestinal dehiscence (which typically occurs 3 to 5 days after surgery). Furthermore, acid-base and electrolyte abnormalities may be noted. Hyperkalemia (and azotemia) may indicate uroperitoneum, particularly if trauma or urinary tract dysfunction has been noted historically. Hypoproteinemia may be a result of the loss of protein within the peritoneal cavity. Patients with a concurrent septic process may be hypoglycemic. Hepatic enzymes, creatinine, and blood urea nitrogen may be elevated, indicating primary dysfunction of these organs or perhaps reflecting a state of decreased perfusion or dehydration. The serum of patients with bile peritonitis is often icteric if the total bilirubin is elevated. Recently, the prevalence of ionized hypocalcemia in cats and dogs with septic peritonitis has been recognized and a failure to normalize calcium levels during hospitalization associated with negative prognosis.12,13 Plain radiographs may reveal a focal or generalized loss of detail that also is known as the ground glass appearance. A pneumoperitoneum (Figure 122-1) suggests perforation of a hollow viscous organ, penetrating trauma (including recent abdominal surgery) or, less commonly, the presence of gas-producing anaerobic bacteria. Intestinal tract obstruction or bowel plication should be ruled out. Prostatomegaly in male dogs and evidence of uterine distention in female dogs should be noted. Thoracic radiographs should be performed to rule out concurrent illness (infectious, neoplastic, or traumatic). The presence of bicavitary effusion increased the mortality rate of patients 3.3-fold compared with that of patients with peritoneal effusions alone.14 Ultrasonography may be useful for defining the underlying cause of peritonitis, in addition to its use in localizing and aiding retrieval of peritoneal effusion. In the case of a confirmed uroabdomen, preoperative contrast radiography (excretory urography or cystourethrography) is recommended to localize the site of urine leakage and aid in surgical planning. All patients should be stabilized hemodynamically and medically before diagnostic imaging is performed. Patients with suspected peritonitis should be evaluated for peritoneal effusion. Little or no fluid may be detected initially if patients arrive early in the disease process or before fluid resuscitation if they are dehydrated (see Table 112-1). Large volumes of effusion may be

CHAPTER 122  •  Peritonitis

obtained via blind abdominocentesis or, alternatively, via ultrasonographic guidance (see Chapter 200). Single paracentesis attempts are successful in only 20% of patients with low volumes of peritoneal effusion (3 ml/kg) and in only 80% with larger volumes (10 ml/kg). Ultrasonographic guidance facilitates the retrieval of smaller volumes of peritoneal fluid. If single-site sampling is negative for fluid, fourquadrant sampling should be performed. A diagnostic peritoneal lavage (DPL, see Chapter 200) should be performed when peritonitis is suspected despite the absence of detectable effusion or when a minimal volume of effusion makes it difficult to obtain a sample. DPL ideally is performed using a peritoneal dialysis catheter but also can be performed using an over-the-needle, large-bore (14- to 16-gauge) catheter. The technique is performed by placing a catheter sterilely into the abdomen, infusing 22 ml/kg of a warmed, sterile isotonic saline solution, then retrieving a sample for analysis and culture and susceptibility testing. The lavage solution dilutes the sample and therefore alters the fluid analysis. A repeated DPL may increase accuracy of the technique when results of the first procedure are equivocal. Whether obtained by paracentesis or DPL, cytologic, biochemical, and microbiologic analyses are useful in diagnosing peritonitis and further classifying type (septic or aseptic) and potential underlying cause (see Table 112-1 for overview). Leukocyte morphology has been suggested to be more reliable than cell counts in diagnosing peritonitis.15 In an experimental study, DPL samples obtained before and after abdominal surgery suggest a nucleated cell count less than 1000 cells/µl (predominantly segmented neutrophils and macrophages) in dogs without intraabdominal pathology, whereas nucleated cell counts increased significantly in postoperative samples.11 In a second experimental study, DPL cell counts between 500 and 10,500 cells/µl consisting predominantly of nondegenerate neutrophils are seen within the first 3 days after uncomplicated intestinal anastomosis.15 Peritoneal leukocyte counts in animals with experimentally induced peritonitis exceed 5000 cells/µl (consistent with an exudate), with primarily degenerative neutrophils. Early in the disease process, lower cell numbers or an absence of degenerate neutrophils may occur in the face of septic peritonitis. The presence of intracellular bacteria, plant material/GI ingesta with associated inflammation, and/or free biliary crystals supports the diagnosis of peritonitis. Furthermore, increasing inflammation (numbers of neutrophils or morphologic features of toxicity in these cells) observed in serial samples and correlated with clinical findings may prove more useful than single leukocyte counts in abdominal fluid samples when deciding whether reoperation is indicated. Dogs receiving antimicrobial therapy may have no observable bacteria in peritoneal fluid samples, despite having peritoneal contamination. In addition to the presence of bacteria and a high nucleated cell count with the presence of degenerate neutrophils, the glucose concentration of abdominal effusion is a useful predictor of bacterial peritonitis in dogs. A concentration difference of more than 20 mg/ dl between paired samples for blood and peritoneal fluid glucose is a reliable predictor of a bacterial peritonitis; intravenous administration of dextrose or the presence of a hemoperitoneum may decrease the accuracy of this test. In addition, an abdominal fluid lactate concentration that is 2.0 mmol/L or greater than the blood lactate is predictive of septic peritonitis in dogs but has not been as useful in cats.16,17 These parameters have been shown to be unreliable indicators of septic peritonitis in the evaluation of postoperative cases in which closed suction drains have been placed.18 Samples for aerobic and anaerobic cultures should be obtained at the time of initial sampling so that additional samples are not required after confirming the presence of a septic process and initiating antimicrobial therapy. The diagnosis of uroperitoneum in dogs can be made if the peritoneal fluid creatinine or potassium concentration exceeds that of

FIGURE 122-2  Microscopic examination of Wright-stained peritoneal fluid reveals markedly degenerative neutrophils, activated macrophages, and extracellular gold-brown pigment. One neutrophil in this high-powered field contains large bacterial rods (lower right hand side). This cytologic evaluation, together with elevated total bilirubin concentration in the peritoneal fluid relative to the serum concentration, confirms a diagnosis of a septic bile peritonitis.

the serum creatinine (more than 2 : 1) or potassium concentration (more than 1.4 : 1).19 Similarly, biliary rupture leads to a bilirubin concentration that is higher in the peritoneal fluid than in the serum. In addition, bile pigment or crystals may be visible on cytologic examination of the peritoneal effusion in animals with bile peritonitis (Figure 122-2). These changes may not be seen in patients with bile peritonitis secondary to a ruptured gallbladder mucocele because the gelatinous bile often fails to disperse throughout the abdomen.

TREATMENT Medical Stabilization The goals for animals with septic peritonitis are to identify and address the source of contamination to resolve the infection and treat the systemic consequences as quickly as possible (i.e., fluid and electrolyte abnormalities and hypoperfusion). Before surgical intervention, a decision must be made whether additional hemodynamic stabilization is indicated before proceeding, or whether this additional time and continued contamination of the abdominal cavity will result in further clinical decline that outweighs the benefits of additional medical treatment. The goals of medical therapy are to restore normal fluid and electrolyte balance and minimize ongoing contamination. Fluid resuscitation is initiated after obtaining pretherapy blood samples for a minimum database (packed cell volume, total solids, BUN, dextrose), hematology, serum chemistry, and coagulation evaluation. Urine should be collected, if possible, for analysis with or without culture and susceptibility testing. Shock doses of crystalloids (up to 90 ml/kg in the dog, 50 ml/kg in the cat) or a combination of isotonic crystalloids (up to 20 to 40 ml/kg) and synthetic colloids (hydroxyethyl starch up to 20 ml/kg in the dog or up to 10 ml/kg in the cat; or 7% to 7.5% hypertonic saline in synthetic colloid solution (1 part 23.4% hypertonic saline to 2 parts synthetic colloid), 3 to 5 ml/kg IV over 5 to 15 minutes) should be administered to effect (see Chapter 60). Because significant amounts of protein are lost into the peritoneal cavity, plasma and/or albumin administration also may be warranted. Judicious fluid therapy is recommended to avoid volume overload. Electrolytes and glucose should be supplemented if indicated (see Electrolyte and Acid-Base Disturbances, Chapters 50 through 56, and Chapter 66). After appropriate volume resuscitation,

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vasopressor therapy may be necessary to alleviate hypotension further. A urinary catheter may aid in diversion of infected urine in the case of a ruptured bladder or proximal urethra and allow time for the necessary correction of any metabolic derangements (typically hyperkalemia and acidosis) before surgery. Analgesia is an important component of preoperative management for peritonitis patients. Opioids often are used as a first-line choice for pain management; however, they must be used with caution because of their negative effects on GI motility, as well as their dose-dependent respiratory depression (see Chapters 144 and 163). Broad-spectrum antimicrobial therapy should be initiated immediately after confirming the diagnosis of septic peritonitis (see Chapters 93 and 94). Escherichia coli, Clostridium spp., and Enterococcus spp. are common isolates. A second-generation cephalosporin such as cefoxitin (30 mg/kg IV q6-8h) may be used as a single agent or combination antimicrobial therapy such as ampicillin or cefazolin (22 mg/kg IV q8h) administered concurrently with either enrofloxacin (10 to 20 mg/kg IV q24h [dog], 5 mg/kg IV q24h [cat]) or an aminoglycoside (amikacin 15 mg/kg IV, IM, SC q24h [dog], 10 mg/kg IV, IM, SC q24h [cat] or gentamicin 10 mg/kg IV, IM, SC q24h [dog], 6 mg/kg IV, IM, SC q24h [cat]). If extended anaerobic coverage is necessary, metronidazole (10 mg/kg IV q12h) may be considered. Aminoglycosides usually are avoided until renal insufficiency or acute kidney injury has been ruled out and the patient is well hydrated. Antimicrobial therapy should be tailored to the results of culture and susceptibility testing.

Surgical Treatment The goals of surgical treatment for patients with septic peritonitis include resolving the cause of the infection, diminishing the infectious and foreign material load, and promoting patient recovery with aggressive supportive care and nutritional supplementation, if indicated. A ventral midline celiotomy from xiphoid to pubis allows a thorough exploratory laparotomy to determine the underlying cause. Monofilament suture material is advocated in animals with a septic process, and surgical gut is avoided because of its shortened half-life in this environment. Placement of nonabsorbable suture material or mesh within the abdominal cavity is not recommended in cases of septic peritonitis because these materials may serve as a nidus for infection. If possible, the surgeon should isolate the offending organ from the rest of the abdomen with laparotomy sponges to prevent further contamination during correction of the problem. Surgical treatment is tailored to the individual case and the underlying cause of the septic peritonitis. If a GI leakage is identified, adjunctive procedures such as serosal patching or omental wrapping of the repaired site are recommended to reduce the incidence of postoperative intestinal leakage or dehiscence. Although heavily contaminated or necrotic omentum may necessitate partial omentectomy, preservation of as much omentum as possible is advised to promote venous and lymphatic drainage from the peritoneal cavity. In addition, potential benefits of surgical applications of the omentum (e.g., intracapsular prostatic omentalization for prostatic abscess formation20 pancreatic abscess omentalization,21 omentalization of enterotomy or intestinal resection and anastomosis sites, and around gastrostomy or enterostomy tube sites) relate to its immunogenic, angiogenic, and adhesive properties. Because enteral nutrition directly nourishes enterocytes and decreases bacterial translocation across the intestinal wall, feeding tube placement (gastrostomy or jejunostomy) should be considered during initial surgical exploration. After addressing the underlying cause to prevent further contamination of the peritoneum, clinicians must reduce the infectious and foreign material load by a combination of debridement and lavage. Localized peritonitis should be treated with lavage of the affected area

initially to minimize dissemination of the infection. A thorough lavage of the entire abdominal cavity with sterile isotonic fluid (warmed to body temperature) is warranted to remove bacteria, as well as GI contents, urine, or bile. The addition of antiseptics and antibiotics to lavage fluid is not beneficial and actually may be detrimental by inducing a superimposed chemical peritonitis. Lavage of the abdominal cavity is continued until the retrieved fluid is clear. All lavage fluid should be retrieved because fluid accumulation in the abdominal cavity impairs bacterial opsonization and clearance.22 If debridement and lavage can resolve gross foreign material or GI spillage and the source of contamination can be controlled, the abdomen should be closed primarily because of the potential complications associated with continued abdominal drainage (described below). All patients with open abdominal drainage are susceptible to superinfection with nosocomial bacteria and may experience massive fluid and protein losses. Open peritoneal drainage is accomplished with a simple continuous pattern of nonabsorbable suture material in the rectus abdominis muscle, placed loosely enough to allow drainage through a gap of 1 to 6 cm in the body wall (Figure 122-3). A preassembled, sterile bandage that comprises a nonadherent contact layer, laparotomy sponges or gauze pads, roll cotton or surgical towels, roll gauze, and an outer water-impermeable layer is placed to absorb fluid and protect the abdominal contents from the environment. Initially, this bandage is replaced twice during the first 24 hours and daily thereafter, although the amount of drainage produced by an individual patient may dictate more frequent changes. A sterile-gloved finger may have to be inserted through the incision to break down adhesions and to allow thorough drainage of the peritoneal cavity. Alternatively, patients with severely contaminated tissues may require daily general anesthesia for repeated abdominal exploration and lavage before reapplying the bandage. The quantity of fluid can be estimated by the difference in weight of the bandage before application and after removal. Abdominal closure typically is performed 3 to 5 days after the initial surgery. The placement of a urinary catheter and collection system helps to limit urine soaking of the bandage and underlying exposed tissues.

FIGURE 122-3  Open abdominal drainage incision. The incision should be closed with a single layer of nonabsorbable suture material to provide an opening that allows drainage but does not allow abdominal viscera or omentum to herniate through the open incision. A preassembled sterile bandage is placed over this incision and is changed daily, or more frequently as required to prevent strike-through.

CHAPTER 122  •  Peritonitis

The use of vacuum-assisted peritoneal drainage (VAPD) recently has been described as a means to provide continued postoperative abdominal drainage (see Chapter 139). Although the caudal one third to two thirds of the abdominal incision is closed primarily, the remainder of the incision is reapposed loosely (as described earlier in the chapter) and subatmospheric pressure applied to the cranial portion of the incision. This approach has been used successfully in human patients and its success demonstrated by significant reductions in open abdominal drainage duration times, number of dressing changes, re-exploration rate, and successful abdominal closure rates.23,24 Superiority of this approach has yet to be established in small animal surgical patients. Survival rates for canine and feline septic peritonitis patients treated with VAPD has been reported as 37.5% (3/8)25 and 50% (3/6),26 which is similar to that seen with other abdominal drainage techniques. However, at this time, insufficient case numbers have been examined to draw conclusions as to whether the success of VAPD seen in human patients can be achieved in veterinary medicine. Dressings are available commercially that provide a barrier between the abdominal wall and viscera to protect the abdominal organs. Alternatively, the abdomen may be closed primarily and drainage accomplished with closed suction (e.g., Jackson-Pratt) drains.27 Closed suction drainage has been advocated for treatment of patients with generalized peritonitis because it has several advantages over open abdominal drainage, including a decreased risk of nosocomial infection, less intensive nursing care and bandaging requirements, decreased risk for evisceration, and the need for only one surgical procedure.27 Disadvantages are that the drains may induce some fluid production and may become occluded, although active drainage was maintained for up to 8 days with this technique in 30 dogs and 10 cats in one study.27 In addition, closed suction drains allow daily quantitative and qualitative assessment of retrieved fluid for evaluating the progression of the peritonitis. Typically, one drain placed between the liver and diaphragm is sufficient for small dogs and cats, whereas two drains are more appropriate for larger dogs (the fenestrated portion of second drain is placed in the caudal abdomen along the ventral body wall). The drain tubes exit the body wall through a paramedian stab incision and are sutured to the abdominal skin with a pursestring and Chinese finger-trap sutures (Figure 122-4). After routine closure of the abdomen, the suction reservoir bulb is attached to the tubing with vacuum (negative pressure) applied. A protective abdominal bandage is placed with sterile contact material around the tube-skin interface and is changed daily to allow assessment of this site. Fluid collected within the bulbs is emptied using aseptic technique, and the volume is recorded every 4 to 6 hours, or more frequently if needed. Drains are removed by applying gentle traction when the volume of fluid production has decreased significantly and cytologic analysis suggests resolution of the peritonitis (i.e., decreasing cell numbers and nondegenerative neutrophils, absence of bacteria). A sterile bandage is reapplied to cover the drain exit site for 24 hours.

Postoperative Care Postoperative care for patients with peritonitis is typically intense because these patients are critically ill and subject to a variety of complications (see Chapter 131).28 Aggressive intravenous fluid therapy is a necessity, particularly in patients with continued fluid losses from the inflamed peritoneal cavity. Electrolytes and acid-base status should be assessed routinely during the postoperative period and corrected as needed. Because anemia and hypoproteinemia are common complications in these patients, blood component therapy and synthetic colloidal support are often necessary, with a goal of maintaining a packed cell volume greater than 20% to 25%, serum protein over 3.5 g/dl, and colloid osmotic pressure higher than 16 mm Hg.

A

B FIGURE 122-4  A, Closed suction drainage may be accomplished by placing a single Jackson-Pratt drain cranial to the liver (a second drain also may be placed in the caudal abdomen along the ventral body wall in large dogs), exiting paramedian to the abdominal incision. B, The tubing is secured to the body wall with a purse-string and Chinese finger trap sutures. Once the abdomen is routinely closed, the suction reservoir is attached and a vacuum is created by compressing the bulb. An abdominal bandage is placed to allow attachment of the drainage tubing and reservoir to prevent entanglement and premature removal by the patient.

Proper nutrition provides a much-needed source of protein and energy in these patients. Failing to meet nutritional demands, either with parenteral or enteral nutrition, may contribute to impaired wound healing and immune defenses. In fact, early nutritional support is associated with shorter hospitalization in dogs.29 Enteral feeding is preferred over parenteral feeding but may be stymied by the anorectic patient unless GI feeding tubes were placed at the time of surgery. If this was not done, a nasoesophageal tube can be placed easily in patients unable to tolerate repeated anesthesia. Alternatively, an esophagostomy tube may prove beneficial in patients that can tolerate general anesthesia. Animals with refractory vomiting typically require parenteral nutrition (see Chapters 129 and 130). Postoperative hypotension may be treated with vasopressor therapy but only after addressing any underlying hypovolemia (see Chapters 8, 157, and 158). Proper analgesia is required to ensure patient comfort and to diminish the negative cardiovascular effects associated with overactive sympathetic stimulation (see Chapter 144). Other complications, including cardiac arrhythmias, disseminated intravascular coagulation, and systemic inflammatory response syndrome can be found in other chapters (see Chapters 6 and 91).

PROGNOSIS The prognosis for animals with peritonitis depends on the underlying cause and whether infection is present. Studies in which patients have benefited from advances in critical care management cite overall

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survival rates of 44% to 71%.* Cats were reported to have a lower survival rate than dogs in two studies3,30; however, two studies focusing on feline septic peritonitis found an approximate 70% survival in animals in which treatment was pursued.1,4 Poor prognostic indicators for animals with septic peritonitis have included refractory hypotension, cardiovascular collapse, disseminated intravascular coagulation, and respiratory disease.27,34 The combination of hypothermia and bradycardia on presentation in feline patients appears to be a negative prognostic indicator.1 Mortality rates in patients with septic peritonitis secondary to GI leakage have been reported to vary between 30% and 85%.2,3,7,8 Bacterial contamination was associated significantly with mortality in animals with bile peritonitis.36 Although survival in dogs with aseptic bile peritonitis was between 87% and 100%, those with septic bile peritonitis had survival rates of only 27% to 45%.32,36 Overall survival rate in cats with uroperitoneum was 62%.31 Survival rates appear to be similar in patients with septic peritonitis treated with primary closure, open peritoneal drainage, closed suction drainage, or vacuum-assisted drainage.25-27,33,35

REFERENCES 1. Ruthrauff CM, Smith J, Glerum L: Primary bacterial septic peritonitis in cats: 13 cases, J Am Anim Hosp Assoc 45:268-276, 2009. 2. Lascelles BDX, Blikslager AT, Fox SM, et al: Gastrointestinal tract perforation in dogs treated with a selective cyclooxygenase-2 inhibitor: 29 cases (2002-2003), J Am Vet Med Assoc 227:1112-1117, 2005. 3. Hinton LE, McLoughlin MA, Johnson SE, et al: Spontaneous gastroduodenal perforation in 16 dogs and seven cats (1982-1999), J Am Anim Hosp Assoc 38:176-187, 2002. 4. Costello MF, Drobatz KJ, Aronson LR, et al: Underlying cause, pathophysiologic abnormalities, and response to treatment in cats with septic peritonitis, J Am Vet Med Assoc 225:897-902, 2004. 5. Grimes JA, Schmeidt CW, Cornell KK, et al: Identification of risk factors for septic peritonitis and failure to survive following gastrointestinal surgery in dogs, J Am Vet Med Assoc 238:486-494, 2011. 6. Allen DA, Smeak DD, Schertel ER: Prevalence of small intestinal dehiscence and associated clinical factors: a retrospective study in 121 dogs, J Am Anim Hosp Assoc 28:70-75, 1992. 7. Wylie KB, Hosgood G: Mortality and morbidity of small and large intestinal surgery in dogs and cats: 115 cases (1991-2000), J Am Anim Hosp Assoc 30: 469-474, 1994. 8. Ralphs SC, Jessen CR, Lipowitz AJ: Risk factors for leakage following intestinal anastomosis in dogs and cats: 115 cases (1991-2000), J Am Vet Med Assoc 223:73-77, 2003. 9. Evans KL, Smeak DD, Biller DS: Gastrointestinal linear foreign bodies in 32 dogs: a retrospective evaluation and feline comparison, J Am Anim Hosp Assoc 30:445-450, 1994. 10. Parsons KJ, Owen LJ, Lee K, et al: A retrospective study of surgically treated cases of septic peritonitis in the cat (2000-2007), J Small Anim Pract 50:518-524, 2009. 11. Bjorling DE, Latimer KS, Rawlings CA, et al: Diagnostic peritoneal lavage before and after abdominal surgery in dogs, Am J Vet Res 44:816-820, 1983. 12. Kellett-Gregory LM, Boller EM, Brown DC, et al: Ionized calcium concentrations in cats with septic peritonitis: 55 cases (1990-2008), J Vet Emerg Crit Care 20(4):398-405, 2010. 13. Luschini MA, Fletcher DJ, Schoeffler GL: Incidence of ionized hypocalcemia in septic dogs and its association with morbidity and mortality: 58 cases (2006-2007), J Vet Emerg Crit Care 20(3):303-312, 2010. 14. Steyn PF, Wittum TE: Radiographic, epidemiologic, and clinical aspects of simultaneous pleural and peritoneal effusions in dogs and cats: 48 cases (1982-1991), J Am Vet Med Assoc 202:307-312, 1993.

*References 1, 3-5, 8, 10, 27, 30-35.

15. Botte RJ, Rosin E: Cytology of peritoneal effusion following intestinal anastomosis and experimental peritonitis, Vet Surg 12(1):20-23, 1983. 16. Bonczynski JJ, Ludwig LL, Barton LJ, et al: Comparison of peritoneal fluid and peripheral blood pH, bicarbonate, glucose, and lactate concentration as a diagnostic tool for septic peritonitis in dogs and cats, Vet Surg 32:161166, 2003. 17. Levin GM, Bonczynski JJ, Ludwig LL, et al: Lactate as a diagnostic test for septic peritoneal effusion in dogs and cats, J Am Vet Med Assoc 40:364371, 2004. 18. Szabo SD, Jermyn K, Neel J, et al: Evaluation of postceliotomy peritoneal drain fluid volume, cytology, and blood-to-peritoneal fluid lactate and glucose differences in normal dogs, Vet Surg 40:444-449, 2011. 19. Schmiedt CW, Tobias KM, Otto CM: Evaluation of abdominal fluid: peripheral blood creatinine and potassium ratios for diagnosis of uroperitoneum in dogs, J Vet Emerg Crit Care 11(4):275-280, 2001. 20. White RAS, Williams JM: Intracapsular prostatic omentalization: a new technique for management of prostatic abscesses in dogs, Vet Surg 24:390395, 1995. 21. Johnson MD, Mann FA: Treatment of pancreatic abscesses via omentalization with abdominal closure versus open peritoneal drainage in dogs: 15 cases (1994-2004), J Am Vet Med Assoc 228:397-402, 2006. 22. Platell C, Papadimitriou JM, Hall JC: The influence of lavage on peritonitis, J Am Coll Surg 191(6):672-680, 2000. 23. Pliakos I, Papavramidis TS, Michalopoulos N, et al: The value of vacuumassisted closure in septic patients treated with laparotomy, Am Surgeon 78:957-961, 2012. 24. Perez D, Wildi S, Demartines N, et al: Prospective evaluation of vacuumassisted closure in abdominal compartment syndrome and severe abdominal sepsis, J Am Coll Surg 205:586-592, 2007. 25. Cioffi KM, Schmiedt CW, Cornell KK, et al: Retrospective evaluation of vacuum-assisted peritoneal drainage for the treatment of septic peritonitis in dogs and cats: 8 cases (2003-2010), J Vet Emerg Crit Care 22(5):601609, 2012. 26. Buote NJ, Havig ME: The use of vacuum-assisted closure in the management of septic peritonitis in six dogs, J Am Anim Hosp Assoc 48:164-171, 2012. 27. Mueller MG, Ludwig LL, Barton LJ: Use of closed-suction drains to treat generalized peritonitis in dogs and cats: 40 cases (1997-1999), J Am Vet Med Assoc 219:789-794, 2001. 28. Hardie EM: Life threatening bacterial infection, Comp Cont Educ Pract 17:763, 1995. 29. Liu DT, Brown DC, Silverstein DC: Early nutritional support is associated with decreased length of hospitalization in dogs with septic peritonitis: a retrospective study of 45 cases (2000-2009), J Vet Emerg Crit Care 224(453):459, 2012. 30. Culp WTN, Zeldis TE, Reese MS, et al: Primary bacterial peritonitis in dogs and cats: 24 cases (1990-2006), J Am Vet Med Assoc 234:906-913, 2009. 31. Aumann M, Worth LT, Drobatz KJ: Uroperitoneum in cats: 26 cases (1986-1995), J Am Anim Hosp Assoc 34:315-324, 1998. 32. Ludwig LL, McLoughlin MA, Graves TK, et al: Surgical treatment of bile peritonitis in 24 dogs and 2 cats: a retrospective study (1987-1994), Vet Surg 26:90-98, 1997. 33. Lanz OI, Ellison GW, Bellah JR, et al: Surgical treatment of septic peritonitis without abdominal drainage in 28 dogs, J Am Anim Hosp Assoc 37:87-92, 2001. 34. King LG: Post-operative complications and prognostic indicators in dogs and cats with septic peritonitis: 23 cases (1989-1992), J Am Vet Med Assoc 204:407-414, 1994. 35. Staatz AJ, Monnet E, Seim HB. Open peritoneal drainage versus primary closure for the treatment of septic peritonitis in dogs and cats, Vet Surg 31:174-180, 2002. 36. Mehler SJ, Mayhew PD, Drobatz KJ, et al: Variables associated with outcome in dogs undergoing extrahepatic biliary surgery: 60 cases (19882002), Vet Surg 33(6):644-649, 2004.

CHAPTER 123  GASTRIC DILATATION-VOLVULUS Claire R. Sharp,

BSc, BVMS(Hons), MS, DACVECC

KEY POINTS • Gastric dilatation-volvulus is a life-threatening condition that requires aggressive emergency medical stabilization, surgical intervention, and intensive postoperative care to optimize management. • The pathogenesis of gastric dilatation-volvulus is complex and has genetic and environmental influences. • Distention and displacement of the stomach cause cardiorespiratory dysfunction and gastrointestinal compromise. • Potential life-threatening postoperative complications include cardiac arrhythmias, persistent hypotension, disseminated intravascular coagulation, peritonitis, and multiple organ dysfunction syndrome. • Client education is key and promotes early intervention and decreased incidence of this condition through breeding and home management practices. • Despite often challenging case management, the overall survival rate for dogs treated appropriately for gastric dilatation-volvulus approaches 85%.

Gastric dilatation–volvulus syndrome, commonly referred to as bloat, includes acute gastric dilatation (GD), acute gastric dilatation with gastric volvulus (GDV), and chronic gastric volvulus (cGV)1, of which GDV is documented most thoroughly in the literature. GDV is a common condition associated with high morbidity and the potential for mortality in large and giant breed dogs presented for emergency care. The pathogenesis of GDV is complex and incompletely under­ stood, although certain predispositions have now been well char­ acterized. An index of suspicion for the condition is vital to direct appropriate and timely diagnostics and facilitate early medical and surgical intervention to restore hemodynamic stability and decom­ press and derotate the stomach. Given the potential for numerous perioperative complications, close monitoring and critical care treat­ ment is indicated. An understanding of the pathogenesis, pathophysi­ ology, and clinical features of this syndrome is important to ensure preparedness to manage this life-threatening condition optimally.

PATHOGENESIS The pathogenesis of GDV is complex and multifactorial, with appar­ ent genetic and environmental influences. GDV is predominantly a syndrome of large and giant breed dogs, although small dogs, cats, and other small mammals can develop GDV. Predisposed breeds include the Great Dane, Weimaraner, Saint Bernard, Gordon Setter, Irish Setter, and Standard Poodle.2 GDV is also common in military working dogs such as German Shepherds.3,4 Most dogs with GDV are adults, and older dogs are at greatest risk. Several large studies have investigated risk factors for the develop­ ment of GDV in affected breeds. Although different studies have slightly different findings, generally considered risk factors for devel­ oping GDV include first-degree relatives that have had GDV; higher

thoracic depth-to-width ratio; lean body condition; advancing age; eating quickly (in large but not giant breed dogs); stressful events (e.g., boarding, traveling, or a vet visit); fearful, nervous, or aggressive temperament; and several diet-related factors, including having a raised food bowl, being fed only dry food, and/or a single large meal each day.5-8 Genetic predisposition to GDV may occur through inheritance of some of the aforementioned risk factors, such as conformation, per­ sonality, and/or temperament. In addition, failure of normal eructa­ tion and pyloric outflow mechanisms may be a prerequisite for gastric dilatation.9 Laxity or agenesis of the perigastric ligaments, a well-characterized cause of GDV in children, also has been proposed a potential contributor to GDV in dogs. However, in a case control study, dogs with GDV had longer hepatogastric ligaments than control dogs because measurements were performed after GDV, the investigators were unable to determine if this was present pre-GDV (and hence potentially causative) or a consequence of GDV.10 Stretch­ ing or transection of perigastric ligaments, as may occur with splenic masses or torsion and splenectomy, respectively, was suggested in earlier studies to increase risk for GDV,11,12 although more recent studies have failed to confirm this association.13,14 Similarly postpran­ dial exercise, once thought to contribute to GDV risk, was not cor­ roborated as a risk factor in subsequent studies,6 and in fact has even been suggested to be beneficial in an Internet survey–based study.15 A recent study suggested that gastric foreign body is a significant risk factor for GDV in at-risk breeds.16 Based on the available data current recommendations are that, as with other polygenic disorders, the breadth of the pedigree increases selective pressure against the condition. Breeders are encouraged to select dogs for breeding with lower thoracic depth-width ratios and whose littermates have not had GDV.17

PATHOPHYSIOLOGY Although whether dilatation or volvulus occurs first in GDV syn­ drome has been debated, it is plausible that either may occur primarily because isolated cases of both conditions are documented. Regardless of the sequence of events, once gastric distention and malpositioning occur, cardiovascular compromise ensues, leading to decreased tissue oxygen delivery (DO2) and the clinical manifesta­ tions of shock. Significant gastric distention results in the compres­ sion of the low-pressure intraabdominal veins (i.e., the caudal vena cava, portal vein, and splenic veins), leading to decreased caudal vena cava flow rate, decreased venous return, and subsequently decreased cardiac output and mean arterial pressure. Decreased DO2 has multisystemic effects, including cardiovascular, respiratory, central nervous system, gastrointestinal (GI), and renal compromise. Decreased venous return and increased venous pressure also results in splanchnic pooling and portal hypertension that can contribute to interstitial edema and loss of intravascular volume. Shock is the lifethreatening abnormality in dogs with GDV, and an understanding of the cause of this state allows rational treatment. 649

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Respiratory compromise is common in dogs with GDV and is likely multifactorial. Gastric distention and increased intraabdomi­ nal pressure decrease total thoracic volume, prevent normal caudal diaphragmatic excursion, and may result in partial lung lobe collapse resulting in decreased tidal volumes and ventilation-perfusion (V/Q) mismatching. To compensate, respiratory rate and effort increase, although these compensatory efforts may become inadequate and both hypercapnia and hypoxemia may result. Aspiration pneumonia is also likely to contribute to respiratory compromise in a proportion of dogs with GDV. Postoperative aspira­ tion pneumonia has long been recognized as a complication of GDV, contributing to mortality.1,18 A more recent study documented that 14% of dogs with GDV, in which preoperative thoracic radiographs were taken, had evidence of aspiration pneumonia.19 Aspiration of pharyngeal contents preoperatively resulting in subclinical pneumo­ nia preoperatively but contributing to morbidity and mortality post­ operatively should be a consideration in the management of these dogs and may warrant preemptive screening thoracic radiographs and antimicrobial coverage. Gastric necrosis is a feared complication of GDV because it is associated with increased morbidity and mortality.20 In dogs with GDV, gastric blood flow likely is decreased because of a combination of factors including compression, thrombosis, or avulsion of the splenic and/or short gastric arteries, elevated intragastric pressure (gastric wall tension that exceeds driving pressure in the gastric wall arterioles and capillaries), and reduced cardiac output. Thus the degree of dilatation and degree and duration of volvulus likely con­ tribute to the risk of gastric necrosis. Clinically, gastric necrosis in dogs with GDV follows a predictable pattern, with the gastric fundus most commonly affected, and progression to the body of the stomach. Necrosis of the cardia also occurs and is likely the result of direct vascular occlusion. Decreased gastric blood flow and gastric venous obstruction initially manifest as gastric mucosal, submucosal, and serosal edema and hemorrhage. Susceptibility of the mucosa to damage by hypoperfusion may be exacerbated by the acidic environ­ ment of the gastric lumen as well as its high metabolic demands. Left untreated, severe compromise to the gastric wall results in necrosis and ultimately perforation, with resultant peritonitis. Intestinal blood flow also is compromised in dogs with GDV, resulting from direct compression of the portal vein and decreased cardiac output. Experimental models of GDV have documented intestinal villous injury and mucosal barrier compromise, leading to translocation and increased circulating concentrations of bacterial lipopolysaccharide, which in turn can contribute to systemic inflam­ mation in these dogs. In combination with perioperative variables, such as anesthetic and analgesic drugs, this may contribute to post­ operative GI ileus. Given the close anatomic association between the stomach and spleen, splenic compromise is not uncommon in dogs with GDV and also is associated with a worse outcome. Splenic vascular avulsion, intravascular thrombosis, splenic torsion, and infarction have been reported in dogs with GDV, and thus intraoperative assessment of splenic viability and consideration of splenectomy is imperative. Rupture of the short gastric arteries commonly results in hemoabdo­ men and is another important surgical consideration. Cardiac arrhythmias, mainly ventricular in origin, occur in approximately 40% of dogs with GDV.1,18 Several factors have been implicated in the cause of cardiac arrhythmias. Coronary blood flow in experimentally induced GDV is decreased by 50%.21 Histologic lesions compatible with myocardial ischemia are seen in experimen­ tal and spontaneous GDV and may establish ectopic foci of electrical activity. Circulating cardiostimulatory substances, such as epineph­ rine, and cardioinhibitory substances, such as proinflammatory cyto­ kines (e.g., tumor necrosis factor-α and interleukin-1β), also have

been implicated in the generation of arrhythmias. Consistent with the suspicion of myocardial injury, cardiac troponins have been proven elevated in dogs with GDV and are associated with the sever­ ity of ECG abnormalities and outcome.22 Abnormalities of acid-base status commonly are seen in dogs with GDV. Mixed acid-base disorders occur frequently, and primary abnormalities may include a high anion gap (lactate) metabolic aci­ dosis (resulting from low DO2), a hypochloremic metabolic alkalosis (resulting from sequestration of gastric HCl acid), and respiratory acidosis (resulting from hypoventilation and hypercapnia). Because of the potential for concurrent and opposing primary disorders pH may be normal.23 Electrolyte abnormalities also occur variably in dogs with GDV. Several pathophysiologic events may promote the development of hypokalemia, including the administration of a large volume of lowpotassium fluids, sequestration of potassium within the stomach or loss through vomiting or lavage, hyperchloremic metabolic alkalosis with transcellular shifting, activation of the renin-angiotensin-aldo­ sterone system, and catecholamine-induced intracellular shifting of potassium. Disseminated intravascular coagulation (DIC) is another of the organ dysfunctions seen frequently in dogs with GDV.11 Likely con­ tributing factors include pooling of blood in the caudal vena cava, portal vein, or splanchnic circulation, tissue hypoxia, acidosis, sys­ temic inflammation, endotoxemia, and potentially sepsis.

HISTORY AND CLINICAL SIGNS Typically, the onset of clinical signs in dogs with GDV is acute, with affected dogs appearing restless, uncomfortable, and anxious. Most affected dogs salivate and may retch unproductively or attempt to vomit. As the condition progresses, they may be found collapsed. The owners may note a distended abdomen, although this can be difficult to appreciate in deep-chested, well-muscled, or obese dogs.

PHYSICAL EXAMINATION Physical examination parameters are manifestations of the circula­ tory and respiratory compromise that results from acute GDV. Dogs often present in early decompensated shock, with depressed menta­ tion, pale mucous membranes, prolonged capillary refill time, tachy­ cardia, and weak pulses. Irregular cardiac rhythms and pulse deficits may be present. Increased respiratory rate and/or effort may be asso­ ciated with discomfort and the aforementioned respiratory compro­ mise. The abdomen can vary from unremarkable on palpation, through distended and firm, to tympanic. Splenic congestion may lead to the finding of splenomegaly and the spleen may be displaced caudally. If presentation has been delayed, dogs can be collapsed and comatose.

DIAGNOSIS GDV generally is diagnosed based on a single right lateral abdominal radiograph.24 Abdominal radiography is used to differentiate simple GD from GDV and to rule out other conditions. The pylorus in a dog with GDV moves cranial and dorsal to, and is separated by a soft tissue opacity from, the gastric fundus (called a reverse C, double bubble, or Popeye sign) in the right lateral projection (Figure 123-1). In comparison, the pylorus lies ventral to the fundus in a dog without volvulus. If the presence or nature of gastric malpositioning is unclear based on the right lateral projection, a dorsoventral or ventrodorsal view may be taken to help delineate gastric position. In dogs with GDV the pylorus is to the left of midline on the dorsoventral view.

CHAPTER 123  •  Gastric Dilatation-Volvulus

FIGURE 123-1  The right lateral recumbent view is the radiographic view of choice for diagnosis of gastric dilatation-volvulus. In this view, the pylorus moves to a cranial position in a dog with gastric dilatation-volvulus and is separated by a soft tissue opacity from the body of the stomach. In addition, in this example, enlargement of the spleen is evident and the serosal surfaces of the stomach, small intestine, and diaphragm are well defined, indicating a pneumoperitoneum.

In comparison, the pylorus lies to the right of midline in a dog without volvulus. Ventrodorsal positioning may lead to further car­ diovascular compromise and may predispose to aspiration pneumo­ nia should the dog regurgitate or vomit. Although gastric pneumatosis (intramural gas) and pneumoperitoneum suggest gastric necrosis and possibly perforation, gastric air may be introduced when a trocar is used in the emergency stabilization of the dog before radiographs are taken.25 Thoracic radiographs also may be indicated in dogs with GDV. Indications include to detect aspiration pneumonia, especially in those with hypoxemia, in older animals that may have coexisting disease, as a check for metastatic disease, or dogs suspected of having concurrent cardiac disease.19 A minimum database should include at least a packed cell volume (PCV), total protein (TP), and lactate measurement. The PCV and TP may be increased because of hemoconcentration. Hyperlactatemia is often present and failure of severe hyperlactatemia to improve with stabilization is a predictor of nonsurvival in dogs with GDV.19,26-28 A complete blood count and biochemical profile may be per­ formed, especially in older animals, or to establish a baseline. Hematologic abnormalities may include hemoconcentration and a stress leukogram. Platelet consumption and/or loss may lead to thrombocytopenia. Although dogs with GDV rarely have bleeding complications, baseline evaluation of coagulation status may be performed. The presence of three or more abnormal hemostatic parameters (pro­ longed prothrombin or activated partial thromboplastin time, hypo­ fibrinogenemia, thrombocytopenia, elevated fibrin degradation products concentration, and antithrombin depletion), consistent with DIC, has been shown to correlate with gastric necrosis in one study.11 DIC is also a negative prognostic indicator for survival.29 Biochemical abnormalities may include elevated hepatic trans­ aminases (associated with hepatocellular damage) and/or azotemia (generally prerenal).

TREATMENT GOALS The most important initial goal of treatment is to improve the car­ diovascular status of the dog. After initial stabilization, treatment

goals for dogs with GDV include gastric decompression, followed by surgery to reposition and pexy the stomach. Fluid resuscitation usually is performed through two large-bore (14- to 18-gauge) cephalic venous catheters. Resuscitation from shock involves admin­ istration of large volumes of isotonic crystalloids (with or without synthetic isotonic colloids) to effect (see Chapter 60), with the under­ standing that the maldistributive and/or obstructive component of shock cannot be resolved completely until the GDV is resolved. After appropriate volume resuscitation, vasopressor therapy may be necessary to manage hypotension. Continuous electrocardiographic (ECG) monitoring should be performed and arrhythmias (typically ventricular) treated if they interfere with cardiac output (see Chapter 48). It is unclear whether antimicrobial therapy is warranted in dogs with GDV; however, indications include evidence of aspiration pneu­ monia on preoperative radiographs, concern regarding GI bacterial translocation, and perioperative concerns, especially with regard to surgery of prolonged duration. Gastric decompression should be attempted only after cardiovas­ cular resuscitation has begun. Decompression further improves car­ diorespiratory function; however, additional cardiovascular insult can occur associated with reperfusion injury. Gastric decompression ideally is accomplished with orogastric intubation after administra­ tion of opioid analgesia, rapid sequence anesthesia induction, and intubation. The smooth-surfaced orogastric tube should be marked to a length of the distance from the nares to the caudal edge of the last rib and the lubricated tube not passed beyond this point. In the event that the orogastric tube cannot be passed easily, trocar insertion should be performed using a large-gauge, short needle or over-theneedle catheter in a region of the left or right cranial, dorsolateral abdomen. This should be performed in an area that exhibits the greatest tympany and that has been clipped and aseptically prepared. Successful trocar placement is confirmed by a hissing sound as gas is released from the distended stomach. Splenic laceration and gastric perforation can occur as potential complications of attempted trocarization. Immediate surgical intervention then is indicated for animals with GDV. Dogs with GD alone typically do not require immediate surgical intervention, although gastropexy is recommended to help prevent the development of GDV in the future. Conservative treat­ ment in these dogs is tailored to the individual dog and may consist of intravenous fluid therapy and orogastric intubation as needed. In addition, simethicone (2 to 4 mg/kg PO q6h) and metoclopramide (0.2 to 0.4 mg/kg SC q8h) may be considered to decrease the amount of gas and promote gastric emptying, respectively. Even in the absence of radiographic evidence of gastric volvulus, surgical exploration should be recommended for GD patients that are unresponsive to medical treatment (repeated bloating, persistent hypotension, and/ or tachycardia).

SURGICAL TREATMENT The goals for surgery are to decompress and reposition the stomach, assess viability of the stomach and spleen, remove irreversibly com­ promised tissue, and create a permanent adhesion between the stomach and body wall to help prevent recurrence of gastric volvulus. A large ventral midline incision is made, taking care not to damage abdominal viscera pushed up to the linea by gastric disten­ tion. Typically, the pylorus has moved from its normal position next to the right body wall toward the left body wall, in a clockwise direc­ tion. The rotation may be 90 to 360 degrees but most commonly is 180 to 270 degrees. With this type of rotation, the greater omentum is found draped over the cranial abdominal organs. The stomach is decompressed by orogastric intubation (by the anesthetist with guidance by the surgeon) or via gastrocentesis and

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is rotated back into its normal position. The pylorus can be located by tracing the duodenum (identifiable by the attached pancreas) forward from the duodenocolic ligament. By gently bringing the pylorus back to the right of midline using one hand and using the other hand to push the body of the stomach dorsally, the stomach is derotated. An orogastric tube may be used to decompress the stomach completely and empty ingesta. Gastrotomy is not recommended for the removal of suspected food particles but is warranted if potentially obstructive material is present within the gastric lumen. Next, the stomach and the spleen should be assessed for viability and gastric resection or splenectomy performed as needed. The spleen should be removed only if it has thrombosed or been damaged by the gastric volvulus. Partial gastrectomy is required when gastric necrosis has occurred, usually along the greater curvature. Gastric viability is assessed by examination of serosal color, palpation of gastric wall thickness, and evidence of arterial bleeding if incised. Gray or black coloration and palpable thinning of the stomach are signs of necrosis. Serosal coloration within areas of viable tissue may improve dramatically within minutes of decompression and reposi­ tioning. Gastric resection may be accomplished by preplacing stay sutures to minimize or prevent additional abdominal contamination, followed by resection of the devitalized area until bleeding tissue is reached and then closure. Whether sutures or stapling (TA-90 or GIA-50) is used for closure, a second inverting suture line is recommended.30 Invagina­ tion of necrotic tissue also has been used to treat gastric necrosis. Because this technique does not require opening of the gastric lumen, it is technically less demanding and is theoretically less likely to result in peritoneal contamination through gross spillage during partial gastrectomy or because of suture dehiscence; however, invagi­ nated tissue may be prone to ulcer formation.31,32 Although risks are associated with gastric resection and invagination, the devastating sequelae of perforation and peritonitis resulting from necrotic tissue that is not excised make it advisable to remove or invaginate any gastric tissue of questionable viability. Gastric necrosis has been associated with the development of several life-threatening com­ plications, including peritonitis, DIC, sepsis, and arrhythmias.29 Although two large retrospective studies examining postoperative outcome in dogs surgically treated for GDV (295 and 166 cases) did not agree whether gastric resection was a risk factor for death, these studies suggest that with aggressive preoperative and postoperative management, 70% to 74% of dogs with gastric resections may survive to discharge.1,28,29 Many procedures have been described to pexy the pyloric antral region of the stomach to the right body wall. These include the tube, incisional, muscular flap, circumcostal, and belt loop gastropexies, as well as various modifications of the above. The aim is to create a permanent adhesion between the antral region of the stomach and the right body wall. An incisional gastropexy is accomplished easily and quickly by making an incision about 5 cm long in the transversus abdominis muscle just caudal to the last rib, and a corresponding incision is made in the gastric seromuscular layer (taking care not to enter the gastric lumen). The orientation of the incisions reflects an attempt to preserve a relatively normal gastric position when the two edges of each incision are sutured together using either polypropyl­ ene or polydioxanone. The pexy site should not be incorporated into the abdominal closure because the stomach could be damaged if cranial abdominal surgery is required at a future date. Although strength of the adhesions formed using the various techniques when tested in vitro varies somewhat, recurrence rates are similar for all of the above techniques when performed properly (percutaneous endoscopic gastrostomy tubes are not recommended because of inconsistent adhesion formation).33 The tube gastropexy may be associated with a higher morbidity because of premature tube

removal and peristomal cellulitis; however, it may be useful for con­ tinued gastric decompression of air and gastric secretions and for administration of medications and nutritional support to anorexic patients postoperatively. The surgical technique used is probably less important than the surgeon’s familiarity with one of the established techniques and the surgeon’s ability to perform it proficiently and efficiently.

POSTOPERATIVE CARE The aim of postoperative management is to maintain DO2. Because of substantial fluid loss into the peritoneal cavity and GI tract, rea­ sonably high fluid rates often are required for the first 48 to 72 hours. Mucous membrane color, capillary refill time, PCV, TP, urine output, ECG, blood pressure, and acid-base balance should be monitored closely postoperatively. Dogs recovering well from surgery can be offered food as soon as they are adequately awake from anesthesia. If nausea is present it can be treated with an antiemetic (see Chapter 162). These dogs can be weaned gradually off their intravenous fluids over 1 to 2 days. Because of the high incidence of gastric mucosal compromise, nonsteroidal antiinflammatory drugs are to be avoided, and histamine-2 receptor antagonists (e.g., famotidine) and gastriccoating agents (sucralfate) should be considered. Cardiac arrhythmias often begin 12 to 24 hours after surgery. Continuous ECG monitoring is ideal. If arrhythmias occur, the afore­ mentioned contributing factors should be sought and treated if present. Antiarrhythmic therapy should be considered if cardiac output is impaired or if serious electrical changes are evident (such as R on T phenomenon, multiform ventricular premature contrac­ tions, or when sustained ventricular tachycardia occurs with a heart rate of more than 180 beats/min) because this rate probably impairs ventricular filling and therefore cardiac output (see Chapters 47 and 48). Reports have been conflicting regarding whether the presence of arrhythmias negatively affects the prognosis.1,18,29 Perioperative risk factors significantly associated with death before suture removal include hypotension at any time during hos­ pitalization, combined splenectomy and partial gastrectomy, perito­ nitis, sepsis, and DIC.29 Dogs with GDV often fulfill criteria of the systemic inflammatory response syndrome and multiple organ dys­ function syndrome may occur in critically ill patients postoperatively (see Chapters 6 and 7).

OWNER RECOMMENDATIONS Based on available information, veterinarians should discuss preven­ tive strategies with owners of large and giant breed dogs. These include not feeding dogs from a raised food bowl and trying to ensure that large breed dogs eat more slowly (although this may be contraindicated in giant breed dogs). This may involve supervising feedings and separating dogs in households with multiple pets to decrease competition at feeding time. On the basis of the findings of Glickman and colleagues,5 one of the strongest recommendations to prevent GDV is to remove from the breeding pools dogs that have a first-degree relative that has had a GDV. Prophylactic gastropexy, either laparoscopically or via a conventional approach, has been shown to reduce the lifetime probability of death resulting from GDV in at-risk breeds and therefore should be offered to owners of these dogs.29,34,35

REFERENCES 1. Brockman DJ, Washabau RJ, Drobatz KJ: Canine gastric dilatation/ volvulus syndrome in a veterinary critical care unit: 295 cases (19861992), J Am Vet Med Assoc 207(4):460-464, 1995.

CHAPTER 123  •  Gastric Dilatation-Volvulus 2. Glickman LT, Glickman NW, Perez CM, et al: Analysis of risk factors for gastric dilatation and dilatation-volvulus in dogs, J Am Vet Med Assoc 204(9):1465-1471, 1994. 3. Moore GE, Burkman KD, Carter MN, et al: Causes of death or reasons for euthanasia in military working dogs: 927 cases (1993-1996), J Am Vet Med Assoc 219(2):209-214, 2001. 4. Jennings PB, Jr., Butzin CA: Epidemiology of gastric dilatation-volvulus in the military working dog program, Mil Med 157(7):369-371, 1992. 5. Glickman LT, Glickman NW, Schellenberg DB, et al: Incidence of and breed-related risk factors for gastric dilatation-volvulus in dogs, J Am Vet Med Assoc 216(1):40-45, 2000. 6. Glickman LT, Glickman NW, Schellenberg DB, et al: Non-dietary risk factors for gastric dilatation-volvulus in large and giant breed dogs, J Am Vet Med Assoc 217(10):1492-1499, 2000. 7. Schellenberg DB, Yi Q, Glickman NW, et al: Influence of thoracic confor­ mation and genetics on the risk of gastric dilatation-volvulus in Irish Setters, J Am Anim Hosp Assoc 34(1):64-73, 1998. 8. Raghavan M, Glickman NW, Glickman LT: The effect of ingredients in dry dog foods on the risk of gastric dilatation-volvulus in dogs, J Am Anim Hosp Assoc 42(1):28-36, 2006. 9. Brockman DJ, Holt DE, Washabau RJ: Pathogenesis of acute gastric dilatation-volvulus syndrome: is there a unifying hypothesis? Comp Cont Ed Pract Vet 22:1108, 2000. 10. Hall JA, Willer RL, Seim HB, et al: Gross and histologic evaluation of hepatogastric ligaments in clinically normal dogs and dogs with gastric dilatation-volvulus, Am J Vet Res 56(12):1611-1614, 1995. 11. Millis DL, Nemzek J, Riggs C, et al: Gastric dilatation-volvulus after splenic torsion in two dogs, J Am Vet Med Assoc 207(3):314-315, 1995. 12. Marconato L: Gastric dilatation-volvulus as complication after surgical removal of a splenic haemangiosarcoma in a dog, J Vet Med A Physiol Pathol Clin Med 53(7):371-374, 2006. 13. Goldhammer MA, Haining H, Milne EM, et al: Assessment of the inci­ dence of GDV following splenectomy in dogs, J Small Anim Pract 51(1):23-28, 2010. 14. Grange AM, Clough W, Casale SA: Evaluation of splenectomy as a risk factor for gastric dilatation-volvulus, J Am Vet Med Assoc 241(4):461-466, 2012. 15. Pipan M, Brown DC, Battaglia CL, et al: An Internet-based survey of risk factors for surgical gastric dilatation-volvulus in dogs, J Am Vet Med Assoc 240(12):1456-1462, 2012. 16. de Battisti A, Toscano MJ, Formaggini L: Gastric foreign body as a risk factor for gastric dilatation and volvulus in dogs, J Am Vet Med Assoc 241(9):1190-1193, 2012. 17. Bell JS: Risk Factors for Canine Bloat. Paper presented at: Tufts’ Canine and Feline Breeding and Genetics Conference, 2003, Tufts Cummings School of Veterinary Medicine. 18. Brourman JD, Schertel ER, Allen DA, et al: Factors associated with peri­ operative mortality in dogs with surgically managed gastric dilatationvolvulus: 137 cases (1988-1993), J Am Vet Med Assoc 208(11):1855-1858, 1996. 19. Green JL, Cimino Brown D, Agnello KA: Preoperative thoracic radiographic findings in dogs presenting for gastric dilatation-volvulus (2000-2010): 101 cases, J Vet Emerg Crit Care 22(5):595-600, 2012.

20. Mackenzie G, Barnhart M, Kennedy S, et al: A retrospective study of factors influencing survival following surgery for gastric dilatationvolvulus syndrome in 306 dogs, J Am Anim Hosp Assoc 46(2):97-102, 2010. 21. Horne WA, Gilmore DR, Dietze AE, et al: Effects of gastric distentionvolvulus on coronary blood flow and myocardial oxygen consumption in the dog, Am J Vet Res46(1):98-104, 1985. 22. Schober KE, Cornand C, Kirbach B, et al: Serum cardiac troponin I and cardiac troponin T concentrations in dogs with gastric dilatationvolvulus., J Am Vet Med Assoc 221(3):381-388, 2002. 23. Wingfield WE, Twedt DC, Moore RW, et al: Acid-base and electrolyte values in dogs with acute gastric dilatation-volvulus, J Am Vet Med Assoc 180(9):1070-1072, 1982. 24. Hathcock JT: Radiographic view of choice for the diagnosis of gastric volvulus: the right lateral recumbent view, J Am Anim Hosp Assoc 20, 1984. 25. Fischetti AJ, Saunders HM, Drobatz KJ: Pneumatosis in canine gastric dilatation-volvulus syndrome, Vet Radiol Ultrasound 45(3):205-209, 2004. 26. Beer KA, Syring RS, Drobatz KJ: Evaluation of plasma lactate concentra­ tion and base excess at the time of hospital admission as predictors of gastric necrosis and outcome and correlation between those variables in dogs with gastric dilatation-volvulus: 78 cases (2004-2009), J Am Vet Med Assoc 242(1):54-58, 2013. 27. Zacher LA, Berg J, Shaw SP, et al: Association between outcome and changes in plasma lactate concentration during presurgical treatment in dogs with gastric dilatation-volvulus: 64 cases (2002-2008), J Am Vet Med Assoc 236(8):892-897, 2010. 28. de Papp E, Drobatz KJ, Hughes D: Plasma lactate concentration as a predictor of gastric necrosis and survival among dogs with gastric dilatation-volvulus: 102 cases (1995-1998), J Am Vet Med Assoc 215(1):4952, 1999. 29. Beck JJ, Staatz AJ, Pelsue DH, et al: Risk factors associated with shortterm outcome and development of perioperative complications in dogs undergoing surgery because of gastric dilatation-volvulus: 166 cases (1992-2003), J Am Vet Med Assoc 229(12):1934-1939, 2006. 30. Hedlund C, Fossum TW: Surgery of the digestive tract. In Fossum TW, editor: Small animal surgery, St Louis, 2007, Mosby. 31. MacCoy DM, Kneller SK, Sundberg JP, et al: Partial invagination of the canine stomach for treatment of infarction of the gastric wall, Vet Surg 15(3):237-245, 1986. 32. Parton AT, Volk SW, Weisse C: Gastric ulceration subsequent to partial invagination of the stomach in a dog with gastric dilatation-volvulus, J Am Vet Med Assoc 228(12):1895-1900, 2006. 33. Waschak MJ, Payne JT, Pope ER, et al: Evaluation of a percutaneous gas­ trostomy as a technique for permanent gastropexy, Vet Surg 26(3):235241, 1997. 34. Rawlings CA, Mahaffey MB, Bement S, et al: Prospective evaluation of laparoscopic-assisted gastropexy in dogs susceptible to gastric dilatation, J Am Vet Med Assoc 221(11):1576-1581, 2002. 35. Ward MP, Patronek GJ, Glickman LT: Benefits of prophylactic gastropexy for dogs at risk of gastric dilatation-volvulus, Prev Vet Med 60(4):319-329, 2003.

653

PART XIII  UROGENITAL DISORDERS CHAPTER 124  ACUTE KIDNEY INJURY Catherine E. Langston,

DVM, DACVIM  •  Adam

E. Eatroff,

KEY POINTS • Acute kidney injury (AKI) resulting from hemodynamic compromise can be reversed rapidly, whereas animals with intrinsic parenchymal injury may take weeks to months to recover. • Aggressive intravenous fluid therapy, beyond that which is necessary to restore and maintain normal renal perfusion, is more likely to result in complications associated with fluid overload than to improve renal function. • Renal replacement therapy is the most is the most efficient means of managing uremic, acid-base, electrolyte, and fluidrelated sequelae of fulminant acute kidney injury. • Polyuric acute kidney injury can be associated with extreme fluid losses from high-volume urine output. • Mortality rates for AKI are high (approximately 50%). Anuric and oliguric AKI carry a worse prognosis than polyuric acute kidney injury. • Small increases in serum or plasma creatinine concentrations may be associated with a worse clinical outcome in hospitalized dogs.

Acute renal failure is a term often used to characterize an abrupt decline in renal function that leads to retention of uremic toxins and dysregulation of fluid, electrolyte, and acid-base balance. However, recent recognition of the wide spectrum of disease (ranging from clinically undetectable, subcellular damage to fulminant, excretory failure) and the association of small decreases in glomerular filtration rate (GFR) with worse clinical outcomes has led to a shift in terminology. The term acute kidney injury (AKI) currently is recognized as the preferred nomenclature for this clinical syndrome because it reflects the entire continuum of clinically relevant disease. Recently, in human medicine, staging schemes that characterize AKI according to minor, relative changes in GFR and serum or plasma creatinine concentrations, as well as quantification of urine output, have been developed and validated. The two most widely accepted schemes include the Risk Injury Failure End Stage Kidney Disease (RIFLE) scheme1 and the Acute Kidney Injury Network (AKIN),2 the latter of which was developed by modification of the former, with the intent to improve the sensitivity of detection of AKI. Both schemes appear to perform equally well when sensitivity for detection of AKI and predictive ability of adverse outcomes are considered. A recent study evaluating AKI in hospitalized cats and dogs, using a modified version of the AKIN scheme (Table 124-1), has confirmed a similar relationship between small increases in plasma creatinine concentra-

DVM, DACVIM

tions and poor clinical outcomes.3 Most notably, the authors showed that relative increases in plasma creatinine of at least 150% or 0.3 mg/ dl from baseline concentrations are associated with increased in-hospital mortality.3 These findings suggest that biomarkers of renal function (e.g., serum or plasma creatinine concentration) should be monitored closely in hospitalized patients. However, currently, most cases of AKI recognized in small animal practice are community-acquired and are characterized by severely increased serum or plasma creatinine concentrations, representing severe renal dysfunction.

ETIOLOGY AKI classically has been categorized into hemodynamic (prerenal), renal parenchymal (intrinsic), and postrenal causes. Hemodynamic causes include decreases in renal perfusion or excessive vasoconstriction and are characterized as rapidly reversible if the inciting cause is eliminated. However, prolonged ischemia can contribute to renal parenchymal injury. Additional intrinsic causes of AKI include infectious diseases, toxins, or systemic diseases with renal manifestations. Removal of the inciting cause of parenchymal injury is often the only means of directly addressing this type of insult. Box 124-14 lists substances with a nephrotoxic potential. Postrenal AKI is due to obstruction or diversion of urine flow, including urethral obstruction, bilateral ureteral obstruction, or unilateral obstruction with a nonfunctional contralateral kidney, or rupture of any portion of the urinary tract. Restoration of urine flow may rapidly reduce the concentrations of circulating uremic toxins. However, prolonged obstruction of urine flow may lead to renal parenchymal injury.5 Obstructive calcium oxalate nephroliths and ureteroliths are encountered in cats with increasing frequency. This condition commonly has many features of AKI, although frequently includes a significant component of chronic kidney disease. The classic causes of AKI frequently produce insults that encompass more than one of the hemodynamic, intrinsic, or postrenal processes. A specific cause is not identified in every case of AKI.

PATHOPHYSIOLOGY The pathophysiologic process of AKI is often multifactorial, with overlapping ischemic, inflammatory, toxic, and septic components. Classically, the clinical course of AKI proceeds through four phases. These phases are defined by experimental models of ischemic acute kidney injury and may not be representative of the multifactorial nature of the disease. The initiation phase is characterized by the first 655

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Table 124-1  Veterinary Acute Kidney Injury Staging Scheme for Dogs3 VAKI Stage

Criteria

Stage 0

Creatinine increase 4.0 mg/dl

stages of renal injury. Intervention at this phase may prevent progression to more severe injury, but injury at this stage occurs on a subcellular level and may not be biochemically evident. During the extension phase, cellular injury progresses to cell death. At this stage, biochemical derangements and clinical manifestations of disease manifest. During the maintenance phase, cell death and regeneration occur simultaneously, and the potential for and length of recovery from this phase may be determined by the balance between these processes. Removal of the initiating cause at this stage does not alter the existing damage but may allow for the balance to shift in favor of parenchymal regeneration. The recovery phase is characterized by improvement in GFR and tubular function; this final phase may last weeks to months.

VAKI, Veterinary acute kidney injury.

BOX 124-1 

Substances with Nephrotoxic Potential4

Therapeutic Agents Antimicrobial Agents Aminoglycosides Aztreonam Carbapenems Cephalosporins Penicillins Polymyxins Quinolones Rifampin Sulfonamides Tetracyclines Vancomycin

Antifungal Agents Amphotericin B

Cancer Chemotherapy Cisplatin and carboplatin Doxorubicin Methotrexate

Antiviral Agents Acyclovir Foscarnet

Antiprotozoal Agents Dapsone Pentamidine Sulfadiazine Thiacetarsamide Trimethoprim-sulfamethoxazole

Miscellaneous Therapeutic Agents Acetaminophen Allopurinol Angiotensin-enzyme converting inhibitors Antidepressants Apomorphine Cimetidine Deferoxamine Dextran-40 Diuretics ε-Aminocaproic acid EDTA Lipid-lowering drugs Lithium Methoxyflurane Nonsteroidal antiinflammatory drugs Penicillamine Phosphorus-containing urinary acidifiers

Streptokinase Tricyclic antidepressants Vitamin D analogs

Immunosuppressive Drugs Azathioprine Calcineurin inhibitors (e.g., cyclosporine, tacrolimus) Interleukin-2

Nontherapeutic Agents Endogenous Compounds Hemoglobin Myoglobin

Heavy Metals Antimony Arsenic Bismuth salts Cadmium Chromium Copper Gold Lead Mercury Nickel Silver Thallium Uranium

Organic Compounds Carbon tetrachloride and other chlorinated hydrocarbons Chloroform Ethylene glycol Herbicides Pesticides Solvents

Miscellaneous Nontherapeutic Agents Bee venom Diphosphonate Calcium antagonists Gallium nitrate Grapes or raisins Illicit drugs Lilies Mushrooms Radiocontrast agents Snake venom Sodium fluoride Superphosphate fertilizer Vitamin D-containing rodenticides

CHAPTER 124  •  Acute Kidney Injury

Anion gap = ( Na + + K + ) − (HCO3− + Cl − )

CLINICAL PRESENTATION History Listlessness, vomiting, diarrhea, and anorexia are common historical findings but are nonspecific and may be the result of a variety of extrarenal diseases. Oliguria, anuria, or polyuria may be reported. When a patient is polyuric, compensatory polydipsia may be present, or it may be overshadowed by anorexia. Less common historical findings include seizures, syncope, ataxia, and dyspnea.

Physical Examination Dehydration is a common finding at the time of initial presentation. However, inaccurate assessment of hydration status by physical examination parameters is common, and many euhydrated and overhydrated patients are categorized erroneously as dehydrated. Other findings specific (but not exclusive) to uremia include halitosis, oral ulceration, tongue tip necrosis, scleral injection, bradycardia, cutaneous bruising, and peripheral edema. A hallmark of AKI is enlarged, painful kidneys. Melena or diarrhea may be present from uremic gastritis or enteritis. Signs of the primary ailment causing AKI (e.g., disseminated intravascular coagulation, vasculitis) may predominate.

DIAGNOSIS Laboratory Tests Care must be taken to examine urine shortly after collection to avoid artifactual changes in composition. The urine specific gravity is frequently isosthenuric (1.007 to 1.015) in cases of intrinsic failure. A urine dipstick may reveal any combination of glucosuria (without hyperglycemia), proteinuria, bilirubinuria, and hemoglobinuria, depending on the underlying etiology. The urine pH is usually acidic, unless there is a concurrent bacterial urinary tract infection. Careful microscopic assessment of urine sediment may disclose dysmorphic red blood cells (suggestive of glomerular disease), pyuria, or casts (most frequently granular, but red and white blood cell casts are observed uncommonly). Calcium oxalate crystals in large numbers are supportive of ethylene glycol intoxication, although a few oxalate crystals may be present in the urine of healthy patients. An in-house variation of a Romanowsky stain is frequently useful for detailed assessment of red and white blood cell morphology, as well as for the identification of bacteria. A bacterial urine culture is important to confirm the presence of a urinary tract infection and guide antimicrobial therapy. The hematocrit may be increased from hemoconcentration or decreased from gastrointestinal blood loss or hemolysis. The platelet count may be normal or low, although uremia and various infectious diseases (e.g., leptospirosis) induce a thrombocytopathy, prolonging the buccal mucosal bleeding time despite a normal coagulation profile. An infectious cause or complications should be suspected when severe leukocytosis is present. The severity of azotemia depends on the cause and duration of AKI. The ratio of blood urea nitrogen to creatinine can be high from GI bleeding or dehydration, or it can be low in early stages of AKI. Ionized calcium concentrations are normal or low (provided that hypercalcemia is not a cause of AKI). Ethylene glycol intoxication causes a profound ionized hypocalcemia, because of severe hyperphosphatemia and chelation of calcium by oxalate. The anion gap is usually high secondary to retained organic and inorganic acids that the injured kidney is unable to excrete but can be normal early in the course of disease, or if hypoalbuminemia is present. A high anion gap without (or before) the presence of azotemia is supportive of intoxication in cases of suspected ethylene glycol exposure. The anion gap is calculated by the formula

where Na+ = sodium, K+ = potassium, HCO3– = bicarbonate, and Cl– = chloride. The normal anion gap is approximately 12 to 26 mEq/L; the average anion gap is 5 mEq/L higher in cats versus dogs.

Imaging Survey abdominal radiographs may show a normal renal silhouette or renomegaly. Nephroliths or ureteroliths may be readily apparent, although obstructing ureteroliths may be smaller than the limit of detection. Abdominal ultrasonography usually shows normal or enlarged kidneys with normal parenchymal architecture. Perirenal fluid is seen commonly with a variety of causes.6 Obstruction is characterized by renal pelvic dilation and lymphosarcoma by a diffusely thickened cortex and perirenal hypoechoic halo. Historically, pyelonephritis has been associated with renal pelvic dilation. However, this ultrasonographic sign is associated with various other lesions and is not pathognomonic for renal infection.7 With ethylene glycol intoxication, oxalate crystal deposition in the kidneys increases the echogenicity, making the renal cortices and, to a lesser extent, the medulla hyperechoic. An intravenous pyelogram can aid in the identification of pelvic, ureteral, and cystic disease processes, especially obstructive renal lesions that are not readily apparent with survey radiography or ultrasound. In addition it can provide information regarding renal function in the contralateral kidney (i.e., if uptake of radiocontrast is not detectable in the renal parenchyma or collecting system, the likelihood of a substantial GFR in that kidney is low). If the GFR in an obstructed kidney is below a certain threshold, an intravenous pyelogram results in inadequate study quality because of poor uptake of contrast. Antegrade pyelography may be a better choice for ureteroliths because this technique does not rely on an adequate GFR. Computed tomography or magnetic resonance imaging can add information about renal architecture and better characterize obstruction but typically requires general anesthesia.

Other Diagnostic Modalities Measurement of GFR (e.g., iohexol clearance, endogenous creatinine clearance, scintigraphy) can be expensive and some techniques are subject to limited availability. These studies have limited applicability in the initial treatment of AKI because the degree of impairment in GFR is almost always detectable by surrogate markers, such as serum or plasma creatinine concentration. Ethylene glycol intoxication is an emergency situation requiring immediate, specific therapy, which makes accurate and timely diagnosis crucial. Commercially available in-house test kits are available. Leptospira serology detects an antibody production in response to organism or vaccine exposure. Care must be taken with interpretation of this test because there are multiple limitations. There is considerable cross-reactivity among different Leptospira serovars, but most available assays are limited in the number of serovars tested. Titers also may be negative within the first 7 to 10 days of illness; a fourfold rise after 2 to 4 weeks is used to confirm exposure when initial titers are negative. A single titer of 1 : 800 or greater, with appropriate clinical signs and in the absence of recent vaccination is also suggestive of Leptospira spp. exposure. However, there is a high degree of discordance in interpretation of leptospirosis among different commercial laboratories, potentially affecting interpretation of borderline results.8 A strong clinical suspicion for leptospirosis must be present with titers in excess of 1 : 800 for serovar Autumnalis because titers often increase parallel to vaccinal serovars and with other diseases. Polymerase chain reaction assays for blood and urine have been developed for rapid, early diagnosis in dogs, but data on their clinical usefulness are lacking. Serologic tests for other infectious diseases known to cause AKI, such as Rocky Mountain spotted

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fever (Rickettsia rickettsii), Ehrlichia canis, Lyme disease (Borrelia burgdorferi), Babesia spp., or Leishmania spp., may be useful in certain areas or in cases of other consistent clinical or pathologic signs, although a positive titer does not prove causality of AKI. Cytology of tissue acquired by fine-needle aspirates can confirm the presence of lymphosarcoma but frequently provides falsenegative results. The risk of bleeding secondary to this procedure is low but possible. Histopathology can be assessed via percutaneous, ultrasonographically guided needle biopsy, laparoscopy, or surgical wedge biopsy. Histopathology may confirm a suspected cause (e.g., ethylene glycol intoxication, renal lymphosarcoma) or it may disclose nonspecific findings. When AKI cannot be distinguished clinically from end-stage chronic kidney disease, histopathology (particularly Masson’s trichrome stain) can aid in assessment of the severity of fibrosis and provide insight into the potential for renal recovery. The risk of significant hemorrhage secondary to renal biopsy is high when uremia is severe.

TREATMENT Treatment of AKI is directed primarily at the underlying disease process (when identified) and supportive measures to minimize the clinical sequelae of uremia.

Fluid Therapy To ensure normal perfusion of the kidneys, extracellular fluid deficits should be corrected with a balanced polyionic solution. Ultimately, the type of fluid administered must be guided by monitoring of serum or plasma concentration of electrolytes because the degree of solute and free water balance varies widely in patients with AKI. Colloidal support also may be considered to reduce the total amount of fluid administered, if oliguria or anuria is suspected, although no benefit over crystalloid therapy has been documented in human or veterinary medicine.9,10 Avoidance of fluid overload (typically defined as fluid accumulation more than 10% of baseline body weight) is essential because ample evidence documents the association between fluid overload and worse clinical outcomes.11,12 The formula used to calculate the volume of fluid to administer for replacement of deficits (percentage of dehydration × body weight [kg] = fluid deficit in liters) can result in administration of inadequate or excess volumes of fluid. Therefore, although this formula can be an initial guide, goal-directed therapy to restore surrogate markers of perfusion (e.g., blood pressure, venous lactate concentration, venous oxygen saturation) should be employed with endpoints set to be reached within 24 hours, if not sooner (see Chapter 59). If oliguria or anuria persists despite achievement of normal surrogate markers of perfusion, additional fluid administration is more likely to result in fluid overload than urine production. Maintenance fluid administration (volume and composition) should be guided by the volume and composition of urine produced, as well as ongoing, sensible losses (vomitus, diarrhea, and yield from gastric suction) and insensible loss (respiration, formed stool). Urine volume can be determined by a variety of methods, including (1) indwelling urinary catheter and closed collection system, (2) collection of naturally voided urine, (3) metabolic cage, (4) weighing cage bedding and litter pans (1 ml of urine = 1 g), and (5) using body weight before and immediately after urination. Urine production can be categorized as anuria (none to negligible amount), oliguria (less than 0.5 ml/kg/hr), or polyuria (more than 2 ml/kg/hr). Ancillary monitoring techniques of urine output include measurement of urine sodium concentration with point of care analyzers. Insensible losses can be estimated between 12 and 29 ml/kg/day and depend on a variety of factors, such as species, patient activity, and body temperature.

Once the patient’s fluid deficit has been corrected and maintenance fluid therapy is initiated, care must be taken to maintain a neutral fluid balance, as well as normal surrogate markers of perfusion. Attempts at fluid diuresis to improve GFR are often futile and frequently result in fluid overload, a condition that has been associated with a higher mortality rate in human and veterinary patients. Careful attention must be given to serial changes in the patient’s body weight because peracute fluctuations in weight are most likely the result of changes in fluid balance rather than changes in lean muscle or fat content. Consideration of the fluid load incurred by administration of parenteral medications, parenteral and enteral nutrition, and catheter flushes (to maintain patency and for techniques such as central venous pressure monitoring) is essential to maintain a neutral fluid balance. An anuric, euhydrated patient should receive intravenous fluid therapy to replace insensible loss only. Frequently, this requirement is met in excess by administration of medications, nutrition, and catheter flushes. If the patient is diagnosed with fluid overload, all fluid therapy should be withheld. Fluid overload with concurrent oliguria or anuria is a clear indication for renal replacement therapy. Monitoring fluid status is an ongoing process that must be repeated frequently. Efforts should be made to adhere to objective monitoring parameters (e.g., body weight, venous lactate concentration) of fluid status because subjective parameters, (e.g., skin turgor, saliva production) are inaccurate and often affected by variables other than hydration status. Body weight should be measured at least twice daily. Central venous pressure measurement traditionally has been recommended as a surrogate marker of cardiac preload, and thus fluid status. However, a thorough understanding of the limitations of this technique is necessary for appropriate interpretation because the correlation between central venous pressure and clinical manifestations of fluid overload is not perfect.

Diuretics Many of the benefits of the most commonly used diuretics in veterinary AKI, furosemide and mannitol, have been only theorized or demonstrated in experimental models of AKI. In fact, little or no clinical evidence in human or veterinary medicine, respectively, demonstrates that diuretics improve outcome in established AKI. A recent meta-analysis of randomized controlled clinical trials of loop diuretic use in human AKI showed a statistically insignificant trend towards an association with increased mortality.13 Some nephrologists have postulated that the ability to respond to diuretics is a marker of less severe renal injury associated with a better prognosis. However, an increase in urine output after diuretic administration does not necessarily preclude the need for renal replacement therapy if severe uremia or acid-base and electrolyte abnormalities persist. In veterinary medicine, because renal replacement therapy is not readily available, diuretic administration plays a primary role in volume management. Conversion from an oliguric or anuric state to normal urine production or polyuria may enhance the clinician’s ability to prevent or manage fluid overload and thus allow administration of necessary parenteral medications and nutrition that would otherwise contribute to fluid overload, (see Chapter 160).

Acid-Base and Electrolyte Balance Metabolic acidosis is a frequent complication in AKI of varying severities. When tubular function is compromised, the ability to reabsorb bicarbonate and excrete hydrogen ions is diminished. Lactic acidosis secondary to compromised tissue perfusion (i.e., either volume deficit or excess) also may contribute. Treatment is directed at restoring perfusion and provision of supplemental alkali, usually

CHAPTER 124  •  Acute Kidney Injury

in the form of parenteral sodium bicarbonate. Hydrogen ions combine with the bicarbonate to form carbonic acid, which quickly dissociates to water and carbon dioxide, the latter of which is removed via gas exchange in the lungs. If the patient is hypoventilating, carbon dioxide accumulates. Bicarbonate administration in this situation can increase the partial pressure of carbon dioxide and can lead to paradoxical CNS acidosis. This phenomenon is due to the ability of carbon dioxide to diffuse across the blood-brain barrier, whereas the charged bicarbonate molecule diffuses across this barrier less readily. An additional consideration when administering parenteral sodium bicarbonate is that most formulations have high osmolality (e.g., 8.4% solution = 1 mEq/ml = 2000 mOsm/L). Therefore this solution must be diluted before administration, and the total volume administered must be factored into the fluid therapy plan. Sodium bicarbonate therapy usually is reserved for patients with a pH less than 7.2 or bicarbonate level less than 12 mEq/L. The bicarbonate dosage can be calculated from the formula

0.3 × body weight (kg) × base deficit = bicarbonate (mEq / L) where the base deficit = 24 mEq/L - patient bicarbonate concentration. One fourth to one third of the dose should be given intravenously as a slow bolus, and an additional one fourth over the next 4 to 6 hours. Subsequent doses should be based on serial venous blood gas analyses. Provision of bicarbonate with renal replacement therapy is as effective in restoring extracellular acid-base status as sodium bicarbonate infusion and has the added advantage of avoiding the fluid load necessary with the latter treatment. Although no evidence in the form of randomized controlled trials supports supplementation of alkali in human AKI,14 it is recommended in veterinary AKI when renal replacement therapy is not available. Hyperkalemia can be an immediately life-threatening complication of AKI and is secondary to a decline in excretory function. The increase in extracellular potassium concentration makes excitable cells refractory to repolarization, thus resulting in decreased conduction of cardiac and neuromuscular tissue. Typical electrocardiographic changes include bradycardia, tall T waves, shortened QT intervals, wide QRS complexes, and small, wide, or absent P waves. Severe hyperkalemia can lead to sine waves, ventricular fibrillation, or standstill. A variety of pharmacologic treatments are available for emergent hyperkalemia (see Chapter 51), but these therapies act to translocate potassium to the intracellular space or increase the resting membrane potential to allow repolarization of excitable cells, rather than enhance excretion of potassium. Therefore the efficacy of these treatments is modest and transient. Only provision of renal replacement therapy or restoration of native renal excretory function can reduce significantly the potassium burden in fulminant AKI. Although ionized hypocalcemia occurs frequently in AKI, clinical signs (e.g., tetany) associated with this problem are rare. When manifestations of hypocalcemia do occur, the minimum dose of supplemental calcium that controls clinical signs should be used to prevent precipitation with phosphorus. Calcium gluconate 10% can be used at a dosage of 0.5 to 1.5 ml/kg IV over 20 to 30 minutes. As with the treatment of hyperkalemia, the electrocardiogram should be monitored closely during infusion.

Management of Gastrointestinal Signs Antiemetic therapy is recommended in all patients with severe AKI, regardless of whether they are vomiting (see Chapter 162). Metoclopramide is used frequently for this purpose, but reduced clearance associated with compromised renal function and resultant adverse effects (primarily neurologic) must be considered. Metoclopramide was found to be inferior to the 5-HT3 antagonist, ondansetron, in prevention of vomiting and nausea in uremic human patients.15 In

addition, in a study of vomiting dogs with presumably normal renal function, metoclopramide was less efficacious than maropitant in preventing emesis.16 The use of antisecretory drugs (e.g., histamine2-receptor antagonists, proton pump inhibitors; see Chapter 161) historically has been recommended for patients with AKI. Although uremic gastritis and stress-related mucosal disease is a concern in human AKI patients, gastric acid output and intragastric pH are not compatible with a hypersecretory state.17 Nonetheless, because of the high incidence of hemorrhage from the gastrointestinal tract in human AKI patients (presumably related to a combination of uremic injury and stress-related mucosal disease) and its association with mortality,18 antisecretory drugs should be considered in high-risk patients. A recent meta-analysis showed superiority of proton pump inhibitors versus histamine-2 receptor antagonists in the prevention of stress related mucosal bleeding.19 These results, in combination with the potential for accumulation of histamine-2 receptor antagonists in patients with diminished renal function favor the use of proton pump inhibitors.

Nutritional Support Nutritional support for AKI has been shown to improve nitrogen balance and thus survival in oliguric or anuric humans.20 Similar results for nitrogen balance (but not survival) have been shown for patients with preserved urine production.21 Enteral feeding is the preferred method of nutrient delivery but often is limited by vomiting and ileus. For those patients that are not vomiting, esophageal, gastric, and jejunal feeding devices can be used. If vomiting cannot be controlled, partial or total parenteral nutrition should be considered. In patients who are anuric or oliguric, the volume and osmolality of nutritional product, whether administered enterally or parenterally, must be taken into consideration and may constitute a relative contraindication unless there is a method of excess fluid and solute removal (e.g., renal replacement therapy). Phosphate binders (e.g., aluminum hydroxide) administered concurrently with enteral feedings may decrease phosphate absorption. However, the benefits of phosphate control in regard to outcome in AKI have not been determined.

Renal replacement therapy Renal replacement therapy (see Chapter 205) is the most efficient means of managing uremic, acid-base, electrolyte, and fluid-related sequelae of AKI. In fulminant cases, available pharmacologic therapies are, at best, incompletely effective at reversing the aforementioned complications, and their effects are transient. However, the cost and limited availability of renal replacement therapy make it impractical for most owners and veterinarians.

Fluid administration during recovery phase polyuria During renal recovery, the patient may convert from oliguria or anuria to a polyuric state. This phenomenon may occur with any cause of AKI, but most commonly occurs in cases of leptospirosis or obstructive disease. Careful monitoring of urine volume, body weight, and surrogate markers of perfusion is necessary to guide fluid administration and avoid fluid depletion. Intravenous fluids often are administered at sustained delivery rates higher on a per-weight basis than any other situation in veterinary medicine. Once the patient’s azotemia and body weight are stable on a fixed delivery rate of intravenous fluids, the rate can be decreased by 10% per day. If the urine output diminishes by a corresponding degree and the patient’s weight and surrogate markers of perfusion remain stable, tapering of the intravenous fluid rate should continue. Recovery phase polyuria can last for weeks, until tubular function returns to a level sufficient to control solute and water losses.

659

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PART XIII  •  UROGENITAL DISORDERS

Specific Treatments In many cases of AKI, the exact cause is not determined, and therapy is aimed at controlling the sequelae of uremia, as well as acid-base, electrolyte, and fluid-related disorders. However, some causes of AKI have specific treatments. Penicillin G or ampicillin (22 mg/kg q8h) is the antibiotic of choice for leptospiremia, although doxycycline is also effective in the leptospiremic phase. The carrier state can be eliminated using doxycycline (5 mg/kg q12h for 2 weeks). Intervention by surgical or endoscopy-guided stent placement is indicated for obstruction of the upper (and less frequently, lower) urinary tract, although ureteral obstructions can resolve spontaneously. Few antidotes are available for nephrotoxic injuries. Antidotes for ethylene glycol (4-methylpyrazole [4-MP, Antizol-Vet] or alcohol) must be administered shortly after ingestion to be effective.

PROGNOSIS The overall mortality rate for AKI in dogs is approximately 60%.22 In the dogs that survive, approximately 60% have chronic kidney disease, and only 40% recover normal renal function.22 In cats, mortality is approximately 40% to 50%, with approximately 50% of survivors left with chronic kidney disease.23 Certain subsets of patients have better prognoses. Approximately 82% to 86% of dogs with leptospirosis survived in one series.24 Patients with polyuria have a better outcome than those with oliguria or anuria.23,25

REFERENCES 1. Bellomo R, Ronco C, Kellum JA, et al: Acute renal failure—definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group, Crit Care 8:R204-212, 2004. 2. Mehta RL, Kellum JA, Shah SV, et al: Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury, Crit Care 11:R31, 2007. 3. Thoen ME, Kerl ME: Characterization of acute kidney injury in hospitalized dogs and evaluation of a veterinary acute kidney injury staging system, J Vet Emerg Crit Care (San Antonio) 2011;21:648-657. 4. Langston CE: Acute uremia. In Ettinger SJ, Feldman EC, editors: Textbook of veterinary internal medicine, St Louis, 2010, Saunders. 5. Wen JG, Frokiaer J, Jorgensen TM, et al: Obstructive nephropathy: an update of the experimental research, Urol Res 27:29-39, 1999. 6. Holloway A, O’Brien R: Perirenal effusion in dogs and cats with acute renal failure, Vet Radiol Ultrasound 48:574-579, 2007. 7. D’Anjou MA, Bedard A, Dunn ME: Clinical significance of renal pelvic dilatation on ultrasound in dogs and cats, Vet Radiol Ultrasound 52:8894, 2011. 8. Miller MD, Annis KM, Lappin MR, et al: Variability in results of the microscopic agglutination test in dogs with clinical leptospirosis and dogs vaccinated against leptospirosis, J Vet Intern Med 25:426-432, 2011.

9. Myburgh J, Cooper DJ, Finfer S, et al: Saline or albumin for fluid resuscitation in patients with traumatic brain injury, N Engl J Med 357:874-884, 2007. 10. Myburgh JA, Finfer S, Bellomo R, et al: Hydroxyethyl starch or saline for fluid resuscitation in intensive care, N Engl J Med 367(20):1901-1911, 2012. 11. Bouchard J, Soroko SB, Chertow GM, et al: Fluid accumulation, survival and recovery of kidney function in critically ill patients with acute kidney injury, Kidney Int 76:422-427, 2009. 12. Sutherland SM, Zappitelli M, Alexander SR, et al: Fluid overload and mortality in children receiving continuous renal replacement therapy: the prospective pediatric continuous renal replacement therapy registry, Am J Kidney Dis 55:316-325, 2010. 13. Bagshaw SM, Delaney A, Haase M, et al: Loop diuretics in the management of acute renal failure: a systematic review and meta-analysis, Crit Care Resusc 9:60-68, 2007. 14. Hewitt J, Uniacke M, Hansi NK, et al: Sodium bicarbonate supplements for treating acute kidney injury, Coch Database Syst Rev 6:CD009204, 2012. 15. Ljutic D, Perkovic D, Rumboldt Z, et al: Comparison of ondansetron with metoclopramide in the symptomatic relief of uremia-induced nausea and vomiting, Kidney Blood Press Res 25:61-64, 2002. 16. de la Puente-Redondo VA, Siedek EM, Benchaoui HA, et al: The antiemetic efficacy of maropitant (Cerenia) in the treatment of ongoing emesis caused by a wide range of underlying clinical aetiologies in canine patients in Europe, J Small Anim Pract 48:93-98, 2007. 17. Wesdorp RI, Falcao HA, Banks PB, et al: Gastrin and gastric acid secretion in renal failure, Am J Surg 141:334-338, 1981. 18. Fiaccadori E, Maggiore U, Clima B, et al: Incidence, risk factors, and prognosis of gastrointestinal hemorrhage complicating acute renal failure, Kidney Int 59:1510-1519, 2001. 19. Barkun AN, Bardou M, Pham CQ, et al: Proton pump inhibitors vs. histamine 2 receptor antagonists for stress-related mucosal bleeding prophylaxis in critically ill patients: a meta-analysis, Am J Gastroenterol 107:507-520, 2012. 20. Scheinkestel CD, Kar L, Marshall K, et al: Prospective randomized trial to assess caloric and protein needs of critically Ill, anuric, ventilated patients requiring continuous renal replacement therapy, Nutrition 19:909-916, 2003. 21. Singer P: High-dose amino acid infusion preserves diuresis and improves nitrogen balance in non-oliguric acute renal failure, Wien Klin Wochenschr 119:218-222, 2007. 22. Vaden SL, Levine J, Breitschwerdt EB: A retrospective case-control of acute renal failure in 99 dogs, J Vet Intern Med 11:58-64, 1997. 23. Worwag S, Langston CE: Acute intrinsic renal failure in cats: 32 cases (1997-2004), J Am Vet Med Assoc 232:728-732, 2008. 24. Adin CA, Cowgill LD: Treatment and outcome of dogs with leptospirosis: 36 cases (1990-1998), J Am Vet Med Assoc 216:371-375, 2000. 25. Behrend EN, Grauer GF, Mani I, et al: Hospital-acquired acute renal failure in dogs: 29 cases (1983-1992), J Am Vet Med Assoc 208:537-541, 1996.

CHAPTER 125  CHRONIC KIDNEY DISEASE Catherine E. Langston,

DVM, DACVIM  •  Adam

E. Eatroff,

KEY POINTS • Chronic kidney disease (CKD) has a high prevalence in geriatric cats and dogs but also occurs in juvenile animals. • Although inciting and perpetuating causes of chronic kidney disease should be investigated, the underlying cause rarely is identified. • Intravenous and subcutaneous fluid therapy should be directed toward the restoration and maintenance, respectively, of normal hydration status. Many cats require large volumes of parenteral fluid to achieve these goals. • Early initiation of enteral nutritional support and treatment with erythropoiesis stimulating agents should be considered in cases of decompensated, end-stage chronic kidney disease. • Clients should be counseled on the progressive and irreversible course of chronic kidney disease.

In recent years the veterinary community has supplanted the term chronic renal failure, which was used previously to describe the multitude of chronic nephropathies that affect cats and dogs, with a new designation, chronic kidney disease. The word failure, which may imply end-stage disease, was eschewed for the more inclusive description, disease, with the intent of emphasizing the broad spectrum of clinically relevant disease that may be present in various types of chronic nephropathies. This paradigm shift was reflected by the fourstage classification system proposed by the International Renal Interest Society (IRIS), which includes two stages of disease severity defined by plasma or serum creatinine concentrations within the normal range of many reference laboratories.1 This classification scheme is depicted in Table 125-1. Despite the growing appreciation for the long-term metabolic and clinical sequelae that may arise from less severe, possibly even biochemically undetectable, ongoing injury, the objective of this chapter is to address the clinical aspects of decompensated or end-stage chronic kidney disease (CKD).

ETIOLOGY In cats and dogs, the underlying cause of CKD rarely is determined. Histopathologic renal lesions consist primarily of inflammatory infiltrates in the tubulointerstitium, in the glomeruli, or in both nephron subunits simultaneously. Concurrent fibrosis is almost always present to varying degrees. Additional findings include tubular atrophy and glomerular sclerosis or senescence. The typical location and specific characteristics of the histopathologic lesions vary with species. In cats, lymphoplasmacytic tubulointerstitial nephritis and fibrosis is the most common morphologic diagnosis, noted in 70.4% of cases in one study.2 In dogs, glomerular lesions appear more commonly, with estimates as high as 52% in one study.3 Another study identified interstitial nephritis as the most common lesion (58.3%).2 It is hypothesized that, in many cases, these lesions are not due to any specific underlying cause but are more likely the final point in a

DVM, DACVIM

pathway common to a variety of renal insults. However, for many congenital forms of CKD (of genetic and other origins), the inciting and ongoing insult is known. These diseases include renal dysplasia, polycystic kidney disease, and amyloidosis (Box 125-1).4 Additional discernible, inciting, and perpetuating causes of CKD include pyelonephritis, nephrolithiasis or ureterolithiasis, infarctions, lymphoma, glomerulonephritis, and incomplete resolution of acute renal failure.

PATHOPHYSIOLOGY CKD progression is speculated to be the result of an ongoing insult or secondary to compensatory changes of surviving nephrons that may be maladaptive in the long-term. Ongoing injury may manifest in the glomerulus, tubulointerstitium, or in both nephron subunits. However, because each nephron operates as a unit, if the glomerulus is damaged irreversibly, the associated tubule degenerates, and vice versa. As functional renal mass is lost, the remaining nephrons hypertrophy. Although initially adaptive, glomerular hyperfiltration damages the surviving nephrons. After a certain amount of damage

Table 125-1  International Renal Interest Society Staging Scheme for Chronic Kidney Disease1 Dogs

Cats

Plasma Creatinine (mg/dl) Stage I 5.0

5.0

Substage Based on Urine Nonproteinuric (NP) Borderline proteinuric (BP) Proteinuric (P)

>0.4

Protein-to-Creatinine Ratio 140 mm Hg) is present. If evidence of the central nervous system ischemic response is present, therapy directed toward lowering ICP should be instituted. Alternatively, hypertension associated with tachycardia suggests pain or anxiety, which should be treated as indicated. Monitoring of the respiratory system focuses on maintenance of oxygenation and ventilation. Oxygenation can be assessed via pulse oximetry, with a goal of maintaining saturation above 94%. When arterial sampling is possible, oxygen tension should be maintained above 80 mm Hg. If oxygenation cannot be monitored, oxygen supplementation should be provided. Failure to maintain oxygenation above these levels may warrant intubation and positive pressure ventilation (see Chapter 30). Ventilation can be assessed by blood gas analysis or end-tidal capnometry (see Chapter 186). Although arterial blood gas sampling is the gold standard for assessing carbon dioxide tension, a venous blood gas can be substituted if tissue perfusion is normal. Venous carbon dioxide concentrations will exceed arterial by 2 to 5 mm Hg; however, this difference is exacerbated with poor tissue perfusion. End-tidal capnometry tends to underestimate arterial carbon dioxide tension by 5 mm Hg, and changes in cardiac output can significantly alter the value obtained. Radiographs of the skull in patients that have sustained head trauma are an insensitive diagnostic tool and rarely provide valuable information. Computed tomography (CT) is the preferred imaging method. CT scans are superior to magnetic resonance imaging (MRI) for assessing bone and areas of acute hemorrhage or edema. As the time from injury increases, or when subtle neurologic deficits are present, MRI becomes a more useful tool.12 Advanced imaging provides information about mass lesions (epidural, subdural, or intraparenchymal hemorrhage) or depressed skull fractures that may require surgical intervention. Such studies should be considered in patients with moderate to severe neurologic abnormalities on presentation, lateralizing signs, failure to improve significantly within the first few days, or those with an acute deterioration in neurologic status.

TREATMENT When formulating a treatment plan for a patient with TBI, both intracranial and extracranial concerns must be addressed. Extracranial priorities include ventilation, oxygenation, and maintenance of normal blood pressure, and intracranial priorities include treatment of intracranial hypertension and control of cerebral metabolic rate.

Extracranial Therapy The first priority in treating a patient with head trauma is extracranial stabilization. As with any severely injured patient, the basics of airway, breathing, and circulation should be evaluated and addressed if necessary. Patency of the airway should be assessed as soon as possible and treated with endotracheal intubation or emergency tracheostomy, if indicated. The pharynx and larynx should be inspected visually and suctioned as needed to maintain airway patency. Hypoxia is also common, and supplemental oxygen is indicated in the initial treatment of all patients with significant head injury. Increases in the blood CO2 concentration can lead to cerebral vasodilation and increased intracranial blood volume, worsening ICP (see Secondary Injury section). Conversely, hypocapnia caused by hyperventilation

can lead to cerebral vasoconstriction, decreasing cerebral blood flow and leading to cerebral ischemia. Therefore CO2 should be maintained at the low end of the normal range in patients with head trauma (e.g., venous CO2 40 to 45 mm Hg, arterial CO2 35 to 40 mm Hg).13 In some patients this will require mechanical ventilation (see Chapter 30). Patients with head trauma commonly present in hypovolemic shock, and volume resuscitation goals should be aggressive (MAP of 80 to 100 mm Hg; see Chapter 60). For patients without electrolyte disturbances, normal saline (0.9%) is the best initial choice for fluid resuscitation because it contains the smallest amount of free water (sodium concentration 154 mEq/L) of the isotonic fluids and is therefore least likely to contribute to cerebral edema. Synthetic colloid resuscitation may also prove beneficial. For hydrated patients with evidence of hypovolemia and increased ICP, a combination colloid and hyperosmotic (hypertonic saline) solution is recommended (see Intracranial Therapy later in this chapter and Table 137-2). Patients that do not respond to volume resuscitation require vasopressor support (see Chapter 157).

Intracranial Therapy Hyperosmotic agents Mannitol has been shown to decrease ICP, increase CPP and CBF, and have a beneficial effect on neurologic outcome in patients with head injury.14 Mannitol may also possess free radical scavenging properties. Its positive effects can be seen clinically within minutes of administration, most likely a result of its rheologic its effects (decreased blood viscosity) causing an increase in CBF and cerebral oxygen delivery. Within 15 to 30 minutes, its osmotic effects predominate, drawing water out of the brain parenchyma (primarily normal tissue) and into the intravascular space. These effects can last from 1.5 to 6 hours. In humans, mannitol may induce acute renal failure if serum osmolarity exceeds 320  mOsm/L, suggesting that serial measurement of serum osmolality may be useful in patients receiving repeated doses.15 Mannitol may cause increased permeability of the blood-brain barrier, allowing it to leak into the brain parenchyma where it can exacerbate edema. Because this effect is most pronounced when mannitol remains in the circulation for long periods, the drug should be administered as repeated boluses rather than as a constant rate infusion.14 Mannitol boluses of 0.5 to 1.5  g/kg have been recommended for the treatment of increased ICP in dogs and cats.16 Treatment must be followed with isotonic crystalloid or colloid solutions, or both, to maintain intravascular volume. Hypertonic saline is an alternative hyperosmotic solution that may have advantages over mannitol in some patients with head injury. Because sodium does not freely cross the blood-brain barrier, hypertonic saline has similar rheologic and osmotic effects to mannitol. In addition, it improves hemodynamic status and has beneficial vasoregulatory and immunomodulatory effects.17 Because sodium is redistributed within the body and reabsorbed in the kidneys, hypotension is a less likely sequela than with mannitol, making it a better choice for patients with increased ICP and systemic hypotension. Hypertonic saline can be administered with a colloid in such cases to allow for a more prolonged volume expansion effect (see Table 137-2).

Corticosteroids Corticosteroids are potent antiinflammatory agents and have historically been used extensively in human and veterinary medicine to treat patients that have sustained head trauma. A clinical trial evaluating more than 10,000 human adults with head injury showed that corticosteroid treatment was associated with worse outcomes at 2 weeks and 6 months after injury.18,19 The Brain Trauma Foundation

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PART XVI  •  TRAUMA

Table 137-2  Drugs, Fluids, and Dosages for the Treatment of Patients with Head Trauma Indication

Drug or Fluid

Dosage

Notes

Any patient with evidence of head trauma and hypotension

Isotonic crystalloid solution (0.9% saline preferred)

Administer boluses of one fourth to one third of the shock dose (shock dose 90 ml/kg for dogs, 50 ml/kg for cats)

May repeat as needed Consider colloid boluses if no response after 2 to 3 crystalloid boluses

Increased ICP in normotensive or hypertensive patients

Mannitol 25%

0.5 to 1.0 g/kg IV over 15 minutes May repeat

Use filter during administration; can lead to severe dehydration; follow with isotonic crystalloids or synthetic colloids to prevent dehydration and hypovolemia Closely monitor intake and output

Increased ICP in hypovolemic or hypotensive patients

HTS (7%)* plus hydroxyethyl starch

3 to 5 ml/kg IV over 15 minutes May repeat

Do not use in hyponatremic patients Monitor serum sodium levels

Increased ICP in normotensive, hypertensive, or hypotensive patients

HTS (7% to 7.8%)†

3 to 5 ml/kg IV over 15 minutes May repeat

Do not use in hyponatremic patients Monitor serum sodium levels

Seizures

Diazepam

0.5 mg/kg IV May repeat Consider CRI 0.2-1.0 mg/kg/hr if refractory 20 mg/kg IV

Monitor ventilation, may lead to profound sedation and hypoventilation Protect from light May repeat as needed; very low toxicity potential Minimal sedation or ventilatory side effects

Levetiracetam

HTS, Hypertonic saline; ICR, intracranial pressure; IV, intravenous. *If using 23.4% HTS, dilute 1 part HTS with 2 parts sterile water. † If using 23.4% HTS, dilute 1 part HTS with 2 parts hydroxyethyl starch. If using 7% to 7.5% HTS, administer separate doses of HTS and colloid (3 to 5 ml/kg HTS, 2 to 3 ml/kg artificial colloid).

recommends against corticosteroid administration in patients with TBI.13

Furosemide Furosemide has been used in patients with head trauma either as a sole agent to reduce cerebral edema or in combination with mannitol to decrease the initial increase in intravascular volume and hydrostatic pressure associated with the drug. However, the use of this drug as a sole agent in patients with head trauma has been called into question because of the potential for intravascular volume depletion and systemic hypotension, leading to decreased CPP.20 The Brain Trauma Foundation guidelines do not recommend the administration of furosemide in combination with mannitol.14 Therefore it should be reserved for those patients in whom it is indicated for reasons other than cerebral edema, such as those with pulmonary edema or oligoanuric renal failure.

Decreasing cerebral blood volume Techniques to decrease cerebral blood volume (CBV) have been proposed as methods for lowering increased ICP. Elevation of the head by 15 to 30 degrees reduces CBV by increasing venous drainage, decreasing ICP, and increasing CPP without deleterious changes in cerebral oxygenation.21 A slant board should be used instead of pillows or towels to prevent occlusion of the jugular veins by bending of the neck. Higher elevations of the head may cause a detrimental decrease in CPP. Prevention of hypoventilation, as described earlier, can reduce cerebral vasodilation and decrease CBV; the goal should be normocapnia (arterial carbon dioxide of 35 to 40 mm Hg). In animals with acute intracranial hypertension, short-term hyperventilation to an arterial carbon dioxide of 25 to 35 mm Hg may be used to reduce CBV and ICP, but long-term hyperventilation is not recommended based on evidence that the decrease in CBF leads to cerebral ischemia and worsens outcome.14

Seizure treatment/prophylaxis Post-TBI seizures are common in people, occurring within 3 years in 4.4% of patients with mild TBI, 7.6% of patients with moderate TBI, and 13.6% of patients with severe TBI in one recent study.22 Recent veterinary studies have documented a similar phenomenon, with seizure rates of 6.8% in dogs and 0% in cats (although the 95% confidence interval was 0% to 5.6%).23,24 Unfortunately, prophylactic anticonvulsant therapy has not been shown to reduce development of delayed seizures after TBI in people.25 However, aggressive treatment of seizures while animals are hospitalized is recommended. Suggested anticonvulsant drugs and doses are listed in Table 137-2 (further details can be found in Chapter 166).

Decreasing cerebral metabolic rate Increased cerebral metabolic rate because of excitotoxicity and inflammation after head injury can lead to cerebral ischemia and cellular swelling, thus increasing ICP. Interventions that decrease cerebral metabolic rate may lessen secondary brain injury. Although rarely used in veterinary medicine, induction of a barbiturate coma and therapeutic hypothermia have been used in experimental studies and clinical trials in humans and can be effective in decreasing ICP and improving outcome in patients with refractory intracranial hypertension.26 There is a single case report in the veterinary literature of successful use of therapeutic hypothermia to treat refractory seizures in a dog after TBI.27 The Brain Trauma Foundation states that there is insufficient evidence to publish treatment standards on the use of barbiturates, but this therapy may be considered in patients with elevated ICP that is refractory to medical and surgical therapy.14 A recent systematic review concluded that mild to moderate therapeutic hypothermia for 48 hours after injury is beneficial in human patients with severe TBI28; further study evaluating the efficacy and practicality of these measures in veterinary medicine is needed.

CHAPTER 137  •  Traumatic Brain Injury

PROGNOSIS The prognosis is difficult to predict after TBI. Although the initial neurologic status may be helpful in predicting outcome, reassessment after stabilizing therapy is recommended because the level of consciousness may improve once tissue perfusion has been corrected. Pupillary dilation, loss of pupillary light responses, and deterioration in the level of consciousness during therapy are poor prognostic indicators (see Table 137-1). It is likely that younger animals, particularly kittens, can make remarkable recoveries despite severe dysfunction immediately after trauma, although definitive research is lacking. Owners should be aware that animals that survive severe TBI may have persistent neurologic deficits for an indefinite period. These animals can also develop delayed seizure disorders. The Small Animal Coma Scale was developed to quantitatively assess functional impact of brain injury (see Chapter 81). This scale assesses three major categories: motor activity, level of consciousness, and brainstem reflexes. Although this scale has not been validated prospectively in animals, it has been shown retrospectively to correlate with 48-hour outcome in dogs with head trauma.6 This may be most useful when evaluated serially in patients to determine if there has been improvement or deterioration after treatment. In human medicine, hyperglycemia at admission and persistence of hyperglycemia have been associated with worsened mortality and outcome.29 In a meta-analysis of the utility of admission laboratory parameters as prognostic indicators for people with TBI, increasing glucose concentrations and decreasing hemoglobin concentrations were the strongest with poor neurologic outcome.30 Hyperglycemia has been associated with more severe injury in head-injured veterinary patients3 but has not been validated as an independent predictor of outcome.

REFERENCES 1. Kolata RJ: Trauma in dogs and cats: an overview, Vet Clin North Am Small Anim Pract 10(3):515, 1980. 2. Shores A: Craniocerebral trauma. In Kirk RW, ed: Current Veterinary Therapy X, Philadelphia, 1989, WB Saunders, pp 847-854. 3. Syring RS, Otto CM, Drobatz KJ: Hyperglycemia in dogs and cats with head trauma: 122 cases (1997-1999), J Am Vet Med Assoc 218(7):1124, 2001. 4. Dewey C, Budsberg S, Oliver J: Principles of head trauma management in dogs and cats. Part II, Compend Contin Educ Pract Vet 15(2):177, 1993. 5. Dewey C, Downs M, Aron D, et al: Acute traumatic intracranial haemorrhage in dogs and cats, Vet Comp Ortho Trauma 6:153, 1993. 6. Platt SR, Radaelli ST, McDonnell JJ: Computed tomography after mild head trauma in dogs, Vet Rec 151(8):243, 2002. 7. Chesnut RM: The management of severe traumatic brain injury, Emerg Med Clin North Am 15(3):581, 1997. 8. Zink BJ: Traumatic brain injury, Emerg Med Clin North Am 14(1):115, 1996. 9. Dietrich WD, Chatzipanteli K, Vitarbo E, et al: The role of inflammatory processes in the pathophysiology and treatment of brain and spinal cord trauma, Acta Neurochir Suppl 89:69, 2004.

10. Platt SR, Radaelli ST, McDonnell JJ: The prognostic value of the modified Glasgow Coma Scale in head trauma in dogs, J Vet Intern Med 15:581, 2001 11. Chesnut RM, Marshall LF, Klauber MR, et al: The role of secondary brain injury in determining outcome from severe head injury, J Trauma 34(2):216, 1993. 12. Lee B, Newberg A: Neuroimaging in traumatic brain imaging, NeuroRx 2(2):372, 2005. 13. Winter CD, Adamides AA, Lewis PM, et al: A review of the current management of severe traumatic brain injury, Surgeon 3(5):329, 2005. 14. Brain Trauma Foundation: Management and prognosis of severe traumatic brain injury, New York, 2000, Brain Trauma Foundation. 15. Dorman HR, Sondheimer JH, Cadnapaphornchai P: Mannitol-induced acute renal failure, Medicine (Baltimore) 69(3):153, 1990. 16. Plumb D: Plumb’s veterinary drug handbook, ed 7, Oxford, UK, 2011, Wiley-Blackwell. 17. Ware ML, Nemani VM, Meeker M, et al: Effects of 23.4% sodium chloride solution in reducing intracranial pressure in patients with traumatic brain injury: a preliminary study, Neurosurgery 57(4):727; discussion 727-736, 2005. 18. Edwards P, Arango M, Balica L, et al: Final results of MRC CRASH, a randomised placebo-controlled trial of intravenous corticosteroid in adults with head injury-outcomes at 6 months, Lancet 365(9475):1957, 2005. 19. Roberts I, Yates D, Sandercock P, et al: Effect of intravenous corticosteroids on death within 14 days in 10008 adults with clinically significant head injury (MRC CRASH trial): randomised placebo-controlled trial, Lancet 364(9442):1321, 2005. 20. Chesnut RM, Gautille T, Blunt BA, et al: Neurogenic hypotension in patients with severe head injuries, J Trauma 44(6):958; discussion 963964, 1998. 21. Ng I, Lim J, Wong HB: Effects of head posture on cerebral hemodynamics: its influences on intracranial pressure, cerebral perfusion pressure, and cerebral oxygenation, Neurosurgery 54(3):593; discussion 598, 2004. 22. Ferguson PL, Smith GM, Wannamaker BB, et al: A population-based study of risk of epilepsy after hospitalization for traumatic brain injury, Epilepsia 51(5):891, 2010. 23. Friedenberg SG, Butler AL, Wei L, et al: Seizures following head trauma in dogs: 259 cases (1999-2009), J Am Vet Med Assoc 241(11):1479, 2012. 24. Grohmann KS, Schmidt MJ, Moritz A, et al: Prevalence of seizures in cats after head trauma, J Am Vet Med Assoc 241(11):1467, 2012. 25. Temkin NR: Preventing and treating posttraumatic seizures: the human experience, Epilepsia 50 Suppl:210, 2009. 26. Vincent J-L, Berré J: Primer on medical management of severe brain injury, Crit Care Med 33(6):1392, 2005. 27. Hayes GM: Severe seizures associated with traumatic brain injury managed by controlled hypothermia, pharmacologic coma, and mechanical ventilation in a dog, J Vet Emerg Crit Care (San Antonio) 19(6):629, 2009. 28. Fox JL, Vu EN, Doyle-Waters M, et al: Prophylactic hypothermia for traumatic brain injury: a quantitative systematic review, CJEM 12(4):355, 2010. 29. Lam AM, Winn HR, Cullen BF, et al: Hyperglycemia and neurological outcome in patients with head injury, J Neurosurg 75(4):545, 1991. 30. Van Beek JGM, Mushkudiani NA, Steyerberg EW, et al: Prognostic value of admission laboratory parameters in traumatic brain injury: results from the IMPACT study, J Neurotrauma 24(2):315, 2007.

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CHAPTER 138  THORACIC AND ABDOMINAL TRAUMA William T.N. Culp,

VMD, DACVS  •  Deborah

C. Silverstein,

KEY POINTS • The extent of thoracic and abdominal trauma is often not known at first evaluation, and extensive diagnostics are typically necessary to fully assess the status of a particular patient. • Many different disease states can occur secondary to thoracic and abdominal trauma and the performance of diagnostic testing, particularly fluid analysis, is essential. • While some animals experiencing thoracic and abdominal trauma can be managed conservatively, surgery is often necessary to correct associated problems.

Thoracic and abdominal trauma is common, and the clinical manifestations of these injuries can range widely. Clinicians faced with these cases should be prepared for the potential diagnostic and treatment options that may need to be considered, as well as the variable prognoses that may be altered according to what is found during surgery, if pursued. General categories of trauma affecting the thorax and abdomen include blunt and penetrating trauma. The internal injuries associated with both categories can be similar; however, it is important to make the distinction because further exploration of skin, muscle, and subcutaneous space over these cavities may be necessary. Additionally, more potentially life-threatening injuries (e.g., brain trauma) may be occurring simultaneously, and these need to be addressed immediately.

TRAUMA CATEGORIES Blunt Trauma Motor vehicle accidents, high-rise falls, and intentional physical injuries are often encountered in an emergency setting, and the effect these events may have on the abdomen and thorax of a patient is immense. When blunt trauma to the thorax or abdomen does occur, the severity of the injury often is not recognized immediately while other life-threatening injuries are being assessed and treated. Recently injuries that can occur secondary to blunt trauma were evaluated.1-3 In a study of 235 canine cases of blunt trauma, 91.1% of all blunt trauma cases were secondary to motor vehicular accidents.1 Common chest injuries included pulmonary contusions (58%), pneumothorax (47%), hemothorax (18%), and rib fractures (14%), and common abdominal injuries included hemoperitoneum (23%), abdominal hernias (5%), and urinary tract ruptures (3%).1 A retrospective study of 600 dogs that were struck with a motor vehicle has also been performed. The most common thoracic injuries were pulmonary contusions, pneumothorax, and hemothorax, and nearly 12% of dogs experienced thoracic trauma.4 That study also noted that when skeletal injuries were found in cases of thoracic trauma, 63% of these were cranial to T13.4 Abdominal trauma was noted in 5% of dogs (as diagnosed by surgery or necropsy).4 The liver was the abdominal organ most often damaged (31% of the abdominal organ injuries), with injuries ranging from fissures of the capsule 728

DVM, DACVECC

or parenchyma to fragmentation of a hepatic lobe. Other commonly injured organs included the urinary bladder, diaphragm, and kidney. Of the 33 dogs that died from their injuries, 8 (24%) had abdominal injury alone and 13 (39%) had both abdominal and thoracic injury. High-rise falls in dogs and cats result in abdominal injuries in 15% and 7% of cases, respectively.5,6 Dogs falling from a height of greater than three stories are more likely to experience abdominal injury than those falling less than or equal to three stories. Also, dogs that fall accidentally more often experience abdominal and hind limb injury than dogs that jump from a height. In both dogs and cats, thoracic trauma was diagnosed more commonly than abdominal trauma, perhaps because of the readily apparent respiratory compromise. In a study evaluating high-rise falls in 119 cats, approximately 34% were noted to have thoracic trauma.7 Pneumothorax and pulmonary contusions were regularly diagnosed, being documented in 60% and 40% of cats with thoracic trauma, respectively.7 Additionally, hemothorax was diagnosed in 10% of cats. Although injury to the chest and bones was common, nearly 97% of cats survived the fall. Falls from the seventh story or higher were more likely to result in thoracic trauma.7 Abdominal injuries were uncommon in this cohort of cats, and the authors hypothesized that this was secondary to the forelimbs absorbing the impact of the landing.7 However, a separate study described pancreatic rupture in four cats,8 and treating clinicians should be aware of abdominal trauma that cannot be externally visualized. Unfortunately, human abuse of companion animals is another cause of blunt trauma. In a study investigating intentional injury9 to animals, internal injury to the abdomen was documented less often than superficial injuries or fractures. However, 13 of 217 (6%) dogs in this study experienced rupture of an organ, including spleen, liver, bladder, and kidney. Cats tended to experience abdominal muscle rupture. Kicking of the animal was the cause of the abdominal injury in most cases.

Penetrating Trauma Penetrating trauma most commonly occurs secondary to bite wounds in companion animals; however, reports of missile injuries, impalement/stab injuries, and evisceration exist. Bite wounds can result in both blunt and penetrating trauma. Exploration of superficial wounds is often necessary to fully recognize the organ damage that has occurred.10 The thorax is the body region most likely to experience trauma from a bite wound in dogs; it is second only to the back region in cats.11 Wounds that do not appear to penetrate the thorax or abdomen still often require surgical exploration because bacteria from the biting animal’s mouth or environment will likely contaminate the wound and result in abscess formation. Additionally, it may not always be obvious if a wound has entered a body cavity.11 In one large retrospective study evaluating bite wounds in dogs and cats, mortality only occurred in those cases with intrathoracic or intra-abdominal injury.11

CHAPTER 138  •  Thoracic and Abdominal Trauma 12-14

Gunshot wounds have been reviewed in several animal studies. Of 84 animals reported in one retrospective study,13 32 thoracic and 14 abdominal injuries were encountered. Animals with thoracic injury were managed conservatively in the majority of cases.13 Animals with abdominal injury also tended to have more cardiovascular compromise on arrival than those that did not have abdominal injury. In a separate study of dogs exposed to high-caliber, highvelocity weapons, only 38% survived the gunshot injury.12 The thorax was the most common site of injury in that study with 50% of dogs afflicted with a thoracic wound.12 Other types of penetrating abdominal wounds include stab wounds, impalement injuries (from sticks or other devices), or after a high-rise fall.9,15 Some of these injuries are self-induced, and others are the result of mismanagement. Either way, early intervention is likely required to maximize a good outcome.

DIAGNOSTICS Clinical Laboratory Tests Blood work is essential in all cases of thoracic and abdominal trauma to assess organ status as well as the ability to undergo anesthesia, should it be necessary. The red blood cell, white blood cell, and platelet counts are assessed by the complete blood count. Bleeding often occurs secondary to trauma, and this can be reflected in the red blood cell count; animals may be anemic on presentation depending on the severity of trauma and the amount of time since the traumatic event. Leukocytosis (specifically neutrophilia) can be increased secondary to stress, inflammation, or infection, all of which may occur with trauma. Thrombocytopenia secondary to consumption of platelets with bleeding may also be encountered. A biochemistry panel should be evaluated, with particular attention paid to the liver and renal values as well as the electrolyte and acid-base balance. Alanine aminotransaminase (ALT) and aspartate transaminase (AST) can be increased when liver trauma has occurred. In cases of biliary trauma and subsequent bile leakage, increases in alkaline phosphatase (ALP), γ-glutamyl transferase (GGT), and bilirubin are often present. Abnormalities of electrolytes may be seen secondary to clinical signs such as vomiting or anorexia or because of specific conditions such as uroabdomen. Similarly, azotemia is often noted in animals with a uroabdomen or those suffering from dehydration or acute kidney injury. Measurement of urine specific gravity before fluid therapy may help the clinician assess renal function.

Imaging Chest radiographs are essential for several reasons. When an abdominal trauma has occurred, the chest radiographs may reveal a diaphragmatic rupture or body wall herniation; herniation of organs such as stomach and intestine may be life threatening. Additionally, pneumothorax, pleural effusion, and pulmonary contusions can be detected with chest radiographs. Some injuries to the skin and subcutaneous tissue can be severe enough that a flail chest may not be noted. Chest radiographs often help the clinician to assess for the presence of rib fractures. Abdominal radiographs are useful in the diagnosis of intraabdominal pathologic conditions, but identifying a specific diagnosis may not always be possible. The presence of intra-abdominal gas suggests that abdominal wall penetration or organ perforation has occurred and requires immediate attention. The general loss of serosal detail in the abdomen is suggestive of the presence of fluid in the peritoneal space, retroperitoneal space, or both. Animals with traumatic pancreatitis or very young or thin animals may also have poor serosal detail on radiographs.

Fluid in the peritoneal space may originate from a bleeding organ or ruptured vessel, urine from the distal ureter, bladder or proximal urethral rupture, bile from a rupture in the biliary system, or a septic exudate in cases of septic peritonitis. Fluid in the retroperitoneal space is most commonly urine from damage to the kidney or proximal ureter or blood. Subcutaneous emphysema can be seen when gas accumulates in the subcutaneous spaces, with or without intraabdominal injury (i.e., tracheal or esophageal perforation may also lead to subcutaneous emphysema). Diaphragmatic and body wall ruptures are commonly diagnosed with radiographs.16-18 Both thoracic and abdominal radiographs should be taken in suspected cases of diaphragmatic rupture. Characteristic changes seen on radiographs in animals with a diaphragmatic rupture include loss of continuity of the diaphragm, loss of intrathoracic detail (specifically cardiac silhouette), and the presence of gas-filled bowel loops or a mass effect in the thorax. These changes are not always present, and further imaging may be necessary to confirm the diagnosis. Ultrasonography is useful in specific cases of abdominal trauma. As with radiographs, ultrasonography can diagnose the presence of air or gas in the abdomen (see Chapter 189). One study found that abdominal ultrasound correctly diagnosed a diaphragmatic hernia in 93% of cases.18 A suspected body wall rupture can be definitively diagnosed with an ultrasound examination, and the organs displaced through the rupture may be assessed. An ultrasonographic modality that is now regularly used in veterinary medicine is the focused assessment with sonography for trauma (FAST) technique.19,20 The early description of the FAST technique was for the evaluation of the abdomen and involved quickly assessing four specific areas (just caudal to the xiphoid process, just cranial to the pelvis, and over the right and left flanks caudal to the ribs at the most gravity-dependent location of the abdomen) with two views (transverse and longitudinal).19 This technique was found to be useful at detecting intraabdominal fluid, even when used by veterinarians with minimal ultrasonographic experience.19 A more recent study evaluated the use of a FAST technique for evaluation of thoracic trauma cases (see Chapter 189).21 In this study, the thoracic FAST (TFAST) procedure is described with the patient placed in right lateral or sternal recumbency.21 There are three main views obtained: bilateral chest tube site views, pericardial site views, and a diaphragmatico-hepatic view.21 This study demonstrated that the TFAST has tremendous potential to diagnose pneumothorax as well as pleural and pericardial effusion and to do so in a short period (median time for TFAST was 3 minutes).21 Other imaging modalities employed in animals with abdominal trauma include fluoroscopy and computed tomography (CT) scans. Both are useful in the diagnosis of urinary tract injuries and body wall or diaphragmatic ruptures, and CT scans are commonly used for surgical planning in human patients that have experienced abdominal trauma.22,23

Fluid Analysis When an abdominal effusion is suspected on physical examination, radiographs, or ultrasound, it is important to obtain a sample of the fluid for evaluation. For a detailed description of abdominocentesis, see Chapter 200. Several analyses should be performed on the fluid sample, including hematocrit, total solids, bilirubin, creatinine, potassium, and glucose (see Chapter 122 for further details). Other potential tests may include PaO2, carbon dioxide, lactate, amylase, and lipase. In addition, a slide of the sample should be obtained for cytologic examination. The presence of red blood cells in an abdominal effusion does not necessarily confirm a hemoperitoneum. With a true hemoperitoneum, red blood cells are usually observed within macrophages,

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signifying erythrophagocytosis (although this may not be present in the acute stages).24 Hemosiderin from the broken down red blood cells usually fills the cytoplasm of the involved phagocyte.24 Alternatively, if the packed cell volume (PCV) of the fluid is increasing or nears the PCV found in the peripheral blood, ongoing hemorrhage should be suspected. Another guideline is that the fluid PCV should be at least 10% to 25% of the peripheral blood PCV to be considered a hemorrhagic effusion.24 Using an abdominal FAST technique (described earlier), one study evaluated an abdominal fluid scoring system, or AFS.3 When using the AFS, clinicians were able to determine a semiquantitative measure of free abdominal fluid.3 Additionally, the AFS was associated with severity of injury; dogs with AFS scores of 3 or 4 were more likely to have a significantly lower PCV and total plasma protein as well as increased serum concentrations of ALT.3 The comparison of the concentration of creatinine and potassium in an abdominal effusion has been shown to be a useful indicator of uroperitoneum in both dogs and cats (see Chapters 112 and 122). In cats, mean serum/abdominal fluid creatinine ratio and mean serum/ abdominal potassium ratio have been found to be 1 : 2 and 1 : 1.9, respectively, in cases of uroperitoneum.25 Therefore a cat with a creatinine or potassium concentration in the abdominal effusion that is 2 times or more the peripheral blood likely has a uroperitoneum. In dogs, the sensitivity and specificity were both 100% when using a ratio of greater than 1.4 : 1 in comparing abdominal fluid potassium concentration with peripheral blood potassium concentration for the diagnosis of uroperitoneum. Similarly, using abdominal fluid creatinine concentration (compared with peripheral blood creatinine concentration) was beneficial, in that a ratio of more than 2 : 1 was 86% sensitive and 100% specific in the diagnosis of uroperitoneum.26 A bilirubin concentration in an abdominal effusion greater than twice that of the peripheral blood is diagnostic for bile leakage (see Chapters 112 and 122). This abdominal effusion generally has a yellow-green to brown tint, and bile crystals are occasionally evident upon cytologic examination.24 Biliary effusions can be septic, especially in animals with cholecystitis, and cytologic evaluation may reveal the presence of bacteria.24 Chylothorax/chylous ascites occur uncommonly secondary to trauma, but suspicion is raised when an opaque effusion is noted. Chylous effusions generally have a triglyceride concentration greater than 100 mg/dl and are considered modified transudates.24 Most of the cells obtained in a chylous effusion are mononuclear (lymphocytes); however, the white cell population can change over time because of the associated inflammatory response.24 The importance of abdominal fluid analysis in the diagnosis of septic peritonitis has been well documented. Cytologic examination is especially important in the diagnosis of septic peritonitis, and the presence of intracellular bacteria confirms the diagnosis as long as gastrointestinal aspiration has not occurred.24 The glucose and lactate concentrations of the peritoneal fluid should also be compared with the respective concentrations in the blood.27,28 A detailed description of the importance of these analyses is found in Chapters 112 and 122.

STABILIZATION Monitoring When thoracic trauma is suspected, an electrocardiogram (ECG) should be performed to assess the patient for signs of traumatic myocarditis. Arrhythmias that require treatment are occasionally encountered. Blood pressure monitoring is also very important in all trauma cases. Animals with hemothorax/hemoperitoneum/ hemoretroperitoneum may develop hypotension secondary to hypovolemia, although patients with pyothorax or septic peritonitis are also often hypotensive. A combination of fluid therapy, blood product

administration, and vasopressors may be necessary in severely affected cases.

Antimicrobial Therapy Antimicrobial therapy may be indicated in trauma cases depending on the organ that is traumatized and the extent of injury to the skin, subcutaneous tissue, and muscles. If a penetrating injury has occurred, antimicrobials should be initiated; all wounds should be cultured and broad-spectrum antimicrobials administered pending the results of the susceptibility. For cases of bowel perforation and pyothorax, antimicrobial therapy should be started immediately with broad-spectrum drugs that also have anaerobic coverage (see Antimicrobial Therapy section, Chapters 175 to 182).29

Fluid Therapy/Blood Product Administration In the initial treatment of these patients, it is essential to treat hemorrhagic shock and improve perfusion by administering isotonic crystalloids (up to 50 ml/kg in cats and 90 ml/kg in dogs) or synthetic colloids (5 to 20 ml/kg; see Chapter 60). A recent study evaluated the effectiveness of intravenous fluid resuscitation in an emergency setting.30 In that cohort of dogs, bolus fluid therapy resulted in increased systolic arterial blood pressure in all dogs and patients that demonstrated a normalized blood pressure within the first hour of fluid therapy were more likely to be discharged alive compared with those that remained hypotensive.30 “Hypotensive resuscitation”31,32 to a mean arterial pressure of 60 mm Hg or systolic blood pressure of 90 mm Hg may prevent excessive bleeding or disruption of clot formation and function. Some animals may also require the use of blood transfusions (see Chapter 61) during the resuscitation period (i.e., whole blood, packed red blood cells, and plasma). Animals that are unresponsive to crystalloid and synthetic colloid fluid resuscitation and have evidence of severe hemorrhage should be given fresh whole blood or packed red blood cells and fresh frozen plasma in an attempt to stabilize the clinical signs of shock, maintain the hematocrit above 25%, and sustain the clotting times within the normal range. Packed red blood cells and fresh frozen plasma are administered at a dose of 10 to 15 ml/kg and fresh whole blood at a dose of 20 to 25 ml/kg (a blood type and crossmatch should be performed if possible).

External Wound Care Although the injuries that are present in the thorax and abdomen often require emergency consideration, any entry wounds or wounds away from those cavities (e.g., limbs, neck, head), should also be evaluated closely. Sterile lubricating jelly or sterile bandaging material can be placed in the wound in an attempt to keep the wound clean before clipping and anesthetic preparation. As soon as the patient is stable, fur should be removed from the wound area and the skin surrounding the wound. Any obvious foreign material should be removed and the wounds flushed with sterile saline (see Chapter 139). It is essential that bite wounds be explored for the presence of more severe disease deeper to the externally located punctures. When a dog or cat sustains bite wounds, there is commonly tearing of the underlying tissue and elevation of the skin away from the body wall.14 Drains are usually required to address these wounds because fluid accumulation in these regions is common; when fluid is left to accumulate, abscess formation is more likely to occur.

SPECIFIC CONDITIONS Diaphragmatic Rupture Trauma is the most common cause of diaphragmatic ruptures in small animals.33,34 Therefore a diaphragmatic rupture should be

CHAPTER 138  •  Thoracic and Abdominal Trauma

suspected in any dog or cat with respiratory distress after a traumatic event. Furthermore, other obvious clinical lesions may not be present in 48% of cases of traumatic diaphragmatic ruptures.34 These animals may have signs of shock upon presentation, and early stabilization and oxygen therapy should be initiated (see Chapter 1). After stabilization, surgery is indicated to repair the rupture. If any gastrointestinal organs are displaced into the thoracic cavity or respiratory stability is unachievable, surgery is indicated on an emergency basis (see Chapter 28). The outcome associated with surgical intervention is good, with an approximate 90% perioperative survival rate in dogs and cats treated on an acute or chronic basis.33

Body Wall Rupture/Abdominal Evisceration Rupture of the body wall with subsequent organ exteriorization can occur secondary to trauma. Organ exteriorization from the thoracic cavity is uncommon as the ribs play a protective role for the intrathoracic organs; additionally, intrathoracic organs are anchored, preventing easy dislodgement. Abdominal evisceration can occur when penetrating trauma results in an opening of the abdominal cavity and subsequent herniation of abdominal contents. Cases of abdominal evisceration should be treated as emergencies and surgery pursued as quickly as possible. The injury causing the development of an abdominal rupture will likely also result in additional trauma to the intra-abdominal organs and treatment of myriad injuries may be indicated. A full abdominal exploration should be performed to evaluate all intra-abdominal organs for injury or compromise. In a study of 12 animals (8 dogs and 4 cats) with major abdominal evisceration, 4 were secondary to trauma (2 motor vehicular accidents, 1 bite wound, 1 penetration by glass shard).35 Although all the study animals had exposure of the intestines with gross contamination, there was 100% survival to discharge from the hospital after a thorough surgical exploration was performed.35 The median duration of hospitalization among all dogs was 4 days; however, dogs developing abdominal evisceration secondary to trauma had a significantly longer hospital stay as compared with dogs developing evisceration after postsurgical dehiscence.35 Eighty-six percent to 88% of cases of abdominal body wall rupture in dogs occur secondary to bite wounds or vehicular trauma.16,36 These patients should also be carefully evaluated for bony trauma because fractures may be the source of the rupture. The timing of the stabilization of fractures will depend on the extent of the injury to the thorax and abdomen, and a staged procedure may be required. Body wall ruptures are generally surgical emergencies, especially if caused by bite wounds. Organs can be entrapped in the defect, resulting in strangulation and rapid demise of the patient. Intestines have been reported to be displaced through the rupture in as many as 54% of cases36 and often require a resection and anastomosis because of devitalized tissue. Other organs commonly displaced include the omentum, liver, and urinary bladder.16,36 In one study 73% of dogs and 80% of cats survived to discharge from the hospital after surgical repair of a body wall rupture.16

Chylothorax/Chylous Ascites Chylothorax is characterized by the accumulation of a chylous effusion (consisting of triglycerides and mononuclear cells) in the thorax. Although the cause of chylothorax in the majority of animals is unknown, and therefore labeled as idiopathic, trauma has been documented to cause chylothorax.37,38 Clinical signs of chylothorax are generally nonspecific (e.g., lethargy, weight loss, anorexia) or related to the respiratory system (e.g., coughing, exercise intolerance, respiratory distress). Several treatment options have been developed for the treatment of chylothorax in companion animals, and mixed results have been

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achieved. Most recommendations for treatment include a combination of the following potential surgical options: thoracic duct ligation, pericardectomy, omentalization of the thoracic cavity, and cisterna chyli ablation. Less invasive options (via thoracoscopy and interventional radiology) are developing and early results are promising.39,44,45 Chylous ascites has been documented in both dogs and cats, but a traumatic etiology has not been noted.

Pyothorax Pyothorax, an inflammatory exudate in the pleural cavity, is generally septic. As with most disease affecting the pleural cavity, the clinical signs often associated with pyothorax include respiratory distress and tachypnea46-48; pyrexia is diagnosed in approximately half of animals with a pyothorax.46,47 In a recent study, 4 of 10 animals with pyothorax were suspected to be secondary to trauma.47 It is difficult to determine the inciting cause in many cases of pyothorax, so the true incidence of traumatically induced pyothorax is unknown. Both medical and surgical treatment of pyothorax may be indicated.29,47,48 Medical management often consists of bilateral thoracostomy tube placement, intravenous antimicrobials, and, potentially, intrapleural lavage. In order to determine the origin of a pyothorax and plan the best surgical approach, advanced imaging with CT is recommended.

Septic Peritonitis Gunshot wounds, bite wounds, and vehicular trauma to the abdomen can result in septic peritonitis either from direct contamination with bacteria or leakage from an intra-abdominal organ. In a retrospective canine study evaluating gunshot and bite wounds to the abdomen, peritonitis was noted in 40% of the dogs with gunshot wounds and 14% of the dogs with bite wounds.49 Another study in cats found that 8 of 51 cases of septic peritonitis occurred secondary to trauma (gunshot wounds, bite wounds, and motor vehicle trauma).50 Animals presenting with septic peritonitis often present in shock and have a palpable abdominal effusion. Initial treatment should target the cardiovascular and respiratory systems. Fluid resuscitation and broad-spectrum antimicrobial therapy are essential (see Chapters 60 and 122). When the patient has been stabilized, surgical exploration should be performed and the inciting cause must be found and eliminated. Postoperative management with either open abdominal drainage or primary closure with closed-suction drains should be performed.51 If drains are placed, the amount of effusion produced should be monitored and recorded every 2 to 6 hours. Cytology of the fluid should be checked regularly to monitor for evidence of recurrence of a septic effusion or a secondary infection.

Bile Peritonitis Leakage of bile from the gallbladder or biliary ducts can occur secondary to blunt or penetrating abdominal trauma.52 It is reportedly more common for blunt trauma to result in ductal rupture than gallbladder rupture, usually just distal to the last hepatic duct.52 Bile leakage should be addressed surgically as soon as possible. Bile in the peritoneal cavity can cause severe peritonitis because bile acids are toxic to most living tissues. In addition, many biliary effusions are septic and may prove life threatening (see Chapter 122). Appropriate antimicrobial therapy and supportive care are vital.

Hemothorax/Hemoperitoneum/ Hemoretroperitoneum The diagnosis of a hemorrhagic effusion may prove challenging on physical examination. However, many of these cases will be presented in shock with obvious signs of blood loss and cardiovascular compromise (i.e., mental depression, pale mucous membranes,

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prolonged capillary refill time, poor pulse quality, and tachycardia; see Chapter 5). After initial stabilization, the decision to manage these cases conservatively (medically) or surgically must be made. External counterpressure can be attempted for control of abdominal hemorrhage via the placement of an abdominal bandage; the use of external counterpressure in stabilizing blood pressure and improving survival has been advocated.53 Other conservative management options include internal counterpressure and autotransfusion.54 The decision to perform surgery is case dependent, but if a patient is not responding to fluid resuscitation efforts, has a rising intra-abdominal PCV, or is continuing to effuse based on ultrasonographic evaluation or physical examination, surgery should be performed. In a retrospective study55 evaluating cases of traumatic hemoperitoneum, the spleen, liver, and kidney were bleeding in 58%, 50%, and 23% of cases, respectively (determined during surgery or necropsy). Of the 28 cases evaluated in that study, 9 underwent exploratory laparotomy; 4 cases survived to discharge, 2 died, and 3 were euthanized. Discounting the euthanized cases, the mortality rate for the animals managed surgically was 33% and the mortality rate for the cases managed medically was 25%.55

Uroperitoneum/Uroretroperitoneum After rupture of the urinary tract, urine can accumulate both in the peritoneal space and in the retroperitoneal space, depending on the location of rupture; if trauma to the distal urethra is severe enough, urine can also be noted in the perineal region. Trauma has been found to be the most likely cause of uroperitoneum in cats (85%), with 59% of cases occurring secondary to blunt trauma.25 In both dogs and cats the bladder is the urinary tract organ most likely to be ruptured after blunt trauma.25 Dogs and cats with urine leakage often are presented azotemic, and these cases should be stabilized as much as possible before undergoing anesthesia or pursuing surgery. Additionally, severe electrolyte abnormalities (in particular, hyperkalemia) can cause arrhythmias, further compromising a patient that is already a high anesthetic risk. Characteristic ECG abnormalities noted in cases of hyperkalemia may include tall, tented T waves, absence of P waves, and bradycardia. If not addressed immediately, this can become life threatening. Medical management may include the administration of drugs such as calcium gluconate, insulin/glucose, bicarbonate, or β agonist therapy (see Chapters 51 and 122). Definitive surgical treatment for cases of uroperitoneum secondary to renal or ureteral injury is generally necessary for a successful outcome and may result in an ureteronephrectomy. Bladder ruptures often require surgical correction, although small leaks may heal with the placement of a urinary catheter and collection system for continuous decompression (see Chapter 208). Surgical correction is typically accomplished by placing sutures over the rupture site. Bladder resection may be necessary if the bladder tissue appears severely damaged. Urethral trauma is managed conservatively in some cases by placing a urethral catheter or a cystostomy tube. If conservative management is unsuccessful, surgical closure of the urethral defect is necessary. Postoperative supportive care and intensive monitoring is important in these animals to ensure a positive outcome. Fluid therapy and urine output must be closely monitored and cessation of azotemia is expected if the injury has been properly addressed.

PROGNOSIS The prognosis for animals that sustain blunt trauma can be good if they receive proper and timely medical attention.1 Several factors

have been identified that may negatively affect survival, however, and include corresponding head trauma, cranium fractures, recumbency at admission, hematochezia, suspicion of acute respiratory distress syndrome, disseminated intravascular coagulation, multiorgan dysfunction syndrome, development of pneumonia, positive pressure ventilation, vasopressor use, and cardiopulmonary arrest.1 Further, hypocalcemia has been investigated as a prognostic indicator after trauma.56 Dogs in the study that demonstrated ionized hypocalcemia were significantly more likely to require therapy with oxygen, colloids, blood products, and vasopressors and spent significantly longer in the hospital and intensive care unit than dogs without hypocalcemia. Dogs with ionized hypocalcemia also had a higher mortality rate.56 The animal trauma triage (ATT) scoring system has been created to aid in the assessment of veterinary trauma patients.57 The score is based on an assessment of six categories, including perfusion, cardiac, respiratory, eye/muscle/integument, skeletal, and neurologic status; a score of 0 to 3 is given to each category with 0 indicating slight or no injury and 3 indicating severe injury (highest possible score would be 18).57 In this study, the mean ATT was significantly lower for survivors than nonsurvivors.57 This finding was corroborated in a more recent study evaluating animals involved in motor vehicle accidents.2 Overall, although several factors affect prognosis and the potential conditions that can occur after blunt and penetrating trauma are vast, many dogs and cats can survive if properly treated. Clinical signs may be vague and the true extent of the disease unknown at the time of first evaluation, and clinicians should be cognizant of the potential diagnostic and treatment options available. Aggressive resuscitation may be required, and surgical exploration of the thorax or abdomen is often an important part of treatment.

REFERENCES 1. Simpson SA, Syring R, Otto CM: Severe blunt trauma in dogs: 235 cases (1997-2003), J Vet Emerg Crit Care (San Antonio) 19:588, 2009. 2. Streeter EM, Rozanski EA, Laforcade-Buress A, et al: Evaluation of vehicular trauma in dogs: 239 cases (January-December 2001), J Am Vet Med Assoc 235:405, 2009. 3. Lisciandro GR, Lagutchik MS, Mann KA, et al: Evaluation of an abdominal fluid scoring system determined using abdominal focused assessment with sonography for trauma in 101 dogs with motor vehicle trauma, J Vet Emerg Crit Care (San Antonio) 19:426, 2009. 4. Kolata RJ, Johnston DE: Motor vehicle accidents in urban dogs: a study of 600 cases, J Am Vet Med Assoc 167:938, 1975. 5. Gordon LE, Thacher C, Kapatkin A: High-rise syndrome in dogs: 81 cases (1985-1991), J Am Vet Med Assoc 202:118, 1993. 6. Whitney WO, Mehlhaff CJ: High-rise syndrome in cats, J Am Vet Med Assoc 191:1399, 1987. 7. Vnuk D, Pirkic B, Maticic D, et al: Feline high-rise syndrome: 119 cases (1998-2001), J Feline Med Surg 2004;6:305, 2004. 8. Liehmann LM, Dorner J, Hittmair KM, et al: Pancreatic rupture in four cats with high-rise syndrome, J Feline Med Surg 14:131, 2012. 9. Munro HM, Thrusfield MV: ‘Battered pets’: non-accidental physical injuries found in dogs and cats, J Small Anim Pract 42:279, 2001. 10. Holt DE, Griffin G: Bite wounds in dogs and cats, Vet Clin North Am Small Anim Pract 2000;30:669-679, viii, 2000. 11. Shamir MH, Leisner S, Klement E, et al: Dog bite wounds in dogs and cats: a retrospective study of 196 cases, J Vet Med A Physiol Pathol Clin Med 49:107, 2002. 12. Baker JL, Havas KA, Miller LA, et al: Gunshot wounds in military working dogs in Operation Enduring Freedom and Operation Iraqi Freedom: 29 cases (2003-2009), J Vet Emerg Crit Care (San Antonio) 23:47, 2013. 13. Fullington RJ, Otto CM: Characteristics and management of gunshot wounds in dogs and cats: 84 cases (1986-1995), J Am Vet Med Assoc 210:658, 1997.

CHAPTER 138  •  Thoracic and Abdominal Trauma 14. Risselada M, de Rooster H, Taeymans O, et al: Penetrating injuries in dogs and cats. A study of 16 cases, Vet Comp Orthop Traumatol 21:434, 2008. 15. Pratschke KM, Kirby BM: High rise syndrome with impalement in three cats, J Small Anim Pract 43:261, 2002. 16. Shaw SR, Rozanski EA, Rush JE: Traumatic body wall herniation in 36 dogs and cats, J Am Anim Hosp Assoc 39:35, 2003. 17. Worth AJ, Machon RG: Traumatic diaphragmatic herniation: pathophysiology and management, Compend Contin Educ Vet 27:178, 2005. 18. Spattini G, Rossi F, Vignoli M, et al: Use of ultrasound to diagnose diaphragmatic rupture in dogs and cats, Vet Radiol Ultrasound 44:226, 2003. 19. Boysen SR, Rozanski EA, Tidwell AS, et al: Evaluation of a focused assessment with sonography for trauma protocol to detect free abdominal fluid in dogs involved in motor vehicle accidents, J Am Vet Med Assoc 225:1198, 2004. 20. Lisciandro GR: Abdominal and thoracic focused assessment with sonography for trauma, triage, and monitoring in small animals, J Vet Emerg Crit Care (San Antonio) 21:104, 2011. 21. Lisciandro GR, Lagutchik MS, Kelly KA, et al: Evaluation of a Thoracic Focused Assessment with Sonography for Trauma (TFAST) protocol to detect pneumothorax and concurrent thoracic injury in 145 traumatized dogs, J Vet Emerg Crit Care 18:258, 2008. 22. Akoglu H, Akoglu EU, Evman S, et al: Utility of cervical spinal and abdominal computed tomography in diagnosing occult pneumothorax in patients with blunt trauma: computed tomographic imaging protocol matters, J Trauma Acute Care Surg 73:874, 2012. 23. Chatoorgoon K, Brown RL, Garcia VF, et al: Role of computed tomography and clinical findings in pediatric blunt intestinal injury: a multicenter study, Pediatr Emerg Care 28:1338, 2012. 24. Alleman AR: Abdominal, thoracic, and pericardial effusions, Vet Clin North Am Small Anim Pract 33:89, 2003. 25. Aumann M, Worth LT, Drobatz KJ: Uroperitoneum in cats: 26 cases (1986-1995), J Am Anim Hosp Assoc 34:315, 1998. 26. Schmiedt CW, Tobias KM, Otto CM: Evaluation of abdominal fluid: peripheral blood creatinine and potassium ratios for diagnosis of uroperitoneum in dogs, J Vet Emerg Crit Care 11:275, 2001. 27. Bonczynski JJ, Ludwig LL, Barton LJ, et al: Comparison of peritoneal fluid and peripheral blood pH, bicarbonate, glucose, and lactate concentration as a diagnostic tool for septic peritonitis in dogs and cats, Vet Surg 32:161, 2003. 28. Levin GM, Bonczynski JJ, Ludwig LL, et al: Lactate as a diagnostic test for septic peritoneal effusions in dogs and cats, J Am Anim Hosp Assoc 40:364, 2004. 29. Scott JA, Macintire DK: Canine pyothorax: clinical presentation, diagnosis, and treatment, Compend Contin Educ Vet 25:2003, 2003. 30. Silverstein DC, Kleiner J, Drobatz KJ: Effectiveness of intravenous fluid resuscitation in the emergency room for treatment of hypotension in dogs: 35 cases (2000-2010), J Vet Emerg Crit Care (San Antonio) 22:666, 2012. 31. Bickell WH, Wall MJ, Jr., Pepe PE, et al: Immediate versus delayed fluid resuscitation for hypotensive patients with penetrating torso injuries, N Engl J Med 331:1105, 1994. 32. Dutton RP: Haemostatic resuscitation, Br J Anaesth 109(Suppl 1):i39, 2012. 33. Gibson TW, Brisson BA, Sears W: Perioperative survival rates after surgery for diaphragmatic hernia in dogs and cats: 92 cases (1990-2002), J Am Vet Med Assoc 227:105, 2005. 34. Wilson GP, 3rd, Hayes HM Jr: Diaphragmatic hernia in the dog and cat: a 25-year overview, Semin Vet Med Surg (Small Anim) 1:318, 1986.

35. Gower SB, Weisse CW, Brown DC: Major abdominal evisceration injuries in dogs and cats: 12 cases (1998-2008), J Am Vet Med Assoc 234:1566, 2009. 36. Waldron DR, Hedlund CS, Pechman R: Abdominal hernias in dogs and cats: a review of 24 cases, J Am Anim Hosp Assoc 22:817, 1986. 37. Birchard SJ, Smeak DD, McLoughlin MA: Treatment of idiopathic chylothorax in dogs and cats, J Am Vet Med Assoc 212:652, 1998. 38. Fossum TW, Birchard SJ, Jacobs RM: Chylothorax in 34 dogs, J Am Vet Med Assoc 188:1315, 1986. 39. Allman DA, Radlinsky MG, Ralph AG, et al: Thoracoscopic thoracic duct ligation and thoracoscopic pericardectomy for treatment of chylothorax in dogs, Vet Surg 39:21, 2010. 40. Carobbi B, White RA, Romanelli G: Treatment of idiopathic chylothorax in 14 dogs by ligation of the thoracic duct and partial pericardiectomy, Vet Rec 163:743, 2008. 41. Fossum TW, Mertens MM, Miller MW, et al: Thoracic duct ligation and pericardectomy for treatment of idiopathic chylothorax, J Vet Intern Med 18:307, 2004. 42. McAnulty JF: Prospective comparison of cisterna chyli ablation to pericardectomy for treatment of spontaneously occurring idiopathic chylothorax in the dog, Vet Surg 40:926, 2011. 43. Stewart K, Padgett S: Chylothorax treated via thoracic duct ligation and omentalization, J Am Anim Hosp Assoc 46:312, 2010. 44. Mayhew PD, Culp WT, Mayhew KN, et al: Minimally invasive treatment of idiopathic chylothorax in dogs by thoracoscopic thoracic duct ligation and subphrenic pericardiectomy: 6 cases (2007-2010), J Am Vet Med Assoc 241:904, 2012. 45. Radlinsky MG, Mason DE, Biller DS, et al: Thoracoscopic visualization and ligation of the thoracic duct in dogs, Vet Surg 31:138, 2002. 46. Barrs VR, Allan GS, Martin P, et al: Feline pyothorax: a retrospective study of 27 cases in Australia, J Feline Med Surg 7:211, 2005. 47. Boothe HW, Howe LM, Boothe DM, et al: Evaluation of outcomes in dogs treated for pyothorax: 46 cases (1983-2001), J Am Vet Med Assoc 236:657, 2010. 48. Rooney MB, Monnet E: Medical and surgical treatment of pyothorax in dogs: 26 cases (1991-2001), J Am Vet Med Assoc 2002;221:86-92. 49. Bjorling DE, Crowe DT, Kolata RJ, et al: Penetrating abdominal wounds in dogs and cats, J Am Anim Hosp Assoc 1982:742, 1982. 50. Costello MF, Drobatz KJ, Aronson LR, et al: Underlying cause, pathophysiologic abnormalities, and response to treatment in cats with septic peritonitis: 51 cases (1990-2001), J Am Vet Med Assoc 225:897, 2004. 51. Mueller MG, Ludwig LL, Barton LJ: Use of closed-suction drains to treat generalized peritonitis in dogs and cats: 40 cases (1997-1999), J Am Vet Med Assoc 219:789, 2001. 52. Neer TM: A review of disorders of the gallbladder and extrahepatic biliary tract in the dog and cat, J Vet Intern Med 6:186, 1992. 53. McAnulty JF, Smith GK: Circumferential external counterpressure by abdominal wrapping and its effect on simulated intra-abdominal hemorrhage, Vet Surg 15:270, 1986. 54. Vinayak A, Krahwinkel DJ Jr: Managing blunt trauma-induced hemoperitoneum in dogs and cats, Compend Contin Educ Vet 26:276, 2004. 55. Mongil CM, Drobatz KJ, Hendricks JC: Traumatic hemoperitoneum in 28 cases: a retrospective review, J Am Anim Hosp Assoc 31:217, 1995. 56. Holowaychuk MK, Monteith G: Ionized hypocalcemia as a prognostic indicator in dogs following trauma, J Vet Emerg Crit Care (San Antonio) 21:521, 2011. 57. Rockar RA, Drobatz KJ, Shofer FS: Development of a scoring system for the veterinary trauma patient, J Vet Emerg Crit Care 4:77, 1994.

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CHAPTER 139  WOUND MANAGEMENT Caroline K. Garzotto,

VMD, DACVS, CCRT

KEY POINTS • The patient should always be stabilized and assessed for internal trauma before treating external wounds. • In the first aid care of wounds, it is important to keep the wound moist, clean, and covered until definitive treatment can be performed. • Open wounds containing penetrating foreign bodies or projecting bone should not be manipulated until the patient has been stabilized. • Once the patient is stable, all wounds should be cleaned and debrided, even if the animal will eventually be transferred to a surgical specialist. Surgical exploration is indicated for all penetrating wounds. • Most wounds can be managed successfully with appropriate technique, close follow-up, cooperative owners, and minimal materials. • Although wet-to-wet or wet-to-dry bandaging has been a mainstay of wound management, consideration of moist wound management techniques including newer dressings and negative pressure wound therapy should be considered. • The diagnosis and prognosis for full return to function should be discussed with the owner as soon as possible. In addition, the patient’s predicted treatment regimen (e.g., daily bandage changes) and total cost estimate should also be discussed.

Most traumatic wounds seen in the small animal veterinary patient include bite wounds, abrasions or shearing injuries resulting from motor vehicle trauma, degloving, lacerations, and punctures. Wounds can also result from decubitus ulcers in the recumbent animal secondary to poor nursing care, or wounds can appear in postoperative surgical incisions that dehisce or become infected.

WOUND HEALING PRINCIPLES Wound Classification Wounds are classified based on degree of contamination as follows1-3: Clean: Atraumatic, surgically created under aseptic conditions (e.g., incisions) Clean contaminated: Minor break in aseptic surgical technique (e.g., controlled entry into the gastrointestinal [GI], urogenital, or respiratory tracts) in which the contamination is minimal and easily removed Contaminated: Recent wound related to trauma with bacterial contamination from street, soil, or oral cavity (e.g., shearing or bite wound); can also be a surgical wound with major breaks in asepsis (e.g., spillage from the GI or urogenital tracts) Dirty or infected: Older wound with exudate or obvious infection (e.g., abscess in a bite wound, puncture wound, or traumatic wound with retained devitalized tissue); contains more than 105 organisms per gram of tissue

• • • •

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If a wound is associated with a broken bone, this is called an open fracture, and these can be classified as follows4: Grade I: Small break in the skin caused by the bone penetrating through Grade II: Soft tissue trauma contiguous with the fracture, often caused by external trauma (e.g., bite wound, low-velocity gunshot injuries) Grade III: Extensive soft tissue injury, commonly in addition to a high degree of comminution of the bone (e.g., distal extremity shearing wounds, high-velocity gunshot injuries) Although definitive repair of an open fracture should be done as soon as possible for patient comfort, initial care of the soft tissues should not be delayed if a surgeon is not immediately available or if the patient is not stable enough to undergo general anesthesia for several hours. Any exposed bone should be covered with sterile lubricating jelly and a sterile bandage but should not be pushed back below the skin surface because this can cause deeper contamination of the wound or further injury to the tissues. Similar guidelines exist for wounds with penetrating foreign bodies such as arrows, large wooden splinters, or knives. The foreign body may be tamponading a large vessel, and removal could lead to severe hemorrhage. These objects should be removed only under controlled surgical conditions. Other wound classifications describe the length of time that the wound has been open because this relates to how quickly bacteria can multiply in a wound. Although this is important to know, it is not as vital as assessing the patient and wound directly. It is more important to understand the local and systemic defenses of the patient and the types and virulence of bacteria that may be present in the wound so that appropriate treatment can be initiated.1

• • •

Phases of Healing A basic understanding of the phases of wound healing gives the clinician an idea of how long it will take for a wound to improve in appearance and for making wound management decisions. Wound healing can be described in four phases: (1) inflammation, (2) debridement, (3) repair/proliferation, and (4) maturation.1 The phases overlap and the transitions are not visible to the naked eye. The inflammatory phase occurs during the first 5 days after injury. Immediately after trauma there is hemorrhage caused by disruption of blood vessels, and then vasoconstriction and platelet aggregation limit the bleeding. Vasodilation follows within 5 to 10 minutes, allowing fibrinogen and clotting elements to leak from the plasma into the wound to form a clot and eventually a scab. The clot serves as scaffolding for invading cells such as neutrophils, monocytes, fibroblasts, and endothelial cells. Also contained in the plasma are inflammatory mediators (cytokines) such as histamine, prostaglandins, leukotrienes, complement, and growth factors. The debridement phase occurs almost simultaneously with the inflammatory phase. It is marked by the entry of white blood cells

CHAPTER 139  •  Wound Management

into the wound. Neutrophils are the first to appear in the wound approximately 6 hours after injury. They remove extracellular debris via enzyme release and phagocytosis. Monocytes appear approximately 12 hours after trauma, and they become macrophages within 24 to 48 hours. The monocytes stimulate fibroblastic activity, collagen synthesis, and angiogenesis. Macrophages remove necrotic tissue, bacteria, and foreign material. The repair phase, also called the proliferative phase,5,6 begins 3 to 5 days after injury and lasts about 2 to 4 weeks. This is the most dramatic healing phase and is characterized by angiogenesis, granulation tissue formation, and epithelialization. Fibroblasts proliferate and start synthesizing collagen, and then capillary beds grow in to form granulation tissue. Granulation tissue provides a surface for epithelialization and is a source of myofibroblasts that play a role in wound contraction. New epithelium is visible 4 to 5 days after injury and occurs faster in a moist environment.1 Wound contraction is first noticeable by 5 to 9 days after injury and continues into the maturation phase.6 Finally, the maturation phase occurs once adequate collagen deposition is present and is marked by wound contraction and remodeling of the collagen fiber bundles. It starts at about 17 to 20 days after injury and may continue for several years. Healed wounds are never as strong as the normal tissue; a scar is only about 80% as strong as the original tissue.6

INITIAL PATIENT ASSESSMENT Before handling the patient, the clinician and patient should be protected by the use of examination gloves. Initial stabilization of the patient should address the cardiac and respiratory system to ensure adequate oxygen delivery to the tissues (see Chapter 1). Intravenous catheter placement, fluid therapy, and supplemental oxygen may be required for severely traumatized patients or patients in shock (see Chapters 14 and 60). A complete blood cell count, biochemical analysis, urinalysis, and venous or arterial blood gas analysis should be performed upon admission. Direct pressure should be applied to any bleeding wounds. If bleeding cannot be controlled by direct pressure, emergent surgical intervention is required. Bleeding from appendages can be controlled with tourniquets by using a pneumatic blood pressure cuff inflated to 200 mm Hg for up to 1 hour.7 It is important to remember that bite wounds commonly result from the penetration of both the upper and lower teeth. If bite marks are seen only on one side of the limb or trunk, then the other side should be shaved to search for the corresponding wounds. Wounds should be kept clean and moist and protected from the hospital environment. A sterile, water-soluble lubricant and saline-soaked sponges can be applied to the wounds initially and then covered with a sterile towel and soft padded bandage if the patient must be moved. It is important that the damaged tissue remain moist because desiccation impairs wound healing. If the animal has wounds associated with trauma, ultrasound is often indicated to assess for other more immediate, life-threatening injuries (see Chapter 189). Radiographs of the spine, chest, abdomen, and pelvic region, in addition to appendages if there is suspicion of a fracture, may also prove beneficial. Blunt trauma, such as motor vehicle trauma or falling from heights, warrants chest and abdominal radiographs or ultrasound to assess for pulmonary contusions, pneumothorax or hemothorax, diaphragmatic hernia, and peritoneal effusion secondary to blood or urinary tract trauma. A thorough neurologic assessment is also important to rule out spinal or neurologic injury. Assessment of perfusion and sensation to the digits is important when severe trauma to peripheral blood supply and nerves might preclude a successful outcome.

DEBRIDEMENT AND LAVAGE Once the patient has been thoroughly examined and stabilized and all diagnostic tests performed, and if sedation or anesthesia can be administered safely, initial assessment and debridement of the wound should be done. The primary goal in the management of all wounds is to create a healthy wound bed with a good blood supply that is free of necrotic tissue and infection in order to promote healing.5 Most wounds will require daily debridement and bandage changes, and the clinician should not be discouraged if the wound cannot be closed initially. The following summarizes the steps for daily wound evaluation: 1. Assess need for or response to antimicrobial therapy. 2. Debride, removing necrotic tissue, and then lavage the wound. 3. Determine if the wound can be closed. 4. Protect the wound with a bandage, Elizabethan collar, or both. Initial debridement will require general anesthesia, local anesthesia, or neuroleptanalgesia. For future wound evaluations, the patient may require only sedation or analgesia and restraint if surgical debridement is minimal. Local anesthetics are ideal in unstable patients that cannot tolerate general anesthesia but have significant injuries to the limbs. In these cases wounds of the pelvic limbs can be debrided using epidural analgesia (see Chapter 144) and thoracic limb wounds can be debrided using a brachial plexus block.8 Sterile lubricating jelly should be applied to the exposed wound to protect it from further contamination and a wide area of fur clipped from the skin around the wound. Gross dirt from the skin around the wound should be cleaned by applying surgical scrub solution (chlorhexidine or povidone-iodine) to unbroken skin, but not to the surface of the wound because these solutions are damaging to exposed tissues. Debridement should be done using aseptic technique: sterile gloves, sterile gown, and cap and mask, and the wound should be draped with sterile towels or water-impermeable drapes. At the time of initial assessment and subsequent bandage changes, necrotic tissue should be excised. All bite wounds should be explored, even if they look minor, because teeth exert a macerating or crushing force that can damage tissues deep below the skin surface (Figure 139-1). The hole around the bite wound should be trimmed and then tented up to evaluate the subcutaneous tissues. A probe, such as a mosquito or Kelly forceps, can be used to assess for dead space or pockets under the skin that could form hematomas, seromas, and abscesses.

FIGURE 139-1  This 12-year-old Sheltie was bitten on the right hind limb by a Pit Bull and suffered extensive destruction of the skin and muscle on the lateral surface of the limb. (Courtesy O. Morgan.)

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PART XVI  •  TRAUMA

BOX 139-1 

Materials for Dressing Changes

• Sterile lubricating jelly, sterile gauze, umbilical tape, sterile

impermeable drape material, cast padding, 18-gauge needles, 35- to 60-ml syringe, Vetrap or Elastikon • Triple antibiotic ointment, silver sulfadiazine • Isotonic crystalloids such as lactated Ringer’s solution or 0.9% saline • 4-0 to 0 monofilament, absorbable and nonabsorbable suture material • A variety of splints for forelimb and hind limb stabilization

FIGURE 139-2  The wound from Figure 139-1 after initial surgical debridement. Only the necrotic tissues were removed initially. Note the loops of sutures surrounding the wound used for a tie-over dressing.

Obviously necrotic tissue (black, green, or gray) is removed first. In areas that have ample skin for closure, initial trimming of skin can be done more aggressively. In areas such as the distal limbs, trimming of skin should be done conservatively and questionable tissues given time to “declare” themselves (Figure 139-2). Bone, tendons, nerves, and vessels are preserved as much as possible unless segments of these vital structures are completely separated from the tissue and obviously nonviable. The wound can be lavaged with a variety of solutions. Wounds that are heavily contaminated with road dirt or soil can be cleaned of debris using lukewarm tap water with a spray nozzle.1 Maggots should be removed from severely necrotic wounds manually or with aggressive flushing. Chlorhexidine and povidone-iodine can be used in dilute form (chlorhexidine 0.05% solution: 1 part chlorhexidine 2% to 40 parts sterile water; povidone-iodine 1% solution: 1 part povidone-iodine 10% to 9 parts sterile saline) as initial lavage in contaminated and infected wounds because of their wide spectrum of antimicrobial activity. Povidone-iodine is more irritating to tissues, toxic to cells needed for wound healing, and inactivated by organic debris,1 so it may not be the preferred lavage solution. Lactated Ringer’s solution or 0.9% saline are the most commonly used lavage solutions. An in vitro study demonstrated that normal saline and tap water cause mild and severe cytotoxic effects on fibroblasts, respectively, whereas lactated Ringer’s solution did not cause significant fibroblast injury.9 Lavage is performed by flushing with a bulb syringe or a 60-ml syringe with an 18-gauge needle. In order to facilitate refilling, the syringe and needle setup are connected to a three-way stopcock and an intravenous fluid bag.

Sugar and Honey Sugar and honey have been used to treat wounds for hundreds of years. They are advantageous because they are readily available, are inexpensive, can be used both for debridement and to treat infections, and adhere to moist wound management principles. Sugar has a bactericidal effect through its osmotic action, and it draws macrophages to the wound, which accelerates sloughing of devitalized tissue.10 It is especially advantageous because it is effective and economical for large wounds. Indications include degloving and shearing injuries, infected wounds (Streptococcus, Escherichia coli, and Pseudomonas spp), burns, and other wounds that require further debridement. The wound is first debrided and lavaged. The area is then patted dry with a sterile towel before applying a coating (up to

1 cm thick) of granulated sugar. Sterile towels or lap sponges are used as the dressing in the primary layer, and then a thick, absorbent secondary layer is applied. Bandages are changed at least daily, or more frequently if strikethrough occurs. Sugar application is stopped when healthy granulation tissue appears. One disadvantage of sugar is that it may cause greater effusion in wounds, thus requiring more frequent bandage changes.11 Honey, in the form of Manuka honey or medicinal honey (Medihoney, Derma Sciences, Princeton, NJ), has many favorable properties in the management of wounds, including burn wounds. Healing properties of honey are varied; honey decreases edema, accelerates sloughing of necrotic tissue, and provides a rich cellular energy source, promoting a healthy granulation bed. In addition, honey has antibacterial properties because of its high osmolarity, acidity, and hydrogen peroxide content. The hydrogen peroxide is present in levels that are harmless to healthy tissue. Honey can be used during the debridement phase and also over infected granulation tissue.12 It has been shown to be more effective in some cases than more expensive commercial products, including silver sulfadiazine and conventional dressings (i.e., impregnated gauze, polyurethane films).13,14 Honey is applied to the wound after hydrotherapy and debridement of necrotic tissue. Gauze sponges soaked in honey are placed directly on the wound as the primary layer, then covered with an absorbent second layer to prevent it from leaking through the bandage. As with sugar, dressings may need to be changed one to three times a day, and the wound should be lavaged and reassessed before each application of honey.

DRESSING AND BANDAGING Good bandaging practice is essential to maintaining and protecting the wound. Ideally a bandage should cover all open wounds. A bandage consists of three layers: (1) primary, (2) secondary, and (3) tertiary. The necessary supplies are listed in Box 139-1. The primary layer is the dressing applied directly to the wound. This layer determines the purpose of the bandage by whether it is an adherent or nonadherent dressing. The secondary layer is composed of padded material that aids in absorption of exudates. The tertiary layer is the outermost protective layer that holds the others in place.15 An adherent dressing is used when the wound is in the debridement phase, providing mechanical debridement. The most common of these is the wet-to-dry dressing, in which sterile gauze sponges soaked with sterile lactated Ringer’s solution or 0.9% saline are wrung out and applied directly to the surface of the wound, then covered with dry, sterile gauze sponges. The dry sponges soak up moisture from the wet ones, and this wicking action causes necrotic tissue and debris to adhere to the sponges when they are removed. It is often necessary to wet the dressing slightly with sterile lactated Ringer’s solution or 0.9% saline to allow easier removal and to make it less uncomfortable for the patient.

CHAPTER 139  •  Wound Management

During the debridement phase, it is necessary to change the wetto-dry dressing and bandage at least once daily. Sometimes it will be necessary to change it up to three times a day initially, depending on how dirty the wound is or if moisture quickly “strikes through” to the outer layer of the bandage. Although adherent dressings are still in common use in veterinary medicine during the debridement phase, they have received criticism because they nonselectively remove both necrotic and healthy tissue alike. Moist wound management principles are becoming increasingly popular in veterinary medicine because of improved wound understanding and technologic advances in wound products. The idea of moist wound healing was first promoted during the early 1960s after research conducted by Winter first demonstrated the benefit of a moist environment in optimizing wound healing by increasing epithelialization compared with leaving wounds open to air.16 By providing a moist wound environment, the process of autolytic debridement can be more effective, which means that the body’s own phagocytic processes will take care of wound debridement.3,17 Alginates, foams, hydrogels, hydrocolloids, and transparent films are examples of some newer types of nonadherent dressings that can be selected based on their specific benefits to promote moist wound management through all phases of wound healing (Table 139-1). These products are more expensive than traditional gauze, but an overall cost savings can be realized because frequency of bandage changes decreases from several times a day to once every 1 to 3 days and improved wound healing leads to faster healing times.17 The more commonly used nonadherent dressings such as Telfa pads

(Kendall, Mansfield, MA) and Adaptic (Johnson & Johnson, New Brunswick, NJ) are most appropriately used once a healthy, pink granulation bed has covered the surface of the wound and it is no longer infected. Once the primary layer is applied, the next layer can be either a soft padded bandage or a tie-over bandage. Soft padded bandages are used to protect soft tissue wounds on the limbs, and a splint can be incorporated between the second and third layers to stabilize distal fractures or ligamentous injuries. The secondary layer is most commonly rolled cotton that is held in place with rolled gauze. The splint is placed over the cotton and under the gauze. The tertiary layer is often Vetrap (3M, St. Paul, NJ) or Elastikon (Johnson & Johnson, New Brunswick, NJ) and is placed over the secondary layer but without compression of the bandage or wound. The tie-over bandage is used for wounds on areas of the body that are not amenable to soft padded bandages, such as the flank, perineum, or hip areas.5 Materials include 2-0 to 0 nylon, umbilical tape, gauze, and water-impermeable drape material. Loose suture loops are applied circumferentially around the wound (see Figure 139-2). The secondary layer consists of several layers of dry gauze squares or laparotomy sponges that are applied for padding and moisture absorption. The tertiary layer is a water-impermeable drape cut to fit the wound, and then all three layers are held in place by the umbilical tape that is looped through the sutures in a shoelace fashion. The bandage should be protected from the patient by judicious use of an Elizabethan collar. If the bandage is on a limb, the foot should be covered with a strong plastic bag taped to the bandage

Table 139-1  Dressings3,17 Type

Uses

Contraindications

Examples

Gauze

Inexpensive, readily available Wet-to-wet; wet-to-dry nonselective debridement

Not appropriate when healthy granulation tissue is present or when trying to get wound to epithelialize.

Surgical sponges

Impregnated gauze

Added zinc, iodine, or petrolatum nonadherent and help prevent desiccation Absorbs bacteria and exudate

Although it increases wound contraction, it can delay epithelialization.

Adaptic (J&J)

Polyester film with cotton

Used primarily during epithelialization phase on surgical wounds, wounds with good granulation tissue and with minimal exudate

May promote excessive granulation tissue.

Telfa pads (Kendall)

Calcium alginates

Absorbs heavy exudate Pad, ribbon or fiber forms gel when absorbing exudate Hemostatic, favors epithelialization and granulation

Do not use over exposed tendon, bone, or necrotic tissue.

Curasorb (Kendall)

Hydrogels

Absorbs minimal exudate Autolytic debridement Rehydrates to soften dry wounds

Discontinue after healthy granulation tissue is present because it can promote exuberant granulation.

Curafil (Kendall) BioDres (DVM Pharmaceuticals) Carravet (Carrington Labs)

Hydrocolloids

Autolytic debridement Increases epithelialization and comfort Promotes granulation

Not for use in exudative or infected wounds. Can promote exuberant granulation.

DuoDERM (Convatec)

Foams

Absorbent and comfortable Used in deep wounds with minimal exudate Promotes epithelialization and contraction

Reduces granulation. May cause maceration.

Hydrasorb (Kendall) Copa Plus (Kendall)

Polyurethane films

Occlusive but permeable to air and water vapor, but impermeable to fluid and microorganisms Autolytic debridement Covering for sutured wounds

Because of occlusive, adherent property, may cause bacterial proliferation and tissue maceration. Should be changed every 1-3 days.

Tegaderm (3M)

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when the patient is taken outside to keep it from getting wet or dirty. The bandage should be changed immediately when it gets wet, dirty, or slips, or when there is strikethrough from the wound.

Exposed Bone Exposed bone is prone to slow healing and must be covered with a granulation bed before skin graft or flap application. Injuries with exposed bone are seen most often with carpal or tarsal shearing injuries caused by motor vehicle trauma. In most cases exposed bone is eventually covered by advancing granulation tissue from surrounding healthy soft tissues when proper moist wound management techniques are applied. Bone perforation can enhance wound healing by encouraging growth of granulation tissue over the exposed bone.1,5,18 Once the wound has entered the repair phase, a Jacob’s chuck and 0.045- to 0.062-inch K-wires may be used to perforate the surface of exposed bone through to the medullary cavity. Blood should not be wiped away. A nonadherent dressing with antibiotic ointment should be applied as the primary layer of the bandage. Bandage changes are done at 3- to 5-day intervals. Once a complete layer of granulation tissue is present (approximately 7 to 10 days), a free skin graft is applied or ongoing wound management continued until secondintention healing is complete. Negative pressure wound therapy has also been shown to improve coverage of exposed bone in the case of distal extremity shearing wounds in dogs.19

WOUND CLOSURE The decision as to when and how to close a wound depends on the cleanliness and extent of the wound. Clean, fresh wounds, small, contaminated wounds or even infected wounds that can be excised completely should be closed primarily. Monofilament absorbable suture should be used in subcutaneous tissue and muscle, and nonabsorbable suture should be used on the skin. Avoid tight sutures and tension on the suture line. Closure should be delayed for contaminated wounds or large wounds with questionable viability. Closure can be performed when a healthy granulation bed is present, which occurs during the repair phase of healing. Healthy granulation tissue should be pink, smooth, or slightly bumpy, should cover the entire wound, and should bleed on the cut surface or when an adhered dressing is removed. If in doubt, the wound should be treated as an open infected wound until the granulation bed is more definitively healthy. Delayed primary closure of a wound is performed 2 to 5 days after the injury. Secondary closure of a wound is defined as closure of a wound 5 or more days after the inciting injury and is usually selected for wounds that were initially classified as dirty (Figure 139-3). If the wound is at least 5 days old, granulation tissue and epithelialized skin edges may need to be excised to allow closure.2 If the wound is too large to be closed, the clinician should consider a skin graft or flap, or closure by second-intention healing. Second-intention healing occurs over a healthy granulation bed by the processes of wound contraction and epithelialization, which continue until the two epithelialized edges of the wound meet. Second-intention healing, even of very large wounds, can often be successful and does not require anything more than diligent bandaging and wound care.

Drains Drain placement is indicated during wound closure in areas with excessive dead space, areas with potential for fluid accumulation, or infected or contaminated areas (e.g., abscess, bite wound). The drain should exit from the dependent portion of the wound via a separate stab incision, not through the suture line. Ideally the drain should be

FIGURE 139-3  The wound from Figure 139-2 2 weeks after a caudal superficial epigastric flap was performed. Note the healthy granulation bed in the distal half of the wound. Skin stretchers were applied to allow harvest of the opposite caudal superficial epigastric flap to cover the distal half of the wound. However, by the time the flap surgery was scheduled, the remainder of the wound contracted enough to allow primary closure by trimming the epithelialized skin edges and undermining the skin circumferentially.

covered with a bandage to prevent removal by the patient, to further compress dead space, and to keep the area clean. Drains are removed when drainage is clear or minimal (2 to 7 days). There are two types of drains, passive and active. A Penrose drain is the best means of passive gravitational drainage. This type of drain can be secured at the proximal extent of the wound pocket with a simple interrupted suture through the skin that catches the flimsy rubber tubing while it is held in position with a hemostat. A separate opening to secure a Penrose drain proximally should never be made because this allows bacteria to migrate into the wound. The Penrose drain should exit the wound pocket at its most dependent location and be secured with a simple interrupted or cruciate suture to the skin edge of the opening where it exits the wound pocket (Figure 139-4). There are many types of active or closed-suction drains, which consist of a vacuum-generating reservoir connected to fenestrated tubing. These can be used only in areas that can be closed completely because a vacuum must be created within the wound. There are numerous commercially available closed-suction drains such as the J-VAC (Johnson & Johnson, Arlington, TX) and the Sil-Med vacuum drain (Sil-Med Corp., Taunton, MA), which has a grenade-type reservoir. There are also several ways to make closed suction devices.1,15 A butterfly catheter and red-top blood collection tube can be used for small spaces. For larger areas of dead space, a drain can be made of intravenous tubing with additional fenestrations cut out of the segment to be placed in the wound using a number 15 scalpel blade. The tubing is then connected to a 60-ml syringe, and the plunger is held open with a needle or pin. An alternative to a closed suction drain that is especially appropriate for very large or very hard to immobilize areas is negative pressure wound therapy (see the next section).

Negative Pressure Wound Therapy Topical negative pressure (TNP) and negative pressure wound therapy (NPWT) are the generic terms used to describe the application of a vacuum to a wound to promote and hasten healing by second intention and to prepare wounds for closure with skin flaps or grafts. Vacuum-assisted closure (VAC) refers to a commercially available device (V.A.C., Kinect Concepts Inc., San Antonio, TX) that was used in some of the earliest published studies20,21 and is also used in the majority of published controlled clinical trials.22 Commercial units

CHAPTER 139  •  Wound Management

FIGURE 139-4  This dog had a skin laceration over its right scapula after a run through the woods. This fresh wound was cleaned and closed primarily. A Penrose drain is seen exiting a wound pocket distal and caudal to the incision. It is secured in place with a tacking suture to the skin edge where it exits distally. Proximally the Penrose is secured also with a tacking suture; however, the drain does not exit the skin.

as well as homemade versions of these devices are used in veterinary medicine. The basic materials needed include open-pore polyurethane foam or open-weave gauze sponges for the contact layer, suction tubing, adhesive occlusive film, and a suction device with a canister to hold the evacuated fluid. The contact layer is fitted to the contours of the wound and then sealed with the adhesive occlusive film that overlaps the wound edges by at least 5 cm21 and that must form a leakproof seal to maintain the vacuum. A drainage tube is connected to the foam dressing through an opening in the adhesive film. The drainage tube is then connected to a vacuum source most commonly set at −125 mm Hg23 (Figure 139-5). Clinical use of NPWT has outpaced appropriate randomized clinical trials to demonstrate efficacy and superiority to traditional methods.24 Evidence-based reviews of the human literature looking at mechanisms of action of NPWT agree on the following mechanisms of action22,25: increased vascularization, improved granulation tissue formation, and a reduction in the wound volume/size. Clinical advantages of NPWT include more optimal fixation of skin grafts, better management of highly exudative wounds, and decreased costs because of the need for less frequent bandage changes.22,25,26 Many studies have attempted to prove that NPWT can decrease bacteria and edema in wounds; however, these studies are contradictory.22 A prospective, controlled veterinary study27 found that NPWT in dogs promoted earlier and less exuberant granulation tissue; however, prolonged use led to decreased wound contraction (at >7 days), higher bacterial load (at day 7), and decreased percent epithelialization (at >11 days) compared with a standard absorbent foam wound dressing (Copa Foam Dressing, Kendall Tyco Healthcare, Mansfield, MA). Contraindications for NPWT as reported by the FDA include the following28: Necrotic tissue with eschar present Untreated osteomyelitis Nonenteric and unexplored fistulas Malignancy in the wound

• • • •

FIGURE 139-5  This 7-year-old female spayed Boxer developed a large abscess over her right and left dorsal pelvic regions while on chemotherapy (prednisone and vinblastine) 1 month after complete excision of a high-grade mast cell tumor from this area. The wounds were opened, cultured, lavaged, and debrided and a VAC (as seen in photo) was applied to decrease dead space, improve removal of exudate, and attain healthy granulation tissue. Interestingly, 24 hours after VAC application, swelling and hematoma formation were noted around the dressing. Tests for possible coagulopathy were negative, and biopsies showed no evidence of remaining mast cell disease. Although the VAC did help initially to clean up the wound, it is important to monitor for such complications. (Courtesy T. Hamilton.)

• Exposed vasculature • Exposed nerves • Exposed anastomotic site • Exposed organs

Patients with active bleeding, bleeding disorders, or those that are receiving anticoagulant therapy should not be treated with NPWT. Deaths have been reported with the use of NPWT as a result of bleeding and worsening of wound infections.28 NWPT should only be applied after appropriate debridement to minimize the potential for fatal infections.24 Reports in the veterinary wound literature have described VAC use in distal limb injuries,19 to decrease the size of large wounds and bolster bandaging of skin grafts,29,30 in cases of surgical dehiscence/ infection over orthopedic implants, in degloving wounds, in chronic nonhealing wounds, and for postoperative edema and seroma prevention.30 Other uses include in cases of peritonitis, for open management of bite wounds over the thorax, and in compartment syndrome.30 Although there are many applications of NPWT for wounds, it is not proven to be a more effective treatment option in all cases. Important considerations include lack of progress with conventional wound management methods, the need for suction/drainage in particularly difficult to bandage locations (axillary, flank, and inguinal wounds or large mass removals), wounds that don’t require daily assessment, patients in which daily sedation/anesthesia may be contraindicated, and patients that will cooperate for the treatment. Further research investigating optimal pressure settings, intermittent versus continuous modes of operation, and optimal materials for the wound contact layer will undoubtedly prove beneficial.22

ADDITIONAL WOUND MANAGEMENT MODALITIES There are many additional strategies to advance wound healing that have been around for decades. Examples of treatments gaining

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increasing attention in veterinary medicine include hyperbaric oxygen therapy, low level laser-light therapy, and shockwave therapy. These treatment modalities are often attempted for management of difficult, chronic nonhealing wounds. Hyperbaric oxygen therapy involves placing patients in a chamber that replaces room air with 100% oxygen under pressure. This creates a gradient that increases the partial pressure of oxygen dissolved in the plasma (PaO2) and that subsequently diffuses across capillary membranes, into the interstitial space and ultimately into peripheral tissues.31 Hyperbaric oxygen therapy has not been well studied in dogs and cats but may promote angiogenesis (which is fostered by the increased oxygen gradient), increased proliferation of fibroblasts, and increased leukocyte oxidative killing of bacteria. In addition, decreased edema after hyperbaric therapy allows better diffusion of oxygen and nutrients to the affected tissues while relieving pressure on surrounding vessels and structures.17,31 Currently there is limited access to hyperbaric oxygen chambers for dogs and cats, but they may become more commonplace in the future.31 Animals that are most likely to benefit include those with crush injuries, compromised skin grafts, severe burns, and infections with anaerobic organisms. Low level laser-light therapy (LLLT), or “cold” laser, is better described by the name photobiomodulation. This technology uses low levels of red and near-infrared light to penetrate tissue and increase ATP production in the mitochondria of chromophores, as well as promote healing via the activation of fibroblasts.32 Initial rodent studies in the 1960s showed that laser light stimulated hair growth and wound healing. LLLT is used routinely in human medicine,32 and more recently in veterinary medicine,33 to reduce inflammation and promote healing of wounds and deeper tissues. Although there appears to be clinical evidence supporting the use of LLLT, good randomized controlled trials are lacking and results are often not repeatable because of differences in laser technology (e.g., LED vs. class 3B vs. class IV lasers) and the need to specify variable parameters, including wavelength, power density, pulse structure, and timing of the applied light. Dosing guidelines for treatments are currently set by the World Association of Laser Therapy (WALT, www.waltza.co.za), which is considered the authoritative body overseeing laser research. Shockwave therapy is a treatment modality that generates acoustic waves that travel through tissue to induce perturbations at the cellular level, which reportedly upregulates immunomodulatory mechanisms.34 Although there is limited evidence in both experimental and clinical studies that shockwave therapy may promote wound healing, there is still no consensus regarding expected results and specific protocols for various types of wounds that might benefit from this treatment modality. Before using one of these devices, the veterinarian must undergo specialized training in order to understand proper use of the equipment, indications, contraindications, and safety concerns. Although there is ongoing research and limited use of these technologies in private and specialty veterinary hospitals, fortunately a majority of wounds will heal uneventfully by following basic wound care principles and techniques.

ANTIMICROBIAL THERAPY The most common bacterial wound pathogens include gram-positive Staphylococcus spp and Streptococcus spp and gram-negative organisms such as Escherichia coli, Enterococcus, Proteus spp, and Pseudomonas spp.3,4,35,36 When humans (or animals) are bitten by dogs and cats, Pasteurella multocida is a common oral pathogen.35 The most common anaerobic isolates in bite wounds include Bacillus spp, Clostridium spp, and Corynebacterium spp.36 Often Pseudomonas will be an acquired infection on the surface of the granulation bed,

Table 139-2  Antimicrobial Use Recommendations in Wound Management1,37 Antimicrobial Use

Situation

Indicated

Obvious local or systemic signs of infection Wounds older than 6 hours Deep tissue injury involving muscle, fascia, bone, tendon Wounds likely to become infected such as bite wounds, penetrating wounds, and wounds involving body orifices Wounds requiring staged debridement, wet-to-dry bandaging Prophylactic use to prevent contamination of surrounding normal tissues To keep bacterial numbers low when planning a flap or graft Chronic nonhealing wounds Immunocompromised patient or one that has other condition that might jeopardize healing (e.g., diabetes or Cushing’s disease)

May not be indicated

Clean wounds Superficial wounds less than 6 hours old A contaminated wound that can be converted easily to a clean wound with primary closure Wounds with a mature, healthy granulation bed

noticeable by the wound’s slimy feel and obvious pungent odor. Rarely does this organism cause systemic infection and thus it does not necessitate systemic antimicrobial therapy. Antimicrobial drug therapy is not an excuse for inappropriate wound care. Debridement, lavage, and bandaging are the most important parts of wound management, promoting healing of the tissues and creating an environment that negatively affects the ability of bacteria to proliferate. Systemic antimicrobials are indicated for contaminated and infected wounds to help eliminate bacteria and promote healing.37 Some clean, recent wounds, such as sharp lacerations, do not require microbial evaluation,1 and superficial wounds that are easily debrided and closed may require only perioperative antimicrobial use (Table 139-2). If a wound appears infected on presentation, a Gram stain can be performed to determine the predominant bacterial population and guide the initial antimicrobial selection. Culture and susceptibility testing of the wound should be done after initial debridement and lavage. Superficial wounds in systemically stable animals are best treated with a bactericidal antimicrobial that is effective against grampositive bacteria, such as cefazolin or cephalexin, pending culture and susceptibility results (see Chapter 175). Infected, deeper wounds may require a broader-spectrum antimicrobial such as amoxicillin with a β-lactamase inhibitor such as clavulanic acid. In one study the most commonly cultured bacteria from bite wounds (Staphylococcus, E. coli, Enterococcus spp) were 100% sensitive to amoxicillin and clavulanic acid.36 Published recommendations for treatment of dogbite wounds36 suggests that initial antimicrobial coverage for severe bite wounds include intravenous ampicillin and either a fluoroquinolone or aminoglycoside. If the wound becomes infected, reculturing the wound is recommended because cultures taken during the first surgical debridement are of little value in predicting the organism involved. These antimicrobial recommendations can also apply to most other types of severe wounds or trauma, resulting in extensive deep tissue disruption, including necrotizing soft tissue infections.38

CHAPTER 139  •  Wound Management

When systemic antimicrobials are administered, they should be started as soon as possible after the injury, given for a minimum of 5 to 7 days, and changed if necessary based on culture and susceptibility results and clinical resolution.1 Wounds can be sampled for repeat culture after 3 to 4 days to determine the effectiveness of antimicrobial therapy. If wound healing is not progressing after the first 2 to 3 days or the animal’s condition is worsening, a change in antimicrobial therapy may be indicated. Once mature granulation tissue has become established, antimicrobial usage is usually unnecessary because this tissue is resistant to infection.1 Topical antimicrobial drugs are often used to decrease bacterial populations on the wound, but they should always be used in conjunction with debridement and lavage.1 The following medications are best used by spreading a thin layer onto a sterile nonadherent pad that serves as the primary layer of the bandage. Triple antibiotic ointment is more effective for preventing infection than treating it, and it has poor activity against Pseudomonas. Silver sulfadiazine cream has a favorable broad-spectrum coverage and is the agent of choice for burn wounds. Nanocrystalline silver dressings (e.g., Acticoat, Smith & Nephew, Andover, MA) have been developed to achieve sustained release of silver into the wound to decrease frequency of

17

dressing changes from daily to every 3 days. Nitrofurazone is a broad-spectrum antimicrobial agent with hydrophilic properties; it dilutes thick exudates for better absorption into bandages. Topical gentamicin sulfate preparations are effective treatment of wounds infected with Pseudomonas and are often used on open wounds before skin grafting is done.1

PATIENT CARE Patients with extensive wounds that require daily debridement and bandage care often require intensive care initially (see Chapter 131). They also require pain management (see Chapter 144) and nutritional therapy (see Chapters 129 and 130) while recovering from trauma. Table 139-3 lists some of the commonly used analgesics and antimicrobials with their dosages.

COMPLICATIONS The major concern for the clinician managing a patient with severe wounds is poor wound healing. Anemia, severe trauma, or hypovolemia can delay wound healing because of poor oxygen delivery to

Table 139-3  Drugs Commonly Used During Wound Management Key Drug

Drug Class

Dosage Range

Frequency

Route

Indications

Amoxicillin or ampicillin

Extended-spectrum penicillin antimicrobial

22 mg/kg

q6-8h

PO (amoxicillin) or IV or IM (ampicillin)

Infection, dirty wounds

Amoxicillinclavulanic acid

Extended-spectrum penicillin antimicrobial with β-lactamase inhibitor

22 mg/kg

q8-12h

PO

Superficial wounds

Amoxicillinsulbactam

Extended-spectrum penicillin antimicrobial with β-lactamase inhibitor

22 mg/kg

q8-12h

IV, IM

Superficial wounds

Cefazolin

First-generation cephalosporin antimicrobial

22 mg/kg

q6-8h; for perioperative use give 20 min before surgery and then q2h until surgery is complete

IV, SC

Infection, dirty wounds

Cefovecin

Third-generation extended-spectrum cephalosporin

8 mg/kg

Once but can repeat after 14 days

SC

Efficacy comparable to cefadroxil for abscesses and infected wounds40

Enrofloxacin

Fluoroquinolone antimicrobial

5-20 mg/kg (do not exceed 5 mg/kg q24h in cats)

q24h (or divided q12h)

IM (IV use is off-label)

Infection, dirty wounds

Metronidazole

Antimicrobial

7-10 mg/kg

q8-12h

PO, IV

Anaerobic infection, dirty wounds

Methadone

Opioid

0.1-0.5 mg/kg

q2-6h

IV, IM, SC

Pain management

Hydromorphone

Opioid

0.05-0.1 mg/kg

q4-6h

IV, IM, SC

Pain management

Acepromazine

Phenothiazine anxiolytic

0.005-0.02 mg/kg

As needed

IV, IM, SC

Used with opioids for restraint during bandage changes

Fentanyl patch (Duragesic)

Opioid

30 kg: 100 mcg

12 hrs to peak effect, lasts 72 hrs

Dermal

Pain management

Fentanyl

Opioid

1-3 mcg/kg bolus, then 2-5 mcg/kg/hr CRI

Short-acting analgesia

IV

Pain management Continued

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Table 139-3  Drugs Commonly Used During Wound Management—cont’d Key Drug

Drug Class

Dosage Range

Frequency

Route

Indications

Epidural morphine (Duramorph)

Opioid

0.1 mg/kg diluted in 0.1 ml/kg 0.9% saline, not to exceed 6 ml

Produces pain relief in 30-60 min and lasts 10-24 hrs

Epidural

Pain management; local analgesia if combined with bupivacaine (use 0.1 ml/kg of 0.5% bupivacaine instead of saline)

Bupivicaine 0.5%

Local anesthetic

1.5 mg/kg maximum dose

Duration of effect 4-6 hrs

Local block

Pain management, early assessment, aid in restraint during debridement

Vitamin A

Vitamin

10,000 IU/dog

Once a day

PO

Antagonizes the effect of corticosteroids on wound healing

CRI, Constant rate infusion; IM, Intramuscular; IV, intravenous; PO, per os; SC, subcutaneous.

the wound. Poor perfusion and nutritional status can also have detrimental effects on healing. Serum total protein levels less than 2 g/ dl impede wound repair by decreasing fibrous tissue deposition.6 Infection and foreign bodies cause intense inflammatory reactions that interfere with healing. Patients with cancer that are receiving chemotherapy or those who have had radiation therapy to the area of the wound will also be prone to delayed wound healing. Patients with diabetes, uremia, liver disease, or hyperadrenocorticism are susceptible to infection or delayed healing as well. Corticosteroids decrease the inflammatory phase of healing and the rate of protein synthesis; however, vitamin A (10,000 IU/dog PO q24h) can antagonize these detrimental effects of corticosteroids.6 Most wounded patients are dogs; however, cats often present the more challenging cases. Axillary wounds in cats can be particularly difficult to manage. An experimental study found that cats have significant differences in wound healing compared with dogs.39 Sutured wounds in cats are only half as strong as those in dogs by day 7, and cats demonstrate significantly less granulation tissue production than dogs in wounds that were evaluated for secondintention healing. Lack of bleeding or negative sensation in a limb indicates a poor prognosis and may necessitate amputation. These changes may not be predictable at the time of initial evaluation. As with any surgery other complications can include infection, dehiscence, and scarring. Contracture of limb wounds that are allowed to close by second intention can result in decreased mobility and may require referral to a specialized surgeon for skin reconstruction.

PROGNOSIS Owners should be advised as early as possible of the prognosis, extent of care involved, and cost. Prognosis depends on the extent of injury and the location. Some wounds may be irreparable, leading to the loss of a limb. Cost depends on the extent of the injury and increases with multiple injuries and if fracture repair or abdominal or thoracic exploration is required. Length of hospitalization depends on the extent of debilitation, whether intravenous fluids or a feeding tube is required, and whether daily bandage changes and wound debridement are needed. Costs of $5000 or more are common if injuries require daily bandage changes and wound debridement, and expenses can reach $10,000 or more if fracture repair or additional surgery is required. In some cases, patients can be treated on an outpatient basis with bandage changes every other day. Complicated wound healing can take several months and require multiple surgical procedures.

REFERENCES 1. Swaim SF, Henderson RA: Small animal wound management, ed 2, Baltimore, 1997, Williams & Wilkins. 2. Waldron DR, Zimmerman-Pope N: Superficial skin wounds. In Slatter DH, editor: Textbook of small animal surgery, ed 3, St Louis, 2003, Saunders. 3. Fossum TW, Hedlund CS, Hulse DA, et al: Surgery of the integumentary system. In Fossum TW, editor: Small animal surgery, ed 3, St Louis, 2007, Mosby. 4. Anson LW: Emergency management of fractures. In Slatter D, editor: Textbook of small animal surgery, ed 2, St Louis, 1993, Saunders. 5. Pavletic MM: Basic principles of wound healing. In Atlas of small animal wound management and reconstructive surgery, ed 3, Ames, IA, 2010, Wiley-Blackwell. 6. Hosgood G: Wound repair and specific tissue response to injury. In Slatter DH, editor: Textbook of small animal surgery, ed 3, St Louis, 2003, Saunders. 7. Crowe DT: Emergency care of wounds, DVM Best Practices Feb:11, 2002. 8. Muir WM, Hubbell JAE, Skarda RT, et al: Handbook of veterinary anesthesia, ed 3, St Louis, 2000, Mosby. 9. Buffa EA, Lubbe AM, Verstraete FJM et al: The effects of wound lavage solutions on canine fibroblasts: an in vitro study, Vet Surg 26:460, 1997. 10. Mathews KA, Binnington AG: Wound management using sugar, Compend Contin Educ Pract Vet 24:41, 2002. 11. Tobias KM, Ayers J: Wound management in action: case presentations, Proc Pro/NAVC Clinicians Brief, November 2012. 12. Mathews KA, Binnington AG: Wound management using honey, Compend Contin Educ Pract Vet 24:53, 2002. 13. Subrahmanyam M: A prospective randomised clinical and histological study of superficial burn wound healing with honey and silver sulfadiazine, Burns 24:157, 1998. 14. Jull AB, Rodgers A, Walker N: Honey as a topical treatment for wounds (review). In The Cochrane Collaboration, Hoboken, NJ, 2009, John Wiley & Sons. 15. Davidson DB: Managing bite wounds in dogs and cats. Part II, Compend Contin Educ Pract Vet 20:974, 1998. 16. Winter GD: Formation of the scab and the rate of epithelisation of superficial wounds in the skin of the young domestic pig, 1962, Nature 4:366, 1995. 17. Murphy PS, Evans GRD: Advances in wound healing: a review of current wound healing products, Plast Surg Int 190436, 2012. 18. Clark GN: Bone perforation to enhance wound healing over exposed bone in dogs with shearing injuries, J Am Anim Hosp Assoc 37:215, 2001. 19. Ben-Amotz R, Lanz OI, et al: The use of vacuum-assisted closure therapy for the treatment of distal extremity wounds in 15 dogs, Vet Surg 36:684, 2007. 20. Morykwas MJ, Argenta LC, Shelton-Brown EI, et al: Vacuum-assisted closure: a new method for wound control and treatment: animal studies and basic foundation, Ann Plast Surg 38:553, 1997.

21. Argenta LC, Morykwas MJ: Vacuum-assisted closure: a new method for wound control and treatment: clinical experience, Ann Plast Surg 38:563, 1997. 22. Mouës CM, Heule F, Hovius SER: A review of topical negative pressure therapy in wound healing: sufficient evidence? Am J Surg 201:544, 2011. 23. Morykwas MJ, Faler BJ, Pearce DJ, et al: Effects of varying levels of subatmospheric pressure on the rate of granulation tissue formation in experimental wounds in swine, Ann Plast Surg 47:547, 2001. 24. Orgill DP, Bayer LR: Update on negative-pressure wound therapy, Plast Reconstr Surg 127(Suppl 1):105S, 2011. 25. Hunter JE, Teot L, Horch R, et al: Evidence-based medicine: vacuumassisted closure in wound care management, Int Wound J 4:256, 2007. 26. Schneider AM, Morykwas MH, Argenta LC: A new and reliable method of securing skin graft to the difficult recipient bed, Plast Reconstr Surg 102:1195, 1998. 27. Demaria M, Stanley BJ, Hauptman JG, et al: Effects of negative pressure wound therapy on healing of open wounds in dogs, Vet Surg 40:658, 2011. 28. Division of Small Manufacturers, International and Consumer Assistance (DSMICA), U.S. Food and Drug Administration: Update on serious complications associated with negative pressure wound therapy systems, Silver Spring, MD, February 24, 2011, U.S. Dept. of Health and Human Services. Available at: http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ ucm244211.htm. 29. Guille AE, Tseng LW, Orsher RJ: Use of vacuum-assisted closure for the management of a large skin wound in a cat, J Am Vet Med Assoc 230:1669, 2007.

30. Kirby K, Wheeler JL, Farese JP, et al: Vacuum-assisted wound closure: clinical applications, Compend Contin Educ Vet 32:E1, 2010. 31. Braswell C, Crowe DT: Hyperbaric oxygen therapy, Compend Contin Educ Vet, 34:E1, 2012. 32. Chung H, Dai T, Sharma SK, et al: The nuts and bolts of low-level laser (light) therapy, Ann Biomed Eng 40:516, 2012. doi: 10.1007/s10439 -011-0454-7 33. Lucroy MD, Edwards BJ, Madewell BR: Low-intensity laser light-induced closure of a chronic wound in a dog, Vet Surg 28:292, 1999. 34. Qureshi AA, Ross KM, Ogawa R, Orgill DP: Shock wave therapy in wound healing, Plast Reconstruct Surg 128(6):721, 2011. 35. Davidson DB: Managing bite wounds in dogs and cats. Part I, Compend Contin Educ Pract Vet 20:811, 1998. 36. Griffin GM, Holt DE: Dog-bite wounds: bacteriology and treatment outcome in 37 cases, J Am Anim Hosp Assoc 37:453, 2001. 37. Walshaw R: Current concepts in antimicrobial therapy in the wounded patient, Proceedings of the ACVS Veterinary Symposium, San Diego, October 27-30, 2005. 38. Buriko Y, Van Winkle TJ, et al: Severe soft tissue infections in dogs: 47 cases (1996-2006). J Vet Emerg Crit Care 18(6): 608, 2008. 39. Bohling MW, Henderson RA, Swaim SF, et al: Cutaneous wound healing in the cat: a macroscopic description and comparison with cutaneous wound healing in the dog, Vet Surg 33:579, 2004. 40. Six R, Cherni J, et al: Efficacy and safety cefovecin in treating bacterial folliculitis, abscesses or infected wounds in dogs. J Am Vet Med Assoc 233: 433, 2008.

CHAPTER 140  •  Thermal Burn Injury

CHAPTER 140  THERMAL BURN INJURY Caroline K. Garzotto,

VMD, DACVS, CCRT

KEY POINTS • Electric heating pads, motor vehicles with hot mufflers, and fire exposures are the most common sources of burn injuries seen in the small animal veterinary patient. • If the injury is from a fire exposure, the patient should be assessed for evidence of pulmonary dysfunction caused by smoke inhalation. • If more than 20% of the total body surface area is involved, cardiovascular shock, major metabolic derangements, and sepsis may occur. These patients will need intensive medical and surgical treatment. • Burn wounds may take several days to “declare” themselves because heat dissipates slowly from burned skin. • The eschar should be removed early to help establish a healthy granulation bed and prevent infection. • Silver sulfadiazine is the mainstay of topical treatment for most burn wounds. • Cost of treatment and prognosis, especially in animals with severe metabolic derangements that necessitate intensive care, should be thoroughly discussed with owners.

Thermal burn wounds are relatively uncommon in veterinary medicine. The most common sources of burns in small animals include electric heating pads, fire exposure, scalding water, stovetops, radiators, heat lamps, automobile mufflers, improperly grounded electrocautery units, and radiation therapy.1 Most burn wounds can be managed the same as traumatic wounds (see Chapter 139). Like traumatic wounds, burn wounds can be labor intensive and expensive for the owner. In addition, numerous metabolic derangements can adversely affect the patient, prolong hospitalization, and complicate recovery.

DEFINITIONS Burn wounds are assessed using two major parameters: the degree of the injury and the percentage of body surface area involved. First, a review of skin anatomy is helpful.1 The most superficial layer of skin is the epidermis and the deeper layer of skin is the dermis. The dermis is composed of a superficial plexus and a middle plexus, where hair and glandular structures arise. Below the dermis lies the hypodermis, which contains the deep or subdermal plexus and the panniculus muscle. The subdermal plexus brings the blood supply to overlying skin through the superficial and middle plexus. Capillary loops in the

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Table 140-1  Burn Wound Assessment and Healing Degree

Depth

Appearance

Healing

First

Superficial—epidermis only

Erythematous Painful to touch

Healing is rapid; reepithelializes in 1 week with topical wound management No systemic affects

Second

Epidermis and superficial part of dermis

Epidermis will be charred and sloughs; plasma leakage occurs Hair follicles spared Painful to touch

Healing by epithelialization from the wound margin with minimal scar in 10 to 21 days May have systemic effects

Second

Epidermis and deeper part of dermis

Skin appears black or yellow-white Hair follicles destroyed Decreased pain sensation

Healing by contraction and epithelialization but scarring is significant without surgical intervention Significant systemic effects expected

Third

Full thickness—entire epidermis and dermis

Skin is black, leathery; eschar insensitive to touch

Healing often requires extensive surgical intervention, possible skin grafts and flaps May have life-threatening systemic effects

Fourth

Full thickness—with extension to muscle, tendon, and bone

Same as above

Skin grafts and flaps usually required to prevent scarring that could restrict joint movements.

superficial plexus supply the epidermis; however, they are poorly developed in the dog and cat compared with humans, thus leading to less severe erythema and blisters than human burn victims.1,2 Although these are now considered older terms, many physicians still like to refer to burn wounds as first-degree, second-degree, thirddegree, and fourth-degree injuries (Table 140-1).1-3 First-degree burn wounds are superficial and are confined to the outermost layer of the epidermis. The skin will be reddened, dry, and painful to touch. Second-degree burn wounds are partial-thickness injuries that involve the epidermis and a variable amount of the dermis. If only the superficial part of the dermis is affected, there will be thrombosis of blood vessels and leakage of plasma. The hair follicles are spared. In deeper partial-thickness burns, hair follicles are usually destroyed, the skin appears yellow-white or brown, and there is decreased sensation except to deep pressure.1 Third-degree burn wounds are full-thickness injuries that have destroyed the epidermis and entire dermis. The skin is leathery and charred and lacks sensation. Fourth-degree burn wounds have the same characteristics as third-degree burn wounds but also affect deeper tissues such as muscle, tendon, and bone.1-3 When burned, skin retains heat, so an accurate assessment of the degree of the wound may not be apparent initially.1 It can take up to 3 days for the burn to “declare” itself, and during that time thermal injury and circulatory compromise from thrombosed vessels can continue. Patients with burns involving more than 20% of their total body surface area (TBSA) can have serious metabolic derangements. Patients with more than 50% of their TBSA involved have a poor prognosis, and euthanasia should be discussed with the owners as a humane alternative. TBSA can be estimated in animals using percentages allotted to body area using the rule of nines as described in Table 140-2.1,4,5 When skin is severely burned, it forms an eschar within 7 to 10 days. Eschar is a deep cutaneous slough of tissue composed of fullthickness degenerated skin.6 It appears as a black, firm, thick movable crust that separates from the surrounding skin. Purulent exudates often lie beneath the eschar, particularly if it covers deep or extensive injuries, and sepsis can result if not treated promptly (Figure 140-1).

PATIENT ASSESSMENT AND MEDICAL MANAGEMENT The patient should be assessed immediately for airway, breathing, and circulatory compromise, as with all trauma patients (see Chapter

Table 140-2  Estimating Total Body Surface Area Burned Area

Percentage (%)

Total %

Head and neck

9

9

Each forelimb

9

18

Each rear limb

18

36

Dorsal trunk

18

18

Ventral trunk

18

18

TOTAL

99

FIGURE 140-1  This dog was burned by a hot paint can that exploded in a fire. Note the large eschar on the dorsum of the patient. This large area of full-thickness necrotic skin impedes granulation tissue formation and allows purulent exudates to accumulate beneath it. The dog was anesthetized to remove the eschar. (Courtesy M. Nicholson.)

1). After a full physical examination, including inspection of the patient from head to foot pads, an assessment of the degree and TBSA of the burn wounds should be performed to help determine prognosis and the extent of treatment necessary. Blood should be collected initially for evaluation of packed cell volume, total solids, electrolyte values, and blood gas parameters at the very minimum.

CHAPTER 140  •  Thermal Burn Injury

Metabolic Derangements If more than 20% of a patient’s TBSA is burned or if the wounds are classified as second or third degree, hypovolemic shock often occurs. As a result of capillary thrombosis and plasma leakage, massive amounts of fluid are retained in the wound, often leading to burn wound edema.5 This results in the loss of fluid and electrolytes, with the most dramatic losses occurring within the first 12 hours. Systemic abnormalities should be anticipated, including anemia, hypoproteinemia, hypernatremia or hyponatremia, hyperkalemia or hypokalemia, acidosis (metabolic and respiratory), oliguria, and prerenal azotemia. The course of the systemic abnormalities changes with time.4 Hemoconcentration will be noted initially because of the dramatic loss of plasma; however, red blood cell hemolysis also occurs from both direct damage and destruction through the damaged microcirculation. The patient should be monitored for disseminated intravascular coagulation (DIC), upper airway edema, and oliguria. Between days 2 and 6, the patient should be assessed for anemia, DIC, immune dysfunction, systemic inflammatory response syndrome, and early burn wound infection. From day 7 and on, the clinician should watch for hyperthermia, hypoxemia, pneumonia, sepsis, and wound demarcation. Fluid losses can result in hypovolemic shock (see Chapter 60). After initial shock resuscitation with isotonic crystalloids (up to 90 ml/kg intravenously [IV] in dogs and 50 ml/kg in cats) and synthetic colloids or blood products, if needed, total fluid delivery rate during the first 24 hours should be 1 to 4 ml/kg body weight × % TBSA burned.4 After 12 to 24 hours, when vascular permeability is stabilized, a constant rate infusion (CRI) of synthetic colloids (e.g., hydroxyethyl starch) may be beneficial at a rate of 20 to 40 ml/kg/ day (see Chapter 58). Fresh frozen plasma is given at 0.5 ml/kg body weight × % TBSA burned in humans, although this has not been investigated in dogs and cats. By 48 hours after injury, plasma volume is mostly restored, and thus patients are at high risk for generalized edema and fluid overload from the high initial demands for fluid replacement.5 Ideally, fluid therapy should be tailored to the individual patient based on hemodynamic and perfusion indices (see Chapter 183).

Nutrition Because of their fragile metabolic state, the importance of adequate nutrition cannot be overemphasized in patients with healing burn wounds. Nutritional requirements should be based on the patient’s needs; an initial estimate is made by calculating the resting energy requirement. The diet should be high calorie and high protein, and the quantity of food can be increased as tolerated by the patient. It is best if the patient can eat voluntarily, but if the animal is not consuming adequate nutrition, an esophagostomy tube should be placed or total parenteral nutrition commenced (see Chapters 129 and 130). Gastrointestinal (GI) protectants (famotidine at 0.5 to 1 mg/kg per os [PO], subcutaneously [SC], intramuscularly [IM], or IV q12-24h) are recommended to manage GI ulceration secondary to GI hypoperfusion (see Chapter 161).

Patient Comfort Although severely damaged skin is often numb, deeper viable tissues and surrounding areas are often hypersensitive and thermal damage may be ongoing; thus one should assume that burn patients experience extreme pain (see Chapters 144 and 163). Good systemic analgesics include methadone (0.1 to 0.5 mg/kg IV q2-6h), hydromorphone (0.05 to 0.1 mg/kg IV q4-6h) or fentanyl as a CRI (2 to 5 mcg/kg/hr IV +/− 1 to 3 mcg/kg bolus). A fentanyl patch may not be appropriate in animals with more than 20% TBSA burned or who are still being

treated for hypovolemic shock because of altered absorption. Good nursing care is important, and animals should be turned every 4 hours if recumbent to prevent decubitus ulcers. Passive range-ofmotion limb exercises can help prevent edema and maintain mobility.4

Antimicrobial Therapy Sepsis is one of the greatest threats to burn patients with extensive TBSA involvement, because bacteria can colonize and proliferate in wounds that have lost the protective skin barrier (see Chapter 182). The best way to prevent local and systemic infection is to protect the wound from contamination in the hospital environment, and to remove all necrotic tissue and purulent exudates from the wound surface as aggressively as possible through serial debridement. Systemic antimicrobials are not indicated unless the patient is immunocompromised, has pneumonia or pulmonary injury, or sepsis is suspected (see Chapter 175). Topical antibiotics are the antimicrobial treatment of choice (see Burn Wound Management in the following section). Because most invasive burn wound infections are caused by Pseudomonas or other gram-negative organisms, antimicrobials against these bacteria are administered empirically until culture and susceptibility testing results are available (see Chapters 93 and 94).5

BURN WOUND MANAGEMENT Although early wound closure is the primary goal to decrease further electrolyte, protein, and fluid losses, this is not usually performed for at least 3 to 7 days while the wound is “declaring” itself. Daily wound care, however, is critical. Once systemically stable, the patient is sedated with neuroleptanalgesia or placed under general anesthesia and the fur is liberally clipped to assess the damage. If fur pulls easily out of the skin, the wound is likely a deep partial-thickness or fullthickness burn1 (see Table 140-1). If the patient presents within 2 hours of the burn injury (which is usually not the case), cold water lavage for 30 minutes will often help to release heat from the skin and limit the depth of injury.1 The temperature of the water should not be below 3° C, and if large body surface areas require treatment, it is important to prevent iatrogenic hypothermia. The affected area can be submerged in a cold water bath if it is on a limb, and cool towels or cool water from a spray nozzle can be applied to other areas. Treatment of the wound then depends on its depth. In patients with superficial burns or superficial partial-thickness burns, it may be appropriate to use daily lavage and topical agents alone until the extent and depth of the wound is determined.1 Deep partial-thickness and full-thickness burns require debridement, which can be done in three ways: conservatively, enzymatically, or surgically.1 Conservative debridement is often used for the first 3 to 7 days as the wound declares itself and the patient stabilizes; then more aggressive surgical debridement can be performed. In human burn patients, prompt removal of burn eschar is positively correlated with improved survival and reduced morbidity because of control of sepsis and reduced scarring.7,8 Daily treatment of burn wounds with conservative debridement involves hydrotherapy, removal of necrotic tissue, topical therapy, and bandaging. This may need to be done more than once a day initially for wounds that are necrotic or exudative. Hydrotherapy consists of gentle lavage of the wound with room temperature sterile saline or lactated Ringer’s solution. This helps to loosen and separate any nonviable or necrotic tissue from the surface of the burn. The lavage solutions should be delivered using a 35-ml syringe and a 19-gauge needle to create a pressure of 8 psi. Higher pressures may induce tissue trauma and cause deeper seeding of bacteria into the burn. A wet-to-wet dressing under a bandage can also be placed on

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FIGURE 140-2  This is the dog from Figure 140-1, 4 weeks after escharectomy. Note the healthy granulation tissue and how the wound has become smaller via contraction and epithelialization. (Courtesy M. Nicholson.)

FIGURE 140-3  Postoperative view of the burn wound of the dog from Figures 158-1 and 158-2; it was closed primarily by elevating the skin edges and taking advantage of the loose, elastic skin over the body of the dog. (Courtesy M. Nicholson.)

burns for several hours at a time to slowly loosen the necrotic tissue and facilitate debridement.1,6 Conservative debridement is characterized by the daily serial piecemeal removal of necrotic tissue (black and hard, burned skin) using aseptic technique, with either sterile gauze or sterile scissors and thumb forceps. Because necrotic tissue is without sensation, this may not require daily general anesthesia; however, manipulation of deeper viable tissues and surrounding hyperemic areas likely will be painful during lavage. This form of debridement is acceptable initially, when there is no clear definition of nonviable tissue, or when it is prudent to be conservative in areas overlying tendons, ligaments, and bone.1 Enzymatic debridement is the use of topical agents to soften, loosen, and digest necrotic tissue, facilitating removal with gentle lavage. The advantages are that it does not require general anesthesia and also spares healthy tissue. Because some of the commercially available agents are expensive, it is most cost effective to use them on small limb wounds. The most commonly used enzymatic topical agent contains trypsin, balsam Peru, and castor oil (Granulex, UDL Laboratories, Inc., Canonsburg, PA). This product should be applied only in the early stages of wound therapy, then discontinued once a healthy bed of granulation tissue has been established.6 Aggressive surgical excision of an entire burn wound requires general anesthesia and is indicated in deep partial-thickness and full-thickness burn wounds that may otherwise take days or weeks with conservative debridement. This is done most easily on large areas of the trunk or small areas of the limbs, which can then be closed primarily (Figures 140-2 and 140-3). If the area cannot be closed primarily, it will take about 5 to 7 days for a healthy granulation bed to form, at which time flap or skin graft surgery can be performed.1

After the first 24 hours, silver sulfadiazine should be applied.2 It has a wide spectrum of bactericidal activity against gram-positive and gram-negative bacteria and Candida. The cream is placed directly on the wound under the contact layer of a bandage using sterile gloves. For very large areas that are not amenable to bandaging, silver sulfadiazine should be slathered over the wound and the patient confined within a low-fomite environment (empty clean cage with no blankets or stuffed toys).1,6 If needed, the cream can be rinsed off gently before reapplication, up to 2 to 3 times a day. Silver sulfadiazine can be used during both the early debridement stage under wet-to-wet dressings and through the repair stages of healing using nonadherent bandages. Alternatively, nanocrystalline silver dressings that allow for slow sustained release of silver are a slightly more expensive option that can be left on the wound for up to 3 to 7 days.2,9 Medicinal honey and sugar can also be used in the treatment of burn wounds; they are beneficial during debridement and help to control secondary infections (see Chapter 139).

Topical Agents After hydrotherapy and debridement, topical agents, dressings, and bandages are applied. Aloe vera and silver sulfadiazine are the most commonly used and readily available topical compounds for burn wounds. Aloe vera cream has antithromboxane effects that prevent vasoconstriction and thromboembolic seeding of the dermal vasculature.2,6 Ideally, using it within the first 24 hours can help prevent progression of superficial partial-thickness burns. Aloe vera is applied liberally to the surface of the wound with a sterile gloved finger while the patient is sedated, because these wounds are painful when touched. The wound should then be covered with a nonadherent hydrophilic dressing and bandage.

Closure Options and Healing Superficial and partial-thickness burn wounds have a favorable outcome with no surgical intervention. These wounds reepithelialize quickly and can heal within 1 to 3 weeks with open wound management. If only the superficial layer of the dermis is involved in partialthickness burns, healing is often rapid. The overlying burned epidermis will slough, and healthy epithelium will be apparent below. Deeper burns involving the hair follicles, especially if they are large, will heal more slowly (up to 3 weeks). Deep dermal partial-thickness and full-thickness burns heal by contraction and epithelialization once a healthy granulation bed has been created by diligent debridement. Eventually, these wounds can be closed primarily. Full-thickness burns covering large areas of the body, or those on the limbs, may require skin grafts or skin flaps for complete closure. Improvement in the healing of extensive burn wounds has been investigated using newer treatment strategies including negative pressure wound therapy and hyperbaric oxygen therapy (see Chapter 139).

Complications Scarring and wound contracture are the biggest complications in patients with burn wounds left to heal by second intention. This is particularly a concern for patients with burn wounds in the axillary or inguinal areas, or around joints, which can lead to decreased mobility and range of motion of the limbs. Wounds in these areas should be managed by someone experienced in reconstructive surgery because they will likely require skin grafts or flaps.

CHAPTER 140  •  Thermal Burn Injury

REFERENCES 1. Pavletic MM: Management of specific wounds: Burns. In Atlas of small animal wound management and reconstructive surgery, ed 3, Ames, IA, 2010, Wiley-Blackwell. 2. Fossum TW, Hedlund CS, Hulse DA, et al: Burns and other thermal injuries. In Fossum TW, editor: Small animal surgery, ed 3, St Louis, 2007, Mosby. 3. Bohling MW: Burns. In Tobias KM, Johnston SA, editors: Veterinary surgery small animal, St Louis, 2012, Elsevier Saunders. 4. Dhupa N, Pavletic MM: Burns. In Morgan R, editor: Handbook of small animal practice, ed 4, 2003, Saunders. 5. Pope ER: Burns: thermal, electrical, and chemical burns and cold injuries. In Slatter DH, editor: Textbook of small animal surgery, ed 3, St Louis, 2003, Saunders.

6. Swaim SF, Henderson RA: Small animal wound management, ed 2, Baltimore, 1997, Williams & Wilkins. 7. Scaffle JR: Critical care management of the severely burned patient. In Parrillo JE, Dellinger RP, editors: Critical care medicine—principles of diagnosis and management in the adult, ed 3, Philadelphia, 2008, Mosby Elsevier. 8. Gallager JJ: Burn wound management. In Cameron JL, Cameron AM, editors: Current surgical therapy, ed 3, Philadelphia, 2011, Elsevier Saunders. 9. Murphy PS, Evans GRD: Advances in wound healing: a review of current wound healing products, Plastic Surg Int 190436, 2012.

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PART XVII  ANESTHESIA AND PAIN MANAGEMENT CHAPTER 141  PAIN AND SEDATION ASSESSMENT Sandra Perkowski,

VMD, PhD, DACVA

KEY POINTS • Pain is considered the fifth vital sign in human medicine (along with temperature, pulse, respiration, and blood pressure), which emphasizes the importance of an effective approach to pain management in the critical care patient. • Pain assessment in the veterinary patient is inherently difficult, especially within the confines of a hospital setting where anxiety and stress can confound the accurate assessment of changes in patient status. • Physiologic changes, although an integral part of the overall patient assessment, are not always reliable indicators of pain. • Observational measures of behavior are an essential part of pain assessment, although they are subject to misinterpretation, especially in the anxious or dysphoric patient. • No single pain scoring system has been universally adopted in veterinary medicine as the gold standard, although descriptions of many systems have been published and some systems have been validated. • Before any assessment tool is applied, it is important to recognize the limits of the technique. • The effectiveness of any treatment should be reevaluated regularly and pain management therapy adjusted as needed. • A return to normal behavior and/or improvement in quality of life are the ultimate goals of any pain management strategy.

The multimodal use of analgesics has become an integral part of small animal practice over the last several years as the awareness of the complexity of pain pathways and the potential for long-term detrimental effects in veterinary patients has increased. Traditionally, it has been believed that some pain persisting into the postoperative period may be helpful to encourage immobility and, in turn, healing and recovery. Similarly, acute pain occurring at the area of injury in the trauma patient can serve to help protect the body part or system, minimizing further injury. However, acute pain also causes significant negative endocrine and metabolic effects that are known to delay recovery. These include immobility, decreased pulmonary function and atelectasis, decreased immune function, higher incidence of pneumonia, catecholamine release leading to increased metabolic rate and oxygen consumption, increased blood pressure and heart rate, cardiac arrhythmias, peripheral vasoconstriction, stress hormone release, inappetence, and insomnia. Most importantly, pain leads to patient suffering. The use of analgesics is especially important in critically ill patients in which any negative physiologic effects may have a profound impact on outcome. Although analgesia may be postponed for a severely injured patient

due to the need for immediate lifesaving interventions, adequate pain control is ultimately essential to offset further detrimental effects. Increased comfort with the use of constant rate infusions and a better understanding of the pharmacokinetic and pharmacodynamics differences between the many veterinary species and humans has led to new and synergistic combinations of multiple analgesic drugs (multimodal analgesia), which allows for decreased doses and reduced adverse effects in the critically ill patient.

DEFINITION OF PAIN Aristotle first envisioned pain as originating from specific types of stimulation, including heat, cold, toxins, and crush, leading to acute awareness of the need to escape. Pain has more recently been defined by the International Association for the Study of Pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.”1 By definition, pain is a subjective event and cannot truly be measured in an accurate fashion by an outside objective observer. The perception of pain and response to a noxious stimulus are determined not only by the degree of injury but also by the individual’s unique experience. Pain assessment becomes inherently more difficult in veterinary patients due to the obvious limitations in verbal communication, with attempts to anthropomorphize the animal’s behavior potentially increasing the degree of error in our assessment. As a result, a number of assessment techniques have been described in the veterinary literature over the past several years, some of which are currently undergoing validation using strict criteria. Nociception involves the series of electrochemical events that start at the site of tissue injury and result in the perception of pain. First, transduction of the noxious stimulus into an electrical stimulus (action potential) occurs in a discrete set of receptors (nociceptors) that detect tissue-injuring stimuli. Second, transmission of the nervous impulse occurs along the primary afferent fibers (A-delta and C-polymodal fibers) from the periphery through the spinal cord and ascending relay neurons in the thalamus to the somatosensory cortex. As the signal travels through the dorsal horn of the spinal cord, modulation (amplification or inhibition) of the message helps determine the strength of the signal reaching higher centers in the brain. In addition, projections to the reticular formation and hypothalamus increase alertness and autonomic functions (e.g., heart rate and respiratory rate) and increase catecholamine and glucocorticoid release. Finally, integration of the aforementioned processes with the unique psychology of the individual results in the final experience of pain perception. 749

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PART XVII  •  ANESTHESIA AND PAIN MANAGEMENT

Knowledge of these processes has stimulated considerable research into endogenous circuits, neurotransmitters, and interactions that either facilitate or inhibit the perception of pain. These processes are no longer viewed as a static system. Long-term anatomic, genetic expression, and circuit changes occur within the peripheral and central nervous system following acute and chronic stimulation. This has led to an emphasis on preemptive analgesia. Patients under anesthesia during surgery may be unconscious and unable to feel pain, but that does not necessarily attenuate the processing of nociceptive input and altered perception upon awakening. The pharmacology of analgesics is different in patients with chronic pain and those with acute pain. For example, opioids appear to be more effective for patients with acute rather than chronic, neuropathic pain. In addition, opioid use rapidly (within hours) leads to the development of opioid tolerance and opioid-induced hyperalgesia, both of which may be attenuated by the addition of an N-methyl-d-aspartate receptor antagonist (e.g., ketamine or methadone) or gabapentin.

PAIN VERSUS STRESS In general, physiologic and behavioral responses to pain have been used to develop a number of pain assessment tools or rating scales to determine the level of pain and/or sedation in the veterinary patient. These scales may change depending on the circumstances under which the scale is being used (e.g., acute pain after trauma or surgery vs. chronic pain of orthopedic or neuropathic origin), the underlying disease process (e.g., cancer vs. orthopedic disease), as well as the location (somatic vs. visceral, deep vs. superficial) and severity of the inciting stimulus. Consideration must also be given to differences in behavior with age, species, breed, and environment. It is important to recognize that these pain scoring systems have little value in optimizing analgesic therapy unless the person applying them has a basic understanding of pain physiology and pathways. Understanding mechanisms of pain transmission and antinociceptive mechanisms allows a logical choice to be made in prescribing analgesics for patients. Analgesia may be directed at minimizing inflammatory changes at the site of injury, inhibiting transduction or transmission of the nerve impulse (both at peripheral and spinal endings), or increasing the activity of descending inhibitory pathways acting at the central nervous system. For example, opioids have traditionally been viewed as centrally acting drugs and are most frequently given systemically. However, opioids may also be given epidurally or intrathecally, stimulating opioid receptors found at the level of the spinal cord to produce analgesia. In addition, there is evidence for the activation of peripheral opioid receptors (e.g., within the joint capsule) following tissue damage or chronic inflammation. Another confounding factor in assessing pain in veterinary patients is that it is frequently accompanied by stress and anxiety. The stress response may occur in the absence of injury and in response to any number of environmental factors, including restraint, new surroundings, the presence of other animals, or other perceived threats to the animal. Stress, anxiety, and sleeplessness can all amplify the animal’s perception of pain. Because anxiety increases the stress response to a painful stimulus, the responses themselves begin to impact the individual negatively. These responses include behavioral changes associated with “fight or flight”; neuroendocrine responses such as cortisol release, hyperglycemia, and catecholamine release; physiologic changes associated with sympathetic nervous system stimulation (e.g., tachycardia, hypertension, vasoconstriction); immunosuppression; and hypercoagulability. In terms of pain assessment, many of the physiologic changes seen during the stress response are similar to those seen in the pain response. The patient may not

eat or sleep well. In conjunction with the neurohormonal responses, this sets up an overall catabolic state in the patient. Although it is incumbent upon the medical provider to treat the animal on the assumption that it may be in pain, frequently it is not possible to quiet the animal using analgesics alone, and administration of a sedative agent such as a benzodiazepine tranquilizer (midazolam 0.1 mg/kg), a phenothiazine tranquilizer (acepromazine 0.005 to 0.01 mg/kg) or a low-dose α2 agonist (e.g., dexmedetomidine 0.5 to 1 mcg/kg) is necessary to reduce the anxiety and allow the animal to rest and recuperate. Midazolam or dexmedetomidine may be given as a constant rate infusion, if needed. In addition, those who interact with the animal should remember to use a soothing tone and gentle demeanor.

PAIN ASSESSMENT Behavior As stated previously, the perception of pain is clearly a subjective experience and can be quite difficult to quantify, especially in veterinary patients. However, there are some basic strategies that may help to assess accurately pain in these patients. First of all, it is important to observe the patient. This should be done with the patient both on its own and while interacting with people. Is the patient displaying one or more signs indicative of pain? These include both physiologic signs associated with sympathetic nervous system stimulation and behavioral signs (Box 141-1). It is apparent that physiologic responses related to catecholamine release and sympathetic nervous system stimulation may be very difficult to differentiate from changes seen in response to anxiety. Therefore physiologic changes are not always reliable indicators of pain. In one study comparing subjective and objective measures for determining the severity of pain after cruciate repair in dogs,2 changes in physiologic parameters did not correspond well with pain threshold testing and correlated only poorly with subjective measures of pain (visual analog or numerical rating scale; see later in

BOX 141-1 

Signs Associated with Acute Pain in Dogs and Cats

Physiologic Signs Increased heart rate with or without arrhythmias Increased respiratory rate (often with decreased tidal volume) Increased blood pressure Increased temperature Salivation Dilated pupils

Behavioral Signs Vocalization: growling, whining, whimpering, groaning (dogs); purring, growling (cats) Restlessness or agitation Resentment of handling of painful area Depression or inactivity Insomnia or reluctance to lie down Inappetence Increased aggression or timidity Abnormal posturing (hunched, prayer position) Alterations in gait, disuse or guarding Licking or chewing at painful area Trembling, increased muscle tension Altered facial expression (fixed stare, squinting) Failure to groom (cats) Increased or decreased urination, failure to use litter box (cats)

CHAPTER 141  •  Pain and Sedation Assessment

chapter). Similar findings have been reported by others in both children3 and dogs.4 In addition, pain produces other neuroendocrine responses similar to those produced in stress situations, including stress hormone (cortisol) release and hyperglycemia. Furthermore, immunocompetency is decreased and a stress leukogram may be present. Observational measures of behavior are also an essential part of pain assessment, although they are subject to limitation, especially in the anxious or dysphoric patient. Most people tend to focus on vocalization and agitation as signs of pain. Unfortunately, these two behaviors are frequently the least specific, especially after administration of opioid analgesics or in the postoperative period when many animals are disoriented or excited due to the anesthetic drugs that were used. Many animals show few outward signs of pain in the presence of other animals or humans. The species, breed, and age of the animal may also affect the signs exhibited. For example, cats are especially difficult to assess for pain. The need for analgesia is frequently overlooked in feline patients, since they tend not to vocalize. One study examining analgesic use in dogs and cats after major surgery in a veterinary teaching hospital5 found that only 1 in 15 cats received any postoperative analgesia and that only one dose of medication was administered. Although much has changed over the ensuing years, this example demonstrates how easy it may be to confuse pain with mental depression in many feline patients. Most cats will merely sit quietly in the back of the cage and not move when they are in pain. They frequently stop grooming. They may be inappetent, insomnolent, or mildly pyrexic. A dramatic improvement in attitude and appetite is often seen after administration of analgesics.

Tools A number of different pain scoring systems are currently in use in both human and veterinary medicine. The large number of these systems is testament to the fact that no one system has yet been universally adopted as the gold standard. It also should be recognized that pain scales used in the acute setting may not be appropriate for use in the chronic setting, in which owner involvement and qualityof-life assessment become increasingly more important.6 However, use of a pain assessment form may be helpful in raising awareness of an individual patient’s pain and/or distress and increasing the use of appropriate analgesic and/or sedative therapy in the hospital setting. In the acute setting, quantification of pain behaviors is often done using variations of a simple descriptive scale, a visual analog scale (VAS), or a numerical rating scale (NRS), which may or may not incorporate changes in physiologic parameters. The simple descriptive scale typically rates pain as “none,” “mild,” “moderate,” or “severe.” Each rating is then assigned a number (e.g., from 1 to 4), which becomes the patient’s score. Although relatively simple to use, such a scale lacks sensitivity due to the relatively small number of categories. In contrast, a human study found that a 10- to 20- point scale was required to provide sufficient sensitivity to assess pain intensity in a group of patients with chronic pain.7 Visual analog (Figure 141-1) and numerical rating scales have been used to evaluate pain in human infants, in laboratory animals, and in several veterinary clinical studies. These scales can give

0 No pain

50

100 Worst pain possible

FIGURE 141-1  Example of a visual analog scale (VAS) used to assess severity of pain by making a mark along a 100-mm line to indicate the patient’s estimated level of pain.

2,8

reproducible results, even when used by multiple observers. In pediatric medicine, a strong correlation exists between ratings provided by patients and ratings of their caregivers when either scale is used.9 The VAS is typically a straight line, 100 mm in length. One end of the line (0 mm) represents no pain and the other end (100 mm) represents the worst pain possible. The observer (or patient) is asked to mark where along the scale the patient’s perceived pain would fall and a measurement is then taken and a number recorded, which allows the observer to track changes over time. Advantages of the VAS are that it avoids the use of descriptive terms and the need to assign a number to the pain. In the hands of an experienced observer, it can be a sensitive tool with reproducible results and has been considered the gold standard pain measurement tool in humans.10 Similarly, owners can be easily taught to track changes in their animal at home. Disadvantages of the technique include observer variability in the interpretation of the term “worst pain possible.” For example, does this mean the worst pain possible for this particular injury or disease, or for any injury or disease? Another disadvantage is that the VAS may be unduly influenced by signs that are easily detectable. For example, one study found that VAS scores were significantly and consistently correlated with increases in vocalization and respiratory rate in dogs after cruciate repair, both of which are easy to recognize at a quick glance.2,11 Although both of these signs may increase in response to pain, they may also increase in response to anxiety or drug-induced dysphoria. These other factors must then be identified and taken into account when using a VAS. Similarly, the clinical significance of a given amount of change in the VAS may change depending on the patient and the disease process. Therefore the VAS is often used in conjunction with other pain assessment tools. The NRS consists of multiple categories with which to evaluate the patient’s behavior. Within each category, different levels of that behavior are given and assigned a whole number. In addition to these specific behaviors, changes in physiologic parameters may also be included. For example, an increase in heart rate or respiratory rate from 0% to 10% of baseline in the postsurgical patient may be assigned a value of 0, a change of 10% to 20% a value of 1, a change of 20% to 30% a value of 2, and so forth, and these scores added to the total. However, it should be noted that multiple studies have shown that changes in heart rate, respiratory rate, and blood pressure correlate poorly or not at all with pain threshold or subjective measures of pain in dogs in the postoperative setting.2,12 A simple NRS is shown in Table 141-1. One disadvantage of the NRS is that it provides an ordinal measurement and assumes that a change from 1 to 2 is equivalent in

Table 141-1  Example of a Numerical Rating Scale Used to Assess Severity of Pain in Dogs Observed Behavior Vocalization

Score 0 1 2

Criteria No vocalizing Vocalizing, responds to calm voice and stroking Vocalizing, does not respond to calm voice and stroking

Movement

0 1 2

None Frequent position changes Thrashing

Agitation

0 1 2 3

Asleep or calm Mild agitation Moderate agitation Severe agitation

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PART XVII  •  ANESTHESIA AND PAIN MANAGEMENT SHORT FORM OF THE GLASGOW COMPOSITE PAIN SCALE Dog’s name Hospital Number

Date

/

/

Time

Surgery Yes/No (delete as appropriate) Procedure or Condition

In the sections below please circle the appropriate score in each list and sum these to give the total score.

A. Look at dog in kennel Is the dog? (i) Quiet Crying or whimpering Groaning Screaming

0 1 2 3

(ii) Ignoring any wound or painful area Looking at wound or painful area Licking wound or painful area Rubbing wound or painful area Chewing wound or painful area

0 1 2 3 4

In the case of spinal, pelvic, or multiple limb fractures. or where assistance is required to aid locomotion do not carry out section B and proceed to C Please tick if this is the case then proceed to C. B. Put lead on dog and lead out of the kennel. C. If it has a wound or painful area including abdomen, apply gentle pressure 2 inches around the site. When the dog rises/walks is it? Does it? (iii) (iv) Normal 0 0 Do nothing Lame 1 1 Look around Slow or reluctant 2 2 Flinch Stiff 3 3 Growl or guard area It refuses to move 4 4 Snap 5 Cry D. Overall Is the dog?

Is the dog? (v) Happy and content or happy and bouncy Quiet Indifferent or nonresponsive to surroundings Nervous or anxious or fearful Depressed or nonresponsive to stimulation

0 1 2 3 4

(vi) Comfortable Unsettled Restless Hunched or tense Rigid

0 1 2 3 4

Total Score (i+ii+iii+iv+v+vi) = FIGURE 141-2  Short form of a validated pain questionnaire developed for assessment of acute pain in dogs. Descriptors are ranked numerically according to the associated severity of pain. The assessment should be performed following closely the procedure described in the questionnaire. The pain score is the sum of the rank scores; the maximum possible score is 24 or 20, depending on whether or not mobility is possible to assess. The recommended analgesic intervention level is 6 out of 24 or 5 out of 20.

degree to a change from 2 to 3. Similarly, the categories themselves are not weighted and instead are assigned equal importance in determining the overall score. Another problem with the simple descriptors used in some NRS systems is their lack of specificity. In an unpublished survey involving the clinically active veterinarians and nurses at the University of Pennsylvania (S.Z. Perkowski, unpublished data, 1992), vocalization was the most commonly cited indicator of pain in dogs. However, vocalization also occurs nonspecifically with a high incidence in the postsurgical patient and can contribute to a falsely high pain score.

Clearly, behavioral changes indicative of pain may be difficult to recognize reliably in the acute clinical setting given the time frame. One study comparing use of an NRS and a quantitative behavioral scoring system over a 24-hour period found that dogs receiving adequate opioid analgesia after ovariohysterectomy had a more rapid return to normal greeting behaviors than dogs that received placebo.13 However, the NRS used was unable to differentiate between the two groups of dogs. A pain scoring system was developed by the University of Melbourne (University of Melbourne Pain Scale) to assess postoperative pain in dogs by comparing preoperative and

CHAPTER 141  •  Pain and Sedation Assessment

postoperative behavior, and an improved degree of interobserver agreement was found using this method.14 This suggests that increased familiarity with the animal can help in overall pain assessment and management. In dogs with osteoarthritis, the owner assessment of the degree of pain correlates better with force plate evaluation than the assessment by veterinarians. Similarly, in cats with osteoarthritis, a subjective assessment by owners performed using a simple yes/no questionnaire to determine changes in activity associated with pain relief correlated well with changes in activity objectively measured using activity counts generated by an accelerometer.15 The Glasgow Composite Measures Pain Scale is among the most completely validated multidimensional pain scale system for use in dogs with acute postoperative pain.16,17 This tool takes the form of a questionnaire, and the behaviors included in the scale fall into several basic categories: posture, comfort, vocalization, attention to wound, demeanor, mobility, and response to touch. Assessment includes both observation from a distance and interaction with the patient. A short form of this scale has been developed that takes only a few minutes to complete (Figure 141-2).

SUMMARY Veterinary patients frequently require analgesics for a period of time after acute trauma or surgery. Before any assessment tool is applied, it is important to recognize the limits of the technique. Learning to anticipate when a patient will be in pain is extremely helpful, since pain is much easier to manage if the patient is treated before it experiences pain and becomes upset than if it is treated afterward. Frequently, knowing what the patient’s underlying disorder is, whether or not a procedure has recently been performed on the animal, and, if so, what type of procedure can guide the appropriate use of analgesics. Usually, analgesics are given before any invasive procedure to take advantage of preemptive analgesia and minimize “wind-up.” It should be remembered that very young and very old patients, as well as critically ill patients, tend to be less tolerant of pain and the neurohormonal and autonomic changes associated with pain. Close attention should be paid as to whether the initial treatment provides adequate analgesia and how long the analgesic effect lasts. Reevaluate the effectiveness of treatment regularly! Response to therapy can help enormously in guiding overall pain management. Do not wait for obvious signs of pain before repeating the treatment, unless the adverse effects are excessive. Individualize the treatment approach. Before administering any drug, carefully observe the animal and consider the underlying disease process. If any expected adverse effects are undesirable or potentially life

threatening, the analgesic technique should be modified. It is important to remember that a return to normal behavior is the ultimate goal of pain management.

REFERENCES 1. Bonica JJ: The need of a taxonomy, Pain 6(3):247-248, 1979. 2. Conzemius MG, Hill CM, Sammarco JL, et al: Correlation between subjective and objective measures used to determine severity of postoperative pain in dogs, J Am Vet Med Assoc 210:1619-1622, 1997. 3. Anand KJ, Hickey PR: Pain and its effects in the human neonate and fetus, N Engl J Med 317:1321-1329, 1987. 4. Holton L, Scott EM, Nolan AM, et al: Relationship between physiological factors and clinical pain in dogs scored using a numerical rating scale, J Small Anim Pract 39:469-474, 1998. 5. Hansen B, Hardie E: Prescription and use of analgesics in dogs and cats in a veterinary teaching hospital: 258 cases (1983-1989), J Am Vet Med Assoc 202:1485-1494, 1997. 6. Yazbek KVB, Fantoni DT: Validity of a health-related quality-of-life scale for dogs with signs of pain secondary to cancer, J Am Vet Med Assoc 226:1354-1358, 2005. 7. Jensen MP, Turner JA, Romano JM: What is the maximum number of levels needed in pain intensity measurement? Pain 58:387-392, 1994. 8. Welsh EM, Gettinby G, Nolan AM: Comparison of visual analogue scale and a numerical rating scale for assessment of lameness, using sheep as a model, Am J Vet Res 54:976-983, 1993. 9. Manne SL, Jacobsen PB, Redd WH: Assessment of acute pediatric pain: do child self report, parent ratings and nurse ratings measure the same phenomenon? Pain 48:45-52, 1992. 10. De Williams AC, Davies HT, Chadury Y: Simple pain ratings scales hide complex idiosyncratic meanings, Pain 85:457-463, 2000. 11. Sammarco JL, Conzemius MG, Perkowski SZ, et al: Postoperative analgesia for stifle surgery: a comparison of intra-articular bupivacaine, morphine, or saline, Vet Surg 25:59-69, 1996. 12. Holton L, Scott EM, Nolan AM, et al: Comparison of three methods used for assessment of pain in dogs, J Am Vet Med Assoc 212:61-66, 1998. 13. Hardie EM, Hansen BD, Carroll GS: Behavior after ovariohysterectomy in the dog: what’s normal? Appl Anim Behav Sci 51:111-128, 1997. 14. Firth AM, Haldane SL: Development of a scale to evaluate postoperative pain in dogs, J Am Vet Med Assoc 214:651-659, 1999. 15. Lascelles BDX, Hansen BD, Roe S, et al: Evaluation of client-specific outcome measures and activity monitoring to measure pain relief in cats with osteoarthritis, J Vet Intern Med 21:410-416, 2007. 16. Holton L, Reid J, Scott EM, et al: Development of a behaviour-based scale to measure acute pain in dogs, Vet Rec 148:525-531, 2001. 17. Morton CM, Reid J, Scott EM, et al: Application of a scaling model to establish and validate an interval level pain scale for assessment of acute pain in dogs, Am J Vet Res 66:2154-2166, 2005.

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CHAPTER 142  SEDATION OF THE CRITICALLY ILL PATIENT Sandra Perkowski,

VMD, PhD, DACVA

KEY POINTS • Evaluation and preparation of the critically ill patient are essential before any drug is administered. The choice of sedative agent depends on the patient’s current physical status, preexisting conditions, reason for presentation, current treatment, and procedure to be performed. • Most sedative techniques in the critically ill patient, especially those with cardiovascular compromise, involve using a sedative or tranquilizer in combination with an opioid analgesic. • Critically ill patients are often depressed and require lower doses of drug to achieve the desired sedative effect; drugs should be titrated to effect carefully to minimize further compromise. • Respiratory depressants, such as opioids, should be used judiciously in patients with severe hypoxemia or upper airway obstruction. • Due to its short duration of action, propofol is ideal for short procedures requiring heavy sedation. However, it may cause significant cardiovascular depression in patients with volume depletion or cardiovascular compromise.

Sedation of critically ill veterinary patients is often required to permit minor surgical procedures and diagnostic measures. Advantages over general anesthesia include flexibility and ease of drug administration as well as avoidance of the need for intubation and inhalant anesthetics (although oxygen supplementation is generally recommended). Significant cardiovascular and respiratory depression may result, however, leading to life-threatening compromise of the patient’s status. To minimize the influence of preexisting conditions and the extent of crises that may occur, a thorough evaluation and adequate preparation of the patient are essential before any drug is administered.

PATIENT EVALUATION AND MANAGEMENT On arrival of the patient to the intensive care unit, immediate attention should be paid to the ABCs (airway, breathing, and circulation; see Chapter 1). These should be deemed adequate before proceeding. Evaluation of neurologic status, including assessment for mental status and evidence of head trauma, should be included. A complete history should be obtained if possible, including presenting complaint, known medical conditions, any current medications, and previous anesthetic history. Oxygen supplementation and ventilatory support are provided as necessary. Indications for securing an airway early include poor ventilation or oxygenation, deteriorating mental status, lack of a gag reflex, and signs of developing airway obstruction. Stabilization of fluid balance and cardiovascular function is also essential before drug administration, although assessing the adequacy of intravascular volume can be difficult (see Chapter 60). The impact of inadequate intravascular volume will be accentuated by the peripheral vasodilation caused by many sedative agents, including acepromazine and 754

propofol, and the generalized decrease in sympathetic tone that occurs with sedation. Adequate intravascular access is essential. Cardiac arrhythmias, especially premature ventricular contractions, are commonly seen in critically ill patients, including those with gastric dilatation or volvulus, hemoabdomen, and thoracic trauma. In addition, they can occur secondary to electrolyte abnormalities, hypoxemia, or hypercarbia. Before sedation, the type and significance of any arrhythmias present should be determined and the underlying cause treated, if possible. Indications for antiarrhythmic therapy before drug administration include frequent, multifocal premature ventricular contractions and paroxysmal ventricular tachycardia that adversely affects blood pressure or perfusion parameters (see Chapter 171). When time and the animal’s condition permit, any electrolyte abnormalities should be corrected before drug administration. Severe hyperkalemia (potassium [K+] > 6.0 mEq/L) is frequently seen in patients with renal compromise, urinary obstruction or rupture, massive tissue trauma, or severe dehydration with acidosis. Drug administration can exacerbate the cardiac effects of hyperkalemia, including arrhythmias and cardiac arrest, and therefore management should be instituted before proceeding. Hypocalcemia may be seen transiently after citrated blood product administration, although this generally resolves once administration is finished.

CHOICE OF AGENT The choice of sedative agent depends on the patient’s current physical status, reason for presentation, pertinent history, and procedure to be performed. Special attention should be paid to both cardio­ vascular and respiratory effects of these agents, but specific con­ traindications to drug use should also be considered. Intravenous administration allows titration of the drugs and is generally preferred. Intramuscular administration may be helpful, especially in the fractious patient or one with severe respiratory distress that does not have an intravenous catheter and becomes easily stressed with restraint.

OPIOIDS Most sedative techniques in the critically ill patient involve the use of a sedative or tranquilizer in combination with an opioid analgesic. This “neuroleptanalgesic” combination generally produces a greater degree of sedation and analgesia with less cardiovascular depression than that achieved by comparable doses of either drug alone. Most of the clinically used pure opioid agonists (morphine, oxymorphone, hydromorphone, methadone, fentanyl, remifentanil) bind primarily to the µ-receptor in the central nervous system, although they interact with the others (κ, δ), especially at higher doses.1 In healthy animals, opioids cause behavioral changes ranging from sedation to excitement; however, in critically ill patients, opioids usually cause sedation (see Chapter 163). Cardiovascular function, including left ventricular function, cardiac output, and systemic

CHAPTER 142  •  Sedation of the Critically Ill Patient

blood pressure, is well maintained. Although morphine may be a useful sedative, histamine release with subsequent vasodilation and hypotension may occur, especially if higher doses are given intravenously (IV).2 In contrast, no increase in plasma histamine level is seen after hydromorphone or oxymorphone administration. The incidence of nausea and vomiting, a risk factor for the development of aspiration pneumonia, is less after oxymorphone (33%) than after hydromorphone (44% to 66%) or morphine (50% to 75%).3,4 Nausea and vomiting are rarely seen after administration of methadone, fentanyl, or remifentanil. A recent report found a significant decrease in the incidence of nausea and vomiting in dogs given the neurokinin-1 receptor antagonist maropitant, 1 mg/kg subcutaneously [SC]) 1 hour before hydromorphone is administered intramuscularly (IM).4 Oxymorphone, hydromorphone, methadone, fentanyl, and remifentanil are all useful intravenous agents, especially in combination with benzodiazepine tranquilizers (midazolam, diazepam), since they provide the most cardiovascular stability (see Chapter 164).5,6 Vagally mediated bradycardia or second-degree atrioventricular block is often seen after opioid administration and can be treated with anticholinergics (atropine, glycopyrrolate) as indicated. Fentanyl and remifentanil are short-acting agents and may be given as a constant rate infusion (CRI). They are often used in combination with a propofol CRI for total intravenous anesthesia (also known as TIVA).7 A low-dose ketamine CRI may be added to provide additional analgesia. Although opioids are relatively sparing of the cardiovascular system, they may act as respiratory depressants, causing a decreased ventilatory response to increased CO2 concentrations. Respiratory depression may be exacerbated by concomitant administration of other sedatives. Therefore opioids should be used judiciously and at decreased doses if respiratory depression and hypoventilation are contraindicated, as in patients with airway obstruction or increased intracranial pressure. Remifentanil is especially potent as a respiratory depressant, although it has a short elimination half-life of about 7 minutes, so spontaneous ventilation usually resumes soon after the infusion is turned off.7 It is important not to mistake panting for effective ventilation; therefore the clinician must look carefully at the depth of each breath as well as the rate.

Methadone is being used with increasing frequency in the critical care setting because it is associated with a lower incidence of nausea and vomiting relative to the other available drugs. In addition to its effects at the opioid receptor, methadone has N-methyl-d-aspartate (NMDA) receptor antagonistic properties (similar to ketamine), which can help prevent the development of opioid tolerance and opioid-induced hyperalgesia.8 Butorphanol, a κ agonist and µ antagonist, and buprenorphine, a partial µ agonist, may cause less respiratory depression and are preferred in some cases. Other clinically significant adverse effects such as vomiting and decreased gastrointestinal motility may also be less pronounced with these drugs, although they also tend to provide less analgesia. If undesirable side effects should occur, the opioid drug can be reversed using naloxone (0.01 to 0.02 mg/kg IV, IM, SC). The effects of buprenorphine may be difficult to reverse, and up to 10 times the naloxone dose may be required. Opioid reversal with naloxone will also remove the analgesia. Alternatively, small doses of butorphanol (0.05 mg/kg IV, IM, SC) may be titrated to reverse some of the sedative effect of a pure µ agonist while retaining part of the analgesia by enhancing the κ effects. Before an opioid (or any other drug) is administered, the animal should be observed carefully and the underlying disease process considered (Tables 142-1 and 142-2).

SEDATIVES AND TRANQUILIZERS Benzodiazepines (see Chapter 164 for further details) Benzodiazepines (diazepam, midazolam) are mild tranquilizers and cause minimal cardiopulmonary depression.8 They are not generally used alone for sedation since the result may be unpredictable and the animal may become more difficult to handle. Benzodiazepines are most commonly given in combination with other drugs to increase their effect. Diazepam and midazolam have similar effects and are given at similar dosages (0.1 to 0.5 mg/kg IV or IM), although midazolam is preferred for intramuscular use since it is water soluble and readily absorbed. In critically ill patients, small intravenous doses of either drug can cause profound sedation. In

Table 142-1  Suggested Doses of Opioids in Small Animals Drug Opioid Agonists* Methadone Morphine

Oxymorphone Hydromorphone Fentanyl Remifentanil

Dose

Route

Duration of Effect (hr)

0.1-0.5 mg/kg 0.5-1.0 mg/kg 0.1 mg/kg (dogs)

IV IM, SC IV

1-2

0.2-1.0 mg/kg (dogs) CRI: 0.1 mg/kg/hr 0.02-0.1 mg/kg 0.05-0.2 mg/kg 0.05-0.2 mg/kg 2-10 mcg/kg CRI: 0.03-0.2 mcg/kg/min CRI: 0.03-0.2 mcg/kg/min

IM, SC

2-6

IV IM, SC IM, IV IV

1-2 2-4 1-4

2-4

May cause excitement or hypotension in dogs IV Vomiting may occur Good CV stability Good CV stability Bradycardia Respiratory depression

Opioid Agonists-Antagonists or Partial Agonists Butorphanol 0.1-0.5 mg/kg

IV, IM, SC

1-4

Buprenorphine

IV, IM, SC

4-12

0.005-0.02 mg/kg

Comments

κ Agonist µ Antagonist (partial agonist?) µ Partial agonist Effects may be difficult to reverse

CRI, Constant rate infusion; CV, cardiovascular; IM, intramuscularly; IV, intravenously; SC, subcutaneously. *Doses in cats are generally half those used in dogs for any of the opioids listed. Cats may be more prone to excitement after opioid administration.

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Table 142-2  Doses of Drugs Commonly Used in Sedation in Small Animals Drug* Anticholinergics Atropine Glycopyrrolate

Dose† (mg/kg) 0.02 0.01 0.01 0.005

Sedatives and Tranquilizers Acepromazine 0.005-0.02 Diazepam 0.1-0.3 Midazolam 0.1-0.3 0.01-0.02 Flumazenil (reversal agent) Dexmedetomidine 0.0005-0.002 Atipamezole Given in equivalent (reversal agent) volume Opioid Agonists/Partial Agonists‡ Buprenorphine 0.005-0.02 Butorphanol 0.1-0.5 0.5 Fentanyl 0.002-0.01 Hydromorphone 0.05-0.2 Methadone 0.1-0.5 0.5-1.0 Morphine 0.2-1.0 Oxymorphone 0.05-0.2 (0.02-0.1) Naloxone 0.02-0.04 (reversal agent) Other Agents Ketamine Propofol

2.0-4.0 2.0-4.0 1.0-4.0

Route IM, SC IV IM IV IM, IV IV IM, IV IV IM, IV IM

IM, IV IV IM IV IM, IV IV IM IM IM(IV) IM, IV

IM (cats only) IV IV (titrate slowly to effect)

IM, Intramuscularly; IV, intravenously; SC, subcutaneously. *Many of these drugs can be given as a constant rate infusion by taking the IV dose listed and administering it over the dosing interval time. Start with the lowest dose and titrate to effect as needed. † All IM doses may be given SC. ‡ Doses in cats are generally half those used in dogs for any of the opioids listed. Cats may be more prone to excitement after opioid administration.

addition, diazepam is metabolized to active metabolites that can have a prolonged duration of action in some animals.9 These effects are readily reversed using the benzodiazepine antagonist flumazenil (0.01 to 0.02 mg/kg IV).

Phenothiazine Tranquilizers Phenothiazine tranquilizers (acepromazine) are commonly used in healthy veterinary patients to provide calming.10 They are generally avoided or used at very low doses in patients with questionable cardiovascular stability since they act as α antagonists, causing peripheral vasodilation and possible hypotension in hypovolemic patients. Acepromazine may be useful in cases of airway obstruction in which calming of the patient may decrease respiratory effort and actually improve ventilation. Respiratory depression is minimal, and intramuscular injection is usually effective if given sufficient time to work (20 to 30 minutes after injection). Lower doses should be used (0.005 to 0.01 mg/kg IV or 0.02 to 0.05 mg/kg IM), especially if a physical examination has been difficult to perform due to the animal’s respiratory status.

α2 Agonists (see Chapter 165 for further details)

The α2 agonists (xylazine, medetomidine, dexmedetomidine) produce sedation, muscle relaxation, and analgesia.10 However, they may cause profound changes in cardiac output and blood pressure, even at very low doses. Cardiac output decreases after drug administration due to decreased heart rate, direct myocardial depression, and increased afterload (decreased stroke volume). In addition, coronary vasoconstriction can lead to myocardial hypoxia and dysfunction. Several surveys have suggested that use of xylazine is associated with a higher incidence of morbidity and mortality than use of other anesthetic agents, and newer α2 agonists are preferred.11 Medetomidine and dexmedetomidine are more specific for the α2 (vs. α1) receptor than xylazine but also have a longer duration of action. Medetomidine is the racemic mixture of dextro and levo isomers, whereas dexmedetomidine contains only the active dextro isomer. Doses for dexmedetomidine are generally half that for medetomidine. Notable adverse effects following their administration include bradycardia (heart rate < 40 beats/min) and peripheral vasoconstriction. Administration of an anticholinergic drug either in combination with the α2-agonist sedative or as a treatment for bradycardia is not recommended because it provides only a minimal increase in cardiac output and leads to an increased myocardial workload and increased incidence of cardiac arrhythmias. Reversal of the drug’s effects with atipamezole is the preferred treatment. Other adverse effects of α2-agonist administration include respiratory depression, vomiting, inhibition of insulin release, and diuresis. The recommended dose range for medetomidine (in the drug insert) is 10 to 40 mcg/kg IV or IM and is associated with moderate to profound sedation and analgesia. However, hemodynamic changes are qualitatively similar irrespective of dose when the drug is administered at between 1 and 20 mcg/kg IV, although less of an effect is seen at 1 to 2 mcg/kg (note: the effect is near maximal at 5 mcg/kg). Administration of medetomidine (1 mcg/kg IV) in dogs decreased cardiac output to less than 40% of resting values and it remained almost 50% below normal for 1 hour.12 Medetomidine and dexmedetomidine may be useful when given as a low-dose CRI as an adjunct sedative in the dysphoric or anxious patient. When given as a low-dose CRI (0.5 to 5 mcg/kg/hr) in combination with fentanyl, medetomidine infusion reduced cardiac index, heart rate, and oxygen delivery compared with fentanyl alone in healthy dogs.13 Doses as low as 1 mcg/kg dexmedetomidine in anesthetized dogs increased coronary vascular resistance, decreased coronary blood flow in all myocardial layers, and increased oxygen extraction. Low-dose infusions also have been shown to decrease blood flow to the splanchnic organs (including the pancreas) and to decrease oxygen delivery to the renal vasculature, which may be of concern in critically ill patients. Therefore in the critically ill patient these drugs should be used only after careful consideration.

OTHER ANESTHETIC AGENTS Ketamine Ketamine is a dissociative anesthetic with a variable effect on the cardiovascular system, depending on the patient’s status. The increases in heart rate, cardiac output, and blood pressure seen with ketamine depend on a centrally mediated sympathetic response and endogenous catecholamine release.14 Due to the potential for increased myocardial contractility and oxygen consumption, ketamine should be used only after careful consideration in patients with underlying cardiac disease (e.g., hypertrophic cardiomyopathy). Catecholamine release may also predispose to arrhythmias. Ketamine has a direct myocardium-depressant effect, and in debilitated patients

CHAPTER 142  •  Sedation of the Critically Ill Patient

with a poor catecholamine response, destabilization of the cardiovascular system and hypotension may occur. Although ketamine causes dose-dependent respiratory depression, this is usually transient and ketamine may be useful in patients in which maintenance of spontaneous ventilation is desirable. Ketamine also has bronchodilator activity and may be considered for use in patients with asthma or other causes of bronchoconstriction. Ketamine is an NMDA receptor antagonist and is a useful adjunct to other analgesic therapy. Ketamine has been shown to prevent the development of opioid tolerance and opioid-induced hyperalgesia and is often given as a low-dose CRI (0.1 to 0.5 mg/kg/hr) in combination with an opioid such as fentanyl. Ketamine increases both intracranial and intraocular pressure and is therefore contraindicated in patients with head or ocular trauma. Ketamine has a rapid onset of action after intramuscular injection and is often used for intramuscular sedation in cats. Ketamine is rarely used IM in dogs, and should not be used alone since it may cause seizure-like activity. More commonly, ketamine is administered IV and is generally given in combination with a benzodiazepine (or other tranquilizer) to minimize the possibility of ketamine-induced seizures and muscle rigidity. Ketamine is metabolized by the liver in most species other than the cat, in which it is eliminated unchanged by the kidneys. Doses should be adjusted accordingly in patients with liver or renal disease. For a recalcitrant feline patient in which sedation is required but a decrease in ketamine dose is desired, a combination of ketamine (2 to 4 mg/kg), oxymorphone (0.05 mg/kg) or methadone (0.2 to 0.5 mg/kg), and midazolam or diazepam (0.1 to 0.3 mg/kg) provides excellent restraint. Telazol is a combination of tiletamine (a dissociative anesthetic) and zolazepam (a benzodiazepine) and has effects similar to those seen with a ketamine-diazepam combination, although recoveries may be prolonged or otherwise unsatisfactory.

Propofol Propofol is an ultrashort-acting intravenous anesthetic with a 5- to 10-minute duration of anesthesia after induction, with the patient being remarkably alert on recovery. Due to its short duration of action, it is ideal for short procedures and sedations. Propofol is a peripheral vasodilator and myocardial depressant and may cause significant cardiovascular depression in patients with volume depletion or cardiovascular compromise.15,16 Propofol should not be used (or used only used after careful consideration) in these cases. Cardiovascular depression is especially pronounced if propofol is given as a large, rapidly delivered bolus, and smaller, slowly administered boluses (1 mg/kg IV) or induction via low-dose infusion (1 mg/kg/ min as a loading dose followed by 0.1 to 0.2 mg/kg/min) is preferred. Propofol can also cause significant respiratory depression—again more pronounced with large, rapidly administered boluses. Animals should receive supplemental oxygen via a face mask before and during propofol administration. Propofol may be given in combination with other cardiovascular system–sparing drugs such as fentanyl, midazolam, or ketamine, which decreases the amount of propofol required for induction. Midazolam or diazepam (0.1 to 0.3 mg/kg IV) also helps to control the myoclonic twitching occasionally seen after propofol administration. Propofol can be given as a CRI (0.1 to 0.2 mg/kg/min) for long-term sedation. Cats occasionally have a prolonged recovery, and Heinz body formation has been reported after repeated or prolonged propofol sedation in cats.17,18 Propofol is provided in a soybean oil–lecithin emulsion and should be handled using strict aseptic technique. The manufacturer states that propofol should not be refrigerated and that once the container is opened, the contents should be used within 6 to 12 hours due to the potential for significant bacterial contamination. More recently, a formulation of propofol was released

for use in dogs that can be used for 28 days after the bottle is opened and also does not require refrigeration.

SEDATION OF ANIMALS WITH SPECIFIC CONDITIONS Cardiovascular Instability Systemic blood pressure depends on cardiac output and systemic vascular resistance and must be kept above the minimum level required to maintain cerebral, coronary, and renal perfusion. Mean arterial blood pressures of less than 65 to 70 mm Hg are generally considered inadequate for maintaining blood flow to the tissues. In patients that are in hemodynamically unstable condition due to hypovolemia, neural and neurohormonal mechanisms can increase systemic vascular resistance and minimize apparent changes in blood pressure, while decreasing blood flow and oxygen delivery to the tissues. In addition, although some animals may have primary cardiac disease at presentation, many have cardiac dysfunction secondary to sepsis or have cardiac signs (e.g., arrhythmias) secondary to trauma or significant metabolic disease. The choice of agent depends on the underlying disease, volume status, presence or absence of heart failure and degree of heart failure, and presence or absence of arrhythmias. Ideally, the patient should undergo fluid resuscitation before drug administration. Stress during patient handling should be avoided if possible to minimize catecholamine release, tachycardia, and increased myocardial work. If sedation is necessary, opioids are generally the drug of choice because cardiovascular function is well maintained. Anticholinergics are not used unless indicated. A combination of an opioid agonist (e.g., oxymorphone 0.05 to 0.1 mg/kg, hydromorphone 0.05 to 0.1 mg/kg, or methadone 0.1 to 0.5 mg/kg) or agonist-antagonist (e.g., butorphanol 0.1 mg/kg or buprenorphine 0.005 to 0.01 mg/kg) and a benzodiazepine tranquilizer (diazepam or midazolam 0.1 to 0.3 mg/kg) or low-dose acepromazine (0.0025 to 0.01 mg/kg) may be used to sedate patients for chest radiography or echocardiography. This combination provides sedation with minimal cardiovascular depression. Some patients may pant if a pure opioid agonist is used, so butorphanol may be preferred. The combination may be repeated IV if necessary or the dosage doubled and given IM. Reversal may be accomplished by using an opioid antagonist such as naloxone (0.01 to 0.02 mg/kg IV) and/or a benzodiazepine antagonist such as flumazenil (0.01 to 0.02 mg/kg IV). Acepromazine should be avoided in hypovolemic or hypotensive patients. However, acepromazine in very low doses may be beneficial in some circumstances because it calms the patient, decreases afterload, and decreases the incidence of arrhythmias. It should be used only after careful consideration, however, since the α blockade may lead to peripheral vasodilation, hypotension, and decreased preload. The α2 agonists are generally avoided. Ketamine should be used only after careful consideration because it can cause catecholamine release, which increases heart rate and contractility and myocardial oxygen demand.

Respiratory Disease Respiratory diseases requiring emergency anesthesia include upper airway diseases that result in the inability to ventilate and primary lung diseases that lead to hypoxemia (see Part II of this book). In addition, some animals with intrathoracic disease (e.g., diaphragmatic hernia) have difficulty both ventilating and oxygenating. Animals will be handled slightly differently depending on whether the primary problem is an inability to ventilate or to oxygenate. Manipulations in both groups should occur with a minimum of stress or excitement. Many patients need supplemental oxygen. All anesthetic agents depress respiration to some degree, and this should be taken into account before administration. Respiratory

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depressants, such as opioids, should be used judiciously in a patient with severe hypoxemia or upper airway obstruction. The animal should always be closely monitored after administration of any drug. Premedication with acepromazine is very useful in patients with upper airway obstruction. Low doses (0.005 to 0.01 mg/kg IM) should be used if a complete physical examination cannot be performed without stressing the patient, although it should be given sufficient time to act (15 to 20 minutes). Ketamine or propofol also may be used. Patient positioning may be important (e.g., in a patient with diaphragmatic hernia). The least affected side should be kept up (or at least an attempt should be made to maintain sternal recumbency) to aid ventilation. Sedating an animal that cannot ventilate due to airway obstruction is among the most potentially catastrophic of all procedures. The clinician should never assume that intubation is possible. The clinician should have available an assortment of endotracheal tubes (which occasionally requires some ingenuity), as well as stylets, a laryngoscope (ideally), and a tracheostomy set (see Chapter 17). Potent respiratory depressants should be avoided when intubation may be difficult or impossible. Induction with low-dose boluses of propofol (to minimize respiratory effects) and midazolam (0.1 to 0.3 mg/kg) may be useful. Alternatively, ketamine (2 to 4 mg/kg) and diazepam may be used. In animals with hypoxemia but no airway obstruction, opioids may be used (see Table 142-2).

CONCLUSION Anesthesia is both an art and a science. The exact choice of drugs and the sequence in which they are given is determined by both knowledge and experience. The specific agent, dose, and route of administration depends in large part on the patient’s overall demeanor and cardiopulmonary profile, including underlying disease process, volume status, presence or absence of cardiac or airway disease, and presence or absence of arrhythmias. In addition, the procedure to be performed must be taken into consideration. Any drug should be titrated carefully to help avoid further compromise in the critically ill patient.

REFERENCES 1. Reisine T, Pasternak G: Opioid analgesics and antagonists. In Hardman JG, Limbird LE, editors: Goodman and Gilman’s The pharmacological basis of therapeutics, ed 9, New York, 1996, McGraw-Hill, pp 521-555.

2. Robinson EP, Faggella AM, Henry DP, et al: Comparison of histamine release induced by morphine and oxymorphone administration in dogs, Am J Vet Res 49:1699-1701, 1988. 3. Valverde A, Cantwell S, Hernandez J, et al: Effects of acepromazine ion the incidence of vomiting associated with opioid administration in dogs, Vet Anaesth Analg 31:40-45, 2004. 4. Hay Kruse BL: Efficacy of maropitant in preventing vomiting in dogs premedicated with hydromorphone, Vet Anaesth Analg 40:28-34, 2013. 5. Copland VS, Haskins SC, Patz JD: Oxymorphone: cardiovascular, pulmonary, and behavioral effects in dogs, Am J Vet Res 48:1626-1630, 1987. 6. Eisele JH, Reitan JZ, Torten M, et al: Myocardial sparing effect of fentanyl during halothane anaesthesia in dogs, Br J Anaesth 47:937-940, 1975. 7. Gimenes AM, Aguiar AJA, Perri SHV, et al: Effect of intravenous propofol and remifentanil on heart rate, blood pressure and nociceptive response in acepromazine premedicated dogs, Vet Anaesth Analg 38:54-62, 2011. 8. Jones DJ, Stehling LC, Zauder HL: Cardiovascular responses to diazepam and midazolam maleate in the dog, Anesthesiology 51:430-434, 1979. 9. Driessen JJ, Vree TB, Van de Pol F, et al: Pharmacokinetics of diazepam and four 3-hydroxy-benzodiazepines in the cat, Eur J Drug Metab Pharmacokinet 12:219-224, 1987. 10. Lemke KA: Anticholinergics and sedatives. In Tranquilli WJ, Thurmon JC, Grimm KA, editors: Lumb and Jones’ veterinary anesthesia, ed 4, Ames, Ia, 2007, Blackwell, pp 209-245. 11. Dyson DH, Maxie MG: Morbidity and mortality associated with anesthetic management in small animal veterinary practice in Ontario, J Am Anim Hosp Assoc 34:325-335, 1998. 12. Pypendop BH, Vergenstegen JP: Hemodynamic effects of medetomidine in the dog: a dose titration study, Vet Surg 27:612-622, 1998. 13. Grimm KA, Tranquilli WJ, Gross DR, et al: Cardiopulmonary effects of fentanyl in conscious dogs and dogs sedated with a continuous rate infusion of medetomidine, Am J Vet Res 66:1222-1226, 2005. 14. Lin HC: Dissociative anesthetics. In Tranquilli WJ, Thurmon JC, Grimm KA, editors: Lumb and Jones’ veterinary anesthesia, ed 4, Ames, Ia, 2007, Blackwell, pp 304-356. 15. Ilkiw JE, Pascoe PJ, Haskins SC, et al: Cardiovascular and respiratory effects of propofol administration in hypovolemic dogs, Am J Vet Res 53:2323-2327, 1992. 16. Quandt JE, Robinson EP, Rivers WJ, et al: Cardiorespiratory and anesthetic effects of propofol and thiopental in dogs, Am J Vet Res 59:11371143, 1998. 17. Branson KR: Injectable and alternative anesthetic techniques. In Tranquilli WJ, Thurmon JC, Grimm KA, editors: Lumb and Jones’ veterinary anesthesia, ed 4, Ames, Ia, 2007, Blackwell, pp 277-303. 18. Andress JL, Day TK, Day D: The effects of consecutive day propofol anesthesia on feline red blood cells, Vet Surg 24(3):277-282, 1995.

CHAPTER 143  ANESTHESIA IN THE CRITICALLY ILL PATIENT Jane Quandt,

BS, DVM, MS, DACVAA, DACVECC

KEY POINTS • Appropriately stabilizing the condition of the critically ill animal before anesthesia is imperative to minimize anesthesia-related complications. • Problems should be anticipated and an appropriate and efficient treatment and therapeutic plan developed before induction of anesthesia. • The use of a balanced anesthesia technique should be considered to minimize potential deleterious effects of single-drug therapy. • The use of positive pressure ventilation is mandatory with the administration of neuromuscular blocking agents. • Neuromuscular blocking agents do not have anesthetic or analgesic properties.

In the critically ill patient a thorough preoperative assessment is necessary to define what type of trauma or compromise the patient is undergoing. The critically ill patient has altered physiology and decreased reserves, which will affect the pharmacokinetic and pharmacodynamic behavior of anesthetic drugs. These patients benefit from minimization of stress and optimization of oxygen delivery. Stabilizing the condition of the critically ill patient before anesthetic drug exposure is essential because induction of anesthesia in a patient in unstable condition increases the risk of anesthesia-related complications.

STABILIZATION A thorough diagnostic assessment, including serial physical examinations, diagnostic imaging, blood chemistry testing, complete blood count, determination of coagulation profile, and measurement of acid-base status, blood glucose level, and lactate level should be performed as indicated before anesthesia. A dehydrated or hypovolemic state along with fluid, acid-base, and electrolyte deficits should be corrected before anesthesia induction. Maintaining venous access is imperative in managing and anesthetizing the critical care patient because it is not uncommon for the critically ill animal to experience hypotension during the anesthesia period. Intravenous administration of drugs is usually preferred because drugs administered by the intramuscular or subcutaneous routes may have delayed absorption, particularly when the patient is dehydrated, hypovolemic, poorly perfused, or hypothermic. Critically ill patients often benefit from placement of more than one intravenous catheter; either a peripheral or central line can be used. The intravenous catheter provides a port not only for drug administration but also for antibiotic delivery, vasopressor and inotropic support, and fluid therapy. Because of different fluid rate requirements and possible incompatibility of various agents, such as vasopressors, sodium bicarbonate, and blood transfusion products, a minimum of two intravenous catheters should be placed before anes-

thesia induction in patients in unstable condition. Blood products should be administered via a dedicated catheter, and no other fluids or drugs should be administered in the same line during the transfusion due to concerns of possible contamination and potential for bacterial growth. This is also true for those patients that are receiving total parenteral nutrition (TPN). The catheter for TPN should be a dedicated line; it should never be disconnected, and no other fluid should be run through the same line due to the risk of sepsis. TPN solution is considered a hyperosmotic crystalloid and should be accounted for as part of the crystalloid fluid volume. It is also important to provide warm intravenous fluids before and during anesthesia to help maintain organ perfusion and body temperature. If fluids need to be given at a rapid, shock bolus rate, use of the shortest, largest-bore catheter (e.g., peripheral cephalic catheter) will allow for the most rapid fluid administration. Placement of an arterial catheter once the animal is under general anesthesia is recommended. An arterial catheter allows for direct arterial blood pressure measurement and can be used to collect samples for arterial blood gas analysis. A packed cell volume (PCV) greater than 25% is necessary for adequate oxygen-carrying capacity and oxygen delivery. During anesthesia the PCV can decrease by 3% to 5%; therefore even a small volume of blood loss may be significant in the anesthetized animal and may warrant a blood transfusion.1 Similarly, patients with hypoproteinemia (total protein ≤ 3.5 g/dl and/or albumin level ≤ 2 g/dl) may benefit from the use of colloids to help maintain normal colloid osmotic pressure (COP; normal = 18 to 24 mm Hg) and to prevent edema formation or vascular leak.2,3 Measurement of COP before anesthesia is helpful in determining the need for colloid support and deciding when to terminate colloid therapy. If patients are hypoproteinemic, colloid options include Hetastarch, VetStarch, 25% human serum albumin, or even Oxyglobin. High-molecular-weight hydroxyethyl starch synthetic colloids such as hetastarch impair coagulation in a dose dependent manner, and this may limit their use in hypocoagulable, hypoproteinemic surgical patients. VetStarch is a lowmolecular-weight tetrastarch that has far fewer coagulation effects than the hetastarches. As a result it may have a role in the support of COP in the surgical patient, although it would seem prudent to minimize its use in high-risk patients with hypocoagulability (see Chapter 58). In small, hypocoagulable, or hypoalbuminemic patients, the use of fresh frozen plasma (FFP) at 6 to 20 ml/kg is warranted. Unfortunately, size, dosing, and cost become a limiting factor in the use of FFP to treat hypoalbuminemia in larger patients because it takes a dose on the order of 45 ml/kg of FFP to increase the albumin level by 1 g/dl.4 The use of 25% human serum albumin has recently been implemented in veterinary medicine, but adverse effects such as polyarthritis, future transfusion reaction, glomerulonephritis, and other immune-mediated effects warrant cautious use.3 (For more information see Chapter 58.) Finally, patients should be carefully evaluated for underlying metabolic disease before anesthesia because this may affect the 759

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anesthetic protocol. In patients with renal insufficiency, a higher fluid rate may be required to maintain renal perfusion, and urine output should be monitored carefully during anesthesia.5 In addition, drugs excreted by the kidney (e.g., ketamine in cats) may have delayed excretion and should be used cautiously. In patients with liver disease, anesthetic protocols and monitoring may be affected due to decreased glucose and albumin production, altered drug metabolism via cytochrome P-450 enzymes, and decreased production of coagulation factors.5 Patients with heart murmurs may have decreased ability to compensate under anesthesia, and fluid overload should be avoided. Blood pressure should also be carefully monitored because anesthesiainduced hypotension may result in decompensation. Finally, one should always determine whether the patient is currently receiving any drug therapy, such as nonsteroidal antiinflammatory drugs, diuretics, anticonvulsants, or cardiac medications.

PREMEDICATION Premedication may not be necessary unless the animal is in severe pain or is extremely fractious. If it is decided that the critically ill patient would benefit from premedication, µ-agonist opioids such as morphine, hydromorphone, or oxymorphone in combination with a tranquilizer such as midazolam or low-dose acepromazine (0.005 to 0.01  mg/kg) can be given intramuscularly to provide analgesia and sedation. If given to the critically ill, acepromazine should be used at lower doses than in a normal animal due to the profound hypotension that can result. A µ agonist is preferred because the κ

agonist butorphanol and the partial µ agonist buprenorphine may not be sufficient for severe pain. Although a µ-agonist narcotic can be combined with an α2 agonist and/or a dissociative drug and administered intramuscularly in an animal that is in severe pain or is extremely fractious, this is rarely indicated in a critically ill patient, which is usually obtunded and easily handled. Anticholinergics are not routinely used unless there is a need to treat bradycardia. Protocols should be implemented to minimize the amount of time the animal is under anesthesia; therefore steps such as preclipping the surgical site with the animal awake should be performed if possible. Preoxygenation of the animal before induction will allow for additional time that may be needed to intubate the animal; this is especially helpful for animals that are in respiratory distress or have a difficult airway. Finally, electrocardiographic and blood pressure monitoring should be in place before induction to detect evidence of arrhythmias, hypotension, or cardiovascular collapse that may occur during induction in the critically ill animal. In the severely compromised animal, arrest drugs such as atropine and epinephrine should be close at hand during the induction and anesthetic period.

INDUCTION In the compromised, critically ill patient, the anesthetic drug doses often can be reduced to half of those for a normal, healthy patient (Table 143-1). Induction drugs should be slowly titrated intravenously (IV) to effect, and the minimal amount of drug necessary to

Table 143-1  Anesthetic Agents and Their Dosages Drugs

Dose

Comments

Anticholinergic agents

Atropine 0.04 mg/kg IM, 0.02 mg/kg IV Glycopyrrolate 0.01 mg/kg IM, IV

May make secretions more viscous Increase anatomic dead space Increase heart rate Can increase myocardial work and oxygen consumption Glycopyrrolate does not cross blood-brain barrier or the placenta

Morphine 0.2 to 2 mg/kg IM, SC; CRI: 0.1 to 0.3 loading dose, then 0.1 mg/kg/hr Oxymorphone 0.05-0.2 mg/kg IM, IV, SC Meperidine 2-5 mg/kg IM, SC Hydromorphone 0.05-0.2 mg/kg IV, IM, SC; CRI: 0.025-0.05 mg/kg IV loading dose, then 0.01-0.04 mg/kg/hr Fentanyl 0.005-0.05 mg/kg IM, IV, SC; CRI for dogs: loading dose 5-10 mcg/kg, then 0.7-1 mcg/kg/min; CRI for cats: loading dose 5 mcg/kg, then 0.3-0.4 mcg/kg/min Remifentanil 3 mcg/kg IV; CRI: 0.1-0.3 mcg/kg/min Buprenorphine 0.005-0.02 mg/kg IM, IV

Complete reversal with naloxone Analgesic Cause respiratory depression Cause bradycardia Minimal effect on CV performance Give anticholinergic drug before starting CRI Monitor for hyperthermia in cats

Opioids   µ Agonists

  Partial µ agonist   κ agonist/ µ antagonist   Opioid antagonist

Butorphanol 0.1-0.8 mg/kg IM, IV, SC; CRI: 0.1-0.2 mg/kg IV loading dose, then 0.1-0.2 mg/kg/hr Naloxone 0.002-0.02 mg/kg IM, IV

Slow onset, effects difficult to reverse Good for moderate pain Partial reversal of µ-agonist drugs Minimal CV effects Not good for severe pain Complete reversal of µ agonist effects

Dissociative agents

Ketamine 4-11 mg/kg IV, IM; CRI: 0.5 mg/kg IV loading dose, then 0.1-0.5 mg/kg/hr Tiletamine and zolazepam (Telazol) 2-4 mg/kg IM, IV

Cause salivation Increase heart rate Increase ICP and intraocular pressure Analgesic Renal elimination in cat

Benzodiazepines

Diazepam 0.2-0.5 mg/kg IM, IV; CRI: 0.1-0.5 mg/kg/hr Midazolam 0.07-0.4 mg/kg IM, IV; CRI: 0.1-0.5 mg/kg/hr

Can decrease required dose of other drugs Mild sedative and muscle relaxant Anticonvulsant Not analgesic Diazepam formulation contains propylene glycol

CHAPTER 143  •  Anesthesia in The Critically Ill Patient

Table 143-1  Anesthetic Agents and Their Dosages—cont’d Drugs

Dose

Comments

Phenothiazine

Acepromazine 0.01-0.1 mg/kg IM, IV; no more than 3 mg total dose

Vasodilatory Long duration of action Not analgesic

Barbiturates

Thiopental 4-20 mg/kg IV Methohexital 4-10 mg/kg IV

Cause cardiovascular depression Cause respiratory depression Provide rapid induction Decrease ICP and intraocular pressure Effects may be potentiated by concurrent acidosis or hypoproteinemia

Propofol

2-8 mg/kg IV; CRI: 0.05-0.4 mg/kg/min

Rapidly acting with short duration of action Causes respiratory depression Causes peripheral vasodilation Myocardial depressant Not analgesic Use with caution in patients with volume depletion or cardiovascular compromise; can cause significant depression Can cause Heinz body anemia in cats

Etomidate

0.5-4 mg/kg IV

Maintains cardiovascular stability Not used alone Suppresses adrenocortical function for 2-6 hr following single bolus dose Contains propylene glycol

α2 Agonist

Dexmedetomidine 3-40 mcg/kg IM, IV; CRI: 1 mcg/kg IV loading dose, then 0.5-2 mcg/kg/hr

  Antagonist

Atipamezole 0.04-0.5 mg/kg IM, IV

Causes cardiovascular depression Can cause vomiting Provides good sedation and analgesia Can be combined with butorphanol or ketamine

Neuroleptanalgesic

Combination of opioid and tranquilizer

Analgesic Causes noise sensitivity Maintains cardiovascular stability

Alfaxalone

2-5 mg/kg IV

Sedation may be needed to improve recovery

Lidocaine

CRI: 1-2 mg/kg IV loading dose, then 1-3 mg/kg/hr

Not recommended in cats

Inhalants

Isoflurane Nitrous oxide Sevoflurane

Produce dose-dependent cardiovascular depression and peripheral vasodilation Anesthesia depth can be adjusted rapidly Potential for hypoxemia Isoflurane and sevoflurane show rapid uptake and recovery Nitrous oxide should be used with caution with closed gas spaces

Neuromuscular blocking agents

Atracurium 0.1 mg/kg IV; or CRI: 3-8 mcg/kg/min IV

  Reversal agents

Cisatracurium 0.1 mg/kg IV; incremental doses of 0.02-0.04 mg/kg IV Neostigmine 0.04-0.06 mg/kg IV Edrophonium 0.5 mg/kg IV

CRI, Constant rate infusion; CV, cardiovascular; ICP, intracranial pressure; IM, intramuscularly; IV, intravenously; SC, subcutaneously.

intubate the patient should be used. In addition, use of a balanced anesthetic technique helps to minimize the adverse effects from any single agent. One can consider the use of local anesthetic blocks and epidural anesthetics if appropriate to decrease the amount of general anesthetic that is required. Intubation should always be performed to control the airway to provide the ability to ventilate the patient and to protect the airway from aspiration. The emergent patient should be considered to have a full stomach and therefore to be at risk of aspiration. A laryngoscope, endotracheal tubes in a variety of sizes, and a breathing circuit that matches the patient’s size should all be readily available. All supplies and machinery should be checked thoroughly before induction and intubation. One should be ready to implement positive pressure ventilation if the patient hypoventilates, becomes apneic, or is to undergo a thoracic procedure.

Ideally there should be a slow transition to general anesthesia that would allow time for the cardiovascular and nervous systems to respond and accommodate appropriately.6 However, the critically ill patient may not be able to respond appropriately, and therapeutic intervention must be available to prevent the demise of the patient. For example, a patient in respiratory distress will require a rapidsequence intubation to gain control of the airway and provide ventilation with 100% oxygen.

Thiopental and Propofol A rapid-sequence induction can be accomplished with agents that have a short onset time, such as thiopental or propofol. These agents have an onset time of approximately 30 seconds and need to be given IV. Their duration of action is also short, with thiopental lasing 10

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to 15 minutes and propofol lasting 5 to 10 minutes; propofol may be the preferred agent due to its shorter duration of action. Both of these drugs can be used in combination with diazepam or midazolam to improve relaxation and to decrease the overall dose needed. Both agents are capable of creating cardiac arrhythmias, hypotension, and apnea; hence intermittent positive pressure ventilation may be necessary.7 Neither agent provides analgesia, so additional analgesics must be given (using inhalant or injectable agents) before the surgical procedure. Thiopental and propofol do decrease intracranial and intraocular pressure and would be indicated for induction in a patient with head trauma.8 The new formulation of propofol, PropoFlo 28, is not labeled for use in cats. The new formulation contains the preservative benzyl alcohol, which can be toxic to cats when given in large doses. Cats have a low capacity for glucuronic acid conjugation and therefore have limited ability to metabolize benzoic acid. However, PropoFlo 28 has been used safely in healthy cats, with no indications of toxicity and with normal recoveries.9 Propofol as an agent is less well tolerated in cats than in dogs, with slower metabolism and excretion, and repeated doses or infusions are associated with prolonged recoveries. It has also been shown that propofol can increase the presence of Heinz bodies.9 It may be prudent to avoid the use of PropoFlo 28 in cats that are debilitated or have liver impairment.

Alfaxalone A new induction agent, alfaxalone, may be useful for anesthesia induction in the critically ill animal. Alfaxalone is a synthetic neuroactive steroid. It is rapidly metabolized and eliminated from the body. Alfaxalone, like thiopental and propofol, is associated with dosedependent changes such as hypoventilation and apnea but has a wide margin of safety. It can also be used as a constant rate infusion (CRI) and provides good muscle relaxation and rapid recovery. There may be some excitement on recovery, with paddling and muscle twitching or even violent movements; sedation improves recovery. Alfaxalone has a short duration of action, 14 to 50 minutes.10 In dogs that were considered a poor anesthetic risk, alfaxalone administered at 1 to 2 mg/kg IV over 60 seconds was shown to be an acceptable induction agent with smooth recovery.11 Alfaxalone can be safely combined with a fentanyl CRI. Use of alfaxalone in cats results in a smooth induction, but there may be paddling and trembling in recovery, and the quality of recovery worsens as the dose of alfaxalone increases. Cats recovering from alfaxalone induction may be more disoriented and nervous than those recovering from propofol induction.12

Etomidate The use of etomidate for anesthesia induction in critically ill patients is appealing due to its minimal cardiovascular effects, which would be helpful in the patient with cardiovascular instability. Etomidate should not be used as the sole induction agent because it may lead to retching and myoclonus. These adverse effects are minimized by giving a benzodiazepine or opioid IV before etomidate is administered. Repeated use of etomidate in cats may lead to hemolysis due to the propylene glycol vehicle.13 The use of etomidate in critically ill human patients is controversial due to its ability to cause adrenal dysfunction, which may lead to an increase in morbidity and mortality. The duration of the adrenal dysfunction can range from 24 to 48 hours in the critically ill patient.14 The use of hydrocortisone to treat the etomidate-induced adrenal insufficiency had no effect on outcome.15 The recommendation in human medicine is to use etomidate cautiously in patients with septic shock.

Ketamine Ketamine may be used IV as part of an induction protocol; it is commonly administered with a benzodiazepine. Ketamine has the poten-

tial to induce seizures when given as a sole agent.8 Ketamine increases heart rate, blood pressure, and cardiac output via a centrally mediated sympathetic response and endogenous catecholamine release. Because of the potential for increased cardiac contractility, it should be used cautiously in animals with hypertrophic cardiomyopathy. Ketamine can have direct myocardial-depressant effects, and in debilitated patients with a decreased endogenous catecholamine response there may be hypotension and cardiovascular instability. As an N-methyl-d-aspartate receptor agonist, ketamine provides analgesia peripherally and somatically.16

Opioids In critically ill patients in stable condition, a more gradual induction technique can be implemented. This may be accomplished with the use of neuroleptanalgesics such as hydromorphone, oxymorphone, or fentanyl and diazepam or midazolam with the addition of either propofol or ketamine to facilitate induction. In dogs and cats with severe liver compromise, remifentanil may be considered for analgesia during general anesthesia. Remifentanil is a synthetic opioid that has a direct action on the µ receptors and an ultrashort duration of action. The elimination of remifentanil is independent of hepatic or renal function, which makes it an attractive agent for use in animals with hepatic or renal compromise. It is metabolized by nonspecific esterases in blood and tissues. Recovery from remifentanil effects is very rapid even following long-term intravenous infusions.17 It has been used in dogs at an initial dose of 3 mcg/kg IV and then a CRI of 0.1 to 0.3 mcg/kg/min, with the drug diluted in normal saline.17,18 Due to the drug’s short duration of action an additional analgesic must be administered upon termination of the remifentanil effects if the painful condition persists. The clinical effects of remifentanil are rapidly dissipated upon discontinuation of the infusion, with dogs recovering in 5 to 20 minutes regardless of the duration of the infusion. Remifentanil administered by CRI, like other opioid CRIs, is a potent respiratory depressant, and therefore mechanical ventilation may be required; however, this respiratory depression does not persist following recovery. Remifentanil has been used in cats. A dose higher than 1 mcg/kg/min was associated with dysphoric behavior and frenetic locomotor activity.19 The use of multiple agents (e.g., hydromorphone, diazepam, ketamine, and lidocaine) is an example of balanced anesthesia. This protocol produces a slower onset but provides analgesia and is more sparing of the cardiovascular system.20 Ketamine may be used to enhance analgesia and increases heart rate and blood pressure.21 When these drugs are used for induction, the dose also serves as the loading dose before their administration as a CRI. Morphine (3.3 mcg/kg/min), lidocaine (50 mcg/kg/min), and ketamine (10 mcg/kg/min) can be administered as a CRI analgesic combination in dogs.20 In addition lidocaine may retard the effects of compromised viscera, reperfusion injury, or ventricular arrhythmias due its free radical scavenging abilities, analgesic effects, and antiarrhythmic properties.22 Use of a lidocaine CRI is not recommended to use a lidocaine CRI in cats due to its depressive effects on the cardiovascular system.23 Propofol is not recommended for use as a single agent for major surgical procedures because it does not prevent hemodynamic responses to noxious stimulation. It can be used in combination with other agents such as lidocaine and ketamine in dogs for total intravenous anesthesia. Propofol has negative chronotropic and inotropic effects and also causes venodilation, which can lead to a decrease in blood pressure.24 In animals with splenic disease such as a tumor or splenic fracture, the use of an appropriate induction agent is indicated because some agents are known to increase splenic size, which could lead to tumor rupture or increased hemorrhage. The administration of

CHAPTER 143  •  Anesthesia in The Critically Ill Patient

acepromazine, thiopental, and propofol can result in splenomegaly. It may be best to avoid these agents in animals with splenic disease or if laparoscopy is planned. Hydromorphone and dexmedetomidine were found not to result in increased splenic size. There was also a reduction in hematocrit in those dogs receiving acepromazine, thiopental, and propofol, which may be of concern in the anemic patient.25

The preferred relaxing agent is a nondepolarizing NMB. There are two types of nondepolarizing NMB: aminosteroidal and benzylisoquinolinium compounds. There are several different NMB drugs in each of these classes. The details of each class are beyond the scope of this chapter. For a full review of NMB drugs the interested reader is directed to Hall et al31 and Lukasik.32

MAINTENANCE

The benzylisoquinolinium compounds are more commonly used and include atracurium, cisatracurium, doxacurium, and mivacurium. Atracurium is intermediate acting and has minimal cardiovascular effects.29 Atracurium is unusual in that its degradation process is independent of enzymatic function; it is inactivated in the plasma by ester hydrolysis and Hofmann elimination, with spontaneous degradation occurring at body temperature and pH.29,31,33 Atracurium is indicated for use in neonates and patients with significant hepatic or renal impairment.31 Atracurium blockade occurs within 3 to 5 minutes of administration and has a duration of 20 to 30 minutes.31 Atracurium can be redosed at 0.1 mg/kg IV or given as a CRI of 3 to 8.0 mcg/kg/min IV.8 Recovery of normal neuromuscular activity usually occurs within 1 to 2 hours after discontinuance of a CRI and is independent of organ function. Long-term CRIs have been associated with the development of tolerance, requiring dose increases or switching to another NMB.29 Atracurium can be used as part of an anesthetic induction protocol. It may be considered when it is desirable to avoid increases in intraocular, intracranial, or intraabdominal pressure caused by patient coughing or a Valsalva maneuver. It may also be used to provide faster control of ventilation in an animal in unstable condition.31 There are two induction techniques. In one method atracurium is given in divided doses of one tenth to one sixth of the calculated dose initially, and then 3 to 6 minutes later the rest of the calculated dose is given along with the induction agent. This method accelerates relaxation after induction. The second technique is to give a single bolus of atracurium and 3 minutes later, at the onset of muscle weakness, to give the induction agent.31 Potential adverse effects that may occur with the use of atracurium include laudanosine formation and histamine release. Laudanosine is a breakdown product of Hofmann elimination that has been associated with central nervous system excitement. This may be a concern in patients that have received extremely high doses of atracurium or that have hepatic failure because laudanosine undergoes liver metabolism.29 At clinically useful doses, 0.1 to 0.30 mg/kg IV, the potential for histamine release does not appear to be a problem.34 Long-term use of atracurium and other NMBs has been associated with persistent neuromuscular weakness.29 A study in dogs in which neuromuscular blockade was produced by atracurium and either sevoflurane or propofol CRI was used for anesthesia demonstrated that the duration of neuromuscular blockade was approximately 15 minutes longer when sevoflurane was used than when propofol was used.34 Cisatracurium is an isomer of atracurium. It is similar in duration of action, elimination profile, and production of laudanosine.29 It produces few if any cardiovascular effects and has a lesser tendency to produce histamine release, and is more potent than atracurium.29,33 As with atracurium, prolonged weakness may occur following longduration use of cisatracurium.29 The dose is 0.1 mg/kg IV, with incremental doses of 0.02 to 0.04 mg/kg IV in the dog to maintain the blockade. The initial dose has a duration of effect of 27.2 ± 9.3 minutes, the incremental doses appear to be noncumulative, and no adverse effects have been noted. The kidney and liver excrete the metabolites of laudanosine, but the hepatic excretion is less important in the dog. Laudanosine can cause hypotension and seizures, but this may be more likely in dogs with kidney or liver disease.33

Inhalants Once the animal is intubated, anesthesia can be maintained via an inhalant agent such as isoflurane or sevoflurane. These two agents are the most commonly used, but both agents cause cardiovascular and respiratory depression. Both agents have a rapid onset and recovery time, and allow for rapid changes in anesthetic concentration.26

Constant Rate Infusion Maintenance anesthesia can also be achieved with a CRI if an animal cannot tolerate the hypotensive effects of inhalant anesthesia. Ketamine-propofol and ketamine-propofol-dexmedetomidine infusions have been used in cats during ovariectomy. Cats were given one of the two combinations IV for induction and then maintained on a ketamine-propofol infusion for the surgery. No adverse effects were seen with either group, but sedation was more profound in the group receiving dexmedetomidine.27 As stated previously, morphine, lidocaine, and ketamine can be used as a CRI to provide analgesia and to decrease the amount of inhalant required in dogs. Additional µ agonists that can be used as a CRI include fentanyl, oxymorphone, and hydromorphone.8 An α2 agonist can also be used as a CRI to enhance analgesia and minimize the amount of inhalant needed.28 Such CRIs that have been used during surgery can be carried over into recovery to provide titratable analgesia, and the dose can usually be lower once surgical stimulation is over.

Neuromuscular Blocking Agents Neuromuscular blocking agents (NMBs) can be used to facilitate positive pressure ventilation as part of a balanced anesthetic technique or as part of an anesthetic technique for animals undergoing intensive care unit mechanical ventilation. Neuromuscular blockade helps to prevent respiratory dysynchrony, stop spontaneous respiratory efforts and muscle movement, improve gas exchange, and facilitate inverse-ratio ventilation. NMBs may also be useful in managing increased intracranial pressure and the muscle spasms of tetanus, drug overdose, or seizures.29 Their use in surgery is to enhance skeletal muscle relaxation, to facilitate control of respiratory efforts during intrathoracic surgery, to immobilize the eye for ocular surgery, and to facilitate intubation of a difficult airway.30 These agents do not have anesthetic or analgesic properties, and therefore it is imperative that they be given only when the animal is adequately insensible to pain and awareness.31 Positive pressure ventilation is mandatory with their use. The duration of action of NMBs can be altered by hypothermia, acid-base abnormalities, and electrolytes disturbances, conditions commonly seen in critically ill patients. NMBs can be given by intermittent intravenous bolus or CRI. Intermittent bolus administration may offer some advantages, including control of tachyphylaxis, monitoring for accumulation, provision of analgesia and amnesia, and limiting of complications related to prolonged or excessive blockade.29 There must be constant supervision when an animal is receiving an NMB because the patient would be incapable of spontaneous respiration should a malfunction of the mechanical breathing circuit occur, and this would lead to death of the animal.

Benzylisoquinolinium agents

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Monitoring of neuromuscular blocking agents Monitoring of NMB effects using a peripheral nerve stimulator is recommended. Monitoring the depth of the blockade allows the lowest dose of NMB to be used and therefore minimizes adverse effects. It will also help to confirm that adequate neuromuscular function has returned before discontinuation of ventilator support and anesthesia. Monitoring is done by observing skeletal muscle movement and respiratory efforts and measuring the twitch response to transcutaneous delivery of electric current to induce peripheral nerve stimulation.29 The peripheral nerves most commonly used include the facial, ulnar, tibial, and superficial peroneal nerves.30 When NMB effects begin to diminish the animal may show decreased chest wall compliance and increased resistance to ventilation and greater peak inspiratory pressure will be generated at the same tidal volume.31 Nystagmus, papillary dilation, and palpebral reflex may be noted. To evaluate the recovery from NMB one should asses the tidal volume using a Wright respirometer as well as the character of ventilation, the ability to swallow, the adequacy of pulse oximetry readings, and end-tidal carbon dioxide. If there is residual weakness, this can be serious and potentially life-threatening. If doubt exists about the strength of recovery, a reversal agent can be given.

Reversal Agents for neuromuscular blocking agents Reversal of the effects of nondepolarizing neuromuscular blocking agents is possible, although not always necessary. Reversal may be considered in the critically ill patient to improve respiratory muscle function. An anticholinesterase inhibitor, edrophonium or neostigmine, is used for reversal. Reversal should not be attempted when no twitches are seen with the train-of-four monitor. Twitch height must be a minimum of 10% of the baseline height for reversal to be successful.31 The accumulation of acetylcholine also produces muscarinic effects such as bradycardia, salivation, increased bronchial secretion, smooth muscle contraction, defecation, urination, and hypotension.30,31 These adverse effects can be minimized by concurrent administration of an anticholinergic agent such as atropine or glycopyrrolate. Neostigmine has peak effects at 7 to 10 minutes after administration and a duration of action of 60 to 70 minutes and is dosed at 0.04 to 0.06 mg/kg IV combined with glycopyrrolate 0.01 mg/kg IV to combat bradycardia.8,31 Edrophonium reaches peak effect within 1 to 2 minutes and has a duration of action of approximately 66 minutes; it is dosed at 0.5 mg/kg IV and combined with atropine 0.01 to 0.02 mg/kg IV.34 It is combined with atropine due to their similar times of onset and duration. The atropine should be given 5 minutes before the edrophonium.8 For further information on reversal of NMB agents, the interested reader is directed to Hall et al31 and Lukasik.32

MONITORING Maintenance anesthesia requires careful and constant monitoring to avoid excessive depth of anesthesia and to preserve cardiovascular function. The electrocardiogram should be monitored closely for changes in heart rate and rhythm, and for the presence of malignant arrhythmias, which may be more prevalent in patients with trauma, splenic disease, septic peritonitis, hypoxia, or gastric dilatationvolvulus. Additional monitoring during the maintenance phase of anesthesia includes maintaining the mean arterial blood pressure above 60 mm Hg to maintain renal perfusion. Physical examination parameters indicative of perfusion, such as capillary refill time, mucous membrane color, and pulse quality, should also be moni-

tored continuously. Depth of anesthesia should be frequently assessed by monitoring eye position, pupil size, jaw tone, response to stimulus, heart rate, blood pressure, and respiratory rate throughout the duration of anesthesia. Other monitoring techniques should be implemented, both during and after anesthesia, to enhance the quality of care and increase survival. The use of pulse oximetry adds information on hemoglobin saturation and oxygenation.35 It is important to remember that patients maintained on pure oxygen (fraction of inspired oxygen of 100%) may have a “normal” pulse oximetry reading despite having abnormal oxygenating ability. The pulse oximeter (assuming it is accurate) will read less than 100% only when the arterial partial pressure of oxygen falls below approximately 140 mm Hg. As a result patients, breathing 100% oxygen can have significant decreases in oxygenating ability that the pulse oximeter cannot recognize. Because of this, arterial blood gas monitoring may be necessary as the gold standard in critically ill patients under anesthesia. Arterial blood gas values will provide information on oxygenation, ventilation, hemoglobin saturation, acid-base balance, and electrolyte levels. Capnography allows monitoring of the adequacy of ventilatory function and provides an indication of adequate cardiac output. Capnography is also used to monitor for the occurrence of esophageal intubation, breathing circuit disconnection, and cardiac arrest, circumstances where in which it will not register any carbon dioxide.35 (For further information see Chapter 190.) Urine output should be monitored carefully, and goals to achieve normal urine output of 1 to 2 ml/kg/hr should be achieved.5 The use of an indwelling urinary catheter can be considered to measure urinary output adequately in patient’s with renal impairment or inadequate blood volume (in which one would clinically see decreased urine output). Fluid balance can be assessed by comparing the volume of fluid administered during anesthesia with the measured losses during the same time period. Preexisting fluid deficits must be considered when making this evaluation. The measurement of central venous pressure may help in the evaluation of fluid therapy but assesses only the right side of the heart.5 (Chapter 183 discusses hemodynamic monitoring in more detail.) Packed cell volume, total protein, and COP should be monitored frequently because rapid changes can occur in the surgical patient. In the absence of colloid osmometry the total protein measurements can be evaluated, although these do not reflect the presence of synthetic colloids accurately. Blood glucose levels should be closely monitored in pediatric animals and those with sepsis, diabetes, or severe liver disease. Finally, body temperature should be continuously monitored because anesthetic drugs disrupt normal thermoregulatory mechanisms and hypothermia leads to prolongation of recovery.36

INTRAOPERATIVE HYPOTENSION Because critically ill patient are often hypotensive during anesthesia, a mean arterial blood pressure of less than 60 mm Hg or a systolic pressure of less than 90 mm Hg requires prompt treatment to maintain appropriate organ perfusion.37 The initial step should be to decrease the administration of inhalant anesthetic agents due to their depressant and vasodilatory properties. Next, administration of a fluid bolus should be initiated. Either a crystalloid (without potassium supplementation) delivered at a rate of 10 to 20 ml/kg IV over 15 to 20 minutes or a colloid bolus of 5 to 10 ml/kg IV administered over 10 to 20 minutes should be given. If no effect is observed, administration of multiple small boluses can be attempted, with consideration of the total volume of fluids that have been given. If the hypotension persists during fluid therapy there may be a need for inotropic and/or vasopressor support in the form of dopamine or dobutamine. Because of their short half-life these agents are given as

CHAPTER 143  •  Anesthesia in The Critically Ill Patient 37

a CRI at 2 to 10 mcg/kg/min IV. Dopamine and dobutamine can be used concurrently. Patients receiving inotropes and vasopressors should be monitored carefully for tachycardia, which may necessitate a decrease in the rate of the infusion or the addition of another inotrope. Other agents that may be used are ephedrine (0.05 to 0.5 mg/kg IV as a single bolus), norepinephrine (0.1 to 1 mcg/kg/min IV as a CRI), and vasopressin (1 to 5 mU/kg/min IV as a CRI).37,38 If the initial inotrope is not successful in correcting the hypotension, a second agent is added while continuing administration of the first agent. For example, norepinephrine is most often used in combination with dopamine or dobutamine, and vasopressin can be used in combination with these agents as well. (See Chapters 8, 157, and 158 for more information on the treatment of hypotension.) If the animal continues to remain hypotensive even after appropriate fluid therapy and inotropic and vasopressor support, it may be necessary to consider discontinuing the inhalant anesthetic agent to eliminate the hypotensive effects of the inhalant and continuing the anesthesia maintenance using an injectable drug. This may involve administration of a CRI of a µ agonist such as fentanyl or morphine in combination with ketamine and lidocaine. Some patients may need only fentanyl as an intermittent intravenous bolus or as a CRI. Recent research suggests that a lidocaine CRI should not be used in the anesthetized cat due to its depressant effects on the cardiovascular system.23

RECOVERY In critically ill patients, continuous cardiovascular support, monitoring, supportive care, and analgesia are imperative during the recovery period. The recovering patient may still require inotropic and/or vasopressor support, which should be continued in the intensive care unit upon recovery. The patient should be kept dry and warm, and should recover in a quiet, stress-free place where the patient can be continuously and carefully monitored. A shivering animal has greatly increased demands for glucose and oxygen, and oxygen supplementation and heat support should be given until the animal is no longer shivering.7 Acid-base, electrolyte, PCV, total protein, and blood glucose levels should also be monitored in the recovering and shivering animal. The use of forced warm air heating blankets can help in the treatment of hypothermia. Finally, the use of analgesics is imperative in these critically ill patients in pain. Although these patients may not exhibit classic pain response symptoms due to their debilitated state, they should be carefully but appropriately treated with analgesics. Pain can lead to catabolism and complications such as delayed wound healing, sepsis, and nosocomial disease.39 (See Chapter 144.)

SUMMARY The condition of critically ill patients should be stabilized aggressively before anesthesia. Appropriate monitoring should be performed at all times to ensure that these delicate patients survive their emergent surgery. Postoperative care includes continued vasopressor and inotropic support, appropriate fluid therapy, analgesic support, oxygen therapy, blood pressure monitoring, and nursing care to improve survival in this critically ill patient population.

REFERENCES 1. Trim CM: Anesthetic considerations and complications. In Paddleford RR, editor: Manual of small animal anesthesia, ed 1, New York, 1999, Churchill Livingstone. 2. Chan DL, Rozanski EA, Freeman LM, et al: Colloid osmotic pressure in health and disease, Compend Contin Educ Pract Vet 23:896, 2001.

3. Mathews KA, Barry M: The use of 25% human serum albumin: outcome and efficacy in raising serum albumin and systemic blood pressure in critically ill dogs and cats, J Vet Emerg Crit Care (San Antonio) 15:110118, 2005. 4. Mazzaferro EM, Rudloff E, Kirby R: the role of albumin replacement in the critically ill veterinary patient, J Vet Emerg Crit Care (San Antonio) 12:113-124, 2002. 5. Raffe MR: Pre-operative and post-operative management of the emergency surgical patient. In Murtaugh RJ, Kaplan PM, editors: Veterinary emergency and critical care medicine, St Louis, 1992, Mosby–Year Book. 6. Jacobson JD: Sedating and anesthetizing patients that have organ system dysfunction, Vet Med 518-524, 2005. 7. Hall LW, Clarke KW, Trim CM: General pharmacology of the injectable agents used in anaesthesia. In Hall LW, Clarke KW, Trim CM, editors: Veterinary anaesthesia, ed 10, London, 2001, Saunders. A good basic anesthesia textbook 8. Macintire DK, Drobatz KJ, Haskins SC, et al: Anesthetic protocols for short procedures. In Macintire DK, Drobatz KJ, Haskins SC, et al, editors: Manual of small animal emergency and critical care, Philadelphia, 2005, Lippincott Williams & Wilkins, pp 38-54. 9. Taylor PM, Chengelis CP, Miller WR, et al: Evaluation of propofol containing 2% benzyl alcohol preservative in cats, J Feline Med Surg 14(8):516526, 2012. 10. Jimenez CP, Mathis A, Mora SS, et al: Evaluation of the quality of the recovery after administration of propofol or alfaxalone for induction of anaesthesia in dogs anaesthetized for magnetic resonance imaging, Vet Anaesth Analg 39:151-159, 2012. 11. Psastha E, Alibhai HIK, Jimenez-Lozano A, et al: Clinical efficacy and cardiorespiratory effects of alfaxalone, or diazepam/fentanyl for induction of anaesthesia in dogs that are a poor anaesthetic risk, Vet Anaesth Analg 38:24-36, 2011. 12. Mathis A, Pinelas R, Brodbelt DC, et al: Comparison of quality of recovery from anaesthesia in cats induced with propofol or alfaxalone, Vet Anaesth Analg 39:282-290, 2012. 13. Carroll G, Martin DD: Trauma and critical patients. In Tranquilli WJ, Thurmon JC, Grimm KA, editors: Lumb and Jones’ veterinary anesthesia and analgesia, ed 4, Ames, Ia, 2007, Blackwell, pp 969-984. 14. de la Granville B, Arroyo D, Walder B: Etomidate in critically ill patients. Con: do you really want to weaken the frail? Eur J Anaesthesiol 29:511514, 2012. 15. Cutherbertson BH, Sprung CL, Annane D, et al: The effects of etomidate on adrenal responsiveness and mortality in patients with septic shock, Intensive Care Med 35:1868-1876, 2009. 16. Perkowski S: Sedation of the critically ill patient. In Silverstein DC, Hopper K, editors: Small animal critical care medicine, ed 1, St Louis, 2009, Saunders pp 700-704. 17. Anagnostou TL, Kazakos GM, Savvas I, et al: Remifentanil/isoflurane anesthesia in five dogs with liver disease undergoing liver biopsy, J Am Anim Hosp Assoc 47:e103-e109, 2011. 18. Allweiler S, Brodbelt DC, Borer K, et al: The isoflurane-sparing and clinical effects of a constant rate infusion of remifentanil in dogs, Vet Anaesth Analg 34:388-393, 2007. 19. Brosnan RJ, Pypendop BH, Siao KT, et al: Effects of remifentanil on measures of anesthetic immobility and analgesia in cats, Am J Vet Res 70:10651071, 2009. 20. Muir WW, Wiese AJ, March PA: Effects of morphine, lidocaine, ketamine, and morphine-lidocaine-ketamine drug combination on minimum alveolar concentration in dogs anesthetized with isoflurane, Am J Vet Res 64(9):1155-1160, 2003. 21. Wagnor AE, Walton JA, Hellyer PW, et al: Use of low doses of ketamine administered by constant rate infusion as an adjunct for postoperative analgesia in dogs, J Am Vet Med Assoc 221(1):72-75, 2002. 22. Cassutto BH, Gfeller RW: Use of intravenous lidocaine to prevent reperfusion injury and subsequent multiple organ dysfunction syndrome, J Vet Emerg Crit Care (San Antonio) 13:137-148, 2003. 23. Pypendop BH, Ilkiw JE: Assessment of the hemodynamic effects of lidocaine administered IV in isoflurane anesthetized cats, Am J Vet Res 66:661-668, 2005. 24. Mannarino R, Luna SPL, Monteiro ER, et al: Minimum infusion rate and hemodynamic effects of propofol, propofol-lidocaine and propofollidocaine-ketamine in dogs, Vet Anaesth Analg 39:160-173, 2012.

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25. Baldo CF, Garcia-Pereira FL, Nelson NC, et al: Effects of anesthetic drugs on canine splenic volume determined via computed tomography, Am J Vet Res 73:1715-1719, 2012. 26. Hall LW, Clarke KW, Trim CM: General pharmacology of the inhalation anesthetics. In Hall LW, Clarke KW, Trim CM, editors: Veterinary anaesthesia, ed 10, London, 2001, Saunders. 27. Ravasio G, Gallo M, Beccaglia M, et al: Evaluation of a ketamine-propofol drug combination with or without dexmedetomidine for intravenous anesthesia in cats undergoing ovariectomy, J Am Vet Med Assoc 241:13071313, 2012. 28. Quandt JE, Lee JA: Analgesia and constant rate infusions. In Silverstein DC, Hopper K, editors: Small animal critical care medicine, ed 1, St Louis, 2009, Saunders. pp 710-716. 29. Murray MJ, Cowen J, DeBlock H, et al: Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient, Crit Care Med 30:142-156, 2002. 30. Hall LW, Clarke KW, Trim CM: Relaxation of the skeletal muscle. In Hall LW, Clarke KW, Trim CM, editors: Veterinary anaesthesia, ed 10, London, 2001, Saunders. 31. Lukasik VM: Neuromuscular blocking drugs and the critical care patient, J Vet Emerg Crit Care 5:99-113, 1995. 32. Martinez EA, Keegan RD: Muscle relaxants and neuromuscular blockade. In Tranquilli WJ, Thurman JC, Grimm KA, editors: Lumb and Jones’

veterinary anesthesia and analgesia, ed 4, Ames, Ia, 2007, Blackwell, pp 419-437. 33. Adams WA, Robinson KJ, Senior JM, et al: The use of the nondepolarizing neuromuscular blocking drug cis-atracurium in dogs, Vet Anaesth Analg 28:156-160, 2001. 34. Kastrup MR, Marsico FF, Ascoli FO, et al: Neuromuscular blocking properties of atracurium during sevoflurane or propofol anaesthesia in dogs, Vet Anaesth Analg 32:222-227, 2005. 35. Wright B, Hellyer PW: Respiratory monitoring during anesthesia: pulse oximetry and capnography, Compend Contin Educ Pract Vet 18:10831097, 1996. 36. Hall LW, Clarke KW, Trim CM: Patient monitoring and clinical measurement. In Hall LW, Clarke KW, Trim CM, editors: Veterinary anaesthesia, ed 10, London, 2001, Saunders. 37. Hall LW, Clarke KW, Trim CM: Anaesthesia of the dog. In Hall LW, Clarke KW, Trim CM, editors: Veterinary anaesthesia, ed 10, London, 2001, Saunders. 38. Pablo LS. The use of vasopressin in critical care patients. In: Proceedings North American Veterinary Conference. Gainesville FL: 2006, p. 280-282. 39. Muir WW: Physiology and pathophysiology of pain. In Gaynor JS, Muir WW, editors: Handbook of veterinary pain management, ed 1, St Louis, 2002, Mosby.

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CHAPTER 144  ANALGESIA AND CONSTANT RATE INFUSIONS Jane Quandt,

BS, DVM, MS, DACVAA, DACVECC  •  Justine

KEY POINTS • There are several general drug classes, administration routes, and techniques by which analgesia can be achieved. • The clinician should be able to develop an appropriate analgesic therapeutic plan that addresses the type and severity of pain. • Patients should be frequently evaluated for response to treatment and treated appropriately with additional analgesics if necessary. • Multimodal or combination analgesic drug therapy may be beneficial in the critically ill patient.

ANALGESIA The critically ill patient benefits from analgesia because it promotes an animal’s overall well-being and has a positive effect on the speed and quality of recovery.1 The goal of pain control is to achieve a state in which the pain is bearable but some of the protective aspects of pain, such as inhibiting use of a fractured leg, still remain.1 There are several general drug classes, administration routes, and techniques by which analgesia can be achieved. General drug classes that are commonly used include the following: opioids, nonsteroidal antiinflammatory drugs (NSAIDs), α2-adrenergic agonists (see Chapter 165 for more information on α2 agonists and antagonists), local anesthetics, N-methyl-d-aspartate (NMDA) antagonists, benzodiazepines, and

A. Lee,

DVM, DACVECC, DABT

phenothiazines. Analgesics can be administered by various methods including the intravenous, subcutaneous, intramuscular, epidural, transmucosal, transdermal, oral, intraarticular, intrapleural, and intraperitoneal routes as well as by local infiltration. The type of treatment may depend on the severity of pain and the nature of the animal. Specific dosages of analgesic drugs are provided in Table 144-1. In intensive care unit (ICU) patients, analgesics should be administered as soon as possible after patient assessment and appropriate patient resuscitation to provide a significant benefit.2 It is vital, however, that the underlying disease process be addressed while pain relief is provided because analgesic therapy may mask the underlying disorders or the hemodynamic status of a patient. Ideally analgesics should be administered before pain develops (e.g., preemptive analgesia) because less drug therapy may be necessary to control pain. This is especially important before surgery or other invasive procedures; however, this is not always feasible in trauma or emergent cases.2,3 Pain development and sensation may involve a multiplicity of pathways; therefore it is important to develop an analgesic therapeutic plan that assesses the type and severity of the pain and the response to treatment. Because pain pathways are complex, it is often unlikely that one agent alone will completely alleviate pain, regardless of how high the dose is.4 The use of more than one class of drug can improve analgesia because the drugs affect multiple receptor types and such

Table 144-1  Analgesics and Their Dosages Generic Name

Dosage

Acetylpromazine, acepromazine

0.01-0.05 mg/kg IM, IV q3-6h; do not exceed a total of 3 mg in large dogs

Atipamezole (reverses α2-adrenergic agonist drugs)

0.05-0.2 mg/kg IM, IV, SC

Bupivacaine

Nerve block: 1-2 mg/kg SC q6h

Buprenorphine

0.005-0.02 mg/kg IM, IV q6-8h Cats: 0.01-0.02 mg/kg q6-8h PO

Butorphanol

0.1-0.4 mg/kg IM, IV q1-4h Partial reversal of µ-opioid agonist: 0.05-0.1 mg/kg IV Loading dose for CRI: 0.1 mg/kg IV Maintenance for CRI: 0.03-0.4 mg/kg/hr IV

Carprofen

2-4 mg/kg SC (single dose)

Cyproheptadine

Dogs: 0.3-2 mg/kg PO q12h Cats: 2 mg/cat PO q12h

Deracoxib

Dogs: 1-2 mg/kg PO q24h Postoperative pain: 3-4 mg/kg PO q24h; do not give for >7 days

Dexmedetomidine

1-5 mcg/kg IV q4h Loading dose: 1 mcg/kg IV Maintenance: 0.5-3 mcg/kg/hr IV CRI

Etodolac

Dogs: 5-15 mg/kg PO q24h

Fentanyl

Dogs: Loading dose: 2 mcg/kg IV Maintenance: 2-5 mcg/kg/hr CRI Cats: Loading dose: 1 mcg/kg IV Maintenance: 1-4 mcg/kg/hr CRI

Fentanyl patch

Cats, dogs < 5 kg: 25-mcg patch Dogs 5-10 kg: 25-mcg patch Dogs 10-20 kg: 50-mcg patch Dogs 20-30 kg: 75-mcg patch Dogs > 30 kg: 100-mcg patch

Gabapentin

1.25-4 mg/kg PO q24h

Hydromorphone HCl

Dogs: 0.05-0.2 mg/kg IM or SC; 0.05-0.1 mg/kg IV q2-4h Cats: 0.05-0.1 mg/kg IM or SC q3-4h; 0.03-0.05 mg/kg IV q3-4h

Indomethacin

No safe dose established

Ketamine

Analgesia without sedation: 0.1-1 mg/kg IV Loading dose: 0.5 mg/kg IV Maintenance during surgery: 10 mcg/kg/min IV CRI Maintenance after surgery: 2 mcg/kg/min CRI for 24 hr

Lidocaine

Nerve block: 1-2 mg/kg SC Loading dose: 1-2 mg/kg IV Maintenance: 2-3 mg/kg/hr IV CRI

2% Lidocaine

Nerve block: 1-2 mg/kg SC

Lidocaine patch

No animal dose established, but patch contains 700 mg of lidocaine. Significant systemic absorption has not been found to occur. Patch should be cut to fit size of area.

Meloxicam

0.1-0.2 mg/kg IV or SC (single dose)

Morphine

Dogs: 0.25-1 mg/kg IM q4-6h

Morphine sulfate

Dogs: 0.5-2 mg/kg IM, SC q4h Cats: 0.05-0.4 mg/kg IM, SC q3-6h Loading dose: 0.15-0.5 mg/kg IV administered slowly to avoid histamine release Maintenance: 0.1-1 mg/kg/hr CRI

Naloxone (opioid reversal)

0.002-0.1 mg/kg IM, IV, or SC

Oxymorphone

Dogs: 0.03-0.1 mg/kg IM or IV q2-4h Cats: 0.01-0.05 mg/kg IM or IV q2-4h

Remifentanil

3 mcg/kg IV, then CRI of 0.1-0.3 mcg/kg/min

Tepoxalin

Dogs: 10 mg/kg PO q24h

Morphine-lidocaine-ketamine infusion

Morphine: 3.3 mcg/kg/min Lidocaine: 50 mcg/kg/min Ketamine: 10 mcg/kg/min Preparation: Mix 10 mg of morphine sulfate, 150 mg of 2% lidocaine, and 30 mg of ketamine into a 500-ml bag of lactated Ringer’s solution Administration rate: 10 ml/kg/hr

CRI, Constant rate infusion; IM, intramuscularly; IV, intravenously; PO, per os; SC, subcutaneously.

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combination therapy may also overcome the problem of varying onset times and durations of action of different drug classes. Examples of effective combinations of analgesic therapy are the administration of opioids with NSAIDs, local anesthetics (e.g., lidocaine patches) with opioids, and an epidural analgesic with systemic opioid therapy. Regardless of what type of analgesic or combination of analgesics is used, patients should be reassessed frequently to ensure that the analgesic regimen is adequate and appropriate. Finally, administration of analgesics may be diagnostic when pain behavior is difficult to recognize in stoic patients.4

OPIOIDS Opioids act centrally to limit the input of nociceptive information to the central nervous system (CNS), which reduces central hypersensitivity.5 Receptors in the brain and dorsal horn of the spinal cord receive impulses from peripheral nerves, which are modulated before being transmitted to higher centers.6 Opioids are commonly used in critically ill patients because they have a rapid onset of action and are safe, reversible, and potent analgesics. As with all analgesic therapy in critically ill patients, opioids should be slowly titrated intravenously (IV) to effect, due to altered drug pharmacokinetics.7 Opioid analgesics vary in effectiveness, depending on which receptor is stimulated and which class of opioid is being administered. The four classes of opioids are pure agonists, partial agonists, agonists-antagonists, and antagonists. Pure receptor agonist stimulation results in a pronounced analgesic effect, whereas partial agonists bind at the same receptor but produce a less pronounced effect.6 Agonists-antagonists have mixed effects, with an agonist effect at one type of receptor and an antagonist effect at a different type of receptor. This results in an analgesic effect at one receptor and no effect (or a less pronounced effect) at the other receptor. Opioid antagonists (e.g., naloxone) bind to the same receptor as agonists but cause no effect and can competitively displace the agonist from the receptor and therefore reverse the agonist effect.6 The partial agonist buprenorphine and mixed agonist-antagonist butorphanol reach maximal effect at the upper end of the dose range. If the pain is severe or the analgesia is inadequate, additional doses of partial or mixed agonistsantagonists are unlikely to be effective. Using a pure µ agonist (e.g., morphine, hydromorphone, fentanyl, oxymorphone, remifentanil) would be more effective because there is no upper limit to the analgesia provided by a pure µ agonist.5 Potent adverse effects such as respiratory depression and bradycardia may be seen at the higher end of the dose range with a pure µ agonist; therefore the higher doses should be used cautiously in critically ill patients.5,6 Additional adverse effects of some µ agonists (e.g., morphine and meperidine) include histamine release, which is of particular concern when these agents are given rapidly IV because this can lead to severe hypotension due to vasodilation.6 Opioids can lead to gastroparesis and ileus, which may result in vomiting, regurgitation, and aspiration of gastrointestinal (GI) contents, particularly in depressed, sedated, weak, or critically ill patients. Gastric distention caused by opioids may also be a concern in patients with abdominal disease (e.g., pancreatitis) because stimulation of pancreatic secretions may occur. Patients at risk of pancreatitis or gastroparesis may require intermittent or constant gastric decompression (via nasogastric, esophagostomy, or gastrostomy tube) if they are treated with opioids for longer than 12 to 24 hours or may require motility drug therapy (e.g., metoclopramide) for treatment of ileus.8 Opioids can be safely administered to cats to provide analgesia.5 Morphine, hydromorphone, or oxymorphone can be administered for analgesia; however, adverse effects such as hyperexcitability or

agitation may occur. It has been shown that the onset of mydriasis following administration of opioids correlates with adequate analgesia in cats; continual dosing after mydriasis is achieved may result in adverse effects such as dysphoria and agitation.8 Another option for cats is the mixed partial µ agonist buprenorphine, which has been shown to be an effective analgesic.6 The newest µ agonist, remifentanil, may offer some advantages over the more commonly used µ opioids. In dogs and cats with severe liver compromise, remifentanil may be considered for analgesia during general anesthesia and as a constant rate infusion (CRI) to provide analgesia in the ICU. Remifentanil is a synthetic opioid with direct action on the µ receptors. It has an ultrashort duration of action, which allows a rapid recovery even after long-term IV infusion. The elimination of remifentanil is independent of hepatic or renal function because the drug is metabolized by nonspecific esterases in blood and tissues, which makes it an attractive agent for use in patients with hepatic or renal compromise.9 Remifentanil has been used in dogs at an initial dose of 3 mcg/kg IV followed by a CRI of 0.1 to 0.3 mcg/kg/min. The clinical effects of remifentanil are rapidly dissipated upon discontinuation of the CRI, with dogs recovering within 5 to 20 minutes regardless of the duration of the infusion.9,10 Due to the drug’s short duration of action, additional analgesic therapy is necessary upon termination of the CRI if clinical signs of pain persist. Like other opioids, remifentanil is a potent respiratory depressant when used as a CRI, and the patient should be monitored for hypoventilation. If depression is severe, the use of naloxone or mechanical ventilation may be required. The respiratory depression associated with remifentanil typically does not persist following recovery.10 In cats, the use of remifentanil at dosages higher than 1 mcg/kg/min has been associated with dysphoric behavior and frenetic locomotor activity.11 Fentanyl, another pure µ agonist, is commonly used in veterinary medicine, both in injectable form and in transdermal patches (Duragesic). The newest formulation of fentanyl is Recuvyra, which has been developed for transdermal application in dogs only. (This product is not to be used in cats.) The canine dose is a single application of 2.6 mg/kg delivered via a specialized syringe to the dorsal scapular area 2 to 4 hours before surgery, with analgesia lasting a minimum of 4 days.12 If accidental overdose occurs, naloxone (40 or 160 mcg/kg intramuscularly [IM] q1h as needed) can be used to reverse any signs of excessive sedation, bradycardia, or hypothermia. The shorter duration of action of naloxone relative to that of transdermal fentanyl may necessitate repeated injections of naloxone.13 One advantage of opioid administration in critically ill patients is that their effects can be reversed if necessary with a pure antagonist such as naloxone. Naloxone can reverse the CNS depression, respiratory depression, and bradycardia associated with the opioid; however, reversal of the sedative effect and analgesia effect can cause acute pain, excitement, emergence delirium, aggression, and hyperalgesia.14 Low-dose naloxone (0.004 mg/kg titrated slowly IV) has been recommended to reverse CNS depression without affecting analgesia.8 The duration of effect for naloxone is relatively short (20 to 30 minutes) because of its rapid metabolism in dogs and cats, which may predispose patients to renarcotization when the drug is used to reverse long-acting opioids.14,15 Agonists-antagonists such as butorphanol (0.05 to 0.1 mg/kg IV) may also be used to reverse sedation and respiratory depression from µ agonists.8,14 The benefit of using butorphanol as a reversal agent is that complete reversal of analgesia does not occur due to the κ-agonist effects of butorphanol. Butorphanol administered as a reversal agent may produce additive analgesia with the µ agonist.14 In contrast, buprenorphine is not as easily reversed as butorphanol because it is difficult to displace from the receptor.6

CHAPTER 144  •  Analgesia and Constant Rate Infusions

NONSTEROIDAL ANTIINFLAMMATORY DRUGS Inflammation plays a significant role in the pain process, and therefore the use of NSAIDs to reduce or eliminate peripheral inflammation may be helpful. NSAIDs decrease the pain input to the CNS, which may aggravate central hypersensitivity.2 There are several commercially available veterinary NSAIDs, including carprofen (Rimadyl), deracoxib (Deramaxx), meloxicam (Metacam), etodolac (Etogesic), tepoxalin (Zubrin), and robenacoxib (Onsior). The analgesic and antiinflammatory effects associated with NSAIDs are related to inhibition of cyclooxygenase (COX) enzyme isoforms. COX-1 is primarily responsible for basal prostaglandin production for normal homeostatic processes within the body, including gastric mucus production, platelet function, and, indirectly, hemostasis, whereas COX-2 is found at sites of inflammation (although COX-2 is responsible for some basal production of constitutive prostaglandins as well). Ideally, selective inhibition of prostaglandins produced primarily by COX-2 would provide analgesic and antiinflammatory effects without the unwanted adverse effects of COX-1 inhibition.16 At present, there is no pure COX-2 inhibitor; rather, certain NSAIDs have varying degrees of COX-1 inhibition. For this reason, NSAIDs should be used cautiously in patients with hypotension, hypovolemia, preexisting renal disease (due to the increased potential for renal vascular vasoconstriction, which would lead to worsening of renal insufficiency), and GI disease or gastric ulceration.5,7,17 Ideally, enteral NSAIDs should be given with food when possible to decrease the incidence of gastric ulceration. In addition, NSAIDs should be used cautiously in the perioperative period because decreased platelet function may increase the incidence of operative hemorrhage. Injectable NSAIDs (e.g., carprofen, meloxicam) have an advantage over oral NSAIDs because injectable drug therapy can be administered to patients that cannot tolerate oral administration due to preoperative fasting for anesthesia, nausea, vomiting, or decreased mentation.5 Finally, although NSAIDs have a slow onset of action (requiring up to 45 to 60 minutes to take effect), they provide analgesia for an extended period of time.18 Carprofen has a 12-hour dosing frequency, whereas other NSAIDs (e.g., deracoxib, meloxicam, etodolac) are labeled for once-daily dosing.16 The new feline-specific NSAID Onsior contains robenacoxib and is a COX-2 inhibitor with a high safety index in cats.19 It has analgesic, antiinflammatory, and antipyretic effects in cats and selectively distributes to inflamed tissues, while sparing COX-1 at the clinically recommended dose.20 It can be given subcutaneously (SC) between the shoulder blades (2 mg/kg) or orally (PO) (6 mg per cat q24h for cats weighing 2.5 to 6 kg and 12 mg per cat q24h for cats weighing 6.1 to 12 kg for 3 days).20,21 Robenacoxib has a terminal half-life of 1.9 hours in cats, with efficacy persisting for 22 hours.20 As mentioned previously, NSAIDs can be used in combination with opioids for a combined therapeutic effect. However, the concurrent use of NSAIDs and corticosteroids is not recommended due to the potentiated adverse GI effects of COX-1 inhibition.5

α2-ADRENERGIC AGONISTS The α2-adrenergic agonists bind to receptors in the CNS, which leads to sedation, peripheral vasoconstriction, bradycardia, respiratory depression, diuresis, muscle relaxation, and analgesia.8,22 Dexmedetomidine is the most common α2-adrenergic agonist administered to small animals. Dexmedetomidine is the dextrorotatory enantiomer of medetomidine, which is the active form. The clinical effects of both drugs are similar, and any comments made about medetomidine in the remainder of this discussion can be applied equally to dexmedetomidine. It is approved for use in dogs and cats,22 and both

dexmedetomidine and medetomidine can be given IM or IV. These drugs are biotransformed by the liver, with inactive metabolites excreted in the urine. Both of these α2-adrenergic agonists have a rapid onset of action.23 The sedative effects of medetomidine have a longer duration of action than do the analgesic effects, which last approximately 30 to 90 minutes.24 Low-dose medetomidine (1 to 10 mcg/kg IV) can be safely used in patients in stable condition or administered in conjunction with opioids to produce analgesic synergism and increase the duration of analgesia up to 4 hours.8,24 At higher doses, medetomidine can be used for sedation of distressed animals and for minor procedures (e.g., restraint and analgesia for radiographic positioning).8 In patients in stable cardiovascular condition, medetomidine can be used as a CRI for analgesia (initial loading dose of 1 mcg/kg IV then a CRI of 1 to 3 mcg/kg/hr).25 One should note that the dose range for dexmedetomidine is half that for medetomidine. As with opioids, the effects of α2-adrenergic agonists can be reversed. Atipamezole is a specific α2-adrenergic antagonist that reverses analgesia, sedation, and respiratory depression. Intramuscular or subcutaneous administration is preferred for reversal because intravenous administration can lead to abrupt hypotension and/or aggression.14 See Chapter 165 for more information on α2 agonists and antagonists.

TRANSDERMAL ANALGESICS Administration of topical analgesics in conjunction with other analgesic therapy is well tolerated by patients and has minimal systemic effects.26 Fentanyl patches can be used to provide long-term analgesia but may vary in time to onset of effects and steady-state concentrations.7,18,27 Because of this variability, systemic analgesia must be provided until the patch becomes effective (typically up to 24 hours in dogs).8 Fentanyl uptake is affected by dermal blood flow, hair, and obesity and may be greatly altered in hypovolemic or hypothermic patients. In cats the drug may reach therapeutic levels in 6 to 12 hours, and steady states can be maintained for approximately 5 days.18,27 It should be noted that therapeutic levels may not be reached with the patch in all animals. If the patient still appears to be in pain 12 to 24 hours after patch application, additional analgesic treatment may be necessary.8 Fentanyl patches are currently available in 25-, 75-, and 100-mcg formulations. Fentanyl patches should not be cut or otherwise altered because this may affect the amount of absorption or drug loss. The pet owner should be specifically instructed regarding the proper disposal of used fentanyl patches because there is potential for human abuse. Lidoderm, a 5% lidocaine patch, was recently introduced to the human and veterinary markets. Lidoderm was approved in 1999 by the U.S. Food and Drug Administration for treatment of postherpetic neuralgia in humans.26 Lidoderm is a nonwoven, polyester, feltbacked patch covered with a polyethylene terephthalate film release liner that should be removed before the patch is applied to the skin. Each 10- × 14-cm adhesive patch contains 700 mg of lidocaine (50 mg per gram of adhesive) in an aqueous base. Lidocaine penetration into intact skin is sufficient to produce an analgesic effect but does not result in complete sensory block. The Lidoderm patch can be safely worn for as long as 24 hours and provides analgesia without numbness or loss of sensitivity to touch or temperature. Therapeutic levels are achieved via absorption within 30 minutes. Unlike the fentanyl patch, the lidocaine patch can be cut to fit patient size without affecting drug delivery. Lidocaine patches can be used back to back for continuous analgesia because toxic blood levels do not develop; however, the skin needs to be monitored for development of localized dermatitis because the most common adverse effects in humans are transient dermal reactions such as localized rash and pruritus.28

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For application of analgesic patches in veterinary patients, the hair must be clipped and cleaned. The lidocaine patch can be stapled in place with surgical staples to ensure appropriate contact with skin.29 The use of staples to aid in adherence of fentanyl patches has not been evaluated. Anecdotally, the Lidoderm patch has been used in dogs and cats to provide analgesia for severe skin abrasions, bruising, and surgical incisions; no apparent toxic effects have been noted thus far. In addition, multimodal analgesia can be initiated with both the lidocaine patch and fentanyl patch applied simultaneously. The lidocaine patch will provide local analgesia, whereas the fentanyl patch will provide systemic analgesia.

N-METHYL-D-ASPARTATE RECEPTOR ANTAGONISTS NMDA receptor antagonists work by blocking multiple binding sites at this receptor, which results in analgesic, amnestic, and psychomimetic effects as well as neuroprotection.30 Ketamine, a noncompetitive NMDA receptor antagonist, can reverse central hypersensitivity by preventing the exaggerated response, wind-up activity, and central sensitization of wide-dynamic-range neurons in the dorsal horn of the spinal cord.5 Ketamine can be administered PO, SC, IM, or IV. Ketamine prevents the response to nociceptive stimuli carried by afferent pain neurons (e.g., C fibers).31,32 Ketamine causes minimal cardiovascular depression, does not depress laryngeal protective reflexes, and produces less ventilatory depression than opioids; however, adverse effects include tremors and sedation along with increased cardiac output due to increased sympathetic tone.32 Subanesthetic or low doses in dogs and cats (0.1 to 1 mg/kg IV, followed by a CRI of 2 mcg/kg/min) may produce analgesic effects without causing anesthesia or profound sedation.5,32 Oral ketamine can also be used (8 to 12 mg/kg PO q6h in dogs) to provide pain relief following burn injuries.7

ACEPROMAZINE The phenothiazine acepromazine (0.01 to 0.05 mg/kg IV, not to exceed a total dose of 3 mg) does not provide analgesia alone and should not be administered as a single agent if analgesia is desired. Rather, it should be used in combination with opioids as an anxiolytic and sedative. However, in the critically ill patient it should be used with caution due to the potential for vasodilation and resultant profound hypotension and hypothermia. Even with IV administration, up to 15 minutes may be required before the sedative effect of acepromazine is clinically observed; therefore repeated doses should be avoided until the full effect is evident.8 Acepromazine can be safely administered to ICU patients if given at low doses (0.005 to 0.01 mg/ kg) in patients in hemodynamically stable condition with adequate respiratory function.33

INFILTRATIVE AND LOCAL ANESTHETICS Local anesthetics (e.g., lidocaine, bupivacaine) provide analgesia by blocking both specific nerve pathways and action potential transmission in nerve fibers (including nociceptive fibers).5 Local anesthetics can be used for local injection (e.g., small bite wounds), intercostal nerve blocks, and intrathoracic or intraperitoneal administration. In addition, 0.5% bupivacaine (2 mg/kg q6h) can be administered to provide analgesia for painful diseases and conditions (e.g., fractures, pancreatitis) or for procedures (e.g., thoracotomy, placement of a thoracostomy tube).5,18 Intercostal nerve blockade can be used to provide analgesia for rib fractures. Bupivacaine (1 to 1.5 mg/kg q6h, not to exceed 4 mg/kg on day 1) can be injected into the area of the intervertebral foramen on the caudal border of the rib to block

the intercostal nerves.5 Bupivacaine can also be administered into the pleural space via a thoracostomy tube to provide analgesia following thoracic surgery or tube placement because the presence of the tube itself may be painful. In cases of pancreatitis or abdominal pain, bupivacaine (2 mg/kg diluted in saline q6h intraperitoneally) can be administered via an aseptically placed, temporary butterfly catheter to provide analgesia. However, it may be ineffective when ascites is present due to dilution of the topical analgesic. When local anesthetics are used, use of an aseptic technique is imperative. The patient should be appropriately positioned so that the medication disperses over the desired site to enhance analgesia.5 In addition, sodium bicarbonate (1 mEq/ml) may be added to lidocaine (at a ratio of 1 to 2 parts bicarbonate to 8 to 9 parts lidocaine) to decrease the burning sensation caused by the administration of lidocaine alone, which is due to the acidity of the local anesthetic.8 When bupivacaine is used, a 1 : 30 ratio of sodium bicarbonate to bupivacaine is sufficient. Potential adverse effects of bupivacaine include arrhythmias and reduced cardiac output; therefore the drug should not be administered to animals with preexisting life-threatening arrhythmias. Also, because bupivacaine is selectively cardiotoxic, only half the canine dose should be administered to cats.8 Certain contraindications to bupivacaine administration exist and warrant the use of alternative analgesics. In patients undergoing pericardectomy, intrapleural bupivacaine should be used judiciously due to the potential risk of cardiotoxicity.5 Although intrapleural bupivacaine has been used safely in healthy dogs with and without an open pericardium, its use in patients with underlying cardiovascular instability or other disease has not been assessed.34 Intrapleural bupivacaine may also interfere with ventilation by inducing diaphragmatic paralysis. Animals with good respiratory reserve capacity rarely develop clinically significant compromise, but administration of intrapleural anesthetics should be avoided in animals with marginal respiratory function.8 Finally, toxicity may occur with higher doses of lidocaine (>10 to 20  mg/kg) and bupivacaine (>4  mg/kg). Clinical signs of toxicosis may include seizures, cardiac arrhythmias, tachycardia, and cardiovascular collapse. The maximum safe dose for most species is 4  mg/kg of lidocaine and 1 to 2  mg/kg of bupivacaine.5 Administration of epinephrine, which normally enhances the duration of effect of local anesthetics, should be avoided in critically ill patients because it may lead to cardiac stimulation or ischemia from vasoconstriction.5

EPIDURAL ANALGESICS Epidural analgesia is an alternative way of delivering analgesia to the caudal half of the body. Depending on the dose or volume of drug used, analgesia of the forelimbs can also be achieved: an injected volume of 1 ml/5 kg blocks to the first lumbar vertebra, and use of a larger volume results in a cranial spread of the analgesia. Lower concentrations of local anesthetics can provide analgesia without secondary motor deficits. Complete anesthesia can be achieved with higher doses of local anesthetics, which result in motor paralysis of the rear limbs. Epidural opioids can provide analgesia without affecting motor function; nociceptive input is reduced but not completely abolished. Higher doses may also lead to vasodilation and subsequent hypotension.5 In critically ill patients, lower doses of local anesthetics should be used epidurally to avoid inducing hypotension. In general, critically ill patients often benefit from epidural analgesia because it decreases anesthetic requirements and provides analgesia without cardiorespiratory effects or excessive sedation. The technique for epidural analgesia has been described elsewhere,5 and readers are referred to those sources for further information on technique. Contraindications for the use of epidural analgesia

CHAPTER 144  •  Analgesia and Constant Rate Infusions

or epidural catheter placement include trauma over the pelvic region (with loss of appropriate landmarks), sepsis, coagulopathy, CNS disease, skin infection over the site of injection, hypovolemic shock, and severe obesity.5,18,35,36 Epidural catheters can also be used to help maintain long-term analgesia, although stringent aseptic protocol must be followed; in addition, these catheters may be technically difficult to place. An epidural catheter can be placed using the same landmarks as those for administration of a single injection. The advantage of epidural catheterization is the ability to provide continuous analgesia without the need for repeated epidural needle punctures. In addition, the catheter can be advanced cranially to improve analgesia to the front limbs or thoracic structures. Catheters must be placed aseptically under anesthesia or heavy sedation and maintained with sterility and care. Proper location of the epidural catheter can be confirmed via lateral radiography or fluoroscopy after catheter placement. If the epidural catheter is not radiopaque, a low dose of myographic contrast agent can be injected into the catheter to allow evaluation and ensure appropriate placement. Catheters have been safely left in place from 1 to 332 hours.36 With epidural catheters, the total volume injected should be limited to 6 ml in a large dog.36 See Table 144-2 for epidural dosing. Adverse effects of epidural anesthesia include vomiting, urinary retention, pruritus, and delayed hair growth at the clipped epidural site.35 Additional complications associated with epidural catheters include catheter dislodgement, discharge from the site, fecal contamination, line or filter breakage, and localized dermatitis.37 When complications occur, removal of the epidural catheter is recommended. Adverse effects of epidural anesthesia should be treated symptomatically. Urinary retention can be treated or prevented by manually expressing the bladder or placing an indwelling urinary catheter. Another complication is inadvertent injection of drug into the subarachnoid space. In dogs, the dural sac ends before the lumbosacral space, so inadvertent injection into the subarachnoid space is less likely. In cats, however, the dural sac ends past the lumbosacral space; therefore care must be taken to avoid subarachnoid injection when administering epidural drugs. If the subarachnoid space is pene-

trated, the nonpreservative formulation of the drug may still be given; however, a significantly reduced dose (50% to 75% of the original dose) should be administered.36 The lower dose is sufficient for an analgesic response because the roots of the spinal cord are more accessible within the subarachnoid space, where they are not protected by the dura.38

CONSTANT RATE INFUSIONS The administration of analgesics as a CRI has the advantage of maintaining effective plasma concentrations for continued pain relief. Anesthesia can also be maintained with a CRI if the animal cannot tolerate the hypotensive effects of inhalant anesthesia. The CRIs that have been administered during surgery can be carried over into recovery to provide titratable analgesia; the dose can usually be lower once surgical stimulation is over. All CRIs should be delivered by syringe pump for accurate dosing.32 To avoid histamine release, which may occur with rapid IV morphine administration, a morphine CRI (0.1 to 1 mg/kg/hr) should be started after administration of an initial loading dose (0.15 to 0.5 mg/kg IV, diluted and delivered slowly over 5 to 10 minutes).7,39 A CRI of morphine (0.12 mg/kg/hr) reportedly induces effects similar to those of intramuscular morphine (1 mg/kg q4h) in dogs undergoing laparotomy.40 Regardless of how morphine is administered, its use may result in bradycardia, hypothermia, and panting. Other opioids (e.g., fentanyl, oxymorphone, hydromorphone) can also be administered as a CRI if undesirable adverse effects of morphine occur.3 In critically ill animals that are poor anesthetic candidates, fentanyl, in conjunction with propofol, can provided adequate, safe, cardiovascular system–sparing anesthesia and therefore reduce or minimize the amount of inhalant anesthesia necessary. Adverse effects such as bradycardia may require treatment with an anticholinergic.41 Butorphanol has been administered at a loading dose of 0.1 mg/ kg followed by 0.03 to 0.4 mg/kg/hr IV CRI.7 Lidocaine can also be administered for pain control at an initial loading dose of 1 to 2 mg/ kg followed by 0.025 mg/kg/min IV CRI.39 Lidocaine doses as high as 2 to 3 mg/kg/hr IV have been reported.17 The α2 agonists can also

Table 144-2  Epidural Dosing33 Dog Dose and Duration   of Action

Cat Dose and Duration   of Action

Morphine (preservative free for epidural use)

0.1-0.4 mg/kg, with maximum volume of 6 ml33 Onset of action: 20-60 min Duration of action: 6-24 hr5,36

Buprenorphine

Epidural Drug

Benefits

Cautions

0.16 mg/kg Duration of action: 20 hr33

Lipid soluble Long acting Longer duration of action than systemic dosing5 Can reverse with naloxone

Use preservative-free formulation when administering

0.003-0.006 mg/kg

0.003-0.006 mg/kg

Preservative free Not a schedule II drug High lipid solubility

Difficult to reverse

Bupivacaine

0.5-2 mg/kg; higher end of dose range may result in transient paralysis33 Onset of action and duration similar to those of morphine

0.5-1 mg/kg Duration of action: 20 hr33

Less likely to result in urinary retention than morphine5,7,35,36

Epidural catheter dosing

When an epidural catheter is used the following drugs and doses are recommended: Morphine 0.1 mg/kg Bupivacaine 0.05-0.12 mg/kg Buprenorphine 0.003-0.006 mg/kg35 When the agent is injected through the epidural catheter, the injection should be given slowly because rapid injection may precipitate vomiting. A CRI of morphine (0.3 mg/kg q24h) or bupivacaine (0.2-0.3 mg/kg q24h) can be given slowly into the epidural space using a syringe pump. Bupivacaine may be administered via CRI through an epidural catheter, but this may result in muscle weakness. If the weakness is excessive, the infusion should be promptly discontinued and the dose of bupivacaine reduced.35

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be administered as a CRI to enhance analgesia and minimize the level of inhalant needed.42 The reader is directed to Table 144-1 for more information on drug dosing. Low doses of ketamine can be used perioperatively to prevent wind-up, do not have undesirable side effects such as dysphoria or hallucination, and can be used for intraoperative and postoperative analgesia in dogs. A loading dose of ketamine (0.5 mg/kg IV) should be immediately followed by a CRI of 10 mcg/kg/min. This should then be reduced to 2 mcg/kg/min during the recovery phase and postoperative phase.32 Combinations of multiple types of analgesics can also be used as a CRI to provide analgesia and to decrease the amount of inhalant required in dogs. Some examples include morphine-lidocaine-ketamine and fentanyl-lidocaine-ketamine, which are described further in the following sections.

MORPHINE-LIDOCAINE-KETAMINE Morphine (3.3 mcg/kg/min), lidocaine (50 mcg/kg/min), and ketamine (10 mcg/kg/min) can be administered as a CRI analgesic combination in dogs.31 These agents can be given separately or mixed together in a single bag. Use of a combination of agents may result in enhanced analgesia through synergism and multiple receptor activation. Ketamine has been found to attenuate and reverse morphine tolerance in rodents and humans, thereby yielding an opioid-sparing effect and providing superior analgesia compared with either drug alone.31 Recent work in the cat has shown that CRIs of lidocaine should be used cautiously (if at all) in this species due to cardiopulmonary depression; this would be an especially important consideration in the critically ill animal.43 Lidocaine has been used as a CRI along with fentanyl to provide analgesia in dogs undergoing ovariectomy. The intravenous dose of lidocaine was 2 mg/kg over 5 minutes followed by a CRI of 50 mcg/ kg/min, with fentanyl dosed at 4 mcg/kg over 5 minutes followed by a CRI of 8 mcg/kg/hour. The lidocaine did not enhance the analgesia but did not adversely affect recovery.44 Lidocaine may be more useful in those dogs that are suspected to have ischemia-reperfusion injury. Lidocaine may help diminish the level of reperfusion injury by inhibiting Na+/Ca2+ exchange and Ca2+ accumulation during ischemia, scavenging hydroxyl radicals, decreasing the release of superoxide from granulocytes, and decreasing polymorphonuclear leukocyte activation, migration into ischemic tissues, and subsequent endothelial dysfunction.45

CONCLUSION Administering analgesics in critically ill animals should be considered as an integral part of a treatment regimen. Critically ill patients may present a challenge when clinicians assess the presence of pain and evaluate the response to analgesic therapy. Because of the potential physiologic effects of some analgesics, the class of analgesic and route of administration should be chosen carefully for ICU patients. Using multimodal therapy that emphasizes lower doses of different classes of drugs may be a safer and more effective way of achieving analgesia in critically ill patients.

REFERENCES 1. Hellebrekers LJ: Pathophysiology of pain in animals and its consequences for analgesic therapy. In Hellebrekers LJ, editor: Animal pain in a practiceoriented approach to an effective pain control in animals, Utrecht, The Netherlands, 2000, Van Der Wees, pp 71-83. 2. Muir WW: Choosing and administering the right analgesic therapy. In Gaynor JS, Muir WW, editors: Handbook of veterinary pain management, St Louis, 2002, Mosby, pp 329-345.

3. Muir WW, Birchard SJ: Questions and answers on analgesia, anesthesia, and sedation. In Proceedings of the North American Veterinary Conference, Orlando, Fla, June 11-15, 1997, pp 1-24. 4. Lamont LA, Tranquilli WJ, Grimm KA: Physiology of pain, Vet Clin North Am Small Anim Pract 30(4):703-728, 2000. 5. Dobromylskyj P, Flecknell PA, Lascelles BD, et al: Management of postoperative and other acute pain. In Flecknell P, Waterman-Pearson A, editors: Pain management in animals, Philadelphia, 2000, Saunders, pp 81-145. 6. Wagnor A: Opioids. In Gaynor JS, Muir WW, editors: Handbook of veterinary pain management, St Louis, 2002, Mosby, 164-183. 7. Pascoe PJ: Problems of pain management. In Flecknell P, WatermanPearson A, editors: Pain management in animals, Philadelphia, 2000, Saunders, pp 161-177. 8. Hansen B: Acute pain management, Vet Clin North Am Small Anim Pract 30(4):899-916, 2000. 9. Anagnostou TL, Kazakos GM, Savvas I, et al: Remifentanil/isoflurane anesthesia in five dogs with liver disease undergoing liver biopsy, J Am Anim Hosp Assoc 47:e103-e109, 2011. 10. Allweiler S, Brodbelt DC, Borer K, et al: The isoflurane-sparing and clinical effects of a constant rate infusion of remifentanil in dogs, Vet Anaesth Analg 34:388-393, 2007. 11. Brosnan RJ, Pypendop BH, Siao KT, et al: Effects of remifentanil on measures of anesthetic immobility and analgesia in cats, Am J Vet Res 70:10651071, 2009. 12. Freise KJ, Newbound GC, Tudan C, et al: Pharmacokinetics and the effect of application site on a novel, long-acting transdermal fentanyl solution in healthy laboratory Beagles, J Vet Pharmacol Ther 35(Suppl 2):27-33, 2012. 13. Freise KJ, Newbound GC, Tudan C, et al: Naloxone reversal of an overdose of a novel, long-acting transdermal fentanyl solution in laboratory Beagles, J Vet Pharmacol Ther 35(Suppl 2):45-51, 2012. 14. Muir WW: Drug antagonism and antagonists. In Gaynor JS, Muir WW, editors: Handbook of veterinary pain management, St Louis, 2009, Mosby, pp 391-401. 15. Plumb DC: Naloxone. In Plumb DC, editor: Veterinary drug handbook, ed 4, Ames, Ia, 2002, Iowa State University Press, pp 575-576. 16. Budsberg S: Nonsteroidal anti-inflammatory drugs. In Gaynor JS, Muir WW, editors: Handbook of veterinary pain management, St Louis, 2009, Mosby, pp 183-209. 17. Hellebrekers LJ: Practical analgesic treatment in canine patients. In Hellebrekers LJ, editor: Animal pain: a practice-oriented approach to an effective pain control in animals, Utrecht, The Netherlands, 2000, Van Der Wees, pp 117-129. 18. Mathews KA: Management of pain in cats. In Hellebrekers LJ, editor: Animal pain: a practice-oriented approach to an effective pain control in animals, Utrecht, The Netherlands, 2000, Van Der Wees, pp 131-144. 19. Sano T, King JN, Seewald W, et al: Comparison of oral robenacoxib and ketoprofen for the treatment of acute pain and inflammation associated with musculoskeletal disorders in cats: a randomized clinical trial, Vet J 193(2):397-403, 2012. 20. Kamata M, King JN, Seewald W, et al: Comparison of injectable robenacoxib versus meloxicam for peri-operative use in cats: results of a randomized clinical trial, Vet J 193(1):114-118, 2012. 21. Onsior (robenacoxib) (package insert). Basel, Switzerland, 2012, Novartis Animal Health. 22. Plumb DC: Dexmedetomidine HCL. In Plumb DC, editor: Veterinary drug handbook, ed 7, Ames, Ia, 2011, Iowa State University Press, pp 298-300. 23. Muir WW, McDonell WN, Kerr CL, et al: Anesthetic physiology and pharmacology. In Grimm KA, Tranquilli WJ, Lamont LA, editors: Essentials of small animal anesthesia and analgesia, ed 2, Ames, Ia, 2011, Wiley-Blackwell, pp 15-81. 24. Lamont L: α2 Agonists. In Gaynor JS, Muir WW, editors: Handbook of veterinary pain management, St Louis, 2009, Mosby, pp 210-230. 25. Campbell VL: Injectable anesthetic techniques. In Proceedings of the 11th International Veterinary Emergency and Critical Care Symposium, 2005, pp 21-24. 26. Gammaitoni AR, Alvarez NA, Galer BS: Safety and tolerability of the lidocaine patch 5%, a targeted peripheral analgesic: a review of the literature, J Clin Pharmacol 43:111-117, 2003.

27. Lee DD, Papich MG, Hardie EM: Comparison of pharmacokinetics of fentanyl after intravenous and transdermal administration in cats, Am J Vet Res 61(6):672-677, 2000. 28. Pasero C: Lidocaine patch 5%: how to use a topical method of controlling localized pain, Am J Nurs 103(9):75-78, 2003. 29. Bidwell LA, Wilson DV, Caron JP: Systemic lidocaine absorption after placement of Lidoderm patches on horses: preliminary findings. In Proceedings of the Veterinary Midwest Anesthesia and Analgesia Conference, 2004, pp 15. 30. Lamont LA, Tranquilli WJ, Mathews KA: Adjunctive analgesic therapy, Vet Clin North Am Small Anim Pract 30(4):805-813, 2000. 31. Muir WW, Wiese AJ, March PA: Effects of morphine, lidocaine, ketamine, and morphine-lidocaine-ketamine drug combination on minimum alveolar concentration in dogs anesthetized with isoflurane, Am J Vet Res 64(9):1155-1160, 2003. 32. Wagnor AE, Walton JA, Hellyer PW, et al: Use of low doses of ketamine administered by constant rate infusion as an adjunct for postoperative analgesia in dogs, J Am Vet Med Assoc 221(1):72-75, 2002. 33. Flecknell P, Waterman-Pearson A, editors: Pain management in animals, Philadelphia, 2000, Saunders. 34. Bernard F, Kudnbig ST, Monnet E: Hemodynamic effects of interpleural lidocaine and bupivacaine combination in anesthetized dogs with and without an open pericardium, Vet Surg 35:252-258, 2006. 35. Troncy E, Junot S, Keroack S, et al: Results of preemptive epidural administration of morphine with or without bupivacaine in dogs and cats undergoing surgery: 265 cases (1997-1999), J Am Vet Med Assoc 221(5):666-672, 2002. 36. Hansen BD: Epidural catheter analgesia in dogs and cats: technique and review of 182 cases (1991-1999), J Vet Emerg Crit Care (San Antonio) 11(2):95-103, 2001.

37. Swalander DB, Crowe DT, Hittenmiller DH, et al: Complications associated with the use of indwelling epidural catheters in dogs: 81 cases (19961999), J Am Vet Med Assoc 216(3):368-370, 2000. 38. Muir WW, Skarda RT: Pain management in the horse. In Gaynor JS, Muir WW, editors: Handbook of veterinary pain management, St Louis, 2002, Mosby, pp 420-444. 39. Smith LJ, Bentley E, Shih A, et al: Systemic lidocaine infusion as an analgesic for intraocular surgery in dogs: a pilot study, Vet Anaesth Analg 31(1):53-63, 2004. 40. Lucas AN, Firth AM, Anderson GA, et al: Comparison of the effects of morphine administered by constant-rate intravenous infusion or intermittent intramuscular injection in dogs, J Am Vet Med Assoc 218(6):884891, 2001. 41. Mendes GM, Selmi AL: Use of a combination of propofol and fentanyl, alfentanil, or sufentanil for total intravenous anesthesia in cats, J Am Vet Med Assoc 223(11):1608-1613, 2003. 42. Quandt JE, Lee JA: Analgesia and constant rate infusions. In Silverstein DC, Hopper K, editors: Small animal critical care medicine, ed 1, St Louis, 2009, Saunders, pp 710-716. 43. Pypendop BH, Ilkiw JE: Assessment of the hemodynamic effects of lidocaine administered IV in isoflurane anesthetized cats, Am J Vet Res 66:661-668, 2005. 44. Columbano N, Secci F, Careddu GM, et al: Effects of lidocaine constant rate infusion on sevoflurane requirement, autonomic responses, and postoperative analgesia in dogs undergoing ovariectomy under opioid-based balanced anesthesia, Vet J 193:448-455, 2012. 45. Cassutto BH, Gfeller RW: Use of intravenous lidocaine to prevent reperfusion injury and subsequent multiple organ dysfunction syndrome, J Vet Emerg Crit Care (San Antonio) 13:137-148, 2003.

CHAPTER 145  •  Rehabilitation Therapy in the Critical Care Patient

CHAPTER 145  REHABILITATION THERAPY IN THE CRITICAL CARE PATIENT Ann M. Caulfield,

VMD, CCRP, CVA

KEY POINTS • Rehabilitation therapy should be included in the treatment plan for most critically ill veterinary patients. • Rehabilitation therapy must be prescribed and performed by (or under the direct supervision of) a trained and experienced rehabilitation therapist. • Patients must be frequently assessed and treatment plans modified based on the current medical status of the patient. • A team approach involving the critical care patient’s primary care veterinarian, nursing staff, and rehabilitation therapist is of absolute necessity in ensuring safe and effective rehabilitation therapy for each patient.

Rehabilitation therapy is a new and rapidly expanding discipline in modern veterinary medicine. Rehabilitation recommendations for a variety of orthopedic and neurologic conditions are now considered standard of care. The veterinary critical care patient is less commonly considered a candidate for rehabilitation therapy. It is well documented that the human critical care patient may experience any number of debilitating multisystem comorbidities associated with serious illness, pharmacologic adverse effects, and especially immobility.1 These include, but are not limited to, neuromuscular disorders, atelectasis, ileus, malnutrition, protein wasting, and depression.2 In the human intensive care unit (ICU), physical therapists specializing in critical care are integral members of a multidisciplinary team working together to optimize outcomes in patient recovery.2,3 Veterinary critical care patients are surviving catastrophic injuries and disease thanks to dramatic advances in critical care medicine.

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BOX 145-1 

Goals for Range-of-Motion Exercises

Maintain or improve pain-free range of motion Maintain or improve flexibility, extensibility, and strength of periarticular soft tissues Maintain or improve synovial fluid diffusion across the articulating surface Prevent joint contracture Improve blood and lymphatic flow Promote proprioceptive responses and facilitate neuromuscular reeducation

The critically ill small animal patient is equally at risk of many of the same comorbidities seen in the human counterpart. Incorporating an individualized rehabilitation therapy program into the critical care patient’s overall treatment plan will enhance the animal’s recovery by minimizing systemic complications associated with immobility, reducing adverse effects of some pharmacologic interventions, improving pain management, and mitigating stress and anxiety associated with ill health and hospitalization. The aim of this chapter is to introduce the concept of rehabilitation therapy for the veterinary critical care patient and discuss the benefits of some basic, easily implemented therapies. The intent is not to provide a “how to” on the details of carrying out a specific treatment but rather to educate the reader on the important role that a comprehensive rehabilitation therapy program has in improving the quality of patient care in the modern veterinary critical care unit. Critically ill patients are in a dynamic physiologic state, and each patient is unique in its pathologic conditions, temperament, and tolerance of therapeutic interventions. To optimize treatment outcomes and ensure the safety of the patient, the importance of a trained and experienced rehabilitation therapist working in close communication with the animal’s primary clinician cannot be overemphasized.

MUSCULOSKELETAL SYSTEM Range-of-Motion Exercise Critical care patients often have or quickly develop range-of-motion (ROM) limitations due to preexisting conditions such as osteoarthritis or orthopedic, neurologic, or soft tissue trauma or disease, or as a consequence of sustained disuse or immobilization.4,5 All joints have a given range through which they normally move. Movement may be passive, active assisted, or active. Normal ROM for any joint is influenced by a number of factors, including flexibility of the periarticular soft tissue structures (joint capsule, muscles, tendons, ligaments, and skin) as well as the structure and health of the joint itself. Limitations in normal joint ROM result from conditions affecting any of these structures. The goals for ROM exercises are provided in Box 145-1.5

Passive Range-of-Motion Exercise Passive range-of-motion (PROM) exercises are passive movements of a joint through its available range. PROM movement incorporates an external force to move the joint and therefore does not involve active muscle contraction.5 Performed regularly, PROM exercises may help prevent joint contracture as well as soft tissue shortening. PROM exercises can also maintain movement across fascial planes and augment lymphatic flow. PROM sessions should be incorporated early in the course of treatment for any animal that is unable or not permitted to actively move its joints on its own. Since PROM exercises do not involve active muscle contraction, they do not prevent muscle atrophy or increase muscle strength. Guidelines for safe,

BOX 145-2 

Guidelines for Performing Passive Range-of-Motion Exercises and Stretching Safely and Effectively

Exercises should be performed in a calm, quiet environment with the animal resting in lateral recumbency. Patient comfort is of the highest priority. Movements should be slow and gentle and limited to the patient’s comfortable range. Overaggressive passive range-of-motion exercises result in pain, cause reflex inhibition, and may promote the formation of fibrous tissue around the joint. Care should be taken to avoid disturbing any peripheral intravenous or arterial lines, indwelling urinary catheters, or electrocardiograph leads or other monitoring equipment. Movement should be limited to a single joint by stabilizing with one hand placed proximal to the joint and producing movement with the opposite hand placed just distal to the joint. To minimize forces being applied, the hands should be placed close to the joint being moved.

effective administration of PROM exercises and stretching are listed in Box 145-2. Generally, PROM exercises are performed three to five times per day for all peripheral joints, including the digits. Each movement is repeated 10 to 15 times.

Active Assisted and Active Range-of-Motion Exercise Active assisted and active ROM exercises encourage movement of a joint through active muscle contraction. In active assisted ROM, the therapist initiates or guides joint movement as the animal participates with active muscle contraction. Active ROM movement achieves joint motion solely through the animal’s muscle contraction.5 Active assisted or active ROM exercises are ideal for animals that are beginning to transition from PROM or those that are weak but capable of independent joint movement. Like PROM exercises, active assisted and active ROM exercises help counter the effects of immobilization and disuse on joints and periarticular structures. However, because they involve active muscle contraction, they can increase muscle strength and even bone strength at the sites of muscle attachment. Active and active assisted ROM exercises improve proprioception and balance. By coordinating movement of the various muscle groups they also facilitate reeducation of normal movement patterns. There are a variety of active assisted and active ROM exercises that can be used in the appropriate critical care patient.

Therapeutic Exercise and the Importance of Early Mobilization In human ICU patients early-intervention mobilization and exercise improve function by increasing oxygenation, strength, and endurance.4,6 Early mobilization has been shown to reduce length of stay in the hospital and in the ICU in particular.7,8 Immobility in the human model has been associated with a number of physiologic changes, including rapid loss of muscle mass and transformation of skeletal muscle fibers resulting in reduced aerobic capacity. Loss of muscle strength was greatest during the first 7 days of immobilization, with as much as a 40% reduction in strength.1 Also contributing to loss of muscle mass and strength in the human critical care patient are the direct effects of hypercapnia, hypoxia, malnutrition, and hemodynamic instability.9 The most profound loss of muscle strength was seen in the elderly and, not surprisingly, the chronically ill (e.g. patients with congestive heart failure).4

CHAPTER 145  •  Rehabilitation Therapy in the Critical Care Patient

Although there is a paucity of studies investigating the effects of early-intervention mobilization in veterinary critical care patients, it is reasonable to assume that its benefits extend to nonhuman patients. For the stable patient, early mobilization through assisted standing and/or facilitated walking should be a priority in the rehabilitation treatment plan.

Assisted Standing Standing requires sophisticated neuromuscular coordination. Standing, even if assisted with a sling or therapy ball, promotes muscular strength in both the supporting peripheral limb muscles and the core muscles. In addition, it improves circulation and respiratory function, stimulates proprioceptive input, and promotes neuromuscular reeducation.5 To be upright and standing often improves a recumbent animal’s sense of well-being and can reduce frustration and associated anxiety. Sessions should be short, with careful attention paid to the patient’s fatigue level as well as any vital parameters of special concern to that individual such as respiratory rate and effort. When the animal is in a normal standing position, an attempt can be made to introduce weight shifts by gently and slowly rocking the animal front to back and side to side. Standing weight shifts are an excellent way to stimulate balance and proprioception as well as promote limb and core muscle strength.

Walking (Assisted and Unassisted) Walking is one of the most important therapeutic exercises prescribed for a rehabilitation therapy patient, including those in the critical care unit.7 Common sense dictates that this be an activity reserved for stable patients with no medical conditions precluding such movement. Walking provides a controlled, low-impact form of active exercise that enhances muscle strength, benefits articular cartilage, and promotes connective tissue health while at the same time improving cardiac, lymphatic, and respiratory system functions. A basic walking program facilitates normal balance and proprioceptive function and enhances a patient’s emotional well-being. There are a variety of mobility aids designed to assist a patient in walking. They range from simple booties that can improve traction on a slippery surface to slings and therapy carts that an ambulatory but weak patient can use as a “walker.” Regardless of the level of assistance an individual patient may need, it is critical that the walks be kept to short sessions several times a day. Careful monitoring of the patient’s status immediately before, during, and after the walk is important to ensure that the patient is not showing signs of weakness, fatigue, or respiratory compromise. Walk lengths can gradually be increased on a regular basis as the patient shows signs of improvement. Individual exercises should be prescribed by a trained rehabilitation therapist working in collaboration with the critical care team. As always, careful assessment of the patient’s current medical status and degree of debilitation should be made before any therapy session.

Neuromuscular Electrical Stimulation and Transcutaneous Electrical Stimulation In human critical care medicine, complications from severe illness and immobilization frequently lead to debilitating and persistent neuromuscular abnormalities.7 These observations have led physical therapists to develop early intervention treatment programs for the human critical care patient. Once a patient is deemed physiologically stable, appropriate rehabilitation therapy is initiated. One modality used in patients at risk of developing muscle weakness is neuromuscular electrical stimulation. Neuromuscular electrical stimulation is easily adapted to the veterinary critical care patient at risk of muscle wasting. Additionally, other electrical current therapy, like transcutaneous electrical stimulation, can be used as an adjunct to pain management in the critical care animal patient.

Neuromuscular electrical stimulation Neuromuscular electrical stimulation (NMES) uses low-voltage electrical current transmitted through electrodes placed on the skin to stimulate passive muscle contraction.7 In some ways, NMES simulates repetitive contractions of mild exercise since NMES-stimulated muscles have increased blood flow, maximal force output, and force endurance.9,10 There is a difference, however, in the order of motor unit recruitment between a physiologically initiated and an electrically induced muscle contraction. Electrical stimulation recruits the larger, fast twitch muscle fibers before the smaller, slow twitch fibers. This is the opposite of the order in which physiologically initiated recruitment occurs.5,11 Clinically, this is important because fast twitch fibers fatigue more quickly than slow twitch fibers; therefore longer rest periods are required between contractions to prevent muscle fatigue in the patient.11 Another important clinical consideration when using NMES for preventing disuse atrophy and strengthening muscles is that electrically stimulated muscle contractions likely recruit different motor units within a muscle than those recruited during a normal physiologic contraction. To optimize muscle strengthening, it is best to combine NMES with physiologic contractions if the patient is capable of some low-level assisted or active assisted exercise.11

Transcutaneous electrical stimulation Transcutaneous electrical stimulation (TENS) uses electrical current to modulate pain, most likely by interfering with transmission of noxious stimuli along A-delta and unmyelinated C nerve fibers. TENS activates nonnociceptor A-beta fibers. When more A-beta fibers are activated than C fibers and A-delta fibers, pain sensation is diminished. TENS may also produce analgesia by stimulating the production and release of endogenous opioids.11

Massage Massage is a highly effective, underutilized treatment in the veterinary critical care patient. Medical massage is recognized in the human medical community for its success in treating muscle, nerve, and fascia disorders as well as disruptions in the normal neurophysiology of the enteric nervous system with consequential disturbances in gastrointestinal motility.12 Specific training in medical massage therapy is now part of the curricula of many physical therapy training programs and medical schools. The benefits of gentle and caring touch delivered by a trained therapist can be wide ranging, from direct effects of increasing blood and lymphatic flow, improving gastrointestinal motility, and reducing muscle spasm to the more indirect effects of stress and anxiety reduction. Massage can easily be incorporated into the treatment plan of nearly every critical care patient in stable condition. Massage is the manual application of pressure to the body though a variety of specific maneuvers such as effleurage (stroking), tapotement (tapping or percussion), vibration, friction, and pétrissage (kneading).13 Fundamentally, therapeutic massage works through direct mechanical effects on muscle fibers, connective tissue, and vessel walls and through neuromodulation of peripheral sensory nerve receptors that relay information to the spinal cord for further processing and projection to higher centers.14 Peripheral stimulation of autonomic nerve fibers within the fascia may modulate the high sympathetic tone that occurs in many animal patients experiencing pain, illness, and/or emotional distress.13,15 Sustained increased sympathetic tone results in a physiologically maladaptive “vicious cycle,” which is counterproductive to healing and contributes to increased morbidity, central hypersensitization, and chronic pain states.13 Therapeutic massage techniques can decrease heart rate and blood pressure, which supports the idea that, in these patients, stimulation of peripheral sensory receptors with vagal nerve affiliation can dial

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down abnormally high sympathetic tone and dial up the parasympathetic system (which is more conducive to healing). As a result, heart rate, blood pressure, and cortisol levels decrease, vessels vasodilate and muscles relax, gastrointestinal motility becomes more normalized, and, at least for a while, the animal may disassociate from its current distressed state and gain a healing advantage. In both human and animal ICU patients it is common to see alterations in gastrointestinal motility caused by immobility, adverse effects of some medications, stress, and pain.12 It is interesting to note that in many human ICU patients ileus, nausea, and constipation are frequently mitigated through the use of specific abdominal massage techniques that promote improved gastrointestinal motility by stimulating dermal and subdermal vagal afferent nerves as well as gastrointestinal mechanoreceptors.12,15 One of the great advantages of properly performed therapeutic massage is the relative safety and low incidence of adverse effects associated with its use, even in a critically ill patient. However, there are contraindications that should be considered. Massage is contraindicated in areas of active infection or acute inflammation, near a tumor, in cases of deep vein thrombosis or coagulopathies, in patients with unstable fractures, and of course in animals intolerant of this type of hands-on therapy.

RESPIRATORY SYSTEM Respiratory system disease and dysfunction are leading contributors to increased morbidity and mortality in both human and veterinary critical care patients. Immobility and prolonged recumbency, mechanical ventilation, pain from chest wall or abdominal surgery or trauma, and sedation and altered states of consciousness secondary to head trauma or seizures can all interfere with the normal respiratory pattern and potentially reduce chest wall and lung expansion.16 Often animals in pain adopt a characteristic rapid and shallow breathing pattern that reduces tidal volume and lung compliance. The end result can be hypoventilation, atelectasis, accumulation of respiratory secretions, and pneumonia. Hypoxemia secondary to hypoventilation, ventilation-perfusion mismatch, or even intrapulmonary shunting necessitates treatment, thus prolonging hospital stays and further compromising an already debilitated patient.16 Respiratory therapists manage these patients daily in the human ICU. Adaptations of the techniques of these professionals can be incorporated into the veterinary treatment model so that the critically ill animal patient is at reduced risk of developing serious respiratory complications while in the critical care unit. It must be remembered that patients with compromised respiratory systems are in a precarious position and can easily decompensate. The following sections provide an overview of some basic techniques that can improve pulmonary function by helping to eliminate secretions, expand lung volume and open atelectatic lung fields, improve oxygenation, and reduce the work of breathing.17 It is critical that the trained therapist work closely with the patient’s primary clinician and be fully knowledgeable about any and all disease processes and health concerns, medications, and treatments for that patient. Constant objective and subjective assessment and reassessment before, during, and after a therapy session is important.

Positioning Proper positioning can positively influence lung function and is an effective treatment for animals with lung disease or a treatment strategy to prevent pulmonary complications in immobile patients. Simply alternating from opposite sides and sternal recumbency every 2 to 4 hours can increase chest wall expansion and lung volume, prevent atelectasis, improve oxygenation and perfusion, prevent

respiratory secretions from settling in dependent lung lobes, and improve patient comfort.18 Regularly changing a recumbent patient’s body position holds benefits beyond the respiratory system that include reduced muscle and joint stiffness, improved skin perfusion, and reduction in the formation of pressure sores, as well as prevention of dependent limb edema.17

Postural Drainage Retention of respiratory secretions interferes with proper oxygenation and ventilation. Postural drainage is a technique employed commonly by respiratory therapists treating human patients with pulmonary disease.18 It uses the force of gravity to aid in removing tracheal and bronchial secretions from a diseased lung segment by placing the patient into specific body positions. The patient is positioned so that the segmental bronchi are vertical to the diseased lung lobe.17 This positioning allows drainage of the secretions into the larger airways so that they are more easily expelled when a cough is elicited. Imaging studies are necessary to determine which lung segments are affected and therefore which positions should be used. It may be beneficial to nebulize the patient just before a treatment.5 Generally, the most affected lung segments are treated first and in the earlier part of the day. Treatment times range from 5 to 10 minutes in each position and treatments are performed several times a day. Following a treatment, the patient is encouraged to cough to aid in removal of the mobilized secretions.18 In animal patients, gentle digital pressure at the larynx or proximal trachea often elicits a cough. In some patients, it may take 30 to 60 minutes following a treatment for the secretions to be mobilized. There are certain patients in which postural drainage is contraindicated or should be approached with increased caution. Administration of supplemental oxygen before a treatment may be beneficial. In some patients, the standard postural drainage positions can actually worsen the animal’s condition. In these cases, postural drainage may not be an option or the standard drainage positions may need to be modified. Box 145-3 lists the conditions that may preclude the use of postural drainage as a treatment option. Postural drainage should be reserved for those patients that are immobile and have no contraindications to this treatment. Movement and exercise are superior to postural drainage in mobilizing respiratory secretions. Regular standing and walking should be used first in all patients that are capable of active mobility.

Percussion (Coupage) and Vibration Percussion and vibration are two chest rehabilitation techniques that can be quite effective in loosening bronchial secretions and then moving them from smaller to larger airways where they are more easily expelled via coughing.17,18 In percussion, the therapist uses cupped hands to gently tap over the diseased lung lobe in an even and steady rhythm. The cupping should produce a hollow tapping rather than a slapping sound and should be done between 100 and

BOX 145-3 

Conditions That May Preclude the Use of Postural Drainage

Active pulmonary edema Congestive heart failure Severe obesity Increased intracranial pressure or head trauma Hemodynamic instability Recent cervical, cranial thoracic, or ocular surgery Vertebral body instability Patient intolerance of the procedure

BOX 145-4 

Contraindications to the Use of Percussion and Vibration

Rib fractures, flail chest, or other thoracic trauma Coagulopathy Pneumothorax, pulmonary contusions, or other chest trauma Cervical or cranial thoracic subcutaneous emphysema Pulmonary embolism Frequent regurgitation Patient intolerance of the procedure

400 times per minute for 2 to 4 minutes. Percussion is done throughout the entire respiratory cycle. Vibration is performed following each percussion cycle and only during the exhalation phase of respiration. The therapist uses full hand contact on the animal’s chest to oscillate or shake the chest wall throughout the entire expiration. The hands should lie flat and remain placed over the area of diseased lung field. Vibration should be done during four to six consecutive exhalations following each set of percussions. Percussion and vibration are contraindicated in the conditions listed in Box 145-4.

SUMMARY Veterinary rehabilitation therapy offers highly effective, noninvasive treatment options for the unique subset of veterinary patients that are critically ill. Early intervention with comprehensive, individualized programs should be considered standard of care for every critical care patient.

REFERENCES 1. Genc A: Early mobilization of the critically ill patients: toward standardization, Crit Care Med 40(4):1346-1347, 2012.

2. Bemis-Dougherty AR, Smith JM: What follows survival of critical illness? Physical therapists’ management of patients with post-intensive care syndrome, Phys Ther 93:179-185, 2013. 3. Denely L, Bernay S: Physiotherapy in the intensive care unit, Phys Ther Rev 11(1):49-56, 2006. 4. Cirio S, Piaggi GS, DeMattia E, et al: Muscle retraining in ICU patients, Minerva Anestesiol 68(5):341-345, 2003. 5. Millis DL, Levine D, Taylor R: Canine rehabilitation and physical therapy, St Louis, 2004, Saunders. 6. Llano-Diez M, Renaud G, Anderson M, et al: Mechanisms underlying intensive care unit muscle wasting and effects of passive mechanical loading, Crit Care 16(5):R209, 2012. 7. Kress J: Clinical trials of early mobilization of critically ill patients, Crit Care Med 37(10):S442-S447, 2009. 8. Morris P, Goad A, Thompson C, et al: Early intensive care unit mobility therapy in the treatment of acute respiratory failure, Crit Care Med 36(8):2238-2243, 2008. 9. Needham DM: Mobilizing patients in the intensive care unit: improving neuromuscular weakness and physical function, JAMA 300:1685-1690, 2008. 10. Needham D, Trvong A, Fan E: Technology to enhance physical rehabilitation of critically ill patients, Crit Care Med 3(10):S436-S441, 2009. 11. Cameron M: Physical agents in rehabilitation: from research to practice, ed 2, St Louis, 2003, Saunders. 12. Robinson N: Acupuncture, massage can get the gut going, Vet Pract News, pp 36-38, February 2011. 13. Robinson N: Small animal manual therapy. In Proceedings Pennsylvania Veterinary Medical Association, 2012, pp 570-575. 14. Beck M: Theory and practice of therapeutic massage, ed 3, New York, 1999, Milady. 15. Tappan F: Healing massage techniques: holistic, classic, and emerging methods, ed 2, Norwalk, Conn, 1988, Appleton & Lange. 16. Powell L: Respiratory support for acute intensive care, NAVC Clin Brief, pp 13-16, April 2007. 17. Dunning D, Halling K, Ehrhart N: Rehabilitation of medical and acute care patients, Vet Clin North Am Small Anim Pract 35(6):1411-1426, 2005. 18. Davis LC: Personal communication, April 2012.

CHAPTER 146  •  Complementary and Alternative Medicine

CHAPTER 146  COMPLEMENTARY AND ALTERNATIVE MEDICINE Narda G. Robinson,

DO, DVM, MS, FAAMA

KEY POINTS • Several complementary and alternative medical approaches such as acupuncture, massage, laser therapy, and music therapy provide clinically meaningful benefits for hospitalized patients; for this reason, these modalities warrant consideration for early inclusion into treatment plans for critical care patients. • Herbal remedies, like medications, can help or harm. Unlike medications, however, their pharmacologic and safety profiles are lacking for veterinary patients. In addition, inadequate regulatory enforcement allows product sales without demonstration of

product purity and full disclosure of the types and quantities of contents. These factors present hurdles when prescribing plant-based drugs in veterinary medicine. • Aromatherapy (essential oil therapy) has shown value to promote relaxation in dogs but risks subjecting staff and other patients to potentially soporific, epileptogenic, or allergy-provoking substances. In small quantities and in limited sections of the clinic, however, aromatherapy could benefit some patients. • High-velocity chiropractic adjustments and other forceful manipulative therapy maneuvers may injure debilitated patients

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The intensive care unit (ICU) can seem frightening, lonely, and stressful to patients. In addition to the illness that caused their admission, ICU inhabitants face mounting stress induced by pain, tension, lack of sleep, loneliness, anxiety, and the inability to communicate their needs adequately.1 According to one of the leading researchers in the ethics of human critical care, “Alleviating the stresses and symptoms of critically ill patients will enhance the quality of their ICU stay, which itself achieves an important beneficial and ethical outcome, an outcome that should be a priority of every intensivist.”2 Sleep deprivation and immobilization impair recovery. They sensitize the central nervous system, causing “wind-up,” which amplifies pain and stress. As a result, cardiac demand, vasoconstriction, blood viscosity, platelet aggregation, and cellular catabolism increase. In fact, “in many patients with severe posttraumatic or postsurgical pain, the ensuing neuroendocrine responses are sufficient to initiate or maintain a state of shock.”3 Pharmaceutical analgesics and sedatives may contribute to constipation and disorientation, however. Certain complementary and alternative medical interventions can offer safe and effective nonpharmacologic alternatives.4 ICU personnel often welcome complementary and alternative medical interventions that support the animals’ quality of life and

BOX 146-1 

potentially improve survival. In human medicine, a 2005 survey published in the American Journal of Critical Care indicated that over 90% of critical care nurses reported eagerness or openness regarding the use of complementary and alternative medical interventions in the ICU setting.5

ACUPUNCTURE Acupuncture works by stimulating nerve endings near acupuncture points and improving blood flow and tissue cytokine balance locally, while also impelling afferent signals toward the central nervous system; that is, the spinal cord and brain. Once there, they serve to neuromodulate brain function toward a restorative, “wound-down” functional state that affects both somatic and visceral structures. Autonomic neuromodulations help to restore the balance between the sympathetic and parasympathetic divisions, augmenting blood flow and reducing inflammatory states in internal organs and the myofascia. Acupuncture improves neurotransmitter and hormone profiles in the central nervous system, activating endogenous analgesic pathways and decreasing anxiety.6 Box 146-1 lists the types of conditions that acupuncture may be of benefit to in patients in the ICU.7,8 Mechanisms that improve internal organ function include reflex neuromodulation8,9 of autonomic function. That is, peripheral nerves supplying acupuncture points link to spinal cord loci that connect somatic and autonomic neurons as well as somatoautonomic convergence centers in the brainstem, such as the nucleus tractus solitarius and the rostroventrolateral medulla.

Conditions for Which Acupuncture May Be Beneficial in Intensive Care Unit Patients

Cardiac Conditions

Neurologic Issues

• Adjunct to cardiopulmonary resuscitation measures • Arrhythmias • Peripheral edema • Acupuncture-assisted anesthesia for high-risk patients

• Anxiety • Peripheral or cranial neuropathy, neuritis, or nerve trauma • Cerebrovascular accident • Seizures • Cognitive disorder • Spinal cord injury • Disk disease • Autonomic dysregulation

Respiratory Conditions

• Nasal blockage • Sinusitis • Bronchospasm • Hiccoughs • Chest wall pain inhibiting diaphragmatic excursion Acute and Chronic Pain

• Neuropathic pain (central or peripheral) • Arthritis pain • Back pain • Postsurgical pain • Phantom limb pain • Abdominal pain • Pain associated with cancer and its treatment • Ocular discomfort • Facial and dental pain Orthopedic Problems

• Muscle tension and restriction • Contractures • Tendonitis, bursitis • Posttraumatic discomfort • Ligamentous injury • Sprain • Fracture • Contusions

Gastrointestinal Disorders

• Nausea • Vomiting • Inappetence • Esophageal spasm • Ileus (posttraumatic and postsurgical) • Gastric hyperacidity • Intestinal motility disorders, including diarrhea, constipation, obstipation, megacolon

Urinary Dysfunction

• Renal impairment • Urinary retention or incontinence

CHAPTER 146  •  Complementary and Alternative Medicine

Patients with spinal cord injury (SCI) should receive acupuncture early after admission and during their stay. Evidence demonstrates the benefit of acupuncture for dogs with SCI in both acute and chronic settings.10 Such treatment not only promotes spinal cord health but improves concomitant sequelae of SCI such as voiding dysfunction and pain. Researchers at São Paulo State University’s School of Veterinary Medicine and Animal Science compared the effectiveness of decompressive surgery, low-frequency electroacupuncture (at 2 and 15 Hz), and a combination of the two for treatment of thoracolumbar intervertebral disk disease (IVDD) in dogs with severe neurologic deficit of longer than 48 hours’ duration.11 Using a retrospective control group, they found electroacupuncture alone or in combination with surgery to be more effective than surgery alone for improving neurologic outcomes. Although this was not an ideal study methodologically, it builds on other work that found similar results. A 2009 review pointed to the accelerated improvements made possible in sensory, motor, and functional outcomes with acupuncture. One study showed a “much larger effect of electroacupuncture on ultimate neurologic recovery from acute SCI than any pharmacologic intervention to date.”12 Another study reported that electroacupuncture cut the time for recovery of proprioception in half and stimulated an even quicker return of motor control when combined with corticosteroid treatment.13 Electroacupuncture combined with conventional approaches for treatment of IVDD shortened the time needed to recover deep pain perception and ambulation compared with standard of care alone in dogs with thoracolumbar IVDD according to a report published in the Journal of the American Veterinary Medical Association in 2007.14 Acupuncture stimulates neuronal regeneration, possibly through stem cell mobilization and differentiation15-17; it also reduces apoptotic cell death after SCI.18 Although some practitioners claim that steroids negate the benefits of acupuncture, a 2003 study in Korea demonstrated the opposite; that is, the combination produced synergistic effects in pain relief, inflammation control, and edema resolution.13 Relative contraindications to acupuncture include severe immune compromise or coagulopathy, widespread skin infections, and pregnancy.

MASSAGE THERAPY Massage, or gentle, rhythmic stroking, can reduce stress, alleviate discomfort stemming from tension and immobility, and help normalize physiologic function.19-23 The comfort massage provides can promote sleep, a vital restorative process.24 Pulmonary function may improve after vibratory massage.25 Patients with burn injuries and scarring may also benefit from massage.26,27 For patients nearing death, massage is gaining recognition as a reliable way to reduce pain, medication requirements, and isolation.28 End-of-life patients who receive massage on a regular basis become more peaceful and comfortable.29,30 Massage alleviates constipation and encourages the elimination of metabolic end products from tissues.31,32 It also benefits circulation, relaxes muscle tension, settles the nervous system, and relieves psychologic strain.31 Along with aromatherapy, massage reduced both anxiety and depression for up to 2 weeks after treatment in a study published in the Journal of Clinical Oncology.33 Dying can be lonely, frightening, and painful. Humans regard pain as one of the most fearful aspects of dying34; what they want is to spend time with family and friends, have pain well controlled, breath comfortably, maintain dignity and self-respect, have peace with dying, be touched, avoid strain on loved ones, and side-step the need for artificial life support.35 With this in mind, massage can and

should become routine in veterinary critical care as well as animal hospice. One human group noted, “Incorporating a 5-minute massage of hands or feet into a schedule of nursing care should be within the capabilities of all palliative care nurses.”36 Regular hands-on treatment yields important opportunities to detect precipitous declines in quality of life, typically more common in patients with cancer.37 The growing veterinary hospice movement commonly extrapolates principles and practices from the human side to animals.38,39 As noted by Downing in a compelling series of articles on veterinary hospice care,28,38 “Our obligation as veterinary health care providers is to advocate on behalf of beings that cannot advocate for themselves.”40 Although medications and subcutaneous fluids may extend lives, sick and dying patients’ emotional, physical, and psychologic needs for touch and movement frequently remain unassessed and unmet, as often happens in human medicine.31 Families feel helpless when watching a loved one linger between life and death. A slow, gentle back rub or neck massage may coax a dying patient to relax41 and shift the autonomic nervous system from fight/flight to rest/restore. Many clients express eagerness to learn simple and safe massage techniques; acquiring a skill to provide a treatment that their animal accepts allows them to regain a sense of purpose and connection. Massage practitioners in a veterinary clinic may also identify environmental and other sources of stress for the patient, such as noise (radio, television, pumps, alarms, loud voices, barking dogs), hygiene and skin-related concerns, patient bedding or mobility issues, and previously unrecognized areas of tenderness or dysfunction.42 When death seems imminent, or in anticipation of a scheduled euthanasia, clients may ask their dog’s or cat’s massage therapist to accompany them during the process to treat the animal and ease the transition from life to death. This final act of loving kindness leaves a cherished memory in the hearts and minds of those left in this world, who are reassured that their treasured companion’s first step on the journey to the beyond was made that much more peaceful through massage. How does massage work? Moderate-pressure massage affects the nervous system through pressure-sensitive mechanoreceptors in the skin, subcutaneous tissue, and myofascia. Signals from treated tissue travel to the spinal cord and brain where neuromodulation occurs that in many ways is similar to that from acupuncture and laser therapy.43 Moderate-pressure massage slows the heart rate, lowers blood pressure, and reduces cortisol levels through its modulatory effects on the autonomic nervous system, specifically the vagal nerve network.44 Investigations eventually identified the vagal nerve network as the final common pathway. This tenth cranial nerve and the associated brainstem nuclei affect nearly every bodily function, serving as a neural expressway mediating the tightly orchestrated, restorative parasympathetic nervous system. Some of the most compelling research on massage and the vagus nerve involves term and preterm infants. For example, massage allows preterm infants to better autoregulate their body temperature.45 Properly massaged infants show less physiologic stress and reactivity,46 higher vagal tone, and significantly less fussing, crying, and stress behavior such as hiccups. Contraindications to massage depend on the patient’s medical status and receptivity to touch. Patients with cardiovascular instability or severe, uncontrolled hypertension may become overstimulated.19,47 Massage should be avoided near sites of fractures, contusions, thrombi, inflammation, pain, and/or infection.

LASER THERAPY The ability of laser therapy to reduce pain, swelling, tissue necrosis, and inflammation is making this therapy a popular adjunctive treatment in the critical care setting (e.g., in cases of snake

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envenomation).48 Laser therapy supports soft tissue and muscle healing after acute injury (e.g., trauma, surgery) through its effects on circulation, inflammation, growth factors, and cytokines.49 Photobiomodulation through laser therapy causes tissue changes that accelerate wound healing through both local and systemic mechanisms.50 Laser therapy has been used in a variety of patients, including patients with pain and inflammatory diseases, neurologic injury (e.g., traumatic brain disorders, SCI, peripheral nerve damage),51 and organ dysfunction.52,53 Because laser therapy speeds cell division, promotes new vessel formation, and limits apoptosis, the safety of laser therapy in patients with cancer remains unknown.54 However, moderate to strong evidence has been gathered in favor of its use for the prevention and treatment of cancer therapy–induced mucositis.55,56

MUSIC THERAPY Therapeutic music has been applied in the human medical setting since the 1800s after the invention of the phonograph, and sound was used to encourage sleep and stimulate endogenous analgesia.57 Currently, music therapy is experiencing a resurgence in human medicine and entering the realm of veterinary medicine; evidence is accruing about its neurophysiologic benefits and suitable applications.58 For instance, playing soothing music in the postanesthesia care unit improves comfort and reduces pain.59 Music reduces anxiety in patients receiving mechanical ventilation and in older adults undergoing cardiovascular surgery.60,61 Listening to classical music reduces potentially detrimental physiologic and psychologic responses to percutaneous coronary interventions, and results in lower pain scores.62 Relaxing music reduces pain after dressing changes for vascular wounds.63 Both classical and self-selected relaxing music reduce negative emotional states and levels of sympathetic nervous system arousal (e.g., pulse and respiratory rates) after stress compared with heavy metal music or complete silence.64 The main adverse effects of music therapy arise from either incorrect selection of music or tempo for the listener’s specific problem, or stimulation of musicogenic seizures (reported only in humans).65 How does music therapy work? Music causes changes in brain activity and in neurohumoral, cardiovascular, and immune responses, although the genre and tempo influence the direction of those changes.66-69 Music listening during the early period after stroke improves cognitive recovery and buoys the mood.70 Functional brain imaging studies demonstrate that listening to music induces brainwide alterations in processing functions related to attention and semantic, music-syntactic, memory, and motor functions.70 Thus researchers are finding that, instead of allowing brain-injured patients to languish in silence for most of the day without any interaction or activity, one could instead fill the neural plasticity window in the postinjury phase with auditory provocation that reduces depression and improves brain function.71 Even during brain development and maturation, exposure to music modifies protein expression in key brain areas associated with verbal learning, mood, and memory.72

HERBS Critical care clinicians should ask clients to provide a complete list of supplements, herbs, and homeopathic compounds their animal receives, along with a full list of ingredients. Veterinarians treating critically ill patients often find themselves in the difficult position of either accommodating or denying clients’ requests to give herbs and supplements, with little substantive information on which to base the decision. In some cases, the decision to decline administering herbs seems obvious, as in the case of proprietary Chinese herbal mixtures

for which a manufacturer refuses to disclose the amount of toxic ingredients such as strychnine (a known neurotoxin) or aconite (a known cardiotoxin).73 In addition, the interactions of strychnine and aconite with conventional pharmaceuticals, combined with the lack of evidence regarding safety or effectiveness, may raise concern as to why veterinarians continue to sell and prescribe these mystery mixtures capable of causing harm.74 Properly educating clients about the risks posed by these products is therefore paramount. The precise ingredients in the popular Chinese herbal formulation known as Yunnan Paiyao (or Yunnan Baiyao) have also been withheld until recently on the grounds that it is an “ancient Chinese secret” and “protected Chinese herbal medicine.”75 In fact, in 2013 the producer and distributors of Yunnan Paiyao were sued for failing to disclose all of the product’s ingredients.76 Problems resulting from the aconite (Kusnezoff monkshood root) found in the formula include kidney damage, allergic reactions, and death. The preparation, administered either orally or topically, has gained widespread acceptance as a treatment or preventative agent for bleeding disorders.77 Research is beginning to emerge that is elucidating its hemostatic effects,78-80 contents,81 and applications in other conditions, including inflammatory bowel disease,82 rheumatoid arthritis,83 and aphthous stomatitis.84 However, although some aspects of Yunnan Paiyao look promising, problems with Chinese herbs persist, including their secret ingredients and suspect manufacturing practices. Herbs pose additional hazards due to the unknowns stemming from unique species-specific metabolism, altered pharmacodynamics and pharmacokinetics in the critically ill patient, and unanticipated drug-herb interactions.85 Botanical substances that affect neurotransmitters, such as serotonin in the case of St. John’s wort and γ-aminobutyric acid in the case of valerian root, can cause excessive sedation when combined with barbiturates, opiates, or other psychoactive medications. Common herbs such as ginkgo, ginseng, garlic, and dong quai may promote bleeding by inhibiting platelet function. Trauma victims or postoperative patients that have been receiving these herbs before entering the clinic may exhibit unexpectedly heavy bleeding. Unanticipated potentiation of anticoagulants is another potential outcome.86 Various Western and Asian plant products affect blood sugar levels; these include Gymnema, psyllium, fenugreek, bilberry, garlic, ginseng, dandelion, burdock, prickly pear cactus, and bitter melon.87 Clinicians also need to take into account any prior coadministration of herbs with insulin to optimize glucose control during hospitalization. Untoward reactions to phytomedicinals commonly involve the liver. As an illustration of how conflicting information can confuse herbal prescribing, one of the Chinese herbs most commonly used for liver disease, Radix bupleurum, or bupleurum, has now been shown actually to cause hepatitis. Traditional Chinese veterinary medicine herbal texts and handbooks have called for the use of bupleurum as a hepatoprotectant, antipyretic, and antiinflammatory agent.88 Despite the concerns, many veterinary herbalists continue to recommend it for patients with acute and chronic hepatitis and even hepatic lymphoma.89 Bupleurum’s role in actually inducing hepatitis rather than remedying it is drawing closer attention, whether the botanical is included in a popular formula such as Xiao Chai Hu Tang (also known as Minor Bupleurum) or tested as the sole saponin in rodent models.90 Xiao Chai Hu Tang is “the most common traditional drug in Asian countries for patients with chronic hepatitis and liver cirrhosis.”90 The revelation that humans have been injured and/or killed by the plant drug comes as a rude awakening. Not only is there obscure language surrounding traditional Chinese veterinary medicine practice, but many of the products veterinary practitioners sell to clients contain undisclosed and unverified amounts of each ingredient. This complicates investigations as to the potential cause of liver injury in

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a dog or cat receiving these medications. Labels also lack warnings. Because of this, clients may fail to report their use to an emergency physician examining a jaundiced cat or dog. As a group of Hong Kong toxicologists put it so well, “Herbal products should be used cautiously and enhanced pharmacovigilance is necessary.”91 Part of the reason why the harmful effects of bupleurum are now coming to light may be the growing study of Kampo medicine, a traditional Japanese herbal system that takes a more scientific approach than does traditional Chinese medicine. Both systems may use similar plant combinations, but Kampo’s emphasis on evidence from clinical and laboratory studies brings to light adverse effects of Asian herbs.92,93 For example, “it has been well demonstrated that several potential side effects such as allergic reactions, cramps, diarrhoea, fever, gastrointestinal disturbances, headaches, haematuria, nausea, photosensitization and vomiting may be experienced when administering Kampo medicine or herbal medicines. In addition, it has been reported that Kampo medicine or herbal medicine may have antagonistic or synergistic interactions with western drugs or with some foods.”93 Many herbs cause adverse effects or drug-herb interactions; underreporting of injury to animals from botanical mixtures makes it impossible to realistically assess the dangers of these products.94

AROMATHERAPY Aromatherapy may play a supportive role in the ICU, although subjecting all animals and staff to volatile substances may be problematic. For example, some inhaled oils such as lavender and passion flower induce relaxation in the short term,95,96 but overexposure (>1 hour) may increase blood pressure and heart rate.97 Oils with high levels of camphor can reportedly promote seizures and for this reason should be avoided near epileptic patients.98 Asthmatic cats may develop bronchoconstriction in response to aromatherapy.

HOMEOPATHY AND FLOWER ESSENCES As Overall and Dunham noted concerning homeopathy, “When an approach declares itself outside the accepted methodologies of science, it should not and cannot be taken seriously by scientists. Hypothesis testing and falsification are at the very core of the scientific approach. If homeopathy and other complementary and alternative medical approaches wish to be considered by scientists, they must be shown to be valid using methods that science uses to evaluate all treatment modalities. If these fields are not willing to comply with these rules they cannot be considered scientific and cannot be used in any set of scientific and medical best practices.”99 Both homeopathy and flower essence therapy use highly diluted “remedies” made from plants, animals, and minerals, or, in the case of flower essences, only flower petals and other plant parts. Neither approach has withstood rigorous scientific testing or been shown to confer therapeutic value beyond the placebo effect. Indeed, as has been noted with parents trying to treat temper tantrums in their 2- to 5-year-old children, the results some claim to witness following administration of these “vibrational medicine compounds” may amount to nothing more than “placebo by proxy.”100,101

CONCLUSION Physical medicine approaches including acupuncture, massage, and laser therapy deserve consideration for most critical care patients, barring specific contraindications. Their ability to support healing, induce relaxation, and relieve pain raises the question of why some practitioners advise waiting before integrating these quality of life– enhancing maneuvers, especially when experience indicates that

patients recover faster with the inclusion of these modalities. Although botanical medicine may one day accrue enough evidence in animals to play a more prominent role in critical care medicine, at this point the attention herbs receive in the ICU needs to focus more on their possible adverse effects and herb-drug interactions. Neither homeopathy nor flower essence therapy belongs in the ICU because researchers have not shown them superior to placebo. Nevertheless, now that clinicians have a range of scientifically verified integrative approaches from which to choose, opting to include them earlier in the critical care setting (rather than as a last-ditch effort before euthanasia) can provide patients the opportunity to recover with more functionality and comfort.

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PART XVII  •  ANESTHESIA AND PAIN MANAGEMENT 17. Sun Z, Li X, Su Z, et al: Electroacupuncture-enhanced differentiation of bone marrow stromal cells in to neuronal cells, J Sports Rehabil 18(3):398-406, 2009. 18. Choi DC, Lee JY, Moon YJ, et al: Acupuncture-mediated inhibition of inflammation facilitates significant functional recovery after spinal cord injury, Neurobiol Dis 39:272-282, 2010. 19. Richards KC, Gibson R, Overton-McCoy AL: Effects of massage in acute and critical care, AACN Clin Issues 11:77, 2000. 20. Hill CF: Is massage beneficial to critically ill patients in intensive care units? A critical review, Intensive Crit Care Nurs 9:116, 1993. 21. Keegan L: Therapies to reduce stress and anxiety, Crit Care Nurs Clin North Am 15:321, 2003. 22. Hansen G: The role of massage in the care of the critically ill, N Z Nurs 8:14, 2002. 23. Hayes J, Cox C: Immediate effects of a 5-minute foot massage on patients in critical care, Intensive Crit Care Nurs 15:77, 1999. 24. Richards KC: Effect of a back massage and relaxation intervention on sleep in critically ill patients, Am J Crit Care 7:288, 1998. 25. Doering TJ, Fieguth HG, Steuernagel B, et al: External stimuli in the form of vibratory massage after heart or lung transplantation, Am J Phys Med Rehabil 78:108, 1999. 26. Field T, Peck M, Krugman S, et al: Burn injuries benefit from massage therapy, J Burn Care Rehabil 19:241, 1998. 27. Roques C: Massage applied to scars, Wound Repair Regen 10:126, 2002. 28. Downing R: The role of physical medicine and rehabilitation for patients in palliative and hospice care, Vet Clin North Am Small Anim Pract 41:591-608, 2011. 29. Polubinski JP, West L: Implementation of a massage therapy program in the home hospice setting, J Pain Symptom Manage 30(1):104-106, 2005. 30. Hodgson NA, Lafferty D: Reflexology versus Swedish massage to reduce physiologic stress and pain and improve mood in nursing home residents with cancer: a pilot trial, Evid Based Complement Alternat Med 2012:456897, 2012. 31. Gray RA: The use of massage therapy in palliative care, Complement Ther Nurs Midwifery 6:77-82, 2000. 32. Preece J: Introducing abdominal massage in palliative care for the relief of constipation, Complement Ther Nurs Midwifery 8:101-105, 2002. 33. Wilkinson SM, Love SB, Westcombe AM, et al: Effectiveness of aromatherapy massage in the management of anxiety and depression in patients with cancer: a multicenter randomized controlled trial, J Clin Oncol 25(5):532-539, 2007. 34. Gorman G, Forest J, Stapleton SJ, et al: Massage for cancer pain: a study with university and hospice collaboration, J Hosp Palliat Nurs 10(4):191197, 2008. 35. Downey L, Engelberg RA, Curtis JR, et al: Shared priorities for the endof-life period, J Pain Symptom Manage 37(2):175-188, 2009. 36. Buckley J: Massage and aromatherapy massage: nursing art and science, Int J Palliat Nurs 8(6):276-280, 2002. 37. Downey L, Engelberg RA: Quality-of-life trajectories at the end of life: assessments over time by patients with and without cancer, J Am Geriatr Soc 58:472-479, 2010. 38. Downing R, Adams VH, McClenaghan AP: Comfort, hygiene, and safety in veterinary palliative care and hospice, Vet Clin North Am Small Anim Pract 41:619-634, 2011. 39. Villalobos A: Qualify of life scale. Available at http://www .veterinarypracticenews.com/images/pdfs/Quality_of_Life.pdf. Accessed October 4, 2012. 40. Downing R: Pain management for veterinary palliative care and hospice patients, Vet Clin North Am Small Anim Pract 41:531-550, 2011. 41. Meek SS: Effects of slow stroke back massage on relaxation in hospice clients, Image J Nurs Sch 25(1):17-21, 1993. 42. Smith MC, Yamashita TE, Bryant LL, et al: Providing massage therapy for people with advanced cancer: what to expect, J Altern Complement Med 15(4):367-371, 2009. 43. Robinson NG: The benefits of medical massage, Vet Pract News, August 2010. Accessed at http://www.veterinarypracticenews.com/vet-practicenews-columns/complementary-medicine/the-benefits-of-medicalmassage.aspx on 01-30-14.

44. Diego MA, Field T: Moderate pressure massage elicits a parasympathetic nervous system response, Int J Neurosci 119:630-638, 2009. 45. Diego MA, Field T, Hernandez-Reif M: Temperature increases in preterm infants during massage therapy, Infant Behav Dev 31(1):149152, 2008. 46. Feldman R, Singer M, Zagoory O: Touch attenuates infants’ physiological reactivity to stress, Dev Sci 13(2):271-278, 2010. 47. Tyler DO, Winslow EH, Clark AP, et al: Effects of a 1-minute back rub on mixed venous oxygen saturation and heart rate in critically ill patients, Heart Lung 19:562, 1990. 48. Nadur-Andrade N, Barbosa AM, Carlos FP, et al: Effects of photobiostimulation on edema and hemorrhage induced by Bothrops moojeni venom, Lasers Med Sci 27(1):65-70, 2012. 49. Fernandes KP, Alves AN, Nunes FD, et al: Effect of photobiomodulation on expression of IL-1β in skeletal muscle following injury, Lasers Med Sci 28(3):1043-1046, 2013. 50. Vilela DDC, Chamusca FV, Andrade JCS, et al: Influence of the HPA axis on the inflammatory response in cutaneous wounds with the use of 670-nm laser photobiomodulation, J Photochem Photobiol B 116:114120, 2012. 51. Hashmi JT, Huang Y-Y, Osmani BZ, et al: Role of low-level laser therapy in neurorehabilitation. PM R 2(12 Suppl 2):S292-S305, 2010. 52. Hentschke VS, Jaenisch RB, Schmeing LA, et al: Low-level laser therapy improves the inflammatory profile of rats with heart failure, Lasers Med Sci 28(3):1007-1016, 2013. 53. Yang Z, Wu Y, Zhang H, et al: Low-level laser irradiation alters cardiac cytokine expression following acute myocardial infarction: a potential mechanism for laser therapy, Photomed Laser Surg 29(6):391398, 2011. 54. e Lima MT, e Lima JG, de Andrade MF, et al: Low-level laser therapy in secondary lymphedema after breast cancer: systematic review, Lasers Med Sci Epub November 29, 2012. 55. Bensadoun RJ, Nair RG: Low-level laser therapy in the prevention and treatment of cancer therapy-induced mucositis: 2012 state of the art based on literature review and meta-analysis, Curr Opin Oncol 24(4):363-370, 2012. 56. Bjordal JM, Bensadoun R-J, Tuner J, et al: A systematic review with meta-analysis of the effect of low-level laser therapy (LLLT) in cancer therapy-induced oral mucositis, Support Care Cancer 19:1069-1077, 2011. 57. Barrera ME, Rykov MH, Doyle SL: The effects of interactive music therapy on hospitalized children with cancer: a pilot study, Psychooncology 11:379-388, 2002. 58. Kogan LR, Schoenfeld-Tacher R, Simon AA: Behavioral effects of auditory stimulation on kenneled dogs, J Vet Behav 7:268-275, 2012. 59. Shertzer KE, Keck JF: Music and the PACU environment, J Perianesth Nurs 16(2):90-102, 2001. 60. Lee OKA, Chung YFL, Chan MF, et al: Music and its effect on the physiological responses and anxiety levels of patients receiving mechanical ventilation: a pilot study, J Clin Nurs 14(5):609-620, 2005. 61. Twiss E, Seaver J, McCaffrey R: The effect of music listening on older adults undergoing cardiovascular surgery, Nurs Crit Care 11(5):224-231, 2006. 62. Chan MF: Effects of music on patients undergoing a C-clamp procedure after percutaneous coronary interventions: a randomized controlled trial, Heart Lung 36:431-439, 2007. 63. Kane FM, Brodie EE, Coull A, et al: The analgesic effect of odour and music upon dressing change, Br J Nurs 13:S4-S12, 2004. 64. Labbe E, Schmidt N, Babin J, et al: Coping with stress: the effectiveness of different types of music, Appl Psychophysiol Biofeedback 32:163-168, 2007. 65. Avanzini G: Musicogenic seizures, Ann N Y Acad Sci 999:95-102, 2003. 66. Leardi S, Pietroletti R, Angeloni G, et al: Randomized clinical trial examining the effect of music therapy in stress response to day surgery, Br J Surg 94:943-947, 2007. 67. Nakamura T, Tanida M, Niijima A, et al: Auditory stimulation affects renal sympathetic nerve activity and blood pressure in rats, Neurosci Lett 416:107-112, 2007. 68. Conrad C, Niess H, Jauch K-W, et al: Overture for growth hormone: requiem for interleukin-6, Crit Care Med 35(12):2709-2713, 2007.

CHAPTER 146  •  Complementary and Alternative Medicine 69. Angelucci F, Ricci E, Padua L, et al: Music exposure differentially alters the levels of brain-derived neurotrophic factor and nerve growth factor in the mouse hypothalamus, Neurosci Lett 429:152-155, 2007. 70. Sarkamo T, Terveniemi M, Laitinen S, et al: Music listening enhances cognitive recovery and mood after middle cerebral artery stroke, Brain 131:866-876, 2008. 71. Thaut MH: Neural basis of rhythmic timing networks in the human brain, Ann N Y Acad Sci 999:364-373, 2003. 72. Xu F, Cai R, Xu J, et al: Early music exposure modifies GluR2 protein expression in rat auditory cortex and anterior cingulated cortex, Neurosci Lett 420:179-183, 2007. 73. Robinson NG: TCVM’s silk road may lead to detour, Vet Pract News, April 2010. Available at http://www.veterinarypracticenews.com/vet -practice-news-columns/complementary-medicine/tcvm-silk-road -may-lead-to-detour.aspx. Accessed December 1, 2012. 74. Xie H: TCVM treatment of intervertebral disk disease, TCVM News (14):1, 2011. Available at http://www.tcvm.com/doc/TCVMNews2011 MayR.pdf. Accessed June 18, 2013. 75. Chang L: TCM med secrets exposed in US. Global Times, December 20, 2010. Available at http://www.globaltimes.cn/china/society/2010-12/ 602827.html. Accessed June 18, 2013. 76. Yunnan Baiyao sued for not listing “secret” ingredients, WantChinaTimes .com website, January 30, 2013. Available at http://www.wantchinatimes .com/news-print-cnt.aspx?id=20130130000117&cid=1103. Accessed June 18, 2013. 77. Robinson NG: Chinese herb known for hemostatic abilities, Veterinary Practice News website. Available at http://www.veterinarypracticenews .com/vet-practice-news-columns/complementary-medicine/chineseherb-known-for-hemostatic-abilities.aspx. Accessed June 18, 2013. 78. Lenaghan SC, Xia L, Zhang M: Identification of nanofibers in the Chinese herbal medicine: Yunnan Baiyao, J Biomed Nanotechnol 5(5):472-476, 2009. 79. Ladas EJ, Karlik JB, Rooney D, et al: Topical Yunnan Baiyao administration as an adjunctive therapy for bleeding complications in adolescents with advanced cancer, Support Care Cancer 20(12):3379-3383, 2012. 80. Tang ZL, Wang X, Yi B, et al: Effects of the preoperative administration of Yunnan Baiyao capsules on intraoperative blood loss in bimaxillary orthognathic surgery: a prospective, randomized, double-blind, placebocontrolled study, Int J Oral Maxillofac Surg 38(3):261-266, 2009. 81. Shmalberg J, Hill RC, Scott KC: Nutrient and metal analyses of Chinese herbal products marketed for veterinary use, J Anim Physiol Anim Nutr (Berl) 97:305-314, 2013. 82. Li R, Alex P, Ye M, et al: An old herbal medicine with a potentially new therapeutic application in inflammatory bowel disease, Int J Clin Exp Med 4(4):309-319, 2011. 83. He H, Ren X, Wang X, et al: Therapeutic effect of Yunnan Baiyao on rheumatoid arthritis was partially due to regulating arachidonic acid metabolism in osteoblasts, J Pharm Biomed Anal 59:130-137, 2012. 84. Liu X, Guan X, Chen R, et al: Repurposing of Yunnan Baiyao as an alternative therapy for minor recurrent aphthous stomatitis, Evid Based Complement Alternat Med 2012:284620, 2012.

85. Lu Y: Herb use in critical care. What to watch for, Crit Care Nurs Clin North Am 15:313, 2003. 86. Rogers EA, Gough JE, Brewer KL: Are emergency department patients at risk for herb-drug interactions? Acad Emerg Med 8:932, 2001. 87. Cicero AFG, Derosa G, Gaddi A: What do herbalists suggest to diabetic patients in order to improve glycemic control? Evaluation of scientific evidence and potential risks, Acta Diabetol 41:91, 2004. 88. Xie H, Preast V, editors: Xie’s Chinese veterinary herbology, Ames, Ia, 2010, Wiley-Blackwell. 89. Marsden S: Chinese herbal treatment of cancer in small animals. Small animal and exotics. In Proceedings of the North American Veterinary Conference, Orlando, Florida, January 16-20, 2010. Gainesville, Fla, 2010, The North American Veterinary Conference, pp 45-52 (AN: 20103181461). 90. Hsu L-M, Huang Y-S, Tsay S-H, et al: Acute hepatitis induced by Chinese hepatoprotective herb, Xiao-Chai-Hu-Tang, J Chin Med Assoc 69(2):8688, 2006. 91. Cheung WI, Tse ML, Ngan T, et al: Liver injury associated with the use of Fructus Psoraleae (Bol-gol-zhee or Bu-gu-zhi) and its related proprietary medicine, Clin Toxicol (Phila) 47:683-685, 2009. 92. Yu F, Takahashi T, Moriya J, et al: Traditional Chinese Medicine and Kampo: a review from the distant past for the future, J Int Med Res 34:231-239, 2006. 93. Ikegami F, Sumino M, Fujii Y, et al: Pharmacology and toxicology of Bupleurum root-containing Kampo medicines in clinical use, Hum Exp Toxicol 25:481-494, 2006. 94. Gompf RE: Nutritional and herbal therapies in the treatment of heart disease in cats and dogs, J Am Anim Hosp Assoc 41:355, 2005. 95. Barocelli E, Calcina F, Chiavarini M, et al: Antinociceptive and gastroprotective effects of inhaled and orally administered Lavandula hybrida Reverchon “Grosso” essential oil, Life Sci 76:213, 2004. 96. Wheatley D: Medicinal plants for insomnia: a review of their pharmacology, efficacy and tolerability, J Psychopharmacol 19:414, 2005. 97. Chuang KJ, Chen HW, Liu IJ, et al: The effect of essential oil on heart rate and blood pressure among solus por aqua workers, Eur J Prev Cardiol Epub November 29, 2012. 98. Betts T: Use of aromatherapy (with or without hypnosis) in the treatment of intractable epilepsy: a 2-year follow-up study, Seizure 12:534, 2003. 99. Overall KL, Dunham AE: Homeopathy and the curse of the scientific method, Vet J 180:141-148, 2009. 100. Whalley B, Hyland ME: Placebo by proxy: the effect of parents’ belief on therapy for children’s temper tantrums, J Behav Med 36(4):341-346, 2013. 101. American Veterinary Medical Association: 2013 HOD resolutions and proposed bylaw amendments. Available at https://www.avma.org/ About/Governance/Pages/2013-HOD-Resolutions-and-ProposedBylaw-Amendments.aspx?utm_source=avma-at-work&utm_medium =web. Accessed December 1, 2012.

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PART XVIII  ENVIRONMENTAL EMERGENCIES CHAPTER 147  SMOKE INHALATION Shailen Jasani,

MA, VetMB, MRCVS, DACVECC

KEY POINTS • The relative lack of clinical veterinary information on smoke inhalation likely reflects a very high incidence of preadmission mortality. Hypoxia from carbon monoxide poisoning is presumed to be the most common cause of immediate death. • Direct thermal injury to the upper respiratory tract can cause laryngeal obstruction. Lower respiratory tract injury from irritant gases and superheated particulate matter can result in atelectasis, pulmonary edema, decreased lung compliance, and acute respiratory distress syndrome. • Bacterial bronchopneumonia typically occurs later in the course of the condition and is usually secondary to therapeutic interventions or sepsis. • Acute neurologic dysfunction may be seen initially or as a delayed syndrome. • Significant dermal burn injury exacerbates morbidity and mortality. • Aggressive oxygen supplementation is the immediate priority to hasten carbon monoxide elimination. Supportive measures for respiratory and neurologic complications follow. • If carbon monoxide poisoning resolves, the prognosis is good in the absence of significant dermal burn injury, bronchopneumonia, or acute neurologic signs.

A significant number of dogs and cats are likely to be involved in residential fires each year, yet little information is available regarding actual clinical cases. This dearth of information is most likely due to a very high incidence of preadmission mortality. A recent case series describing 21 dogs trapped in a kennel fire has increased the available information to some extent.1

PATHOPHYSIOLOGY Carbon Monoxide Carbon monoxide is a nonirritant gas that competitively and reversibly binds to hemoglobin at the same sites as oxygen but with an affinity that is 230 to 270 times greater and results in marked anemic hypoxia.2,3 It is produced by incomplete combustion of carboncontaining materials and is therefore most significant in enclosed fires because there is increasingly less oxygen available.4 The resultant carboxyhemoglobin (COHb) also shifts the oxygen-hemoglobin dissociation curve to the left, which results in less offloading at the tissue level.2 There are three possible outcomes in pure, uncomplicated carbon monoxide poisoning: (1) complete recovery with possible transient hearing loss but no permanent effects, (2) recovery with

permanent central nervous system abnormalities, and (3) death.2,5-9 Carbon monoxide poisoning is the main cause of immediate death from smoke inhalation in humans, and death is due to cerebral and myocardial hypoxia.6,7

Hydrogen Cyanide Hydrogen cyanide (HCN) is most prevalent in fires involving wools, silks, and synthetic nitrogen-containing polymers (e.g., urethanes, nylon). It is a nonirritant gas that interferes with the utilization of oxygen by cellular cytochrome oxidase and thereby causes histotoxic hypoxia.3,6 The incidence and significance of cyanide toxicity in veterinary smoke inhalation victims remain undefined.4,10

Thermal Injury Direct thermal injury caused by hot, dry air is highly unusual distal to the larynx because heat is dissipated effectively by the thermal regulatory system of the nasal and oropharyngeal areas.6,11 Thermal injury can manifest as mucosal edema, erosions, and ulceration. Of greatest concern is the potential for laryngeal edema, which may result in fatal upper respiratory tract obstruction. Although these changes may not be apparent initially, they can be progressive. In one study, a tracheostomy was required because of laryngeal obstruction in 2 of 27 dogs with smoke exposure and was performed 24 and 72 hours after admission.8 Steam has a much greater heat capacity than dry air and is therefore likely to produce more extensive injury throughout the respiratory tract.6 Inhalation of superheated particulate matter (mainly soot) can result in thermal injury to the trachea and lower respiratory tract.

Irritant Gases and Superheated Particulate Matter A variety of irritant noxious gases can be inhaled during a fire, depending on the nature of the materials undergoing combustion. These include short-chain aldehydes, gases that are converted into acids in the respiratory tract (e.g., oxides of sulfur and nitrogen), highly water-soluble gases (e.g., ammonia, hydrogen chloride), and benzene (from plastics).6,11 Particulate matter acts as a vehicle by which these gases can be carried deep into the respiratory tract. The pathophysiologic consequences depend on the types of gases and particulate matter inhaled, the duration of exposure, and underlying host characteristics.6,12

Reduced lung compliance Lung compliance may be markedly reduced as a result of alveolar atelectasis due to impaired pulmonary surfactant activity, as well as pulmonary edema caused by increased permeability (see Chapter 21).3,6,13,14 Pulmonary edema can occur within minutes of smoke 785

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inhalation, although it typically develops over a period of up to 24 hours.6 Ventilation-perfusion alterations also occur, and acute lung injury and acute respiratory distress syndrome are potential sequelae (see Chapter 24). A recent case report described the successful management of a dog that developed acute respiratory distress syndrome following smoke inhalation.14a

Airway damage and obstruction The mucociliary escalator is significantly impaired following smoke inhalation. Progressive mucosal edema may be accompanied by mucosal sloughing over several hours, and the damaged epithelium gives rise to pseudomembranous casts.6,14 Marked tracheobronchitis, necrotizing bronchiolitis, alveolar hyaline membrane formation, and intraalveolar hemorrhage all may follow.6,14 Smoke inhalation induces a reflex bronchoconstriction, and airway obstruction is exacerbated by the copious secretions and edema fluid.6

Bacterial pneumonia Smoke inhalation may increase the likelihood of bacterial pneumonia by impairment of alveolar macrophage function. In addition, the stagnant luminal contents create a milieu conducive to bacterial colonization. Nevertheless, bacterial pneumonia is thought typically to occur as a secondary phenomenon following therapeutic interventions such as endotracheal intubation and tracheostomy, or due to sepsis associated with dermal burn injuries.12,15 Infection usually is not seen for at least 12 to 24 hours and is associated with a higher incidence of respiratory failure.6,12,15 Pseudomonas aeruginosa, Staphylococcus spp, and Streptococcus spp are most commonly involved in humans, but it is unknown if the same is true in dogs and cats.

Dermal Burn Injury The morbidity and mortality associated with smoke inhalation are much greater when significant concurrent dermal burn injury is present.8,10,11 This is due to both the pulmonary pathophysiology associated with dermal burns (pulmonary edema, bacterial pneumonia, acute lung injury, and acute respiratory distress syndrome) and to burn management requirements, including more aggressive fluid therapy and repeated general anesthesia (see Chapter 140).10,11

HISTORY If owner contact is possible, a full medical history should be obtained at the appropriate time. The current illness is usually related to being involved in an enclosed-space fire, and the duration of exposure and types of materials involved in the fire should be ascertained. The patient’s neurologic status at the scene predominantly reflects the degree of carbon monoxide poisoning. Paroxysmal or intractable coughing may suggest the inhalation of more irritating gases.

PHYSICAL EXAMINATION Physical examination findings depend on a number of factors, including the type, severity, and duration of smoke inhalation; the presence of dermal burn injuries; the use or nonuse of oxygen supplementation by human paramedics; the delay in arrival at the hospital; and the patient’s preexisting health status. Neurologic abnormalities on admission may include reduced mental status, from depression through coma, as well as anxiety, agitation, ataxia, and convulsions. In one case series dogs with altered mental status at the time of presentation had a significantly increased COHb concentration at presentation compared with normal dogs.1 New neurologic signs have been reported after 2 to 6 days in dogs that had neurologic dysfunction initially.16,17 Lethargy may be a common finding in cats.18

Respiratory signs may be absent initially and can take 24 hours or more to develop; however, two studies found that animals without respiratory abnormalities at admission typically did not go on to develop any significant problems.8,14,18 Clinical signs include tachypnea, panting (dogs), open-mouth breathing, dyspnea, inspiratory stridor, harsh lung sounds, expiratory wheezes, and crackles.1,6,8 In one report dogs with increased respiratory effort and abnormal auscultation findings had significantly greater carboxyhemoglobinemia than normal dogs.1 Cardiovascular findings may or may not be normal and depend on both the myocardial effects of carbon monoxide and HCN toxicity and the coexistence of significant dermal burn injury. Cardiovascular status tends to normalize quickly in uncomplicated cases, but complicated cases are more likely to show a range of cardiovascular abnormalities that persist for a longer period.6,12,18 The cherry red appearance of mucous membranes (and skin) attributed to carboxyhemoglobinemia is rarely witnessed in clinical cases. This probably reflects a high level of preadmission mortality in patients that would fall into this category.7 Individuals that live long enough to be treated are more likely to have either normal or hyperemic mucous membranes. Hyperemia may be due to carboxyhemoglobinemia, cyanide toxicosis, systemic vasodilation, and local vasodilation due to mucosal irritation, and this may mask both concurrent perfusion abnormalities and cyanosis.8 Rectal temperature may be normal, decreased, or increased.1,8 The animal’s coat is likely to smell of smoke. Ptyalism may be present and there may be evidence of soot in the oral cavity (or on microscopic examination of saliva). Mucosal edema and burns inside the oral cavity as well as on the face and lips may suggest smoke inhalation injury to the respiratory tract, but such findings are associated with a high incidence of false positives in humans.14 In two retrospective veterinary studies of smoke exposure, only 1 of the 27 dogs and none of the 22 cats had a major dermal burn injury; minor injuries such as singed hair and skin lacerations were more common in dogs.8,18 Evidence of ocular irritation and injury may be present.

CLINICAL EVALUATION Arterial Blood Gas Analysis Initially, when carbon monoxide (and HCN) poisoning is likely to be the predominant cause of morbidity, arterial partial pressure of oxygen (PaO2) may remain within normal limits.2,3,6 Oxygen saturation based on pulse oximetry may also appear normal because these devices do not differentiate between COHb and oxyhemoglobin.4 Co-oximetry allows direct measurement of oxyhemoglobin and COHb (see Chapter 186).10 A reduction in the arterial-venous oxygen gradient may be suggestive of significant HCN toxicity.10,19 Repeated arterial blood gas measurements are invaluable in detection and monitoring of the potentially progressive respiratory complications of smoke inhalation and may reveal impaired oxygenation and/or ventilation.

Acid-Base Status Acidemia is likely and may be of respiratory, metabolic, or mixed origin.6,11,12 Hyperlactatemia may be present as a result of tissue hypoxia, and excessively high plasma lactate levels at admission are a sensitive indicator of HCN intoxication (independent of hypoxemia) in humans.19

Thoracic Radiography Thoracic radiographic abnormalities may be absent initially when injury is confined to the airways but usually appear within the first 24 hours and can be expected in 70% to 80% of affected dogs and

CHAPTER 147  •  Smoke Inhalation

cats.* Radiographic changes do not always correlate with either the severity of respiratory tract injury or patient morbidity; serial studies may be needed.6,8,18 An asymmetric radiographic pattern consistent with pulmonary edema is typical with alveolar, interstitial, and peribronchial changes.6,8,18,20 Diffuse coalescing consolidation, collapse of the right middle lung lobe, and pleural effusion (especially in cats) have all been reported.6,8,18 If bacterial pneumonia develops, a more pronounced alveolar pattern with air bronchograms can be expected.6 Computed tomography is likely to offer a more sensitive means of detecting lung injury earlier, but currently there is only limited published information on this topic for human patients and experimental animals.

Laryngoscopy, Bronchoscopy, and Transtracheal Aspiration Laryngoscopy is useful in sedated or unconscious animals to detect potentially progressive laryngeal obstruction. Fiberoptic bronchoscopy is used widely in humans to examine the lower airway. The presence of carbonaceous particulate matter in the airway confirms the diagnosis, and direct visualization of the anatomic level and extent of airway injury is possible along with sample collection.4 Serial examinations may need to be performed as respiratory changes progress.10 General anesthesia is required in veterinary patients in the absence of a tracheostomy, so a risk-benefit assessment must be made in considering this procedure. Transtracheal aspiration may be used in veterinary patients. Samples may reveal carbonaceous particulate matter as well as cytologic changes consistent with thermal injury affecting the ciliated epithelial cells in particular.21 This technique is also useful for the diagnosis of bacterial bronchopneumonia and for the procurement of samples for culture and susceptibility testing.

DIAGNOSIS Smoke inhalation is suspected in a patient with a history of involvement in an enclosed-space fire along with facial burns, especially if carbonaceous particulate matter is present in the oral cavity or on microscopic examination of saliva. The results of physical examination and clinical evaluation support the diagnosis. In animals with significant dermal burn injury, and in the absence of a COHb measurement, the use of a transtracheal wash or bronchoscopy may be necessary to diagnose smoke inhalation as the cause of respiratory abnormalities.

TREATMENT Smoke inhalation victims can be divided broadly into the following groups: (1) those that have no clinical signs and are assessed to be at low risk of progression, (2) those that have only mild signs but are assessed to be at high risk of progression, and (3) those that require intensive treatment from the outset.4 Treatment must be tailored to this initial assessment and adapted thereafter based on regular patient evaluation.

Oxygen Supplementation Oxygen supplementation is the immediate priority for presumed carbon monoxide toxicity and may cause significant clinical improvement within minutes.8,15,17 The half-life of carbon monoxide is approximately 250 minutes in patients with normal respiratory exchange breathing room air but is reduced to 26 to 148 minutes at a fraction of inspired oxygen (FiO2) of 100%.6,22 In one case series the change in COHb 24 hours following presentation was signifi-

*References 4, 6, 8, 10, 18, 20.

cantly greater in dogs that received oxygen therapy (78% reduction; range, 59% to 84%) than in dogs that did not (48% reduction; range, 32% to 68%).1 The use of hyperbaric oxygen therapy to potentially reduce the half-life of carbon monoxide still further has been reported in humans; other beneficial effects are also postulated. However, a recent Cochrane review evaluated seven randomized controlled trials that used hyperbaric oxygen therapy in carbon monoxide poisoning and concluded that there was insufficient evidence to support its use in human patients for this purpose.23 Providing an FiO2 of 100% via endotracheal tube is an effective, readily available alternative that allows access to the patient. Treatment periods ranging from 30 minutes to 6 hours have been described.6,24,25 Oxygen supplementation clearly has a crucial therapeutic role in treating the respiratory complications that may develop subsequently.

Cyanide Toxicity Usual treatment of cyanide toxicity involves administration of intravenous sodium nitrite followed by intravenous sodium thiosulfate. However, sodium nitrite may not be appropriate in smoke inhalation victims because it results in the formation of methemoglobin and further compromises oxygen-carrying capacity.6 Sodium thiosulfate should therefore be used alone.

Airway Management A tracheostomy may be required to treat laryngeal obstruction; strict aseptic technique must be maintained during the procedure, with regular suctioning and humidification thereafter, because secondary infection may be life-threatening. The empiric use of bronchodilators is indicated, especially in patients with wheezes on auscultation. Options include terbutaline (0.01 mg/kg intravenously [IV] or intramuscularly in both dogs and cats), aminophylline (dogs: 10 mg/kg slowly IV, diluted; cats: 4 mg/kg slowly IV, diluted), and inhaled albuterol. Supplemental oxygen must be humidified, and regular saline nebulization followed by coupage should also be performed. Human clinical studies have suggested that coupage is contraindicated in the presence of bacterial pneumonia (see Chapter 22). Gentle activity is to be encouraged if possible, and mucolytics such as bromhexine and acetylcysteine may also be helpful. Antitussives are best avoided because they reduce airway clearance.

Sedation Animals that are agitated at initial contact may be exhibiting neurologic symptoms associated with carbon monoxide (and HCN) toxicity. Use of appropriate chemical restraint to allow more aggressive oxygen supplementation is empirically justified in such cases. Thereafter, sedation may be required to minimize anxiety associated with dyspnea. Low-dosage opioids may be adequate, and additional sedation (e.g., acepromazine) may be necessary, especially in patients with upper respiratory tract compromise (see Chapter 142).

Mechanical Ventilation Assisted ventilation may be required due to either inadequate spontaneous ventilation or respiratory failure (see Chapter 30).10 A lungprotective strategy is warranted. Continuous positive airway pressure, provided to spontaneously breathing patients, may be an alternative in the absence of hypoventilation, but this usually necessitates orotracheal intubation or tracheostomy.26,27

Intravenous Fluid Therapy Fluid requirements are significantly increased in patients with dermal burns (see Chapter 140), but this is not necessarily the case in isolated smoke inhalation injury. Moreover, overresuscitation may increase pulmonary microvascular pressures and edema formation under the high-permeability conditions in early lung injury. Both overzealous

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fluid administration and excessive fluid restriction may potentially be harmful in patients with isolated smoke inhalation injury.10,14,28,29

Additional Therapies Prophylactic antibiotics are not recommended due to the risk of selecting for resistant organisms. In animals with suspected bacterial pneumonia, antibiotic selection should be based on culture and susceptibility testing of samples collected by transtracheal wash or bronchoscopy. Gram stain examination of these samples can guide drug selection while results are awaited. Otherwise, broad-spectrum coverage for both gram-negative and gram-positive infections should be instituted and then amended if necessary once test results are obtained. Blood cultures are recommended in animals that are thought to have developed bacterial pneumonia due to sepsis.4 The use of glucocorticoids following smoke inhalation has been widely investigated. Experimental studies report variable effects associated with this treatment, but the vast majority of clinical reports point to an increased incidence of bacterial pneumonia with no clear clinical benefit.4,8,11,14,30 The use of glucocorticoids is therefore not recommended in these patients.4,10,14 The permeability edema following smoke inhalation was said to be less responsive to standard diuretic therapy than high-pressure edema. However, there is more recent evidence in support of multimodal beneficial effects of judicious furosemide administration in such cases in the absence of hypovolemia or dehydration (see Chapter 21). A variety of inhaled drugs are under investigation in human patients and/or experimental animals. Nebulized heparin and N-acetylcysteine have been used in some human patients; topical antiinflammatory drugs, nitric oxide inhibitors, and antioxidants are other agents being explored.31

PROGNOSIS Mortality rates in people following admission for smoke inhalation have been reported to be less than 10% without and 25% to 65% with dermal burn injury.10 Of the 27 dogs with smoke exposure in one retrospective canine study, 4 died and a further 4 were euthanized. In uncomplicated cases, dogs recovering from the initial carbon monoxide poisoning had a favorable prognosis, with improvements in respiratory signs over 24 hours. However, dogs that were clinically worse the following day were more likely to die, to be euthanized, or to require prolonged hospitalization.8 In one retrospective case series of 21 dogs trapped in a kennel fire, 5 dogs had worsening of respiratory or neurologic signs following admission, but only 1 of the dogs failed to survive to discharge (euthanized after developing pneumonia).1 In another study, smoke-exposed dogs admitted with acute neurologic signs had an overall mortality rate of 46%.16 Despite initial improvement, acute, delayed neurologic signs developed in 46% of the dogs within 2 to 6 days. Mortality rate for this group was 60%.16 In a retrospective feline study, none of the 22 cats with smoke exposure died, but 2 were euthanized due to severe respiratory or neurologic signs.18 Animals with concurrent dermal burn injury should be given a more guarded prognosis from the outset. Although smoke inhalation can result in permanent changes to lung structure, any long-term effects on lung function are unlikely to be clinically significant.4,6,8,10

REFERENCES 1. Ashbaugh EA, Mazzaferro EM, McKierman BC, et al: The association of physical examination abnormalities and carboxyhemoglobin concentra-

tions in 21 dogs trapped in a kennel fire, J Vet Emerg Crit Care (San Antonio) 22:361, 2012. 2. Winter PM, Miller JN: Carbon monoxide poisoning, JAMA 236:1502, 1976. 3. West JB: Respiratory physiology: the essentials, ed 9, Baltimore, 2012, Lippincott Williams & Wilkins. 4. Ruddy RM: Smoke inhalation injury, Pediatr Clin North Am 41:317, 1994. 5. Berent AC, Todd J, Sergeeff J, et al: Carbon monoxide toxicity: a case series, J Vet Emerg Crit Care (San Antonio) 15:128, 2005. 6. Fitzgerald KT, Flood AA: Smoke inhalation, Clin Tech Small Anim Pract 21:205, 2006. 7. Thom SR: Smoke inhalation, Emerg Med Clin North Am 7:371, 1989. 8. Drobatz KJ, Walker LM, Hendricks JC: Smoke exposure in dogs: 27 cases (1988-1997), J Am Vet Med Assoc 215:1306, 1999. 9. Rozanski E: Acute lung injury: near-drowning and smoke inhalation. In Proceedings of 10th International Veterinary Emergency and Critical Care Symposium, San Diego, Calif, September 2004. 10. Clark WR: Smoke inhalation: diagnosis and treatment, World J Surg 16:24, 1992. 11. Trunkey DD: Inhalation injury, Surg Clin North Am 58:1133, 1978. 12. Stephenson SF, Esrig BC, Polk HC Jr, et al: The pathophysiology of smoke inhalation injury, Ann Surg 182:652, 1975. 13. Nieman GF, Clark WR Jr, Wax SD, et al: The effect of smoke inhalation on pulmonary surfactant, Ann Surg 191:171, 1980. 14. Herndon DN, Langner F, Thompson P, et al: Pulmonary injury in burned patients, Surg Clin North Am 67:31, 1987. 14a.  Guillaumin J, Hopper K: Successful outcome in a dog with neurological and respiratory signs following smoke inhalation, J Vet Emerg Crit Care 33(3):328-334, 2013. 15. Zikria BA, Weston GC, Chodoff M, et al: Smoke and carbon monoxide poisoning in fire victims, J Trauma 12:641, 1972. 16. Jackson CB, Drobatz KJ: Neurologic dysfunction associated with smoke exposure in dogs, J Vet Emerg Crit Care (San Antonio) 12:193, 2002. 17. Mariani CL: Full recovery following delayed neurologic signs after smoke inhalation in a dog, J Vet Emerg Crit Care (San Antonio) 13:235, 2003. 18. Drobatz KJ, Walker LM, Hendricks JC: Smoke exposure in cats: 22 cases (1986-1997), J Am Vet Med Assoc 215:1312, 1999. 19. Band FJ, Bairiot P, Toffis V, et al: Elevated blood cyanide concentrations in victims of smoke inhalation, N Engl J Med 325:1761, 1991. 20. Teixidor HS, Rubin E, Novick G, et al: Smoke inhalation: radiologic manifestations, Radiology 149:383, 1983. 21. Tams TR: Aspiration pneumonia and complications of inhalation of smoke and toxic gases, Vet Clin North Am Small Anim Pract 15:971, 1985. 22. Weaver LK, Howe S, Hopkins R, et al: Carboxyhemoglobin half-life in carbon monoxide-poisoned patients treated with 100% oxygen at atmospheric pressure, Chest 117:801, 2000. 23. Buckley NA, Juurlink DN, Isbister G, et al: Hyperbaric oxygen for carbon monoxide poisoning, Cochrane Database Syst Rev (4):CD002041, 2011. 24. Piantadosi CA: Hyperbaric oxygen for acute carbon monoxide poisoning, N Engl J Med 347:1053, 2002. 25. Hart GB, Strauss MB, Lennon PA, et al: Treatment of smoke inhalation by hyperbaric oxygen, J Emerg Med 3:211, 1985. 26. American Association for Respiratory Care: Application of continuous positive airway pressure to neonates via nasal prongs, nasopharyngeal tube, or nasal mask: 2004 revision and update, Respir Care 49:1100, 2004. 27. Orton CE, Wheeler SL: Continuous positive airway pressure therapy for aspiration pneumonia in a dog, J Am Vet Med Assoc 188:1437, 1986. 28. Clark WR, Nieman GF, Goyette D, et al: Effects of crystalloids on lung fluid balance after smoke inhalation, Ann Surg 208:56, 1988. 29. Hughes D: Fluid therapy with lung disease: is wetter better or drier desired? In Proceedings of the 9th International Veterinary Emergency and Critical Care Symposium, 2003. 30. Nieman GF, Clark WR, Hakim T: Methylprednisolone does not protect the lung from inhalation injury, Burns 17:384, 1991. 31. Toon MH, Maybauer MO, Greenwood JE, et al: Management of acute smoke inhalation injury, Crit Care Resusc 12:53, 2010.

CHAPTER 148  HYPOTHERMIA Jeffrey M. Todd,

DVM, DACVECC

KEY POINTS • Hypothermia causes severe cardiovascular, respiratory, electrolyte, nervous system, acid-base, and coagulation abnormalities. • Early and aggressive treatment can decrease morbidity and mortality in the critically ill patient. • Rewarming shock is a common complication resulting from peripheral vasodilation when the periphery is warmed before the core.

severity of hypothermia based on the clinical consequences at each stage, not strictly on the CBT (see Table 148-1). Briefly, in mild hypothermia the thermoregulatory mechanisms, such as shivering and heat-seeking behavior, are still intact, but ataxia may be observed. Moderate hypothermia brings about the progressive loss of the thermoregulatory system, with decreasing levels of consciousness and initial cardiovascular instability. Further progression into severe hypothermia is marked by complete loss of the thermoregulatory system, an inability to shiver, comatose states and susceptibility to ventricular fibrillation.2,3

REVIEW OF THERMOREGULATION Hypothermia is the end result of an animal’s inability to maintain thermoregulatory homeostasis. It occurs when the individual or combined effects of excessive heat loss, decreased heat production, or a disruption of the normal thermoregulatory functions permit the core (vital organ) body temperature (CBT) to drop below speciesspecific physiologic parameters. The sequelae of hypothermia can disrupt the normal physiologic processes of all organ systems. Although this disruption negatively affects the majority of functions, it can be positively applied in a small subset of clinical conditions and disease states. Hypothermia is a relatively common complication in both acutely ill or injured patients and chronically ill critical care patients. Deleterious effects may be observed on the cardiovascular, respiratory, and nervous systems as well as on acid-base balance, coagulation, and electrolyte levels. Although the normal behavioral thermoregulatory defense mechanisms, such as huddling or heat seeking, may be enough in healthy patients, critically ill patients must depend on their autonomic defenses and caretakers.1 The goal of therapy is to provide early and aggressive treatment to prevent further decreases in core temperature, stabilize the vital cardiopulmonary functions, and provide a means of achieving normothermia at a safe rewarming rate.

CLASSIFICATION Hypothermia is defined as either a primary or secondary condition in which the CBT is less than 37° C (see conversion table in the inside cover for conversion of Celsius values to Fahrenheit). Primary hypothermia, or “accidental” hypothermia, is a subnormal temperature caused by excessive exposure to low environmental temperatures. Secondary hypothermia is a result of disease, trauma, surgery, or drug-induced alteration in heat production and thermoregulation.2 Although the underlying causes may differ, the clinical consequences associated with hypothermia are similar. Hypothermia traditionally has been classified as “mild,” “moderate,” or “severe” based purely on the CBT (Table 148-1). Although this classification is simple, it does not capture the functional changes that characterize the differing levels of symptoms not directly related to a specific CBT. Therefore some have proposed classifying the

A normal CBT is maintained by an intricate balance of metabolic heat production and heat loss. The main thermostat of the body is the hypothalamus, with temperature changes sensed by the preoptic and anterior hypothalamic nuclei. Secondary temperature sensors are located within the skin and deep body tissues; namely, the spinal cord, abdominal viscera, and great veins.4 Temperature is sensed by the transient receptor potential family of ion channels, which are activated at distinct temperature thresholds.1 This peripheral input from the skin travels to the spinal cord or trigeminal dorsal horn for passage to the midbrain and thalamus. This thermal information is then output to the sensory cortex, producing the sensation of hot and cold. The behavioral and autonomic responses are linked to the reticular inputs in the brainstem.5 This system is so precise that, in humans, changes in CBT of fractions of a degree Celsius result in autonomic thermoregulatory responses. Amazingly, this can lead to a change from sweating to shivering within a span of 0.6° C.6 The core is defined by well-perfused tissues in which the temperature remains relatively uniform, such as within the abdominal and thoracic cavities, or the cerebrum.7 The peripheral temperatures can vary significantly based on activity, distance from areas of thermal production, environmental temperature, and vascular responses. This can lead to dramatic

Table 148-1  Classification of Hypothermia Based on Temperature and Clinical Signs Core Temperature9

Severity of Hypothermia

Clinical Signs3,9

32°-37° C

Mild

Shivering, ataxia, vasoconstriction

28°-32° C

Moderate

Decreased level of consciousness, hypotension, ± shivering

15 mcg/kg/ min), although this scaling of effects is difficult to demonstrate clinically. Dopamine has been reported to increase renal blood flow at dosages of less than 5 mcg/kg/min (and to decrease it to baseline at 10 mcg/kg/min) and may increase urine output,1-3 but dopamine therapy does not appear to provide any low-dose renal-protective efficacy in people.4,5 When administered to critically ill people,6 septic dogs7 (in the author’s experience), anesthetized dogs,8-10 and anesthetized cats,11 dopamine generally causes a modest vasoconstriction and increase in blood pressure with little change or modest increases in cardiac output. In one study of anesthetized cats,12 dopamine was associated with vasodilation and increases in heart rate, cardiac output, and blood pressure.

Dobutamine Dobutamine is a synthetic analog of dopamine with strong β1-agonist activity as well as some effects on β2- and α1-receptors, but without dopaminergic effects. When dobutamine is given to critically ill humans,6,13 septic dogs7 (in the author’s experience), anesthetized dogs,8-10,14 anesthetized cats,12,15 and anesthetized foals,16,17 it generally causes modest vasodilation and a marked increase in cardiac output with little change in blood pressure. Although dopamine is primarily used to raise arterial blood pressure in hypotensive patients, dobutamine is primarily used to increase forward flow when baseline blood pressure is acceptable.

Ephedrine Ephedrine is a sympathomimetic amine (but not, strictly speaking, a catecholamine) that primarily acts by increasing the release of norepinephrine from the sympathetic nerve endings. It may also have some direct β-agonist effects. Ephedrine is a general cardiovascular stimulant and bronchodilator. Ephedrine can be used as a first-line therapy in cardiovascular support instead of dopamine, but, given its mode of action, it will not be as effective or as reliable. The

CHAPTER 157  •  Catecholamines

administration of ephedrine to anesthetized dogs caused a modest decrease in heart rate and an increase in cardiac output, vascular resistance, and arterial blood pressure.18 The effects of a single dose may last 5 to 15 minutes; it may also be administered as a constantrate infusion (0.02 to 0.2 mg/kg/min). Prolonged use can deplete norepinephrine stores, which results in tachyphylaxis. Ephedrine crosses the blood-brain barrier and has a mild analeptic effect. In veterinary medicine it is also given orally for urinary incontinence (to increase urethral sphincter tone). In humans it is used topically as a nasal decongestant.

Norepinephrine Norepinephrine is primarily an α-receptor agonist and is associated with arteriolar and venous constriction. It also exhibits minimal β1-receptor agonist activity (in contrast to phenylephrine and vasopressin, norepinephrine may increase heart rate and contractility). Norepinephrine generally causes vasoconstriction and increases blood pressure, with variable effects on heart rate; cardiac output may increase,16,19-24 decrease,17,24 or remain unchanged.25,26 These different cardiac output consequences are attributed to differences in baseline effective circulating volume and myocardial contractility, and the relative effect of venoconstriction on venous capacitance (decreased capacitance would tend to increase venous return) and venous resistance to blood flow (increased flow resistance would tend to decrease venous return). Animals with an effective circulating volume but with vasodilation would be expected to experience an increase in cardiac output due to venoconstriction of capacitance vessels. Hypovolemic animals are already vasoconstricted, and further venoconstriction of resistance vessels associated with the administration of a vasoconstrictor would be expected to lead to a further decrease in venous return and cardiac output. Norepinephrine has, in addition, some β1-receptor activity, which would tend to increase contractility and cardiac output, particularly in patients with poor baseline myocardial contractility. Norepinephrine is commonly used to raise blood pressure after dopamine therapy alone has proven ineffective. Norepinephrine is usually added to the dopamine infusion but could simply replace the dopamine if the inotropic augmentation provided by dopamine is deemed unnecessary.

Phenylephrine Phenylephrine is an α-receptor agonist without β-agonist activity. Its administration causes vasoconstriction and an increase in arterial blood pressure, and a decrease in heart rate. Cardiac output may decrease13,27,28 or increase.11,12,29 The earlier discussion regarding the different consequences of venoconstriction for norepinephrine apply also to phenylephrine. Phenylephrine is used to raise blood pressure after dopamine has proven ineffective. Phenylephrine is usually added to the dopamine but can simply replace the dopamine if the inotropic augmentation provided by dopamine is deemed unnecessary. The decision between norepinephrine and phenylephrine is, for the most part, made with a coin toss. Norepinephrine may provide marginally better heart rate and inotropic support.

Vasopressin Vasopressin is a noncatecholamine vasoconstrictor acting via the vasopressin V1 receptor that increases intracellular calcium and vasomotor tone (see Chapter 158). It is a pure vasoconstrictor with no direct effect on the heart. Its administration is usually associated with an increase in systemic vascular resistance, a baroreceptor reflex decrease in heart rate, no change in contractility, and no change or a decrease in cardiac output.13,16,29,30-36 Arterial blood pressure is usually increased. Terlipressin is a long-acting synthetic analog of vasopres-

sin and is associated with increased systemic vascular resistance and arterial pressure, and a decreased heart rate and cardiac output in people21,37 and in normal and endotoxemic sheep.38 The choice between norepinephrine, phenylephrine, and vasopressin is, for the most part, arbitrary. Norepinephrine may provide marginally better heart rate and inotropic support. Vasopressin may be effective in patients hyporesponsive to catecholamines since it operates via different receptors than do the catecholamines.33,39-41

Angiotensin Angiotensin II is a hormone derived from angiotensin I by angiotensin-converting enzyme primarily in the lung but also in many other tissues. Angiotensin II causes vasoconstriction and aldosterone release. Aldosterone increases sodium reabsorption in the collecting tubules of the kidney. The administration of angiotensin II generally results in an increase in systemic vascular resistance, little change in heart rate, no change in contractility, and little change or a decrease in cardiac output.30,32,42 Angiotensin may be a less potent venoconstrictor than vasopressin, which tends to preserve venous return and cardiac output better than vasopressin.30,32 Although angiotensin has not been promoted as a therapy for cardiovascular instability, limited evidence suggests that it could be at least as effective as vasopressin.

Epinephrine Epinephrine is a potent β1-, β2-, α1-, and α2-receptor agonist. It is a potent inotrope and chronotrope, arteriolar and venular vasoconstrictor, and bronchodilator. It potently increases arterial blood pressure and can cause ventricular ectopic pacemaker activity. Epinephrine administration increases heart rate, systemic vascular resistance, cardiac output, and arterial blood pressure in anesthetized cats12 and people with sepsis1 or heart failure.43 Epinephrine is used primarily in supraphysiologic doses (5 to 20 mcg/kg) in emergency situations such as anaphylaxis and cardiac arrest in which the sum of its effects are highly important. Epinephrine can be used to support cardiovascular dysfunction in critically ill patients, but its therapeutic margin may not be as liberal as that of the other catecholamines (higher incidence of sinus tachycardia, ventricular arrhythmias, and increased lactate level),43 and it is a potent vasoconstrictor. Epinephrine is not a first-choice drug in the support of cardiovascular dysfunction in critically ill patients but can be used for rescue therapy when dopamine and other vasoconstrictors have failed to work.

Isoproterenol Isoproterenol is a potent β-receptor agonist with no α-receptor activity. As such, it is a potent vasodilator and hypotensive agent. In anesthetized dogs, isoproterenol increases heart rate and cardiac output, and decreases blood pressure.8 If isoproterenol is administered very carefully while blood pressure is monitored and maintained, it can provide potent augmentation of forward blood flow and tissue perfusion.

Dopexamine Dopexamine is a synthetic analog of dopamine that is a potent β2 and D1 receptor agonist without substantial β1 or α1 activity. Dopexamine is primarily an arteriolar vasodilator without substantial venous effects and without substantial chronotropic or inotropic impact. Its administration is usually associated with a decrease in systemic vascular resistance and blood pressure, and an increase in cardiac output.13,44,45 In contrast to other catecholamines, dopexamine is not arrhythmogenic. Dopexamine is not commonly used in veterinary medicine. It is used in humans for short-term support in congestive heart failure, in which the major benefit is attributed to

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afterload reduction. Although dopexamine is a catecholamine, it might more appropriately be listed under the heading “vasodilator.” In this context, its therapeutic siblings are drugs like angiotensinconverting enzyme inhibitors, calcium channel blockers, acepromazine, hydralazine, and nitroprusside. For this reason it has little role as a cardiovascular tonic.

CHOOSING THE RIGHT CATECHOLAMINE There is much heterogeneity in responses to an individual catecholamine (e.g., norepinephrine may increase or decrease cardiac output). Since catecholamines have different receptor activities and different vasculature beds have varying distributions of receptors, different dosages are expected to have different effects (e.g., low, physiologic doses of epinephrine cause systemic vasodilation, whereas high, pharmacologic doses cause systemic vasoconstriction). In addition to individual and species variations, the underlying disease (or experimental model) and the pretreatment baseline values have much to do with both the direction and the magnitude of the response to therapy. The coadministration of other drugs can also impact responses. For general cardiovascular support in critically ill patients, the first-choice drug is either dopamine or dobutamine. Ephedrine could also be considered a first-choice drug. These drugs generally increase heart rate and contractility, and may thereby improve cardiac output. They have modest effects on vasomotor tone; dopamine tends to moderately increase systemic vascular resistance (and blood pressure), whereas dobutamine tends to moderately decrease systemic vascular resistance (and increase forward flow).6,9 Consequently, when hypotension is the problem, dopamine is the drug of choice; dopamine is the “pressure” drug of the two. When blood pressure is acceptable, dobutamine is the drug of choice to augment forward flow; dobutamine is the “flow” drug of the two. Generally, and insofar as is possible, the idea is to identify the specific problem or problems that need to be addressed in the therapy plan (bradycardia, poor contractility, low cardiac output, hypotension, weak pulse quality, poor tissue perfusion) and then to start treatment with either dopamine or dobutamine in increasing dosages until the problem is resolved (or until it is decided that the chosen drug will not solve the problem). When, for instance, higher dosages of dopamine fail to increase blood pressure to acceptable levels, stronger vasoconstrictors such as norepinephrine, phenylephrine, or vasopressin can be added to the therapeutic cocktail. Isoproterenol and dopexamine are considered too vasodilatory for routine use in critically ill patients with a precariously balanced blood pressure system. If they are used for forward flow augmentation, continuous, accurate, direct blood pressure monitoring is recommended. Norepinephrine, phenylephrine, and vasopressin are considered too vasoconstrictive for primary use, but one should not hesitate to employ them if dopamine or dobutamine fails to correct the identified problems. Epinephrine is used primarily in conditions of serious cardiovascular collapse such as anaphylaxis or cardiac arrest but can be used for cardiovascular support as a last resort when other therapies have failed.

COMBINATION THERAPIES Combinations of two or more of the sympathomimetics described earlier are often used at the clinician’s discretion. When two drugs are used in equipotent dosages, one would expect a net effect approximately midway between that of the two drugs. For instance, one part dopamine plus one part dobutamine would be expected to increase contractility by about the same amount as either two parts dopamine or two parts dobutamine, but with less vasoconstriction than two parts of dopamine and less vasodilation than two parts of dobuta-

mine. Adding dobutamine to dopamine (rather than simply doubling the dose of dopamine) would be expected to further increase contractility and relieve some of the vasoconstriction.10 The addition of norepinephrine or phenylephrine or vasopressin to dobutamine or dopamine generally increases systemic vascular resistance and blood pressure.43 One part dopamine and one part norepinephrine would be expected to provide better blood pressure support and fewer arrhythmogenic side effects than two parts of dopamine and better inotropic support than two parts of norepinephrine. Sympathomimetic drugs can be administered in any combination. The clinician just must be clear about what the treatment is intended to improve (inotropy, cardiac output, blood pressure, tissue perfusion) and select drugs and dosages than seem most likely to achieve those goals.

VASOMOTOR TONE Of the two determinants of arterial blood pressure—cardiac output and vascular resistance—the latter is the much more powerful contributor. The effect of a drug or disease on blood pressure usually parallels its effect on vasomotor tone. Arteriolar vasomotor tone is also a primary determinant of visceral perfusion. In veterinary medicine, it is common to measure blood pressure and to initiate therapy when it is low. Parameters of tissue perfusion are less precise but no less important than blood pressure and receive less attention during therapy. Focusing therapy on arterial blood pressure without reference to the adequacy of tissue perfusion can be problematic. Vasoconstriction is a good thing to the extent that it supports arterial blood pressure but a bad thing to the extent that it impairs tissue perfusion. Vasodilation, if it could be accomplished without hypotension, would, in fact, be an ideal cardiovascular goal. Dobutamine’s claim to fame is specifically that it usually causes a modest, but not excessive, vasodilation coupled with good augmentation of contractility; forward flow is increased, whereas blood pressure does not change much. Although blood pressure is important and continued vigilance of it is imperative, a focused consideration of flow parameters such as cardiac output, pulse quality, and indicators of tissue perfusion is also necessary when choosing and evaluating a cardiotonic/vasoactive therapy plan. Because vasoconstriction tends to decrease tissue perfusion, vasoconstrictors have a bad reputation embodied in the maxim that “to administer a vasoconstrictor is to impair tissue perfusion and harm the patient.” Such an all-or-nothing concept is incorrect. Norepinephrine is commonly used in human intensive care to improve blood pressure and can be administered without adversely affecting visceral tissue perfusion.22,23,43,46,47 One meta-analysis47 found that dopamine was associated with an increased relative risk of death compared with norepinephrine. Although vasoconstrictors may not be a first-choice therapy for cardiovascular support because of this concern regarding vasoconstriction, they can, in fact, be very effective in the management of unstable cardiovascular systems (by increasing cardiac output, blood pressure, and visceral tissue perfusion). Venular vasomotor tone is an important determinant of venous return. Venous return is an important determinant of cardiac output. Veins have two important functions: (1) to store blood volume, and (2) to serve as conduits for venous return. Venoconstrictor drugs have two significant effects: (1) they decrease venous capacitance (which increases venous return and cardiac output), and (2) they increase resistance to venous blood flow (which decreases venous return and cardiac output).13 Venodilators have the opposite effects. The net effect on venous return and cardiac output depends on the relative strengths of these two opposing influences.23 Potent vasoconstrictors like norepinephrine and phenylephrine have been variously reported to either increase or decrease cardiac output, and the reason

CHAPTER 157  •  Catecholamines

for this disparity is the relative effect on these two opposing processes. The net effect of vasoconstrictors is determined largely by the pretreatment status of the cardiovascular system and drug dosages. From a baseline of venodilation, one might expect an increase in venous return, whereas from a baseline of venoconstriction, one might expect a decrease in venous return. Venodilation might be expected in diseases like anaphylaxis and sepsis and during general anesthesia. Although administration of fluids would “refill” the expanded blood volume capacity and restore venous return in these patients, such therapy would carry the risk of the disadvantageous effects of the particular fluid used (e.g., systemic or pulmonary edema with crystalloid therapy). For this reason, when infusion of a small dose of fluids to first restore cardiovascular homeostasis has failed, vasoconstrictor therapy is commonly initiated. Venoconstriction might be expected to be the normal response to hypovolemia (in which case fluids should be administered) and to excessive administration of a vasoconstrictor (in which case the vasoconstrictor therapy should be reduced). Although vasoconstrictor administration might improve arterial blood pressure in hypovolemic patients as a lifesaving maneuver in the short term, it will most likely diminish venous return, cardiac output, and tissue perfusion in the long term.

CATECHOLAMINES AND CORTISOL Cortisol has an important regulatory function in the action of the sympathetic nervous system and catecholamine on cardiovascular function; the cardiovascular system does not function well in the absence of cortisol. Acute glucocorticoid deficiency results in cardiovascular collapse and death in as little as a few hours to a few days in the dog48,49 and cat.50,51 Cardiovascular changes in such cases are uniformly profound hypotension48-53 with poor cardiac output and impaired myocardial contractility.48,50,51,53 Vasodilation and vasoparesis are most common,48,49,51 although vasoconstriction has been reported in some studies.50,52 Impaired vasomotor responsiveness to catecholamine and sympathetic nerve stimulation is consistently reported48,49,53 in acute glucocorticoid deficiency. Humans with heparin-induced thrombocytopenia sometimes experience bilateral adrenal hemorrhage secondary to adrenal venous thrombosis, which leads to acute adrenal insufficiency and hemodynamic collapse characterized by hypotension unresponsive to fluids and catecholamines, and death.54 A condition labeled relative adrenal insufficiency or critical illness– related adrenal insufficiency has been identified in critically ill people55,55a and dogs,56,57 as well as in patients following resuscitation from cardiac arrest.58-61 This condition entails a suboptimal cortisol response to stress and to adrenocorticotropic hormone (ACTH) administration and has been reported to have an adverse effect on survival. In addition, inflammatory conditions induce the expression of proinflammatory cytokines that inhibit the expression of genes for receptors for α1 agonists,62 angiotensin II,63 and vasopressin64 and thereby decrease vasomotor responsiveness to endogenous and exogenous vasoconstrictors. Proinflammatory cytokine expression during sepsis is mediated by the nuclear transcription factor NF-κB.65 Glucocorticosteroids decrease proinflammatory cytokine production via inhibition of NF-κB activity and tend to reverse vascular hyporeactivity in sepsis.66-72 Early studies reported that steroid supplementation in these cortisol-deficient patients improved survival,67,68,73,74 although a recent study did not confirm this result.75 One of the findings in the literature on administration of steroids for septic shock, including studies using both high-dose76 and low-dose66-68,73 treatment, has been the ability to withdraw catecholamine therapy following the implementation of steroid therapy (“shock reversal”). Dogs with

relative adrenal insufficiency were found to be more likely to require catecholamine therapy in one study.57 This author is aware of a few septic dogs that have experienced dramatic improvement in cardiovascular parameters and general well-being at the same time that sympathomimetic support was reduced or stopped following lowdose hydrocortisone therapy. Although corticosteroid supplementation cannot be universally efficacious, the evidence is suggestive that some critically ill patients requiring exogenous sympathomimetic support of cardiovascular function would benefit from low-dose hydrocortisone therapy (1 mg/kg followed by either 1 mg/kg q6h or an infusion of 0.15 mg/kg/hr, which is then tapered as the patient’s condition allows), as evidenced by improved cardiovascular function with reduced or no exogenous catecholamine therapy.

OTHER EFFECTS OF CATECHOLAMINES Catecholamines have many other effects of which users should be aware. For instance, blood glucose and lactate levels may increase, particularly with epinephrine infusion.46 The α agonism tends to increase blood glucose levels by decreasing insulin secretion and glycogenolysis. The β agonism contributes to the rise in blood glucose level by increasing glucagon and ACTH secretion (cortisol decreases tissue uptake of glucose) and lipolysis. The β2 agonism increases cellular potassium uptake, which reduces plasma potassium concentration.46,77 This may be important in animals that have severe total-body potassium depletion at presentation. Catecholamines are limited in their effectiveness in the treatment of hyperkalemia by their cardiovascular effects. Catecholamines increase metabolic oxygen consumption.78 The increase in oxygen delivery usually is greater than the increase in oxygen consumption, and so this is of limited clinical importance unless therapy fails to increase cardiac output and oxygen delivery. Exogenous catecholamine therapy may increase shear-induced platelet reactivity.79,80 This may be important in animals with underlying hypercoagulopathies. There is evidence that this effect may be caused by α2-receptor agonism and the opening of a sodium-chloride cotransporter in the platelet membrane. Studies suggest that this effect could be diminished by blocking chloride transport with loop80 or thiazide81 diuretics.

REFERENCES 1. Day NPJ, Phu NH, Mai NTH, et al: Effects of dopamine and epinephrine infusions on renal hemodynamics in severe malaria and severe sepsis, Crit Care Med 28:1353-1362, 2000. 2. Ichai C, Soubielle J, Carles M, et al: Comparison of the renal effects of low to high doses of dopamine and dobutamine in critically ill patients: a single-blind randomized study, Crit Care Med 28:921-928, 2000. 3. Ichai C, Passeron C, Caries M, et al: Prolonged low-dose dopamine infusion induces a transient improvement in renal function in hemodynamically stable, critically ill patients: a single-blind, prospective, controlled study, Crit Care Med 28:1329-1335, 2000. 4. Holmes CL, Walley KR: Bad medicine: low-dose dopamine in the ICU, Chest 123:1266-1275, 2003. 5. Beale RJ, Hollenberg SM, Vincent JL, et al: Vasopressor and inotropic support in septic shock: an evidence-based review, Crit Care Med 32:S455S465, 2004. 6. Shoemaker WC, Appel RL, Kram HB, et al: Comparison of hemodynamic and oxygen transport effects of dopamine and dobutamine in critically ill surgical patients, Chest 96:120-126, 1989. 7. Vincent JL, Van der Linden P, Domb M, et al: Dopamine compared with dobutamine in experimental septic shock: relevance to fluid administration, Anesth Analg 66:565-571, 1987. 8. Driscoll DJ, Gillette PC, Fukushige J, et al: Comparison of the cardiovascular action of isoproterenol, dopamine, and dobutamine in the neonatal and mature dog, Pediatr Cardiol 1:307-314, 1980.

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PART XX  •  PHARMACOLOGY 9. Abdul-Rasool IH, Chamberlain JH, Swan PC, et al: Cardiorespiratory and metabolic effects of dopamine and dobutamine infusions in dogs, Crit Care Med 15:1044-1050, 1987. 10. Rosati M, Dyson DH, Sinclair MD, et al: Response of hypotensive dogs to dopamine hydrochloride and dobutamine hydrochloride during deep isoflurane anesthesia, Am J Vet Res 68:483-494, 2007. 11. Wiese AJ, Barter LS, Ilkiw JE, et al: Cardiovascular and respiratory effects of incremental doses of dopamine and phenylephrine in the management of isoflurane-induced hypotension in cats with hypertrophic cardiomyopathy, Am J Vet Res 73:906-916, 2012. 12. Pascoe PJ, Ilkiw JE, Pypendop BH: Effects of increasing infusion rates of dopamine, dobutamine, epinephrine, and phenylephrine in healthy anesthetized cats, Am J Vet Res 67:1491-1499, 2006. 13. Funk DJ, Jacobsohn E, Kumar A: The role of venous return in critical illness and shock. Part 1: Physiology, Crit Care Med 41:255-262, 2013. 14. Orchard CH, Chakrabarti MK, Sykes MK: Cardiorespiratory responses to an IV infusion of dobutamine in the intact anaesthetized dog, Br J Anaesth 54:673-679, 1982. 15. Hori Y, Euchi M, Indou A, et al: Changes in the myocardial performance index during dobutamine administration in anesthetized cats, Am J Vet Res 68:385-388, 2007. 16. Valverde A, Giguere S, Sanchez C, et al: Effects of dobutamine, norepinephrine, and vasopressin on cardiovascular function in anesthetized neonatal foals with induced hypotension, Am J Vet Res 67:1730-1737, 2006. 17. Craig CA, Haskins SC, Hildebrand SV: The cardiopulmonary effects of dobutamine and norepinephrine in isoflurane-anesthetized foals, Vet Anesth Analg 14:177-187, 2007. 18. Wagner AE, Dunlop CI, Chapman PL: Effects of ephedrine on cardiovascular function and oxygen delivery in isoflurane-anesthetized dogs, Am J Vet Res 54:1917-1922, 1993. 19. Van Der Linden R, Gilbart E, Engelman E, et al: Adrenergic support during anesthesia in experimental endotoxin shock: norepinephrine versus dobutamine, Acta Anaesthesiol Scand 35:134-140, 1991. 20. Nouira S, Elatrous S, Dimassi S, et al: Effects of norepinephrine on static and dynamic preload indicators in experimental hemorrhagic shock, Crit Care Med 33:2339-2343, 2005. 21. Albanese J, Leone M, Delmas A, et al: Terlipressin or norepinephrine in hyperdynamic septic shock: a prospective, randomized study, Crit Care Med 33:1897-1902, 2005. 22. Jhanji S, Stirling S, Patel N, et al: The effect of increasing doses of norepinephrine on tissue oxygenation and microvascular flow in patients with septic shock, Crit Care Med 37:1961-1966, 2009. 23. Persichini R, Silva S, Teboul JL, et al: Effects of norepinephrine on mean systemic pressure and venous return in human septic shock, Crit Care Med 40:3146-3153, 2012. 24. Maas JJ, Pinsky MR, de Wilde RB, et al: Cardiac output responses to norepinephrine in postoperative cardiac surgery patients: interpretation with venous return and cardiac function curves, Crit Care Med 41:143150, 2013. 25. Schreuder WO, Schneider AJ, Groeneveld ABJ, et al: Effect of dopamine vs norepinephrine on hemodynamics in septic shock, Chest 95:1282-1288, 1989. 26. Martin C, Eon B, Saux P, et al: Renal effects of norepinephrine used to treat septic shock patients, Crit Care Med 18:282-285, 1990. 27. Crystal GJ, Kim SJ, Salem R, et al: Myocardial oxygen supply/demand relations during phenylephrine infusions in dogs, Anesth Analg 73:283288, 1991. 28. Nygren A, Thorén A, Ricksten SE: Vasopressors and intestinal mucosal perfusion after cardiac surgery: norepinephrine vs phenylephrine, Crit Care Med 34(3):722-729, 2006. 29. Malay MB, Ashton JL, Dahl K, et al: Heterogeneity of the vasoconstrictor effect of vasopressin in septic shock, Crit Care Med 32:1327-1331, 2004. 30. Heyndrickx GR, Boettcher DH, Vatner SF: Effects of angiotensin, vasopressin, and methoxamine on cardiac function and blood flow distribution in conscious dogs, Am J Physiol 231:1579-1587, 1976. 31. Montani JP, Liard JF, Schoun J, et al: Hemodynamic effects of exogenous and endogenous vasopressin at low plasma concentrations in conscious dogs, Circ Res 47:346-355, 1980.

32. Lee RW, Standaert S, Lancaster LD, et al: Cardiac and peripheral circulatory responses to angiotensin and vasopressin in dogs, J Clin Invest 82:413-419, 1988. 33. Tsuneyoshi I, Yamada H, Kakihana Y, et al: Hemodynamic and metabolic effects of low-dose vasopressin infusions in vasodilatory septic shock, Crit Care Med 29:487-493, 2001. 34. Westphal M, Stubbe H, Sielenkamper AW, et al: Effects of titrated arginine vasopressin on hemodynamic variables and oxygen transport in healthy and endotoxemic sheep, Crit Care Med 31:1502-1508, 2003. 35. Luckner G, Dunser MW, Jochberger S, et al: Arginine vasopressin in 316 patients with advanced vasodilatory shock, Crit Care Med 33:2659-2666, 2005. 36. Luckner G, Mayr VD, Jochberger S, et al: Comparison of two dose regimens of arginine vasopressin in advanced vasodilatory shock, Crit Care Med 35:2280-2285, 2007. 37. Therapondos G, Stanley AJ, Hayes PC: Systemic, portal and renal effects of terlipressin in patients with cirrhotic ascites: pilot study, J Gastroenterol Hepatol 19:73-77, 2004. 38. Scharte M, Meyer J, Van Aken H, et al: Hemodynamic effects of terlipressin (a synthetic analog of vasopressin) in healthy and endotoxemic sheep, Crit Care Med 29:1756-1760, 2001. 39. Silverstein DC, Waddell LS, Drobatz KJ, et al: Vasopressin therapy in dogs with dopamine-resistant hypotension and vasodilatory shock, J Vet Emerg Crit Care 17:399-408, 2007. 40. Lange M, Van Aken H, Westphal M, et al: Role of vasopressinergic V1 receptor agonists in the treatment of perioperative catecholaminerefractory arterial hypotension, Best Pract Res Clin Anaesthesiol 22(2):369-381, 2008. 41. Scroggin RD, Quandt J: The use of vasopressin for treating vasodilatory shock and cardiopulmonary arrest, J Vet Emerg Crit Care 19:145-157, 2009. 42. Lee RW, Lancaster LD, Buckley D, et al: Peripheral circulatory control of preload-afterload mismatch with angiotensin in dogs, Am J Physiol 253:H126-H132, 1987. 43. Levy B, Perez P, Perny J, et al: Comparison of norepinephrine-dobutamine to epinephrine for hemodynamics, lactate metabolism, and organ function variables in cardiogenic shock. A prospective, randomized pilot study, Crit Care Med 39:450-455, 2011. 44. Vincent JL, Reuse C, Kahn RJ: Administration of dopexamine, a new adrenergic agent, in cardiorespiratory failure, Chest 96:1233-1236, 1989. 45. Meier-Hellman A, Bredle DL, Specht M, et al: Dopexamine increases splanchnic blood flow but decreases gastric mucosal pH in severe septic patients treated with dobutamine, Crit Care Med 27:2166-2171, 1999. 46. Bellomo R, Wan L, May C: Vasoactive drugs and acute kidney injury, Crit Care Med 36:S179-S186, 2008. 47. DeBacker D, Aldecoa C, Njimi H, et al: Dopamine versus norepinephrine in the treatment of septic shock: a meta-analysis, Crit Care Med 40:725730, 2012. 48. Remington JW: Circulatory factors in adrenal crisis in the dog, Am J Physiol 165:306-318, 1951. 49. Brown FK, Remington JW: Arteriolar responsiveness in adrenal crisis in the dog, Am J Physiol 182:279-284, 1955. 50. Weiner DE, Verrier RL, Miller DT, et al: Effect of adrenalectomy on hemodynamics and regional blood flow in the cat, Am J Physiol 213:473-476, 1967. 51. Lefer AM, Verrier RL, Carson WW: Cardiac performance in experimental adrenal insufficiency in cats, Circ Res 22:817-827, 1968. 52. Reidenberg MM, Ohler EA, Sevy RW, et al: Hemodynamic changes in adrenalectomized dogs, Endocrinology 72:918-923, 1963. 53. Lefer AM, Sutfin DC: Cardiovascular effects of catecholamines in experimental adrenal insufficiency, Am J Physiol 206:1151-1155, 1964. 54. Rosenberger LH, Smith PW, Sawyer RG, et al: Bilateral adrenal hemorrhage: the unrecognized cause of hemodynamic collapse associated with heparin-induced thrombocytopenia, Crit Care Med 39:833-838, 2011. 55. Rothwell PM, Udwadia ZF, Lawler PG: Cortisol response to corticotropin and survival in septic shock, Lancet 337:582-583, 1991. 55a.  Marik PE: Critical illness-related corticosteroid insufficiency, Chest 135(1):181-193, 2009. 56. Burkitt JM, Haskins SC, Nelson RW, et al: Relative adrenal insufficiency in dogs with sepsis, J Vet Intern Med 21:226-231, 2007.

57. Martin LG, Groman RP, Fletcher DJ, et al: Pituitary-adrenal function in dogs with acute critical illness, J Am Vet Med Assoc 233:87-95, 2008. 58. Miller JB, Donnino MW, Rogan M, et al: Relative adrenal insufficiency in post-cardiac arrest shock is under-recognized, Resuscitation 76:221-225, 2008. 59. Pene F, Hyvernat H, Mallet V, et al: Prognostic value of relative adrenal insufficiency after out-of-hospital cardiac arrest, Intensive Care Med 31:627-633, 2005. 60. Tsai MS, Huang CH, Chang WT, et al: The effect of hydrocortisone on the outcome of out-of-hospital cardiac arrest patients: a pilot study, Am J Emerg Med 25:318-325, 2007. 61. Mentzelopoulos SC, Zakynthinos SG, Tzoufi M, et al: Vasopressin, epinephrine, and corticosteroids for in-hospital cardiac arrest, Arch Intern Med 169:15-24, 2009. 62. Bucher M, Kees F, Taeger K, et al: Cytokines down regulate alpha1adrenergic receptor expression during endotoxemia, Crit Care Med 31:566-571, 2003. 63. Bucher M, Hobbhahn J, Kurtz A: Nitric oxide-dependent down-regulation of angiotensin II type 2 receptors during experimental sepsis, Crit Care Med 29:1750-1755, 2001. 64. Schmidt C, Höcherl K, Kurt B, et al: Role of nuclear factor-kappaBdependent induction of cytokines in the regulation of vasopressin V1Areceptors during cecal ligation and puncture-induced circulatory failure, Crit Care Med 36:2363-2372, 2008. 65. Liu SF, Malik AB: NF-kappa B activation as a pathological mechanism of septic shock and inflammation, Am J Physiol 290:L622-L645, 2006. 66. Oppert M, Reinicke A, Graf KJ, et al: Plasma cortisol levels before and during “low-dose” hydrocortisone therapy and their relationship to hemodynamic improvement in patients with septic shock, Intensive Care Med 26:1747-1755, 2000. 67. Briegel J, Kellermann W, Forst H, et al: Low-dose hydrocortisone infusion attenuates the systemic inflammatory response syndrome. The Phospholipase A2 Study Group, Clin Investig 72:782-787, 1994. 68. Briegel J, Forst H, Haller M, et al: Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double-blind, single-center study, Crit Care Med 27:723-732, 1999.

69. Briegel J, Jochum M, Gippner-Steppert C, et al: Immunomodulation in septic shock: hydrocortisone differentially regulates cytokine responses, J Am Soc Nephrol 12:870-874, 2001. 70. Annane D, Bellissant E, Sebille V, et al: Impaired pressor sensitivity to noradrenaline in septic shock patients with and without impaired adrenal function reserve, Br J Clin Pharmacol 46:589-597, 1998. 71. Bellissant E, Annane D: Effect of hydrocortisone on phenylephrine— mean arterial pressure dose-response relationship in septic shock, Clin Pharmacol Ther 68:293-303, 2000. 72. Laviolle B, Donal E, Maguet PL, et al: Low doses of fludrocortisones and hydrocortisone, alone or in combination, on vascular responsiveness to phenylephrine in healthy volunteers, Br J Pharmacol 75:423-430, 2012. 73. Bollaert PE, Charpentier C, Levy B, et al: Reversal of late septic shock with supraphysiologic doses of hydrocortisone, Crit Care Med 26:645-650, 1998. 74. Annane D, Sébille V, Charpentier C, et al: Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock, JAMA 288:862-871, 2002. 75. Sprung CL, Annane D, Keh D, et al: Hydrocortisone therapy for patients with septic shock, N Engl J Med 358:111-124, 2008. 76. Sprung CL, Caralis PV, Marcial EH, et al: The effects of high-dose corticosteroids in patients with septic shock, N Engl J Med 311:1137-1143, 1984. 77. Follett DV, Loeb RG, Haskins SC, et al: Effects of epinephrine and ritodrine in dogs with acute hyperkalemia, Anesth Analg 40:400-406, 1990. 78. Scheeren TWL, Arndt JO: Different response of oxygen consumption and cardiac output to various endogenous and synthetic catecholamines in awake dogs, Crit Care Med 28:3861-3868, 2000. 79. Ikarugi H, Taka T, Nakajima S, et al: Norepinephrine, but not epinephrine, enhances platelet reactivity and coagulation after exercise in humans, J Appl Physiol 86:133-138, 1999. 80. Spalding A, Vaitkevicius H, Dill S, et al: Mechanism of epinephrineinduced platelet aggregation, Hypertension 31:603-607, 1998. 81. Vaitkevicius H, Turner I, Spalding A, et al: Chloride increases adrenergic receptor-mediated platelet and vascular responses, Am J Hypertens 15:492-498, 2002.

CHAPTER 158  •  Vasopressin

CHAPTER 158  VASOPRESSIN Deborah C. Silverstein,

DVM, DACVECC

KEY POINTS • Vasopressin, also known as antidiuretic hormone, is a peptide hormone synthesized in the hypothalamus and stored or released from the posterior pituitary gland. • There are four vasopressin receptors in the body: V1R, V2R, V3R, and the oxytocin receptor. • In health, vasopressin aids in the regulation of free water balance (via V2R) in the renal medullary and cortical collecting ducts. • During states of circulatory shock, vasopressin levels are markedly increased, and vasopressin functions as a potent nonadrenergic vasoconstrictor (via V1R). Vasopressin also stimulates the release of adrenocorticotropic hormone (via V3R).

• Vasopressin is used therapeutically for the management of pituitary-dependent diabetes insipidus, von Willebrand disease, vasodilatory hypotension, hemorrhagic shock, and cardiopulmonary resuscitation. • Long-acting vasopressin analogs and V1R-specific drugs are currently under investigation. • The recent clinical and experimental use of vasopressin antagonists for the treatment of various disease states shows early promising results.

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PHYSIOLOGY OF VASOPRESSIN Arginine vasopressin (AVP, also known as antidiuretic hormone, 8-arginine-vasopressin, and β-hypophamine) is a natural, nineamino-acid glycopeptide with a disulfide bond that is synthesized in the magnocellular neurons in the hypothalamus before transport down the pituitary stalk for storage in the pars nervosa of the posterior pituitary gland.1 The entire process of AVP synthesis, transport, and storage in the pituitary takes 1 to 2 hours. AVP is metabolized rapidly by hepatic and renal vasopressinases, and the half-life of AVP is 10 to 35 minutes. Vasopressin has shown teleologic persistence and is found in more than 120 species spanning four invertebrate phyla and the seven major vertebrate families.2 In most mammals (dogs, cats, humans), the natural hormone is arginine vasopressin, but the porcine species has a lysine in place of arginine, which renders the compound less potent than AVP. The most potent stimuli for AVP release are increased plasma osmolality, decreased blood pressure, and a decrease in circulating blood volume.3-5 Additional abnormalities that cause AVP release include pain, nausea, hypoxia, hypercarbia, pharyngeal stimuli, glycopenia, drugs or chemicals (e.g., acetylcholine, high-dose opioids, dopamine, angiotensin II, prostaglandins, glutamine, histamine), certain malignant tumors, and mechanical ventilation.6-8 Release of AVP is inhibited by drugs such as glucocorticoids, lowdose opioids, atrial natriuretic factor, and γ-aminobutyric acid. Hyperosmolality is sensed by both peripheral and central osmoreceptors. Central osmoreceptors are located in the third ventricle and detect changes in systemic osmolality. Peripheral osmoreceptors in the mesenteric and portal veins enable early detection of the osmolality of ingested food and liquids. Afferent impulses ascend via the vagus nerve to the paraventricular and supraoptic nuclei in the brain to stimulate AVP release. In addition, plasma hypertonicity depolarizes the magnocellular neurons of the hypothalamus to cause more AVP release. Decreases in blood volume or pressure also stimulate exponential increases in AVP. Hypovolemia and hypotension shift the osmolalityvasopressin response curve so that higher AVP levels are required to maintain a normal osmolality in hypotensive states.9 Afferent impulses from the left atrium, aortic arch, and carotid sinus stretch receptors tonically inhibit AVP secretion. Atrial stretch receptors respond to increases in blood volume, and the receptors in the aortic arch and carotid sinuses respond to increases in arterial blood pressure. A decrease in arterial baroreceptor activity causes “disinhibition” of AVP release during hypotensive states and results in increased AVP secretion.

VASOPRESSIN RECEPTORS Vasopressin receptors are G protein–coupled receptors. The cellular effects of vasopressin are mediated by interactions of the hormone with several types of receptors (Table 158-1).10 V1 receptors (V1Rs), previously known as V1a receptors, are found primarily on vascular smooth muscle cells and cause vasoconstriction in most vascular beds that is mediated by Gq protein–coupled activation of the phospholipase C and phosphoinositide pathways. Increased levels of inositol phosphate and diacylglycerol activate voltage-gated calcium channels. This results in increased intracellular calcium levels and subsequent vasoconstriction. Vasopressin also causes inactivation of the potassium–adenosine triphosphate (ATP) channels in vascular smooth muscle cells. Opening of these channels (as occurs with acidosis or hypoxia) allows an efflux of potassium from the endothelial cells, subsequent hyperpolarization, and prevention of calcium entry into the cells. (An increase in cytosolic calcium is essential for vasoconstriction.) In

Table 158-1  Vasopressin Receptors, Tissues Affected, and Principal Effects Receptor

Tissues

Principal Effects

V1 (V1a)

Vascular smooth muscle

Vasoconstriction at high dosages Vasodilation in cerebral, renal, pulmonary, and mesenteric vessels at low dosages

V2

Renal collecting duct Endothelial cells Platelets Vascular endothelium

Increased water permeability Increased von Willebrand factor release Stimulation of aggregation Vasodilation

V3 (V1b)

Pituitary

Adrenocorticotropic hormone release

Oxytocin

Uterus, mammary gland, Gastrointestinal tract Endothelium

Contraction Vasodilation

contrast, inactivation of the potassium–ATP channel by AVP leads to depolarization, opening of the voltage-gated calcium channels, and an increase in cytosolic calcium with subsequent vasoconstriction. Interestingly, vasodilation may occur in some vascular beds, most likely mediated by nitric oxide. V1Rs are found in the vascular endothelium of the kidney, skin, skeletal muscle, pancreas, thyroid gland, myometrium, bladder, hepatocytes, adipocytes, and spleen. Platelets also express the V1R, which facilitates thrombosis due to an increase in intracellular calcium upon stimulation. V1Rs in the kidneys lead to reduced blood flow to the inner medulla, limit the antidiuretic effects of AVP, and selectively cause contraction of the efferent arterioles to increase glomerular filtration rate. There is considerable variation among species with respect to the location and function of the V1R. V2 receptors (V2Rs) are found primarily on the basolateral membrane of the distal tubule and in the principal cells of the cortical and medullary renal collecting duct. Coupling of the V2R with the Gs signaling pathway increases intracellular cyclic adenosine monophosphate (cAMP). The increased cAMP triggers fusion of the aquaporin-2–bearing vesicles with the apical plasma membrane of the collecting duct principal cells to increase free water absorption. AVP regulates water homeostasis in two ways: (1) by regulating the fast shuttling of aquaporin-2 to the cell surface, and (2) by stimulating the synthesis of messenger ribonucleic acid–encoding aquaporin-2. Most animals with nephrogenic diabetes insipidus have V2R gene mutations. V2R activation also stimulates the release of platelets from the bone marrow and enhances the release of von Willebrand factor and factor VIII from endothelial cells. It causes a mild increase in the activity of factor VIII–related antigen and ristocetin cofactor. There are also V2Rs in the vascular endothelium; the potent V2R agonist 1-deamino-8-d-arginine vasopressin (DDAVP) therefore causes vasodilation in addition to the release of von Willebrand factor and factor VIII. The V3 pituitary receptors (V3Rs, previously known as V1bRs) are located in the anterior pituitary gland and activate Gq protein to release intracellular calcium after activation of phospholipase C and the phosphoinositol cascade. V3R activation stimulates release of adrenocorticotropic hormone.11 These receptors are also responsible for the actions of AVP on the central nervous system, where they act as a neurotransmitter or a modulator of memory, blood pressure, body temperature, sleep cycles, and release of pituitary hormones.

CHAPTER 158  •  Vasopressin

The oxytocin receptor is a nonselective vasopressin receptor with equal affinity for both AVP and oxytocin. Activation of the oxytocin receptor leads to smooth muscle contraction, primarily in the myometrium and mammary myoepithelial cells. AVP also acts on oxytocin receptors in the umbilical vein, aorta, and pulmonary artery, where it causes a nitric oxide–mediated vasodilation. Stimulation of cardiac oxytocin receptors leads to the release of atrial natriuretic peptide. Vasopressin also stimulates the P2 class of purinoreceptors (ATP receptors), which leads to vasodilation mediated by nitric oxide and prostacyclin. P2 receptors are also positive inotropic agents without direct effects on heart rate.

PHYSIOLOGIC EFFECTS OF VASOPRESSIN Vasopressin causes direct systemic vasoconstriction via the V1Rs. In vitro, AVP is a more potent vasoconstrictor than angiotensin II, norepinephrine, or phenylephrine on a molar basis. It is vital for osmoregulation and maintenance of normovolemia, mediated by the V2Rs. In addition, AVP maintains hemostasis and assists with temperature modulation, memory, sleep, and secretion of adrenocorticotropic hormone. During normal physiologic states, AVP’s primary role is the regulation of free water balance. Vasopressin levels in fasting humans are less than 4 pg/ml. Small increases in plasma osmolality lead to an increase in AVP to 10 pg/ml. A maximum increase in urine osmolality is seen with AVP levels greater than 20 pg/ml. Vasopressin does not control vascular smooth muscle constriction in normal animals, but it is vital in states of hypotension.11-13 Plasma AVP levels of 50 pg/ml must be attained before a significant increase in arterial pressure is achieved in humans. The pressor (vasoconstrictive) effects of AVP are nonadrenergic and are thought to be mediated by its direct and indirect effects on arterial smooth muscle. Stimulation of the V1R leads to vasoconstriction of the skin, skeletal muscles, fat, bladder, myometrium, liver, spleen, pancreas, and thyroid gland. Low levels of AVP lead to vasodilation in the cerebral, pulmonary, mesenteric, and renal vessels. Even with potent stimuli for release, only 10% to 20% of the AVP stored in the pituitary can be readily released, and further release occurs at a much slower rate that results in a biphasic response to vasodilatory shock.11

ingestion is very low.) It binds primarily to V2Rs and therefore has more potent antidiuretic and procoagulant activity and less vasopressor action than AVP on a per-weight basis. Both formulations of the drug should be stored in the refrigerator (although the nasal formulation is stable at room temperature for 3 weeks). Desmopressin acetate causes a dosage-dependent increase in plasma levels of factor VIII and plasminogen factor. It also causes smaller increases in factor VIII–related antigen and ristocetin cofactor activities, but the effect is sustained for only 3 to 4 hours. The onset of antidiuretic action in dogs usually occurs within 2 hour of administration, peaks in 2 to 8 hours, and may persist for up to 24 hours. The metabolism of desmopressin is not well understood. The terminal half-life in humans after intravenous administration ranges from 0.4 to 4 hours. Tolvaptan, a V2R antagonist, may have therapeutic potential in animals with congestive heart failure. It has been found to elicit a potent aquaretic response and reduce cardiac preload without causing the undesirable effects on systemic or renal hemodynamics, the renin-angiotensin-aldosterone system, or the sympathetic nervous system. Further research is underway.21-23

CLINICAL USES Indications and dosages for the use of vasopressin or DDAVP are summarized in Table 158-2.

Cardiopulmonary Resuscitation The use of AVP to manage cardiac arrest has been studied extensively in laboratory animals, and a meta-analysis found that AVP was at least equivalent to epinephrine in its ability to aid in the return of spontaneous circulation or survival in humans.24 A randomized, prospective clinical study in 60 dogs did not reveal an advantage in survival or 6-minute return of spontaneous circulation when AVP (0.5 to 1 U/kg) was compared with low-dose epinephrine (0.01 to 0.02 mg/kg). Further studies would be helpful, especially since the dose of AVP used in most of the dogs was below the recommended dose of 0.8 U/kg and the underlying disease states were extremely variable.25 Another observational study in canines reported a possible association between the use of AVP therapy and successful resuscitation.26 Additionally, experimental cardiopulmonary resuscitation studies in pigs showed that AVP improved cerebral oxygen delivery,

PHARMACOLOGY Exogenous AVP (8-arginine vasopressin) is sold as a sterile aqueous solution of synthetic AVP for intravenous, intramuscular, or subcutaneous administration. It is destroyed within the gastrointestinal tract and should only be given parenterally. It is not protein bound and has a volume of distribution of 140 ml/kg and a half-life of approximately 24 minutes. The drug is cleared by renal excretion (65%) and metabolism by tissue peptidases (35%). Terlipressin (triglycyl-lysine vasopressin) is a synthetic prodrug that is converted to lysine vasopressin in the circulation and has a greater V1R selectivity and prolonged duration of action, with an effective half-life of approximately 6 hours. To the author’s knowledge, this form of vasopressin has not been used clinically in veterinary medicine, but human and experimental research has advised caution due to potentially detrimental effects.14-17 Selepressin, a novel selective V1R, agonist has been studied in humans with septic shock and experimental sheep with sepsis, as well as in healthy research dogs.18-20 Healthy experimental dogs given selepressin were found to have a reduced risk of coronary ischemia compared with those given AVP.20 Desmopressin acetate is a synthetic vasopressin analog that is available in both an intranasal and an injectable form. (An oral tablet form is also manufactured, but the bioavailability following oral

Table 158-2  Indications for and Dosages of Vasopressin or DDAVP Therapy Indication

Dosage

Cardiopulmonary resuscitation

0.4-0.8 U/kg IV ± 1-4 mU/kg/min AVP IV CRI (dogs)*

Vasodilatory shock

0.5-5 mU/kg/min AVP IV CRI (dogs)*

Central diabetes insipidus

0.1 mg/ml intranasal solution DDAVP: 1-4 drops into conjunctival sac q12-24h or 0.01-0.05 ml SC q12-24h Alternatively, aqueous AVP may be used at 3-5 IU/dog or 0.5 IU/kg (cats) SC q4h or as needed

von Willebrand disease

1-4 mcg/kg DDAVP SC q3-4h (dogs)

Gastrointestinal disease, hemorrhagic shock

Unknown

AVP, Arginine vasopressin; CRI, constant rate infusion; DDAVP, 1-deamino8-D-arginine vasopressin; IV, intravenously; SC, subcutaneously. *Extrapolated from human dosage; dosage in cats is unknown.

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resuscitation success, neurologic outcome, and blood flow to major organs, compared with epinephrine. Vasopressin has been listed in the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care for the treatment of unstable ventricular tachycardia and ventricular fibrillation since 2000. The RECOVER veterinary guidelines also list AVP therapy (0.8 U/kg) as an acceptable alternative to epinephrine therapy during cardiopulmonary resuscitation in both dogs and cats.27 In a large human study comparing AVP with epinephrine, there was a significant increase in survival following asystolic arrest in patients given AVP.28 A recent pediatric study also revealed an increase in 24-hour survival (80% vs. 30%) in children experiencing cardiopulmonary arrest refractory to 1 dose of epinephrine.29 Vasopressin levels are elevated following cardiopulmonary arrest, and levels are significantly higher in humans who are resuscitated than in patients who do not survive.30 Vasopressin has a shorter duration of effect and produces a greater vasoconstrictive effect during hypoxic and acidemic episodes of cardiopulmonary arrest than does epinephrine. Results of its use in newborn piglets with experimentally induced severe hypoxia and reoxygenation are also very promising.31 In normal experimental animals, the half-life of AVP is 10 to 20 minutes.32 Extrapolated doses in dogs are 0.4 to 0.8 U/kg given intravenously, with a constant rate infusion of 1 to 4 mU/kg/min, if needed. Endobronchial administration has been studied in pigs. A systematic review and meta-analysis has been published.24

Vasodilatory Shock Vasopressin deficiency can play an important role in animals with vasoplegia secondary to sepsis, prolonged hemorrhagic shock, or cardiac arrest. Experimentally, exogenous AVP infusions to yield plasma AVP concentrations of 20 to 30 pg/ml can restore blood pressure with minimal adverse effects on organ perfusion. Low-flow states secondary to hypovolemia or septic shock are associated with a biphasic response in serum AVP levels. There is an early increase in the release of AVP from the neurohypophysis in response to hypoxia, hypotension, or acidosis that leads to high levels of serum AVP. This plays a role in the stabilization of arterial pressure and organ perfusion in the initial stages of shock. Agents that block the V1R lower arterial pressure in both acute hemorrhagic shock and septic shock. Previous studies in dogs have found concentrations of AVP in the range of 300 to 1000 pg/ml during the early phase of hemorrhagic shock and 500 to 1200 pg/ml following experimentally induced endotoxemia (further details are given later in this chapter). During the later phase of shock, however, the AVP levels are decreased, presumably as a result of degradation of released AVP and depletion of the neurohypophyseal stores, which take time to replenish through resynthesis. The AVP concentration in the experimental dogs decreased to 29 pg/ml during the late phase of hemorrhagic shock. Humans with advanced vasodilatory shock have both a deficiency of AVP secretion and an enhanced sensitivity to AVP-induced blood pressure changes. Additionally, AVP levels are markedly increased in animal models of acute sepsis, but this increase is followed by a rapid decline over the ensuing few hours. Additional hypotheses to explain the low levels of AVP include a decrease in baroreceptor stimulation of AVP release in hypotensive patients secondary to impaired autonomic reflexes, as seen in sepsis, or tonic inhibition by atrial stretch receptors secondary to volume loading or mechanical ventilation. In addition, AVP release may be inhibited by nitric oxide or high circulating levels of norepinephrine. Several human studies and reports have demonstrated promising results in the treatment of people with refractory hypotension using

an AVP intravenous infusion. Many human patients were subsequently weaned off catecholamine support by the addition of AVP therapy. In addition, there is an increase in urine output, presumably secondary to an increase in renal perfusion pressure due to renal efferent arteriolar constriction, as well as nitric oxide–induced vasodilation; oxytocin receptor stimulation, which increases natriuresis; and an increase in atrial natriuretic peptide. AVP therapy may also reduce the rate of progression of acute kidney injury to renal failure and decrease mortality in people with septic shock.33 Humans who received AVP therapy before their doses of norepinephrine exceeded 0.5 mg/kg/min had an improved outcome.34 A recent meta-analysis of publications between 1996 and 2011 showed a reduction in norepinephrine requirement in patients receiving AVP as well as reduced mortality rates in people with septic shock. There was no difference between the AVP treatment group and the control group in adverse events.35 Interestingly, people who received both physiologic levels of corticosteroids and AVP therapy had decreased mortality compared with those who were treated with norepinephrine and corticosteroids, or with either drug without corticosteroid therapy.36 Animal trials thus far support the potential benefits of AVP in animals in hypotensive states. However, high-dose therapy is associated with excessive coronary and splanchnic vasoconstriction, as well as a hypercoagulable state. The excessive vasoconstriction can lead to a reduction in cardiac output or even fatal cardiac events, especially in patients with decreased myocardial function. Guzman et al37 compared the effects of intravenous norepinephrine with those of intravenous AVP on systemic splanchnic and renal circulation in anesthetized dogs with experimentally induced endotoxic shock. Except for a more pronounced bradycardia in the AVP group, the systemic and splanchnic blood flow changes were comparable. However, the AVP infusion restored renal blood flow and oxygen delivery, but the norepinephrine therapy did not. These types of studies are not representative of patients that have catecholamineresistant hypotension, but the end-organ results are expected to be similar. Another canine study by Morales et al38 examined the effect of AVP administration in dogs with experimental hemorrhagic shock and subsequent requirement for a norepinephrine infusion (3 mcg/ kg/min) to maintain a mean arterial pressure of 40 mm Hg. An AVP infusion resulted in an increase in mean arterial pressures from 39 ± 6 mm Hg to 128 ± 9 mm Hg. The serum AVP levels were markedly elevated during the acute hemorrhage but decreased from 319 ± 66 to 29 ± 9 pg/ml before administration of AVP. Clinically, AVP has been used in dogs with refractory vasodilatory shock.39 A dosage of 0.5 mU/kg/min was administered intravenously and titrated higher as needed to achieve a mean arterial pressure above 70 mm Hg and a heart rate below 140 beats/min. There was a significant increase in mean arterial pressure with minimal adverse effects. The mean dosage used was 2.1 mU/kg/min. There is no information regarding survival because all of the dogs in this clinical study were euthanized or died.

Hemorrhagic Shock There have been several experimental animal studies and preliminary human clinical studies evaluating the use of AVP therapy for the treatment of hemorrhagic shock. Its ability to sustain arterial blood pressure and decrease blood loss during hemorrhage deserves further study. Because AVP redirects blood from the skin, skeletal muscle, and periphery, it minimizes blood loss from bleeding extremities. The suggestion that AVP therapy may replace fluid therapy has received much attention; administration of AVP decreased fluid requirements and mortality in one human trauma study,40 and further studies will be telling.

CHAPTER 158  •  Vasopressin

Central Diabetes Insipidus Animals with central diabetes insipidus and subsequent deficiency of endogenous AVP can benefit from treatment with either aqueous vasopressin or DDAVP. Caution should be exercised to prevent water intoxication, and serial electrolyte levels should be analyzed during treatment. DDAVP is often preferred because it has more antidiuretic activity and less potential vasopressor properties on a per-weight basis. One to four drops of the 0.1 mg/ml intranasal solution is typically given into the conjunctival sac q24h or q12h. Alternatively, subcutaneous doses of 0.01 to 0.05 ml can be used in dogs q12-24h. Aqueous vasopressin has been administered in subcutaneous doses of 3 to 5 U per dog or 0.5 U/kg in cats q4h or as needed (see Chapter 67).

von Willebrand Disease DDAVP may be useful in patients with von Willebrand disease, except in those animals with type IIB or platelet-type (pseudo) forms, because platelet aggregation and thrombocytopenia may occur. In addition, treatment with DDAVP is often confounded by its short duration of activity (2 to 4 hours), development of resistance, and expense. It is not effective for dogs with severe type II and III von Willebrand disease. Dosage is 1 to 4 mcg/kg of DDAVP subcutaneously q3-4h. Onset of activity is typically within 30 minutes, and the effects last approximately 2 hours. DDAVP can improve platelet function in a range of disease states in addition to von Willebrand disease (see Chapter 170).

Gastrointestinal and Pulmonary Disease Several uses of AVP in humans have not yet been studied in dogs. These include the acute treatment of esophageal varices and gastrointestinal hemorrhage, stimulation of peristalsis in patients with postoperative ileus, and dispelling of intestinal gas before abdominal imaging. AVP has also been shown to improve cardiopulmonary function in ovine acute lung injury secondary to burns and smoke inhalation.41 This looks like a promising area for further research.

ADVERSE EFFECTS AVP can cause contraction of the bladder and gallbladder smooth muscle and can increase peristalsis (especially of the colon). The drug may decrease gastric secretions and increase gastrointestinal sphincter pressure. Potential adverse effects of AVP administration include local irritation at the injection site, skin necrosis if extravasated, and skin reactions. Humans treated with AVP for vasodilatory shock have developed an increase in liver enzyme and bilirubin levels, decrease in platelet count, hyponatremia, anaphylaxis, bronchospasm, abdominal pain, hematuria, and urticaria, although the incidence of adverse effects appears to be quite low. Theoretically, because AVP causes a release of von Willebrand factor, it enhances platelet aggregation and may increase the risk of thrombosis. Water intoxication has been reported with high-dose therapy for the treatment of diabetes insipidus. Vasopressin or DDAVP may cause irritation when administered in the conjunctival sac.

VASOPRESSIN ANTAGONISTS Investigation into vasopressin antagonist therapy is currently underway for a variety of diseases. V1R antagonists may prove useful for the management of subarachnoid hemorrhage, whereas V2R antagonists may be preferable to the use of loop diuretics in people and dogs with congestive heart failure.22,42 A full review of these emerging

treatments is beyond the scope of this chapter, but vasopressin antagonists appear to hold great promise for the treatment of a variety of disease states in which elevated endogenous AVP levels are detrimental to the patient.

CONCLUSION Vasopressin is a drug with many actions, several receptors, and multiple therapeutic uses. It is important to understand the mechanisms of action of the various receptors and the mechanisms of action of the various formulations to treat animals safely and appropriately. The use of this drug in veterinary medicine is expanding as research in people and experimental models continues.

REFERENCES 1. Robinson A, Verbalis J: Posterior pituitary gland. In Larsen P, Kronenberg H, Melmed S, et al, editors: Williams textbook of endocrinology, Philadelphia, 2002, Saunders. 2. Hoyle CH: Neuropeptide families and their receptors: evolutionary perspectives, Brain Res 848:1, 1999. 3. Bourque CW, Oliet SH: Osmoreceptors in the central nervous system, Annu Rev Physiol 59:601, 1997. 4. Quail AW, Woods RL, Korner PI: Cardiac and arterial baroreceptor influences in release of vasopressin and renin during hemorrhage, Am J Physiol 252:H1120, 1987. 5. Norsk P, Ellegaard P, Videbaek R, et al: Arterial pulse pressure and vasopressin release in humans during lower body negative pressure, Am J Physiol 264:R1024, 1993. 6. Holmes CL, Landry DW, Granton JT: Science review: vasopressin and the cardiovascular system. Part 2: Clinical physiology, Crit Care 8:15, 2004. 7. Leng G, Dyball RE, Luckman SM: Mechanisms of vasopressin secretion, Horm Res 37:33, 1992. 8. Day TA, Sibbald JR: Noxious somatic stimuli excite neurosecretory vasopressin cells via A1 cell group, Am J Physiol 258:R1516, 1990. 9. Kam PC, Williams S, Yoong FF: Vasopressin and terlipressin: pharmacology and its clinical relevance, Anaesthesia 59:993, 2004. 10. Holmes CL, Landry DW, Granton JT: Science review: vasopressin and the cardiovascular system. Part 1: Receptor physiology, Crit Care 7:427, 2003. 11. Holmes CL, Patel BM, Russell JA, et al: Physiology of vasopressin relevant to management of septic shock, Chest 120:989, 2001. 12. Graybiel A, Glendy R: Circulatory effects following the intravenous administration of pitressin in normal persons and in patients with hypertension and angina pectoris, Am Heart J 21:481, 1941. 13. Schwartz J, Keil LC, Maselli J, et al: Role of vasopressin in blood pressure regulation during adrenal insufficiency, Endocrinology 112:234, 1983. 14. Singer M: Arginine vasopressin vs. terlipressin in the treatment of shock states, Best Pract Res Clin Anaesthesiol 22(2):359-368, 2008. 15. Lange M, Ertmer C, Westphal M: Vasopressin vs. terlipressin in the treatment of cardiovascular failure in sepsis, Intensive Care Med 34(5):821832, 2008. 16. Rodriguez-Nunez A, Lopez-Herce J, Gil-Anton J, et al: Rescue treatment with terlipressin in children with refractory septic shock: a clinical study, Crit Care 10(1):R20, 2006. 17. Ishikawa K, Wan L, Calzavacca P, et al: The effects of terlipressin on regional hemodynamics and kidney function in experimental hyperdynamic sepsis, PLoS One 7(2):e29693, 2012. 18. Russell J, Vincent JL, Kjølbye AL, et al: Selepressin, a novel selective vasopressin V1a agonist, reduces norepinephrine requirements and shortens duration of organ dysfunction in septic shock patients, Crit Care Med 40(12):62, 2012. 19. Rehberg S, Ertmer C, Vincent JL, et al: Role of selective V1a receptor agonism in ovine septic shock, Crit Care Med 39(1):119-125, 2011. 20. Boucheix OB, Milano SP, Henriksson M, et al: Selepressin, a new V1A receptor agonist: hemodynamic comparison to vasopressin in dogs, Shock 39(6):533-538, 2013. 21. Laszlo FA, Laszlo F Jr, De Wied D: Pharmacology and clinical perspectives of vasopressin antagonists, Pharmacol Rev 43:73, 1991.

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22. Onogawa T, Sakamoto Y, Nakamura S, et al: Effects of tolvaptan on systemic and renal hemodynamic function in dogs with congestive heart failure, Cardiovasc Drugs Ther 25(Suppl 1):S67-S76, 2011. 23. Gheorghiade M, Gattis WA, O’Connor CM, et al: Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: a randomized controlled trial, JAMA 291(16):1963-1971, 2004. 24. Aung K, Htay T: Vasopressin for cardiac arrest: a systematic review and meta-analysis, Arch Intern Med 165:17, 2005. 25. Buckley GJ, Rozanski EA, Rush JE: Randomized, blinded comparison of epinephrine and vasopressin for treatment of naturally occurring cardiopulmonary arrest in dogs, J Vet Intern Med 25(6):1334-1340, 2011. 26. Scroggin RD Jr, Quandt J: The use of vasopressin for treating vasodilatory shock and cardiopulmonary arrest, J Vet Emerg Crit Care (San Antonio) 19(2):145-157, 2009. 27. Rozanski EA, Rush JE, Buckley GJ, et al: RECOVER evidence and knowledge gap analysis on veterinary CPR. Part 4: Advanced life support, J Vet Emerg Crit Care (San Antonio) 22(Suppl 1):S44-S64, 2012. 28. Wenzel V, Krismer AC, Arntz HR, et al: A comparison of vasopressin and epinephrine for out-of-hospital cardiopulmonary resuscitation, N Engl J Med 350:105, 2004. 29. Carroll TG, Dimas VV, Raymond TT: Vasopressin rescue for in-pediatric intensive care unit cardiopulmonary arrest refractory to initial epinephrine dosing: a prospective feasibility pilot trial, Pediatr Crit Care Med 13(3):265-272, 2012. 30. Lindner KH, Strohmenger HU, Ensinger H, et al: Stress hormone response during and after cardiopulmonary resuscitation, Anesthesiology 77:662, 1992. 31. Cheung DC, Gill RS, Liu JQ, et al: Vasopressin improves systemic hemodynamics without compromising mesenteric perfusion in the resuscitation of asphyxiated newborn piglets: a dose-response study, Intensive Care Med 38(3):491-498, 2012.

32. Errington ML, Rocha e Silva M Jr: The secretion and clearance of vasopressin during the development of irreversible haemorrhagic shock, J Physiol 217:43P, 1971. 33. Gordon AC, Russell JA, Walley KR, et al: The effects of vasopressin on acute kidney injury in septic shock, Intensive Care Med 36(1):83-91, 2010. 34. Luckner G, Dunser MW, Jochberger S, et al: Arginine vasopressin in 316 patients with advanced vasodilatory shock, Crit Care Med 33:2659, 2005. 35. Serpa NA, Nassar AJ, Cardoso SO, et al: Vasopressin and terlipressin in adult vasodilatory shock: a systematic review and meta-analysis of nine randomized controlled trials, Crit Care 16(4):R154, 2012. 36. Russell JA, Walley KR, Gordon AC, et al: Interaction of vasopressin infusion, corticosteroid treatment, and mortality of septic shock, Crit Care Med 37(3):811-818, 2009. 37. Guzman JA, Rosado AE, Kruse JA: Vasopressin vs. norepinephrine in endotoxic shock: systemic, renal, and splanchnic hemodynamic and oxygen transport effects, J Appl Physiol 95:803, 2003. 38. Morales D, Madigan J, Cullinane S, et al: Reversal by vasopressin of intractable hypotension in the late phase of hemorrhagic shock, Circulation 100:226, 1999. 39. Silverstein DC, Waddell LS, Drobatz KJ, et al: Vasopressin therapy in dogs with dopamine-resistant hypotension and vasodilatory shock, J Vet Emerg Crit Care 17(4):399-408, 2007. 40. Cohn SM, McCarthy J, Stewart RM, et al: Impact of low-dose vasopressin on trauma outcome: prospective randomized study, World J Surg 35(2):430-439, 2011. 41. Westphal M, Rehberg S, Maybauer MO, et al: Cardiopulmonary effects of low-dose arginine vasopressin in ovine acute lung injury, Crit Care Med 39(2):357-363, 2011. 42. Hockel K, Scholler K, Trabold R, et al: Vasopressin V(1a) receptors mediate posthemorrhagic systemic hypertension thereby determining rebleeding rate and outcome after experimental subarachnoid hemorrhage, Stroke 43(1):227-232, 2012.

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PART XX  •  PHARMACOLOGY

CHAPTER 159  ANTIHYPERTENSIVES Mary Anna Labato,

DVM, DACVIM (Internal Medicine)

KEY POINTS • Clinically, hypertension is divided into two categories: primary and secondary. • Secondary hypertension accounts for almost all identified cases of elevated blood pressure in veterinary medicine. • Normal blood pressure values are not identical for dogs and cats. Normal values for dogs are breed specific to some degree. • Blood pressure values in the dog higher than 150/95 mm Hg (systolic/diastolic) and/or 115 mm Hg (mean) on three separate occasions are consistent with hypertension. For cats, arterial pressures higher than 135/100 mm Hg (mean, 115 mm Hg) on three separate occasions are consistent with hypertension. • A blood pressure higher than 150/95 mm Hg (mean, 115 mm Hg) on a single occasion in a patient with evidence of organ damage is compatible with hypertension and should be addressed. If the blood pressure exceeds 180/120 mm Hg (mean, 140 mm Hg) , emergent therapy to lower blood pressure should be instituted.

• There are a number of classes of substances used for antihypertensive therapy, and often multiple modalities are necessary. • Angiotensin-converting enzyme inhibitors and calcium channel blockers are the most commonly used antihypertensive agents in veterinary medicine.

The definition of normal blood pressure in dogs and cats has been quite elusive. It has been the subject of significant research, debate, and confusion.1 Normal values for dogs have been shown to be somewhat breed specific, whereas for cats blood pressure values are not related to breed.2 The pressure defining hypertension has been lowered in recent years. At this time, blood pressure values higher than 150/95 mm Hg

CHAPTER 159  •  Antihypertensives

(mean, 115 mm Hg) on three separate visits in a patient that demonstrates no clinical signs are considered compatible with hypertension; in addition, a single reading higher than 150/95 mm Hg (mean, >115 mm Hg) in a patient with evidence of clinical disease in those organs susceptible to end-organ damage (e.g., brain, eyes, kidneys) is also deemed to be hypertension requiring treatment. A blood pressure measurement higher than 180/120 mm Hg (mean arterial pressure, >140 mm Hg) is a medical emergency and must be treated as soon as possible.1,3-5

ETIOLOGY OF HYPERTENSION Patients are classified as having primary (essential) or secondary hypertension. In the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure in humans, a third category termed prehypertension was established.6 Prehypertension is defined as a systolic blood pressure ranging from 120 to 139 mm Hg and/or a diastolic pressure of 80 to 89 mm Hg. This new designation is intended to identify those individuals in whom early intervention such as changing to a healthy lifestyle and diet could reduce blood pressure or decrease the rate of progression of blood pressure to hypertensive levels.6 Primary hypertension is the result of an imbalance in the relationship between cardiac output and systemic vascular resistance. The exact cause has not been determined. Little is known about the prevalence of primary hypertension in animals. There have been reports of both dogs and cats considered to have primary hypertension because secondary causes could not be identified.7-10 Secondary hypertension is elevated blood pressure that occurs because of systemic disease or medication. Secondary hypertension accounts for almost all identified cases of elevated blood pressure in veterinary patients. The following disorders have been reported to be associated with a significant risk of developing hypertension: kidney disease, diabetes mellitus, hyperadrenocorticism, hyperthyroidism, and hepatic disease. Additionally, more uncommon causes include pheochromocytoma, hyperaldosteronism, polycythemia, and chronic anemia. The use of drugs such as erythropoietin and glucocorticoids has also been associated with elevations in blood pressure.8-16

PROPOSED MECHANISM OF BLOOD PRESSURE ELEVATION A number of diseases and a variety of causes have been associated with elevations in blood pressure. In patients with hyperadrenocorticism, glucocorticoids induce hepatic production of angiotensinogen, which results in an exaggerated response of the renin-angiotensin system.11 The hypertension that develops in animals with hyperthyroidism is secondary to the increased cardiac output caused by the effect of thyroid hormone on cardiac muscle.15-20 The two predominant mechanisms of renal regulation of blood pressure are pressure natriuresis and the renin-angiotensin-aldosterone system.5 It has been hypothesized that increased blood volume secondary to either a maladaptive increase in renin secretion or inability of the kidneys to process fluids and electrolytes properly may lead to increased venous return of blood to the heart.14 Increased levels of endogenous vasoconstrictors such as endothelin, thromboxane, and adrenergic stimuli combined with decreased levels of endogenous vasodilators such as prostacyclin and nitric oxide may also be contributing factors. The mechanism by which hepatic disease results in hypertension is undetermined. In patients with diabetes mellitus, there are possibly four different mechanisms. In humans with type 1 diabetes, hypertension is thought to develop due to the effects of diabetes on renal

function (i.e., diabetic nephropathy characterized by nephritic syndrome and glomerulosclerosis). For type 2 diabetes three different mechanisms have been proposed.17 One suggested mechanism is that hyperinsulinemia secondary to insulin resistance causes sodium and water retention and increased sympathetic activity. This leads to increased peripheral resistance via changes in blood volume and vasoconstriction, respectively. The second proposed mechanism is that there is hypertrophy of vascular smooth muscle secondary to the mitogenic effects of insulin. The last mechanism that has been proposed is that elevations in insulin levels lead to increased levels of intracellular calcium. The increased calcium results in hyperresponsive vascular smooth muscle contraction and increased peripheral vascular resistance. Chromocytomas release epinephrine and norepinephrine, which results in vasoconstriction and increased cardiac output (see Chapter 71).18 The administration of erythropoietin has been associated with the development of hypertension. Anemia leads to chronically dilated capillary beds. With resolution of the anemia, overcompensation of capillary constriction occurs, which results in an increase in peripheral vascular resistance.19

ANTIHYPERTENSIVE DRUGS Angiotensin-Converting Enzyme Inhibitors Mechanism of action Angiotensin-converting enzyme (ACE) inhibitors are often used as the initial treatment of choice to control hypertension. ACE inhibitors competitively inhibit the conversion of angiotensin I to angiotensin II. Angiotensin II is one of the most powerful endogenous vasoconstrictors; its inhibition results in systemic vasodilation (Table 159-1). The primary effects of ACE inhibitors result in a decrease in angiotensin I and II as well as an increase in bradykinin. Drugs in this class induce arterial and venous vasodilation. Since angiotensin II directly stimulates the kidneys to retain sodium, its inhibition results in a reduced plasma volume. In addition, ACE inhibitors prevent aldosterone release, which leads to a decrease in sodium and water retention and decreased blood volume. There is a reduction in both preload and afterload. The other beneficial effect of ACE inhibitors is that they reduce intraglomerular pressure and inhibit growth factors that lead to glomerular hypertrophy and sclerosis.1,21-26

Indications ACE inhibitors are used to reduce blood pressure in all forms of hypertension. They are also used frequently in the treatment of mitral insufficiency and congestive heart failure due to dilated cardiomyopathy. ACE inhibitors also appear to reduce proteinuria by maintaining the heparan sulfate layer of the glomerular basement membrane. For example, benazepril administration has been associated with (1) lowering of glomerular capillary hypertension, (2) decreased release of extracellular matrix and collagen from mesangial and tubular cells, and (3) reduction in the degree of glomerular and interstitial fibrosis.27,28 Although there are a number of different ACE inhibitors, the ones used most commonly in veterinary medicine are enalapril, benazepril, ramipril, and lisinopril (Table 159-2). The effects of ACE inhibitors are less predictable in cats. As many as 50% of hypertensive cats do not respond to enalapril, although benazepril has demonstrated a statistically significant antihypertensive effect in cats with kidney disease.1

Adverse effects ACE inhibitors are relatively safe drugs. Adverse effects include weakness and lethargy attributable to a drop in blood pressure. Reversible

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PART XX  •  PHARMACOLOGY

Table 159-1  Summary of Antihypertensive Drugs Drug

Effect

Indications

Angiotensin-converting enzyme inhibitors Benazepril, enalapril, lisinopril, enalaprilat

Arterial and venous vasodilation Decreased preload Decreased afterload

Hypertension Heart failure Proteinuria

Calcium channel blockers Amlodipine, nicardipine

Arterial vasodilation

Hypertension Hypertensive crisis

β-adrenergic antagonists Propranolol, atenolol

Decreased cardiac output Decreased sympathetic outflow Decreased blood pressure Cardiodepression Nonselective (β1 and β2) Cardioselective (β1)

Hypertension Hypertrophic cardiomyopathy Arrhythmias Pheochromocytoma

α-Adrenergic antagonist Prazosin

Balanced vasodilation

Hypertension Pheochromocytoma

Arteriolar vasodilator Hydralazine

Nonspecific arterial vasodilation Reduced peripheral vascular resistance Reduced blood pressure

Hypertension Hypertensive crisis

Arteriolar vasodilator Sodium nitroprusside

Nitric oxide donor Vasodilation

Hypertensive crisis

Angiotensin II receptor blockers Losartan, irbesartan, telmisartan

Arterial and venous vasodilation

Hypertension

Aldosterone blockers Spironolactone, eplerenone

Vasodilation

Hypertension Proteinuria

Dopamine-1 agonist Fenoldopam

Vasodilation Decreased blood pressure Natriuresis Increase in renal blood flow

Hypertension Hypertensive crisis Acute kidney injury

Table 159-2  Commonly Used Antihypertensive Agents and Their Dosages Drug

Class

Canine Dosage

Feline Dosage

Amlodipine

Calcium channel blocker

0.05-0.2 mg/kg q24h PO or rectally

0.625-1.25 mg q24h PO or rectally

Atenolol

β-Adrenergic blocker

0.25-1 mg/kg q12-24h PO

6.25-12.5 mg q12-24h PO

Benazepril

ACE inhibitor

0.25-0.5 mg/kg q12-24h PO

0.25-0.5 mg/kg q12-24h PO

Enalapril

ACE inhibitor

0.5-1.0 mg/kg q12-24h PO

0.25-0.5 mg/kg q12-24h PO

Enalaprilat

ACE inhibitor

0.1-1.0 mg q6h IV

Unknown

Propranolol

β-Adrenergic blocker

0.04-0.1 mg/kg q8-12h IV or 0.5-1 mg/kg q8-12h PO

0.02-0.06 mg/kg q8-12h IV or 0.2-1.0 mg/kg q8-12h PO

Prazosin

α-Adrenergic blocker

0.5-4 mg q8-12h PO

0.25-0.5 mg/cat q12-24h PO

Spironolactone

Aldosterone inhibitor

1-2 mg/kg q12h PO

1 mg/kg q12h PO

Hydralazine

Arterial vasodilator

0.25-4 mg/kg q12h

0.25-2 mg/kg q12h

Sodium nitroprusside

Nonspecific vasodilator

1-3 mcg/kg/min IV CRI

1-2 mcg/kg/min IV CRI

Losartan

Angiotensin II receptor blocker

0.5 mg/kg q24h

Unknown

Lisinopril

ACE inhibitor

0.25-0.75 mg/kg q24h PO

0.25-0.5 mg/kg q24h PO

Fenoldopam

Dopamine-1 agonist

0.1-0.8 mcg/kg/min IV CRI

0.1-0.8 mcg/kg/min IV CRI

Nicardipine

Calcium channel blocker

0.5-5 mcg/kg/min IV CRI

Unknown

Ramipril

ACE inhibitor

0.125-0.25 mg/kg q24h PO

Unknown

Irbesartan

Angiotensin II receptor blocker

5 mg/kg q24h PO

Unknown

Telmisartan

Angiotensin II receptor blocker

1.0-3.0 mg/kg q24h PO

Unknown

ACE, Angiotensin-converting enzyme; CRI, constant rate infusion; IV, intravenously; PO, per os.

CHAPTER 159  •  Antihypertensives

increases in blood urea nitrogen and creatinine levels may result from a reduction in kidney function (which causes reversible elevation of creatinine and blood urea nitrogen levels and decrease in glomerular filtration rate). These effects are especially likely if ACE inhibitors are used in conjunction with diuretics. Hyperkalemia frequently occurs secondary to aldosterone inhibition. A rare adverse effect is the production of a dry cough induced by bradykinin.

blood pressure. They are also used to manage hypertrophic cardiomyopathy and supraventricular and ventricular tachycardias. α-Adrenergic antagonists have been used as primary or adjunctive therapy for hypertension in dogs. However, these agents have found greater use in micturition disorders as smooth muscle relaxants of the urethra and for the treatment of hypertension associated with pheochromocytomas.

Angiotensin II Receptor Blockers Mechanism of action

Adverse effects

Angiotensin II receptor blockers (ARBs) have been shown to be well tolerated, safe, and effective for blood pressure control in humans. Several studies have demonstrated that this class of drugs confers renal benefits in people with diabetic nephropathy. It is controversial whether ARBs are better at protecting the kidney than ACE inhibitors in patients with type 2 diabetes mellitus.23 Signaling through both angiotensin type 1 receptors (AT1Rs) and dopamine D1 receptors (D1Rs) modulates renal sodium excretion and arterial blood pressure. Thus the antihypertensive effect may be due to both inhibition of AT1R signaling and enhancement of D1R signaling.29 ARBs displace angiotensin II from its specific AT1R, antagonizing all of its known effects (i.e., vasoconstriction, sympathetic activation, aldosterone release, renal sodium resorption) and resulting in a dosedependent fall in peripheral resistance and little change in heart rate or cardiac output.30

Indications In humans, ARBs (losartan, irbesartan, telmisartan) are used to treat hypertension and cardiovascular disease. Their efficacy for the treatment of hypertension in dogs and cats is not known. Losartan, telmisartan, and irbesartan have been used in dogs, but more investigation into their role in the veterinary armamentarium is necessary. Losartan was ineffective as an antihypertensive agent in cats with experimentally induced kidney hypertension.5,31

Adverse effects This class of drugs appears to be safe with few adverse effects. In virtually every human trial, ARBs given to hypertensive patients have been better tolerated than other classes of antihypertensive medications.30

Adrenergic Receptor Antagonists Mechanism of action Drugs that may be useful in the treatment of hypertension are those that block activation of α- adrenergic or β-adrenergic receptors. Propranolol, a β1- and β2-adrenergic receptor antagonist; atenolol, a β1-selective antagonist; and prazosin, an α1-adrenergic receptor antagonist have been used to treat hypertension in dogs and cats. The mechanism of action of β-adrenergic blocking agents includes blockade of renin release, reduction of heart rate and contractility, decrease in peripheral vascular resistance, and reduction in central adrenergic drive.1,30 α-Adrenergic blockers exert their antihypertensive effects by selectively antagonizing α-adrenergic receptors on systemic vessels. Prazosin acts as a competitive antagonist of postsynaptic α1-receptors. It blocks activation of the postsynaptic α1-receptors by circulating or neurally released catecholamines, an activation that normally induces vasoconstriction. Peripheral resistance falls with minimal changes in cardiac output.1,30

Indications β-Adrenergic blockers are useful in dogs and cats when primary antihypertensive treatment fails to produce the desired decrease in

Nonselective β-adrenergic blockers, such as propranolol, should not be used in asthmatic cats because they may induce bronchospasm. Additional adverse effects include hyperkalemia, bradycardia, insulin resistance, and depression. Some of these adverse effects occur because the antagonists are not selective for β-receptors or α-receptors. Prazosin, and other α-adrenergic antagonists, selectively block vascular α1-receptors and may cause severe hypotension that is unresponsive to α1-agonist therapy. Consequently, caution should be exercised when anesthetizing patients that are receiving prazosin therapy.

Aldosterone Blockers Mechanism of action and indications The aldosterone antagonist spironolactone blocks the effects of aldosterone on the renal distal convoluted tubule and collecting duct and thereby decreases sodium reabsorption and potassium excretion. Its antihypertensive effects arise not only from its action as a weak diuretic but from its effect on the renin-angiotensin-aldosterone system. It is useful in treating hyperaldosteronism, iatrogenic steroid edema, and refractory edema, and may be used in conjunction with other diuretics. Aldosterone is a mineralocorticoid that regulates sodium and potassium balance in its target tissues (kidney, colon, salivary gland). Mineralocorticoid receptors have been discovered in fibroblasts in cardiac, endothelial, vascular smooth muscle, and brain cells. Aldosterone is considered proinflammatory and profibrotic and causes endothelial dysfunction secondary to vasoconstriction and vascular remodeling. It plays a role in mediating hypertension and kidney injury.28 Eplerenone is a novel agent that antagonizes the aldosterone receptor. Its use has been associated with severe hyperkalemia, so potassium levels must be monitored closely. Its major advantage over the nonselective aldosterone receptor antagonist spironolactone is the lack of binding to progesterone and androgen receptors. It has been approved for the treatment of hypertension in people. Aldosterone blockers also have been experimentally shown to reduce proteinuria and attenuate kidney injury by decreasing renal fibrosis and decreasing inflammation.32,33

Adverse effects Hyperkalemia may occur with either spironolactone or eplerenone but is uncommon in the absence of kidney insufficiency or concomitant use of a β-blocker, ACE inhibitor, ARB, or potassium supplements.

Calcium Channel Blockers Mechanism of action Calcium channel blockers (CCBs) act by blocking the influx of calcium into vascular smooth muscle cells that is necessary to cause smooth muscle contraction and thereby decreasing systemic vascular resistance.21 These drugs inhibit the slow transmembrane calcium influx into the cell via voltage-gated L-type calcium channels.34 The selectivity of the vascular and cardiac effects of the different CCBs varies. Those drugs that cause vasodilation at arterioles and

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coronary arteries lead to a reduction of peripheral resistance and a decrease in blood pressure. Those that have negative chronotropic, negative dromotropic, and negative inotropic actions have antiarrhythmic and cardiodepressant effects.22 The dihydropyridines (amlodipine, manidipine, nicardipine, nifedipine, nimodipine, nitrendipine) are the family of CCBs that primarily act on blood vessels.22 They relax the vascular smooth muscles (in arteries, arterioles, and coronary arteries) and exert minimal direct effect on the heart. Dihydropyridines may produce arterial vasodilation and reflex tachycardia.

Indications The indications for the use of CCBs are hypertension and hypertensive crises. Amlodipine is considered the drug of choice to treat hypertension in cats with chronic kidney disease. Amlodipine is long acting, which allows once-daily dosing, and has a gradual effect that prevents rapid reductions in blood pressure. In animals that cannot tolerate oral medications, rectal amlodipine administration has been used, although the pharmacokinetic data are lacking. A recent study in dogs with acute kidney injury suggested that amlodipine was beneficial in reducing systemic hypertension in this species.35

Adverse effects Adverse effects noted with CCBs are tachycardia, nausea, constipation, and weakness. There is concern about using a CCB as a primary antihypertensive agent. CCBs were thought to have renoprotective effects equivalent to those of the ACE inhibitors. However, studies have shown that the afferent arteriolar vasodilation is greater than the efferent arteriolar vasodilation on the opposite side of the glomerulus, and this decrease in perfusion pressure may actually decrease glomerular filtration and, at higher dosages, lead to kidney damage.1,21,34

Arteriolar Vasodilators Hydralazine Mechanism of action and indications Hydralazine is an arteriolar dilator acting directly on the smooth muscle of arterioles by mechanisms that are incompletely understood but result in reduced peripheral vascular resistance and reduced blood pressure. Although not a first-choice antihypertensive drug for patients with chronic kidney disease, hydralazine has been used to treat hypertension in dogs and cats, especially in cases of a hypertensive crisis. Sodium retention and reflex tachycardia may occur. Hydralazine has been known to act as an antioxidant, inhibiting vascular production of reactive oxygen species.30 Hydralazine may induce arteriolar vasodilation by preventing oxidation of nitric oxide and thereby lowering blood pressure.30

Adverse effects

light-chain kinase. This in turn decreases the phosphorylation of myosin light chains, which decreases smooth muscle contraction and causes vasodilation. Sodium nitroprusside induces minimal change in renal blood flow and only a slight increase in heart rate. It is indicated for treatment of a hypertensive crisis, rapid reduction of preload and afterload in acute heart failure, and controlled blood pressure reduction during surgery. Because of its high potency, it should be used only if blood pressure can be closely monitored.1,22,30,36,37

Adverse effects

Shock and severe hypotension may occur. Cyanide intoxication may be seen in patients who have reduced hepatic function or receive nitroprusside for prolonged periods of time or in high dosages. Upon infusion, sodium nitroprusside oxidizes sulfhydryl groups present in erythrocytes and cell membranes or reacts with hemoglobin to produce methemoglobin. This reaction results in the production of nitric oxide (as well as five cyanide groups), which leads to direct vasodilation through the action on vascular smooth muscle. Free cyanide is converted to thiocyanate by either thiocyanate oxidase within erythrocytes or a transsulfuration reaction with thiosulfate by the rhodanese enzyme in the liver.38 Thiocyanate is freely filtered at the glomerulus, which results in definitive elimination. Both cyanide and thiocyanate are toxic and are of concern in patients with renal insufficiency (decreased thiocyanate clearance), patients with liver insufficiency (decreased thiosulfate stores and decreased metabolism), and patients receiving diuretics (decreased thiosulfate and decreased metabolism). In addition, neonatal and geriatric patients may have reduced rhodanese enzyme levels and cyanide metabolism. Due to the greater sensitivity of feline patients to erythrocyte oxidative damage, the total dose and rate of infusion must be lower than in canine patients. Clinical signs of cyanide toxicity include the development of nitroprusside resistance, depression and stupor, seizures, and metabolic acidosis (increased lactate level and increased venous oxygen tension) due to the inhibition of mitochondrial cytochrome c oxidase. Similar clinical signs result from thiocyanate toxicity.38 Treatment of cyanide toxicity typically includes discontinuation of the drug and hydroxocobalamin therapy. This form of vitamin B12 binds to the cyanide in the vascular space and cells to form cyanocobalamin. Exogenous thiosulfate and nitrite administration may be necessary in severe cases, but potential adverse effects limit their use. When sodium nitroprusside is used, it is imperative to monitor carefully, administer cautiously, or try other options in patients with kidney or liver dysfunction and to give the drug for only short periods of time.

Fenoldopam Mechanism of action

In humans three kinds of adverse effects are seen. The first kind is due to a reflex sympathetic activation. The second type involves a lupus-like reaction. The third kind includes nonspecific problems such as anorexia, nausea, vomiting, diarrhea, muscle cramps, and tremor. In veterinary medicine, adverse effects have primarily included a reflex tachycardia, weakness, and gastrointestinal upset.

Fenoldopam is a peripheral dopamine-1 agonist and is a parenteral antihypertensive agent. It maintains or increases renal perfusion while lowering blood pressure. It maintains most of its efficacy for 48 hours as a constant rate infusion without rebound hypertension on discontinuation.36,37 There is a paucity of data on the use of fenoldopam in clinical veterinary patients, most likely due to the cost of this drug.

Sodium Nitroprusside

Indications

Mechanism of action and indications

The indications for fenoldopam are severe hypertension and hypertensive crisis. The drug may also be useful in the management and prevention of certain forms of acute kidney injury with oligoanuria.37

Sodium nitroprusside is a nonspecific vasodilator and a potent antihypertensive agent that brings about immediate relaxation of resistance and capacitance vessels. This is the result of nitric oxide release, which stimulates the production of cyclic guanine monophosphate (cGMP) in the vascular smooth muscle. cGMP activates a kinase that subsequently leads to the inhibition of calcium influx into the smooth muscle cell and decreased calcium-calmodulin stimulation of myosin

Adverse effects Adverse effects include reflex tachycardia and increased intraocular pressure. In humans, headache and flushing is also reported.37

CHAPTER 159  •  Antihypertensives

HYPERTENSIVE URGENCY A hypertensive urgency exists when there is a marked elevation in blood pressure but the animal does not demonstrate clinical signs directly attributed to the elevation. The patient is in danger of developing end-organ damage or a vascular accident such as hemorrhage or intravascular coagulation. In these animals it is imperative that blood pressure be lowered, but this should be done in a gradual and controlled fashion.

Treatment of Hypertensive Urgency Most identified cases of hypertension in veterinary medicine are secondary to other disease processes. The first course of action is to determine the predisposing cause and to institute appropriate therapy. In addition to treatment of the underlying disease, an antihypertensive drug therapy protocol needs to be incorporated for most patients. An important principle in treating hypertension is to allow 1 to 2 weeks before evaluating the efficacy of a particular drug or dosage adjustment.1 The therapeutic goal is not to normalize blood pressure but rather to lower systolic blood pressure to 170 mm Hg or less, mean arterial pressure to 140 mm Hg or less, and/or diastolic pressure to 100 mm Hg or less.

HYPERTENSIVE EMERGENCY A hypertensive emergency occurs when the animal has a marked elevation in blood pressure as well as clinical signs directly attributable to hypertension. These patients should be treated quickly and require monitoring in a critical care facility.11,21 According to the current recommendations for people as outlined in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, the initial goal of therapy in hypertensive emergencies is to reduce mean arterial blood pressure by no more than 25% (within minutes to 1 hour); then, if the patient’s condition is stable, to reduce blood pressure to 160/100 to 160/110 mm Hg within the next 2 to 6 hours. Excessive falls in pressure that may precipitate renal, cerebral, or coronary ischemia should be avoided.6

Treatment of Hypertensive Emergency Hypertensive emergencies should be treated at facilities that provide 24-hour critical care. Continuous blood pressure monitoring is imperative, preferably using direct arterial pressure monitoring, although indirect methods are also acceptable (see Chapter 183). Potentially dangerous medications such as nitroprusside and hydralazine may be used. Sodium nitroprusside is a potent arterial and venous dilator that may begin to act in seconds and has a half-life of 2 to 3 minutes. It needs to be administered as a constant rate infusion. Hydralazine is a rapid arteriolar dilator with unpredictable effects and has been associated with profound episodes of hypotension.1 Nicardipine, a dihydropyridine calcium channel–blocking agent, is another fast-acting, injectable antihypertensive agent with minimal cardiac effects. Enalaprilat is a parenteral ACE inhibitor similar in action to enalapril; however, it is fast acting. It is used in hypertensive emergencies. The dosage in human medicine is 0.625 to 1.25 mg intravenously over 5 minutes q6h. The dosage has been extrapolated for use in veterinary medicine, and the author uses 0.1 to 1.0 mg q6h intravenously.37

REFERENCES 1. Acierno MJ, Labato MA: Hypertension in dogs and cats, Compend Contin Educ Pract Vet 26(5):336, 2004.

2. Egner B: Blood pressure measurement. In Egner B, Carr A, Brown S, editors: Essential facts of blood pressure in dogs and cats, ed 3, Babenhauser, Germany, 2003, BE VetVerlag. 3. Kraft W, Egner B: Causes and effects of hypertension. In Egner B, Carr A, Brown S, editors: Essential facts of blood pressure in dogs and cats, ed 3, Babenhauser, Germany, 2003, BE VetVerlag. 4. Brown S, Atkins C, Bagley R, et al: Guidelines for the identification, evaluation and management of systemic hypertension in dogs and cats, J Vet Intern Med 21(3):542-558, 2007. 5. Syme H: Hypertension in small animal kidney disease, Vet Clin North Am Small Anim Pract 41:63-89, 2011. 6. Chobanian AV, Barkus GL, Black HR, et al: Seventh report of the joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, Hypertension 42:1206, 2003. 7. Bovee KC, Littman MP, Crabtree GJ, et al: Essential hypertension in a dog, J Am Vet Med Assoc 195(1):81, 1989. 8. Snyder PS, Henik RA: Feline systemic hypertension, Proc Twelfth Annual Vet Med Forum, San Francisco, p 126, 1994. 9. Morgan RV: Systemic hypertension in four cats: ocular and medical findings, J Am Anim Hosp Assoc 22:615, 1986. 10. Jepson R: Feline systemic hypertension: classification and pathogenesis, J Feline Med Surg 13:25-34, 2011. 11. Brown SA, Henik RA: Diagnosis and treatment of systemic hypertension, Vet Clin North Am Small Anim Pract 28(6):1481, 1998. 12. Stiles J, Polzen DJ, Bistmer SL: The prevalence of retinopathy in cats with systemic hypertension and chronic renal failure or hyperthyroidism, J Am Hosp Assoc 30(6):564, 1994. 13. Syme HM, Barber PJ, Markwell PJ, et al: Prevalence of systolic hypertension in cats with chronic renal failure at initial evaluation, J Am Vet Med Assoc 220(12):1799, 2002. 14. Bartges JW, Willis AM, Polzen DJ: Hypertension and renal disease, Vet Clin North Am Small Animal Pract 26(6):1331, 1996. 15. Panciera DC: Cardiovascular complications of thyroid disease. In Bonagura JD, editor: Kirk’s current veterinary therapy XIII, ed 13, Philadelphia, 2000, Saunders, p 716. 16. Littman MP: Spontaneous systemic hypertension in 24 cats, J Vet Intern Med 8(2):79, 1994. 17. Struble AL, Feldman EC, Nelson RW, et al: Systemic hypertension and proteinuria in dogs with diabetes mellitus, J Am Vet Med Assoc 213(6):822, 1998. 18. Mellian C, Peterson ME: The incidentally discovered adrenal mass. In Bonagura JD, editor: Kirk’s current veterinary therapy XIII, ed 13, Philadelphia, 2000, Saunders p 368. 19. Cowgill LD, James KM, Levy JK, et al: Use of recombinant human erythropoietin for management of anemia in dogs and cats with renal failure, J Am Vet Med Assoc 212(4):521, 1998. 20. Maggio F, DeFrancesco TC, Atkins CE, et al: Ocular lesions associated with systemic hypertension in cats: 69 cases (1985-1998), J Am Vet Med Assoc 217(5):695-702, 2000. 21. Brown SA, Henik RA: Therapy for systemic hypertension in dogs and cats. In Bonagura JD, editor: Kirk’s current veterinary therapy XIII, ed 13, Philadelphia, 2000, Saunders, p 838. 22. Ungemach FR: Hypertension. In Egner B, Carr A, Brown S, editors: Essential facts of blood pressure in dogs and cats, ed 3, Babenhauser, Germany, 2003, BE VetVerlag. 23. Messerli FH, Grossman E: Therapeutic controversies in hypertension, Semin Nephrol 25:227, 2005. 24. Steele JL, Henik RA, Stepien RL: Effects of angiotensin-converting enzyme inhibitor on plasma aldosterone concentration, plasma rennin activity, and blood pressure in spontaneously hypertensive cats with chronic renal disease, Vet Ther 3(2):157, 2002. 25. Brown SA, Brown CA, Jacobs G, et al: Effects of the angiotensin converting enzyme inhibitor benazepril in cats with induced renal insufficiency, Am J Vet Res 62(3):375, 2001. 26. Chetboul V, Lefebvre HP, Pinhas C, et al: Spontaneous feline hypertension: clinical and echocardiographic abnormalities, and survival rate, J Vet Intern Med 17:89, 2003. 27. Tenhundefeld J, Wefstaedt P, Nolte IJ: A randomized controlled clinical trial of the use of benazepril and heparin for the treatment of chronic kidney disease in dogs, J Am Vet Med Assoc 234 (8):1031-1037, 2009.

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28. Buoncompagni S, Bowles MH: Treatment of systemic hypertension associated with kidney disease, Compend Contin Educ Vet 35(5):E1-E6, 2013. 29. Dong L, Scott L, Crambert S, et al: Binding of losartan to angiotensin AT I receptors increases dopamine D1 receptor activation, J Am Soc Nephrol 23(3):42-48, 2012. 30. Kaplan NM: Treatment of hypertension: drug therapy. In Kaplan’s clinical hypertension, ed 9, Philadelphia, 2006, Lippincott Williams & Wilkins, p 217. 31. Reynolds V, Mathur S, Sheldon S, et al: Losartan fails to block angiotensin pressor response in cats. ACVIM Forum, J Vet Intern Med 16(3):341, 2002. 32. Epstein M: Aldosterone as a mediator of progressive renal disease: pathology and clinical implications, Am J Kidney Dis 36:677, 2001. 33. Hostetter TH, Ibrahim HN: Aldosterone in chronic kidney and cardiac disease, J Am Soc Nephrol 14:2395, 2003.

34. Mathur SM, Syme H, Brown CA, et al: Effects of the calcium channel antagonist amlodipine in cats with surgically induced hypertensive renal insufficiency, Am J Vet Res 63(6):833, 2002. 35. Geigy CA, Schweighauser A, Doherr M, et al: Occurrence of systemic hypertension in dogs with acute kidney injury and treatment with amlodipine besylate, J Small Anim Pract 52(7):340-346, 2011. 36. Kaplan NM: Hypertensive crises. In Kaplan’s clinical hypertension, ed 9, Philadelphia, 2006, Lippincott Williams & Wilkins, p 311. 37. Fenves AZ, Ram CVS: Drug treatment of hypertensive urgencies and emergencies, Semin Nephrol 25:272, 2005. 38. Proulx J: Intensive management of heart failure. In Proceedings of the 75th Western Veterinary Conference, 2003, Las Vegas, Nevada.

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PART XX  •  PHARMACOLOGY

CHAPTER 160  DIURETICS Thierry Francey,

DrMedVet, DACVIM

KEY POINTS • A thorough clinical and laboratory evaluation is necessary to define clear therapeutic goals for diuretic therapy and to choose the most appropriate drug. • The main goals for diuretic therapy are the enhanced excretion of retained water, solutes, and toxins; the promotion of urine flow; and a decrease in the urinary concentration of solutes and toxins. • The most common indications for diuretic use in the critical care patient are oligoanuric acute renal failure, decompensated chronic kidney disease, congestive heart failure, ascites from liver failure, and other fluid and electrolyte disorders. • The use of diuretics in acute renal failure might improve urine production and the ability to provide therapy, but it does not change the likelihood of renal recovery directly. • The use of diuretics to treat edema is justified only in cases of fluid retention caused by increased hydrostatic pressure. When vascular permeability is increased, further depletion of the vascular volume with diuretics is rarely indicated and is often detrimental.

Disturbances in the regulation and balance of fluid and electrolytes are very common, and they contribute significantly to the morbidity and mortality of animals treated in the critical care setting. Fluid and solute excesses are often corrected by administering diuretics, a heterogeneous group of drugs acting on various segments of the nephron, where they block the reabsorption of water and solutes and promote their urinary excretion. The correct assessment of electrolyte and mineral disorders is hampered by their compartmentalization, and correction of their serum concentrations is sometimes better achieved by translocation into the proper compartment. The appropriate use of diuretics in the critical care patient requires a careful clinical and laboratory assessment and a good

understanding of the underlying disease and pathophysiology to define clear therapeutic goals for the various fluid compartments, electrolytes, and minerals, and to choose the most appropriate diuretic, its route of administration, and dosage. Because of the complex disease processes in most critically ill animals, the limitations of their clinical assessment, and the limited data from clinical studies in small animals, this therapy remains often empiric and based on pathophysiologic justifications and clinical experience rather than on objective experimental data. Exaggerated diuresis may activate further the renin-angiotensin-aldosterone axis by reducing the intravascular volume and ventricular filling and may subsequently decrease perfusion of peripheral tissues. Careful therapeutic monitoring should therefore aim to assess treatment success more objectively and to anticipate or recognize side effects.

PHYSIOLOGY OF DIURESIS AND ANTIDIURESIS One of the main characteristics of kidney function is the kidney’s ability to regulate the excretion of water and most individual solutes independently of each other.1 In the normal animal the rate of urine excretion (diuresis) depends mostly on renal handling of water and thus on the concentration of antidiuretic hormone (ADH, or vasopressin). ADH production is increased in response to elevated plasma osmolality or hypovolemia/hypotension and, to a lesser extent, in response to nausea and increased angiotensin II concentration. ADH production is suppressed and diuresis is increased by atrial natriuretic hormone and ethanol.1 To perform its antidiuretic function, ADH requires a functional tubular system, a medullary concentration gradient of sodium and urea, and a functional ADH receptor system to use this gradient. Failure of these mechanisms results in an inappropriately increased diuresis. Two additional diuretic mechanisms are involved in pathologic conditions: (1) pressure natriuresis, a negative feedback involved

CHAPTER 160  •  Diuretics

Table 160-1  Site of Action and Effect of the Most Commonly Used Diuretics Global Effect on Class

Prototype Drug

Site of Action

Water

Electrolytes

Minerals

Acid-Base Balance

Osmotic diuretics

Mannitol

All segments (mostly LH)

↓ TBW ↓ ICF ↑ ECF

↓ Na, K, Cl

↓ Ca, P, Mg

—

Carbonic anhydrase inhibitors

Acetazolamide

PT (+ late DT)

↓ TBW

↓ Na, K, Cl

↓P

Metabolic acidosis

Loop diuretics

Furosemide

TAL

↓ TBW

↓ Na, K, Cl

↓ Ca, P, Mg

Metabolic alkalosis

Thiazide diuretics

Hydrochlorothiazide

Early DT

↓ TBW

↓ Na, K, Cl

↓ P, Mg ↓ Ca

—

Aldosterone antagonists

Spironolactone

Late DT, CD

↓ TBW

↓ Na, Cl ↑K

↓ Ca

Metabolic acidosis

Distal diuretics

Amiloride, triamterene

Late DT, CD

↓ TBW

↓ Na, Cl ↑K

± ↑ Ca

—

↓/↑ Decreased/increased balance; Ca, calcium; CD, collecting duct; Cl, chloride; DT, distal tubule; ECF, extracellular fluid volume; ICF, intracellular fluid volume; K, potassium; LH, loop of Henle; Mg, magnesium; Na, sodium; P, phosphorus; PT, proximal tubule; TAL, thick ascending limb of the loop of Henle; TBW, total body water.

in hypervolemic hypertensive states leading to increased natriuresis and restoration of normovolemia and normotension; and (2) osmotic diuresis, a passive diuretic mechanism resulting from abnormal urinary concentrations of osmotically active solutes such as glucose or sodium.1 Therefore increased diuresis can be achieved therapeutically through exogenous loading with water or salt, administration of poorly reabsorbed solutes, and pharmacologic inhibition of the tubular reabsorption mechanisms for sodium or water. Depending on the mechanisms involved, the diuretic effect will be associated with extracellular fluid (ECF) volume expansion (hypervolemic diuresis) or depletion (hypovolemic diuresis).

PHARMACOLOGY Diuresis can be induced osmotically or, more commonly, by pharmacologic blockade of sodium reabsorption at various sites along the nephron. The basic rule is that, although proximal diuretics can modulate a greater bulk of sodium, their efficacy may be overcome by distal compensatory increases in sodium reabsorption in the loop of Henle. The efficacy of distal diuretics on the other side is limited by the small amount of sodium actually reaching the distal tubule. Diuretics acting at the loop of Henle are thus most effective because of the large amount of filtrate delivered to this site and the lack of an efficient reabsorptive region beyond their locus of action.2 Diuretics are grouped according to their mechanism of action and include, in order of their renal tubular target, osmotic diuretics, carbonic anhydrase (CA) inhibitors, loop diuretics, thiazide diuretics, aldosterone antagonists, and other potassium-sparing distal diuretics (Table 160-1). Mannitol and furosemide are used most frequently in the critical care setting; consequently, the other diuretics are mentioned here only briefly. Usual dosage recommendations are summarized in Table 160-2. In using diuretics it is important to note that fluid therapy should be adjusted closely to the desired goals of the global therapy. For example, if the therapeutic goal is a depletion of the ECF with furosemide in an animal with congestive heart failure (CHF), it does not make sense to administer intravenous fluids concomitantly. Partial free water replacement with 5% dextrose in water may be an exception in this scenario. All diuretics except spironolactone reach their tubular sites of action through the urinary space. Mannitol is freely filtered in the glomeruli, and the other highly protein-bound diuretics are secreted

Table 160-2  Dosages of the Most Commonly Used Diuretics Drug

Indication/Action

Dosage

Mannitol

Renal failure

0.25-1 g/kg IV q4-6h CRI 1-2 mg/kg/min when diuresis instituted 1-3 g/kg IV once 1-1.5 g/kg IV once

Glaucoma Cerebral edema Acetazolamide

Glaucoma

50 mg IV once, then 2-10 mg/kg q8-12h PO 7 mg/kg PO q8h in the cat

Furosemide

Diuretic

0.5-4 (max 8) mg/kg IV, IM, SC, PO q8-12h CRI 2-15 mcg/kg/min

Hydrochlorothiazide

Diuretic

0.5-5 mg/kg PO q12-24h

Spironolactone

K-sparing diuretic

1-4 mg/kg PO q12-24h

Amiloride

K-sparing diuretic

0.1-0.3 mg/kg PO q24h

Triamterene

K-sparing diuretic

1-2 mg/kg PO q12h

CRI, Constant rate infusion; IM, intramuscularly; IV, intravenously; K, potassium; PO, per os; SC, subcutaneously.

actively through the organic acid and organic base pathways into the proximal tubule.2 This explains the decreased efficacy of most diuretics in animals with renal disease. However, the impaired tubular secretion and delivery to the site of action can be compensated partially by a progressive titration to higher plasma concentrations. In animals with proteinuria and nephrotic syndrome, the serum diuretic concentration remains low as a result of hypoproteinemia and results in decreased tubular secretion of the diuretic, which is then partially neutralized by binding to urinary proteins. Dose and frequency adjustments can partially compensate for this and provide sufficient concentrations of the active drugs at the site of action.2,3 Serial measurements of urinary electrolytes can provide a more objective

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assessment of diuretic efficacy to help guide therapeutic decision making, such as adjusting dosage and combining diuretics from different classes. Tolerance and inefficacy of diuretic therapy can occur after a single dose as a result of depletion of the ECF. In the long term, hypertrophy of the distal nephron reflects increased compensatory solute reabsorption at the distal sites to compensate for proximal tubular blockade. This hypertrophy parallels a progressive loss of drug efficacy and the requirement for higher doses or a sequential blockade of multiple sodium reabsorption sites.2-4

Osmotic Diuretics Mannitol is an osmotically active, nonreabsorbed sugar alcohol that is administered intravenously for its osmotic or diuretic properties, or both. The resulting hyperosmolality of the ECF creates a water shift from the intracellular fluid (ICF) compartment and an initial expansion of the ECF. The contraction of the ICF is used therapeutically in animals with cerebral edema associated with increased ICF and increased intracranial pressure (as in trauma, fluid shifts secondary to a rapid correction of hyperglycemia, hypernatremia, or azotemia).5-7 Mannitol is freely filtered by the glomerulus (molecular weight, 182 Da) and does not undergo tubular reabsorption, which results in increased tubular flow rate and osmotic diuresis. The increased urine flow reduces the tubular reabsorption of urea, increasing its urinary clearance and thus decreasing its serum concentration.1,4 This property can be used to intensify fluid diuresis and to accelerate recovery of clinical and metabolic stability in animals with decompensated chronic renal disease, even in nonoliguric states. Additional potential benefits of mannitol for acute renal injury include decreased renal vascular resistance, decreased hypoxic cellular swelling, decreased renal vascular congestion, decreased tendency of erythrocytes to aggregate, protection of mitochondrial function, decreased free radical damage, and even renoprotection when administered before a toxic or ischemic insult.1,4,8 There are, however, no data to support a clinical benefit in animals with established renal failure, and its use is based purely on extrapolations and pathophysiologic justifications. Very high doses of mannitol have been described as causing acute tubular injury in humans, and thus it should be used cautiously in oliguric animals to avoid accumulation, volume overload, hyperosmolality, and further renal damage.1,9

Carbonic Anhydrase Inhibitors Acetazolamide inhibits mostly the type II (cytoplasmic) and type IV (membrane) CAs from the proximal tubular epithelium, which leads to a net decrease in the proximal reabsorption of sodium bicarbonate. The resulting metabolic acidosis and natriuresis are self-limiting because progressively less bicarbonate is filtered and the proximal tubular epithelium becomes less responsive to CA inhibition. Furthermore, the proximal site of action of CA inhibitors leads to a compensatory increase in the distal sodium absorption. CAs are also located in other organs and their inhibition is variable: blockade of ocular and brain CA decreases the production of aqueous humor and cerebrospinal fluid, respectively; blockade of red blood cell CA hampers carbon dioxide removal from the tissues; the gastric CA is affected only minimally by inhibitors. CA inhibitors rarely are used as diuretics except in some combination protocols, and their main clinical application is for the treatment of elevated intraocular pressure in glaucoma.1,2,4

Loop Diuretics The prototypical loop diuretic furosemide binds to and inhibits the Na-K-2Cl cotransporter on the apical membrane of epithelial cells of the thick ascending limb of the loop of Henle. The decreased sodium and chloride reabsorption results in marked natriuresis and

diuresis, and rapidly dissipates the medullary osmotic gradient.10 Increased distal delivery of sodium leads to a sodium-potassium exchange and promotes kaliuresis. The blockade of the secondary active Na-K-2Cl cotransporter decreases the energy expenditure and the oxygen consumption of the tubular epithelial cells and can be beneficial in ischemic conditions. Furosemide further improves the renal parenchymal oxygen supply by decreasing renal vascular resistance and increasing renal blood flow. Blockade of the chloride flux in the macula densa inhibits the important regulatory tubuloglomerular feedback, and the kidney may not be able to adjust its glomerular filtration in response to tubular loss of solutes.1-4 The potential concerns about and benefits of furosemide in renal disease are based mostly on pathophysiologic justifications and not on results of controlled clinical studies. The combination of mannitol with furosemide seems to be synergistic in inducing diuresis in dogs with acute renal failure. The use of furosemide for ECF contraction in small animals with CHF is better described. The decreasing responsiveness to loop diuretics in heart failure is mostly a result of the compensatory increase in reabsorption of sodium in the distal tubule, and it commonly requires that the loop diuretic be combined with a more distal diuretic for sequential nephron blockade. The relatively long dosing interval for furosemide compared with its elimination half-life (1 to 1.5 hours in dogs) can result in intermittent rebound sodium retention and diminish its efficacy. Frequent administration or constant rate infusion is required when maximal efficacy is desired.3,11

Thiazide Diuretics Thiazide diuretics exert their action by inhibiting the NaCl cotransporter on the apical membrane of the distal tubule. They have only a few indications in small animal medicine, in which they are used mostly for their anticalciuretic properties in the long-term prevention of calcium-containing uroliths or with other diuretics in combination protocols.2,12 Thiazides paradoxically reduce urine production in severely polyuric animals with diabetes insipidus by inducing a mild hypovolemia and increasing proximal tubular sodium conservation.1,13

Aldosterone Antagonists Spironolactone and eplerenone competitively antagonize aldosterone by binding to its receptor on the late distal tubule and the collecting duct to increase sodium, calcium, and water excretion and decrease potassium loss. Spironolactone is most efficacious in hyperaldosteronism, and this defines its main clinical applications in liver and heart failure, usually in combination with a more efficient loop diuretic.1,2,4 Spironolactone also seems to have a positive effect on myocardial remodeling and reduction of cardiac fibrosis.14 It is commonly combined with other diuretics to reduce their potassiumwasting effects. Recent studies have reported that spironolactone is safe and well tolerated as an adjunctive therapy in dogs with CHF, but there have been contradictory findings with regard to the impact on outcome.15-17

Other Potassium-Sparing Distal Diuretics Amiloride and triamterene inhibit the electrogenic sodium reabsorption in the late distal tubule and the collecting duct, suppressing the driving force for potassium secretion. Their distal site of action gives them only weak diuretic and natriuretic properties, and they are used mostly to enhance the efficacy and counterbalance the potassiumwasting effect of proximal diuretics.2,4

Aquaretics The main mode of action of most diuretics in clinical use is increasing renal sodium excretion, and therefore they can be classified as

CHAPTER 160  •  Diuretics

natriuretics. Aquaretics are a newer class of diuretics that antagonize the vasopressin V2 receptor in the kidney and promote solute-free water clearance. These vasopressin receptor antagonists, called vaptans, include compounds of varying V1-V2 receptor selectivity such as conivaptan, tolvaptan, mozavaptan, satavaptan, and lixivaptan. Their main uses are in the treatment of free water retention in hypervolemic hyponatremia (e.g., heart or liver failure) or normovolemic hyponatremia (e.g., syndrome of inappropriate ADH secretion).18 However, use of these drugs in a clinical setting has not been reported in small animals so far.

INDICATIONS FOR DIURETIC THERAPY Diuretics are used commonly in the critical care setting, mostly for treatment of urinary and cardiac diseases. A partial list of further indications is provided in Table 160-3.

Urinary Diseases The use of diuretics to convert the oligoanuria of acute renal failure to a nonoliguric state is controversial. Although successful initiation of diuresis can facilitate or even simply allow the conventional treatment of previously anuric animals, it has no prognostic value and it does not imply further improvements in renal function. Urine production, although necessary, does not equate with renal recovery. High dosages of furosemide are often combined with mannitol after initial rehydration of the oligoanuric animal. The addition of a so-called renal dosage of dopamine (0.5 to 3 mcg/kg/min) is no longer recommended because of a lack of demonstrable survival benefit and the potential for adverse effects such as vasoconstriction and hypertension.19,20 When dialytic therapy is available, these diuretic maneuvers are neither indicated nor necessary because the electrolyte and fluid disturbances can be corrected directly by dialysis. The oliguria of chronic renal disease is rarely an indication for diuresis in animals because most patients in this terminal stage can no longer be managed conventionally. Fluid overload is a feature of end-stage disease and would be treated with dialytic fluid removal

and restriction of water intake. The efficacy of diuretics is markedly decreased at this stage because of their poor delivery to the tubular site of action (see previous discussion). However, mannitol is used in animals with decompensated chronic renal disease to intensify the diuretic support (fluid therapy) and temporarily improve the azotemia by decreasing the tubular reabsorption of urea and increasing its urinary clearance. This strategy can accelerate the clinical and metabolic recovery of these animals. Treatment of the edematous state of nephrotic syndrome is oriented toward decreasing the proteinuria and improving the hypoalbuminemia to correct the disturbances of this overhydrated but hypovolemic condition. In some animals, however, proteinuria is associated to an inappropriate renal tubular sodium retention contributing to nephrotic edema by an overfill mechanism. The use of a natriuretic drug such as furosemide may therefore be indicated when the clinical response is delayed or insufficient to reduce edema and effusions and to improve the quality of life. These drugs need to be titrated to the minimal clinically effective dosage to overcome the decreased efficacy in this disease (see previous discussion) and to avoid further depletion of the vascular volume and renal decompensation.2-4 Diuretic therapy is sometimes indicated in lower urinary tract diseases of dogs and cats to decrease the concentration of inflammatory mediators (idiopathic feline lower urinary tract disease in cats) or calculogenic minerals (urolithiasis). This is typically a long-term therapy achieved mostly by hypervolemic diuresis using increased water or salt intake, along with dietary modifications. Thiazide diuretics selectively decrease calciuresis and can be indicated in animals with recurrent calcium oxalate urolithiasis.12

Congestive Heart Failure CHF usually is treated with loop diuretics, if possible, in combination with dietary sodium restriction, despite the potential for activation of the renin-angiotensin-aldosterone system.21 The progressive tolerance to loop diuretics can be balanced by combining them with distal diuretics, mostly thiazides, although spironolactone is used increasingly for its beneficial effect on myocardial remodeling.2,14 Serum

Table 160-3  Indications and Goals for Diuretic Therapy Indication

Main Goal(s)

Diuretic Strategy

Oligoanuria (acute renal failure)

Restore diuresis ↓ Tubular obstruction ↑ Kaliuresis

Furosemide, mannitol (after rehydration)

Uremic crisis (chronic kidney disease)

↓ Blood urea nitrogen

Mannitol (after rehydration) + fluid therapy

Nephrotic syndrome

↓ Interstitial fluid volume

Furosemide

Urinary diseases (urolithiasis, cystitis)

↑ Urine flow

Water, ± salt, thiazides

Congestive heart failure

↓ Preload and extracellular fluid volume ↓ Pulmonary edema or pleural effusion

Furosemide, ± combination with spironolactone

Hypertension

↓ Preload and intravascular volume

Thiazides, furosemide

Liver failure

↓ Interstitial fluid volume

Spironolactone, ± furosemide

Hypercalcemia

↑ Calciuresis

Furosemide + NaCl 0.9%

Hyperkalemia

↑ Kaliuresis

NaCl 0.9%, furosemide

Iatrogenic fluid overload

↓ Total body water

Furosemide

Intracranial pressure

↓ Intracellular fluid volume

Mannitol

Glaucoma

↓ Intraocular pressure

Acetazolamide (mannitol)

Diabetes insipidus

↓ Polyuria

Thiazides

↓/↑ Decrease/increase; NaCl, Sodium chloride.

849

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PART XX  •  PHARMACOLOGY

potassium concentration should be monitored carefully when potassium-wasting diuretics are used in patients with cardiac disease because hypokalemia enhances the risk of digoxin toxicity.2

Liver Failure Animals with end-stage liver failure commonly develop ascites and edema as a result of hypoalbuminemia, activation of the reninangiotensin-aldosterone system, and portal hypertension.2 Symptomatic relief of the resulting abdominal distention can be obtained by abdominocentesis, but rapid refill of the abdominal cavity can result in hypovolemia and shock. The aldosterone antagonist spironolactone is the first-choice diuretic for this disease process, and it is often combined with loop diuretics for a sustained and progressive reduction of ascites. Because this diuretic effect occurs at the expense of an already depleted intravascular volume, the diuretics should be titrated to the minimally effective dosage necessary to obtain acceptable symptomatic relief of discomfort, as in animals with proteinlosing nephropathy and enteropathy.2

Electrolyte and Mineral Disorders Fluid therapy and loop diuretics can help temporarily correct hyperkalemia in an animal with a functional urinary system until the underlying cause can be identified and corrected.2 Similarly, severe hypercalcemia can be reduced and renal function preserved with high dosages of furosemide and matching rates of physiologic saline infusion until a diagnosis is obtained and a treatment of the cause is instituted. The efficacy of this treatment in severe hypercalcemia is often insufficient, and additional calcium-reducing therapies are required.2,4

Systemic Hypertension Treatment of systemic hypertension in small animals is based mostly on the use of vasodilators, which can activate the renin-angiotensinaldosterone system over the long term and lead to salt and water retention. Because spontaneous and iatrogenic expansion of the ECF are frequent in hypertensive animals with renal disease, refractory cases commonly require combinations of vasodilators, negative chronotropic drugs, and loop or thiazide diuretics.2

REFERENCES 1. Rose BD, Post TW: Clinical physiology of acid-base and electrolyte disorders, ed 5, New York, 2001, McGraw-Hill. 2. Boothe DM: Drugs affecting urine formation. In Boothe DM, editor: Small animal clinical pharmacology and therapeutics, ed 2, St Louis, 2012, Saunders. 3. Brater DC: Diuretic therapy, N Engl J Med 339:387, 1998.

4. Ellison DH, Hoorn EJ, Wilcox CS: Diuretics. In Taal MW, Chertow GM, Marsden PA, et al, editors: Brenner and Rector’s the kidney, ed 9, Philadelphia, 2012, Saunders. 5. Qureshi AI, Wilson DA, Traystman RJ: Treatment of elevated intracranial pressure in experimental intracerebral hemorrhage: comparison between mannitol and hypertonic saline, Neurosurgery 44:1055, 1999. 6. Silver P, Nimkoff L, Siddiqi Z, et al: The effect of mannitol on intracranial pressure in relation to serum osmolality in a cat model of cerebral edema, Intensive Care Med 22:434, 1996. 7. Hartwell RC, Sutton LN: Mannitol, intracranial pressure, and vasogenic edema, Neurosurgery 36:1236, 1993. 8. Finn WF: Recovery from acute renal failure. In Molitoris BA, Finn WF, editors: Acute renal failure: a companion to Brenner and Rector’s The kidney, Philadelphia, 2001, Saunders. 9. Visweswaran P, Massin EK, DuBose TD Jr: Mannitol-induced acute renal failure, J Am Soc Nephrol 8:1028, 1997. 10. McClellan JM, Goldstein RE, Erb HN, et al: Effects of administration of fluids and diuretics on glomerular filtration rate, renal blood flow, and urine output in healthy awake cats, Am J Vet Res 67:715, 2006. 11. Adin DB, Taylor AW, Hill RC, et al: Intermittent bolus injection versus continuous infusion of furosemide in normal adult greyhound dogs, J Vet Intern Med 17:632, 2003. 12. Lulich JP, Osborne CA, Lekcharoensuk C, et al: Effects of hydrochlorothiazide and diet in dogs with calcium oxalate urolithiasis, J Am Vet Med Assoc 218:1583, 2001. 13. Takemura N: Successful long-term treatment of congenital nephrogenic diabetes insipidus in a dog, J Small Anim Pract 39:592, 1998. 14. Suzuki G, Morita H, Mishima T, et al: Effects of long-term monotherapy with eplerenone, a novel aldosterone blocker, on progression of left ventricular dysfunction and remodeling in dogs with heart failure, Circulation 106:2967, 2002. 15. Lefebvre HP, Ollivier E, Atkins CE, et al: Safety of spironolactone in dogs with chronic heart failure because of degenerative valvular disease: a population-based, longitudinal study, J Vet Intern Med 27(5):1083-1091, 2013. Epub July 19, 2013. 16. Bernay F, Bland JM, Häggström J, et al: Efficacy of spironolactone on survival in dogs with naturally occurring mitral regurgitation caused by myxomatous mitral valve disease, J Vet Intern Med 24:331-341, 2010. 17. Schuller S, Van Israël N, et al: Lack of efficacy of low-dose spironolactone as adjunct treatment to conventional congestive heart failure treatment in dogs, J Vet Pharmacol Ther 34:322-331, 2011. 18. Mahajan S, Sivaramakrishnan R: New weapons for management of hyponatremia: vaptans, Med Update 22:611-614, 2012. 19. Cowgill LD, Francey T: Acute uremia. In Ettinger SJ, Feldmann EC, editors: Textbook of veterinary internal medicine, St Louis, 2005, Saunders. 20. Sigrist NE: Use of dopamine in acute renal failure, J Vet Emerg Crit Care 17:117-126, 2007. 21. Lovern CS, Swecker WS, Lee JC, et al: Additive effects of a sodium chloride restricted diet and furosemide administration in healthy dogs, Am J Vet Res 62:1793, 2001.

CHAPTER 161  GASTROINTESTINAL PROTECTANTS Michael D. Willard,

DVM, MS, DACVIM (Internal Medicine)

KEY POINTS • Histamine-2 receptor antagonists (H2RAs) are competitive inhibitors of gastric acid secretion; they lower gastric acid secretion but do not abolish it. They also diminish pepsin secretion. • Ranitidine and nizatidine are H2RAs that purportedly have gastric prokinetic activity. • Cimetidine inhibits hepatic P-450 cytochrome enzyme activity. It can be used therapeutically (e.g., to minimize acetaminophen toxicity) or can cause drug interactions by delaying hepatic metabolism of drugs given concomitantly. • Proton pump inhibitors are noncompetitive inhibitors of gastric acid secretion. They inhibit gastric acid secretion to a greater extent than H2RAs. It can take 2 to 5 days for them to achieve maximal effectiveness when given orally, but these drugs still have reasonable effectiveness immediately after therapy is begun. • Sucralfate is an unabsorbed drug that binds to ulcerated or eroded mucosa. It can adsorb other drugs, delaying or inhibiting their absorption. • Misoprostol is a prostaglandin analog designed to prevent ulceration and erosion due to nonsteroidal antiinflammatory drug (NSAID) use. It is not as effective or reliable in preventing NSAID-induced ulceration in dogs as it is in humans. • Orally administered antacids used to neutralize gastric acid have a short duration of action and should not be used to manage or prevent ulcers and erosions in veterinary medicine.

Gastrointestinal ulceration and erosion (GUE) is an important problem in dogs but is less common in cats. Stress (i.e., an event causing substantial hypoperfusion or anoxia of the gastric mucosa) and drug therapy (especially with nonsteroidal antiinflammatory drugs [NSAIDs] and dexamethasone) are especially common causes of GUE in dogs. Prednisolone at commonly administered dosages is rarely ulcerogenic unless there is concurrent gastric hypoxia or hypoperfusion, severe spinal disease, or concurrent use of NSAIDs. Stress ulceration may be due to hypotensive shock, systemic inflammatory response syndrome, severe life-threatening illness, or extreme exertion. Marked hyperacidity (e.g., gastrinoma, mast cell tumor) may cause GUE but more commonly causes duodenal lesions. Hepatic failure, tumors, and, to a lesser extent, foreign bodies may also cause GUE. Gastrointestinal (GI) protectants are primarily indicated to heal existing gastric ulcers and erosions. Removing the cause of the ulceration or erosion markedly enhances efficacy, as does maintaining GI perfusion. Protectants are often poorly effective at preventing ulceration when the cause (e.g., NSAID use, poor gastric mucosal perfusion) persists. However, when there is a known cause of GUE that cannot be readily alleviated, these drugs are often given in the hope that they will at least retard, if not prevent, ulceration. See Table 161-1 for a list of commonly used GI protectants and dosages. Proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) prevent GI ulceration caused by certain forms of stress

(probably a combination of poor gastric mucosal blood flow, hypoxia, and possibly other factors) in dogs.1 There are no drugs that have shown efficacy in preventing GUE caused by the use of steroids (especially dexamethasone).2-4 Although PPIs are somewhat prophylactic against NSAID-induced GUE, they are not completely effective.5-9 There is no evidence that combination therapy (e.g., an H2RA plus sucralfate) is any more effective than administration of just one drug. Drugs that decrease gastric acid secretion are not antiemetics (i.e., they have no effect on the medullary vomiting center or the chemoreceptor trigger zone); however, they can have an antidyspeptic effect that lessens nausea. They may be used to stimulate appetite or to enhance the efficacy of true antiemetics. When they are used to manage existing ulcers or erosions, evidence of improvement (e.g., less nausea, less bleeding) is expected within 2 to 5 days of beginning therapy, assuming that the initiating cause has been treated or eliminated. If there is no evidence of improvement within that time, endoscopic evaluation and/or surgical removal may be considered.

HISTAMINE-2 RECEPTOR ANTAGONISTS The most commonly used H2RAs in dogs and cats are cimetidine, ranitidine, and famotidine. The H2RAs block the histamine receptor on the gastric parietal cell.10-12 They are competitive inhibitors of gastric acid secretion, which means that they do not decrease gastric acid secretion as well as the noncompetitive PPIs. Their maximal effect in decreasing gastric acid secretion occurs almost immediately upon initiation of therapy. Nizatidine and ranitidine reportedly have some gastric prokinetic activity, probably via antiacetylcholinesterase activity. However, one study failed to find ranitidine effective in preventing gastroesophageal reflux in anesthetized dogs.13 Cimetidine and ranitidine are the least potent H2RAs and famotidine the most potent, with nizatidine being intermediate. Famotidine has the longest duration of action. With oral administration, cimetidine absorption is delayed by food, but absorption of ranitidine, nizatidine, and famotidine is not. Famotidine, ranitidine, and cimetidine undergo substantial first-pass hepatic metabolism but nizatidine does not. Nizatidine is the most bioavailable and famotidine the least when administered orally. Cimetidine and ranitidine are metabolized extensively by the liver, but famotidine and nizatidine are excreted almost completely unchanged in the urine. It has been suggested that the dosage of cimetidine and famotidine be reduced in patients with renal failure; however, it is not known how important such a dosage reduction is. Cimetidine markedly inhibits hepatic P-450 enzymes and has been used therapeutically to lessen the severity of acetaminophen intoxication. However, cimetidine also decreases metabolism of theophylline, lidocaine, metronidazole, and many other drugs, which results in higher blood levels that can cause toxicity in some cases. Ranitidine has less effect on these enzymes, and famotidine and nizatidine have almost no such effect. Cimetidine also decreases hepatic blood flow by about 20%. 851

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PART XX  •  PHARMACOLOGY

Table 161-1  Selected Gastrointestinal Protectants Used in Dogs and Cats Drug

Mechanism of Action

Dosage

Special Considerations

Cimetidine

H2-receptor antagonist

5-10 mg/kg IV, IM, SC, PO q6-8h

Potent inhibitor of hepatic P-450 enzymes Can affect metabolism of toxins or other drugs Decreases hepatic blood flow Food delays absorption

Ranitidine

H2-receptor antagonist

Dogs: 0.5-2 mg/kg IV or 1-4 mg/kg PO q8-12h Cats: 2.5 mg/kg IV or 3.5 mg/kg PO q8-12h daily

Has prokinetic activity Has minimal effect on hepatic enzyme function

Famotidine

H2-receptor antagonist

0.5-1 mg/kg IV, IM, SC, PO q12-24h

Longest acting and most potent H2-receptor antagonist

Nizatidine

H2-receptor antagonist

Dogs: 2.5-5 mg/kg PO q24h

Exclusively eliminated by the kidneys

Omeprazole

Proton pump inhibitor

1.0-2.0 mg/kg PO q12-24h

Inhibits hepatic P-450 enzymes May cause elevations in liver enzymes Sometimes causes diarrhea

Esomeprazole

Proton pump inhibitor

0.5-1 mg/kg IV q24h*

Lansoprazole

Proton pump inhibitor

1 mg/kg IV q24h*

Anecdotal

Pantoprazole

Proton pump inhibitor

1 mg/kg IV q24h*

Anecdotal

Misoprostol

Prostaglandin analog

2-5 mcg/kg PO q6-12h

Can cause abortion Often causes transient diarrhea

Sucralfate

Local-acting barrier

Dogs: 0.25-1 g PO q6-12h Cats: 0.25 g PO q6-12h

Adsorbs many other drugs, slowing their absorption

H2, Histamine-2; IM, intramuscularly; IV, intravenously; PO, per os; SC, subcutaneously. *Extrapolated dosage.

A new H2RA, lafutidine, seems unique in that it has additional mechanisms of action (i.e., nitric oxide–mediated and histamineindependent mechanisms).14 It has a mucosa-protective action that is mediated by capsaicin-sensitive sensory nerves. In one study it was more effective than lansoprazole in inhibiting gastric acid secretion.15 It also appears to have mild intestinal protective activity.16 Adverse effects are uncommon with H2RAs, with cimetidine tending to be associated with more than ranitidine or famotidine. However, a recent abstract reported a high incidence of apathy, nausea, and vomiting when ranitidine was administered intravenously to healthy dogs.17 Central nervous system aberrations and cytopenias are reported in humans and are anecdotally reported in dogs. There are anecdotal reports of famotidine’s causing hemolytic anemia in uremic cats, but this effect could not be reproduced experimentally. Famotidine administration can be associated with thrombocytopenia in people, which has prompted some to recommend that it not be used in coagulopathic patients.18 Famotidine administration causes only transient increases in serum gastrin concentrations, which is important to recognize when testing for gastrinomas.19

PROTON PUMP INHIBITORS Omeprazole is the PPI that has been most commonly used in veterinary medicine; there is more limited experience with lansoprazole, pantoprazole, esomeprazole, and dexlansoprazole. In people, lansoprazole has greater bioavailability than omeprazole (80% to 85% vs. 30% to 40%, respectively). Lansoprazole, esomeprazole, and pantoprazole can be given intravenously, an advantage in vomiting patients. Dexlansoprazole is administered orally and is formulated in a dual delayed-release system that produces the longest duration of effect of any PPI; it can be given with food.20 The PPI drugs irreversibly inhibit hydrogen-potassium adenosine triphosphatase on the luminal side of the parietal cell, thus stopping secretion of hydrogen ions into the gastric lumen.10,11 Omeprazole (which is actually a prodrug) is susceptible to destruction by gastric

acid, so it is administered as enteric-coated granules that are absorbed in the duodenum. Absorption is diminished by food; therefore this drug should be given on an empty stomach. Once absorbed, omeprazole undergoes first-pass hepatic metabolism, and the rest is selectively sequestered in the acidic environment of the parietal cells, where it is transformed to the active drug. Therefore it is best to administer omeprazole about 1 hour before feeding so as to maximize the acidity of the parietal cell and thereby increase the amount of omeprazole sequestered there. Because of this complex pharmacologic pathway, it usually takes 2 to 5 days before maximal acid suppression from omeprazole occurs. However, the PPIs are more effective than the H2RAs21,22; in fact, the immediate effects of omeprazole were superior to those of high-dose famotidine when sled dogs were treated.23 Furthermore, suppression of gastric acid secretion continues for a few days after cessation of PPI therapy because of the irreversible inhibition of the proton pump enzyme. Historically, H2RAs were typically administered to patients with uncomplicated GUE first and a PPI used only if the initial therapy failed; however, PPIs are increasingly becoming first-line therapy due to their superior efficacy in lessening gastric acid secretion. Animals with severe esophagitis or duodenal ulceration due to paraneoplastic hyperacidity (e.g., mast cell tumors or gastrinomas) generally should be treated with PPIs as first-line therapy. PPIs are relatively effective in lessening gastric acid reflux during anesthesia, but reflux still occurs in some dogs.24 In people, PPIs are superior to misoprostol for preventing duodenal but not gastric lesions due to NSAIDs.25 Adverse effects associated with PPIs are rare. Toxicologic studies have shown that pantoprazole is relatively safe in dogs.26 Diarrhea is reported in humans and dogs taking various PPIs.27 Omeprazole and esomeprazole inhibit hepatic P-450 enzymes. Omeprazole has thus decreased antiplatelet activity by clopidogrel and decreased clearance of diazepam in people (pantoprazole and lansoprazole appear to have fewer such interactions). Hypomagnesemia has been suggested as an adverse effect in people, and elevated liver enzyme levels have been

CHAPTER 161  •  Gastrointestinal Protectants

noted. A wide range of hypersensitivity reactions to PPIs (e.g., anaphylaxis, urticaria, angioedema, cutaneous vasculitis, cytopenias, interstitial nephritis) have been reported in people, but they tend to be rare.28 A markedly increased gastric pH can affect absorption of some drugs such as ketoconazole and digoxin. Currently there is interest in the antineoplastic29 and antiprotozoal activities30 of PPIs (pantoprazole and rabeprazole have strong activity against Giardia and Trichomonas in vitro), but few data are currently available on the clinical relevance of these findings.

SUCRALFATE Sucralfate is the octasulfate of sucrose combined with aluminum hydroxide.31 It is a locally acting drug that is administered orally as a tablet or a suspension. It becomes viscous and binds tightly to epithelial cells in the acidic environment of the stomach, especially to the base of erosions and ulcers, where it may remain for 6 hours. It serves as a physical barrier while adhered to the ulcer or erosion and thus protects the ulcer from pepsin and bile acids; it also stimulates local production of prostaglandins and binding to epidermal growth factor (which favors mucosal repair). Sucralfate has almost no adverse effects besides sometimes causing constipation, which can be useful in patients with diarrhea. Sucralfate can adsorb other drugs (e.g., enrofloxacin), which slows their systemic absorption. It should be given before antacid therapy to maximize efficacy and theoretically should not be given with enteral feedings because it may bind the fat-soluble vitamins. Sucralfate can only be given orally, which limits its usefulness in vomiting patients.

PROSTAGLANDIN ANALOGS Misoprostol is a prostaglandin E1 analog with both antacid and mucosal protective properties (it stimulates secretion of mucus and bicarbonate and increases gastric mucosal blood flow).32 The antisecretory effect on gastric acid is probably more important. Misoprostol acts directly on parietal cells to inhibit both nocturnal acid secretion and secretions in response to food, pentagastrin, and histamine. The drug is absorbed rapidly (in the absence of food) and undergoes first-pass metabolism in the liver to the active form. Misoprostol has a short half-life and must be given two to three times daily. This drug was developed to prevent ulceration caused by NSAIDs. Its greater cost, need for frequent administration, and higher rate of adverse effects usually mean that it is administered only when other therapies for GUE have failed or when patients have difficulty tolerating NSAIDs that they must receive to maintain a good quality of life. It is not as clearly effective in protecting dogs receiving NSAIDs as has been reported in people. Adverse effects include diarrhea and uterine contraction (which can result in abortion in pregnant females). Diarrhea often subsides after 2 to 5 days.

ANTACIDS Numerous drugs are administered orally to neutralize gastric acid. These drugs are generally not appropriate for treating or preventing GUE because they usually have a relatively short half-life compared with H2RAs and PPIs. Furthermore, each set of antacid drugs tends to have its own idiosyncrasies. For example, aluminum and magnesium compounds delay or prevent absorption of other drugs.

FUTURE DRUG THERAPY Troxipide is a new gastric cytoprotective drug.33 It does not appear to affect gastric acid secretion but was more effective than ranitidine in a preclinical study in people with spontaneous gastritis. Data for

dogs are lacking. Another new gastroprotectant that has been studied in people is irsogladine.34 It seems to protect the gastric mucosa through endogenous nitric oxide and increased cyclic adenosine monophosphate. Irsogladine appears to prevent reduced mucosal blood flow, suppress formation of reactive oxygen radicals, and enhance gap junctional intracellular communication. The drug is currently available only in Japan.

POTENTIAL COMPLICATIONS OF INCREASED GASTRIC pH Gastric acid is a major defense mechanism that prevents many infectious agents from gaining access to the intestinal tract since few bacteria can withstand the low pH of the stomach. Hence, there is concern that a prolonged increase in gastric pH may result in complications. In critically ill humans,35,36 it has been hypothesized that patients receiving long-term acid-suppression therapy are at increased risk of bacterial pneumonia following an aspiration event. However, studies have failed to find any consistent risk. Similarly, human patients in such settings have not been found to have an increased risk of gastric carcinoid formation or rebound hyperacidity. There is an increased risk of Clostridium difficile infection in some populations, but since dogs and cats are rarely adversely affected by this bacterium, the risk to them appears minimal.

REFERENCES 1. Davis MS, Willard MD, Nelson SL, et al: Efficacy of omeprazole for the prevention of exercise-induced gastritis in racing Alaskan sled dogs, J Vet Intern Med 17:163, 2003. 2. Neiger R, Gaschen F, Jaggy A: Gastric mucosal lesions in dogs with acute intervertebral disc disease: characterization and effects of omeprazole or misoprostol, J Vet Intern Med 14:33, 2000. 3. Rohrer CR, Hill RC, Fischer A, et al: Efficacy of misoprostol in prevention of gastric hemorrhage in dogs treated with methylprednisolone sodium succinate, Am J Vet Res 60:982, 1999. 4. Hanson SM, Bostwick DR, Twedt DC, et al: Clinical evaluation of cimetidine, sucralfate and misoprostol for prevention of gastrointestinal tract bleeding in dogs undergoing spinal surgery, Am J Vet Res 58:1320, 1997. 5. Jenkins CC, DeNovo RC, Patton CS, et al: Comparison of effects of cimetidine and omeprazole on mechanically created gastric ulceration and on aspirin-induced gastritis in dogs, Am J Vet Res 52:658, 1991. 6. Johnston SA, Leib MS, Marini M, et al: Endoscopic evaluation of the stomach and duodenum after administration of piroxicam to dogs, Proc Am Coll Vet Intern Med 15:664, 1997 (abstract). 7. Bowersox TS, Lipowitz AJ, Hardy RM, et al: The use of a synthetic prostaglandin E1 analog as a gastric protectant against aspirin-induced hemorrhage in the dog, J Am Anim Hosp Assoc 32:401, 1996. 8. Ward DM, Leib MS, Johnston SA, et al: The effect of dosing interval on the efficacy of misoprostol in the prevention of aspirin-induced gastric injury, J Vet Intern Med 17:282, 2003. 9. Murtaugh RJ, Matz ME, Labato MA, et al: Use of synthetic prostaglandin E1 (misoprostol) for prevention of aspirin-induced gastroduodenal ulceration in arthritic dogs, J Am Vet Med Assoc 202:251, 1993. 10. Boothe DM: Gastrointestinal pharmacology. In Boothe DM, editor: Small animal clinical pharmacology and therapeutics, ed 2, St Louis, 2012, Saunders, pp 672-739. 11. Wallace JL, Sharkey KA: Pharmacotherapy of gastric acidity, peptic ulcers, and gastroesophageal reflux disease. In Brunton LL, Chabner BA, Knollmann BC, editors: Goodman’s and Gilman’s The pharmacological basis of therapeutics, ed 12, New York, 2012, McGraw-Hill, pp 1308-1322. 12. McQuaid KR: Drugs used in the treatment of gastrointestinal diseases. In Katzung BG, editor: Basic and clinical pharmacology, ed 9, New York, 2004, Lange Medical Books/McGraw-Hill, pp 1034-1063. 13. Favarato ES, Souza MV, Costa PRS, et al: Evaluation of metoclopramide and ranitidine on the prevention of gastroesophageal reflux episodes in anesthetized dogs, Res Vet Sci 93:466, 2012.

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14. Nakano M, Kitano S, Nanri M, et al: Lafutidine, a unique histamine H2-receptor antagonist, inhibits distention-induced gastric acid secretion through an H2 receptor-independent mechanism, Eur J Pharmacol 658:236, 2011. 15. Yamagishi H, Koike T, Ohara S, et al: Stronger inhibition of gastric acid secretion by lafutidine, a novel H2 receptor antagonist, than by the proton pump inhibitor lansoprazole, World J Gastroenterol 14:2406, 2008. 16. Amagase K, Ochi A, Sugihara T, et al: Protective effect of lafutidine, a histamine H2 receptor antagonist, against loxoprofen-induced small intestinal lesions in rats, J Gastroenterol Hepatol 25(Suppl 1):S111, 2010. 17. Cavalcanti GAO, Feliciano MAR, Silveira T, et al: Adverse effects of ranitidine applied in the therapeutic dosage in healthy dogs, Cienc Rural 40:326, 2012. 18. Compoginis JM, Gaspard D, Obaid A: Famotidine use and thrombocytopenia in the trauma patient, Am Surg 77:1580, 2011. 19. Mordecai A, Sellon RK, Mealey KL: Normal dogs treated with famotidine for 14 days have only transient increased in serum gastrin concentrations, J Vet Intern Med 25:1248, 2011. 20. Hershcovici T, Jha LK, Fass R: Dexlansoprazole MR—a review, Ann Med 43:366, 2011. 21. Bersenas A, Mathews K, Allen D, et al: Effects of ranitidine, famotidine, pantoprazole, and omeprazole on intragastric pH in dogs, Am J Vet Res 66:425, 2005. 22. Tolbert K, Bissett S, King A, et al: Efficacy of oral famotidine and 2 omeprazole formulations for the control of intragastric pH in dogs, J Vet Intern Med 25:47, 2011. 23. Williamson KK, Willard MD, Payton ME, et al: Efficacy of omeprazole versus high-dose famotidine for prevention of exercise-induced gastritis in racing Alaskan sled dogs, J Vet Intern Med 24:285, 2010.

24. Panti A, Bennett RC, Corletto F, et al: The effect of omeprazole on oesophageal pH in dogs during anaesthesia, J Small Anim Pract 50:540, 2009. 25. Lazzaroni M, Porro GB: Management of NSAID-induced gastrointestinal toxicity: focus on proton pump inhibitors, Drugs 69:51, 2009. 26. Mansell P, Robinson K, Minck D, et al: Toxicology and toxicokinetics of oral pantoprazole in neonatal and juvenile dogs, Birth Defects Res B Dev Reprod Toxicol 92:345, 2011. 27. Shimura S, Hamamoto N, Yoshino N, et al: Diarrhea caused by proton pump inhibitor administration: comparisons among lansoprazole, rabeprazole, and omeprazole, Curr Ther Res 73:112, 2012. 28. Chang Y: Hypersensitivity reactions to proton pump inhibitors, Curr Opin Allergy Clin Immunol 12:348, 2012. 29. De Milito A, Marino ML, Fais S: A rationale for the use of proton pump inhibitors as antineoplastic agents, Curr Pharm Des 18:1395, 2012. 30. Perez-Villanueva J, Romo-Mancillas A, Hernandez-Campos A, et al: Antiprotozoal activity of proton pump inhibitors, Bioorg Med Chem Lett 21:7351, 2011. 31. Dallwig B: Sucralfate, J Exotic Pet Med 19:101, 2010. 32. Laine L, Takeuchi K, Tarnawski A: Gastric mucosal defense and cytoprotection; bench to bedside, Gastroenterol 135:41, 2008. 33. Dewan B, Balasubramanian A: Troxipide in the management of gastritis: a randomized comparative trial in general practice, Gastroenterol Res Pract 2010:758397, 2010. 34. Akagi M, Amagase K, Murakami, et al: Irsogladine: overview of the mechanism of mucosal protective and healing-promoting actions in the gastrointestinal tract, Curr Pharm Des 19:106, 2013. 35. Abraham NS: Proton pump inhibitors: potential adverse effects, Curr Opin Gastroenterol 28:615, 2012. 36. Moayyedi P, Leontiadis GI: The risks of PPI therapy, Nat Rev Gastroenterol Hepatol 9:132, 2012.

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CHAPTER 162  ANTIEMETICS AND PROKINETICS Michael D. Willard,

DVM, MS, DACVIM (Internal Medicine)

KEY POINTS • The medullary vomiting center (MVC) probably is not a focal, discrete area in the brain; rather, it is spread throughout the medulla. • Centrally acting antiemetics are more effective than peripherally acting antiemetics. Centrally acting antiemetics that work on the MVC typically are more effective than those that act only at the chemoreceptor trigger zone. • Maropitant (a neurokinin-1 antagonist) is highly effective in dogs and cats with minimal adverse effects other than pain upon subcutaneous injection. • The serotonin (5-HT3) receptor antagonists ondansetron and dolasetron are usually effective in dogs and cats and have few adverse effects. • Metoclopramide is a dopamine receptor antagonist that works at the chemoreceptor trigger zone and is also a gastric prokinetic. Metoclopramide can sometimes cause abnormal behavior and even vomiting (possibly due to excessive gastric prokinetic activity). It tends to be less effective in cats than in dogs.

• Promazine derivatives (e.g., chlorpromazine, prochlorperazine) are effective centrally acting antiemetics that can cause sedation and hypotension due to α-adrenergic blocking activity.

ANTIEMETICS Antiemetics are indicated primarily when vomiting makes it difficult to maintain energy, fluid, or electrolyte homeostasis or when quality of life is adversely impacted by nausea (Table 162-1). Not every vomiting patient should receive an antiemetic; sometimes it is more appropriate to allow a patient to vomit once or twice a day to assess the effectiveness of treatment for the underlying disease. Typical indications for antiemetics include pancreatitis, gastritis, enteritis, peritonitis, hepatic disease, renal insufficiency, and motion sickness; they are also used in patients at risk of aspiration pneumonia. With

CHAPTER 162  •  Antiemetics and Prokinetics

Table 162-1  Centrally Acting Antiemetics Commonly Used in Dogs and Cats Drug

Dosage

Special Considerations

Maropitant

1 mg/kg SC q24h or 2 mg/kg PO q24h 8 mg/kg PO q24h for up to 2 days for motion sickness in dogs; 1 mg/kg SC, IV, PO q24h in cats

Approved antiemetic for dogs and cats

Ondansetron

0.1-1 mg/kg IV, PO q8-12h

—

Granisetron

0.1-0.5 mg/kg IV q8-24h

—

Dolasetron

0.6-1 mg/kg IV, SC, PO q12-24h

—

Metoclopramide

0.1-0.5 mg/kg IV, IM, PO q8-12h or CRI of 1-2 mg/kg/24 h for nausea

Gastric prokinetic Can cause extrapyramidal effects if overdosed Note: for treatment of gastroesophageal reflux/ileus, 0.3 mg/kg/hr IV after a 0.4 mg/kg loading dose IV

Chlorpromazine

0.5 mg/kg IV, IM, SC q6-8h in dogs 0.2-0.4 mg/kg IM, SC q6-8h in cats

Can cause hypotension and sedation

Prochlorperazine

0.1-0.5 mg/kg IV, IM, SC q8-12h

Can cause hypotension and sedation

CRI, Constant rate infusion; IM, intramuscularly; IV, intravenously; PO, per os; SC, subcutaneously.

the exception of the neurokinin-1 (NK-1) receptor antagonists, antiemetic drugs are usually ineffective in patients with gastrointestinal (GI) obstruction. Parenteral administration is typically preferred in actively vomiting patients because oral administration will be ineffective if the drug is vomited before absorption.

Neurokinin-1 Receptor Antagonists Maropitant is an NK-1 receptor antagonist that blocks the action of substance P in the central nervous system as well as at peripheral NK-1 receptors in the GI tract.1 It is approved for use in dogs and cats and is considered a safe and effective drug. Dogs are typically treated with 1 mg/kg subcutaneously (SC) or 2 mg/kg orally (PO) q24h for up to 5 consecutive days. Anecdotally, maropitant has been administered intravenously in patients with poor peripheral perfusion and as a way to avoid the pain associated with subcutaneous administration. This appears to be a safe, effective route, but pharmacokinetic studies are lacking. Maropitant often causes pain when injected and is reported to cause bone marrow hypoplasia when administered to puppies younger than 11 weeks old. The drug undergoes extensive first-pass metabolism in the liver; hence, it has a much higher bioavailability when given subcutaneously (90%) than when given orally (23% to 37%, which is not affected by feeding). It can have nonlinear kinetics as the dose is changed.2 It is effective in preventing vomiting due to motion sickness,3 vomiting caused by various spontaneous illnesses,4 and nausea associated with chemotherapy (doxorubicin and cisplatinum)5 in dogs, as well as motion sickness6 and xylazine-induced emesis in cats when used at 1 mg/kg SC, PO, or intravenously [IV]. NK-1 antagonists are thought to have many other effects beyond antiemesis (e.g., antiinflammatory, neuroprotectant, hepatoprotectant), although their clinical usefulness for these purposes is as yet unproven.7 Reduction of diarrhea in patients receiving chemotherapy has been reported, and there is some suggestion that NK-1 antagonists may have antitumor activity. They appear to reduce visceral pain in cats and dogs and reduce the minimum alveolar concentration of sevoflurane during anesthesia if given intravenously.8,9

5-HT3 Receptor Antagonists10 Ondansetron, granisetron,11 and dolasetron,12 were developed to alleviate chemotherapy-associated nausea in people. These drugs are competitive blockers of the serotonin (5-HT3) receptors, which are found both peripherally (where they are responsible for intestinal

vagal afferent input) and centrally (in the chemoreceptor trigger zone [CRTZ] and medullary vomiting center [MVC]). Ondansetron has been used off label in veterinary medicine for over a decade and has been anecdotally reported to stop vomiting effectively in patients not responding to metoclopramide or promazine treatment (e.g., puppies with parvoviral enteritis). Ondansetron is metabolized by the liver and is usually administered at a dosage of 0.1 to 1.0 mg/kg IV q8-12h. It has the unusual characteristic in people of inhibiting emesis at low and high dosages while enhancing emesis at intermediate dosages (the same has been shown for metoclopramide in humans). Dolasetron is metabolized into the active fraction (hydrodolasetron) by the ubiquitous carbonyl reductase. It is eliminated from the body by hepatic P-450 enzymes. It usually is administered to dogs and cats at a dosage of 0.6 to 1 mg/ kg SC, IV, or PO q12-24h. The antiemetic effects of these drugs linger after the drug disappears from the blood; therefore they need to be administered only q8-24h. They are ultimately eliminated in the urine and bile. There is a wide margin of safety in humans, and adverse effects seem to be rare in dogs and cats. Adverse effects in humans may include constipation, diarrhea, and somnolence. Prolongation of the QT interval is reported with dolasetron, but the importance of this in veterinary medicine is doubtful. These drugs have minimal interactions with other drugs. Ondansetron is reported to decrease the efficacy of tramadol. It has been suggested that because there are many 5-HT3 receptors in the GI tract, administering dolasetron orally might produce both a peripheral and a central antiemetic effect. Dolasetron is reported to have excellent bioavailability when given orally. Combining dolasetron with metoclopramide is often effective for chemotherapyinduced nausea that is resistant to other antiemetics.11 Ondansetron is effective in preventing emesis caused by dexmedetomidine when the latter is used as a preanesthetic in cats, but it must be given at the same time as the dexmedetomidine.13

Metoclopramide Metoclopramide is a popular antiemetic. Its antidopaminergic activity and ability to block 5-HT3 receptors make it a potent blocker of the CRTZ. However, cats are thought to have a paucity of dopamine receptors, which may explain why the drug seems less effective in that species. Typically given at 0.1 to 0.5 mg/kg IV, SC, or PO, metoclopramide also has gastric prokinetic activity that facilitates gastric

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emptying and decreases gastroesophageal reflux, although markedly higher dosages may be required in order to achieve these actions. This combination of mechanisms should be very effective; however, clinical practice has shown that metoclopramide is often inadequate in patients with a strong stimulus to vomit (e.g., severe pancreatitis or renal failure). Its effectiveness can be enhanced if it is administered as a constant rate infusion. Intravenous dose recommendations vary and lower dosages are typically adequate for antiemetic actions (1 to 2 mg/kg q24h), but higher doses are necessary to promote gastrokinesis and prevent gastroesophageal reflux (loading dose of 0.4 mg/ kg IV, followed by 0.3 mg/kg/hr IV). The drug is sensitive to light, so the intravenous solution should be covered to prevent loss of efficacy. In people undergoing chemotherapy, metoclopramide’s effectiveness may be enhanced by concurrent administration of low-dose dexamethasone, but this practice has not been critically evaluated in dogs or cats. Metoclopramide is excreted by the kidneys, and care must be taken when using it in patients with substantially decreased glomerular filtration. If high blood levels occur due to renal dysfunction or overdosage, extrapyramidal signs (e.g., behavioral changes, apparent hallucinations) may occur. Such patients may display clinical signs similar to those seen with amphetamine intoxication (e.g., hyperactivity, frenzied behavior).

Promazine Derivatives Promazine derivatives are broad-spectrum, inexpensive, centrally acting antiemetics14-16 that are effective against most causes of nausea except inner ear problems. They have antidopaminergic and antihistaminic effects that block the CRTZ and, at higher dosages, the MVC. These drugs also have anticholinergic, antispasmodic, and α-adrenergic blocking effects. The promazine derivatives used most commonly as antiemetics in small animal veterinary medicine are chlorpromazine, prochlorperazine,17 and acepromazine. Chlorpromazine typically is used at 0.1 to 0.5 mg/kg IV, SC, or intramuscularly (IM) q6-8h, and prochlorperazine is used at 0.1 to 0.5 mg/kg IV, IM, or SC q8-12h in dogs. The antiemetic effect of these drugs is typically evident at dosages lower than those causing sedation; however, varying degrees of vasodilation may occur, producing hypotension. Therefore caution is necessary in dehydrated or hypotensive patients; concurrent intravenous fluid therapy may be necessary. Promazine drugs have been reported to increase central venous pressure and change the heart rate (bradycardia or tachycardia), and they possess antiarrhythmic qualities in the dog. These drugs were once believed to lower the seizure threshold, but this is now doubted.18 The promazines are metabolized by the liver and can cause central nervous system signs in patients with substantial hepatic insufficiency, especially those with congenital portosystemic shunts. It has been suggested that prochlorperazine and perhaps other promazine derivatives not be used concurrently with metoclopramide because these drugs may potentiate extrapyramidal effects. The clinical importance of this is uncertain.

Anticholinergic Agents Aminopentamide (0.01 to 0.03 mg/kg IM, SC, or PO q8-12h) is an anticholinergic agent that has been used as an antiemetic in dogs. There are cholinergic receptors in the brain involved in the vomiting center and in the upper GI tract via the vagus nerve. The latter are muscarinic receptors. It is uncertain which receptors aminopentamide affects, but the drug appears to have relatively few of the typical adverse effects that other anticholinergic agents have on the GI tract (e.g., paralysis, distention). Clinically, aminopentamide appears to be less effective than metoclopramide and is certainly inferior to the 5-HT3 and NK-1 antagonists. Other anticholinergic medications (e.g., atropine, propantheline, glycopyrrolate) tend to be less effective

or have more adverse effects (e.g., greater inhibition of GI motility). Aminopentamide should be used with caution in animals with glaucoma, cardiomyopathy, tachyarrhythmias, hypertension, myasthenia gravis, or gastroesophageal reflux.

Other Drugs Trimethobenzamide has antidopaminergic properties but appears to be a relatively weak antiemetic in dogs. Steroids, especially dexamethasone and methylprednisolone, have been used to prevent nausea in humans undergoing chemotherapy or general anesthesia.19 There are limited data on the efficacy of steroids in cats,11,20 but their common use and apparent effectiveness in vomiting cats diagnosed with inflammatory bowel disease at least raises the question of whether they have primary antiemetic actions. In humans, steroids are primarily used as an antiemetic in combination with other drugs such as metoclopramide. Megestrol acetate21 and gabapentin22 have been used as adjuncts in people receiving highly emetogenic chemotherapy protocols in whom vomiting is not adequately controlled with other combination antiemetic therapy. Their use for this purpose has not been reported in veterinary medicine but might be considered in severe cases that are resistant to more traditional therapy. Propofol has a variety of nonanesthetic effects, including antiemesis. Its use for induction and/ or maintenance of anesthesia has been associated with less vomiting in human patients.23 Based on the apparent response of some patients with “limbic epilepsy” and sialomegaly to phenobarbital, there is some thought that phenobarbital might have antiemetic activity.24 No studies clearly confirm or deny this possibility in dogs or cats. Finally, it may be worth noting that acupuncture has been reported to lessen postoperative nausea in people.25

Peripherally Acting Antiemetics Drugs that soothe inflamed mucosal lesions (e.g., bismuth subsalicylate or barium sulfate) or relieve dyspepsia (e.g., antacid drugs) can be used to alleviate vomiting (see Chapter 161). However, they are typically much less effective than the other drugs that have been discussed.

PROKINETIC DRUGS Prokinetic drugs promote the orad to aborad movement of intraluminal contents. In veterinary medicine, they are primarily used to promote gastric emptying and colonic emptying.

5-HT4 Serotonergic Agonists 5-HT4 serotonergic agonists26 are the most effective class of prokinetic drugs in veterinary medicine. Cisapride is no longer available for use in people but is available to veterinarians from compounding pharmacies. It has been the primary drug of this class used in veterinary medicine for treating gastroesophageal reflux, poor gastric emptying, and chronic constipation. The drug is well absorbed after oral administration and is primarily eliminated by first-pass metabolism in the liver (hence, elimination may be delayed in animals with severe hepatic insufficiency). Cisapride has approximately 30% bioavailability after oral administration in cats. Cisapride (0.5 to 1.0 mg/kg PO q8-24h in dogs; 2.5 to 5 mg/cat q8-12h PO in cats) enhances gastric emptying while simultaneously increasing gastroesophageal sphincter pressure.27,28 It is more effective than metoclopramide in treating patients with gastroesophageal reflux and delayed gastric emptying. Although frequently used to try to enhance esophageal motility in patients with megaesophagus, it is ineffective on striated muscle. The fact that cisapride increases gastroesophageal sphincter tone may make regurgitation worse in such patients (unless gastroesophageal reflux is a major contributing

CHAPTER 162  •  Antiemetics and Prokinetics

factor to the patient’s regurgitation). Cisapride has been effective in treating idiopathic constipation in cats with mild to moderate disease; however, severe disease responds poorly. Finally, cisapride increases small intestinal motility; however, this effect has not found a major application in small animal medicine, probably because many critically ill postoperative patients cannot tolerate oral medications. Cisapride has been responsible for several human deaths due to its effect on cardiac conduction; however, death has not been reported in dogs or cats. Other adverse effects seem rare. Mosapride (0.25 to 1 mg/kg PO q12h) has recently become available in Japan.29 It is somewhat similar to cisapride except that it has minimal effects on colonic motility. It can be administered intravenously, which would be advantageous in many critically ill patients. Tegaserod (0.05 to 0.1 mg/kg PO q12h) and prucalopride (0.01 to 0.2 mg/kg PO q12h) are similar drugs currently available in Europe. Tegaserod primarily enhances colonic motility, whereas prucalopride can increase both gastric and colonic motility. There is currently minimal clinical experience with these drugs in veterinary medicine.

Cholinomimetic Drugs Bethanechol, ranitidine, and nizatidine are the primary examples of the cholinomimetic class of prokinetic drugs. Ranitidine and nizatidine inhibit acetylcholinesterase, whereas bethanechol is a true cholinomimetic drug that binds to muscarinic receptors. Bethanechol (5 to 15 mg/dog PO q8-12h) affects motility throughout the GI tract, whereas ranitidine (1 to 2 mg/kg PO or IV q12h) and nizatidine (2.5 to 5 mg/kg PO or IV q12h) seem more effective for promoting gastric emptying than colonic motility.

Motilin Receptor Agonists Erythromycin (0.5 to 1 mg/kg PO or IV q8h) stimulates motilin receptors and has been used to promote GI motility in a variety of clinical situations in dogs. It increases lower esophageal sphincter pressure as well as small and large bowel peristalsis.30 There is some concern that tolerance will develop with sustained use of the drug, rendering it less effective.

Metoclopramide Metoclopramide is probably the most commonly used prokinetic in veterinary medicine. It was discussed in detail earlier in the section on antiemetics. Metoclopramide’s method of action is somewhat debated and appears to involve more than just dopamine receptors; it may increase the sensitivity of the smooth muscle in the small intestine to the effects of acetylcholine. Its primary use in veterinary medicine is as a moderately effective gastric prokinetic. Cisapride is a more effective prokinetic, but metoclopramide can be administered by constant IV infusion, which is advantageous in some patients. Rather high doses are required to cause prokinesis and reduce gastroesophageal reflux: 0.4 mg/kg IV as a loading dose and then 0.3 mg/kg/hr is recommended for this purpose (note this is higher than typically recommended to prevent nausea: 1 to 2 mg/kg/24 h). Intermittent dosing is also possible (0.2 to 0.5 mg/kg PO, SC, or IM q6-8h).

Misoprostol Misoprostol, a prostaglandin E analog, is discussed in Chapter 161. It appears to enhance colonic motility and has been used in patients with nonresponsive constipation.

REFERENCES 1. Sedlacek HS, Ramsey DS, Boucher JF, et al: Comparative efficacy of maropitant and selected drugs in preventing emesis induced by centrally

or peripherally acting emetogens in dogs, J Vet Pharmacol Ther 31:533, 2008. 2. Benchaoui HA, Cox SR, Schneider RP, et al: The pharmacokinetics of maropitant, a novel neurokinin type-1 receptor antagonist, in dogs, J Vet Pharmacol Ther 30:336, 2007. 3. Conder GA, Sedlacek HS, Boucher JF, et al: Efficacy and safety of maropitant, a selective neurokinin1 receptor antagonist, in two randomized clinical trials for prevention of vomiting due to motion sickness in dogs, J Vet Pharmacol Ther 31:528, 2008. 4. Ramsey DS, Kincaid K, Watkins JA, et al: Safety and efficacy of injectable or oral maropitant, a selective neurokinin1 receptor antagonist, in a randomized clinical trial for treatment of vomiting in dogs, J Vet Pharmacol Ther 31:538, 2008. 5. Rau SE, Barber LG, Burgess KE: Efficacy of maropitant in the prevention of delayed vomiting associated with administration of doxorubicin in dogs, J Vet Intern Med 24:1452, 2010. 6. Hickman MA, Cox SR, Mahabir S, et al: Safety, pharmacokinetics and use of the novel NK-1 receptor antagonist maropitant (Cerenia™) for the prevention of emesis and motion sickness in cats, J Vet Pharmacol Ther 31:220, 2008. 7. Munoz M, Covenas R: NK-1 receptor antagonists: a new paradigm in pharmacological therapy, Curr Med Chem 18:1820, 2011. 8. Boscan P, Monnet E, Mama K, et al: Effect of maropitant, a neurokinin 1 receptor antagonist, on anesthetic requirements during noxious visceral stimulation of the ovary in dogs, Am J Vet Res 72:1576, 2011. 9. Alvillar BM, Boscan P, Mama KR, et al: Effect of epidural and intravenous use of the neurokinin-1 (NK-1) receptor antagonist maropitant on the sevoflurane minimum alveolar concentration, Vet Anaesth Analg 39:201, 2012. 10. Machu TK: Therapeutics of 5-HT3 receptor antagonists: current uses and future directions, Pharmacol Ther 130:338, 2011. 11. Rudd JA, Tse JYH, Wai MK: Cisplatin-induced emesis in the cat: effect of granisetron and dexamethasone, Eur J Pharmacol 391:145, 2000. 12. Ogilvie GK: Dolasetron: a new option for nausea and vomiting, J Am Anim Hosp Assoc 36:481, 2000. 13. Santos PCP, Ludders JW, Erb HN, et al: A randomized, blinded, controlled trial of the antiemetic effect of ondansetron on dexmedetomidineinduced emesis in cats, Vet Anaesth Analg 38:320, 2011. 14. Boothe DM: Gastrointestinal pharmacology. In Boothe DM, editor: Small animal clinical pharmacology and therapeutics, ed 2, St Louis, 2012, Saunders, pp 672-739. 15. Sharky KA, Wallace JL: Treatment of disorders of bowel motility and water flux; antiemetics; agents used in pancreatic and biliary tract disease. In Brunton LL, Chabner BA, Knollmann BC, editors: Goodman’s and Gilman’s The pharmacological basis of therapeutics, ed 12, New York, 2012, McGraw-Hill, pp 1323-1349. 16. McQuaid KR: Drugs used in the treatment of gastrointestinal diseases. In Katzung BG, editor: Basic and clinical pharmacology, ed 9, New York, 2004, Lange Medical Books/McGraw-Hill, pp 1034-1063. 17. Bezek DM: Use of prochlorperazine in treatment of emesis in dogs, Can Pract 23:8, 1998. 18. Tobiad K, Marion-Henry K, Wagner R: A retrospective study on the use of acepromazine maleate in dogs with seizures, J Am Anim Hosp Assoc 42:283, 2006. 19. Grunberg SM: Antiemetic activity of corticosteroids in patients receiving cancer chemotherapy: dosing, efficacy, and tolerability analysis, Ann Oncol 18:233, 2007. 20. Ho CM, Ho ST, Wang JJ, et al: Dexamethasone has a central antiemetic mechanism in decerebrated cats, Anesth Analg 99:734, 2004. 21. Zang J, Hou M, Gou HF, et al: Antiemetic activity of megestrol acetate in patients receiving chemotherapy, Support Care Cancer 19:667, 2011. 22. Cruz FM, Cubero DIG, Taranto P, et al: Gabapentin for the prevention of chemotherapy-induced nausea and vomiting: a pilot study, Support Care Cancer 20:601, 2012. 23. Vasileiou I, Xanthos T, Koudouna E, et al: Propofol: a review of its nonanaesthetic effects, Eur J Pharmacol 605:1, 2009. 24. Boydell P, Pike R, Crossley D, et al: Sialadenosis in dogs, J Am Vet Med Assoc 216:872, 2000.

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25. Pettersson PH, Wengstrom Y: Acupuncture prior to surgery to minimize postoperative nausea and vomiting: a systematic review, J Clin Nurs 21:1799, 2012. 26. DeMaeyer JH, Lefebvre RA, Schuurkes JAJ: 5-HT4 receptor agonists: similar but not the same, Neurogastroenterol Motil 20:99, 2008. 27. Washabau RJ, Holt DE: Pathophysiology of gastrointestinal disease. In Slatter D, editor: Textbook of veterinary surgery, ed 3, Philadelphia, 2003, Saunders, pp 530-552.

28. Azcuto AC, Marks SL, Osborn J, et al: The influence of esomeprazole and cisapride on gastroesophageal reflux during anesthesia in dogs, J Vet Intern Med 26:518, 2012. 29. Tsukamoto A, Ohno K, Madea S, et al: Prokinetic effect of the 5-HT4R agonist Mosapride on canine gastric motility, J Vet Med Sci 73:1635, 2011. 30. Melgarejo LT, Simon DA, Washabau RJ: Erythromycin stimulates canine but not feline longitudinal colonic muscle contraction, J Vet Intern Med 15:333, 2001.

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CHAPTER 163  NARCOTIC AGONISTS AND ANTAGONISTS Ralph C. Harvey,

DVM, MS, DACVAA

KEY POINTS • Opioids are an important class of drugs for critically ill veterinary patients because of their effectiveness and relative cardiovascular safety. • Opioids are most commonly used for analgesia but may also be prescribed for antitussive or sedative therapy. • The most commonly used opioids include morphine, methadone, fentanyl, hydromorphone or oxymorphone, buprenorphine, and butorphanol. • It is important that the veterinarian understand the clinical effectiveness, potencies, and potential adverse effects of the various opioids before using them. • Opioid antagonists include naloxone, nalmefene, and naltrexone. Butorphanol and nalbuphine commonly are used for partial reversal of pure µ-agonist drugs.

Opiate The term opiate specifically refers to drugs derived from opium. The first of these was morphine, isolated and recognized in 1803 as the active ingredient in laudanum by Friedrich Wilhelm Adam Ferdinand Serturner, an assistant apothecary. This contribution has been recognized as the beginning of the modern era of pharmacology.

Opioid The term opioid is a more precise, yet broadly inclusive, term for synthetic as well as opium-derived compounds that bind specifically to several opioid receptors and thereby have some morphine-like effects.

Narcotic Opioids play a variety of roles in veterinary critical care. The foremost of these is as the foundation of analgesic therapy, but they are also used for their sedative and antitussive effects. Less frequent applications include supporting right-sided heart function and controlling compulsive behaviors. In the past, opioids were also used to decrease gastrointestinal (GI) motility. As analgesics, the opioids are the first line of defense in managing pain due to injury and disease. The remarkable cardiovascular system–sparing effects and inherent safety of opioid therapy in critically ill patients are prominent advantages of this class of drugs. Opioids anchor contemporary balanced or multimodal strategies for pain management (see Chapter 144). Although this chapter deals specifically with the opioids, other publications extend the topic of analgesia in critical care to encompass complementary classes of analgesic drugs and other approaches to pain management.1,2

TERMINOLOGY AND HISTORY Opium At least 20 distinct alkaloids are derived from the juice of the poppy. Among these, the phenanthrenes are represented by morphine and the benzylisoquinoline derivatives by papaverine.

The word narcotic was derived from a Greek word for sleep or stupor. Because this group of compounds does not readily and reliably produce sleep in all veterinary patients, the term is a less than appropriate descriptor in veterinary medicine. Law enforcement organizations may refer to many substances with a potential for diversion and abuse as narcotics. This term includes both opioid and nonopioid controlled substances and often leads to confusion. Controlled substances, including the opioids, must be kept secure under lock and key. Accurate and appropriate inventory control is required, with the level of control for each drug related to the relative potential for abuse.

STRUCTURE-ACTIVITY RELATIONSHIP The phenanthrene opioid compounds have a three-ring nucleus and a piperidine ring structure with a tertiary amine nitrogen. The levorotatory forms are much more active agonists than the dextrorotary forms.

MECHANISM OF ACTION Opioids bind to stereospecific opioid receptors located most notably in the central nervous system (CNS) but also in many other sites

CHAPTER 163  •  Narcotic Agonists and Antagonists

throughout the body. The receptor affinity correlates well with analgesic potency for the opioids classified as pure agonists only. Receptor binding of endogenous or exogenous ligands activates G proteins as second messengers, modulates adenylate cyclase activity, and thereby alters transmembrane transport of effectors. Opioids also interfere presynaptically with the release of neurotransmitters. These changes result in interruption of the pain message to the brain and a decreased sensation of pain within the brain. Opioids do not alter the responsiveness of afferent nerve endings to noxious stimuli, nor do they impair conduction of nerve impulses along peripheral nerves.

OPIOID RECEPTORS There are a variety of opioid receptors and subtypes of receptors within many tissues throughout the body. Differential binding and activation at specific receptors (µ-receptor, κ-receptor, δ-receptor, and the more recently recognized opiate-like receptor 1, also known as OLR-1 or nociceptin receptor), principally in the CNS and the gut, serve to mediate the spectrum of opioid effects. Alternative terminology for the opioid receptors (OP-1 to OP-4) recognizes the order of discovery of the opioid receptor proteins. Another nomenclature, MOP, DOP, KOP, and NOP, has also been suggested, but the traditional µ-, κ-, and δ-receptor designation remains predominant.

PHYSIOLOGIC EFFECTS OF OPIOIDS The occupation of CNS receptor sites by opioids produces analgesia, sedation, muscle relaxation, and behavior modification. The CNSdepressant action of the opioids results from their effects on the cerebral cortex. In contrast to the more typical sedation and narcosis produced in human patients, disorientation and excitement may also occur in veterinary patients receiving opioid therapy. The excitatory behavioral activity results from the effects of the drug on the hypothalamus. The ability of the opioids to cause depression or excitement is highly drug and species dependent. Excitatory responses may be linked to an indirect activation of dopaminergic receptors. The major tranquilizers, the benzodiazepines and phenothiazines, can block this activation. Combinations of some opioids and tricyclic antidepressants can produce hypotension. Meperidine, and occasionally other opioids, when administered to patients receiving monoamine oxidase inhibitors (e.g., selegiline hydrochloride, L-deprenyl [Anipryl]) can result in rare but severe and immediate reactions that include excitation, rigidity, hypertension, and severe respiratory depression. Opioids can be potent respiratory depressants, reducing both respiratory rate and tidal volume. Although this is rarely a clinically significant problem in healthy patients, special attention is warranted in critically ill patients. Animals with increased susceptibility to respiratory effects include those with underlying airway obstruction (e.g., brachycephalic animals) and those with pulmonary disease. The opioids directly depress the pontine and medullary respiratory centers. They also produce a delayed response (altered threshold) and decreased response (altered sensitivity) to arterial carbon dioxide, which leads to retention of carbon dioxide. Tachypnea is sometimes observed after opioid administration and may be due to excitation and/or alteration of the thermoregulation center. Panting in dogs is most notable with oxymorphone and hydromorphone administration. Bronchoconstriction may also occur. A rare and incompletely understood complication of opioid therapy is a phenomenon known as wooden chest. In this syndrome, the patient’s chest wall muscles become spastic, which makes ventilation difficult. Treatment involves

reversal of the effects of the opioid drug and, if necessary, muscle relaxant therapy. At therapeutic dosages, the opioids have minimal effects on the cardiovascular system. There is little or no change in blood pressure and myocardial contractility. The opioids can produce a vagally mediated bradycardia that is responsive to atropine or other anticholinergic agents. The decrease in heart rate may also be a manifestation of effective pain relief. The opioids affect the ability of the vascular system to compensate for positional and blood volume changes, although orthostatic hypotension is presumably more problematic in bipedal than quadrupedal patients. Among the opioids, morphine, methadone, and meperidine can cause histamine release, leading to marked hypotension. To minimize histamine-related complications following intravenous administration of morphine, the drug should be diluted with saline and the injection given slowly over 10 to 20 minutes.1,3 Morphine, methadone, and meperidine are contraindicated in patients with mast cell tumors or other histamine-based diseases. Other opioids are much less likely to cause significant histamine release. A variety of other physiologic effects may be of interest in the critical care setting. The opioids produce an initial stimulation of the GI tract (vomiting, defecation, or both) followed by a decrease in motility. Most opioids cause release of antidiuretic hormone. Urine retention due to bladder atony is an infrequent, but clinically significant, problem in some animals receiving opioid therapy. Bladder emptying should be verified in all patients. Some animals receiving opioids may unexpectedly overrespond to noises or sensory stimuli. When this occurs, it can contribute to dysphoria and increase stress in the critically ill patient. The importance of a quiet and calming environment is recognized, but this is challenging to achieve in many critical care settings. Placing cotton balls or foam earplugs in the ears may help to alleviate the noise sensitivity. Decreased body temperature may be observed in patients receiving opioids because the thermoregulatory center in the hypothalamus is reset to a lower setting. Panting in dogs is one manifestation of altered body temperature regulation. Alternatively, significant increases in body temperature occasionally occur after opioid administration. This appears to be most common in cats and somewhat drug and dosage dependent. Cats receiving higher than usual clinical dosages of morphine, meperidine, and hydromorphone frequently developed increased body temperature (40° to 41.7° C [104° to 107° F]) in one study. Buprenorphine did not result in hyperthermia in feline clinical or research models.4

METABOLISM AND EXCRETION Metabolic elimination of most opioids is accomplished by hepatic conjugation and metabolite excretion in the urine (the exception is remifentanil, which is rapidly metabolized by nonspecific plasma esterases). The principal metabolites can be highly active, as in the case of morphine in humans. The meperidine metabolite normeperidine is a convulsant. Extended therapy with meperidine can lead to neurotoxicity and seizures. Opioid overdoses can effectively change the kinetics of elimination from first order to zero order by saturating the processes responsible for elimination and thereby greatly prolonging the duration of action. This is perhaps most notable with large overdoses of butorphanol, which lead to a prolonged period of sedation but, as a result of the presumed ceiling effect seen with this agonist-antagonist opioid, cause little increase in the magnitude of sedation or analgesia. Independent of any conditions altering elimination, the duration of action of the clinically useful opioids ranges widely, from less than 30 minutes (e.g., remifentanil and fentanyl) to as long as 8 hours (e.g., buprenorphine).

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CHARACTERISTICS OF CLINICALLY USEFUL OPIOIDS

Table 163-1  Relative Potencies of Opioids Opioid

Relative Potency

Morphine

1

Methadone

1

Meperidine (Demerol) Codeine Butorphanol (Torbugesic) Nalbuphine (Nubain)

1

5

1 10

3-5 0.5-0.9

Hydromorphone (Dilaudid)

10

Oxymorphone (Numorphan)

10

Buprenorphine (Buprenex)

50-100

Fentanyl (Sublimaze)

100-150

Remifentanil (Ultiva)

200-300

Pentazocine (Talwin) Etorphine (M-99)

1

3

1000-80,000

POTENCY AND EFFECTIVENESS OF OPIOIDS The relative potencies of opioids are compared with the potency of morphine on an “equal-analgesic” basis (Table 163-1). For the pureagonist opioids, maximum biologic effect (e.g., analgesia or respiratory depression) is relatively dosage dependent. The relative potency and the relative lack of analgesic efficacy of butorphanol, typically classified as a mixed agonist-antagonist opioid, provide an excellent example of the difference between effectiveness and potency. Clinical effectiveness helps identify medications useful for a specific purpose, and potency helps define dosage within the limits of effectiveness. Recommended dosages of several opioids for analgesia in critical care patients are listed in Table 163-2. Dosage ranges are broad for the opioid analgesics, and titration to achieve the desired effect is needed to care for this group of critically ill patients.

EPIDURAL OPIOIDS Spinal or epidural (neuroaxial) opioid analgesia has been well described and proven effective in veterinary medicine. Epidural morphine analgesia is widely used and is increasingly popular as a method for providing long-lasting profound analgesia. The resultant reduced dosage requirement for systemic opioids decreases dose-dependent undesirable systemic effects, which makes neuroaxial analgesia techniques especially useful in critically ill animals. These techniques are rather simple, are easily implemented using basic clinical skills, and can be cost effective for providing substantial analgesia. A relatively small dose of morphine (0.1 mg/kg) is typically administered by epidural injection after induction of general anesthesia or heavy sedation. Effective pain relief begins within approximately 30 minutes and persists for 12 to 24 hours. Addition of a local anesthetic, typically bupivacaine (0.5 mg/kg), to the epidural injection further provides a blunting of deleterious postoperative or injury-associated increases in stress hormone levels and the metabolic response to surgery. An epidural catheter can also be placed to facilitate repeated dosing or provide a constant rate infusion (CRI) into the epidural space (see Chapter 144). Contraindications to epidural injection or catheter placement include local infection, coagulopathy, neurologic dysfunction, marked obesity (which increases difficulty), and hypovolemia with hypotension (one should avoid the local anesthetics or compensate with intravenous fluids for volume expansion).

Morphine Morphine, a pure-agonist opioid, is not only the standard of comparison for other opioids but remains one of the most useful analgesic medications. Morphine confers sedation in addition to analgesia, and both effects are dosage dependent, reliable, and effective in many clinical settings. Vomiting, diarrhea, and bradycardia may occur, but these are seen less commonly when morphine is given to treat existing pain than when it is given in the absence of pain. Vomiting may also be less common when diluted morphine is injected slowly intravenously rather than intramuscularly or subcutaneously. There is rapid absorption and almost complete bioavailability of morphine administered by either subcutaneous (if well-hydrated) or intramuscular injection.5 Dosage recommendations do not differ with the route of injection. When possible, opioids should be administered by the intravenous rather than the intramuscular or subcutaneous route to reduce trauma and stress in critically ill patients. Hypotension and bronchoconstriction occur in some patients as a result of histamine release, especially in dogs and following intravenous administration. Morphine is contraindicated in patients with mast cell tumors or other histamine-release abnormalities (see earlier section on the physiologic effects of opioids). A CRI of morphine (with or without other analgesics) is very useful in the treatment of critical care patients experiencing pain. The relatively long plasma half-life of morphine can lead to an increasing plasma concentration when the drug is given as a CRI. This potential problem is minimized by adjusting the infusion as needed to balance analgesia and sedation. The CRI becomes an adjustable rate infusion, with drug dosage titrated to achieve the desired effect. The use of a neuroleptanalgesic (an opioid combined with an anxiolytic drug) or the mixture of morphine, lidocaine, and ketamine delivered as a CRI is effective in many patients.1,6 One of many recipes for the latter cocktail is given in the next paragraph. See Chapters 142 and 144 for more useful information on sedation and analgesia and CRIs suitable for delivery using controlled syringe or bag-based delivery pumps. Morphine-lidocaine-ketamine CRI: 1. Remove 73 ml from a 1-L bag of saline or balanced electrolyte fluids. 2. Add 68 ml of 2% lidocaine, 4 ml of morphine (15 mg/ml), and 0.6 ml ketamine (100 mg/ml). 3. Begin CRI at 1 to 2 ml/kg/hr. 4. Adjust as needed for comfort and sedation. Oral administration of morphine may be effective in some dogs, but the drug is poorly and erratically absorbed from the GI tract.7 Individual variability in bioavailability following oral dosing suggests that use of the oral route is not to be recommended or at least requires assessment of pharmacodynamics and biologic effectiveness in the individual animal.

Methadone Methadone acts similarly to morphine in small animals in terms of the degree of analgesia provided and the duration of effect. It is a µ-receptor agonist that also noncompetitively inhibits N-methyl-daspartate receptors. It is more lipid soluble than morphine but causes less sedation and vomiting.

Hydromorphone and Oxymorphone Hydromorphone is also a pure-agonist opioid. Vomiting and diarrhea are associated with it less frequently than with morphine, but panting is frequently seen in dogs. Hydromorphone does not

CHAPTER 163  •  Narcotic Agonists and Antagonists

Table 163-2  Opioid Analgesics and Recommended Dosages Drug

Dosage*

Duration of Effect

Effects/Uses

Adverse Effects

Comments

Morphine

Dogs: 0.5-1 mg/kg IV, IM, SC; 0.05-0.5 mg/ kg/hr IV CRI, reduce 50% after 24 hr Cats: 0.05-0.2 mg/kg IV, IM, SC; 0.0250.1 mg/kg/hr IV CRI; reduce if agitation develops

4-6 hr

Sedation accompanying analgesia

Vomiting, diarrhea, and bradycardia may occur Hypotension and bronchoconstriction possible (histamine release with rapid IV administration)

Dilute with saline for slow IV injection

Hydromorphone (or oxymorphone)

Dogs: 0.05-0.1 mg/kg IV, IM, SC; 0.010.05 mg/kg/hr IV CRI Cats: 0.05-0.1 mg/kg IV, IM, SC; 0.010.025 mg/kg/hr IV CRI; reduce if hyperthermia or agitation develops

4 hr

Useful for managing substantial pain

Panting, vomiting, diarrhea, bradycardia, dysphoria Dosage-dependent sedation or excitement, hyperthermia in cats

Fentanyl

Dogs and cats: 2-10 mcg/kg/hr as CRI after IV loading dose of 2-10 mcg/kg; reduce if hyperthermia or agitation develops (cats more susceptible)

Rapid onset and short duration

Excellent for procedural uses and as a CRI for sustained and titratable analgesia

Dysphoria

May be combined with lidocaine CRI (see text)

Methadone

Dogs: 0.1-1.0 mg/kg IV Cats: 0.05-0.5 mg/kg IV (up to two times this dose if given IM or SC)

4-6 hr

Sedation accompanying analgesia

Vomiting, diarrhea, bradycardia

Causes less sedation and vomiting than morphine

Butorphanol (Torbutrol, Torbugesic, Stadol)

Dogs: 0.1-0.5 mg/kg IV, IM, SC; 0.1-1 mg/kg/ hr IV CRI Cats: 0.1-0.5 mg/kg IV, IM, SC; 0.1-0.5 mg/ kg/hr IV CRI

Dogs: 1-2 hr (analgesic effect) for IV, IM, SC Cats: 2-4 hr (analgesic effect) for IV, IM, SC

Ceiling effect, limited analgesia, useful for mild sedation and cough suppression, minimal systemic effects

Partial opioid reversal

Nalbuphine (Nubain)

Dogs and cats: 0.2-4 mg/kg IV, IM, SC

30-60 min

Minimal analgesia and minimal sedation, used in combination with sedatives or tranquilizers

Partial reversal of µ-agonist opioids

Buprenorphine (Buprenex, Temgesic)

Dogs: 0.01-0.05 mg/kg IV, IM, SC; 0.020.12 mg/kg oral transmucosal Cats: 0.005-0.05 mg/kg IV, IM, SC, oral transmucosal

Slow onset and long duration of effect (6-8 hr)

Some ceiling effect on respiratory depression, vomiting not commonly seen

Oral transmucosal absorption is excellent in cats and adequate in dogs for an alternative route to injection

CRI, Constant rate infusion; IM, intramuscularly; IV, intravenously; SC, subcutaneously. *Rates for IV CRI are from Hansen BD: Analgesia and sedation in the critically ill, J Vet Emerg Crit Care 15:285, 2005, and are recommended analgesic drug dosages used for administration as fluid additives in critical care. Other dosages are taken from the suggested references and the author’s experience.

stimulate histamine release. There may be less excitement or dysphoria than with morphine, but the literature and anecdotal reports are mixed on this subject. Hyperthermic reactions are occasionally seen in cats receiving hydromorphone. This is a very useful opioid for managing substantial pain and is quite similar to the formerly popular opioid oxymorphone.

Fentanyl and Remifentanil Fentanyl has been a useful opioid in veterinary medicine for many years. Fentanyl is combined with droperidol in the preparation Innovar-Vet, a once-popular neuroleptanalgesic. Fentanyl formulated in a controlled-release transdermal patch for human pain

treatment has been used (extralabel) in many veterinary species. The pharmacokinetics and pharmacodynamics of transdermal fentanyl have been described for many species, including dogs and cats. This formulation is useful for sustained analgesia in animals with significant trauma (e.g., multiple fractures after vehicular trauma), as part of the treatment of postoperative pain, in critically ill animals with painful systemic disease (e.g., pancreatitis), and in some cancer patients. Fentanyl patches can be useful in cats as well as in dogs. Breakthrough pain may require a supplemental analgesic strategy, often with a complementing class of nonopioid analgesic. Recently, a delayed-release transdermal solution of fentanyl (Recuvyra) that penetrates intact canine skin and serves as a reservoir within the skin

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has been formulated for use in dogs to provide sustained analgesic action. The fentanyl patches are available with various rates of drug delivery: 25, 50, 75, and 100 mcg/hr. Effectiveness has been reported for 50-mcg patches in small and medium-sized dogs. The 25-mcg patches have been used extensively in cats and dogs weighing less than 5 kg. The behavioral effects of dysphoria and dementia are unacceptable in some animals and may require tranquilization or removal of the patch. The practice of uncovering only one half of the barrier layer before application has been used to reduce the dosage and minimize this problem, particularly in smaller dogs and cats. Patches are applied to clipped skin. Uptake is somewhat variable among patients, and clinical efficacy may be related in part to differences in uptake of fentanyl. Onset of analgesia does not occur until 12 to 24 hours after application of the patch. Hence, other options, such as injected opioids or other medications, should be used initially to provide analgesia. It is important to prevent the patient from damaging or ingesting these patches or the contents. Of note, application of a heat source over the area of the patch can greatly increase uptake of the drug, with significant overdose possible. Duration of effectiveness is roughly 4 days. Fentanyl is a highly abused opioid, and there have been reports of clients removing fentanyl patches from their animals for drug abuse or diversion purposes. Some clinicians use the patches only for hospitalized, closely observed patients. Others find the fentanyl patches a very useful part of managing cancer pain in outpatients, including the terminally ill. The patch can help provide a steady level of opioid for a prolonged period in a way that is cost effective and reasonably convenient for clients. It is essential to emphasize to owners the potential dangers and the importance of protecting other pets and children from ingestion or other possible exposures. Expended (used) patches still contain fentanyl and should be folded onto themselves and flushed down the toilet (in the United States) or returned to a veterinarian for disposal. Injectable fentanyl has such a short duration of action that a bolus dose, by itself, is of limited benefit for treatment of prolonged (e.g., postoperative) pain, it but may be excellent as a component of procedural pain management (e.g., for bone marrow aspiration or sedation or analgesia for other diagnostic procedures such as radiography). The rapid onset and relatively short duration of action of injected fentanyl make it an excellent choice for administration as a CRI for sustained and titrated analgesia in critical care. For dog and cats, a 2- to 10-mcg/kg/hr intravenous CRI is initiated after an intravenous loading dose of 2 to 10 mcg/kg. As a CRI, fentanyl (50 mg/ml) may be combined with an equal volume of 2% lidocaine as follows: 0.1 to 0.3 ml/kg/hr of a 1 : 1 mixture (by volume) of fentanyl and lidocaine administered as needed for comfort and sedation. After longterm infusion, the recovery from fentanyl is more prolonged. In marked contrast, the fast elimination of remifentanil allows for very reliable and rapid recovery after even a long-term infusion. The very short context-sensitive half-life of remifentanil is preserved during infusions given for analgesia or as a component of sedative or anesthetic combinations. Combined infusions of remifentanil and propofol can provide deep sedation or anesthesia in critically ill patients while preserving the option of rapid recovery.

Butorphanol Butorphanol was first available in veterinary medicine as an antitussive medication. It can be a useful sedative and cough suppressant, but weak analgesic in the critical care patient and is often combined with nonopioid analgesics and sedatives. There is a recognized ceiling effect that limits the analgesic effectiveness of this mixed-acting agonist-antagonist opioid, and butorphanol has been overused inappropriately to the exclusion of the more effective µ-agonist

medications. In many cases a pure-agonist opioid, such as morphine, hydromorphone, or fentanyl, should be selected for more effective analgesia. The analgesic actions of butorphanol are limited not only by its mild contribution to pain relief but also by its short duration of effect, particularly in dogs. Because the ceiling effect with butorphanol also limits respiratory depression, it has less potential than agonist opioids to cause reflexive increases in intracranial pressure (ICP). This decreased potential for respiratory depression adds a safety component in the use of butorphanol as an opioid sedative for patients with cranial trauma or those that for other reasons are at risk of increased ICP or increased intraocular pressure. Vomiting is rarely a feature of the drug, which avoids another risk factor for increases in ICP or intraocular pressure. When used for partial reversal of the effects of µ-agonist opioids, butorphanol can provide a gentle reversal of excessive µ-agonist– mediated depression (or dysphoria in cats), yet maintain some effects of weak analgesia and sedation.8 For this reason, as an alternative to naloxone, it can serve as a very useful partial antagonist in critical care patients.

Nalbuphine Much like butorphanol, nalbuphine is a weak analgesic that is usually classified as a mixed agonist-antagonist opioid. The sedation provided by nalbuphine is minimal, but it contributes to the sedation afforded by simultaneously administered tranquilizers or sedatives. Nalbuphine is used in combination with acepromazine, benzodiazepines, or α2 agonists. Like butorphanol, nalbuphine can be used for partial reversal of µ-agonist opioids. Nalbuphine is not currently a scheduled drug in the United States.9

Buprenorphine Buprenorphine typically has been classified as a partial-agonist opioid, with limited agonist activity at µ-receptors. Research suggests that the ceiling effect with this drug may apply more to respiratory depression than to its analgesic actions. Because of this, it provides a relatively moderate analgesic effect. The duration of analgesic action is greater than that of any other clinically available opioids (with the exception of controlled-release formulations and drugs administered by neuroaxial routes). Buprenorphine, like butorphanol, does not stimulate vomiting and similarly may be a good choice for patients at risk of increased ICP or intraocular pressure. Concurrent administration of monoamine oxidase inhibitors with buprenorphine should be avoided. In cats, and to a somewhat lesser degree in dogs, buprenorphine has excellent bioavailability from the oral mucosa. Transmucosal (oral or sublingual but not orogastric) administration of the injectable product is well tolerated and provides a convenient noninjectable option for relatively long-lasting substantial analgesia in cats. It still has useful bioavailability in dogs when give in the cheek pouch or sublingually but not when administered via the orogastric route.10

Tramadol Tramadol provides a mild analgesic effect similar to that of weak opioids and nonsteroidal antiinflammatory drugs (NSAIDs). There is slight µ-opioid binding activity, but the analgesic action is attributed more to interference with both serotonin storage and norepinephrine reuptake. Analgesic action exceeds µ-receptor binding characteristics. The principal metabolite has greater µ binding than does the parent compound. Tramadol may be effective when a weak opioid such as codeine would be chosen and is most useful as an adjunctive analgesic in combination with NSAID analgesics. It is available only as an oral medication in the United States, which might limit its use in critically ill patients.

CHAPTER 163  •  Narcotic Agonists and Antagonists

Codeine Codeine is a pure µ agonist that has one tenth the potency (analgesic properties) of morphine. It is available only as an oral formulation (which limits its use in the intensive care unit) and is readily absorbed from the GI tract. Codeine is a potent oral analgesic for dogs that require long-term analgesic administration (e.g., as a component of cancer pain management).

OPIOID ANTAGONISTS: NALOXONE, NALMEFENE, NALTREXONE Three significant opioid antagonists are naloxone (very short acting) and nalmefene and naltrexone (both long acting). These compounds bind with great affinity to the µ, κ, and δ opioid receptors, competitively displacing agonists with lesser affinity and thereby reversing the actions of the agonist agents. The antagonists convey no analgesic activity. Naloxone has been used primarily for reversal of opioid agonist effects but also has been used experimentally in the treatment of shock in dogs.11 With the infusion of high doses of naloxone in a model of hypovolemic shock, splanchnic capacitance was reduced, which led to an improvement in venous return, mean arterial pressure, and cardiac output. In displacing morphine and other opioids from receptor sites, the antagonist can reverse all opioid effects. Sedation, respiratory depression, and analgesia can be reversed abruptly, which precipitates acute reactions of severe pain, excitement, and profound stress. If naloxone is used for reversal of adverse or excessive opioid agonist effects in a critical care setting, the diluted drug should be given slowly and titrated by intravenous infusion to the desired effect. Patients should be observed for relapse into sedation or a return of adverse effects (renarcotization). It is difficult to titrate opioid reversal to arouse a patient from excessive sedation and still preserve analgesia. Partial reversal using butorphanol or nalbuphine is an alternative approach that is suitable for many patients. Buprenorphine binds with great affinity to the receptors and its effects can be difficult to reverse. Fortunately, few critical care patients require complete opioid reversal. Supportive care and treatment of opioid-induced sedation or excessive undesirable effects with partial reversal agents are generally recommended. Naltrexone and nalmefene (the latter has a longer duration of effect) similarly compete for opioid receptors, displacing agonists, both exogenous and endogenous. For this reason, these drugs have been used to treat compulsive behavior disorders. The lack of any

significant naltrexone metabolite in dogs (in contrast to humans) might limit the effectiveness of this strategy.12

CONCLUSION Opioids as a class are among the safest of analgesic medications, with profound usefulness in the critical care setting. Pain relief is the most significant application of the opioids, but they also offer sedation and cough suppression and are essential components of critical care anesthesia. The variety of opioids and the variety of administration routes and strategies available allow for many creative applications to the benefit of critically ill veterinary patients.

REFERENCES 1. Hansen BD: Analgesia and sedation in the critically ill, J Vet Emerg Crit Care 15:285, 2005. 2. Hellyer PW: Pain management. In Wingfield WE, Raffe MR, editors: The veterinary ICU book, Jackson Hole, Wyo, 2002, Teton New Media. 3. Dobromylskyj P, Flecknell PA, Lascelles BD, et al: Pain assessment. In Flecknell P, Waterman-Pearson A, editors: Pain management in animals, London, 2000, Saunders. 4. Niedfeldt RL, Robertson SA: Postanesthetic hyperthermia in cats: a retrospective comparison between hydromorphone and buprenorphine, Vet Anaesth Analg 33:381, 2006. 5. Dohoo S, Tasker RA, Donald A: Pharmacokinetics of parenteral and oral sustained-release morphine sulphate in dogs, J Vet Pharmacol Ther 17:426, 1994. 6. Muir WW, Wiese AJ, March PA: Effects of morphine, lidocaine, ketamine and morphine-lidocaine-ketamine drug combinations on minimum alveolar concentration in dogs anesthetized with isoflurane, Am J Vet Res 64:1155, 2003. 7. Kukanich B, Lascalles BDX, Papich MG: Pharmacokinetics of morphine and plasma concentrations of morphine-6-glucuronide following morphine administration to dogs, J Vet Pharmacol Ther 28:371, 2005. 8. McCrackin MA, Harvey RC, Sackman JE, et al: Butorphanol tartrate for partial reversal of oxymorphone-induced postoperative respiratory depression in the dog, Vet Surg 23:67, 1994. 9. Veterinary Anesthesia and Analgesia Support Group website. Available at http://www.vasg.org. Accessed March 12, 2007. 10. Robertson SA, Taylor PM, Sear J: Systemic uptake of buprenorphine by cats after oral mucosal administration, Vet Record 152:675, 2003. 11. Bell L, Maratea E, Rutlen DL: Influence of naloxone on the total capacitance vasculature of the dog, J Clin Invest 75:1894, 1985. 12. Luescher A: Compulsive behavior in companion animals, IVIS veterinary drug database, Document No. B2410.0403, Ithaca, NY, 2004, International Veterinary Information Service. Available at http://www.ivis.org. Accessed August 7, 2007.

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CHAPTER 164  BENZODIAZEPINES Ralph C. Harvey,

DVM, MS, DACVAA

KEY POINTS • Benzodiazepines are associated with less adverse respiratory and cardiovascular effects than most alternative tranquilizers or sedatives. • Benzodiazepines are a first line of defense for rapid seizure control. • Small doses of benzodiazepines are often successful for short-term appetite stimulation in critically ill cats. • Accidental ingestion of benzodiazepines is treated with supportive care, emetics, and/or activated charcoal. Flumazenil may be administered in severe cases that are associated with marked central nervous system depression.

Benzodiazepines have a wide range of applications in critically ill patients. As a group these drugs offer effects that include sedation, anxiolysis, and anticonvulsant activity, with minor cardiovascular and respiratory effects. They can be used as part of an anesthetic induction protocol for balanced anesthesia, given along with analgesic drugs to enhance patient comfort and sedation, or administered for treatment of status epilepticus. The most commonly used benzodiazepines in veterinary medicine are diazepam and midazolam. Benzodiazepines are considered scheduled substances in the United States (C-IV), and for this reason appropriate storage and documentation is required.1

ACTION Benzodiazepines are believed to act primarily via the inhibitory neurotransmitter γ-aminobutyric acid (GABA); benzodiazepines bind to stereospecific receptors that facilitate the inhibitory actions of GABA.1,2 The mechanism of action may also involve antagonism of serotonin and diminished release or turnover of acetylcholine in the central nervous system (CNS).1 Benzodiazepines act at the limbic, thalamic, and hypothalamic level of the CNS with anxiolytic, sedative, hypnotic, skeletal muscle relaxant, and anticonvulsant properties. In humans, benzodiazepines are also recognized to have anterograde amnestic effects, providing amnesia for events that occur subsequent to the administration of the drug.2 Benzodiazepines are generally considered to provide no analgesia. Benzodiazepines are metabolized in the liver to active metabolites that, after conjugation, are excreted in the urine.2

DIAZEPAM VERSUS MIDAZOLAM Diazepam and midazolam have similar pharmacologic actions in dogs and cats. The major difference between these drugs is that diazepam is not water soluble; it is formulated in a 40% propylene glycol and 10% alcohol vehicle.1 Propylene glycol is an irritant to blood vessels and causes phlebitis and thrombosis after repeated or continuous administration through a peripheral vein. For this reason, 864

diazepam should be given only as a constant rate infusion (CRI) or in multiple repeated intermittent doses via a central vein. Prolonged administration of diazepam can also cause propylene glycol toxicity, which may have life-threatening effects including metabolic acidosis, hyperosmolality, neurologic abnormalities, and organ dysfunction.3 Propylene glycol toxicity is of particular concern in cats; therefore diazepam infusions are not recommended in this species.4 Diazepam also adsorbs to plastic, so doses should not be stored in plastic syringes for any length of time, and infusion lines may require precoating with the drug before administration. Both diazepam and midazolam should be protected from light. Infusion lines for either diazepam or midazolam should also be tinted or covered to block light exposure. In contrast to diazepam, midazolam is water soluble and is well absorbed after intramuscular injection. However, midazolam is poorly bioavailable when given per rectum to dogs, so this route of administration is not recommended.1,5 Diazepam rectal gel is available for human use and may offer a viable alternative for at-home treatment of seizures. Intranasal administration for at-home treatment of seizures is another practical and readily accepted option.6,7 Midazolam can be given as a CRI through a peripheral vein.

BENZODIAZEPINE EFFECTS The sedative effects of benzodiazepines are highly variable in dogs and cats. Animals may demonstrate aberrant behavior after benzodiazepine administration, including excitation, irritability, and depression. Patients that are already somewhat obtunded are likely to be effectively sedated, particularly if the benzodiazepine is combined with an opioid. Healthier dogs and cats may demonstrate dysphoria; this is more likely when the drugs are used as sole agents.

BENZODIAZEPINES AND CATS A rare complication of oral diazepam administration in cats is fulminant hepatic failure. This has been reported as an idiosyncratic reaction resulting in acute hepatic necrosis.8 This reaction has not been reported in association with other routes of administration.

INDICATIONS Sedation As a sole drug, benzodiazepines are rarely sufficient to sedate neurologically normal dogs and cats. Benzodiazepines commonly are combined with opioids to provide sedation for intensive care procedures or to relieve distress and anxiety in critically ill patients when analgesic therapy alone is insufficient.4 Benzodiazepines are also commonly incorporated into anesthetic protocols for induction and maintenance of anesthesia. These drugs can be given to reduce the required dosage of other anesthetic agents such as propofol or barbiturates in an effort to minimize their adverse effects (see Chapters 142 through 144).

CHAPTER 164  •  Benzodiazepines

The shorter-acting drug midazolam is often given intravenously (IV) and is generally preferred to diazepam. It can be titrated easily to a desired level to prevent drug accumulation that might delay recovery. Water-soluble midazolam, with its short elimination halflife and duration of action, may be more suitable for continuous infusion in critically ill patients than diazepam. The more slowly eliminated benzodiazepine lorazepam is also water soluble and has been recommended as a more suitable alternative for long term use in human patients, but there is little experience with this drug in veterinary patients.4,9 The most important adverse effects of long-term benzodiazepine infusions are dysphoric or excitatory signs and, occasionally, delayed awakening. The antagonist flumazenil and the inverse agonist sarmazenil have each been used to reverse CNS depression or dysphoria due to benzodiazepine agonists in human patients. Significantly delayed recovery or marked dysphoria attributable to benzodiazepines may be responsive to reversal with these agents, but neither can be recommended for routine use in animals in stable condition. Marked excitement and dysphoria can be precipitated by either drug. Significant adverse effects, such as seizures and acute benzodiazepine withdrawal, have been reported. In most animals in stable condition, the delayed recovery or adverse effects of the benzodiazepines are less problematic than the potential for more severe adverse outcomes with either flumazenil or sarmazenil use. Even in cases of severe benzodiazepine overdose, as from oral ingestion of multiple tablets, the toxic effects generally can be managed with supportive care and administration of emetics and/ or activated charcoal (see Chapter 74). Benzodiazepine antagonist therapy with flumazenil is rarely indicated in patients in stable condition, although its use in critically ill patients with cardiovascular or pulmonary instability is more commonly justified.10 When flumazenil therapy is deemed necessary, a dosage of 0.01 to 0.02 mg/kg IV has been recommended for reversal of benzodiazepine effects in dogs and cats. Alternative routes are effective, with some limitations.11 Animals requiring frequent redosing may benefit from a temporary IV flumazenil infusion of 0.005 to 0.02 mg/kg/hr.

Anticonvulsant Therapy Benzodiazepines are the drugs of choice for initial control of status epilepticus in both dogs and cats.12,13 Midazolam can be given intramuscularly if intravenous access is not available. Intramuscular administration of diazepam is not recommended, and the rectal or intranasal route is preferred in the absence of intravenous access.1,14,15 Diazepam rectal gel (Diastat) is available, however, for rectal administration in animals having seizures at home or in the hospital before intravenous access is obtained. Its use has not been extensively studied in small animals, but it is expected to act similarly to diazepam given by other routes. For patients with recurrent seizure activity that responds to benzodiazepine administration, an intravenous CRI of diazepam or midazolam may be effective. See Table 164-1 for some suggested anticonvulsant dosages. Chapters 82 and 166 provide a detailed discussion of anticonvulsant therapy and the approach to the patient with seizures.

Appetite Stimulation Low doses of benzodiazepines can stimulate appetite in many species, especially in cats. The hyperphagic effect is separate from sedation or anxiolysis, involves binding to benzodiazepine receptors, and appears to increase the attraction to tastes. Increases in both the amount of food consumed and the rate of consumption are noted. In experimental models, the hyperphagic response is seen in satiated (fully fed) animals. As an appetite stimulant, diazepam is administered to cats at a dosage of 0.005 to 0.4 mg/kg IV q24h or 1 mg orally q24h (risk of hepatic toxicity in cats should be considered). Food should

Table 164-1  Suggested Parenteral Dosages for Benzodiazepines in Dogs and Cats Use

Diazepam

Midazolam

Sedation

IV: 0.2-0.6 mg/kg CRI: 0.1-1 mg/kg/hr (central vein)

IV, IM: 0.1-0.4 mg/kg CRI: 0.1-0.5 mg/kg/hr

Anticonvulsant therapy

IV, intranasally: 0.5-1 mg/kg; can repeat 2 or 3 times PR: 2 mg/kg CRI: 0.5-1 mg/kg/hr (central vein)

IV, IM: 0.2-0.5 mg/kg; can repeat 2 or 3 times CRI: 0.2-0.5 mg/kg/hr

CRI, Constant rate infusion; IM, intramuscularly; IV, intravenously; PR, per rectum.

be readily available because the animal may begin eating within a few seconds of administration.1

HEPATIC ENCEPHALOPATHY Hepatic encephalopathy (HE) commonly accompanies the syndrome of portosystemic shunting or significant hepatic insufficiency due to other causes (see Chapters 88 and 116). Human patients with HE have occasionally shown arousal following administration of the benzodiazepine antagonist flumazenil. This observation suggests that the syndrome may involve increased endogenous benzodiazepine agonist activity. In contrast, a lack of arousal in other species, including dogs and cats in both clinical and research models of HE, has been interpreted as evidence that endogenous benzodiazepines are not increased in this syndrome. Administration of the benzodiazepine inverse agonist sarmazenil, but not the antagonist flumazenil, in animal research models of both acute and chronic HE has resulted in improvement of encephalopathic signs. This is consistent with an increased GABAergic constitutive activity in HE, rather than an increase in endogenous benzodiazepine agonist ligands.16 Although sarmazenil has been useful in elucidating the pathophysiology of HE, it should not be considered part of the therapeutic modality for this disorder. Sarmazenil has also been used for reversal of GABA-mediated toxicity due to moxidectin in a foal. However, this application remains somewhat controversial at this time, as is the use of benzodiazepines for the treatment of HE-induced seizures.

REFERENCES 1. Plumb DC: Diazepam. In Plumb’s veterinary drug handbook, ed 5, Ames, Ia, 2005, Blackwell. 2. Charney DS, Mihic SJ, Harris RA: Hypnotics and sedatives. In Hardman JG, Limbird LE, editors: Goodman’s and Gilman’s The pharmacological basis of therapeutics, ed 10, New York, 2001, McGraw-Hill. 3. Wilson KC, Reardon C, Theodore AC, et al: Propylene glycol toxicity: a severe iatrogenic illness in intensive care unit patients receiving IV benzodiazepines: a case series and prospective, observational pilot study, Chest 128:1674, 2005. 4. Hansen BD: Analgesia and sedation in the critically ill, J Vet Emerg Crit Care (San Antonio) 15:285, 2005. 5. Schwartz M, Muñana KR, Nettifee-Osborne JA, et al: The pharmacokinetics of midazolam after intravenous, intramuscular, and rectal administration in healthy dogs, J Vet Pharmacol Ther 36(5):471-477, 2013. 6. Musulin SE, Mariani CL, Papich MG: Diazepam pharmacokinetics after nasal drop and atomized nasal administration in dogs, J Vet Pharmacol Ther 34(1):17-24, 2011. 7. Eagleson JS, Platt SR, Elder Strong DL, et al: Bioavailability of a novel midazolam gel after intranasal administration in dogs, Am J Vet Res 73(4):539-545, 2012.

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8. Center SA, Elston TH, Rowland PH, et al: Fulminant hepatic failure associated with oral administration of diazepam in 11 cats, J Am Vet Med Assoc 209:618, 1996. 9. Notterman DA: Sedation with intravenous midazolam in the pediatric intensive care unit, Clin Pediatr 36:449, 1997. 10. Wismer TA: Accidental ingestion of alprazolam in 415 dogs, Vet Hum Toxicol 44:22, 2002. 11. Unkel JH, Brickhouse TH, Sweatman TWS, et al: A comparison of three routes of flumazenil administration to reverse benzodiazepine-induced desaturation in an animal model, Pediatr Dent 28(4):357-362, 2006. 12. Parent J, Poma R: Single seizure, cluster seizures, and status epilepticus. In Wingfield WE, Raffe MR, editors: The veterinary ICU book, Jackson Hole, Wyo, 2002, Teton NewMedia.

13. Papich MG, Alcorn J: Absorption of diazepam after its rectal administration in dogs, Am J Vet Res 56:1629, 1995. 14. Platt SR, Randell SC, Scott KC, et al: Comparison of plasma benzodiazepine concentrations following intranasal and intravenous administration of diazepam to dogs, Am J Vet Res 61:651, 2000. 15. Meyer HP, Legemate DA, van den Brom W, et al: Improvement of chronic hepatic encephalopathy in dogs by the benzodiazepine-receptor partial inverse agonist sarmazenil, but not by the antagonist flumazenil, Metab Brain Dis 13:241, 1998. 16. Muller JM, Feige K, Kastner SB, et al: The use of sarmazenil in the treatment of a moxidectin intoxication in a foal, J Vet Intern Med 19:348, 2005.

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PART XX  •  PHARMACOLOGY

CHAPTER 165  α2 AGONISTS AND ANTAGONISTS Bruno H. Pypendop,

DrMedVet, DrVetSci, DACVAA

KEY POINTS • α2 Agonists can be used to produce sedation and analgesia. • α2 Agonists reduce the required analgesic dose of drugs like opioids when used in combination with these drugs. • α2 Agonists produce minimal respiratory effects. • α2 Agonists have pronounced cardiovascular effects, including bradycardia and vasoconstriction. • α2 Agonists should be used with caution in patients with compromised organ blood flow. • Dexmedetomidine is the α2 agonist of choice for sedation and analgesia in intensive care; it should be administered as a continuous intravenous infusion when used for purposes other than short-term sedation. • α2 Antagonists can be used to reverse the effects of α2 agonists; atipamezole is suitable for antagonizing the action of dexmedetomidine.

is currently of little clinical relevance since there is no subtypeselective agonist in clinical use. The interaction of an α2 agonist with its receptor typically results in the inhibition of adenylyl cyclase, the activation of receptor-operated K+ channels, the acceleration of Na+/H+ exchange, and the inhibition of voltage-gated Ca++ channels.2 α2-Adrenoceptors are present on the presynaptic membrane of noradrenergic neurons; their activation inhibits the release of norepinephrine (negative feedback).3 Postsynaptic α2-adrenoceptors exist in various tissues, where they exert a distinct physiologic function; these tissues include the vascular smooth muscle, liver, pancreas, platelets, kidney, adipose tissue, and eye. The medullary dorsal motor complex in the brain has a high density of α2-adrenoceptors.

EFFECTS OF α2 AGONISTS Central Nervous System

Agonists of α2-adrenergic receptors (α2 agonists) produce a variety of effects, some of them potentially beneficial in critically ill patients. They are most often used for sedation and analgesia to facilitate handling and performance of minor procedures. They also inhibit the sympathetic nervous system and therefore decrease autonomic responses. However, their cardiovascular effects may be detrimental, and they have many additional effects of concern in critically ill patients such as the inhibition of insulin and antidiuretic hormone secretion.

α2 ADRENOCEPTORS The α2-adrenergic receptors (α2-adrenoceptors) are Gi/o protein– coupled receptors with seven transmembrane domains of the aminebinding subfamily.1 There are three receptor subtypes; however, this

Stimulation of presynaptic α2-adrenoceptors in the central nervous system decreases the release of norepinephrine. α2 Agonists produce sedation by inhibition of noradrenergic neurons in the locus ceruleus (upper brainstem).4-6 Sedation produced by α2 agonists is characterized by an increase in stage I and II sleep and a decrease in rapid eye movement sleep, and results from the activation of endogenous sleep pathways; it therefore mimics normal sleep better than sedation produced by other agents.7,8 α2 Agonists produce analgesia via stimulation of receptors in the dorsal horn of the spinal cord9-16 and in the brainstem, where modulation of nociceptive signals is initiated.17,18 α2-Agonist–induced antinociception likely results from inhibition of nociceptive neurons. However, a recent study suggests that direct activation of γaminobutyric acid–ergic inhibitory interneurons can be produced by norepinephrine.19 α2 Agonists, even when administered at very low doses, have been demonstrated to potentiate opioid-induced analgesia.15,20-29 The addition of ketamine may further potentiate the effect.30

CHAPTER 165  •  α2 AGONISTS AND ANTAGONISTS

In addition, α2 agonists decrease the development of tolerance to opioids.31 α2-Adrenoceptor agonists administered systemically have been shown to produce synergistic analgesic effects with nonsteroidal antiinflammatory drugs and acetaminophen in models of visceral pain.32-34 Administration of α2 agonists decreases the requirements for anesthetic drugs by up to approximately 80% in dogs and cats and 100% in rats.35-37 This effect is thought to be mediated by the decrease in norepinephrine release, mainly from the locus ceruleus.38 However, because minimal alveolar concentration is reduced by a maximum of 40% when noradrenergic transmission is totally abolished, additional mechanisms may be responsible for this anestheticsparing effect.39 α2-Adrenoceptor agonists have neuroprotective effects, even though high doses may worsen ischemic brain injury.40-47 These effects may be due to an α2-adrenoceptor–mediated decrease in norepinephrine or glutamate, or to the activation of imidazoline receptors.48,49 Other possible neuroprotective mechanisms include the inhibition of acute expression of immediate early genes involved in cerebral damage and the inhibition of massive norepinephrine release following brain injury.50,51 α2 Agonists may prevent vasospasm after subarachnoid hemorrhage.52 α2 Agonists also appear to have anticonvulsant effects.53-59 α2-Adrenoceptor agonists induce hypothermia.60-63 This effect is due to the inhibition, at the hypothalamic level, of central noradrenergic mechanisms responsible for the control of body temperature.64 α2 Agonists may also prevent the thermoregulatory response to infection.65

Cardiovascular System The typical cardiovascular response to the administration of an α2 agonist is biphasic. Initially, blood pressure and systemic vascular resistance increase, whereas heart rate and cardiac output decrease.66-69 The increase in blood pressure may not be seen after intramuscular administration.69 These effects are followed by a decrease in arterial pressure; heart rate and cardiac output remain lower than normal. Systemic vascular resistance either declines progressively toward normal or remains elevated, depending on the drug and probably the dose and the species. The bradycardia may be accompanied by other arrhythmias. The cardiovascular effects of α2 agonists are usually considered to be dose dependent.70 This typical response is initiated by a vasoconstrictive effect caused by stimulation of α2-adrenoceptors located on the vascular smooth muscle of both arteries and veins.71,72 This vasoconstrictive effect results in an increase in arterial blood pressure, which, in turn, causes bradycardia via a baroreceptor response.73 In addition, bradycardia may also be related to the central sympatholytic action of α2 agonists that leaves vagal tone unopposed, to an increase in parasympathetic efferent neuronal activity, or to a presynaptically mediated reduction of norepinephrine release in cardiac sympathetic nerves.73,74 Cardiac output decreases in parallel to heart rate, and stroke volume is usually minimally affected. α2Adrenoceptor agonists do not seem to induce direct negative inotrope effects.75 Because the decrease in cardiac output appears to be related mainly to the bradycardia, combining these drugs with an anticholinergic agent has been advocated. However, such combinations result in large increases in arterial pressure, with mean blood pressure around 200 mm Hg in dogs in one study.76 In cats, the addition of glycopyrrolate to xylazine appeared detrimental to cardiovascular performance.77 Similar results have been reported for the combination of romifidine and glycopyrrolate in dogs.78 α2 Agonists induce blood flow redistribution.79-81 Blood flow to more vital organs (e.g., heart, brain, kidney) might be partially or totally preserved at the expense of poor blood flow to less vital organs

79,80,82

(e.g., skin, muscle, intestine). It has been reported that, despite its marked cardiovascular effects, dexmedetomidine maintains the balance between myocardial oxygen demand and supply.83 Cerebral blood flow decreases in response to α2 agonist administration, and during hypoxia, adequate cerebral oxygenation may not be maintained.84-86 α2 Agonists have historically been reported to be arrhythmogenic or to potentiate the arrhythmogenic effects of other drugs administered concomitantly. These arrhythmias are caused by a number of factors. The reduction in heart rate may reveal foci that are normally inhibited by the impulses coming from the sinoatrial node. Older α2 agonists such as xylazine activate α1-adrenoceptors, and stimulation of these receptors is known to sensitize the heart to catecholamineinduced arrhythmias. More recently developed drugs that are more specific for the α2-adrenoceptors do not appear to induce arrhythmias and may actually increase the threshold for epinephrineinduced arrhythmias. This effect could be mediated by imidazoline receptors, since imidazoline but not nonimidazoline α2 antagonists reversed this effect.87,88 α2-Adrenoceptor stimulation is protective against ventricular tachycardia or fibrillation after ischemiareperfusion.89 Similarly, perioperative use of these drugs may decrease the incidence of arrhythmias after cardiac surgery.90 Calcium channel blockers may inhibit the peripheral vascular effects of α2 agonists (i.e., vasoconstriction) while preserving their central effects (i.e., sedation, analgesia), therefore preserving the beneficial effects with fewer hemodynamic changes.91 More recently, elegant studies have shown that similar results may be obtained by the coadministration of α2 agonists and the peripheral α2 antagonist MK-467.92-94 These studies in dogs also showed that the bradycardic effect of the α2 agonist was almost entirely abolished, which suggests that, at least in dogs, the bradycardia produced by α2 agonists is peripherally rather than centrally mediated. As with most effects, α2-agonist–induced cardiovascular effects appear to be dose dependent. However, near-maximum effects are likely reached at dosages close to the lower end of the clinically recommended range, which implies that using low dosages in that range minimally reduces these cardiovascular effects.67,68,95

Other Effects In dogs and cats, the effects of α2 agonists on the respiratory system are considered minimal. Usually, respiratory rate decreases but minute ventilation is maintained. Therefore arterial carbon dioxide and oxygen pressures remain within the normal physiologic range.96,97 However, α2 agonists can potentiate the depression induced by other agents such as opioids.98 α2 Agonists inhibit sympathetic outflow and modulate the stress response to anesthesia and surgery.99 They also decrease the plasma level of circulating catecholamines.100-102 Stimulation of α2adrenoceptors on the beta cells of the islets of Langerhans causes direct inhibition of insulin release, resulting in hyperglycemia.102-109 The effect appears dose dependent, and 10 to 20 mcg/kg of medetomidine was reported to decrease plasma insulin level without causing significant hyperglycemia in dogs.110 α2 Agonists increase the release of growth hormone, which could contribute to the observed hyperglycemia.111-113 α2 Agonists inhibit the release of antidiuretic hormone and its effect on renal tubules.114-117 α2 Agonists promote diuresis and natriuresis.109,118 They are thought to inhibit the release of renin and to increase the secretion of atrial natriuretic factor.119,120 α2 Agonists induce a decrease in salivation; gastroesophageal sphincter pressure; esophageal, gastric, and small intestinal motility; and gastric secretion.121-130 Vomiting after α2-agonist administration has been reported in 8% to 20% of dogs and up to 90% of cats.131-137 This effect appears to be related to the stimulation of α2-adrenoceptors in the chemoreceptor trigger zone.138

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IMIDAZOLINE RECEPTORS In addition to binding α2-adrenoceptors, the α2 agonists currently in clinical use, with the exception of xylazine, also activate imidazoline receptors. Two types of imidazoline receptors have been identified and are labeled I1 and I2. I1 receptors are involved in blood pressure regulation and may act synergically with α2-adrenoceptors.139 Imidazoline receptor agonists seem also to increase sodium excretion and urine flow rate.140 They may have neuroprotective effects.141 Stimulation of I1 receptors may inhibit catecholamine-induced arrhythmias. I2 receptors have been reported to exert control on central noradrenergic and hypothalamic-pituitary-adrenal axis activity to a greater extent than α2-adrenoceptors.142 I2 receptors also appear to be involved in the regulation of small intestinal motility.143 They may modulate the effects of opioids.144,145 Imidazoline receptors could also play a role in the α2-agonist–induced inhibition of insulin secretion and subsequent hyperglycemia.146

DRUGS The α2-agonists xylazine, medetomidine, and dexmedetomidine have been approved for use in dogs and cats. Other drugs such as romifidine have been studied in small animal species but have not received regulatory approval. Xylazine has moderate selectivity for α2-adrenoceptors and activates α1-adrenoceptors at clinical doses. This may be responsible for additional adverse effects; its use would therefore not be recommended in critically ill patients. Medetomidine is highly selective for α2-adrenoceptors. It is a racemic mixture of dexmedetomidine and levomedetomidine. Within the clinical dosage range, levomedetomidine appears devoid of effects and does not appear to significantly influence the disposition of dexmedetomidine.147,148 Dexmedetomidine is the active isomer. It is commercially available in many countries; in the United States, only the purified dexmedetomidine isomer is currently available for animal use.

CLINICAL USE α2 Agonists are widely used for sedation and analgesia to facilitate handling or performance of minor procedures and for premedication before general anesthesia. As mentioned earlier, in critically ill patients, the agent of choice is (dex)medetomidine. Dexmedetomidine is used for sedation and analgesia in human critical care patients. Its advantages over other sedative or hypnotic agents include the ability to arouse treated patients quickly when necessary, the lack of respiratory depression, maintenance of hemodynamic stability and sympatholysis, and decreased opioid consumption.149 It is also used to control delirium. Although there is no specific literature on the use of dexmedetomidine in small animal intensive care, it is likely that some of the benefits would be similar to those seen in humans. However, the cardiovascular effects, in particular the vasoconstriction, may be more pronounced and/or last longer in dogs and cats than in humans. This may be of concern in many critically ill patients, especially if organ blood flow is already compromised. Because the sedation and the analgesia induced by dexmedetomidine following single administration are of short duration, intravenous infusion is the preferred mode of administration when this drug is used for purposes other than short-term sedation. One study evaluated the use of dexmedetomidine for the management of postoperative pain in dogs150; in that study, a loading dose of 25 mcg/m2 followed by a constant rate infusion of 25 mcg/m2/hr provided adequate analgesia in some (but not all) patients; the sedation was similar to that produced by a constant rate infusion of morphine. These dosages are based on body surface

area, the dosing method often recommended for medetomidine and dexmedetomidine because of the early observations that at similar dosages based on body weight, the level of sedation was lower in smaller dogs than in larger dogs; the dosages used in the study correspond to a 0.9-mcg/kg loading dose and 0.9-mcg/kg/hr infusion in a 20-kg dog. The dose of dexmedetomidine should be titrated to the lowest dose producing the desired effect. See Chapter 144 for further dosage recommendations.

α2 ANTAGONISTS The effects of α2 agonists can be reversed by administration of an α2 antagonist. Atipamezole is highly selective for α2-adrenoceptors and is suitable for antagonizing the effects of medetomidine and dexmedetomidine. The recommended dose is 5 and 10 times the administered dose of medetomidine and dexmedetomidine, respectively. After intramuscular administration of atipamezole, the sedative, analgesic, and cardiovascular effects induced by an α2 agonist are reversed within 5 to 10 minutes. Intravenous administration should be used with caution because it may result in transient but sometimes severe dysphoria. The use of MK-467, an α2 antagonist that does not cross the blood-brain barrier, has been proposed to prevent the peripheral (i.e., vasoconstrictive) effects of medetomidine and dexmedetomidine in dogs without affecting the central effects (i.e., sedation or analgesia). However, this drug is not commercially available at this time.

CONCLUSION α2 Agonists can be used to provide sedation and analgesia in dogs and cats. They do not produce significant respiratory depression but have pronounced cardiovascular effects, including vasoconstriction and bradycardia, and cause hyperglycemia. They should be used with caution in patients in which organ blood flow is compromised.

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CHAPTER 166  ANTICONVULSANTS Adam Moeser,

DVM, DACVIM (Neurology)  •  Sheldon

KEY POINTS • Treatment of seizures in veterinary medicine depends on the underlying cause. Potential causes include reactive seizures, symptomatic epilepsy, and primary (idiopathic) epilepsy. • The main drugs used to treat seizures in an emergency setting (e.g., cluster seizures, status epilepticus) include benzodiazepines (diazepam, midazolam) and levetiracetam. • The primary anticonvulsants used in dogs include phenobarbital, potassium bromide, zonisamide, and levetiracetam. • Less commonly used anticonvulsants in dogs include felbamate, gabapentin, and pregabalin. • The primary anticonvulsants used in cats include phenobarbital, levetiracetam, and zonisamide. • A good understanding of potential side effects, drug-related toxicity, and the pharmacokinetics of a particular anticonvulsant should be obtained before using an anticonvulsant.

The treatment of epilepsy in veterinary medicine is based mainly on anecdotal evidence rather than evidence-based medicine. Although phenobarbital and bromide anticonvulsants have been used for many decades, there are still very few well-designed published studies evaluating their effectiveness. Similarly, the number of prospective, randomized, double-blind studies evaluating the use of newer anticonvulsants (e.g., levetiracetam, zonisamide, gabapentin, pregabalin) is also small. Not only is there a paucity of well-designed studies, but most studies involve small numbers of patients that are monitored for short periods of time. Therefore, when reading the information in this chapter, one should keep in mind that most of the referenced sources do not provide definitive evidence for the effectiveness of the different compounds for treating seizures in dogs and cats. Nevertheless, the need for additional therapies for patients with refractory epilepsy is real, and therefore the use of the anticonvulsants discussed here cannot be discouraged based solely on the lack of well-designed studies.

SEIZURES Seizures and epilepsy are a common presenting complaint of small animal patients seen at veterinary clinics. In fact, 0.6% to 2.3% of all cases reporting to veterinary referral centers have been estimated to involve epilepsy.1 Seizure is defined as a transient and involuntary change in behavior or neurologic status due to the abnormal activity of populations of central nervous system (CNS) neurons.2 Seizures can be further classified as either generalized or partial seizures. Generalized seizures involve both cerebral hemispheres and typically manifest as either convulsive (motor) or nonconvulsive (behavioral, absence) seizures. Partial seizures are believed to result from a focal electrical event in one hemisphere and are further subdivided into simple partial and complex partial seizures. Simple partial seizure episodes do not result in impairment of consciousness, whereas 872

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VMD, DMSc, DACVIM (Neurology), DECVN

complex partial seizures do. Partial seizures can develop into generalized seizures. Epilepsy refers to the recurrence of seizures over time.3 Epilepsy in dogs and cats can be classified by its cause. Symptomatic epilepsy is the result of a known intracranial disease process such as neoplasia, meningoencephalitis, congenital hydrocephalus, or head trauma. When symptomatic epilepsy is suspected but evidence cannot be found, the term cryptogenic epilepsy is used. Finally, idiopathic epilepsy is the term applied to the seizure state when no cause is discovered and the patient appears otherwise normal. An inherited cause or predisposition has been proposed for such cases. When seizures are due to an extracranial insult such as a toxin or metabolic disturbance, the term reactive seizures is used. In addition to the lack of structural CNS disease and lack of an extracranial disease process associated with idiopathic epilepsy, this diagnosis is also typically associated with a particular signalment. Seizures that result from idiopathic epilepsy in dogs usually first occur between the ages of 1 and 5 years, but onset of the disorder has been reported in younger and older dogs.4 In dogs, idiopathic epilepsy occurs at a higher incidence than reactive and symptomatic seizures whereas in cats reactive and symptomatic seizures are more common than idiopathic epilepsy.4 Finally, there is no reason to believe that all occurrences of idiopathic epilepsy have the same underlying cause. Regardless of the cause of the seizures recurrent seizures (epilepsy) should be treated with anticonvulsants. Typically, treatment is strongly recommended if the frequency of seizures is increasing, if symptomatic epilepsy is suspected, or if cluster seizures (more than one seizure in 24 hours) or status epilepticus (any one seizure lasting >5 minutes, or a cluster event without return to normal between seizures) is noted. If an identifiable cause of the seizures (symptomatic epilepsy) is found, treatment of the underlying cause should also be pursued simultaneously with the administration of anticonvulsant therapy. There is some evidence that dogs with idiopathic epilepsy have a better response to treatment if it is started earlier in the course of disease.5 The anticonvulsants most commonly used in veterinary medicine include phenobarbital, bromide (potassium bromide, sodium bromide), zonisamide, and levetiracetam. Felbamate is another option but is not used as commonly (see later). Benzodiazepines (diazepam, midazolam, clorazepate, lorazepam) are potent anticonvulsants, but due both to their short half-life and the development of tolerance their use is generally limited to emergency treatment of episodes of cluster seizures or status epilepticus (Table 166-1). Phenytoin, which has a very short half-life in dogs and a very long halflife in cats, is not currently used with any regularity in veterinary medicine.

PHENOBARBITAL Phenobarbital is a barbiturate that facilitates γ-aminobutyric acid (GABA)-ergic activity by prolonging the opening of the chloride channel associated with the GABAA receptor.4,6 In addition to having GABAergic activity, phenobarbital is believed to inhibit glutamate

CHAPTER 166  •  Anticonvulsants

Table 166-1  Anticonvulsant Drugs and Recommended Dosages for Dogs Drug

Route

Dosage

Phenobarbital*

PO, IV, IM

3-5 mg/kg q12h

Potassium bromide*

PO, PR

20-40 mg/kg/day

Zonisamide

PO

5-10 mg/kg q12h

Levetiracetam

PO, IV

20 mg/kg q8h (higher dosages tolerated well)

Diazepam†

PO, IV, PR, IN

0.5-1 mg/kg (1-2 mg/kg for rectal administration)

Midazolam†

IV, IM, IN

0.25 mg/kg

Gabapentin

PO

10 mg/kg q8h

Pregabalin

PO

2-4 mg/kg q8h

Felbamate

PO

15 mg/kg q8-12h (dose may be increased every 2 wk by 15 mg/kg/dose until effective or adverse effects noted; toxic dose is 300 mg/kg/day)

IM, Intramuscularly; IN, intranasally; IV, intravenously; PO, per os; PR, per rectum. *May be given via a loading dose to achieve steady-state levels more rapidly. † Most commonly used for emergency treatment of status epilepticus or cluster seizures due to rapid development of tolerance.

receptors and voltage-gate calcium channels.6 The mechanism of action is not fully understood. Phenobarbital has a high bioavailability after oral administration (86% to 96%), and about 45% of the drug is protein bound in the plasma.6 Phenobarbital is metabolized mainly in the liver, with about 25% being excreted unchanged via the kidneys.6 Therapeutic levels in the CNS are reached after 15 to 20 minutes with intravenous administration.6 Phenobarbital is considered a primary treatment option for epilepsy in dogs and cats. In dogs, phenobarbital has been reported to lead to a clinical response (≥50% reduction in seizure frequency) in 60% to 80% of dogs with idiopathic epilesy.7-9 There are very limited data concerning the effectiveness of phenobarbital in cats, but successful treatment has been documented.10 The suggested dose of phenobarbital in dogs is 3 to 5 mg/kg by mouth (PO) or intravenously (IV) q12h, and in cats a starting dose of 2.5 mg/kg PO/IV q12h is suggested. If a patient has cluster seizures or status epilepticus at presentation, a 16- to 20-mg/kg IV loading dose can be administered. This dose is usually divided into four to six equal doses and administered over 24 hours. The animal should be closely monitored for extreme sedation (e.g., loss of gag reflex), hypoventilation, and/or hypotension during administration of a loading dose, and the next dose should be delayed if any of these adverse effects are noted. This loading dose is intended to achieve a serum phenobarbital concentration of 20 to 40 mcg/ml. The therapeutic serum concentration referenced in the literature ranges from 15 to 40 mcg/ml.7,9,11 However, dosing should be based on clinical efficacy and signs of toxicity rather than serum levels alone. The risk of hepatotoxicity appears to increase above a serum level of 40 mcg/ ml.12 The half-life of phenobarbital in dogs varies among dogs and over time in the same dog, which may be due to autoinduction of hepatic enzymes responsible for its metabolism. In dogs, the half-life of phenobarbital has been reported to range from 37 to 89 hours.8 Consumption of a low-fat and/or low-protein diet may lower the half-life and therefore the serum concentration of phenobarbital.13 In cats, the half-life of phenobarbital has been reported to range from

14

34 to 43 hours. Serum drug steady-state levels are reached in 97% of patients after five half-lives.4 Therefore it is recommended that serum levels of phenobarbital be checked 2 to 3 weeks after a dosage change. Also, due to autoinduction of hepatic enzymes and potential lowering of serum phenobarbital levels with time, serum level should be measured every 6 to 12 months to evaluate the maintenance dosage. Adverse effects commonly reported in dogs and cats receiving phenobarbital include sedation, ataxia/proprioceptive deficits, polydipsia/polyuria, and polyphagia. The sedation and ataxia/ proprioceptive deficits tend to be transient and resolve within 2 to 3 weeks of starting an appropriate dosage of phenobarbital. Less commonly observed adverse effects include excitation, bone marrow suppression, hepatotoxicity, and superficial necrolytic dermatitis. Elevations in alkaline phosphatase level are common in dogs and by themselves do not signify hepatotoxicity. Elevations in alanine transaminase level are less frequent and therefore may be a more specific indicator of hepatotoxicity than elevations in alkaline phosphatase level. Thyroid hormone levels may be decreased in dogs receiving phenobarbital, and therefore therapy for hypothyroidism should not be based on blood levels alone. Elevations in canine pancreatic lipase immunoreactivity have been noted in dogs receiving phenobarbital, but many of these dogs were concurrently receiving potassium bromide.15

BROMIDE Bromide (potassium bromide [KBr] or sodium bromide [NaBr]) is a halide anticonvulsant used in veterinary medicine for the treatment of epilepsy. KBr was first used in the treatment of epilepsy in humans in 1857 but since then has been replaced by newer anticonvulsants with fewer adverse effects.16 However, KBr is still used as a primary or add-on anticonvulsant in dogs. The suspected mechanism of action of bromide anticonvulsants is hyperpolarization of the neuron via the movement of the bromide ions intracellularly through chloride channels. Bromide is administered as a compounded KBr or NaBr product. Bromide is not metabolized and is excreted unchanged in the urine. KBr has been used with success in veterinary medicine, decreasing seizure frequency in 72% to 74% of epileptic dogs.16,17 Bromide is not recommended for use in cats due to the risk of development potentially fatal pneumonitis. The recommended maintenance dosage of KBr is 20 to 40  mg/ kg/day; the dosage is reduced by about 15% when the NaBr formulation is used. Patients that have cluster seizures or status epilepticus at presentation can be given a loading dose of KBr of 400 to 600  mg/ kg PO or per rectum, divided into equal doses and administered over 1 to 5 days. Rectal administration may cause transient gastrointestinal disturbances. The recommended serum level of bromide is 0.8 to 3.0  mg/ml when bromide is used alone and 0.8 to 2.4  mg/ ml when it is used in combination with phenobarbital.16 However, dosing should be based on clinical efficacy and signs of toxicity rather than serum levels alone. The half-life of KBr in dogs is approximately 25 days, whereas in cats it is approximately 12 days, and can be affected by renal disease or decreased glomerular filtration rate.6,16 Also, since bromide is reabsorbed in the renal tubules through chloride channels, a change the amount of chloride in the diet can affect the clearance of bromide from the body. Therefore it is generally recommended that patients receiving bromide as an anticonvulsant maintain a relatively constant diet (in terms of chloride intake). Adverse effects related to bromide therapy include neurologic deficits (sedation, agitation or excitability, caudal paresis, ataxia, decreased pelvic limb flexor withdrawals), polyphagia, polyuria, polydipsia, and vomiting, and bromide use may be associated with

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the development of pancreatitis. The term bromism is used to denote toxic serum concentrations of bromide. Clinical signs of bromism include altered mentation, ataxia, and upper or lower motor neuron paresis. There is no clear serum concentration cutoff value at which bromism occurs, but one study found a mean serum bromide concentration of 3.7 mg/dl in dogs with bromism compared with 1.7 mg/dl in control dogs.18 However, some dogs without clinical signs of bromism had higher levels than 3.7 mg/dl, and likewise some affected dogs had lower values. Treatment of bromism involves dosage reduction or administration of intravenous 0.9% NaCl. Another potential consequence of KBr administration is pancreatitis. A significant increase in median serum pancreatic lipase immunoreactivity was noted in dogs treated with KBr alone or KBr and phenobarbital together compared with healthy dogs.15 However, many dogs receiving KBr therapy are polyphagic, which may lead to ingestion of high-fat food and subsequent pancreatitis. Also, KBr can cause gastric irritation resulting in clinical signs similar to those seen with pancreatitis. KBr use in cats has been associated with the development of potentially fatal pneumonitis in 35% to 42% of cats receiving bromide and is therefore not recommended in this species.19

ZONISAMIDE Zonisamide is one of the newer anticonvulsant options available for treatment of epilepsy in dogs and cats. Zonisamide is used both as a primary anticonvulsant and as an add-on therapy for epilepsy. Zonisamide is a sulfonamide drug with multiple reported mechanisms of action, including inhibition of voltage-gated sodium channels, inhibition of T-type calcium channels, modulation of dopaminergic activity, enhancement of GABA activity in the CNS, and inhibition of carbonic anhydrase activity. Zonisamide has a bioavailability of about 70%, with 40% of the drug protein bound in the plasma.20 Zonisamide is mostly excreted in the urine as metabolites (70%), although approximately 10% is excreted in the urine as the parent compound. Based on studies in humans, hepatic metabolism is important. Zonisamide has not been studied extensively in veterinary medicine, but limited reports suggest that zonisamide is an effective primary or add-on anticonvulsant. One report showed that 60% of patients responded (>50% reduction in seizure frequency) when zonisamide was used as a primary anticonvulsant, and 58% to 82% of dogs responded when zonisamide was used as an add-on anticonvulsant.21-23 The efficacy of zonisamide in cats has not been well studied, but it appears to be a safe alternative for treatment of epilepsy in cats. The recommended dosage of zonisamide is 5 to 10 mg/kg PO q12h in dogs and 10 mg/kg PO q24h in cats. Despite these recommendations, higher dosages have been used safely in both species. The recommended therapeutic serum concentrations are adapted from the human literature, and 10 to 40 mcg/ml is usually cited.22 The half-life of zonisamide in dogs is reported to be about 17 hours.20 Levels should be measured no sooner than 4 days after initiating or changing the dose of zonisamide in dogs. The coadministration of phenobarbital has been shown to shorten the half-life of zonisamide as well as the maximum serum concentration of zonisamide in healthy dogs; this effect remained for 10 weeks after discontinuation of phenobarbital therapy.24 It is not completely clear how one should alter the zonisamide dose when both phenobarbital and zonisamide are administered simultaneously. The half-life in cats is reported to be about 32 hours, and therefore once-daily dosing is indicated.25 Adverse effects in both species are usually mild, but include ataxia, sedation, and gastrointestinal abnormalities (vomiting, anorexia). Adverse effects in dogs can also include those associated with other sulfonamide drugs like keratoconjunctivitis sicca (KCS) and decreases in the total thyroxine concentration. There are several case reports

of an idiosyncratic hepatopathy associated with zonisamide use in dogs.26,27

LEVETIRACETAM Levetiracetam is a novel anticonvulsant that is currently being used as an add-on and primary anticonvulsant in dogs and cats. Levetiracetam’s suspected mechanism of action involves binding to the synaptic vesicle protein SV2A. This binding to SV2A is believed to result in decreased release of neurotransmitter into the synapse. The reported bioavailability of orally administered levetiracetam is 100%.28,29 There is little protein binding (300 U/kg SC) and/or more frequent dosing (q6h) to obtain target anti-Xa levels.11 In one study of 18 dogs with immune-mediated hemolytic anemia, administration of UFH at 300 U/kg SC q6h resulted in presumed therapeutic anti-Xa levels (≥0.35 U/ml) in 44% of dogs after the first 40 hours of therapy.34 Higher doses of UFH may also be necessary in animals with acute inflammation because of the tendency of UFH to bind to other acutephase proteins.26 High-dose UFH (900 U/kg/day intravenous constant rate infusion [CRI]) in dogs considered to be at risk of venous thrombosis resulted in hemorrhage in four of six dogs, whereas a lower dosage (300 U/kg/day CRI) did not result in target anti-Xa activity levels.35 The study of UFH use in cats has been limited. Cats with cardiac disease are at risk of arterial thromboembolism, but there are no studies evaluating the effects of any UFH protocol for cats with this disease. Empirical dosing of UFH ranges from 50 to 300 U/kg SC q6-8h.20,36 In healthy cats, a UFH dosage of 250 U/kg SC q6h for 5 days resulted in anti-Xa values in the therapeutic range (0.35 to 0.7 U/ml) in most cats for the majority of the study (see Table 168-1).37 LMWHs have been studied in dogs and cats. The expense of these drugs is still a large consideration when they are used in the clinical setting. The optimal dose and dosing interval for LMWH is not yet known in veterinary species. In dogs with TF-induced DIC, dalteparin was given as an intravenous CRI to produce anti-Xa activity levels between 0.6 and 0.9 U/ml. Achieving the target anti-Xa levels in this model was associated with less severe hematologic changes.38 In a study of dogs in an intensive care unit, treatment with dalteparin at 100 U/kg SC q12h failed to achieve plasma anti-Xa levels greater than 0.5 U/ml.35 Another study investigating dalteparin in dogs used a dosage of 175 U/kg SC q12h and documented mean plasma anti-Xa levels between 0.5 and 1.0 U/mL at 2 and 4 hours after administration, but suggested that a lower dose at more frequent intervals would better maintain therapeutic concentrations for the entire dosing interval without excessive anticoagulation.39 Dogs given enoxaparin at a dosage of 0.8 mg/kg SC q6h showed consistent anti-Xa levels within the range of 0.5 to 2.0 U/ml for the length of the study period (36 hours) (see Table 168-1).40 In cats dalteparin and enoxaparin have rapid absorption and elimination, which results in the need for frequent injections. The bioavailability of dalteparin in cats after subcutaneous injection is approximately 100%.41 Dalteparin given to cats at 100 U/kg SC q12h did not reliably produce target anti-Xa values (0.3 to 0.6 U/ml).42 Results from another study confirmed that in cats LMWH needs to be dosed frequently to maintain anti-Xa levels within the therapeutic range. In this study, dalteparin given at 150 U/kg SC q4h and enoxaparin given at 1.5 mg/kg SC q6h provided more reliable achievement of target anti-Xa levels in healthy cats (see Table 168-1).37 Dalteparin

CHAPTER 168  •  Anticoagulants

is well tolerated in cats but has not been shown to prevent the occurrence, reduce the severity, or decrease the frequency of arterial thromboembolic disease in cats.43

DIRECT THROMBIN INHIBITORS Direct thrombin inhibitors are small molecules that bind to thrombin at one of two sites44 and are indicated for prevention of arterial or venous thrombosis in humans, primarily in patients who have experienced heparin-induced thrombocytopenia or other heparinrelated complications. This class of drugs includes argatroban (licensed under no trade name), dabigatran (Pradaxa), lepirudin (Refludan), bivalirudin (Angiomax), and ximelagatran (Exanta). The direct thrombin inhibitors have activity against fibrin-bound thrombin and also circulating thrombin. They also do not require AT as a cofactor for this inhibition.44 They are attractive alternatives for thromboprophylaxis because they do not have as many drug interactions as warfarin and they do not require intensive monitoring with INR determinations.45 Dabigatran has been shown to be noninferior to warfarin for prevention of thromboembolism and stroke in people with atrial fibrillation, but the cost of this drug has remained prohibitive.46 Argatroban is available for intravenous administration and has been studied in an experimental dog model of cardiopulmonary bypass. This study found that argatroban was safe and decreased coagulation system activation while dogs were on cardiopulmonary bypass circuits.47 There are no published clinical studies of the use of direct thrombin inhibitors in veterinary species.

FACTOR Xa INHIBITORS Oral FXa inhibitors are novel anticoagulants that have been recently approved for use in people for the prevention of venous thromboembolism after total hip replacement and prevention of stroke in patients with atrial fibrillation.48-52 Unlike UFH and LMWH, these drugs do not require AT for FXa-inhibitory activity. Rivaroxaban (Xarelto) is a direct inhibitor of factor Xa with approximately 80% bioavailability in people after oral administration.53 The ROCKET AF study in humans compared rivaroxaban with warfarin in patients with atrial fibrillation and found rivaroxaban to be noninferior to warfarin for the prevention of stroke and systemic thromboembolism.54 In addition, treatment with rivaroxaban was associated with less risk of intracranial hemorrhage and fatal bleeding episodes.54 In vitro studies of the anticoagulant effect of rivaroxaban on canine and feline blood indicate that these drugs have anticoagulant effects similar to those seen in humans.55,56 In vivo studies are ongoing and are a necessary step to determine whether veterinary species may benefit from this drug. Apixaban (Eliquis) is another oral FXa inhibitor that appears safe and has an acceptable adverse event profile in humans. An in vitro human model showed that apixaban can also inhibit platelet aggregation through the prevention of thrombin generation via the TF coagulation pathway.57 Studies in people who have deep vein thrombosis or who require thromboprophylaxis for potential systemic thromboembolism after knee replacement surgery have shown apixaban to be as effective as or superior to currently used anticoagulants.58,59 Apixaban has not yet been evaluated in veterinary species. Although the anti-Xa drugs can provide an attractive and safe means of oral anticoagulation in veterinary species, prospective studies are necessary to further define the indications for their use.

CONCLUSION Coagulation abnormalities are commonly encountered in small animal practice. Diseases associated with hypercoagulability and thrombosis include immune-mediated hemolytic anemia, protein-

losing enteropathies, protein-losing nephropathies, neoplasia, systemic inflammation, hyperadrenocorticism, and cardiac disease. The most effective anticoagulant and dose regimen for these diseases has yet to be elucidated through controlled, prospective studies. In addition, the tests of choice for monitoring of anticoagulant therapy and the ideal target values for aPTT, anti-Xa activity, and TEG have yet to be discovered. With new anticoagulant drugs on the horizon, the treatment and prophylaxis of thrombosis may become more tailored to the veterinary species.

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PART XX  •  PHARMACOLOGY 23. Abildgaard U: Heparin/low molecular weight heparin and tissue factor pathway inhibitor, Haemostasis 23(Suppl 1):103, 1993. 24. Bentley AM, Mayhew PD, Culp WT, et al: Alterations in the hemostatic profiles of dogs with naturally occurring septic peritonitis, J Vet Emerg Crit Care (San Antonio) 23(1):14, 2013. 25. Donahue SM, Brooks M, Otto CM: Examination of hemostatic parameters to detect hypercoagulability in dogs with severe protein-losing nephropathy, J Vet Emerg Crit Care (San Antonio) 21(4):346, 2011. 26. Breuhl EL, Moore G, Brooks MB, et al: A prospective study of unfractionated heparin therapy in dogs with primary immune mediated hemolytic anemia, J Am Anim Hosp Assoc 45:125, 2009. 27. Hirsh J, Bauer KA, Donati MB, et al: Parenteral anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition), Chest 133:141S, 2008. 28. Babski DM, Brainard BM, Ralph AG, et al: Sonoclot evaluation of single and multiple dose unfractionated heparin therapy in healthy adult dogs, J Vet Intern Med 26(3):631, 2012. 29. Spinler SA, Wittkowsky AK, Nutescu EA, et al: Anticoagulation monitoring part 2: unfractionated heparin and low molecular weight heparin, Ann Pharmacother 39:1275, 2005. 30. Brooks MB: Evaluation of a chromogenic assay to measure the factor Xa inhibitory activity of unfractionated heparin in canine plasma, Vet Clin Pathol 33:208, 2004. 31. Brooks M: Coagulopathies and thrombosis. In Ettinger SJ, editor: Textbook of veterinary internal medicine, Philadelphia, 2000, Saunders. 32. Couto CG: Disseminated intravascular coagulation in dogs and cats, Vet Med 94:547, 1999. 33. Mischke RH, Schuttert C, Grebe SI: Anticoagulant effects of repeated subcutaneous injections of high doses of unfractionated heparin in healthy dogs, Am J Vet Res 62:1887, 2001. 34. Breuhl EL, Moore G, Brooks MB, et al: A prospective study of unfractionated heparin therapy in dogs with primary immune-mediated hemolytic anemia, J Am Anim Hosp Assoc 45:125, 2009. 35. Scott KC, Hansen BD, DeFrancesco TC: Coagulation effects of low molecular weight heparin compared with heparin in dogs considered to be at risk for clinically significant venous thrombosis, J Vet Emerg Crit Care (San Antonio) 19:74, 2009. 36. Schoeman JF: Feline distal aortic thromboembolism: a review of 44 cases (1990-1998), J Feline Med Surg 1:221, 1999. 37. Alwood AJ, Downend AB, Brooks MB, et al: Anticoagulant effects of lowmolecular weight heparins in healthy cats, J Vet Intern Med 21:378, 2007. 38. Mischke R, Fehr M, Nolte I: Efficacy of low molecular weight heparin in a canine model of thromboplastin-induced acute disseminated intravascular coagulation, Res Vet Sci 79:69, 2005. 39. Brainard BM, Koenig A, Babski DM, et al: Viscoelastic pharmacodynamics after dalteparin administration to healthy dogs, Am J Vet Res 73:1577, 2012. 40. Lunsford KV, Mackin AJ, Langston VC, et al: Pharmacokinetics of subcutaneous low molecular weight heparin (enoxaparin) in dogs, J Am Anim Hosp Assoc 45:261, 2009. 41. Mischke R, Schmitt J, Wolken S, et al: Pharmacokinetics of low molecular weight heparin dalteparin in cats, Vet J 192(3):299, 2012.

42. Vargo CL, Taylor SM, Carr A, et al: The effect of a low molecular weight heparin on coagulation parameters in healthy cats, Can J Vet Res 73:132, 2009. 43. Smith CE, Rozanski EA, Freeman LM, et al: Use of low molecular weight heparin in cats: 57 cases (1999-2003), J Vet Med Assoc 225(8):1237, 2004. 44. Siller-Matula JM, Schwameis M, Blann A, et al: Thrombin as a multifunctional enzyme: focus on in vitro and in vivo effects, Thromb Haemost 106:1020, 2011. 45. Garcia D, Libby E, Crowther MA: The new oral anticoagulants, Blood 115(1):15, 2010. 46. Connolly SJ, Ezekowitz MD, Yusuf S, et al: Dabigatran versus warfarin in patients with atrial fibrillation, N Engl J Med 361(12):1139, 2009. 47. Sakai M, Ohteki H, Narita Y, et al: Argatroban as a potential anticoagulant in cardiopulmonary bypass studies in a dog model, Cardiovasc Surg 7:187, 1999. 48. Eriksson BI, Borris L, Dahl OE, et al: Oral, direct Factor Xa inhibition with BAY 59-7939 for the prevention of venous thromboembolism after total hip replacement, J Thromb Haemost 4:121, 2006. 49. Eriksson BI, Borris LC, Dahl OE, et al: Dose-escalation study of rivaroxaban (BAY 59-7939)—an oral, direct Factor Xa inhibitor—for the prevention of venous thromboembolism in patients undergoing total hip replacement, Thromb Res 120:685, 2007. 50. Turpie AG, Fisher WD, Bauer KA, et al: BAY 59-7939: an oral, direct factor Xa inhibitor for the prevention of venous thromboembolism in patients after total knee replacement. A phase II dose-ranging study, J Thromb Haemost 3:2479, 2005. 51. Abdulsattar Y, Bhambri R, Nogid A: Rivaroxaban (Xarelto) for the prevention of thromboembolic disease: an inside look at the oral direct factor Xa inhibitor, P T 34:238, 2009. 52. Wittkowsky AK: New oral anticoagulants: a practical guide for clinicians, J Thromb Thrombolysis 29(2):182, 2010. 53. Kubitza D, Becka M, Voith B, et al: Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor, Clin Pharmacol Ther 78:412, 2005. 54. Patel MR, Mahaffey KW, Garg J, et al: Rivaroxaban versus warfarin in nonvalvular atrial fibrillation, N Engl J Med 365(10):883, 2011. 55. Conversy B, Blais M-C, Gara-Boivin C, et al: In vitro evaluation of the effect of rivaroxaban on coagulation parameters in healthy dogs, J Vet Intern Med 26:776, 2012 (abstract). 56. Brainard BM, Cathcart CJ, Dixon AC, et al: In vitro effects of rivaroxaban on feline coagulation indices, J Vet Intern Med 25:687, 2011 (abstract). 57. Wong PC, Pinto DJP, Zhang D: Preclinical discovery of apixaban, a direct and orally bioavailable factor Xa inhibitor, J Thromb Thrombolysis 31(4):478, 2011. 58. Lassen MR, Raskob GE, Gallus A, et al: Apixaban or enoxaparin for thromboprophylaxis after knee replacement, N Engl J Med 361(6):594, 2009. 59. Buller H, Deitchman D, Prins M, et al: Efficacy and safety of the oral direct factor Xa inhibitor apixaban for symptomatic deep vein thrombosis. The Botticelli DVT dose-ranging study, J Thromb Haemost 6(8):1313, 2008.

CHAPTER 169  THROMBOLYTIC AGENTS Daniel F. Hogan,

DVM, DACVIM (Cardiology)

KEY POINTS • Thrombolytic agents are used to return patency to obstructed blood vessels and improve blood flow to infarcted organs. • The thrombolytic process occurs primarily on recently formed thrombi because older thrombi have extensive fibrin polymerization that makes them more resistant to thrombolysis. Therefore the use of thrombolytic agents carries the greatest chance of success if they are administered as soon as possible following identification of a thrombus. • Thrombolytic agents are used frequently in emergent patients and are commonly associated with complications such as bleeding and reperfusion injury. • The thrombolytic agents most commonly used in veterinary medicine are tissue plasminogen activator, streptokinase, and urokinase. • There is very little clinical experience with the use of these agents in small animals. Additionally, these drugs are quite expensive, which may limit their clinical usefulness in veterinary medicine.

SPECIFIC THROMBOLYTIC AGENTS Streptokinase Streptokinase combines with plasminogen to form an activator complex that converts plasminogen to the proteolytic enzyme plasmin. Plasmin degrades fibrin, fibrinogen, plasminogen, coagulation factors, and streptokinase. The streptokinase-plasminogen complex converts circulating and fibrin-bound plasminogen and is therefore considered a nonspecific activator of plasmin. This results in a systemic proteolytic state that may predispose to bleeding from loss of coagulation factors and fibrinogen, and an increase in fibrin degradation products. Although the half-life of streptokinase is relatively short (30 minutes), fibrinogenemia can persist for 24 hours.1 Streptokinase is produced by streptococci, which can lead to antigenic stimulation in the patient, especially with repeated administrations. Anisoylated purified streptokinase activator complex is a complex of streptokinase and plasminogen that does not require free circulating plasminogen to be effective. Although it does have many theoretic benefits over streptokinase, antigenic stimulation may still

BOX 169-1  Thrombolysis is the dissolution of thrombi within the cardiovascular system through the enzymatic breakdown of fibrin (fibrinolysis) by the serine protease plasmin. Endogenous thrombolysis is mediated by tissue plasminogen activator (t-PA), synthesized in the vascular endothelial cells, which facilitates the conversion of plasminogen to active plasmin. Plasmin formation takes place in an intimate association among t-PA, plasminogen, and fibrin. Endogenous thrombolysis via t-PA is modulated by multiple substances, of which plasminogen activator inhibitor and thrombin-activatable fibrinolysis inhibitor are the most notable. Therapeutic thrombolysis is used for conditions including venous thrombosis, pulmonary embolism, systemic arterial occlusive disease, ischemic stroke, and acute myocardial infarction (Box 169-1). Supraphysiologic levels of exogenous plasminogen activators are administered intravenously to cause thrombus dissolution. The thrombolytic process works primarily on recently formed clots; older thrombi have extensive fibrin polymerization that makes them more resistant to thrombolysis. Therefore the use of thrombolytic agents carries the greatest chance for success if they are administered as early as possible following identification of a thrombus (see Box 169-1). Multiple agents have been approved for use in people to manage pathologic thromboses, including streptokinase, urokinase, anisoylated plasminogen streptokinase, t-PA, and modified forms of t-PA (reteplase and tenecteplase). These agents vary with respect to pharmacokinetics, fibrin specificity, thrombolytic activity, and clinical response. However, there is not a tremendous amount of experience with the use of these agents in veterinary medicine, and scientific reports are limited to examination of streptokinase, urokinase, and t-PA.

Recommendations for Thrombolytic Therapy in Small Animals

Clinical Scenarios in Which Thrombolytic Therapy Should Be Considered* Infarction of organs causing life-threatening consequences • Cerebral infarction • Complete bilateral renal infarction • Complete splanchnic infarction • Symptomatic and progressive pulmonary embolism Infarction that may cause irreversible organ dysfunction • Severe bilateral infarction of the pelvic limbs • Complete unilateral renal infarction • Severe unilateral infarction of a thoracic or pelvic limb Infarction with severe clinical consequences that causes owner to consider euthanasia

Clinical Scenarios in Which Thrombolytic Therapy Could Be Considered Incomplete infarction of pelvic or thoracic limbs Symptomatic but static (nonprogressive) pulmonary embolism

Clinical Scenarios in Which Thrombolytic Therapy Should Not Be Considered Suspected or proven coagulopathies, thrombocytopenia Evidence of active bleeding Infective endocarditis Intracavitary (cardiac) thrombi Vascularly invasive neoplastic processes *Some thrombotic states may require surgical intervention instead of thrombolytic therapy.

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occur. Use of this product has not been investigated in clinical veterinary patients. Streptokinase typically is administered by giving 90,000 IU intravenously over 1 hour followed by an infusion of 45,000 IU/hr for up to 12 hours (dogs and cats). Unfortunately, streptokinase is no longer commercially available.

Urokinase The renal tubular epithelium, not the endothelium, appears to be the primary in vivo source of the proteolytic enzyme urokinase or urokinase plasminogen activator (u-PA). Urokinase is similar in activity to streptokinase but is considered more fibrin specific because of the physical characteristics of the compound. Commercial preparations, derived from human fetal cell cultures, consist of both highmolecular-weight (HMW) and low-molecular-weight (LMW) fractions. Although the HMW fraction predominates, it is converted quickly and continuously within the circulation to the LMW form, which exhibits greater binding to the lysine-plasminogen form of plasminogen.2,3 Lysine-plasminogen, in contrast with the glutamate-plasminogen form, differentially accumulates within thrombi and thereby confers fibrin specificity to the u-PA. In addition, glutamate-plasminogen is converted to lysine-plasminogen during thrombolysis, so that the binding of u-PA to plasminogen within the thrombus is increased. It is interesting to note that for u-PA to interact with many cell types, including epithelial cells, the high-affinity u-PA receptor (u-PAR) is required.4,5 HMW u-PA, but not LMW u-PA, binds to u-PAR, and u-PA associated with the u-PAR is susceptible to the physiologic inhibitor plasminogen activator inhibitor, which suggests a possible clearance mechanism.6,7 It also appears that u-PA associated with u-PAR is involved mostly in nonproteolytic activities such as cellular adhesion and migration.8 Prourokinase, a relatively inactive precursor that must be converted to urokinase before it becomes active in vivo, is under investigation in humans. It is inactive in plasma and does not bind to or consume circulating inhibitors. As with t-PA, prourokinase is somewhat thrombus specific because the presence of fibrin enhances the conversion of prourokinase to active urokinase by an unknown mechanism. Use of this fibrinolytic agent in clinical veterinary patients has not yet been studied. Urokinase is typically administered as a loading dose of 4400 IU/ kg given over 10 minutes, followed by 4400 IU/kg/hr for 12 hours.9,10 Urokinase is not currently available in the United States, but it may become available again in the near future.

Tissue Plasminogen Activator The serine protease t-PA is the primary activator of plasmin in vivo; however, it does not readily bind circulating plasminogen and therefore does not induce a systemic proteolytic state at physiologic levels. Plasminogen and t-PA both have a high affinity for fibrin and thereby form an intimate relationship within thrombi, which results in a relatively fibrin-specific conversion of plasminogen to plasmin. However, the fibrin specificity is relative, and when t-PA is given at the recommended high clinical dosages, a systemic proteolytic state and bleeding can be seen.11 Although the half-life of t-PA is very short (2 to 3 minutes), a sustained fibrinolytic state may persist as a result of protection from the physiologic inhibitors of fibrinolysis (plasminogen activator inhibitor, thrombin-activatable fibrinolysis inhibitor).12 The recommended dosing protocol for human recombinant t-PA (Activase) in cats is an intravenous constant rate infusion of 0.25 to 1 mg/kg/hr for a total dose of 1 to 10 mg/kg.13 Although the clinical experience in dogs is very limited, one dog received multiple 1-mg/ kg intravenous boluses every 60 minutes and another received one

dose of 1 mg/kg administered intravenously over 60 minutes.14,15 It would appear reasonable to parallel the cat treatment protocol of 0.25 to 1 mg/kg/hr intravenously for a total dosage of 1 to 10 mg/kg. Activase is supplied in 50-mg and 100-mg bottles with an estimated cost of $1500 and $3000, respectively. Smaller amounts of t-PA can be purchased (Cathflo Activase) for approximately $100 per 2 mg. This formulation may be more cost effective for small cats or dogs and may also enable owners with budget constraints to afford treatment at the low end of the dosage range. For example, a typical cat weighing 4.5 kg could receive 2.2 mg/kg for about $500. An average-sized dog (15 kg) would require from 15 mg to 150 mg at an approximate cost of $800 to $4500. The concentration of t-PA is 1 mg/ml when reconstituted, and the preparation is good for up to 8 hours when stored at 2° to 8° C (35.6° to 46.4° F). t-PA has been frozen in a regular freezer (−20° C [−4° F]) for up to 6 months without losing thrombolytic activity in an in vitro feline whole blood thrombus model.16 This may allow unused portions of the drug to be stored and administered to other animals later. This has been done routinely by ophthalmologists to remove fibrin from within the anterior chamber of the eye. However, there are no preservatives in the final solution, so sterility cannot be guaranteed.

ADVERSE EFFECTS OF THROMBOLYTIC THERAPY The most common and predictable complication of thrombolytic therapy in humans is bleeding, which may be secondary to thrombocytopenia, platelet dysfunction, hypofibrinogenemia, systemic lytic state, dissolution of hemostatic plugs, or disruption of altered vascular sites.1,17-20 Fibrin specificity does not appear to have a large clinical effect based on human trials, in which the incidence of bleeding was similar for streptokinase and t-PA.20 Intracranial hemorrhage, which is the bleeding complication causing most concern, is seen more commonly in patients treated with high levels of t-PA.19 The reasons for this are not known, but the presence of abnormal vascular sites is suspected based on an increased risk in patients of advanced age.20 Reperfusion injury can be seen when metabolic waste and electrolytes are released from infarcted tissues. This most commonly occurs in people who develop arrhythmias after receiving thrombolytic therapy for acute myocardial infarction. The severity of reperfusion injury is proportional to the amount of infarcted tissue, and the more clinically relevant comparison with veterinary medicine may be Leriche syndrome, in which there is infarction of the distal aorta causing ischemia of the pelvic limb musculature. Thrombolytic therapy in these patients results in severe metabolic acidosis and hyperkalemia that often requires aggressive therapy, including hemofiltration or hemodialysis. Similar complications are seen with thrombolytic therapy in cats with distal aortic infarction from cardiogenic embolism (e.g., aortic thromboembolism or saddle thrombus).9,13,21,22

THROMBOLYTIC THERAPY IN DOGS Streptokinase There is very little reported experience with this thrombolytic agent in dogs. Ramsey et al described a case series of four dogs with thromboembolic disease (one pulmonary, three distal aorta) treated with streptokinase.23 Partial resolution of the thrombus was noted in one dog, and the other three had complete resolution after one to three doses of streptokinase. All animals experienced partial or complete resolution of clinical signs, with only minor bleeding seen in three that resolved with discontinuation of streptokinase infusion. There was no evidence of reperfusion injury in this study.

CHAPTER 169  •  Thrombolytic Agents

Urokinase Whelan et al10 described u-PA use in four dogs. Distal aortic infarction was identified by abdominal ultrasonography in three of the dogs, and pulmonary embolism was diagnosed by echocardiography in one dog. The three dogs with aortic infarction had femoral arterial pulses and voluntary motor function before u-PA administration, and there was no identifiable difference after u-PA therapy. Additionally, there was persistence of the thrombi on abdominal ultrasonography. Even though there was no beneficial effect from u-PA therapy in these three dogs, one dog did develop hyperkalemia and metabolic acidosis suggestive of reperfusion injury. All three dogs with aortic thromboembolism were euthanized or died during hospitalization. The dog with pulmonary embolism was reported to have improved clinically with improved echocardiographic indexes, which suggested partial resolution of the pulmonary embolism following u-PA therapy.

Tissue Plasminogen Activator There are two reports of t-PA therapy for aortic infarction in dogs in the literature. In one report14 a dog showed a return of femoral arterial pulses after receiving ten 1-mg/kg bolus injections given at 1-hour intervals. However, pulses were again absent 6 days after therapy. Pulses returned after an additional two doses of t-PA, and pulse quality improved after two more doses were given within 24 hours. Short-term follow-up revealed persistence of femoral arterial pulses, normal pelvic limb gait, and resolution of the thrombus on abdominal ultrasonography. The second report examined the use of t-PA after distal aortic infarction in six dogs.15 All six dogs failed to improve with the administration of 1 mg/kg of t-PA over a 60-minute period with concurrent heparin therapy.

THROMBOLYTIC THERAPY IN CATS Many more clinical data are available for cats because of the higher frequency of cardioembolic disease in this species. The incidence of hyperkalemia and reperfusion injury following embolus dissolution with thrombolytic therapy ranges from 40% to 70%.13,21,22 Reperfusion injury represents the most common cause of death in cats receiving thrombolytic agents, with survival rates ranging from 0% to 43%.9,13,21,22 Cats that have more complete infarction, such as bilateral paralysis, appear more likely to develop hyperkalemia and metabolic acidosis, probably because of the larger area of ischemia.13,21

Streptokinase There are two retrospective studies evaluating streptokinase therapy for aortic infarction in cats. The first study evaluated eight cats, and all experienced respiratory distress and died suddenly during the maintenance phase of streptokinase therapy.22 However, two of these cats did have intracavitary thrombi within the left atrium, generally considered a contraindication for thrombolytic therapy. One of these cats was diagnosed as having a right coronary arterial infarction on necropsy that may have resulted from fragmentation of the left atrial thrombus induced by the thrombolytic therapy. The second study evaluated 46 cats treated for cardioembolic disease.21 In this study approximately 50% had a return of femoral pulses within 24 hours of initiation of streptokinase therapy. Motor function returned in 30% of the cats, while 80% of those cats regained motor function within 24 hours. Cats with single limb infarction did dramatically better, with 100% regaining pulses and 80% regaining motor function. Of those cats that had infarction of both limbs, only about 50% regained pulses and approximately 25% regained motor function. Adverse effects were seen in 65% of cats that developed

abnormal coagulation values after beginning streptokinase therapy. However, some of these cats were also receiving heparin. Spontaneous bleeding from oral, rectal, or catheter sites was seen in 24% of cats, including 36% of those with abnormal coagulation parameters. Bleeding was severe enough to require transfusions in 27%, with only 18% of these cats surviving streptokinase therapy. Increased respiratory rates were seen in 30% of cats, although this was found to be caused by worsening of congestive heart failure in 21% of the small number of cats in which the underlying cause was pursued (14 of 46). Hyperkalemia developed in approximately 40% of cats and was more likely to be seen with longer infusion periods, which may be related to more complete or severe obstruction. There was an overall survival rate of 33% during hospitalization. However, about 50% of the cats that did survive the hospital stay were euthanized because of complications of therapy or poor prognosis.

Urokinase There is one retrospective study in 12 cats reporting on the use of u-PA for the treatment of cardioembolic disease.9 Bilateral aortic infarction was present in 10 of 12 cats (83%), with no palpable pulse in the affected limb(s) in 10 of 12 (83%) and no motor function in 9 of 12 (75%). Urokinase infusion resulted in the return of pulses in 3 of 10 (30%) and return of motor function in 5 of 9 (56%). It is interesting to note that more cats regained motor function than had return of pulses, which suggests that collateral circulation and not thrombolysis resulted in the return of function in at least some cats. Hyperkalemia developed in 3 of 12 cats (25%), including 3 of 7 (43%) that did not have return of pulses or function (which again possibly suggests a role for collateral circulation). There was no evidence of clinical bleeding. Five out of 12 cats survived (42%) and all nonsurvivors were euthanized. There is also a case report of intraarterial infusion of urokinase in a cat, delivered after intravenous administration of urokinase as well as conservative anticoagulant and antiplatelet therapy failed to result in thrombolysis.24 A catheter was inserted into the carotid artery and advanced to a location just distal to the renal arteries in the abdominal aorta. Urokinase (60,000 IU) was administered through the intraarterial catheter over 5 minutes and during the third urokinase administration patency of the femoral arteries was noted. Arterial flow to the pelvic limbs was considered partial, so intravenous infusion of urokinase once a day was continued for an additional 6 days with arterial flow considered normal on day 4. The cat did not exhibit any adverse clinical effects from the urokinase therapy, which may be due to the collateral circulation documented on angiography before the intraarterial administration.

Tissue Plasminogen Activator There have been two clinical trials of t-PA therapy in cats with cardioembolic disease.13,25 The first study reported a short-term survival rate of 50%, with deaths attributable to reperfusion injury and cardiogenic shock. Of the cats that survived, 100% had bilateral pelvic limb infarction. Perfusion was restored within 36 hours and motor function returned within 48 hours in 100% of surviving cats. Complications included minor hemorrhage from catheter sites (50%), fever (33%), and reperfusion injury (33%).13 A more recent study of t-PA therapy in cats with arterial thromboembolism reported a 64% survival rate at 24 hours, but only 27% survived to discharge; 91% of the cats had bilateral pelvic limb infarction.25 In the cats that survived, 50% of infarcted limbs had a palpable pulse at 4 hours after beginning therapy, and 62% had a palpable pulse at 24 hours. Complications were reported in 100% of cats and included azotemia, neurologic signs (45%), arrhythmias (45%), hyperkalemia (36%), acidosis (18%), and sudden death (9%). The study was ended early due to the high incidence of complications.

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CONCLUSION The use of rheolytic thrombectomy machines (e.g., AngioJet system) for rapid removal of pathologic thrombi is under investigation in veterinary medicine. Only one study has been published thus far and described the use of this technology in cats with aortic thromboembolism; successful thrombus dissolution was achieved in five of six cats, and three survived to discharge.26 Surgical thrombectomy may also be indicated in some animals, especially those with organ infarction (e.g., splenic infarction). Prevention of further thrombus formation in animals with thrombotic disease, regardless of the species or cause, remains a challenging subject in veterinary medicine (see Chapter 168).

REFERENCES 1. Rao AK, Pratt C, Berke A, et al: Thrombolysis in myocardial infarction (TIMI) trial phase I: hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase, J Am Coll Cardiol 11:1, 1988. 2. Gulba DC, Bode C, Runge MS, et al: Thrombolytic agents: an overview, Ann Hematol 73:S9, 1996. 3. Comerota AJ, Cohen GS: Thrombolytic therapy in peripheral arterial occlusive disease: mechanisms of action and drugs available, Can J Surg 36:342, 1993. 4. Blasi F, Conese M, Moller LB, et al: The urokinase receptor: structure, regulation and inhibitor-mediated internalization, Fibrinolysis 8:182, 1994. 5. Barnathan E, Kuo A, Rosenfeld L, et al: Interaction of single-chain urokinase-type plasminogen activator with human endothelial cells, J Biol Chem 265:2865, 1990. 6. Cubellis MV, Andreasson P, Ragno P, et al: Accessibility of receptor-bound urokinase to type-1 plasminogen activator inhibitor, Proc Natl Acad Sci U S A 86:4828, 1989. 7. Ellis V, Wun TC, Behrendt N, et al: Inhibition of receptor-bound urokinase by plasminogen activator inhibitor, J Biol Chem 265:9904, 1990. 8. Blasi F, Carmeliet P: uPAR: a versatile signaling orchestrator, Nat Rev Mol Cell Biol 3:932, 2002. 9. Whelan MF, O’Toole TE, Chan DL, et al: Retrospective evaluation of urokinase use in cats with arterial thromboembolism, J Vet Emerg Crit Care (San Antonio) 15:S8, 2005 (abstract). 10. Whelan MF, O’Toole TE, Chan DL, et al: Retrospective evaluation of urokinase use in dogs with thromboembolism (four cases: 2003-2004), J Vet Emerg Crit Care (San Antonio) 15:S8, 2005 (abstract).

11. Agnelli G: Rationale for bolus t-PA therapy to improve efficacy and safety, Chest 97:161S, 1990. 12. Eisenberg PR, Sherman LA, Tiefenbrunn AJ, et al: Sustained fibrinolysis after administration of t-PA despite its short half-life in the circulation, Thromb Haemost 57:35, 1987. 13. Pion PD, Kittleson MD: Therapy for feline aortic thromboembolism. In Kirk RW, editor: Current veterinary therapy X, ed 10, Philadelphia, 1989, Saunders. 14. Clare A, Kraje BJ: Use of recombinant tissue-plasminogen activator for aortic thrombolysis in a hypoproteinemic dog, J Am Vet Med Assoc 212:539, 1998. 15. Boswood A, Lamb CR, White RN: Aortic and iliac thrombosis in six dogs, J Small Anim Pract 41:109, 2000. 16. Hogan DF: Unpublished data. 17. Gore JM, Sloan M, Price TR, et al: Intracerebral hemorrhage, cerebral infarction, and subdural hematoma after acute myocardial infarction and thrombolytic therapy in the Thrombolysis in Myocardial Infarction Study. Thrombolysis in Myocardial Infarction, Phase II pilot and clinical trial, Circulation 83:448, 1991. 18. Stump DC, Califf RM, Topol EJ, et al: Pharmacodynamics of thrombolysis with recombinant tissue-type plasminogen activator. Correlation with characteristics of and clinical outcomes in patients with acute myocardial infarction, Circulation 80:1222, 1989. 19. Carlson SE, Aldrich MS, Greenberg HS, et al: Intracerebral hemorrhage complicating intravenous tissue plasminogen activator treatment, Arch Neurol 45:1070, 1988. 20. Berkowitz SD, Granger CB, Pieper KS, et al: Incidence and predictors of bleeding after contemporary thrombolytic therapy for myocardial infarction. The Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) I Investigators, Circulation 95:2508, 1997. 21. Moore KE, Morris N, Dhupa N, et al: Retrospective study of streptokinase administration in 46 cats with arterial thromboembolism, J Vet Emerg Crit Care 10:245, 2000. 22. Ramsey CC, Riepe RD, Macintire DK, et al: Streptokinase: a practical clot-buster? In Proceedings of the 5th International Veterinary Emergency and Critical Care Symposium, San Antonio, Texas, September 16-20, 1996. 23. Ramsey CC, Burney DP, Macintire DK, et al: Use of streptokinase in four dogs with thrombosis, J Am Vet Med Assoc 209:780, 1996. 24. Koyama H, Matsumoto H, Fukushima R, et al: Local intra-arterial administration of urokinase in the treatment of a feline distal aortic thromboembolism, J Vet Med Sci 72:1209, 2010. 25. Welch KM, Rozanski EA, Freeman LM, et al: Prospective evaluation of tissue plasminogen activator in 11 cats with arterial thromboembolism, J Feline Med Surg 12:122, 2010. 26. Reimer S, Kittleson MD, Kyles AE: Use of rheolytic thrombectomy in the treatment of feline distal aortic thromboembolism, J Vet Intern Med 20:290, 2006.

CHAPTER 170  HEMOSTATIC DRUGS Angela Borchers,

DVM, DACVIM, DACVECC

KEY POINTS • Coagulopathies may arise from defects in primary hemostasis, secondary hemostasis, or the fibrinolytic system or may be of multifactorial origin. • In situations in which transfusional therapy is not effective, is not available, or should be avoided altogether, the administration of hemostatic drugs may be considered. • Several hemostatic agents are currently being used as bloodsaving agents in the bleeding human and veterinary patient. However, they cannot replace good medical therapy and surgical technique.

Coagulopathies may arise from defects in primary hemostasis, secondary hemostasis, or the fibrinolytic system, or maybe of multifactorial origin. Although specific defects in primary or secondary hemostasis are often treated with blood products to replenish deficiencies, patients with multiple coagulation abnormalities, severe single coagulation defects, hyperfibrinolysis, or unclassified coagulopathies may not respond adequately to blood product administration. In these cases, administration of nontransfusional hemostatic drugs may be considered as alternative treatment. Clinical disorders in small animals that may benefit from nontransfusional hemostatic drugs include von Willebrand disease (vWD), hemophilia A and B, and other hereditary coagulation factor deficiencies; hereditary thrombopathies such as Glanzmann’s thromboasthenia; acquired thrombopathies; and enhanced hyperfibrinolytic states after surgery or trauma. Briefly, according to our current understanding, the hemostatic system involves a delicate balance between procoagulation pathways, anticoagulant pathways, and fibrinolysis. Primary hemostasis initiates the formation of a platelet plug in response to injury to a blood vessel. This process is mediated by von Willebrand factor (vWF), which triggers the adhesion and activation of platelets in response to exposed subendothelium and the formation of the primary platelet plug. Secondary hemostasis leads to thrombin generation, which mediates the production of a fibrin fiber meshwork that stabilizes the platelet plug. This process is initiated by the exposure of perivascular tissue factor (TF) to factor VII in blood, which leads to the activation of both the extrinsic and intrinsic coagulation pathways, cumulating in thrombin production (see Chapter 104). Anticoagulant pathways include antithrombin-mediated factor inactivation, protein C activation via the thrombin-thrombomodulin complex, and TF pathway inhibitor (TFPI). Fibrinolysis is initiated as tissue plasminogen activator and/or urokinase, which cleave plasminogen into plasmin, are released from the endothelium following injury, ischemia, or exposure to thrombin. Plasmin degrades fibrin into soluble fibrin degradation products.1-5

ANTIFIBRINOLYTIC DRUGS The antifibrinolytic agents most commonly used in human and veterinary medicine are the synthetic lysine analogs ε-aminocaproic acid (6-aminohexanoic acid; EACA) and tranexamic acid (trans-4aminomethyl cyclohexane carboxylic acid; TXA).2,6-11 Aprotinin was previously used widely in human medicine for both its antifibrinolytic and its antiinflammatory properties. The drug was removed from the world markets in May 2008 due to patient safety concerns, including sudden death, thrombotic complications, kidney failure, and myocardial infarction.8,12 Plasminogen acts as a fibrinolytic substance by binding to fibrin at a lysine-binding site. Plasminogen is then converted into plasmin, its activated form, which breaks down fibrin into fibrin degradation products. Both, EACA and TXA reversibly block the lysine-binding site on plasminogen, which is essential for binding to fibrin. This step consequently blocks the activation of plasminogen on the surface of fibrinogen and thereby prevents the breakdown of fibrin, although plasmin generation does occur.6-8

Indications In human medicine antifibrinolytic drug therapy has been used extensively for the treatment of intraoperative hemorrhage, particularly in cardiac surgery, liver transplantation, spinal surgery, and orthopedic surgery. Other indications include gastrointestinal bleeding, urinary tract and uterine hemorrhage (both the urinary tract and the endometrium are rich in plasminogen activators),2,6 and hyperfibrinolytic states, often seen after traumatic events with hypoperfusion or extensive tissue injury.3,4 A recent comprehensive Cochrane review reported a significant reduction in blood loss and need for blood transfusions after the use of in EACA in patients undergoing major surgery.13 A similar finding was reported for TXA in a meta-analysis of bleeding surgical patients.14 Antifibrinolytic drugs have also been used to reduce hemorrhage associated with thrombocytopenia.15

Contraindications Use of antifibrinolytic drugs may be contraindicated in patients with prothrombotic disease processes because there is a concern of promoting thrombus formation. In veterinary medicine these include patients with disseminated intravascular coagulation, aortic thromboembolism, immune-mediated hemolytic anemia, and hyperadrenocorticism.5 A few case reports have described diffuse thrombotic events and pulmonary embolism in association with antifibrinolytic drug therapy, but a recent comprehensive Cochrane review did not find any supporting evidence for an increased incidence of thrombotic events with the use of EACA or TXA.2,6,13 Use of antifibrinolytic drugs for treatment of upper urinary tract hemorrhage should be avoided because urinary tract obstruction can occur with thrombus formation. 893

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Table 170-1  Suggested Drug Dosages for Commonly Used Hemostatic Drugs Drug

Dosage

Special Considerations

ε-aminocaproic acid

50-100 mg/kg IV loading dose (over 1 hr) followed by 15 mg/kg/hr CRI or q8h until bleeding is controlled5,* 15-40 mg/kg IV bolus followed by 500-1000 mg PO q8h10

Dilute in 0.9% saline, LRS, or D5W to 20-25 mg/ml

Tranexamic acid

10-15 mg/kg SC, IM, or slow IV followed by 1 mg/ kg/hr CRI for 5-8 hr5,*

10 mg/kg q12-24h in renal disease

Desmopressin

Intranasal product: 1-3 mcg/kg SC5 Parenteral product: 0.3-1 mcg/kg SC, IV (slow)5,28-30,35,38 Parenteral product: 0.3 mcg/kg IV, SC q12-24h41*

Give slowly IV Tachyphylaxis after repeat administration Dilute: 10 ml (10 kg BW) 0.9% saline for IV administration

Protamine

1 mg for every 1 mg (100 U) heparin slowly IV Decrease dose by 50% for every 30 min elapsed since heparin administration5,45,*

May cause severe anaphylaxis, hypotension, and pulmonary hypertension

Conjugated estrogens

0.6 mg/kg IV q24h for 4-5 days47,* 50 mg PO q24h for 7 days46,* 0.02 mg/kg PO q24h for 5-7 days, then every 2-4 days60†

Doses of 1-2 mg/kg may cause myelotoxicity

Recombinant factor VIIa

90 mcg/kg bolus q2h until hemostasis is achieved49*

Yunnan Paiyao

Dogs: 30 kg—2 capsules PO q8h61‡ Cats: 1/2 capsule PO q12h61‡

Capsules can also be opened and sprinkled on wound

CRI, Constant rate infusion; D5W, 5% dextrose in water, IM, intramuscularly; IV, intravenously; LRS, lactated Ringer’s solution; PO, per os; SC, subcutaneous. *Dosage extrapolated from human literature. † Dosage extrapolated from veterinary literature for the treatment of urinary incontinence. ‡ Dosage based on anecdotal evidence.

Use of Antifibrinolytic Drugs in Cats Little information is available to date on the use of antifibrinolytic drugs in cats. The few reports of the use of antifibrinolytic drugs in cats in experimental studies report adverse effects, including seizures and myocardial injury.16,17 It is important to note, however, that the dosing of antifibrinolytic drugs in these studies may not mimic clinical use, and it is difficult to determine if the adverse effects were due to the inhibition of fibrinolysis or were a direct effect of the drug itself. For this reason, the author recommends caution in the use of these drugs in feline patients until more information regarding safety is available.

ε-Aminocaproic acid EACA competitively inhibits plasminogen activation and at higher doses may also directly inhibit plasmin. The elimination half-life of EACA is 1 to 2 hours in adult human patients. The majority of the drug is eliminated unchanged by renal excretion (65%); about 30% to 35% undergoes hepatic metabolism to adipic acid, which is also excreted in the urine.6-11,18 Reported adverse effects in human patients are dose dependent and include hypotension, which is usually associated with rapid intravenous administration, as well as nausea, vomiting, diarrhea, generalized weakness, myonecrosis with myoglobinuria, and rhabdomyolysis. Limited data are available on the use of EACA in veterinary medicine. In two separate studies, postoperative administration of EACA significantly decreased the prevalence of postoperative bleeding in greyhounds undergoing gonadectomy or limb amputation due to appendicular bone tumors. Neither study reported clinical adverse effects or thrombotic events.9,10

EACA can be administered intravenously or orally. The dosages used in veterinary patients are largely extrapolated from human medicine (Table 170-1). Reported dosages in dogs are in the range of 15 to 40 mg/kg intravenously over 30 minutes (rapid administration can cause hypotension and vomiting) and/or 500 to 1000 mg orally per greyhound dog q8h for 5 days, beginning the night of surgery.9,10 In human medicine EACA is given as a loading dose in an amount on the order of 50 to 100 mg/kg over the first hour, followed by a constant rate infusion of 15 mg/kg/hr thereafter.19

Tranexamic Acid TXA is also a competitive inhibitor of plasminogen activation and at high concentrations is a noncompetitive inhibitor of plasmin. Additionally, TXA competitively inhibits the activation of trypsinogen by enterokinases and noncompetitively inhibits trypsin and thrombin, hence prolonging activated thrombin time at high doses. TXA is about 6 to 10 times more potent in vitro than EACA, with higher and more sustained antifibrinolytic activity,7,20 and was shown to increase thrombus formation in animal models in a dose-dependent manner.21 Similar to EACA, TXA is predominantly excreted unchanged via the kidneys (95%). TXA has a terminal half-life of 2 to 3 hours. Clinical indications are comparable to those for EACA, and a recent randomized multicenter human trial (Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage 2 [CRASH-2]) found that TXA safely reduced mortality in trauma patients with or at risk of significant bleeding if given early (within 3 hours). TXA given after 3 hours seemed to increase the risk of death due to bleeding.22,23 Adverse effects are similar to those reported for EACA in human patients and include hypotension after rapid administration and

CHAPTER 170  •  Hemostatic Drugs

clinical signs associated with the gastrointestinal tract (nausea, vomiting, diarrhea, abdominal cramps). Concerns regarding thromboembolic complications were not supported by a recent Cochrane review,8 but care should be taken in patients with renal disease.24 Convulsive seizures have been reported postoperatively after high doses of TXA were given during cardiac surgery. A potential mechanism for seizures is the structural similarity of TXA with γ-aminobutyric acid.7 Limited data are available on the use of TXA in veterinary medicine. An abstract presentation of a retrospective study evaluating 68 dogs with bleeding disorders severe enough to necessitate blood transfusions reported no apparent difference in the total number of blood products used in the group given TXA compared with a control group. TXA was administered intravenously at a mean dose of 8 mg/kg; adverse effects reported were vomiting in two dogs.25 The human dose used in the CRASH trials was a loading dose of 1 g (~15 mg/kg for a 70-kg person) over 10 minutes followed by 1 g infused over the following 8 hours (~1.8 mg/kg/hr for a 70-kg person).22 See Table 170-1 for more details regarding dosing.

Topical Antifibrinolytic Therapy There is a growing interest in human medicine in the efficacy of topical EACA and TXA in major surgical procedures associated with significant blood loss.26 In addition, antifibrinolytic mouthwashes can be beneficial in controlling bleeding associated with dental procedures in patients who have hemophilia or are taking anticoagulant medications.27

DESMOPRESSIN Desmopressin acetate (1-desamino-8-d-arginine vasopressin, or DDAVP) is a synthetic vasopressin analog. DDAVP is pharmacologically altered from vasopressin by substitution of D-arginine for L-arginine, which virtually eliminates the vasopressor activity (via V1 receptors) and significantly enhances antidiuretic activity and the stimulation of endothelial release of factor VIII and vWF (via V2 receptors).6,18,28 The terminal half-life of DDAVP after intravenous administration is 2.5 to 4.4 hours.6 The bioavailability of orally administered DDAVP is not reliable because DDAVP is destroyed in the gastrointestinal tract; hence, oral administration of DDAVP is not recommended in the acutely bleeding patient. Plasma concentrations of factor VIII and vWF approximately double to quadruple 30 to 60 minutes after intravenous administration and 60 to 90 minutes after subcutaneous or intranasal administration.2 For this reason, patients with hemophilia A (congenital deficiency of factor VIII) or type I vWD (low circulating amount of vWF) who are bleeding spontaneously or are scheduled to have surgery benefit from the administration of DDAVP, often in conjunction with blood products. Administration of DDAVP does not shorten the bleeding times in patients with type II vWD (deficiency of high-molecular-weight vWF multimers) or severe type III vWD (absence of vWF).2,5 DDAVP enhances platelet function in uremic thrombocytopathia and other congenital defects of platelet function and also appears to be effective in bleeding disorders caused by chronic liver disease, even though these patients often have normal plasma concentrations of vWF and factor VIII. Patients with prolonged bleeding times due to antiplatelet drugs such as aspirin, ticlopidine, and clopidogrel may also benefit from DDAVP administration. The mechanism of action of DDAVP in human patients is not well understood and may be associated with the induction of supranormal plasma concentrations of vWF, greater concentrations of large multimers of vWF, or high plasma concentrations of factor VIII.2 In Doberman Pinschers with type 1 vWD disease, DDAVP administration increased both the quantity of vWF and its functional

activity, and there was also a proportional increase in vWF multimer of all sizes in plasma; these results indicate that the primary effect of DDAVP on hemostasis cannot be explained solely by a preferential increase in large vWF multimers, as postulated in humans.29,30 In addition, the quantitative increase in vWF appears much less pronounced, with an approximately 25% to 70% increase above baseline; in comparison, in humans increases of twofold to fivefold were reported.30,31 The effect of DDAVP on factor VIII is dose dependent, and increases ranged from 37% to 140% above baseline in dogs with vWD and in healthy dogs, whereas German Shepherds with hemophilia A did not show substantial increases in plasma factor VIII activity after DDAVP administration.32-34 Administration of DDAVP improved hemostatic function in Doberman Pinschers with type 1 vWD.29,35 DDAVP is often used in human patients who undergo cardiac surgery and other nonurgent elective surgical procedures that are associated with relatively large blood losses, but the true benefit is questionable in patients who do not have an underlying congenital bleeding disorder. A recent Cochrane review did not find any convincing evidence that DDAVP reduces the need for blood transfusions in patients who do not have congenital bleeding disorders.36 Adverse effects of DDAVP administration include water retention and hyponatremia due to its antidiuretic actions. Hypotension has been reported after rapid intravenous administration in human patients. The therapeutic effectiveness of DDAVP tends to vary, and tachyphylaxis has been reported after repeat administration within 48 hours, probably because all available factor VIII and vWF has been mobilized from the endothelium.6,18 Thrombotic events have been reported in individual studies in human patients but did not reach statistical significance in a multicenter review.36 DDAVP administration may induce transient thrombocytopenia due to excess platelet aggregation in type II vWD.37 German Shorthaired and Wirehaired Pointers are the only dog breeds reported to be affected with type II vWD; hence, care should be taken when administering DDAVP to these breeds of dogs. In veterinary medicine, DDAVP has been used for the treatment of diabetes insipidus and congenital bleeding disorders as well as perioperatively in dogs undergoing removal of mammary gland tumors to minimize spread of metastasis and survival of residual cancer cells.38 DDAVP also proved to be effective in shortening bleeding times in dogs with canine monocytic ehrlichiosis, aspirin-induced platelet dysfunction, and chronic liver disease.39,40 DDAVP is available for oral, parenteral, and nasal administration. For hemostatic purposes the oral form is not recommended. Parenteral DDAVP is ideal but its use maybe limited due to cost. The human dose for intravenous desmopressin is 0.3 mcg/kg infused over 15 to 30 minutes.41 In veterinary patients it is common to use the nasal product and inject it subcutaneously at doses of 1 to 2 mcg/kg (see Table 170-1). The dose can be repeated every 6 hours for three to four consecutive doses, after which the therapy should be discontinued for 24 to 48 hours due to concerns of tachyphylaxis.

PROTAMINE Protamine is a strongly positively charged, alkaline, low-molecularweight, polycationic amine derived from the sperm of salmon. Approximately 67% of the amino acid composition in protamine is arginine, which contributes to its strong alkalinity. Protamine is routinely used in human medicine after cardiopulmonary bypass to reverse the anticoagulant effects of heparin but is also indicated for the treatment or prevention of bleeding due to administration of either unfractionated or low-molecular-weight heparin.18,42

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The positively charged, polycationic protamine combines with the negatively charged, polyanionic heparin, forming a protamineheparin complex that is devoid of anticoagulant activity. Excess protamine is required to neutralize heparin because protamine competes with antithrombin III for binding with heparin.18,42 Adverse reactions due to protamine administration in people are often divided into three categories: (1) systemic hypotension, which is thought to be the result of histamine release by mast cells after rapid administration of protamine and the involvement of the nitric oxide pathway42,43; (2) anaphylactic reactions, including antibody-mediated and antibody-antigen complex–mediated anaphylaxis, which is often a problem after repeat administration of protamine in diabetic patients who take protamine-containing insulin daily; and (3) severe pulmonary hypertension, which is thought to be due to protamineheparin complex–induced complement activation and generation of thromboxane A2 and release of endothelin-1.42,44 Other reported adverse effects include delayed, noncardiogenic pulmonary edema and paradoxic bleeding due to thrombocytopenia, thrombocytopathia, and altered thrombin activity after administration of high doses of protamine. The “heparin-rebound effect” is thought to be due to protein-bound heparin that is incompletely bound by protamine. After the protamine-heparin complexes are cleared from the circulation, remaining protein-bound heparin dissociates slowly and binds to antithrombin III to produce an anticoagulant effect. Other causes may include liberation of excess heparin from extravascular spaces or intravascular surfaces, or excess breakdown of protamine by protaminases. Both excess doses of protamine and the heparin-rebound effect can lead to excess bleeding after protamine administration, and the two conditions may be difficult to distinguish from each other and could be misinterpreted as residual heparin anticoagulation.18,42 Little is known about the use of protamine in veterinary medicine, but in experimental research it appears to be effective in stopping bleeding in animals that received unfractionated or low-molecular-weight heparin. Adverse effects such as pulmonary hypertension, anaphylactoid reactions, and bleeding after protamine administration have been experimentally induced in dogs.18,42-44 The protamine dose is based on the original heparin dose given; each milligram of protamine neutralizes 100 U or more of unfractionated heparin.45 Given the short half-life of heparin, the dose of protamine should be reduced in accordance with the time elapsed since the original heparin administration. A general guideline is to halve the protamine dose for every 30 minutes that has elapsed (see Table 170-1).45 Protamine should be given by slow injection over 10 minutes in an effort to avoid hypotension or anaphylactoid reactions.

CONJUGATED ESTROGENS Conjugated estrogens shorten prolonged bleeding times and stop hemorrhage in patients with uremia. They can be given orally or intravenously and have reportedly shortened the bleeding time by 50% for at least 2 weeks in uremic patients.6,46 The effect of conjugated estrogens on bleeding times is longer lasting (10 to 15 days) than that of DDAVP (6 to 8 hours); hence, their use should be considered when prolonged hemostasis is desired. Accordingly, conjugated estrogens should be administered for at least 4 to 5 days before an event such as elective surgery to prevent bleeding in patients with renal disease.6,18,47 The mechanism of action of conjugated estrogens on bleeding time is unknown, but there is evidence that they increase the levels of vWF and factors VII and XII.5,6 However, administration of recombinant erythropoietin has become a routine treatment in the management of uremic patients with chronic renal disease because

it helps to increase the hematocrit, shortens bleeding times, and improves platelet adhesion. Hence, it appears that administration of conjugated estrogens is rarely required in this subset of patients, and they should be reserved for patients with acute and subacute renal failure and used in combination with DDAVP.48 There is limited information about the usefulness of conjugated estrogens for perioperative hemostasis in human and veterinary patients. A few small human studies reported beneficial effects, and conjugated estrogens were well tolerated with negligible adverse effects.5,6,18 See Table 170-1 for dosing information.

RECOMBINANT FACTOR VIIa Recombinant factor VIIa (rFVIIa) was developed for the treatment of hemophilia A and B patients with antibodies against factor VIII and IX, respectively. Factor VIIa is a vitamin K–dependent glycoprotein consisting of up to 406 amino acid residues that is originally produced in baby hamster kidney cells and proteolytically converted via chromographic purification into the active two-chain form of rFVIIa.6,49 Even though hemophilia A and B are primarily deficiencies of factor VIII and IX, respectively, the extrinsic pathway involving TF and factor VII may also be impaired in hemophilia A patients.50 The rFVIIa is believed to act in two ways: through the formation of a TF–factor VIIa complex at the site of endothelial damage, which initiates coagulation, production of thrombin, and clot formation; and through a TF-independent mechanism in which rFVIIa at supraphysiologic doses binds directly to the phospholipid membrane of activated platelets, activating factor X and leading to a massive rise in thrombin generation at the platelet surface.6 Hence, high doses of rFVIIa (up to 10 times higher than physiologic concentrations of factor VII) can compensate for a lack of factor VIII or IX in hemophilia A and B patients. This is called the bypass effect and may also explain the effectiveness of rFVIIa in patients with platelet function disorders.6,49 rFVIIa has been used successfully in human patients with bleeding problems caused by hemophilia A and B, quantitative and qualitative platelet disorders, vWD, uremia, liver disease, trauma, and surgical procedures, and it may also be administered to patients without preexisting hemostatic defects.6 The half-life of rFVIIa is short (2.7 hours), and it therefore needs to be administered frequently (every 2 hours) or as a continuous infusion. Adverse effects are rare, and reports of thromboembolic complications have been limited to a few case studies in human patients.51 In experimental dog models, rFVIIa administration resulted in a type 1 hypersensitivity reaction.50 rFVIIa has been used experimentally in dogs with hemophilia A and B and vWD; it was effective in stopping nail cuticle bleeding in dogs with hemophilia A and B but not in dogs with vWD.50 The reported half-life in dogs was 2.8 hours, which is very similar to that in humans. It is unclear if rFVIIa will find its way into veterinary medicine. Clinical indications would be comparable to those in human patients, but current cost and the occurrence of hypersensitivity reactions in dog models may limit its future use.

YUNNAN PAIYAO Yunnan Paiyao (or Yunnan Baiyao) is a Chinese herb mixture that is commonly used to stop bleeding but is also employed for pain relief, reduction of inflammation, and promotion of wound healing. The herbal mixture was developed in the Yunnan province of China in the early 1900s and was historically carried by foreign soldiers as a hemostatic agent for trauma. The exact ingredients of this herbal formula are kept secret, but the main active ingredient is thought to

CHAPTER 170  •  Hemostatic Drugs

be a pseudoginseng root called Panax notoginseng. Biochemical analysis also revealed high concentrations of polysaccharides (94% starch), calcium, and phosphorus.52-54 Yunnan Paiyao markedly shortened bleeding and clotting times after experimental oral and topical administration in rabbits, rats, and humans.53,55 Other mechanisms of action include dose-dependent platelet activation.56 No adverse effects have been reported after oral and topical administration, but in general, quality control and manufacturing regulations may be lacking for Chinese herbal products, and there is concern about contamination with mycotoxins, heavy metals, microbial agents, and pesticides.57 Yunnan Paiyao is currently not approved by the U.S. Food and Drug Administration. Yunnan Paiyao has been widely used in human and veterinary medicine, but evidence supporting the clinical use of Yunnan Paiyao is scarce. One randomized controlled trial evaluating the effect of Yunnan Paiyao on the severity of exercise-induced pulmonary hemorrhage (EIPH) in horses showed no effect of the drug on EIPH severity and other coagulation variables,58 but Yunnan Paiyao significantly decreased blood loss in a group of human patients undergoing maxillary surgery.59 See Table 170-1 for dosing information.

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18. Franck M, Sladen RN: Drugs to prevent and reverse anticoagulation, Anesthesiol Clin North Am 17:799-811, 1999. 19. Aminocaproic acid injection, solution. Available at: http://dailymed .nlm.nih.gov/dailymed/lookup.cfm?setid=1c5bc1dd-e9ec-44c1-9281-67 ad482315d9. Accessed 11/12/2012. 20. Verstraete M: Clinical application of inhibitors of fibrinolysis, Drugs 29:236-261, 1985. 21. Sperzel M, Huetter J: Evaluation of aprotinin and tranexamic acid in different in vitro and in vivo models of fibrinolysis, coagulation and thrombus formation, J Thromb Haemost 5:2113-2118, 2007. 22. CRASH-2 Trial Collaborators: Effect of tranexamic acid on death, vascular occlusive events and blood transfusion in trauma patients with significant hemorrhage (CRASH-2): a randomized, placebo controlled trial, Lancet 376:23-32, 2010. 23. CRASH-2 Trial Collaborators: The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised trial, Lancet 377:1096-1101, 2011. 24. Martin K, Wiesner G, Breuer T, et al: The risks of aprotinin and tranexamic acid in cardiac surgery: a one-year follow-up of 1188 consecutive patients, Anesth Analg 107:1783-1790, 2008. 25. Kelmer E, Marer Y, Bruchim S, et al: Retrospective evaluation of the safety and efficacy of tranexamic acid (Hexacapron®) for the treatment of bleeding disorders in dogs. In Proceedings of the 11th International Veterinary Emergency and Critical Care Symposium, San Antonio, Texas, 2011. 26. Ipema HJ, Tanzi MG: Use of topical tranexamic acid or aminocaproic acid to prevent bleeding after major surgical procedures, Ann Pharmacother 46:97, 2012. 27. Patatanian E, Fugate SE: Hemostatic mouthwashes in anticoagulated patients undergoing dental extraction, Ann Pharmacother 40:2205, 2006. 28. Kraus KH, Turrentine MA, Jergens AE, et al: Effect of desmopressin acetate on bleeding times and plasma von Willebrand factor in Doberman Pinscher Dogs with von Willebrand’s disease, Vet Surg 18:103-109, 1989. 29. Callahan MB, Giger U, Catalfamo JL: Effect of desmopressin on von Willebrand factor multimers in Doberman Pinschers with type 1 von Willebrand disease, Am J Vet Res 66:861-867, 2005. 30. Johnstone IB: Desmopressin enhances the binding of plasma von Willebrand factor to collagen in plasmas from normal dogs and dogs with type I von Willebrand’s disease, Can Vet J 40:645-648, 1999. 31. Mannucci PM: Desmopressin (DDAVP) in the treatment of bleeding disorder: the first twenty years, Haemophilia 6:60-67, 2000. 32. Mansell PD, Parry BW: Changes in factor VIII: coagulant activity and von Willebrand factor antigen concentration after subcutaneous injection of desmopressin in dogs with mild hemophilia A, J Vet Intern Med 5:191194, 1991. 33. Meyers KM, Wardrop KJ, Dodds WJ, et al: Effect of exercise, DDAVP, and epinephrine on the factor VIIIC/von Willebrand factor complex in normal dogs and von Willebrand factor deficient Doberman pinscher dogs, Thromb Res 57:97-108, 1990. 34. Johnstone IB, Crane S: The effect of desmopressin on plasma factor VIII/ von Willebrand factor activity in dogs with von Willebrand’s disease, Can J Vet Res 2:189-193, 1987. 35. Callahan MB, Giger U: Effect of desmopressin acetate administration on primary hemostasis in Doberman Pinschers with type-1 von Willebrand disease as assessed by a point-of-care instrument, Am J Vet Res 63:17001706, 2002. 36. Carless PA, Stokes BJ, Moxey AJ, et al: Desmopressin use for minimizing perioperative allogeneic blood transfusion, Cochrane Database Syst Rev (4):1-52, 2008. 37. Frederici AB, Mannucci PM: Advances in the genetics and treatment of von Willebrand disease, Curr Opin Pediatr 14:23-33, 2002. 38. Hermo GA, Turic E, Angelico D, et al: Effect of adjuvant perioperative desmopressin in locally advanced canine mammary carcinoma and its relation to histologic grade, J Am Anim Hosp Assoc 47:21-27, 2011. 39. Giudice E, Giannetto C, Gianesella M: Effect of desmopressin on immunemediated haemorrhagic disorders due to canine monocytic ehrlichiosis: a preliminary study, J Vet Pharmacol Ther 33:610-614, 2010. 40. Sakai M, Watari T, Miura T, et al: Effects of DDAVP administration subcutaneously in dogs with aspirin-induced platelet dysfunction and hemostatic impairment due to chronic liver diseases, J Vet Med Sci 65:83-86, 2003.

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41. Desmopressin acetate injection. Daily Med website. Available at. http:// www.dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=5fe83452-1670487d-feb4-27d4bd75a147. Accessed 11/12/2012. 42. Carr JA, Silverman N: The heparin-protamine interaction. A review, J Cardiovasc Surg 40:659-666, 1999. 43. Oguchi T, Doyrsout MF, Kashimoto S, et al: Role of heparin and nitric oxide in the cardiac and regional hemodynamic properties of protamine in conscious chronically instrumented dogs, Anesthesiology 94:10161025, 2001. 44. Freitas CF, Faro R, Dragosavac D, et al: Role of endothelin-1 and thromboxane A2 in the pulmonary hypertension induced by heparin-protamine interaction in anesthetized dogs, J Cardiovasc Pharmacol 43:106-112, 2004. 45. Protamine sulfate injection, solution. Daily Med website. Available at http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=e196412933f4-4e4e-86e3-8e6a4e65bd83. Accessed 11/12/2012 46. Shemin D, Elnour M, Amarantes B, et al: Oral estrogens decrease bleeding time and improve clinical bleeding in patients with renal failure, Am J Med 89:436-440, 1990. 47. Livio M, Mannucci PM, Vigano G, et al: Conjugated estrogens for the management of bleeding associated with renal failure, N Engl J Med 315:731-735, 1986. 48. Moia M, Mannucci PM, Vizzotto L, et al: Improvement in the haemostatic defect of uremia after treatment with recombinant human erythropoietin, Lancet 2:1227-1229, 1987. 49. Kristensen AT, Edwards ML, Devey J: Potential uses of recombinant human factor VIIa in veterinary medicine, Vet Clin Small Anim 33:14371451, 2003. 50. Brinkhous KM, Hedner U, Garris JB, et al: Effect of recombinant factor VIIa on the hemostatic defect in dogs with hemophilia A, hemophilia B, and von Willebrand disease, Proc Natl Acad Sci U S A 86:1382-1386, 1989.

51. Roberts HR: Clinical experience with activated factor VII: focus on safety aspects, Blood Coagul Fibrinolysis 9(Suppl):S115-S118, 1998. 52. Polesuk J, Amodeo JM, Ma TS: Microchemical investigation of medicinal plants. X. Analysis of the Chinese herbal drug Yunnan Bai Yao, Mikrochim Acta 61:507-517, 1973. 53. Ogle CW, Dai S, Ma JC: The haemostatic effects of the Chinese herbal drug Yunnan Bai Yao: a pilot study, Am J Chin Med 4:147-152, 1976. 54. Shmalberg J, Hill RC, Scott KC: Nutrient and metal analyses of Chinese herbal products marketed for veterinary use, J Anim Physiol Anim Nutr (Berl) 97(2):305-314, 2013. Epub January 31, 2012. 55. Ogle CW, Dai S, Cho CH: The hemostatic effects of orally administered Yunnan Bai Yao in rats and rabbits, Comp Med East West 5:155-160, 1977. 56. Chew EC: Effects of Yunnan Bai Yao on blood platelets: an ultrastructural study, Comp Med East West 5:169-175, 1977. 57. Leung KS-Y, Chan K, Chan C-L, et al: Systematic evaluation of organochlorine pesticide residues in Chinese material medica, Phytother Res 19:514-518, 2005. 58. Epp TS, McDonough P, Padilla DJ, et al: The effect of herbal supplementation on the severity of exercise-induced pulmonary hemorrhage, Equine Comp Exerc Physiol 1:17-25, 2004. 59. Tang Z-L, Wang X, Yi B, et al: Effects of the preoperative administration of Yunnan Baiyao capsules on intraoperative blood loss in bimaxillary orthognathic surgery: a prospective, randomized, double blind, placebocontrolled study, Int J Oral Maxillofac Surg 38:261-268, 2009. 60. Lane IF: Managing refractory urinary incontinence in dogs. In Proceedings of the 84th Annual Western Veterinary Conference, Las Vegas, 2012. 61. Graham L: Everything you need to know about Yunnan Baiyao: a simple and effective herbal therapeutic. In Proceedings of the Wild West Veterinary Conference, Reno, Nevada, 2008.

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CHAPTER 171  ANTIARRHYTHMIC AGENTS Kathy N. Wright,

DVM, DACVIM (Cardiology)

KEY POINTS • Antiarrhythmic agents are useful for managing various tachyarrhythmias, but the clinician must have knowledge of the patient and the arrhythmia, as well as the indications for and adverse effects of each medication. • Drugs that prolong atrioventricular (AV) nodal refractoriness are useful for AV nodal–dependent and atrial tachyarrhythmias, whereas drugs that prolong myocardial refractoriness are used in atrial, accessory pathway, and ventricular tachyarrhythmias. • Most antiarrhythmic agents have multiple channel effects, not simply those of their Vaughan Williams class. This must be considered in predicting their potential beneficial and adverse effects. • Disappointing results regarding the ability of antiarrhythmic agents to prevent sudden death have emerged from several large-scale human studies, and this goal now is pursued largely through device- or catheter-based therapy. Antiarrhythmic agents can be useful in limiting clinical signs related to tachyarrhythmias and thus potentially can prevent euthanasia of veterinary patients.

Antiarrhythmic agents have undergone critical reevaluation during the past two decades with publication of the results of large-scale human studies that have brought to light some of the risks and shortcomings of drug therapy for arrhythmias.1,2 Once more cavalier in their use of these agents, veterinarians and physicians alike are having to analyze carefully the potential benefits and risks (including proarrhythmic effects) in each patient. Basically, there are two reasons to treat arrhythmias: (1) to alleviate significant clinical signs such as weakness, syncope, or precipitation or exacerbation of congestive heart failure by an arrhythmia, and (2) to prolong survival. Antiarrhythmic drugs, in general, have not been shown to do the latter, although they may in veterinary patients by controlling clinical signs and avoiding an owner decision for euthanasia. Antiarrhythmic devices and procedures are used in human medicine (and increasingly in veterinary cases) to prolong survival. Drugs can be very useful, however, in alleviating clinical signs in individual patients.

CHAPTER 171  •  Antiarrhythmic Agents

CLASSIFICATION SCHEMES No completely satisfactory or intuitive classification scheme for antiarrhythmic agents has been developed. The most commonly used is the Vaughan Williams classification system, which attempts to group drugs according to their major ion channel or receptor effects. The limitations of this system have been well documented, including the fact that most antiarrhythmic drugs act on multiple channels or receptors, and one must know that when predicting their beneficial and adverse effects. The actions of antiarrhythmic drugs are actually very complex and vary by species (important to veterinarians because much of the data are from humans), age, tissue drug concentration, acid-base and electrolyte balance, presence or absence of myocardial damage, and indirect hemodynamic or autonomic actions.3 In spite of its shortcomings, the Vaughan Williams system remains the most widely used to date. An attempt to improve on this system led electrophysiologists to develop the Sicilian Gambit in 1991.4 This approach attempted to identify the vulnerable parameter for various arrhythmias and did account for the multiple channel and receptor actions of each antiarrhythmic agent, but it was too unwieldy for widespread general use. Grouping antiarrhythmic agents according to their main use (i.e., supraventricular arrhythmias or ventricular arrhythmias) would seem logical (Box 171-1), but many agents are used to treat multiple types of arrhythmias, so overlap would be inevitable. Despite its inherent limitations, the Vaughan Williams classification is used as the framework for this chapter. Agents that are commonly used in small animal cardiology are discussed.

CLASS I ANTIARRHYTHMIC AGENTS Class I agents act primarily by inhibiting the fast sodium channel and decreasing the slope of phase 0 of the action potential. The relative potency of their sodium channel effects, whether blockade of the activated or inactivated channel occurs, and their effects on other channels and receptors determine their subclassification.

Class Ia Antiarrhythmic Agents Class Ia agents have powerful, fast sodium channel–blocking effects and also exhibit moderate blockade of the rapid component of the delayed rectifier potassium current (IKr). This IKr blockade results in action potential prolongation and can account for the proarrhythmic

effects associated with these drugs in some genetically predisposed individuals.5 In addition, potent depression of conduction velocity can predispose to intramyocardial reentry. Quinidine, procainamide, and disopyramide are class Ia drugs. Procainamide is the prototypical agent of this class used in small animal cardiology. It depresses conduction velocity and prolongs the effective refractory period in a wide variety of tissues, including the atrial and ventricular myocardium, accessory atrioventricular (AV) pathways, and retrograde fast AV nodal pathways.5 Procainamide can thus be effective in a wide variety of arrhythmias, either as a single agent or combined with other agents. It can be administered parenterally for acute termination of severe ventricular or supraventricular tachyarrhythmias. It must be administered slowly intravenously (over 5 to 10 minutes) to prevent hypotension. Procainamide is more effective than lidocaine for acutely terminating ventricular tachyarrhythmias in human patients.6 Agents that prolong AV nodal conduction time are given first for acute treatment of atrial tachyarrhythmias, because procainamide can enhance AV nodal conduction and thus worsen the ventricular response rate. Parenteral procainamide is administered in doses of 6 to 8 mg/kg intravenously (IV) over 5 to 10 minutes or 6 to 20 mg/kg intramuscularly (IM) in dogs. A constant rate infusion (CRI) of 20 to 40 mcg/kg/min can be used once a therapeutic response is obtained with slow bolus administration. In cats parenteral procainamide is used cautiously at doses of 1 to 2 mg/kg IV or 3 to 8 mg/kg IM and a CRI of 10 to 20 mcg/kg/min. Sustained-release oral procainamide is not commercially available anymore; however, certain compounding pharmacies offer compounded and presumably sustained-release procainamide. The dosage in dogs is 10 to 30 mg/kg orally (PO) q8h. Adverse effects commonly are associated with procainamide use but appear to be more frequent in humans and cats than in dogs. Gastrointestinal adverse effects such as anorexia, nausea, and vomiting are seen most commonly in dogs. Adverse effects reported in humans soon after oral procainamide therapy is instituted include rash and fever. Later adverse effects include arthralgia, myalgia, and agranulocytosis. The development of systemic lupus erythematosus is identified rarely in veterinary patients but is reported in one third of human patents who take procainamide for longer than 6 months.7 A four-way trial of antiarrhythmic drugs in Boxer dogs with ventricular tachyarrhythmias showed that sustained-release procainamide administered at 20 to 26 mg/kg PO q8h reduced the frequency of ventricular ectopy but did not alter the frequency of syncope.8

Class Ib Antiarrhythmic Agents BOX 171-1 

Antiarrhythmic Agents: General Uses

Drugs Used to Manage Ventricular Tachyarrhythmias Class Ia: procainamide, quinidine Class Ib: lidocaine, mexiletine Class Ic: flecainide, propafenone Class II: β-blockers—atenolol, propranolol, metoprolol Class III: d,l-sotalol, amiodarone

Drugs Used to Manage Supraventricular Tachyarrhythmias Drugs used to slow atrioventricular nodal conduction Class II: β-blockers—atenolol, propranolol Class IV: calcium channel blockers Other: digoxin

Drugs used to inhibit intramyocardial conduction or prolong myocardial repolarization Class Ia: procainamide Class Ic: flecainide, propafenone Class III: d,l-sotalol, amiodarone

Class Ib antiarrhythmic agents inhibit the fast sodium channel, primarily in the open state with rapid onset-offset kinetics. The window sodium current is also inhibited, which results in the shortening of action potential duration in normal myocardial tissue. This window current is considered to be the steady-state component of the fast sodium current (INa) resulting from the crossover of the activation and inactivation curves, which govern the opening of the sodium channel. Computer modeling studies support a role for this current in the dispersion of action potential duration across the ventricular wall. Their rapid kinetics explain why class Ib agents have minimal effects on the shorter atrial action potential. The ability of lidocaine and its congeners to block INa is enhanced in the presence of acidosis, increased extracellular potassium concentrations, and partially depolarized cells. Thus these drugs selectively suppress automaticity and slow conduction velocity in ischemic and diseased ventricular myocardium. Lidocaine is an intravenous antiarrhythmic agent and typically is the first drug used in the acute treatment of serious ventricular tachyarrhythmias in dogs. It has the benefit of minimal hemodynamic, sinoatrial, and AV nodal effects at standard dosages. A bolus

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dose of 2 to 4 mg/kg is administered IV over 2 minutes. The bolus can be repeated to a maximum of 8 mg/kg within a 10-minute period, provided adverse effects do not occur. If the lidocaine bolus is successful in converting the ventricular tachycardia to sinus rhythm, it can be followed by a CRI of 25 to 75 mcg/kg/min. Hepatic clearance of lidocaine determines its serum concentration, and this is directly related to hepatic blood flow. Heart failure, hypotension, and severe hepatic disease can therefore result in decreased lidocaine metabolism and predispose the patient to lidocaine toxicity. The incidence of adverse effects is much higher in cats, with earlier reports of bradyarrhythmias and sudden death. For this reason, caution is recommended in this species. Lower doses of 0.25 to 0.75 mg/kg are administered slowly IV, followed by infusion at rates of 10 to 20 mcg/kg/min. The most common adverse effects of lidocaine include nausea, vomiting, lethargy, tremors, and seizure activity. These typically resolve quickly with cessation of the infusion. Diazepam may be administered to treat lidocaine-induced seizures. Mexiletine is the most commonly used oral class Ib agent in dogs. It is highly protein bound and eliminated by renal excretion. Its use and adverse effect profile mirror those of lidocaine. It has been used in dogs in which ventricular tachyarrhythmias are acutely responsive to lidocaine and can be combined with class Ia, II, or III agents. Typical dosing in dogs is 4 to 8 mg/kg PO q8h. There are no data on its use in cats. Tocainide, another lidocaine congener, rarely is used in small animals because of the high incidence of serious adverse effects, including renal failure and corneal dystrophy.9,10

Class Ic Antiarrhythmic Agents Potent blockade of the fast sodium channel with greater effects as the depolarization rate increases (use dependence) highlights class Ic antiarrhythmic drugs.11 Limited data are available on the use of these agents in clinical veterinary patients. Flecainide and propafenone have been used by veterinary cardiologists to treat certain supraventricular or ventricular tachyarrhythmias in canine patients. Their expense, propensity for proarrhythmia in humans with structural heart disease, and negative inotropic properties, however, have impeded their widespread use in veterinary patients.

CLASS II ANTIARRHYTHMIC AGENTS β-Adrenergic antagonists, or β-blockers, are some of the most universally useful cardiovascular drugs. β-Blockers have even found their way into the management of dilated cardiomyopathy, a disease for which they were once thought strictly contraindicated. In human patients with stable controlled heart failure, β-blockers reduce allcause, cardiovascular, and sudden death mortality rates.12-15 The clinician must be ever cognizant of the animal’s underlying heart disease when prescribing β-blockers, however, because this will determine how well the animal tolerates the drug and how slowly it must be introduced. As antiarrhythmics, class II agents (1) inhibit the current If, an important pacemaker current that also promotes proarrhythmic depolarization in damaged cardiomyocytes, and (2) inhibit the inward calcium current, ICa-L, indirectly by decreasing tissue cyclic adenosine monophosphate levels. The magnitude of their antiarrhythmic effect depends on the prevailing sympathetic tone, with the effect increased in higher adrenergic states. β-Adrenergic antagonists are used to slow AV nodal conduction in supraventricular tachyarrhythmias, slow sinus nodal discharge rate in inappropriate sinus tachycardia (such as that associated with pheochromocytomas), and suppress ventricular tachyarrhythmias thought to be caused, at least in part, by increased sympathetic tone. Their ability to slow AV nodal conduction in dogs appears to be inferior to that of the calcium channel blockers or class IV agents.16

β-Blockers are often used as first-line antiarrhythmic agents in cats with ventricular or supraventricular tachyarrhythmias. They are often combined with class I or class III agents in dogs with severe ventricular tachyarrhythmias. β-Blockers are contraindicated in patients that have evidence of sinus nodal dysfunction (sinus arrest, sinoatrial block, persistent sinus bradycardia), AV nodal conduction disturbances, pulmonary disease (particularly true for nonspecific β-blockers or high-dose β1-selective blockers), or overt congestive heart failure.5 Fluid retention must be frequently evaluated in patients with congestive heart failure and their condition must be stabilized before β-blockade is instituted. Extremely low dosages must be used in patients with systolic myocardial dysfunction and a course of very slow up-titration followed. Thus, in this subclass of patients, β-blockers are not the choice for acute antiarrhythmic therapy because the amounts required are not generally tolerated. The drug used can vary according to the situation and the clinician’s preference. Esmolol is the intravenous class II agent of choice in small animal cardiology because of its short half-life. A comparison of intravenous negative dromotropic agents in healthy dogs showed that esmolol was a significantly less effective negative dromotrope than diltiazem and caused a severe drop in left ventricular contractility measurements at dosages required to prolong AV nodal conduction.16 Esmolol is given as an intravenous bolus over 1 to 2 minutes at 0.5 mg/kg. This can be followed by a CRI of 50 to 200 mcg/ kg/min. Continuous careful monitoring of the electrocardiogram and blood pressure must be performed during administration of this drug. The most commonly used oral β-blockers in small animals are atenolol and metoprolol, given their relative β1 selectivity and long half-life compared with those of propranolol. Heart rate monitoring is useful to determine the appropriate dosage of β-blocker for an individual animal. Atenolol is water soluble and eliminated by the kidney, whereas metoprolol undergoes hepatic metabolism and elimination. These pharmacokinetic differences should be remembered in choosing a β-blocker and dosage for a particular patient.

CLASS III ANTIARRHYTHMIC AGENTS Class III antiarrhythmic drugs block the repolarizing IK, which results in prolongation of action potential duration and effective refractory period. Although this effect is beneficial if it occurs at tachyarrhythmia rates, the intrinsic problem is that most class III agents block the rapid component of IK (IKr) rather than the slow component (IKs); thus their effects are accentuated at slower heart rates. This puts the patient at risk of early afterdepolarization and accounts for the proarrhythmic effect of class III antiarrhythmic drugs. This risk is increased with concurrent hypokalemia, bradycardia, intact status in females, increasing age, macrolide antibiotic therapy, and a number of other drugs.17 Amiodarone, with its blockade of both IKs and IKr, makes the action potential pattern more uniform throughout the myocardium and has the least reported proarrhythmic activity of any of the class III agents. The two class III agents used in small animal cardiology are sotalol and amiodarone, both of which have multiple channel and receptor effects. d,l-Sotalol combines nonselective β-blockade with IKr inhibition. It is an effective antiarrhythmic agent in both supraventricular and ventricular tachyarrhythmias. Its class II effects predominate at lower dosages and include sinus and AV nodal depression. Its class III effects, seen at higher dosages (>160 mg q24h in humans) are prolongation of the atrial and ventricular myocardial action potential, prolongation of the atrial and ventricular refractory periods, and inhibition of bidirectional conduction along any bypass tract. Prolongation of the action potential duration can result in

CHAPTER 171  •  Antiarrhythmic Agents

enhanced calcium entry during the action potential plateau and may explain why the negative inotropic effect of sotalol is far less than expected. Sotalol is hydrophilic, non–protein bound, and excreted solely by the kidneys. The same absolute and relative contraindications apply to sotalol as to β-blockers in general, although, as mentioned earlier, it is better tolerated in animals with significant myocardial dysfunction than other β-blockers. Two studies of Boxer dogs with familial ventricular arrhythmias compared d,l-sotalol with other antiarrhythmic agents. In the first study, dogs were grouped into asymptomatic, syncopal, and heart failure groups. The dosage of sotalol administered to these dogs was 0.97 to 6.1 mg/kg PO q24h, divided q12h, titrated to effect. Syncopal signs diminished with sotalol therapy, and dogs with systolic dysfunction did not appear to experience untoward drug effects.18 The second study compared four antiarrhythmic drug regimens for treatment of familial ventricular arrhythmias in Boxers. Sotalol 1.47 to 3.5 mg/kg PO q12h significantly reduced the maximum and minimum heart rates, number of premature ventricular contractions, and ventricular arrhythmia grade. No significant change in the occurrence of syncope, however, was found for sotalol or for any of the other three treatments studied.8 Finally, a study in German shepherd dogs with inherited ventricular arrhythmias concluded that a sotalol-mexiletine combination was superior to either agent alone.19 Sotalol typically is administered at 1 to 3 mg/kg PO q12h in dogs and cats. Amiodarone is the antiarrhythmic agent with the broadest spectrum, exhibiting properties of all four antiarrhythmic classes. It opposes electrophysiologic heterogeneity, which underlies some severe ventricular arrhythmias. The efficacy of amiodarone exceeds that of other antiarrhythmic compounds, including sotalol, in human patients. Furthermore, the incidence of torsades de pointes with amiodarone is much lower than expected from its class III effects. A retrospective study of dogs with severe ventricular or supraventricular tachyarrhythmias concluded that amiodarone resulted in an improvement in the severity of the tachyarrhythmia and clinical signs in 26 of 28 dogs.20 A major drawback is that amiodarone is associated with a host of multisystemic, potentially serious adverse effects that do not occur with sotalol. A retrospective evaluation of the use of amiodarone in Doberman Pinschers with severe ventricular tachyarrhythmias documented adverse effects in 30% of the 20 patients studied.21 These adverse effects included vomiting, anorexia, hepatopathies, and thrombocytopenia, and were more common with higher maintenance dosages. Amiodarone typically is reserved for life-threatening ventricular or supraventricular tachyarrhythmias that are not responding to other therapy. Published amiodarone dosages in dogs vary and typically include a loading period.22 The author usually administers 15 mg/kg PO q24h for 7 to 10 days, then 10 mg/kg PO q24h for 7 to 10 days, then 5 to 8 mg/kg PO q24h long term. Serum amiodarone levels can be measured but may not correlate with tissue concentrations. Amiodarone has not been used in cats. The most common intravenous formulation of amiodarone (Cordarone IV) can result in severe hypotension. This effect has been attributed to the vasoactive solvents of the formulation, polysorbate 80 and benzyl alcohol, both known to exhibit negative inotropic and hypotensive effect. An aqueous formulation of intravenous amiodarone (Amio-Aqueous) does not contain vasoactive excipients and has been shown to be less toxic and cause less hypotension than Cordarone IV.23 The cost of Amio-Aqueous is significantly more than that of Cordarone IV, however.

CLASS IV ANTIARRHYTHMIC AGENTS Class IV antiarrhythmics comprise the group of calcium channel– blocking drugs. Nondihydropyridine calcium channel blockers slow

AV nodal conduction and prolong the effective refractory period of nodal tissue. This effect is most notable at faster stimulation rates (use dependence) and in depolarized fibers (voltage dependence).3 These drugs are effective in slowing the ventricular response rate to atrial tachyarrhythmias and can prolong the AV nodal effective refractory period to the point that an AV node–dependent tachyarrhythmia is terminated. They are generally contraindicated in widecomplex tachyarrhythmias. Diltiazem has gained preference over verapamil because of its more favorable hemodynamic profile (i.e., minimal negative inotropic effect) at effective antiarrhythmic dosages. Intravenous diltiazem (0.125 to 0.35 mg/kg slowly IV over 2 minutes) has been used in dogs to immediately terminate a severe AV nodal–dependent tachyarrhythmia or slow the ventricular response rate to an atrial tachyarrhythmia. A comparison of the electrophysiologic and hemodynamic responses to intravenous diltiazem, esmolol, and adenosine in healthy dogs demonstrated the superior efficacy of diltiazem in slowing AV nodal conduction while maintaining a favorable hemodynamic profile.16 Nonetheless, adverse effects can be seen, including hypotension and bradyarrhythmias. Standard oral diltiazem is administered three times daily, which can be difficult, particularly for cat owners. Sustained-release preparations appear to have more variable absorption in companion animals but have been used successfully in dogs with certain supraventricular tachyarrhythmias. A higher incidence of adverse effects of these preparations has been reported in cats, including vomiting, inappetence, and hepatopathies.24

OTHER ANTIARRHYTHMIC AGENTS Digoxin The electrophysiologic effects of digoxin primarily occur indirectly through the autonomic nervous system by enhancing central and peripheral vagal tone. This results in slowing of the sinus nodal discharge rate, prolongation of AV nodal refractoriness, and shortening of atrial refractoriness. Digoxin is used orally as an antiarrhythmic agent to slow AV nodal conduction in dogs, particularly those with impaired left ventricular systolic function. The ventricular rate is almost never slowed adequately when digoxin is used as a single agent, however, and other drugs must be added. The dosage is 0.005 to 0.01 mg/kg PO q12h in a normokalemic dog with normal renal function and 0.0312 mg PO q24-48h in a normokalemic cat with normal renal function. Digoxin has a low therapeutic index; owners must be educated about the signs of toxicity. Renal dysfunction, hypokalemia, advancing age, chronic lung disease, and hypothyroidism all predispose to digoxin toxicity and should be corrected (if possible) or the dosage adjusted downward. Serum digoxin concentrations should be monitored to determine the appropriate dosage for an individual animal. The trend in human medicine is toward lower dosages, which appear to be safer and confer benefit with less risk of toxicity. The ideal blood levels remain unknown, but a goal of about 0.5 to 1  ng/ml or 0.6 to 1.2  nmol/L (much lower than before) seems reasonable.25

Magnesium Sulfate Magnesium sulfate intravenous injection is the first-line antiarrhythmic treatment for torsades de pointes and has been used with variable success to treat drug-refractory ventricular tachyarrhythmias or arrhythmias in patients with known hypomagnesemia.26 It is administered slowly IV at 30 mg/kg (equivalent to 0.243 mEq/kg) over 5 to 10 minutes. Adverse effects include central nervous system depression, weakness, bradycardia, hypotension, hypocalcemia, and QT prolongation.

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Adenosine Adenosine is used widely in the emergency department in human patients to terminate AV node–dependent tachyarrhythmias. A study performed by the author showed that adenosine, even at doses of 2 mg/kg, was ineffective in slowing canine AV nodal conduction.16 The same result has been found with electrophysiologic study of numerous dogs with orthodromic AV reciprocating tachycardia. A similar study has not been performed in cats.

ANTIARRHYTHMIC DEVICES AND PROCEDURES Certain supraventricular tachyarrhythmias in dogs can be cured, rather than simply controlled, with transvenous radiofrequency catheter ablation.27-30 The tachyarrhythmia circuit is first mapped with numerous multielectrode catheters. Once detailed mapping has identified a site in the reentrant circuit or an automatic focus for ablation, a larger-tipped electrode catheter is coupled to a cardiac-specific radiofrequency ablation unit. Radiofrequency energy is delivered to the tip electrode causing thermal desiccation of a small volume of tissue to permanently interrupt the tachycardia circuit. This technique has been used by this author and others in a large number of canine cases. Permanent pacemaker implantation is a necessary component of the management of certain bradyarrhythmias, such as persistent high-grade AV nodal block and sick sinus syndrome. Rate responsiveness and dual-chamber pacing are all options that are being used or explored by veterinary cardiologists in an attempt to improve patient quality of life and decrease pacing-related complications. Implantable cardioverter-defibrillators have revolutionized treatment for humans with life-threatening ventricular tachyarrhythmias, playing a crucial role in the prevention of sudden cardiac death related to ventricular tachycardia and fibrillation. These devices have been used experimentally in dogs, and their application has been described in one clinical report.31 For further information on pacing the reader is directed to Chapter 203.

REFERENCES 1. Echt DS, Liebson PR, Mitchell LB, et al: Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial, N Engl J Med 324:781, 1991. 2. Kuck K, Cappato R, Siebels J, et al: Randomized comparison of antiarrhythmic drug therapy with implantable defibrillators in patients resuscitated from cardiac arrest, Circulation 102:748, 2000. 3. Miller JM, Zipes DP: Therapy of cardiac arrhythmias. In Braunwald E, Zipes DP, Libby P, et al, editors: Braunwald’s heart disease: a textbook of cardiovascular medicine, ed 7, Philadelphia, 2005, Saunders. 4. Task Force of the Working Group on Arrhythmias of the European Society of Cardiology: The Sicilian gambit. A new approach to the classification of antiarrhythmic drugs based on their actions on arrhythmogenic mechanisms, Circulation 84:1831, 1991. 5. Opie LH, DiMarco JP, Gersch BJ: Antiarrhythmic drugs and strategies. In Opie LH, Gersch BJ, editors: Drugs for the heart, ed 7, Philadelphia, 2009, Elsevier. 6. Gorgels AP, van den Dool A, Hofs A, et al: Comparison of lidocaine and procainamide in terminating sustained monomorphic ventricular tachycardia, Am J Cardiol 78:43, 1996. 7. Kosowsky BD, Taylor J, Lown B, et al: Long-term use of procaine amide following acute myocardial infarction, Circulation 47:1204, 1973. 8. Meurs KM, Spier AW, Wright NA, et al: Comparison of the effects of four antiarrhythmic treatments for familial ventricular arrhythmias in Boxers, J Am Vet Med Assoc 221:522, 2002.

9. Calvert CA, Pickus CW, Jacobs GJ: Efficacy and toxicity of tocainide for the treatment of tachyarrhythmias in Doberman Pinschers with occult cardiomyopathy, J Vet Intern Med 10:235, 1996. 10. Jacobs G: Tocainide in ventricular arrhythmias. In Proceedings of the 13th American College of Veterinary Internal Medicine Forum, Orlando, Florida, May 18-21, 1995. 11. Ramos E, O’Leary ME: State-dependent trapping of flecainide in the cardiac sodium channel, J Physiol 560(Pt 1):37, 2004. 12. Dargie HJ: β-Blockers in heart failure, Lancet 362:2, 2003. 13. MERIT-HF Study Group: Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL Randomized Trial in Congestive Heart Failure (MERIT-HF), Lancet 353:2001, 1999. 14. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial, Lancet 353:9, 1999. 15. Fonarow GC, Albert NM, Curtis AB, et al: Incremental reduction in risk of death associated with guideline-recommended therapies in patients with heart failure: a nested, case-control analysis of IMPROVE HF, J Am Heart Assoc 1:16, 2012. 16. Wright KN, Schwartz DS, Hamlin R: Electrophysiologic and hemodynamic responses to adenosine, diltiazem, and esmolol in dogs, J Vet Intern Med 12:201, 1998. 17. Benoit SR, Mendelsohn AB, Nourjah P, et al: Risk factors for prolonged QTc among US adults: Third National Health and Nutrition Examination Survey, Eur J Cardiovasc Prev Rehabil 12:363, 2005. 18. Meurs KM, Brown WA: Update on Boxer cardiomyopathy. In Proceedings of the 16th American College of Veterinary Internal Medicine Forum, San Diego, May 23-25, 1998. 19. Gelzer AR, Krause MS, Rishniw M, et al: Combination therapy with mexiletine and sotalol suppresses inherited ventricular arrhythmias in German shepherd dogs better than mexiletine or sotalol monotherapy, J Vet Cardiol 12:93, 2010. 20. Pedro P, Lopex-Alvarex J, Fonfara S, et al: Retrospective evaluation of the use of amiodarone in dogs with arrhythmias (from 2003 to 2010), J Small Anim Pract 53:19, 2012. 21. Kraus MS, Ridge LG, Gelzer ARM, et al: Toxicity in Doberman Pinscher dogs with ventricular arrhythmias treated with amiodarone. In Proceedings of the 23rd American College of Veterinary Internal Medicine Forum, Baltimore, June 1-4, 2005. 22. Côté E: Electrocardiography and cardiac arrhythmias. In Ettinger S, Feldman B, editors: Textbook of veterinary medicine, ed 7, St Louis, 2010, Elsevier. 23. Somberg JS, Cao W, Cvetanovic I, et al: Pharmacology and toxicology of a new intravenous amiodarone (Amio-Aqueous) as compared with Cordarone IV, Am J Ther 12:9, 2005. 24. Wall M, Calvert CA, Sanderson SL, et al: Evaluation of extended-release diltiazem once daily for cats with hypertrophic cardiomyopathy, J Am Anim Hosp Assoc 41:98, 2005. 25. Poole-Wilson PA, Opie LH: Digitalis, acute inotropes, and inodilators: acute and chronic heart failure. In Opie LH, Gersch BJ, editors: Drugs for the heart, ed 7, Philadelphia, 2009, Saunders. 26. Keren A, Tzivoni D: Magnesium therapy in ventricular arrhythmias, Pacing Clin Electrophysiol 13:937-945, 1990. 27. Wright KN: Interventional catheterization for tachyarrhythmias, Vet Clin North Am Small Anim Pract 34(5):1171-1185, 2004. 28. Wright KN, Knilans TK, Irvin HM: When, why, and how to perform radiofrequency catheter ablation, J Vet Cardiol 8:95-107, 2006. 29. Santilli RA, Spadacini G, Moretti P, et al: Anatomic distribution and electrophysiologic properties of accessory pathways in dogs, J Am Vet Med Assoc 231:393-398, 2007. 30. Santilli RA, Perego M, Perini A, et al: Radiofrequency catheter ablation of the cavotricuspid isthmus as treatment of atrial flutter in two dogs, J Vet Cardiol 12:59-66, 2010. 31. Nelson OL: Implantable cardioverter defibrillators: a viable option for veterinary patients? In Proceedings of the 22nd American College of Veterinary Internal Medicine Forum, Minneapolis, June 9-12, 2004.

CHAPTER 172  INHALED MEDICATIONS Carrie J. Miller,

DVM, DACVIM (Internal Medicine)

KEY POINTS • The use of inhaled aerosol medications has stemmed primarily from the need to manage a variety of respiratory diseases in dogs and cats effectively and with minimal adverse effects. • Aerosol therapy (also known as nebulization) is the production of a liquid particulate suspension within a carrier gas (the aerosol) that is inhaled by the patient. Many factors determine whether an inhaled medication will have the desired effect in its desired location. • Medicinal aerosolized particles are generally described by their mass median diameter (MMD), defined as the average particle diameter by mass. • The MMD of a particle must be less than 5 µm to reach the small bronchioles and alveoli. • Three types of systems have been used in veterinary medicine: jet nebulizers, ultrasonic nebulizers, and metered dose inhalers. • Inhaled bronchodilators and glucocorticoids have been investigated for the treatment of feline bronchopulmonary disease and canine allergic airway disease. • Inhaled antibiotics have been investigated for the treatment of canine infectious tracheobronchitis and bacterial pneumonia. • Although nebulized particles are known to reach the lower airways in cats (and presumably in dogs), whether a sufficient number of drug particles are deposited in the lower airways of clinical patients at the recommended drug dosages is unknown.

INTRODUCTION Administration of medications via inhalation has been commonplace in human medicine for decades.1 Only recently has inhalant therapy begun to emerge in veterinary medicine, and its use remains primarily empiric. Although few published peer-reviewed studies exist for dogs and cats, clinical use of inhalant medications is clearly on the rise. This chapter summarizes the principles behind aerosol therapy, describes the various delivery systems, and discusses the common respiratory diseases in dogs and cats for which inhalant therapy is prescribed.

Aerosol therapy (also known as nebulization) is the production of a liquid particulate suspension within a carrier gas (the aerosol). Many factors determine whether an inhaled medication will have the desired effect in the correct location. The particles must be small enough in size to travel to the lower airways. Aerosolized particles generally are described by their aerodynamic equivalent diameter (AED). AED is defined as the diameter of a sphere with a standard density of 1 g/cm3 that falls in air at the same rate as the particle in question.5 For a particle to be deposited in the small bronchioles and alveoli, it must have an AED of 0.5 to 5 µm. Particles larger than 10 µm usually are deposited in the larynx and nasal turbinates (Table 172-1). The AED is a concept that applies only to aerosols in which the particles are homogenous in size, which is not typical of most therapeutic aerosols. Because therapeutic aerosols contain a range of particle sizes (termed heterodisperse aerosols), the unit that is more widely used is mass median diameter (MMD). MMD is defined as the average particle diameter by mass.6 Other important factors that affect the deposition of aerosolized particles in the airways are the rate of gravitational fall (gravitational sedimentation), the tendency of the particles to resist change in airflow speed and direction (inertial impaction), and the inherent random motion of particles created by collision with gas molecules (Brownian diffusion). Inertial impaction occurs when there is a sudden change in the direction of gas flow. This is most common in the nasal turbinates and bronchial bifurcations, so it tends to have the most impact in the upper airways for large particles that are larger than 5 µm AED. Gravitational sedimentation has a greater impact in the lower airways where smaller particles travel. Brownian diffusion is thought to affect only particles smaller than 0.1 µm and is probably not clinically relevant.1,5,6 It is important to remember that the degree of particle deposition by these mechanisms also depends on patient variables such as inspiratory air velocity, tidal volume, and ventilatory pattern.5

DELIVERY SYSTEMS Jet Nebulizers Compressor (jet) and ultrasonic nebulizers (also called atomizers) are commonplace in human medicine, and they are becoming more

PRINCIPLES OF AEROSOL DEPOSITION IN THE LUNGS The use of aerosol medication has stemmed mainly from the need to manage a variety of respiratory diseases in dogs and cats effectively and with minimal adverse effects. Many of the more common respiratory diseases require glucocorticoids and bronchodilators, which can have severe and costly adverse effects when given systemically.2,3 In addition, many owners have difficulty administering medications to their cats or dogs, which results in poor owner compliance and inappropriate dosing. Aerosolization may also allow the clinician to effectively manage a disease that may be difficult to treat with systemic medications (e.g., Bordetella bronchiseptica infection).4

Table 172-1  Site of Aerosolized Particle Deposition in the Respiratory Tree Site of Deposition Nasopharynx Trachea Bronchi Peripheral airways

Aerodynamic Diameter (µm) >20 10-30 5-25 0.5-5

903

904

PART XX  •  PHARMACOLOGY

FIGURE 172-1  Example of a jet nebulizer. The tubing delivers the highvelocity gas that comminutes the solution in the nebulizer compartment into a mist. The mist then travels through the tubing and face mask, which will be attached to the patient.

FIGURE 172-3  A patient using a metered dose inhaler attached to a feline spacer and face mask.

Use of disposable nebulizers is not recommended because their efficacy tends to decrease significantly after each use.5 It is typically recommended that jet nebulizations occur over 5 to 10 minutes.

Ultrasonic Nebulizers

FIGURE 172-2  A patient receiving a nebulization treatment with gentamicin solution. A tight-fitting face mask with minimal dead space should be used.

popular for use in dogs and cats as well. The jet nebulizer uses a narrow, high-velocity stream of gas (typically oxygen) that travels through the designated medicated solution to comminute the liquid into an aerosol mist.7 The mist is then delivered to the patient through a spacer and face mask (Figures 172-1 and 172-2). Most nebulizers of this type are capable of producing 50 µl of usable aerosol per liter of carrier gas, with an MMD of 3 to 6 µm.6 This allows a significant portion of the respirable particles to travel to the bronchioles and alveoli, so that they settle principally by gravitational sedimentation in the lower airways. Certain guidelines must be followed for effective nebulization. The nebulizer and face mask should be kept in an upright position to maximize the effect of nebulization. To enhance particle deposition in the lower airways, it is recommended that a high-output compressor (20 to 30 psi, 8 to 10 L/min) be used. This flow rate will minimize the effects of inertial impaction in the upper airways, and this compressor pressure will ensure adequate particle size as well as decrease the time needed for nebulization. Because inertial impaction can also be affected by the face mask and tubing properties, a shorter tube length, which decreases dead space within the nebulizing system, is recommended. Exhalation into the nebulized mist of medication decreases the proper delivery of the drug, so a one-way inspiratory valve is preferred to maximize drug delivery to the lungs.5 Because nebulizers can quickly become contaminated with bacteria and fungi, all parts must be properly disinfected after each use.

Ultrasonic nebulizers are very similar to jet nebulizers. The source of particle generation, however, is a piezoelectric transducer crystal that converts electrical energy into ultra-high-frequency oscillations that create aerosol particles from the surface of the liquid. There is no need for a compressor gas setup, so these nebulizers are more portable and are even sold for home use. Although the MMD particle size is similar in the two types of nebulizers (3 to 7 µm for ultrasonic nebulizers), the ultrasonic nebulizers can create a denser mist, with aerosols up to 200 µl/L.6 It is typically recommended that ultrasonic nebulizations occur over 5 to 10 minutes.

Metered Dose Inhalers Metered dose inhalers (MDIs) have been used in human medicine since 1956.7 They have made it possible for complete outpatient portable inhalation devices to be used conveniently in human medicine. During the last 20 years, veterinarians have been experimenting with MDIs, and material has been published on how best to use these devices in cats and dogs.2,8 MDIs consist of a plastic mouthpiece and a holder attached to a sealed aerosol canister, with a metered valve that releases a precisely measured dose of medication when the canister is pressed into the actuator (Figure 172-3). Once the device is actuated, the medication is propelled through the nozzle at a high velocity to form a spray.7 Because of the high velocity of the spray and the large MMD, holding chambers have been developed to decrease the velocity and particle size produced by MDI devices. This aids in decreasing the amount of inertial impaction in the upper airways and allows the patient to breathe independently of the actuation of the device. These chambers are termed spacers and should be attached to a form-fitting, low-dead-space face mask for veterinary patients. Not only do the spacers provide the aforementioned benefit of decreasing inertial impaction, but they also allow the mist to be sprayed into the chamber before the face mask is applied to the animal patient, which decreases the likelihood that the MDI device will scare the animal. Aerosols are delivered rapidly over 1 to 2 minutes, with an average of 7 to 10 breaths suggested. There are veterinary spacers and face masks manufactured specifically for dogs and cats (AeroKat and AeroDawg, Trudell Medical International, London, Ontario, Canada). Another option is to use a human pediatric spacer and face mask or a veterinary anesthesia face mask.

CHAPTER 172  •  Inhaled Medications

CLINICAL APPLICATIONS Feline Bronchopulmonary Disease Feline bronchopulmonary disease (FBPD) is a syndrome that encompasses a group of common, although incompletely understood, respiratory diseases. Clinical signs are similar to those seen in dogs with chronic bronchitis. The mainstay of treatment for these inflammatory and allergic respiratory diseases is glucocorticoids and bronchodilators (see Chapter 20).2,3,9 As stated earlier, these medications often have detrimental side effects: glucocorticoids commonly are associated with polyphagia and subsequent weight gain, polydipsia, polyuria, changes in personality, ulceration of the gastrointestinal tract, immunosuppression, hypercoagulability, and diabetes mellitus (with long-term use). Some of the xanthine derivatives (theophylline, aminophylline) can cause vomiting, diarrhea, and inappetence, and all bronchodilators can cause excessive central nervous system stimulation and cardiac arrhythmias.10 Use of inhaled medications may allow the clinician to control the respiratory disease more effectively without causing undesirable systemic side effects.

Inhaled bronchodilators Inhaled β2-adrenergic receptor agonists (albuterol, salmeterol) commonly are used to manage bronchoconstriction secondary to inflammatory lower airway disease. Stimulation of the β2-receptor causes an increase in intracellular levels of adenylate cyclase, which decreases intracellular calcium levels and subsequently causes smooth muscle relaxation of the bronchial wall.11,12 β2-Adrenergic receptor agonists have been administered by nebulization experimentally to dogs at high doses and have had minimal systemic effects. In rats, ulcerated mucosal lesions may develop in the rostral aspect of the nasal cavity, but this was not reported in dogs.13 Minimal clinical studies have been published in the small animal veterinary literature evaluating the use of inhaled β2-agonists for the management of bronchopulmonary disease in veterinary patients. One study showed improvement in lung function following the use of an albuterol inhaler in cats with FBPD.14 Additional investigators have recommended use of an albuterol inhaler (88 mcg/dose, two puffs with 7 to 10 breaths q12h) for cats with moderate to severe signs of FBPD.2,8 There is recent research demonstrating that the R-albuterol MDI (levalbuterol [Xopenex HFA]) is ideally recommended for cats and dogs; the racemic mixture that includes S-albuterol in an MDI (albuterol [ProAir HFA or Ventolin HFA]) may cause an increase in lower airway inflammation due to the proinflammatory effects of the S-enantiomer.15

Inhaled glucocorticoids Inhaled glucocorticoids have been studied extensively in laboratory dogs as a model for human asthma, but very few controlled, randomized studies have evaluated the use of inhalant glucocorticoids in the veterinary clinical setting. Interestingly, there are studies showing that the administration of systemic glucocorticoids for at least 48 hours before administration of inhaled bronchodilators causes a significantly greater sensitivity to subsequent β2-agonist administration. It is thought that glucocorticoids upregulate β2-adrenergic receptors on bronchial smooth muscle.16,17 The newer inhaled glucocorticoids tend to have very low systemic absorption and a longer duration of action due to increased lipophilicity.5 Inhaled glucocorticoids (e.g., fluticasone propionate [Flovent]) have been suggested for management of FBPD. Use of either a 220, 110, or 44 mcg/dose MDI for fluticasone propionate has been suggested.2,18,19 Recent studies in cats with experimentally induced asthma indicate that use of the 44 mcg/dose MDI significantly decreases airway eosinophilia. The recommended dosage is two puffs with 7 to 10 breaths q12h in cats with bronchopulmonary disease.20,21

Table 172-2  Published Dosages for Inhaled Medications Commonly Used in the Management   of Feline Bronchopulmonary Disease Generic Name

Trade Name

Activity

Dosage

Albuterol

Proventil HFA, ProAir HFA

β2 Agonist

88 mcg/dose, 2 puffs q12h

Albuterol

Xopenex HFA

β2 Agonist

44 mcg/dose, no published dosage

Salbutamol

Ventolin HFA

β2 Agonist

100 mcg/dose, 2 puffs q12h

Salmeterol

Serevent HFA

β2 Agonist

50 mcg/dose, no published dosage

Fluticasone

Flovent HFA

Glucocorticoid

220 mcg/dose or 110 mcg/ dose, 2 puffs q12h

Flunisolide

AeroBid HFA

Glucocorticoid

250 mcg/dose, 2 puffs q12h

Because it takes approximately 2 weeks to obtain steady-state concentrations with fluticasone propionate, oral glucocorticoids should be administered for at least 2 weeks after inhalant therapy is started.2 At that time, if the cat appears clinically normal, the oral steroids should be tapered slowly. The suggested dosages of inhaled glucocorticoids and bronchodilators commonly used in small animal veterinary medicine are listed in Table 172-2.

Other inhaled medications Ipratropium bromide is an acetylcholine antagonist that helps to relax smooth muscle. It has minimal systemic absorption and minor inhibitory effects on salivation. It has been used in human medicine in the treatment of patients with bronchitis, although its use for this indication has not been evaluated in veterinary medicine. Additionally, there are some studies in cats with experimentally induced with asthma that show a decrease in airway resistance after long-term treatment with nebulized lidocaine.22

Canine Infectious Tracheobronchitis and Pneumonia The most common bacterial agent in infectious tracheobronchitis is Bordetella bronchiseptica. This gram-negative bacterium is predominantly extracellular and has several characteristics that allow the organism to attach to the tracheal cilia. This makes it difficult to decrease Bordetella numbers with systemic antimicrobial therapy.4 Bemis and Appel have shown that parenteral antibiotics do not significantly decrease tracheal numbers of Bordetella organisms. They were able to show, however, that aerosolized gentamicin did significantly decrease Bordetella numbers in experimentally infected dogs.23 Animals with symptomatic infectious tracheobronchitis that are treated with aerosolized gentamicin may show significant clinical improvement compared with other patients that are managed with commonly used oral medications.24 Systemic absorption of aerosolized gentamicin is minimal ( MIC). Additional time-dependent drugs include other cell wall inhibitors, folic acid inhibitors, and drugs considered to be bacteriostatic. The duration of T > MIC varies with the drug: for first-tier aminopenicillins, T > MIC ideally is 100% of the dosing interval, whereas for third- or fourth-tier carbapenems, the duration should be at least 25% of the dosing interval.24,26 For time-dependent drugs with

very short half-lives (e.g., aminopenicillins), dosing intervals must be shortened. Indeed, for such drugs, constant rate infusions27 might be ideal, as was demonstrated in an in vitro model of the use of a ceftazidime constant rate infusion for treatment of P. aeruginosa infection.28 The use of slow-release formulations might be more effective than intermittent administration as long as the target maximum concentration (Cmax) is reached.29 The impact of drugs with very long half-lives (e.g., cefovecin) on emergent antimicrobial resistance is not clear, but in general their use complicates attempts at deescalation of antimicrobial use by virtue of their prolonged presence in the patient. Administration of a loading dose might be indicated for drugs with a long half-life (e.g., azithromycin). In contrast to time-dependent drugs, concentration-dependent drugs tend to bind their target irreversibly. These drugs are best represented by the fluoroquinolones and aminoglycosides (both of which result in irreversible inhibition of their targets). Their effectiveness depends on achieving a sufficient concentration of drug molecules at the site so that all target microbial molecules are bound. Their effectiveness is predicted by comparing the Cmax with the MIC of the infecting organism.3,24,26 Concentration-dependent drugs often exhibit an excellent postantibiotic effect; that is, effectiveness is maintained even after brief exposure to the drug. A long postantibiotic effect allows a longer dosing interval than might be expected based on the elimination half-life.30 For such drugs, the magnitude of Cmax : MIC generally should be a minimum of 10 to 12 and should be higher for more difficult infections (e.g., P. aeruginosa infections or those caused by multiple organisms).31,32 More recently, the effectiveness of concentration-dependent drugs has been best predicted by the area under the inhibitory curve (AUIC), the ratio of the AUC (area under the curve for 24 hours, which is influenced by both dose and interval) to the MIC. An AUIC of over 100 to 125 is generally associated with bacterial killing and decreased resistance.2 Thus, for treatment of some infections, the dosing regimen might be designed to maximize both the Cmax : MIC and the AUC : MIC (i.e., a higher dosage, targeting a higher Cmax : MIC, and a shorter dosing interval, targeting a higher AUC : MIC). For example, if the target Cmax : MIC of a fluoroquinolone cannot be achieved with a single dose, the addition of a second dose in a 24-hour period may enhance effectiveness by increasing the AUC : MIC. Concentration-dependent drugs, and especially the fluorinated quinolones, demonstrate the importance of going beyond MIC when designing dosing regimens. Dosing regimens that reach the mutant-prevention concentration rather than the MIC at the site of infection are most likely to be effective.5

Site of Infection Among the most important host factors influencing drug concentrations at the location of infection is drug penetrability at the infection site and host response to the infection. Three levels of drug penetration exist in normal tissues. Sinusoidal capillaries, found primarily in the adrenal cortex, pituitary gland, liver, and spleen, present essentially no barrier to bound or unbound drug movement. Fenestrated capillaries such as those located in kidneys and endocrine glands contain pores that do not present a barrier to unbound drug, and movement is thus facilitated between the plasma and interstitium.33 However, culture and susceptibility testing may be based on an MIC determined in vitro in the absence of protein. Therefore, for those drugs characterized by a high percentage of binding to plasma proteins (e.g., doxycycline), the MIC may underestimate the total plasma concentration of drug necessary for effectiveness. Continuous (nonfenestrated) capillaries, such as those found delivering drug to the brain, cerebrospinal fluid, testes, prostate, muscle, and adipose tissue, present a barrier of endothelial cells with tight junctions that preclude drug movement. For infections in such tissues, the dosing regimen of water-soluble drugs (e.g., β-lactams and aminoglycosides,

923

PART XX  •  PHARMACOLOGY

Cumulative Antimicrobial Susceptibility Report Canine Isolates from 1/ 1/ 07 to1/ 1/ 10

68

53

71

75 57 85 70 (444) (442)

69

85

71

Klebsiella pneumoniae

100 67

60

0

58

61

70

63

64

64

Proteus mirabilis

136 99

95

91

90

98 91 90 96 (117) (129)

95

92

98

Pseudomonas aeruginosa

250 98

56

80 89 (223)

Staphylococcus aureus

30

57

58

(87) (93)

6

(246)

21

69

55

68

73

59

0

61

71

0

94 100 90

Penicillin

Rifampin

96

46 54 (116)

13

27

54

(46)

25

(48) (439) (93) (129)

94

37

17

37

33

50

37

90

50

37

20

Staphylococcus intermedius b 480 94

77

20

76

72 78 49 63 69 (411) 98 (477) (441)

49

90

67

78

98 53 18 (476) (430)

65

0

65

65

47 100 100 (19)

100

Group G Beta Streptococci

20

45

100 100 100 65

100 100 70 (12) (19)

95

60

93

87

96

97

(28)

37 100 37

Trimethoprim/Sulfa

486 98

Ticarcillin/CA

Escherichia coli

54

(110)

12

Ticarcillin

6

Tetracycline

96

Oxacillin + 2% NaCl

27

Marbofloxacin

31

Gentamicin

52

Erythromycin

Enterococcus faecium

Enrofloxacin

17 52 (127)

Clindamycin

84

Cephalothin b

96

Ceftiofur

98

Cefpodoxime

128

Cefazolin

Ampicillin

Enterococcus faecalis

Amikacin

Amoxicillin/CA

Chloramphenicol

PERCENT SUSCEPTIBLE (No. ISOLATES TESTED) a

No. of Isolates

924

93

a. Numbers in parentheses represent actual number tested if different from total. b. Cephalothin acts as a class drug representing cephalothin, cephapirin, cephalexin, cephradine, cefaclor, and cefadroxil. c. Represents what is presently known as S. intermedius group. FIGURE 175-2  Example of a hospital-based antibiogram, which demonstrates susceptibility patterns. Each cell indicates the percentage of isolates of the organism (delineated by row) susceptible to the drug against which the isolate was tested (delineated by column). If not all isolates were tested against that drug, the number in the cell is in parenthesis. For example, during the data collection period, 68% of Escherichia coli isolates collected from dogs during 2007 through 2010 were considered susceptible (based on guidelines promulgated by the Clinical and Laboratory Standards Institute) to amoxicillin–clavulanic acid, which is the model drug for ampicillin-sulbactam. This represents an improvement over the previous years (2003 to 2005) during which only 46% of isolates were susceptible. Cells lacking data represent drugs to which isolates are inherently resistant or for which in vitro data do not predict patient response.

selected sulfonamides, and selected tetracyclines) should be adjusted for potentially poor drug distribution to the site of infection. Indeed, dosages of β-lactams are often adjusted up to 10-fold in treating human central nervous system infections. The bronchus-blood barrier presents an example. Based on studies in human medicine, only 2% to 30% of β-lactams or aminoglycosides in plasma reach bronchial secretions, compared with 30% to 80% of lipid-soluble drugs. For azithromycin, concentrations in bronchial secretions are 17-fold higher than plasma concentrations (as reviewed by Boothe3). The effectiveness of some drugs is enhanced because of accumulation of the active (unbound) form in tissues (e.g., macrolides34) or phagocytes; such drugs may be of particular efficacy in the presence of marked inflammatory debris. Culture and susceptibility testing underestimates the effectiveness of drugs that accumulate in tissues or can be applied topically at the site of infection. Note, however, that accumulated drug is not necessarily active drug. Further, drugs excreted in the urine may not concentrate there in the face of altered renal function and may not be

able to penetrate uroepithelial cells or biofilm protecting organisms causing cystitis. For topically accessed sites, a level of several thousandfold the MIC may be reached. Although topical application of antimicrobial drugs in the CCP is not common, selected indications should be considered. An example is drug aerosolization for treatment of infections of the respiratory tract, but limited aerosol penetrability and potential adverse effects of aerosolized particles preclude aerosolization as the sole method of drug administration for respiratory tract infections (see Chapter 172). Topical wound management (with or without antimicrobials) may be preferred to systemic antimicrobial therapy. Disease or other factors can influence drug movement to the site of infection. Pathophysiologic changes associated with the critical nature of a patient’s illness have an impact on each drug’s disposition, including absorption, distribution, metabolism, and excretion (see Chapter 182). Changes in absorption associated with subcutaneous or intramuscular drug administration can be circumvented by using intravenous administration in critically ill patients. However,

CHAPTER 175  •  Antimicrobial Use in the Critical Care Patient

distribution may also be impacted by changes in tissue perfusion. The patient in cardiovascular shock may be particularly predisposed to adverse events affecting the cardiovascular and central nervous systems because these organs receive preferential blood flow. Volume replacement may correct some of these changes. Changes in plasma drug concentration are influenced by changes in the volume to which the drug is distributed.24 An increase in the volume of distribution decreases plasma drug concentration and vice versa. However, the clinical impact differs with the lipophilicity of the drug. For water-soluble drugs (aminoglycosides, β-lactams, and glycopeptides), distribution is limited to interstitial and other extracellular fluids. Because of this, the volume of distribution can be increased by the accumulation of fluids in peripheral tissues, including the pleural space and peritoneal cavity.1 Septic shock and trauma are the two most common causes of expansion of volume of distribution in the CCP.1 Aggressive fluid therapy may also decrease drug concentrations. In each of the foregoing examples, tissue antimicrobial exposure is decreased. Several studies have associated therapeutic failure of aminoglycosides with decreased plasma drug concentrations in septic patients.1 Dosages should be increased proportionately in these situations. Monitoring of drug concentrations might be considered for patients receiving aminoglycosides to ensure that therapeutic concentrations are achieved at the chosen dosage. Both a peak serum sample collected 1 to 2 hours after administration and a second sample obtained 4 to 6 hours later ideally are collected so that both peak concentration (important for efficacy) and trough concentration (important for safety) can be predicted. Interestingly, hypoalbuminemia also contributes to decreased antimicrobial exposure, even for drugs that traditionally are not significantly protein bound, probably due to peripheral fluid retention and increased volume of distribution. In general, dosage increases of 1.5-fold to 2-fold are indicated in such cases.1 Although volume contraction associated with dehydration may cause the opposite effect (higher plasma drug concentrations), volume repletion rather than dosage modification should be implemented. For lipid-soluble drugs, dosage is calculated on a milligram-per-kilogram basis. In addition to affecting plasma drug concentrations, volume of distribution influences drug elimination, expressed as changes in elimination half-life. Elimination half-life is affected by both volume of distribution (directly proportional) and clearance (inversely proportional). For this reason, both may change profoundly (e.g., both volume of distribution and clearance decrease), yet half-life will not be impacted. In general, critical illness decreases drug clearance, although an exception is the hyperdynamic state of septic shock, which is frequently associated with increased clearance. The impact on clearance, like that on volume of distribution, also varies with lipophilicity by virtue of its impact on the site of drug excretion. Water-soluble drugs are generally excreted renally, and their clearance changes proportionately with glomerular filtration. In contrast, lipophilic drugs generally are passively resorbed in the tubules and must be metabolized before clearance. Excretion of these drugs may be decreased in animals with profound hepatic disease (i.e., altered albumin concentration). Predicting the proper dosing regimen is complicated by the complex pathophysiology of critical diseases. For example, the increased clearance associated with the hyperdynamic state of septic shock may be balanced by decreased renal function; fluid therapy may increase the volume of distribution and thus decrease plasma drug concentrations.

Host Immune Response On the one hand, immunocompromise increases the risk of infection or therapeutic failure, mandating the need for achievement of bactericidal concentrations of drug at the site of infection. Bactericidal

concentrations are paramount to therapeutic success in immunocompromised hosts (e.g., patients with viral infections, patients with granulopoiesis, those receiving immunoinhibiting drugs) or at immunocompromised sites (septicemia, meningitis, valvular endocarditis, and osteomyelitis). However, classification of bactericidal versus bacteriostatic actions is based on in vitro methods, and dosages should be designed to ensure that the minimum bactericidal concentration is achieved at the site of infection in the patient. Nevertheless, for some bacteriostatic drugs, bactericidal concentrations can be achieved in some tissues (e.g., if the drug accumulates at the site of infection). Although an adequate host immune response facilitates therapeutic success, the host inflammatory response can also profoundly alter drug efficacy. Acute inflammation may initially increase drug delivery to the site of infection. However, marked or chronic inflammation may preclude drug movement and efficacy. Reduced oxygen tension decreases the efficacy of some drugs. Aminoglycosides in particular require active transport into the microbe and may be ineffective in an anaerobic environment, even against facultative anaerobes such as E. coli.

Impact of Microbial Factors In addition to developing resistance, microbes can negatively affect antimicrobial therapy in other ways. Materials released from microbes facilitate invasion, impair cellular phagocytosis, and damage host tissues. The “inoculum effect” increases the risk of failure for several reasons. Larger inocula present more bacterial targets and thus require more drug molecules (higher doses). Moreover, larger inocula present a greater risk of spontaneous mutations resulting in resistance and also produce greater concentrations of destructive enzymes. For example, production of extended-spectrum β-lactamases more often results in cephalosporin resistance with a larger (107) than with smaller (105) inoculum. Infection in epithelial tissues (e.g., uroepithelium and respiratory epithelium) is facilitated by bacterial adherence. Materials secreted by organisms often contribute to the marked inflammatory host response and clinical signs of infection. Soluble mediators released by organisms (hemolysin, epidermolytic toxin, leukocidin) may damage host tissues or alter host response. Among the more problematic microbial factors are glycocalyx or biofilm, a virulence factor that facilitates microbe adaptation to new environments. A biofilm is a community that effectively allows a single-cell microbe to become a multicell organism. It consists of microcolonies of both pathogenic and host microbes embedded in a polysaccharide produced by microbes adhering to flat surfaces. These include foreign bodies, wound surfaces, or other tissues.35 Symbiosis and survival are supported through sophisticated communication and complex patterns of antimicrobial resistance as well as an ability to avoid host immune response. Organisms within the community are often quiescent and thus nonresponsive to antimicrobial therapy. Translocation of the biofilm microflora to sterile tissues may ultimately cause infection, as was demonstrated in dogs undergoing experimental catheterization of the portal vein.36 However, organism growth in catheters does not necessarily lead to infection, and isolates cultured from urinary catheter tips are not necessarily those causing urinary tract infection.37

Adverse Drug Events Because host (patient) cells are eukaryotic whereas bacterial targets are prokaryotic, antimicrobial drugs generally are safe as a class. Exceptions include those drugs that target shared structures, such as cell membranes (e.g., colistin and polymyxin). Aminoglycosides are predictably nephrotoxic, with toxicity related to the duration of exposure. Toxicity is minimized by dosing once daily so that trough

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plasma drug concentration (and subsequently urine drug concentration) drops below a threshold ( MIC. For some of the long-acting time-dependent drugs with postantibiotic effects, the AUC : MIC also predicts clinical success. Examples of how these relationships affect drug regimens are provided in the following sections.

Aminoglycosides Aminoglycosides (e.g., gentamicin, amikacin) are concentrationdependent bactericidal drugs; therefore the higher the drug concentration, the greater the bactericidal effect. An optimal bactericidal effect occurs if a high enough dose is administered to produce a peak of 8 to 10 times the MIC. This can be accomplished by administering a single dose once daily. This regimen is at least as effective, and perhaps less nephrotoxic, than administration of lower doses more frequently.20 Current regimens for small animals employ this strategy. The single daily dose is based on the drug’s volume of distribution (typically in the range of 0.2 to 0.25 L/kg for aminoglycosides in animals). A dosage for gentamicin is 5 to 8 mg/kg q24h for cats and 10 to 14 mg/kg q24h for dogs. An appropriate dosage for amikacin is 10 to 15 mg/kg q24h for cats and 15 to 30 mg/kg q24h for dogs. The efficacy of these regimens has not been tested for conditions encountered in veterinary medicine, but the relationships are supported by experimental evidence. These regimens assume some competency of the immune system. If the animal is immunocompromised, a more frequent interval of administration may be considered. In animals with decreased renal function, longer intervals may be considered, or aminoglycosides should be avoided altogether.

Fluoroquinolones For the fluoroquinolone antimicrobials, as reviewed by Drusano et al,21 Papich and Riviere,22 and Wright et al,23 investigators have shown that either the peak plasma concentration above bacterial MIC (also known as the CMAX : MIC ratio) or the total AUC above the MIC (also known as the AUC : MIC ratio) may predict clinical cure in studies of laboratory animals and in a limited number human clinical studies. The optimum value for these surrogate markers has not been determined for treatment of infections in dogs or cats. However, based on other studies, a CMAX : MIC of 8 to 10 or an AUC : MIC of more than 125 has been associated with a cure. As reviewed by Wright et al,23 in some clinical situations AUC : MIC ratios as low as 30 to 55 have been associated with a clinical cure. For susceptible bacteria isolated from small animals, the MIC for fluoroquinolones is expected to be low enough that administration of the lowest label dose of any of the currently available fluoroquinolones usually meets the goal of a CMAX : MIC ratio or an AUC : MIC ratio in the range cited earlier. For organisms with MIC values that are slightly higher but still in the susceptible range a higher dose may be required. To take advantage of the wide range of safe doses for fluoroquinolones, low doses have been administered to treat susceptible organisms with low MICs, such as E. coli or Pasteurella. But for bacteria with higher MICs (e.g., gram-positive cocci) a slightly higher dose is recommended. To achieve the necessary peak concentration

for a bacteria such as P. aeruginosa, which usually has the highest MIC among susceptible bacteria, use of the highest dose within a safe range is recommended. Bacteria such as streptococci and anaerobes are more resistant, and even at high doses, a sufficient peak concentration or AUC : MIC ratio will be difficult to achieve. An exception to these guidelines is the new fluoroquinolone pradofloxacin, which has an extended spectrum of activity that includes gram-positive cocci and anaerobes.

β-Lactam Antibiotics β-Lactam antibiotics such as penicillins, potentiated aminopenicillins, and cephalosporins are slowly bactericidal. Their concentrations should be kept above the MIC throughout most of the dosing interval (long T > MIC) for the optimal bactericidal effect.24 Dosage regimens for the β-lactam antibiotics should consider these pharmacodynamic relationships. Therefore for treating a gram-negative infection, especially a serious one, some regimens for penicillins and cephalosporins require administration three or four times per day. Some long-acting formulations have been developed to prolong plasma concentrations. Some of the third-generation cephalosporins have long half-lives, and less frequent dosing regimens have been used for some of these drugs (e.g., cefpodoxime proxetil). (The long half-life for ceftriaxone seen in people does not occur in animals because of differences in drug protein binding.) Gram-positive organisms are more susceptible to the β-lactams than are gramnegative bacteria, and lower doses and longer intervals are possible when treating infections caused by these bacteria. Additionally, because antibacterial effects occur at concentrations below the MIC (postantibiotic effect) for Staphylococcus, longer dose intervals may be possible for staphylococcal infections. For example, cephalexin or amoxicillin-clavulanate has been used successfully to treat staphylococcal infections when administered only once daily (although twicedaily administration is recommended to obtain maximum response). Cefpodoxime proxetil is effective with once-daily administration because of both its high activity (low MIC values) and longer half-life compared with other cephalosporins. In critical care patients, for optimum treatment β-lactam antibiotics may be administered via CRI to ensure a long T > MIC. Rates of infusion are readily calculated using available parameters for volume of distribution and systemic clearance (Table 182-4). The amount of drug administered over 24 hours is much less with a CRI than with intermittent bolus injections.

Other Time-Dependent Drugs Drugs such as tetracyclines, macrolides (azithromycin), lincosamides (clindamycin), and chloramphenicol act in a time-dependent manner

Table 182-4  Suggested Loading Doses and ConstantRate Infusion (CRI) Rates for Selected Antibiotics Used In Critical Care* Drug Cefazolin

Intravenous Loading Dose (mg/kg)

Intravenous CRI (mg/kg/hr)

1.3

1.21

Ceftazidime

1.2

1.56

Cefotaxime

3.2

5.04

Ceftriaxone

1.9

1.9

Cefepime

1.4

1.04

*Clinicians should verify the compatibility of each drug with the fluid administered and the stability of the drug for the duration of infusion by consulting the package insert before administration.

CHAPTER 182  •  Strategies for Treating Infections in Critically Ill Patients

against most bacteria, but because they can have long-acting, or postantibiotic, effects the total drug exposure, measured as AUC : MIC, has been used to predict clinical success. The time-dependent activity of these drugs is demonstrated by studies showing that effectiveness is highest when drug concentrations are maintained above the MIC throughout the dosing interval. Drugs in this group should be administered frequently to achieve this goal. However, a property of some is that they persistent in tissues for a prolonged time, which allows long dosing intervals. The macrolide derivative azithromycin (Zithromax) has shown a tissue half-life as long as 70 to 90 hours in cats and dogs, which permits infrequent dosing. Tissue concentrations of trimethoprimsulfonamides persist long enough to allow once-daily dosing for many infections. Most published dosing regimens are designed to take the pharmacokinetic properties of these drugs into account.

REFERENCES 1. Martinez MN, Papich MG, Drusano GL: Dosing regimen matters: the importance of early intervention and rapid attainment of the pharmacokinetic/pharmacodynamic target, Antimicrob Agents Chemother 56(6):2795-2805, 2012. 2. Mouton JW, Ambrose PG, Canton R, et al: Conserving antibiotics for the future: new ways to use old and new drugs from a pharmacokinetic and pharmacodynamic perspective, Drug Resist Updat 14:107-117, 2011. 3. Drusano GL, Louie A, Deziel M, et al: The crisis of resistance: identifying drug exposures to suppress amplification of resistant mutant subpopulations, Clin Infect Dis 42:525-532, 2006. 4. Oluoch AO, Kim C-H, Weisiger RM, et al: Nonenteric Escherichia coli isolates from dogs: 674 cases (1990-1998), J Am Vet Med Assoc 218:381384, 2001. 5. Torres SM, Diaz SF, Nogueira SA, et al: Frequency of urinary tract infection among dogs with pruritic disorders receiving long-term glucocorticoid treatment, J Am Vet Med Assoc 227:239-243, 2005. 6. Shaheen BW, Boothe DM, Oyarzabal OA, et al: Antimicrobial resistance profiles and clonal relatedness of canine and feline Escherichia coli pathogens expressing multidrug resistance in the United States, J Vet Intern Med 24:323-330, 2010. 7. Boothe DM, Debavalya N: Impact of Routine Antimicrobial Therapy On Canine Fecal Escherichia coli antimicrobial resistance: a pilot study, Int J Appl Res Vet Med 9(4):396-406, 2011. 8. Rubin J, Walker RD, Blickenstaff K, et al: Antimicrobial resistance and genetic characterization of fluoroquinolone resistance of Pseudomonas

aeruginosa isolated from canine infections, Vet Microbiol 131(1-2):164172, 2008. 9. Papich MG: Selection of antibiotics for methicillin-resistant Staphylococcus pseudintermedius: time to revisit some old drugs? Vet Dermatol 23(4):352-360, 2012. 10. Nix DE, Goodwin SD, Peloquin CA, et al: Antibiotic tissue penetration and its relevance: impact of tissue penetration on infection response, Antimicrob Agents Chemother 35:1953-1959, 1991. 11. Lees GE, Rogers KS: Treatment of urinary tract infections in dogs and cats. J Am Vet Med Assoc 189:648-652, 1986. 12. Clinical and Laboratory Standards Institute: Performance standards for antimicrobial disk and dilution susceptibility tests for bacteria isolated from animals; approved standard—third edition, CLSI document M31A3, Wayne, Pa, 2008, Clinical and Laboratory Standards Institute. 13. Stamey TA, Fair WR, Timothy MM, et al: Serum versus urinary antimicrobial concentrations in cure of urinary-tract infections, N Engl J Med 291:1159-1163, 1974. 14. Pascual A: Uptake and intracellular activity of antimicrobial agents in phagocytic cells, Rev Med Microbiol 6:228-235, 1995. 15. Habash M, Reid G: Microbial biofilms: their development and significance for medical device-related infections, J Clin Pharmacol 39:887-898, 1999. 16. Smith AW: Biofilms and antibiotic therapy: is there a role for combating resistance by the use of novel drug delivery systems? Adv Drug Deliv Rev 57:1539-1550, 2005. 17. Hyatt JM, McKinnon PS, Zimmer GS, et al: The importance of pharmacokinetic/pharmacodynamic surrogate markers to outcome, Clin Pharmacokinet 28:143-160, 1995. 18. Nicolau DP, Quintiliani R, Nightingale CH: Antibiotic kinetics and dynamics for the clinician, Med Clinics North Am 79:477-495, 1995. 19. Pankey GA, Sabath LD: Clinical relevance of bacteriostatic versus bactericidal mechanisms of action in the treatment of gram-positive bacterial infections, Clin Infect Dis 38:864-870, 2004. 20. Freeman CD, Nicolau DP, Belliveau PP, et al: Once-daily dosing of aminoglycosides: review and recommendations for clinical practice, J Antimicrob Chemother 39:677, 1997. 21. Drusano G, Labro M-T, Cars O, et al: Pharmacokinetics and pharmacodynamics of fluoroquinolones, Clin Microbiol Infect 4(Suppl 2):2S272S41, 1998. 22. Papich MG, Riviere JE: Fluoroquinolone antimicrobial drugs. In Riviere JE, Papich MG, editors: Veterinary pharmacology and therapeutics, ed 9, Ames, Ia, 2009, Wiley-Blackwell, chap 38. 23. Wright DH, Brown GH, Peterson ML, et al: Application of fluoroquinolone pharmacodynamics, J Antimicrob Chemother 46:669-683, 2000. 24. Turnidge JD: The pharmacodynamics of β-lactams, Clin Infect Dis 27:1022, 1998.

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PART XXI  MONITORING CHAPTER 183  HEMODYNAMIC MONITORING Lori S. Waddell,

DVM, DACVECC  •  Andrew

J. Brown,

KEY POINTS • Hemodynamic monitoring is essential in the treatment of many critically ill patients because it is important in guiding fluid and pharmacologic therapy to optimize cardiovascular function. • Assessment of hemodynamic status is typically based on physical examination parameters and monitoring of any of the following: continuous electrocardiogram, arterial blood pressure, central venous pressure, mixed venous and central venous oxygen saturation, pulmonary artery pressure, lactate and base deficit, and cardiac output measurements. • Continuous electrocardiogram monitoring enables the clinician to detect intermittent arrhythmias, determine whether treatment is indicated, and monitor therapeutic effectiveness. • Direct blood pressure monitoring is the gold standard for blood pressure measurement, but indirect blood pressure monitoring is more readily available and better tolerated by most patients. • Central venous pressure is relatively easy to monitor and can guide fluid therapy, particularly in patients that are hypovolemic or have septic shock, heart disease, or renal disease.

Hemodynamic monitoring includes monitoring of basic physical examination parameters, continuous electrocardiogram (ECG) and blood pressure, central venous pressure (CVP), central venous oxygen saturation (ScvO2), and lactate clearance and base deficit, as well as the most advanced forms including pulmonary artery pressure (PAP) monitoring, mixed venous oxygen saturation (SvO2) monitoring, and other technologies to measure cardiac output, cardiac index, systemic vascular resistance, oxygen delivery, and oxygen uptake. See Chapters 184 and 202 for further information on these procedures. The type of monitoring chosen depends on the severity of illness, equipment availability, and the clinician’s comfort with the various modalities.

CONTINUOUS ELECTROCARDIOGRAM MONITORING Continuous ECG monitoring can be very useful in critically ill patients; it provides continuous, hands-off access to the heart rate and rhythm. It allows the clinician to catch arrhythmias that may be intermittent and infrequent, and monitor the need for treatment based on the rate and rhythm. Both standard and telemetric systems are available, with the telemetric models allowing for easier patient movement and less tangling and disconnection of the leads compared with standard systems.

MA, VetMB, MRCVS, DACVECC

BLOOD PRESSURE MONITORING Arterial blood pressure monitoring is extremely useful in critical cases and is commonly employed to permit fluid therapy to be tailored to the patient’s needs, especially when combined with monitoring of physical examination parameters, urine output, and CVP. It is essential in guiding the use of inotropic agents and vasopressors; these therapies should not be used unless blood pressure can and will be measured frequently. Normal arterial blood pressure values for dogs are as follows: systolic pressure, 150 ± 20 mm Hg; mean pressure, 105 ± 10 mm Hg; and diastolic pressure, 85 ± 10 mm Hg. For cats, normal ranges are 125 ± 10 mm Hg for systolic, 105 ± 10 mm Hg for mean, and 90 ± 10 mm Hg for diastolic.1 Mean arterial blood pressure can be calculated from these measured values as follows:

Mean arterial blood pressure = diastolic +

systolic − diastolic 3

Hypotension is defined as a systolic blood pressure of less than 90 mm Hg or a mean arterial pressure of less than 60 mm Hg in either species. Causes of hypotension include decreased cardiac output secondary to reduced circulating volume, myocardial failure, severe bradyarrhythmia or tachyarrhythmia, or decreased systemic vascular resistance due to peripheral vasodilation secondary to sepsis or systemic inflammatory response syndrome. Treatment of hypotension should always be aimed at correcting the underlying problem (see Chapter 8). Hypertension can be primary (essential hypertension), which is rare in both cats and dogs, or secondary to another disease process that alters renal or neurohormonal function. Kidney injury or failure, whether acute or chronic, is the most frequent cause of secondary hypertension, but hyperthyroidism, diabetes mellitus, hyperadrenocorticism, pheochromocytoma, and various medications (glucocorticoids, cyclosporine A, phenylpropanolamine, and erythropoietin) have also been associated with hypertension. Blood pressure monitoring can be divided into two main categories, noninvasive and invasive methods. The noninvasive oscillometric or Doppler methods are used most commonly in veterinary patients, although photoplethysmography is also available. Invasive blood pressure monitoring provides direct arterial pressure measurement and is the most accurate method available.

Noninvasive Blood Pressure Monitoring Noninvasive blood pressure monitoring is based on inflation of a cuff to occlude arterial flow, followed by measurement of the pressure at which flow returns. These methods are technically easy to use and require relatively inexpensive equipment but are prone to error, 957

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usually due to selection of an inappropriate cuff size. The guideline for the cuff width is approximately 40% of the circumference of the limb for dogs and 30% of the circumference of the limb for cats. If the cuff is too small, a falsely high pressure will be obtained; if the cuff is too large, a falsely low reading will result.2 The cuff should be at the level of the right atrium while measurements are being obtained. Keeping the patient motionless in lateral recumbency is ideal for obtaining accurate indirect blood pressure measurements. The Doppler method is used most commonly in smaller animals such as cats, very small dogs, and exotic species. It is also useful in patients with hypotension or those that have arrhythmias because the oscillometric methods are commonly inaccurate or do not give any readings at all in these circumstances. The Doppler method uses a 10-MHz ultrasound probe to detect blood flow in an artery. The probe is placed over an artery distal to the cuff. Doppler sounds become audible when pressure in the cuff is less than the pressure in the artery. Although the Doppler method typically is regarded as measuring the systolic pressure, one study that compared Doppler readings with direct blood pressure monitoring in anesthetized cats found that the Doppler reading consistently underestimated systolic pressures by 10 to 15 mm Hg and was more closely correlated with mean arterial pressure. This study was performed only in anesthetized healthy cats, so limitations are present.3 The oscillometric method of blood pressure determination is commonly used in veterinary medicine. There are a number of different veterinary systems available. The cuff is alternately inflated and deflated, and during deflation alterations in cuff pressure due to pulse pressure changes are sensed by the transducer. The peak amplitude of oscillations equals the mean arterial pressure. Systolic pressure equals the pressure at which oscillations are first detected, and diastolic pressure equals the pressure at which oscillations decrease rapidly. Oscillometric machines calculate systolic and diastolic blood pressure from the mean arterial pressure using built-in algorithms, so that the mean arterial pressure is the most accurate value. The heart rate is measured as the number of oscillations occurring per minute and should always be compared with the patient’s heart rate as determined manually or by ECG. Many of the oscillometric units have been used in studies comparing systolic, mean, and diastolic pressures in anesthetized and awake dogs and cats with variable results, some of which showed acceptable correlation between values obtained with these units and direct arterial blood pressure measurements.4-9 Later-generation units claim to be more accurate in smaller dogs and cats, but these claims have not held up in more recent studies. Poor agreement was seen using one oscillometric unit in anesthetized dogs compared with direct arterial blood pressure measurements.10 Readings obtained using three different units were compared with direct arterial blood pressure measurements in anesthetized cats and had poor correlation.11 Another study showed that pressures measured in awake, ill dogs using the Doppler method and two oscillometric units also were not well correlated with values obtained via direct arterial blood pressure monitoring.12 Although none of the units currently available would meet validation criteria for humans, these units are readily available, are simpler to use and are associated with fewer potential complications than direct arterial blood pressure monitoring. The American College of Internal Medicine recently drafted a consensus statement on hypertension and proposed new validation recommendations for veterinary devices.1 High-definition oscillometry (HDO) is a newer modality for blood pressure monitoring in veterinary medicine. HDO devices are purported to have advantages over standard oscillometric monitors because HDO performs real-time analysis of arterial wall oscillations to obtain pressure-wave amplitudes, so systolic and diastolic pressures are measured instead of calculated. Other reported benefits

include accurate readings of values from 5 to 300 mm Hg and highspeed analysis that allows for measurements at heart rates of up to 500 beats/min and during arrhythmias. However, recent studies have not shown good correlation with other blood pressure monitoring methods, although none compared HDO with direct arterial blood pressure monitoring.13,14 More studies are needed to evaluate HDO, including studies comparing HDO results with values obtained via direct arterial blood pressure monitoring.

Photoplethysmography Originally designed for use on the human finger, photoplethysmography is based on the “volume clamp” principle. The blood volume in an extremity varies in a cyclic pattern with each cardiac cycle. The variation is detected by a photoplethysmograph attached to a finger (or to the foot or tail in veterinary patients). If the cuff is inflated and deflated fast enough to maintain a constant volume in the finger (or distal extremity), the cuff pressure will equal intraarterial pressure. This allows for a constant, real-time display of cuff pressure, and therefore intraarterial pressure, and measurement of systolic and diastolic pressures.15 Photoplethysmography has been evaluated in dogs and cats and found to be accurate, but has not come into common use.3,8

Invasive Blood Pressure Monitoring Invasive or direct arterial blood pressure monitoring is considered the gold standard for blood pressure measurement in both veterinary and human patients, both awake and anesthetized. It is usually performed after inserting an arterial catheter that is connected to a pressure transducer and monitor, which allows for continuous monitoring of systolic, diastolic, and mean pressures. Techniques for direct arterial puncture and single-pressure measurement have also been described. See Chapter 201 for further details on placement of these catheters. When a display monitor is employed, continuous direct arterial pressure monitoring allows for observation of pressure changes and trends (Figure 183-1). Another advantage of placing an arterial catheter is that it can be used to obtain blood samples for arterial blood gas analysis and laboratory testing. Despite its many advantages, direct monitoring should be limited to critically ill patients that will benefit from having blood pressure measured continuously over a defined period (e.g., during anesthesia in a patient with a high anesthetic risk or while hospitalized in an intensive care unit). Direct arterial blood pressure monitoring in patients with hypovolemic or septic shock is extremely helpful in guiding volume replacement and the use of pressors to maintain an acceptable systemic blood pressure. By evaluating the pressure waveform with various arrhythmias, the clinician can distinguish which ones are causing poor pressures or even pulse deficits, and this can influence the decision to initiate treatment. Direct arterial blood pressure monitoring is not indicated in active, relatively healthy patients because of possible morbidity from arterial catheter placement and the risk of hemorrhage due to disconnection of the arterial line or premature removal by the patient. Animals with arterial catheters must be strictly supervised at all times. Once an arterial catheter is placed, it is connected to semirigid tubing that has been primed with heparinized saline from a bag of 0.9% sodium chloride with 1 unit of heparin per milliliter of saline. The fluid bag is pressurized to 300 mm Hg to prevent backward flow of arterial blood into the tubing.16 The tubing from the catheter is attached to a pressure transducer that is connected to a cable and mounted on a board placed at the level of the patient’s heart. The pressure transducer converts the pressure changes into an electrical signal that is carried to the monitor by the transducer cable, and then the signal is amplified and displayed on a monitor as a pressure

CHAPTER 183  •  Hemodynamic Monitoring

FIGURE 183-1  Direct arterial blood pressure waveform and continuous electrocardiogram. Note that one arterial pressure waveform is seen just after completion of each cardiac complex.

waveform showing the peak systolic pressure, dicrotic notch (which is created by closure of the aortic valve), and diastolic pressure. Monitors can also display numeric values for the systolic, diastolic, and mean arterial pressures. Although direct arterial monitoring is considered the gold standard for blood pressure monitoring, it can give erroneous results if compliant tubing is used, the catheter is lodged up against the arterial wall, a clot forms at the tip of the catheter, air bubbles are present in the catheter or tubing, or the catheter or tubing becomes kinked. All of these problems can result in the waveform becoming damped, which gives falsely low systolic and falsely high diastolic values. Direct arterial blood pressure monitoring is associated with higher morbidity than noninvasive methods, including hematoma formation at the site of arterial puncture, infection, thrombosis of the artery, or necrosis of the tissues distal to the catheter (particularly in cats that have an indwelling catheter for longer than 6 to 12 hours). Keeping the arterial line patent requires heparinization of the line and catheter, which can be of concern in very small patients. Fortunately, all of the complications other than hematoma formation are quite rare.

Telemetric Blood Pressure Monitoring Telemetric units are available for implantation into dogs and potentially cats (Data Sciences International, St. Paul, Minn.). These require surgical implantation of a transmitting device that sends digital information to a receiver; this information can then be either collected by a computer and evaluated later or converted into an analog signal for recording on a strip chart. The device is placed subcutaneously and has a polyurethane catheter with an antithrombogenic coating and a biocompatible gel at the end that is fed into the femoral artery. This technology has been used in laboratory settings for a number of years and is currently used experimentally in both feline and canine patients. These devices allow for free patient movement and prevent the stress of handling and restraint from affecting the blood pressure measurements obtained. These devices are not used commonly in clinical patients but may be a viable option in the future for those that require longterm hospitalization or repeated blood pressure monitoring.

CENTRAL VENOUS PRESSURE MONITORING CVP is the hydrostatic pressure in the intrathoracic vena cava and, in the absence of a vascular obstruction, is approximately equal to right atrial pressure. When the tricuspid valve is open, right atrial pressure equals right ventricular end-diastolic pressure. This pressure is used to estimate right ventricular end-diastolic volume and the

relationship between blood volume and blood volume capacity. It also gives a measure of the relative ability of the heart to pump the volume of blood that is returned to it. Patients that most commonly benefit from CVP monitoring include those that are hypovolemic or have septic shock, heart disease, or renal disease (especially oliguric or anuric kidney injury). CVP monitoring typically requires a central venous catheter, usually a 16-gauge or 19-gauge jugular catheter, but a femoral vein catheter that extends into the abdominal vena cava has been shown to measure CVP accurately in cats without significant intraabdominal disease17 and in puppies.18 The size of the catheter has no effect on measurement of CVP.19 A study evaluating the correlation between peripheral venous pressure and CVP in awake dogs and cats found that peripheral venous pressure could not be used to approximate CVP.20 The tip of the catheter should be positioned in the cranial or caudal vena cava just outside of the right atrium. The catheter is then connected to a three-way stopcock via noncompliant tubing and to a manometer containing heparinized saline or to a pressure transducer as described earlier for direct arterial blood pressure monitoring. The central catheter can be used for CVP monitoring as well as fluid administration or intermittent blood sampling. However, if the CVP is to be monitored continuously and the patient requires additional venous access, a multilumen venous catheter should be placed so that the other ports remain available for fluid therapy, infusions, and blood sampling. Double-lumen and triple-lumen catheters are available in a variety of sizes and lengths (see Chapter 195). When the central venous catheter is connected to the system, the zero reference point for the bottom of the manometer or the pressure transducer should be the manubrium for a patient in lateral recumbency or the point of the shoulder for a patient in sternal recumbency. Normal ranges for mean CVP are 0 to 5 cm H2O, but they can vary in individual animals.21 This makes trends in the CVP much more significant than individual readings. Values can be affected by patient position, so a consistent position should be used when comparing values. Catheter position also affects readings and can be confirmed by radiography or fluoroscopy. A recent study evaluated the use of ultrasonographically measured hepatic vein diameter, caudal vena cava diameter, and hepatic venous flow velocities, which are multiphasic and correlate with changes in the cardiac cycle in Foxhounds. The investigators found that CVP could be predicted by a multiple linear regression equation using a combination of caudal vena cava diameter, hepatic vein diameter, and the velocity of the v wave (the small retrograde wave that occurs during right atrial overfilling near the end of the T wave of

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the ECG complex—see the later discussion of CVP waveform analysis).22 This study was limited to Foxhounds that did not have a lot of variation in size; therefore it is difficult to know if this technique would be useful in other breeds or sizes of dogs. The CVP varies throughout the respiratory and cardiac cycles because CVP reflects right atrial pressure. During inspiration, intrathoracic pressure decreases and the CVP falls. The reverse occurs during exhalation. If a patient has an upper airway obstruction and has difficulty inspiring, these changes will be exaggerated. Positive pressure ventilation will reverse this pattern. The complexity of the CVP waveform can be seen when it is displayed on a monitor, and the variations that occur during the cardiac cycle can be observed (Figure 183-2, A and B). Three positive waves are seen, a, c, and v waves, and two negative depressions are seen, x and y descents. The a wave represents the increase in the CVP caused by right atrial contraction. The c wave is caused by bulging of the tricuspid valve into the right atrium, which increases right atrial pressure and CVP as the right ventricle contracts. The x descent is caused by the decrease in atrial pressure during ventricular ejection. The v wave is caused by increasing pressure from blood flowing into the right atrium before the tricuspid valve opens. The y descent represents rapid emptying of the right atrium as the tricuspid valve opens, allowing blood to flow into the right ventricle. Careful

ECG HR = 84

A

a

PULMONARY ARTERY PRESSURE MONITORING

c

v

x1 x2

evaluation of the waveform allows abnormalities in each part of the cycle to be detected and differential diagnoses to be considered; for example, large c waves are often associated with tricuspid regurgitation.23,24 A low CVP (10 cm H2O) may indicate volume overload, rightsided heart failure, or significant pleural effusion.25,26 CVP readings of higher than 16 cm H2O often lead to edema formation or body cavity effusions. Some causes of right-sided cardiac dysfunction are right-sided myocardial failure, pericardial effusion and tamponade, restrictive pericarditis, and volume overload from excessive intravenous fluid administration. If a CVP reading is questionable, a small test bolus of 10 to 15 ml/kg of an isotonic crystalloid or 5 ml/kg of a synthetic colloid may be given over 5 minutes or less (see Chapter 58). The vascular bed is a very compliant system, able to accommodate changes in volume with minimal changes in pressure. If the patient has a low CVP due to hypovolemia, the CVP will either show no change or will have a transient rise toward normal, then rapidly decrease again. The mean arterial pressure may also increase with the test bolus, then return toward prebolus measurements. A small increase of 2 to 4 cm H2O with a return to baseline within 15 minutes is usually seen in euvolemic patients. A large increase (>4 cm H2O) and slow return to baseline (>30 minutes) is seen in hypervolemic animals or those with reduced cardiac compliance.26 Contraindications for CVP measurement are few and relate to central venous catheter placement. These include coagulopathies that would make puncture of the jugular or femoral vein an unacceptable risk; high risk of thromboembolic disease, such as in animals with protein-losing nephropathy, hyperadrenocorticism, or immunemediated disease; and suspicion of increased intracranial pressure, such as in patients with head trauma, seizures, or intracranial disease. The biggest limitation of CVP monitoring is that it measures the pressures on the right side of the heart instead of the left side because it is the left side that supplies the systemic circulation and drains the pulmonary circulation. Pressures in the left side are more accurate in guiding fluid therapy, but their measurement requires use of a pulmonary artery catheter, which is much more expensive, risky, time consuming, and technically challenging. This makes CVP more readily available and acceptable as an alternative to PAP and pulmonary artery occlusion pressure (PAOP) monitoring.

y

B FIGURE 183-2  A, Central venous pressure (CVP) waveform and continuous electrocardiogram. Each phase of the cardiac cycle is reflected in the CVP waveform. B, CVP waveform with waves and depressions labeled. a, a wave, which represents the increase in the CVP caused by right atrial contraction; c, c wave, caused by bulging of the tricuspid valve into the right atrium; v, v wave, caused by increasing pressure from blood flowing into the right atrium before the tricuspid valve opens; xl, xl descent; x2, x2 descent, caused by decreased atrial pressure during ventricular ejection; y, y descent, which represents rapid emptying of the right atrium as the tricuspid valve opens.

PAP monitoring requires that a catheter be placed in the jugular vein, through the right atrium and ventricle, and into the pulmonary artery. A pulmonary artery catheter allows for measurement of the systolic, diastolic, and mean PAP (see Chapter 202). If the catheter is equipped with a balloon, PAOP (also called the pulmonary wedge pressure) can be measured when the balloon at the end of the catheter is inflated in a distal branch of the pulmonary artery. Inflation of the balloon eliminates PAP created by blood flow, and the measured pressure reflects the left atrial filling pressure as it equilibrates across the pulmonary capillary bed. When the mitral valve is open, left atrial pressure equals left ventricular end-diastolic pressure. This pressure provides the best measure of left ventricular preload and is the best predictor of pulmonary edema secondary to fluid overload. Preload is the amount of stretch in the ventricle at the end of diastole and is an important determinant of cardiac output. Like CVP, PAP and PAOP can be used for (and are more accurate at) determining the fluid volume status of a patient. Normal PAOP in dogs is 5 to 12 mm Hg.23 Low PAOP usually signals volume

CHAPTER 183  •  Hemodynamic Monitoring

depletion and the need for fluid administration, whereas increased PAOP is indicative of volume overload or cardiac dysfunction so that additional fluid is contraindicated. Additional parameters that can be monitored with a Swan-Ganz type of catheter are right atrial pressures (used in place of CVP), which are measured via the proximal port of the catheter, and cardiac output, which is determined using the thermodilution technique (thermodilution cardiac output). A known quantity of solution (either saline or 5% dextrose) at a known temperature is injected rapidly into the proximal port of the catheter. The cooler solution mixes and cools the surrounding blood, and the temperature difference is sensed by a thermistor at the distal tip of the catheter. The change in temperature is plotted on a time-temperature curve. The area under the curve is inversely proportional to the cardiac output, which is calculated by a cardiac output monitor. Normal values for cardiac output are 125 to 200 ml/kg/min for dogs and 120 ml/kg/min for cats.27,28 Other values that can be calculated include cardiac index (cardiac output ÷ body surface area in square meters), stroke volume (cardiac output ÷ heart rate), stroke volume index (stroke volume ÷ body surface area), systemic vascular resistance ([mean arterial pressure − right atrial pressure] ÷ cardiac index), and pulmonary vascular resistance ([mean PAP − PAOP] ÷ cardiac index).28 Some catheters are also equipped with an oximeter that will measure central venous hemoglobin saturation (SvO2). This information, combined with the arterial oxygen saturation (SaO2), allows for determination of the oxygen content of both arterial and mixed venous blood, oxygen delivery, oxygen consumption, and oxygen extraction (see Chapters 184, 186, and 202). Placement of these catheters is not without risk because arrhythmias, damage to the tricuspid and pulmonic valves, rupture of a pulmonary artery, and pulmonary thromboembolism have all been reported in humans undergoing the procedure.29

MIXED VENOUS AND CENTRAL VENOUS OXYGEN SATURATION Measurement of SvO2 (mixed venous oxygen saturation) and ScvO2 (central venous oxygen saturation) is also useful for cardiovascular monitoring. SvO2 is measured from the pulmonary artery, as mentioned earlier in the section on PAP monitoring, and therefore requires the placement of a catheter in the pulmonary artery. ScvO2, which can be measured from a catheter in the vena cava or the right atrium, is much more accessible. Samples of blood can be removed via these catheters and analyzed with a co-oximeter or a fiberoptic fiber can be embedded in a centrally placed catheter and attached to a monitor for real-time measurements. The normal SvO2 is greater than 75% and ScvO2 is normally greater than 65%. Typically there is a very strong correlation between the two values, although they can differ by up to 18% in severe shock states.30,31 Tissue hypoxia causes increased extraction of oxygen from venous blood, which results in a decrease in both SvO2 and ScvO2. Increased venous oxygen extraction and resulting venous desaturation is one of the major compensatory responses to help maintain delivery of oxygen to the peripheral tissues in low flow states. Measurements of SvO2 and ScvO2 reflect systemic oxygen balance and cumulative oxygen debt. The importance of measurement and optimization of ScvO2 was highlighted in the Rivers et al study in 2001.32 In this study, patients with severe sepsis or septic shock were treated according to an early goal-directed therapy (EGDT) protocol. One of the endpoints of resuscitation was a ScvO2 of greater than 70%. The goals were to be met within the first 6 hours of therapy. The ScvO2 was increased through the use of vasoactive agents, red blood cell transfusions, and

inotropes, in addition to standard therapy. The EGDT group had a significantly lower mortality rate than the conventionally treated group.32 The EGDT group also had reduced organ dysfunction and injury severity scores, as well as lower lactate concentrations and base deficits, additional values that can be useful in monitoring the cardiovascular status of critically ill patients (see later in chapter for details). A recent veterinary study evaluated the use of tissue perfusion parameters as predictors of outcome in dogs with severe sepsis or septic shock. ScvO2 and base deficit (see next section) were found to be the best discriminators between survivors and nonsurvivors.33 There are some limitations to the measurement of SvO2 and ScvO2. Both hemoglobin concentration and SaO2 influence these variables. ScvO2 is much easier to measure, but there can be a loss of correlation between ScvO2 and SvO2 in very-low-flow states. And finally, if there is an underlying defect in oxygen extraction, as often occurs in patients with severe sepsis, the SvO2 and ScvO2 values can be normal or even high despite significant oxygen debt.30

LACTATE AND BASE DEFICIT Lactate is produced primarily in periods of insufficient oxygen delivery to the tissues, during anaerobic glycolysis. It is produced from pyruvate by lactate dehydrogenase in the cytosol of cells. When oxygen balance at the cellular level is restored, the process is reversed; and the lactate is used for regeneration of pyruvate, and aerobic metabolism within the mitochondria is resumed. Normally, the liver (and to lesser degree, the kidneys) clears any lactate that is produced, but blood levels increase when production exceeds clearance (see Chapter 56). Lactate levels at presentation as well as lactate clearance after treatment have been evaluated for prognostic value extensively in humans and to a lesser degree in veterinary patients.30 Response to therapy, particularly fluid resuscitation, has been shown to have predictive value in humans with trauma and severe sepsis or septic shock. The base deficit has also been evaluated as a marker of anaerobic metabolism. In human studies, patients with persistently high base deficit have higher rates of multiple organ failure and death compared with patients whose base deficit normalizes. The use of lactate and base deficit together may be most helpful in assessing a patient’s need for fluid resuscitation and response to fluid therapy. A recent study found that a lower base deficit at presentation was associated with greater survival in dogs with sepsis or septic shock secondary to pyometra.33 As noted earlier, ScvO2 and base deficit were found to be the best discriminators between survivors and nonsurvivors; lactate level was measured but did not prove useful in this study.33 Additional studies are needed to prospectively evaluate the outcome prediction utility of lactate and base deficit response to volume resuscitation in dogs and cats.

REFERENCES 1. Brown S, Atkins C, Bagley R, et al: Guidelines for the identification, evaluation, and management of systemic hypertension in dogs and cats, J Vet Intern Med 21:542, 2007. 2. Valtonen MH, Eriksson LM: The effect of cuff width on accuracy of indirect measurement of blood pressure in dogs, Res Vet Sci 11:358, 1970. 3. Caulkett NA, Cantwell SL, Houston DM: A comparison of indirect blood pressure monitoring techniques in the anesthetized cat, Vet Surg 27:370, 1998. 4. Bodey AR, Young LE, Diamond MJ, et al: A comparison of direct and indirect (oscillometric) measurements of arterial blood pressure in anaesthetized dogs, using tail and limb cuffs, Res Vet Sci 57:265, 1994. 5. Bodey AR, Michell AR, Bovee KC, et al: Comparison of direct and indirect (oscillometric) measurements of arterial blood pressure in conscious dogs, Res Vet Sci 61:17, 1996.

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6. Stepien RL, Rapoport GS: Clinical comparison of three methods to measure clinical blood pressure in nonsedated dogs, J Am Vet Med Assoc 215:1623, 1999. 7. Meurs KM, Miller MW, Slater MR: Comparison of the indirect oscillometric and direct arterial methods for blood pressure measurements in anesthetized dogs, J Am Anim Hosp Assoc 32:471, 1996. 8. Binns SH, Sisson DD, Buoscio DA, et al: Doppler ultrasonographic, oscillometric sphygmomanometric, and photoplethysmographic techniques for noninvasive blood pressure measurement in anesthetized cats, J Vet Intern Med 9:405, 1995. 9. Pedersen KM, Butler MA, Ersboll AK, et al: Evaluation of an oscillometric blood pressure monitor for use in anesthetized cats, J Am Vet Med Assoc 221:646, 2002. 10. Acierno MJ, Fauth E, Mitchell MA, et al: Measuring the level of agreement between directly measured blood pressure and pressure readings obtained with a veterinary-specific oscillometric unit in anesthetized dogs, J Vet Emerg Crit Care 23:37, 2013. 11. Acierno MJ, Seaton D, Mitchell MA, et al: Agreement between directly measured blood pressure and pressures obtained with three veterinaryspecific oscillometric units in cats, J Am Vet Med Assoc 237:402, 2010. 12. Bosiack AP, Mann FA, Dodson JE, et al: Comparison of ultrasonic Doppler flow monitor, oscillometric and direct arterial blood pressure measurements in ill dogs, J Vet Emerg Crit Care 20:207, 2010. 13. Petric AD, Petra Z, Jerneja S, et al: Comparison of high definition oscillometric and Doppler ultrasonic devices for measuring blood pressure in anaesthetised cats, J Feline Med Surg 12:731, 2010. 14. Chetboul V, Tissier R, Gouni V, et al: Comparison of Doppler ultrasonography and high-definition oscillometry for blood pressure measurements in healthy awake dogs, Am J Vet Res 71:766, 2010. 15. Farquhar IK: Continuous direct and indirect blood pressure measurement (Finapres) in the critically ill, Anaesthesia 46:1050, 1991. 16. Burkitt Greedon JM, Raffe MR: Fluid-filled hemodynamic monitoring systems. In Burkitt Creedon JM, Davis H, editors: Advanced monitoring and procedures for small animal emergency and critical care, Ames, Ia, 2012, Wiley-Blackwell. 17. Machon RG, Raffe MR, Robinson EP: Central venous pressure measurements in the caudal vena cava of sedated cats, J Vet Emerg Crit Care 5:121, 1995. 18. Berg RA, Lloyd TR, Donnerstein RL: Accuracy of central venous pressure monitoring in the intraabdominal inferior vena cava: a canine study, J Pediatr 120:67, 1992.

19. Oakley RE, Olivier B, Eyster GE, et al: Experimental evaluation of central venous pressure monitoring in the dog, J Am Anim Hosp Assoc 33:77, 1997. 20. Chow RS, Kass PH, Haskins SC: Evaluation of peripheral and central venous pressure in awake dogs and cats, Am J Vet Res 67:1987, 2006. 21. Jennings PB, Anderson RW, Martin AM: Central venous pressure monitoring: a guide to blood volume replacement in the dog, J Am Vet Med Assoc 151:1283, 1967. 22. Nelson NC, Drost WT, Lerche P, et al: Noninvasive estimation of central venous pressure in anesthetized dogs by measurement of hepatic venous blood flow velocity and abdominal venous diameter, Vet Radiol Ultrasound 51:313, 2010. 23. De Laforcade AM, Rozanski EA: Central venous pressure and arterial blood pressure measurements, Vet Clin North Am Small Anim Pract 31:1163, 2001. 24. Ahrens TS, Taylor LA: Hemodynamic waveform analysis, Philadelphia, 1992, Saunders. 25. Gookin JL, Atkins CE: Evaluation of the effect of pleural effusion on central venous pressure in cats, J Vet Intern Med 13:561, 1999. 26. Hansen B: Technical aspects of fluid therapy. In DiBartola SP, editor: Fluid, electrolyte, and acid-base disorders in small animal practice, ed 4, St Louis, 2012, Saunders. 27. Haskins S, Pascoe PJ, Ilkiw JE, et al: Reference cardiopulmonary values in normal dogs, Comp Med 55:156, 2005. 28. Mellema M: Cardiac output, wedge pressure, and oxygen delivery, Vet Clin North Am Small Anim Pract 31:1175, 2001. 29. Headley JM: Invasive hemodynamic monitoring: physiological principles and clinical applications, Irvine, Calif, 2002, Edwards Scientific. 30. Prittie J: Optimal endpoints of resuscitation and early goal-directed therapy, J Vet Emerg Crit Care 16:329, 2006. 31. Reinhart K, Kuhn HJ, Hartog C, et al: Continuous central venous and pulmonary artery oxygen saturation monitoring in the critically ill, Intensive Care Med 30:1572, 2004. 32. Rivers E, Nguyen B, Havstad S, et al: Early goal-directed therapy in the treatment of severe sepsis and septic shock, N Engl J Med 19:1368, 2001. 33. Conti-Patara A, de Araújo Caldeira J, de Mattos-Junior E, et al: Changes in tissue perfusion parameters in dogs with severe sepsis/septic shock in response to goal-directed hemodynamic optimization at admission to ICU and the relation to outcome, J Vet Emerg Crit Care 22:409, 2012.

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CHAPTER 184  CARDIAC OUTPUT MONITORING Matthew S. Mellema,

DVM, PhD, DACVECC  •  Robin

KEY POINTS • Cardiac output is the volume of blood transferred by the heart to the systemic circulation over time. • It is a key determinant of oxygen delivery and an early indicator of hemodynamic instability. • Cardiac output should be measured in any patient for which appropriate clinical decisions cannot be made without this information.

L. McIntyre,

DVM

• Both invasive and minimally invasive methods of cardiac output measurement are available for clinical use in dogs and cats. • Disease states can have a profound and complex impact on cardiac output. • Complications of pulmonary artery catheters are rare, but placement should be done either by, or under the supervision of, experienced personnel.

CHAPTER 184  •  Cardiac Output Monitoring

Delivery of oxygen to the body and the removal of cellular metabolic waste are the fundamental roles of the cardiovascular and pulmonary systems. To accomplish these vital functions the pulmonary and cardiovascular systems must work in concert in a complex yet deeply integrated fashion. Each system relies on a pumping mechanism to accomplish the transport of blood or respiratory gases to the sites where the exchange of substrates and waste occurs. In the case of the cardiovascular system, the heart provides the pumping force and the blood vessels serve to conduct and distribute the pumped blood to the tissues. The elastic properties of the vascular tree allow the force generated by the heart to be stored and applied to the column of flowing blood throughout the cardiac cycle. The volume of blood transferred to the systemic circulation over time is termed cardiac output. Cardiac output in humans is typically measured in liters per minute (L/min). Veterinary patients come in a broad range of shapes and sizes, and for this reason, cardiac output is often referenced in terms of milliliters of blood per kilogram of body weight per minute (ml/kg/min). Technically, this is a form of cardiac index because the values are being normalized (or indexed) to body mass; however, the term cardiac output is more generally applied to this parameter. Normal values for dogs and cats typically range from 120 to 200 ml/kg/min.1,2 A related measure is formally called cardiac index and relates the volume of blood pumped over time to the animal’s body surface area rather than body mass because the former is thought to correlate with metabolic rate (a principal determinant of cardiac output). The cardiac index is expressed in liters per minute per square meters (L/min/m2).2 The term combined cardiac output is used to describe the total volume of blood ejected into the systemic circulation over time when both the right and left ventricles can directly transfer blood to the arterial tree (e.g., fetal circulation, right-to-left patent ductus arteriosus). Cardiac output is an important measure of cardiovascular function. It provides insights into bulk blood delivery to the body as a whole. When taken together with measurements of the oxygen content of blood, it allows for the determination of whole body oxygen delivery.1,2 If one knows the patient’s heart rate, then knowledge of cardiac output allows the clinician to determine stroke volume. Cardiac output measurements also make it possible for the caregiver to determine important physiologic indicators such as intrapulmonary shunt, systemic and pulmonary vascular resistance, and oxygen consumption. This large array of additional parameters that can be derived once cardiac output is known allow the clinician to potentially make better informed decisions about the need for, or adequacy of, therapeutic interventions and provides a more detailed picture of the patient’s cardiovascular status.

INDICATIONS FOR CARDIAC OUTPUT MEASUREMENT When performed by an experienced and attentive clinician, physical examination of the patient can reveal a great deal about the adequacy of oxygen delivery and cardiac output. Many of the findings of the physical examination relate directly to regional or organ-specific blood flow (e.g., capillary refill time, pulse pressure, mentation). Although these physical examination parameters are invaluable in the repeated assessment of patients and require little more equipment than a wristwatch, some are subjective measures and correlate poorly with an individual patient’s actual cardiovascular status.3 However, it must be noted that although an individual value for capillary refill time, for example, may correlate poorly with more direct measures of cardiac output, the trends in serial physical examination findings in an individual patient typically provide the best and most reliable measure of alterations in that patient’s cardiovascular status. Unfortunately, the converse is not true: a patient whose

physical examination findings are not changing may be experiencing a decline in cardiac performance that will not be detectable until compensatory mechanisms are exhausted or overcome. The findings of a thorough physical examination, particularly when complemented with hemodynamic monitoring (see Chapter 183), are sufficient to guide the clinician in directing the care of most patients. However, there exists a subset of critically ill veterinary patients in which more direct assessment of cardiac output (and its derived parameters) is essential for proper case management. Patients with sepsis, septic shock, systemic inflammatory response syndrome, and multiple organ dysfunction syndrome make up the bulk of veterinary patients for which more invasive measures of cardiac output are likely to be required. In patients with severe compromise of the pulmonary or cardiovascular system cardiac output monitoring may also be required to optimize their care. It is in the care of these patients that clinicians may find themselves unable to make appropriate decisions regarding management without the additional information provided via cardiac output monitoring. In patients with complex disease states such as those mentioned earlier, the individual’s cardiovascular and pulmonary systems may be compromised to such an extent that the typical measures of cardiovascular status and performance give contradictory information and suggest therapies that have opposing mechanisms of action (e.g., expanding or depleting extracellular fluid volume). An all-too-common example is a septic patient that has developed capillary leak syndrome (enhanced permeability of systemic capillaries and venules, promoting tissue edema). This patient typically has a low central venous or mean arterial pressure, or both (which suggests that additional intravenous fluid therapy might be of benefit), while at the same time exhibiting marked peripheral edema (which might lead the clinician to want to be less aggressive with fluid administration). The treatment of such a patient would be enhanced by knowledge of cardiac output and oxygen delivery, which are always of primary importance and can mandate a course of action in the face of conflicting findings. Cardiac output can also be a much earlier indicator of deteriorating cardiovascular status because compensatory mechanisms such as reflex vasoconstriction can maintain other indicators like mean arterial pressure near normal levels in the face of worsening cardiac performance.

MEASUREMENT OF CARDIAC OUTPUT Invasive Methods of Determining Cardiac Output Nearly all invasive techniques for measuring cardiac output rely on one of two methods: the Fick oxygen consumption method or the indicator dilution method. The commonly used thermodilution method is, in principle, a modification of the indicator dilution method using thermal energy as the indicator. Both methods are discussed here.4

Fick oxygen consumption method The Fick oxygen consumption method is considered the gold standard and is the oldest method of measuring cardiac output. This technique relies on the Fick principle, which states that the total uptake (or release) of a substance by the peripheral tissues is equal to the product of the blood flow to the peripheral tissues and the arteriovenous concentration difference (gradient) of the substance. For a substance that is taken up by the tissues (such as oxygen), the Fick principle says in effect that “what went in minus what came out must equal what was left behind.” The Fick principle when applied to cardiac output and oxygen uptake can be expressed as follows:

Cardiac output =

Oxygen consumption Arteriovenous oxygen content difference

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When one uses the original Fick method to determine cardiac output, oxygen consumption is determined by measuring the oxygen concentration difference in the inhaled air and the exhaled air collected from the patient over time (typically 3 minutes). Alternatively, the arteriovenous oxygen content difference can be determined by measuring the oxygen content of both an arterial and a mixed venous blood sample. Although oxygen content analyzers are available, it is more typical for the clinician to measure the oxygen partial pressure (PO2), hemoglobin saturation (SO2), and hemoglobin concentration ([Hb]) with a blood gas analyzer and manually calculate oxygen content using the following formula:

Oxygen content = ([Hb] × 1.36 × SO2 ) + (0.003 × PO2 ) The principal drawbacks to this approach in veterinary medicine are that it is not a continuous real-time measure of cardiac output and that reliable collection of respiratory gases requires that the patient be intubated. In addition, use of the Fick method relies on the patient’s remaining in a stable hemodynamic and metabolic state throughout the period of gas or blood collection; thus the less stable the patient’s condition, the less reliable this method becomes. Lastly, results obtained by the Fick method are largely invalid in the presence of significant intracardiac or intrapulmonary shunting of blood.

Carbon dioxide rebreathing methods The Fick equation can be used to determine cardiac output using carbon dioxide production rather than oxygen uptake. There are two methods, the complete rebreathing technique and the partial rebreathing technique. The following equation is used to calculate cardiac output using the complete rebreathing technique:

Cardiac output =

CO2 elimination by the lungs Arteriovenous CO2 difference

This technique requires breathholding and does not provide continuous measurements. A monitor has been developed for the partial rebreathing technique (NICO). The partial rebreathing technique combines measurements obtained during a nonrebreathing period with values obtained during a rebreathing period. The following equation is used:

Difference in CO2 elimination and end-tidal CO2 Cardiac output = Difference in arterial CO2 between baseline and rebreathing phase The monitor is connected to a flow and carbon dioxide sensor and an adjustable dead-space breathing loop in the circuit between the patient and the Y piece. The monitor controls a valve that diverts gas flow through the breathing loop during the rebreathing phase. Values for cardiac output are determined every 3 minutes. This method measures only the pulmonary capillary blood flow that participates in gas exchange and calculates the shunt fraction. Values obtained using the NICO monitor have been shown to compare well with those obtained using the lithium dilution method in dogs; however, lower tidal volumes such as those used in lung-protective ventilation strategies have been shown to promote underestimation of cardiac output by partial rebreathing methods compared with the thermodilution technique.1 The NICO monitor may not provide an accurate determination of cardiac output in smaller dogs.2 The size of the rebreathing circuit also limits the use of the device in dogs and cats.

Indicator dilution method (including thermodilution) In actuality, the indicator dilution method is simply an adaptation of the Fick method using indicators that are more easily collected and

measured than elemental oxygen. The basis still lies in the Fick principle and conservation of matter (or thermal energy). In this method an exogenous indicator is injected into the patient’s mixed venous blood via a pulmonary artery catheter5 (see Chapter 202), and the dilution of the indicator is followed continuously until both the original concentration peak associated with injection and a secondary peak due to recirculation are observed. By plotting the concentration of the indicator against time, one can obtain the area under the curve of the concentration versus time plot. Cardiac output is determined by taking the known amount of indicator and dividing it by the area under the curve. Typically this process is an integrated function of the software packages included with modern cardiac monitoring equipment. In the laboratory setting the indicator maybe a dye such as indocyanine green; however, this method is seldom used in clinical patients. The indicator of choice is often thermal energy. Modern pulmonary artery catheters can be equipped with a sensitive thermocouple that can give highly accurate continuous measurements of blood temperature. This type of pulmonary artery catheter has been termed a Swan-Ganz catheter after the physicians who developed it and introduced it into clinical practice in human medicine. Although the technology has advanced, the technique still relies on the Fick principle. By injecting a known volume of saline at a known temperature (typically room temperature; chilling is no longer needed with modern catheters) into the right-sided circulation, one can use the thermocouple to follow the dilution of this cool sample in the larger, warmer blood volume of the patient. Integration of this temperature signal can provide the clinician with a reliable measure of cardiac output. Recorded values are usually the average of three measurements taken in a short time, one after another. Good agreement is considered to be values that do not vary by more than 10%. In thermodilution, the indicator is injected into the right atrium and dilution is measured in the pulmonary artery. Dye dilution is performed by injecting dye into the pulmonary artery and measuring the dilution at an arterial site. Transpulmonary thermodilution uses a central venous catheter and a thermistor that is inserted into the femoral artery. This method is potentially as accurate as using a pulmonary artery catheter, and studies in human patients have shown good agreement between the two in the values obtained.3 Advances in ion-specific electrode technology have led to novel means of applying indicator dilution principles to determine cardiac output in humans and animals. One such advance is the development of an electrode for lithium ions that can be placed in communication with the patient’s arterial bloodstream via an indwelling arterial catheter. Such an electrode can be used to record the dilution of small doses of lithium chloride injected into the venous circulation at either a peripheral or central site. Cardiac output determination by this method has been studied in both dogs and cats, and agreement with cardiac output values obtained via thermodilution methods has generally been good.6,7 Although the lithium dilution method for determining cardiac output can be termed minimally invasive, it is not truly noninvasive because it requires placement of both venous and arterial catheters. Placement of pulmonary arterial catheters is not a benign procedure, and indications for pulmonary artery catheterization in human patients are controversial. In a large population of critically ill patients, pulmonary artery catheterization was associated with increased 30-day mortality, increased cost of health care, and a longer hospital stay.4 Another large study found no benefit to therapy directed by pulmonary artery catheter data over standard care.5 A Cochrane Database systematic review of pulmonary artery catheterization found no difference in mortality or length of stay in critically

CHAPTER 184  •  Cardiac Output Monitoring

ill or surgical patients, but it did find increased health care costs associated with pulmonary artery catheterization.6

Noninvasive or Minimally Invasive Methods of Determining Cardiac Output No consensus for pulmonary artery catheter use exists in veterinary medicine. Noninvasive or minimally invasive methods of measuring cardiac output have been developed due to concerns about complications and reliability of pulmonary artery catheterization. Techniques include transesophageal echocardiography, pulse contour analysis, and thoracic bioimpedance. Transesophageal echocardiography has been used in humans and a number of animal species as a minimally invasive means of tracking changes in cardiac output and performance. Measurement of blood velocity (using Doppler frequency shifts) and aortic diameter (using echocardiography) allow estimates of stroke volume to be made. To obtain truly reliable and quantifiable measurements of cardiac output, one should initially (and periodically) calibrate transesophageal echocardiography measurements against measurements obtained by one of the more invasive methods discussed earlier. In studies involving anesthetized dogs, results using this method are mixed compared with results using thermodilution.2,7 The utility of this method is also somewhat limited in small animal practice because of equipment limitations, the time required to obtain acceptable studies, patient tolerance of the probe, and the need for highly trained personnel to be on hand to make the measurements. However, it does hold promise in limited applications (e.g., evaluation and monitoring of anesthetized patients). Measurement of thoracic electrical bioimpedance is a noninvasive method of evaluating changes in the conductivity of the thorax resulting from the pulsatile flow of blood within the thoracic cavity. Sets of electrodes similar to electrocardiograph electrodes are located superficially on the thorax. Although electrocardiograph electrodes simply measure voltage changes resulting from the intrinsic electrical activity of the heart, the electrodes used in the thoracic electrical bioimpedance method both measure and apply voltage. The principle behind the method is Ohm’s law, according to which the conductivity (and impedance) of the thorax to the flow of current can be determined by applying a small known voltage to the patient’s thorax and then measuring what portion of that initial voltage reaches a distant sensing electrode. Changes in thoracic blood volume (blood and tissue are good conductors, air-filled lungs are not) can be detected, and estimates of stroke volume and cardiac output can be made using computer algorithms. Although this method holds promise in humans, in whom the size and shape of the thorax are somewhat uniform, the variety of species and breeds seen by the small animal clinician may make any single algorithm of limited utility, and estimates may need to be compared with some frequency with results obtained using invasive methods. Analysis of the arterial pressure waveform, or pulse contour analysis, is an additional form of algorithm-dependent monitoring and can allow real-time determination of cardiac output. Some computers using this technology require calibration before use (PiCCO and PiCCO plus) and some do not (FloTrac). Transpulmonary thermodilution (PiCCO, PiCCO plus) or lithium dilution (PulsCO/LidCO) is used for the initial calibration, and the PulsCO/LidCO system requires calibration every 8 hours. Determination of cardiac output by transpulmonary thermodilution requires a central venous catheter in addition to an arterial catheter. Once the system has been calibrated, heart rate, area under the curve, aortic compliance, and shape of the pressure curve are used to calculate cardiac output for each pulse waveform. There was good correlation between PiCCO plus determinations and cardiac output as assessed by an aortic flow probe in a canine model of hemorrhagic shock.1 In dogs that have

anesthesia-induced hypotension or have rapid changes in cardiac output, the PulsCO system does not accurately predict cardiac output compared with the lithium dilution method.8,9 A potential disadvantage of the pulse contour analysis approach is that the manufacturers of these monitoring devices often advise that central arterial (aortic) waveforms be monitored rather than peripheral arterial waveforms. In a small animal patient this would generally be achieved by advancing a long catheter into the aorta from a femoral artery insertion site. Any device that requires this more labor-intensive form of achieving arterial access is likely to be used less frequently than those for which peripheral arterial access is known to be sufficient for accurate readings.

NORMAL VALUES The normal values for cardiac output (and related and derived indexes) for dogs and cats are presented in Table 184-1. Values other than cardiac output and cardiac index are given for the reader’s consideration but are discussed in greater detail elsewhere (see Chapters 183 and and 202). The normal values listed in Table 184-1 represent composite values obtained from the literature and measurements made on clinical patients and research animals at the School of Veterinary Medicine at the University of California, Davis.2 These composites include values from animals that were sedated as well as lightly anesthetized animals. Values for fully awake animals might be considered true “normal” values but would not represent normal values for the setting in which clinical measurements are generally obtained.

POTENTIAL CAUSES OF ERROR Any form of measurement of any parameter carries an intrinsic degree of error. It is the responsibility of the clinician and the nursing staff to avoid compounding this form of uncertainty by introducing additional sources of error (Table 184-2). To this end, clinicians seeking to measure cardiac output using any of the techniques discussed earlier should ensure that they have been trained by

Table 184-1  Normal Cardiopulmonary Values for Dogs and Cats Parameter (Unit) Heart rate (beats/min) Mean arterial pressure (mm Hg) Cardiac output (ml/kg/min) Cardiac index (L/min/m2) Stroke volume (ml/beat/kg)

Dog

Cat

100-140

110-140

80-120

100-150

125-200

120

3.5-5.5

—

40-60

—

0.5-0.8

—

10-20

—

0.04-0.06

—

Central venous pressure (cm H2O)

0-10

—

Pulmonary artery wedge pressure (mm Hg)

5-12

—

20-35

—

4-11

3-8

20-30

—

Systemic vascular resistance (mm Hg/ml/kg/min) Mean pulmonary artery pressure (mm Hg) Pulmonary vascular resistance (mm Hg/ml/kg/min)

Oxygen delivery (ml/kg/min) Oxygen consumption (ml/kg/min) Oxygen extraction (%)

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Table 184-2  Sources of Error in Cardiac Output Measurement (Thermodilution Method) Error Source

Brief Description

Adjustments

Respiratory cycle

Pulmonary artery blood cools during inspiration. Venous return varies with intrathoracic pressure.

Make measurements at end expiration.

Arrhythmias

Arrhythmias cause rapid and marked variations in stroke volume.

Treat arrhythmias as indicated.

Altered intracardiac flow

Shunting and regurgitation can cause some of the injectate to bypass the thermistor or delay arrival of some of the bolus volume.

Thermodilution technique may be invalid in patients with significant flow abnormalities.

Low cardiac output

Slow ejection causes warming of the injectate before it reaches the thermistor.

Further therapeutic interventions will be required to increase cardiac output before values will be valid or repeatable.

Injectate factors

Injectate may be the wrong solution, wrong volume, wrong temperature.

Triple-check all aspects of the bolus before injecting.

Thermistor factors

Thrombus may form on the catheter tip. Catheter may migrate. Catheter may be defective.

Check position and reposition or replace catheter as needed.

Additional infusions

Simultaneous infusion of large volumes of crystalloid or colloid solutions can interfere with thermistor detection of the bolus.

Either interrupt the fluid bolus or postpone cardiac output measurements as dictated by patient’s needs.

experienced personnel and have suitable hands-on experience with the method before using it in clinical decision making. Misuse of data from Swan-Ganz catheters by insufficiently trained personnel has on occasion led to iatrogenic injury and poor outcomes, and subsequently the devices have fallen out of favor in some segments of human medicine. All of the methods for measuring cardiac output that have been discussed rely on the patient’s having stable hemodynamics throughout the study period (typically several minutes). In the case of the Fick method, reliable measurements also require that the patient have only small fluctuations in metabolic rate during the study period. With each of the methods discussed, the serial evaluation of measurements is of greater use than any single determination.

DISEASE STATES AND CARDIAC OUTPUT MEASUREMENT Cardiac output is the product of stroke volume and heart rate. Disease processes that alter either of these factors may alter cardiac output (unless the disease affects both in opposite directions and to equal degrees). Decreasing heart rates may either improve or worsen cardiac output depending on the individual patient. Patients with stiff, noncompliant ventricles or tachyarrhythmias, for example, may benefit from a reduction in heart rate because of greater filling during diastole. Alternatively, a patient with advanced atrioventricular node disease may have reduced cardiac output due to low (ventricular) heart rate. The relationship between heart rate and stroke volume is complex. Moderate increases in heart rate can increase stroke volume via the “staircase effect,” whereas greater increases in heart rate may instead reduce stroke volume via impairment of diastolic filling. Generally, any condition that reduces stroke volume reduces cardiac output if heart rate changes are minimal. Stroke volume is determined by preload, afterload, and contractility. Preload is determined largely by cardiac compliance and filling pressures. Any disease state that reduces filling pressures (e.g., hemorrhage, dehydration) or ventricular compliance (e.g., pericardial tamponade) can reduce preload and cardiac output. Afterload is a complex determinant of stroke volume and is largely dependent on the tone of the vasculature (particularly arterioles) and compliance of the aorta, but in some patients it is influenced by physical abnormalities in the

cardiovascular system (e.g., aortic stenosis, arteriovenous fistulas) or the rheology of the blood itself (e.g., hyperviscosity syndromes). Any process that increases afterload may reduce cardiac output (e.g., α-adrenergic stimulation), and processes that reduce afterload (e.g., reduced blood viscosity, arteriolar dilation) may increase cardiac output. Contractility is a measure of the myocardium’s intrinsic ability to generate force and eject blood independent of loading conditions. Contractility may, for example, be depressed by circulating mediators (e.g., sepsis, pancreatitis) or enhanced by β-adrenergic stimulation. Any alteration in a patient’s cardiac output should prompt a careful consideration of how disease states may be altering heart rate, preload, afterload, and contractility. Factors known to adversely affect these determinants of cardiac output should be addressed whenever possible.

POTENTIAL COMPLICATIONS The vast majority of patients in which cardiac output measurements are made experience no direct complications due to the instrumentation or procedures required. However, many complications can occur when hemodynamic data are misinterpreted, and this issue has been discussed earlier in the chapter. A small subset of patients in which Swan-Ganz or other pulmonary artery catheters are placed will experience complications related to the placement, presence, or maintenance of the catheter.8 These complications include, but are not limited to, the following: catheter-related sepsis, pulmonary artery rupture, damage to cardiac structures, catheter knotting (possibly requiring thoracotomy), hemorrhage, and embolization. For these reasons and others, it is stressed that pulmonary artery catheter placement is not a technique to be learned without the guidance of experienced personnel. Complications from lithium chloride injection have not been reported in dogs or cats. The other methods of cardiac output determination discussed earlier also are considered to have a very large margin of safety.

REFERENCES 1. Brown AJ: Cardiac output monitoring, MDR notes. Proceedings of the International Veterinary Emergency and Critical Care Symposium, 2008, Phoenix, AZ.

2. Yamashita K, Miyoshi K, Igarashi R, et al: Minimally invasive determination of cardiac output by transthoracic bioimpedance, partial carbon dioxide rebreathing, and transesophageal Doppler echocardiography in beagle dogs, J Vet Med Sci 69(1):43-47, 2007. 3. Busse L, Davison DL, Junker C, et al: Hemodynamic monitoring in the critical care environment, Adv Chronic Kidney Dis 20(1):21-29, 2013. 4. Connors AF Jr, Speroff T, Dawson NG, et al: The effectiveness of right heart catheterization in the initial care of critically ill patients. SUPPORT investigators, JAMA 276:889-897, 1996. 5. Sandham JD, Hull RD, Brant RF, et al: A randomized, controlled trial of the use of pulmonary-artery catheters in high-risk surgical patients, N Engl J Med 348:5-14, 2003.

6. Harvey S, Young D, Brampton W, et al: Pulmonary artery catheters for adult patients in intensive care, Cochrane Database Syst Rev (3):CD003408, 2006. 7. Scansen BA, Bonagura JD, Schober KE, et al: Evaluation of a commercial ultrasonographic hemodynamic recording system for the measurement of cardiac output in dogs, Am J Vet Res 70(7):862-868, 2009. 8. Cooper ES, Muir WW: Continuous cardiac output monitoring via arterial pressure waveform analysis following severe hemorrhagic shock in dogs, Crit Care Med 35(7):1724-1729, 2007. 9. Cheng HC, Sinclair MD, Dyson DH, et al: Comparison of arterial pressure waveform analysis with the lithium dilution technique to monitor cardiac output in anesthetized dogs, Am J Vet Res 66:1430-1436, 2005.

CHAPTER 185  •  Electrocardiogram Evaluation

CHAPTER 185  ELECTROCARDIOGRAM EVALUATION Matthew S. Mellema,

DVM, PhD, DACVECC

KEY POINTS • The electrocardiogram (ECG) is an extremely useful and cost-effective monitoring tool. • ECG monitoring is indicated for nearly all critically ill patients. • Rather than a limited study of multiple leads, continuous monitoring of a single lead is the basis of most ECG monitoring in the critically ill patient. • Interpretation of the ECG should be systematic and thorough to gain the most benefit from its use. • Trends in ECG alterations may alert the clinician to changes in the patient’s condition even when the absolute values of the parameters still fall within the normal ranges. • Electrolyte abnormalities, hypoxemia, effusions, and pain may cause acute detectable ECG changes without necessarily altering the underlying rhythm.

Disorders of cardiac rhythm and conduction are encountered frequently in critically ill veterinary patients. Arrhythmias may be encountered in patients with primary cardiac disease or may be one manifestation of systemic illness. The severity of rhythm and conduction disturbances can range from inconsequential to acutely life threatening and can progress rapidly from one extreme to the other in some patients. The electrocardiogram (ECG) is the diagnostic and monitoring tool used to confirm, detect, and define cardiac conduction and rhythm disturbances. In addition, the ECG provides the clinician with continuous real-time data regarding the patient’s heart rate and rhythm, which can be informative even in the absence of gross abnormalities. Moreover, the ECG provides clinicians with real-time, continuous information regarding the balance between adrenergic and cholinergic efferent inputs to the heart, and thus insights into the status of the autonomic nervous system can be gained as well. This

chapter focuses on the use of the ECG as a monitoring tool. For details on the recognition and treatment of specific cardiac rhythm disorders the reader is referred to other sections of this book (see Chapters 46 to 48).

INDICATIONS The ECG is an extraordinarily cost effective and useful monitoring tool. In veterinary intensive care the ECG may be second only to serial, well-performed physical examinations in terms of its usefulness in overall patient monitoring. Although a brief multiple-lead evaluation of a patient’s ECG is an important part of any diagnostic workup for suspected intrathoracic disease, in the intensive care setting continuous monitoring of cardiac rate and rhythm (typically one or a few leads at a time) is of greatest utility. Some might argue that all critically ill animals warrant continuous ECG monitoring, and such a statement may be true. However, some patients may have conditions that preclude continuous ECG monitoring and mandate that intermittent evaluations be performed instead. One example of such a patient is a dog with central nervous system disease that is exhibiting circling. In this case, ECG lead wires may present a significant tangling, tripping, or choking hazard to the patient. Also, patients with diffuse dermatologic disease or surface burns may not tolerate typical lead placement. With such exceptions in mind, one can state that most critically ill patients may benefit from continuous ECG monitoring. In particular, any patient with an irregular rhythm, increased heart rate, or decreased heart rate detected on physical examination should undergo ECG monitoring.

ELECTROCARDIOGRAPHIC PRINCIPLES During depolarization and repolarization of the myocardium, the heart generates an electrical field that can be detected at the surface

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of the body by ECG leads. The electrocardiographic system used in clinical practice consists of a series of positive and negative leads that when placed around the heart (roughly in the frontal plane either on the trunk or the limbs) will record complexes associated with the various phases of the cardiac electrical cycle. The ECG records the sum of all the electrical impulses generated by the individual myocytes during each cycle. When a positive deflection is seen on the ECG tracing it signifies that the sum of the heart’s electrical impulses was moving toward the positive electrode of that lead. A negative deflection signifies that the sum of the impulses was moving away from the positive electrode at that time. Impulses traveling perpendicular to an electrode do not cause a deflection in the tracing. When these deflections are plotted over time, a series of waveforms (P, QRS, and T) are revealed.1 The standard leads used in veterinary practice include the three bipolar leads (I, II, and III) and the augmented leads (aVR, aVL, and aVF). Each lead can produce a tracing of the heart’s electrical activity from a different orientation. In combination, the information obtained from multiple leads can aid in the diagnosis of rhythm and conduction disturbances. When measurements are made of the P-QRS-T waveforms, these measurements should be taken using a lead II tracing.

TECHNIQUE Many electrode attachment systems are available. When a system is selected, it is important to bear in mind that high-quality ECG recordings require good contact between the electrodes and the patient’s skin. If commercially available self-adhesive electrode pads are to be used, then it is advised that the hair be clipped and the skin cleaned and dried before application. Generally, two electrode pads placed over the lateral thorax on each side and a third pad placed in the left inguinal region are sufficient to obtain good-quality tracings. Use of alligator clips is not advised for continuous monitoring because their prolonged use can damage the patient’s skin and cause discomfort. Once the electrode pads are placed and clips or wires attached, it is often helpful to place a mesh stockinette shirt around the patient’s trunk so that all wires can be collected into a single “stalk” exiting the mesh shirt dorsally. This can enhance patient comfort, prevent lead detachment, and reduce obstacles to patient repositioning. Leads are created by comparing the voltage signals from one or more electrodes with a reference (e.g., ground or another electrode). When selecting a lead to display during continuous ECG monitoring one should choose the lead that the caregiver believes provides the most easily recognizable waveforms. Lead II is used for rhythm evaluation in cardiac examinations because in most patients this lead lies well within the mean electrical axis of the heart and produces easily recognizable waveforms. However, in the critically ill patient the caregiver may need to evaluate several leads to find the one that gives the most robust signal. If one is relying on the monitor to calculate heart rates automatically, one will often get more accurate readings if a lead is picked in which the QRS amplitude is markedly different from that of the P and T waves (otherwise, double or triple counting may occur, giving erroneously high heart rate readings). It should always be noted in the patient’s record which lead is being monitored. It is essential that the clinician and nursing staff bear in mind that the reference values for canine and feline ECGs are obtained from still animals in right lateral recumbency. During continuous monitoring patients are seldom, if ever, in the ideal position, and changes in waveform amplitude are to be expected relative to normal values. The utility of the continuous ECG is predominantly in monitoring heart rate and rhythm; however, it can also indicate to the clinician whether a

QRS complex R

ST segment P

T

Q PR interval

S QT interval

FIGURE 185-1  Component waveforms, segments, and intervals of the normal electrocardiogram.

standardized recording of all six leads and a rhythm strip should be obtained.

ELECTROCARDIOGRAM WAVEFORMS Figure 185-1 shows a normal canine lead II P-QRS-T complex with the waveforms, intervals, and ST segment identified. The P wave is a reflection of the depolarization of the atria. Its duration and amplitude should be noted. The PR interval is measured from the beginning of the P wave to the start of the QRS complex and is a measure of the time it took for the electrical impulse to travel from the sinoatrial node to the ventricular myocardium (including the normal delay that occurs as the impulse travels through the atrioventricular node). The QRS complex is a reflection of ventricular depolarization. As with the P wave, the duration and amplitude of the QRS complex should be evaluated. The ST segment is measured from the end of the QRS complex to the beginning of the T wave. Disease states can cause the ST segment to be shifted upward or downward from the baseline, and any such shifts should be noted. The T wave is the result of ventricular repolarization. Although the shape and amplitude of the T wave can be extremely variable in normal dogs, progressive or acute changes in the conformation of the T wave in an individual patient can be a marker of important disease states such as hypoxemia. The QT interval is an indicator of the time required for both ventricular depolarization and repolarization to occur. This interval is measured from the start of the QRS complex to the end of the T wave. The duration of the QT interval can be an important indicator of electrolyte abnormalities but also is strongly dependent on heart rate and must be interpreted in light of this parameter.1-3

ELECTROCARDIOGRAM INTERPRETATION The most important principle in ECG interpretation is that each ECG should be evaluated in the same systematic way. Any thorough evaluation should include the following1,2: 1. Calculation of heart rate 2. Determination of the rhythm

CHAPTER 185  •  Electrocardiogram Evaluation

Table 185-1  Normal Canine and Feline Lead II Electrocardiogram Values5 Canine

Feline

Heart rate

Puppy: 70-220 beats/min Toy breeds: 70-180 beats/min Standard: 70-160 beats/min Giant breeds: 60-140 beats/ min

120-240 beats/min

Rhythm

Sinus rhythm Sinus arrhythmia Wandering pacemaker

Sinus rhythm

Maximum: 0.4 mV

P Wave   Amplitude   Duration

Maximum: 0.04 sec (giant breeds, 0.05 sec)

Maximum: 0.02 mV Maximum: 0.04 sec

PR interval

0.06-0.13 sec

0.05-0.09 sec

Small breeds: 2.5 mV Large breeds: 3 mV Small breeds: 0.05 sec maximum Large breeds: 0.06 sec maximum

Maximum: 0.9 mV Maximum: 0.04 sec

No more than 0.2 mV No more than 0.15 mV

None None

QT interval

0.15-0.25 sec at normal heart rate

0.12-0.18 sec at normal heart rate

T wave

May be positive, negative, or biphasic Not more than one fourth of R-wave amplitude

Usually positive

QRS   Amplitude   Duration

ST segment   Depression   Elevation

3. Identification of the waveforms (P-QRS-T) with particular attention paid to changes relative to previous ECG results for this same patient 4. Evaluation of the PR and QT intervals 5. Inspection of the ST segment for elevation or depression Each of these parameters should be compared with normal values (Table 185-1) and with previous measurements made for the same patient. Serial evaluation can provide important early indications of changes in the patient’s condition, even when values fall within the normal range. For example, progressive elongation of the QT interval or QRS duration may signal worsening hyperkalemia in a patient long before the absolute values of these measurements exceed the accepted normal range. Care must be taken when evaluating the amplitude or orientation of the waveforms relative to normal values if they were not obtained from a still animal in right lateral recumbency (as the normal values were). Changes in the durations of the intervals and waveforms seldom are affected by patient position, whereas the orientation and amplitude of the waveforms can vary markedly.

EFFECTS OF DISEASE STATES ON THE ELECTROCARDIOGRAM Specific arrhythmias and their management are discussed elsewhere in this book (see Chapters 46 to 48). However, many disease states can produce detectable changes in the ECG before they become so severe that they alter the rhythm or shift the heart rate outside the normal range.

Electrolyte Abnormalities The normal action potentials generated by both contractile and noncontractile cardiac cells are dependent on the sequential opening of a multitude of ion channels and the flow of ionized sodium, potassium, and calcium through these channels across the cell membranes. Further, other electrolytes such as magnesium serve as important cofactors in cellular actions relying on adenosine triphosphate, such as the function of cellular pumps that reestablish resting membrane potential after a depolarization. Magnesium is unusual in that it has a double shell of hydrating water molecules that require a large amount of free energy to be shed. Magnesium must shed this hydration shell before entering divalent cation channels. Thus magnesium is thought to act as an endogenous calcium channel blocker. It is not surprising, therefore, that alterations in electrolyte concentrations can cause alterations in cardiac electrical and mechanical functions.1-5

Hyperkalemia Although most critically ill patients are faced with large ongoing potassium losses or translocation of extracellular potassium to the intracellular compartment, a subset of animals may arrive with (or develop) elevated extracellular potassium levels. Such hyperkalemia may occur as a result of the underlying disease process (e.g., Addison’s disease), as a result of treatment (e.g., lysis of a saddle thrombus with subsequent reperfusion), or because of inadvertent administration of excess parenteral potassium ions (e.g., poorly mixed fluids supplemented with potassium chloride). Regardless of the cause, the ECG can serve as an invaluable tool in the detection of hyperkalemia. As serum potassium levels rise above 5.5 mEq/L, the ECG may begin to show tall, peaked T waves. As potassium levels rise to 8 to 9 mEq/L, QRS duration may become prolonged and P-wave amplitude may diminish. With further increases in potassium, the QRS waves may take on a sinusoidal appearance, P waves may no longer be apparent, and ST-segment elevation or depression may be noted. ECG changes are not entirely consistent with varied levels of hyperkalemia. Other factors such as serum ionized calcium concentrations factor into whether ECG changes will manifest at a given serum potassium level.

Hypokalemia Low serum potassium levels are a common finding in the critically ill patient and frequently need to be addressed when a fluid plan is formulated. When hypokalemia develops it may result in nonspecific ECG changes such as prolongation of the QT interval, reduced T-wave amplitude, and ST-segment depression. Severe hypokalemia may lead to both atrial and ventricular tachyarrhythmias.

Hypercalcemia Just as they have difficulty in regulating potassium levels, many sick and injured animals struggle to maintain a normal serum ionized calcium level. However, hypercalcemia may occur, resulting from either a primary disease state or administration of intravenous calcium preparations, or both; the elevation in the levels of this ion may be reflected by changes in the ECG. The most notable of these changes is QT-interval shortening, and this finding can be an important signal to the clinician to measure both total and ionized calcium levels.

Hypocalcemia As one might expect, the effects of hypocalcemia on the ECG are in direct contrast to those caused by hypercalcemia. Prolongation of the QT interval may be an indication of reduced serum calcium concentrations. Nonspecific changes in the shape of the T wave may be noted as well.

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Magnesium level In humans, hypermagnesemia may cause prolonged PR intervals and QRS durations. Little is known about elevated magnesium levels in critically ill dogs and cats, although hypomagnesemia is a recognized condition occurring in a significant number of critically ill veterinary patients. Low magnesium levels cause ECG changes quite similar to those noted for hypokalemia.

Hypoxemia Low partial pressure of arterial oxygen has a profound effect on cardiac function, sympathetic nervous system activation, and, not surprisingly, the ECG. Severe or prolonged hypoxemia can produce both tachyarrhythmias and bradyarrhythmias and may lead to cardiac arrhythmias. However, in many patients the ECG can also provide early warning signs of worsening tissue oxygenation. Myocardial hypoxia may be reflected by elevation or depression of the ST segment. The sudden appearance of large T waves can herald hypoxemia; thus any abrupt change in T-wave appearance warrants an evaluation of the patient’s blood gases.6

Intrathoracic Effusions The accumulation of effusions (or tissues, as may be seen with diaphragmatic hernias) within the pericardial or pleural spaces can result in damping of the ECG waveforms. Diminished or variable

amplitude of the QRS complex should prompt the clinician to pursue further diagnostic measures to rule out intracavitary effusions.3

Pain Patient discomfort can lead to nonspecific alterations in the ECG. A progressively increasing heart rate with or without changes in T-wave conformation can be a sign of increasing sympathetic nervous system output. When these changes are seen in a patient exhibiting other signs of discomfort, alleviation of pain may lead to normalization of the ECG parameters.

REFERENCES 1. Tilley LP: Essentials of canine and feline electrocardiography, ed 3, Philadelphia, 1992, Lea & Febiger. 2. Tilley LP, Miller MS, Smith FW Jr: Canine and feline arrhythmias: self-assessment, Philadelphia, 1993, Lea & Febiger. 3. Bonow RO, Mann DL, Zipes DP, et al: Braunwald’s heart disease: a textbook of cardiovascular medicine, ed 9, Philadelphia, 2011, Saunders. 4. Darke P, Bonagura JD, Kelly DF: Color atlas of veterinary cardiology, London, 1996, Mosby-Wolfe. 5. Tilley LP, Goodwin J, editors: Manual of canine and feline cardiology, ed 3, St Louis, 2001, Saunders. 6. Channer K, Morris F: ABC of clinical electrocardiography: myocardial ischemia, BMJ 324(7344):1023-1026, 2002.

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CHAPTER 186  BLOOD GAS AND OXIMETRY MONITORING Laurie Sorrell-Raschi,

DVM, DACVAA, RRT

KEY POINTS • Interpretation of blood gas values requires an understanding of acid-base and respiratory physiology. • There are six basic steps to follow when analyzing arterial blood gas values. • Pulse oximetry provides a noninvasive means of monitoring oxygenation. • The final step in blood gas analysis is to evaluate the significance of the findings as they relate to the patient.

The interpretation of blood gas analysis may be very difficult because it requires an understanding of not only the physiology of acids and bases, but also the physiology of ventilation and gas exchange, the dynamics of electrolyte and water movement, plasma composition, and the renal mechanisms of hydrogen ion, electrolyte and water excretion.1 Rawlston and Qunlan

Blood gas analysis is an invaluable tool for assessing the physiologic status of critically ill patients. It is necessary, therefore, to develop a method of efficiently and effectively evaluating this information to treat the patient appropriately Although a thorough description of acid-base regulation and blood gas analysis is beyond the scope of this chapter (the reader is directed to Chapters 54 and 55, as well as several additional references2-11 for a more detailed description of these subjects), what follows is a brief overview of acid-base physiology and a practical method of interpreting blood gas measurements.

HYDROGEN IONS The proton is one of the basic chemical units of matter. The term proton has become synonymous with the term hydrogen ion or H+ in medical physiology. This electrolyte is the end product of many metabolic processes within the body, and the normal H+ concentration ([H+]) in the extracellular fluid is maintained at around 40 nEq/L. Comparatively, the normal concentrations of most physiologically important electrolytes (e.g., Na+, K+, Ca2+, Mg2+, Cl−,

CHAPTER 186  •  Blood Gas and Oximetry Monitoring −

HCO3 ) are present in the body in the range of milliequivalents per liter. Although [H+] is one millionth the concentration of other electrolytes in the body, its regulation is of paramount importance to normal homeostasis. Hydrogen ions are highly reactive and therefore readily interact with dissociable moieties on proteins. Because proteins play a major role in all biologic functions, alterations in protein structure or function as a result of changes in [H+] within the body can have catastrophic effects on biologic homeostasis.

BUFFERS Changes in [H+] are opposed by buffer systems within the body. These systems consist of an acid (H+ donator) and its conjugate base (H+ acceptor) as follows:

HA ↔ H + + A − acid

base

The law of mass action states that the velocity of a reaction is proportional to the concentration of reactants on either side of the equation and their dissociation constants (k):

k1 [H + ][ A − ] = Ka = k2 [HA] Weak acids and their conjugate bases constitute the most effective buffer pairs in the body since they are more capable of accepting or donating H+ in the presence of changes in H+ load than are strong acids, which are highly dissociated in many biologic fluids.

HENDERSON-HASSELBALCH EQUATION In the early 1900s, L.J. Henderson revolutionized the study of acidbase physiology by noting that CO2 (a primary end product of cellular metabolism) combines with H2O in the presence of carbonic anhydrase to form H2CO3 (carbonic acid). This acid further dissociates into its conjugate base, bicarbonate (HCO3−), and H+: carbonic anhydrase CO2 + H 2O ← → H 2CO3 ↔ HCO3− + H +

By applying the laws of mass action and because H2CO3 exists in equilibrium with dissolved CO2, Henderson substituted the value of dissolved CO2 in his equation. Thus

 [CO2 ]  [H + ] = K a   HCO3−  This equation had major implications because it not only described one of the first known buffer pairs (H2CO3 and HCO3−) but also illuminated a process by which the body could buffer changes in H+ load; namely, ventilation. Later K.A. Hasselbalch would add further utility to the equation by substituting the partial pressure of CO2 in blood (PCO2) for dissolved CO2 and expressing the equation as a logarithm of [H+], or pH:

 HCO3−  pH = pK a + log   PCO2 × SC  where pKa = the logarithm of the ionization constant Ka for H2CO3, and SC = the solubility coefficient of CO2 in blood (or 0.03). This is the classic Henderson-Hasselbalch equation.

Regulation of pH On a daily basis, pH changes within the body are opposed by multiple complex processes that, for the sake of simplicity, can be presented as (1) the actions of intracellular and extracellular buffering systems (chemical buffering), (2) modulation of ventilation (physiologic buffering of the volatile acid CO2), and (3) renal clearance of titratable (nonvolatile) acid. The three primary chemical buffering systems

within the body are proteins (primarily intracellular buffers) and PO4− and HCO3− (predominately extracellular buffers). Although HCO3− comprises only 20% of the total body buffer capacity, its role in [H+] regulation cannot be overemphasized. The reasons are twofold. Not only is the HCO3− buffering system capable of responding to an acute change in [H+], its role in the HCO3−-H2CO3-CO2 equilibrium equation allows changes in pH to be further modulated by changes in ventilation. The ventilatory arc of the system is capable of reacting within minutes of an acid or alkali load, and this “open system” greatly enhances the buffering capacity of the HCO3− system. Finally, the kidneys play a major role in maintaining pH by increasing or decreasing acid elimination in the urine. This system takes hours to days to reach completion but is the most capable of all the processes for returning the body’s pH to normal.

BLOOD GAS ANALYSIS: GETTING STARTED Although blood gas analysis may be performed on venous blood (see Venous Blood Gases later in this chapter), arterial blood gas analysis yields information about oxygenation as well as ventilation and acidbase disorders and is preferentially performed, when possible. There are several potential sites for arterial puncture (e.g., the dorsopedal artery, the digital artery in the front paw, the auricular artery, the lingual artery, the femoral artery). However, the dorsopedal artery is chosen most often due to its size, superficial location, and ease of ensuring adequate hemostasis. A small amount of local anesthetic such as 0.05 to 0.1 ml of 2% lidocaine injected subdermally 2 to 3 minutes before sampling may aid in restraint. Placement of an arterial catheter may allow for repeated blood gas sampling with less stress for the patient (see Chapter 201). Blood should be drawn into a syringe coated with sodium or lithium heparin (1000 IU/ml) to coat the inside of the syringe. Excess should be discarded since heparin is acidic and excessive amounts in the syringe may alter blood gas values.12 Any air bubbles should be expelled from the sample, and the sample should be corked or attached to a stopper to prevent further exposure to room air, which could decrease the sample’s PCO2 to zero and the sample’s partial pressure of oxygen (PO2) to that of room air (150 mm Hg at sea level).12 The sample should be analyzed immediately or held in an ice-water bath at 4° C (39.2° F) (for up to 2 hours) to minimize the effects of cellular metabolism on sample pH, PCO2, and PO2.13

Temperature Correction Whether or not to correct blood gas values for temperature remains a controversial subject in both human and veterinary medicine. The issue centers around the hypothesis that as temperature changes, blood gas solubility also changes, and blood gas values may be altered as well. The pH-stat strategy suggests that blood gas values be corrected for patient temperature and the corrected values be maintained within accepted norms for pH and PCO2. The α-stat strategy assumes that hemoglobin’s buffering capacity, which is related to the ionization of the imidazole group of histidine residues, is not affected by temperature changes. Under these circumstances there would be no need to temperature-correct blood gas values. According to the literature, most attempts at critically applying one strategy versus the other have been made in the context of achieving improved neurologic outcomes in human patients after coronary artery bypass surgery and have shown differing and confounding results.14,15 There is no clear indication that routine temperature correction in the clinical setting is necessary. It is up to the clinician, therefore, to decide which strategy seems most reasonable and to apply that strategy consistently to serial sampling.

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Table 186-1  Normal Arterial Blood Gas Values for Dogs and Cats16,17 Parameter

Value (Dogs)

Value (Cats)

pH

7.39 ± 0.03

7.39 ± 0.08

PaCO2 (mm Hg)

37 ± 3

31 ± 6

PaO2 (mm Hg)

102 ± 7

107 ± 12

HCO3− (mEq/L)

21 ± 2

18 ± 4

Base excess (mEq/L)

−2 ± 2

−2 ± 2

HCO3−, Bicarbonate; PaCO2, partial pressure of arterial carbon dioxide; PaO2, partial pressure of arterial oxygen.

Table 186-2  Acid-Base Disturbances Acid-base Disturbance

pH

Primary Disorder

Compensation

Respiratory acidosis

Decreased

Increased PCO2

Increased HCO3−

Respiratory alkalosis

Increased

Decreased PCO2

Decreased HCO3−

Metabolic acidosis

Decreased

Decreased HCO3−

Decreased PCO2

Metabolic alkalosis

Increased

Increased HCO3−

Increased PCO2

HCO3−, Bicarbonate concentration measured in mEq/L or mmol/L; PCO2, partial pressure of carbon dioxide measured in mm Hg.

Step-by-Step Acid-Base Analysis Number 1: Evaluate the pH Table 186-1 shows normal arterial blood gas values in dogs and cats.16,17 Because pH varies inversely with [H+], any process that increases H+ load will decrease pH and produce acidosis. Conversely, any process that decreases [H+] will tend to increase pH and produce alkalosis. The terms alkalemia and acidemia imply that blood pH is outside the normal range, which may or may not be true depending on the nature of the acid-base disorder and the effectiveness of the organism’s compensatory mechanisms (see Chapter 54). According to the Henderson-Hasselbalch equation, the pH has two components: a ventilatory component (PCO2) and a metabolic component (HCO3−). The pH varies directly with changes in the metabolic component and inversely with changes in the respiratory component. It would follow that pH changes produced by one component may be opposed by opposite changes in the other component. For instance, to compensate for a respiratory acidosis the organism will attempt to increase the concentration of HCO3− in the blood. The compensation may be strong, but rarely is it complete, and overcompensation does not normally occur.4

Number 2: Evaluate PCO2 (see also Chapter 16) Control of ventilation arises from respiratory centers within the brainstem that are sensitive to CO2-induced changes in cerebral pH.18 Arterial CO2 levels are held steady by balancing minute ventilation with metabolic production of CO2; however, normal ventilatory response to changes in PCO2 are so sensitive that a 1-mm Hg change in PCO2 can quadruple minute ventilation. Although ventilation may exceed the production of CO2, it is unlikely that CO2 production exceeds ventilatory capacity in healthy animals. Respiratory acidosis therefore is almost always caused by some aspect of ventilatory failure.18 Table 186-2, Table 186-3, and Box 186-1 show the most common causes of respiratory acidosis and alkalosis in dogs and cats and the expected acid-base changes that subsequently occur.6,19-24 It is important to note that although dogs and cats respond similarly to acute respiratory acidosis, there is some question as to whether cats adjust as well to chronic respiratory acidosis as do dogs. This may be because cats lack the adaptive process of urinary ammoniagenesis that allows dogs to bring their pH very close to normal in longstanding chronic respiratory acidosis (>30 days).21 Also of note is that the normal renal response to respiratory acidosis and alkalosis (namely, HCO3− retention and excretion, respectively) takes several hours to days to correct after correction of the primary respiratory acid-base disorder. The patient may require treatment of the electrolyte changes (in chloride in particular) that accompany the renal response to respiratory acid-base disorders before full correction to baseline HCO3− values can be achieved.6,9

Table 186-3  Expected Compensatory Changes to Primary Acid-Base Disorders Primary Disorder

Expected Compensation

Metabolic acidosis

↓ PCO2 of 0.7 mm Hg per 1 mEq/L decrease in [HCO3−] ±3

Metabolic alkalosis

↑ PCO2 of 0.7 mm Hg per 1 mEq/L decrease in [HCO3−] ±3

Respiratory acidosis—acute

↑ [HCO3−] of 0.15 mEq/L per 1 mm Hg ↑ PCO2 ±2

Respiratory acidosis—chronic

↑ [HCO3−] of 0.35 mEq/L per 1 mm Hg ↑ PCO2 ±2

Respiratory alkalosis—acute

↓ [HCO3−] of 0.25 mEq/L per 1 mm Hg ↓ PCO2 ±2

Respiratory alkalosis—chronic

↓ [HCO3−] of 0.55 mEq/L per 1 mm Hg ↓ PCO2 ±2

[HCO3−], Bicarbonate concentration measured in mEq/L; PCO2, partial pressure of carbon dioxide measured in mm Hg, ↑ increased; ↓, decreased.

BOX 186-1 

Causes of Respiratory-Induced Acid-Base Disorders

Causes of Respiratory Acidosis Pulmonary and small airway disease Respiratory center depression Neuromuscular disease Restrictive extrapulmonary disorders Large airway obstruction Marked obesity Ineffective mechanical ventilation

Causes of Respiratory Alkalosis Iatrogenic (mechanical ventilation) Hypoxemia Pulmonary disease without hypoxemia Centrally mediated hyperventilation Pain, anxiety, fear

Number 3: Evaluate the metabolic indices Metabolic acid-base disturbances are among the most common acid-base disorders described in veterinary medicine. In the classic approach for characterizing acid-base balance, the HendersonHasselbalch equation, pH is described as being proportional to log

CHAPTER 186  •  Blood Gas and Oximetry Monitoring

BOX 186-2 

Causes of Metabolically Induced Acid-Base Disorders Based on the Base Excess Approach

Causes of Metabolic Acidosis Normochloremic causes

Causes of Metabolic Alkalosis Chloride-responsive causes

Lactic acidosis Ketoacidosis Toxins Renal failure

Vomiting Diuretic therapy Correction of respiratory acidosis

Hyperchloremic causes

Chloride-resistant causes

Gastrointestinal losses Renal failure Renal tubular acidosis Other

Primary hyperaldosteronism Hyperadrenocorticism Overadministration of alkaline fluids Other

([HCO3−]/PCO2). HCO3− was used to determine the metabolic component of the body’s acid-base status. However, unlike PCO2, which is an independent variable that the body senses and manipulates to control [H+], HCO3− levels within the body are dependent on many factors (with CO2 levels being only one of them). Consequently, many attempts were made to find an index that would better reflect whole body buffering capacity. Base excess/base deficit (BE/BD) is derived from the whole blood buffer curve developed by Siggaard-Anderson in the 1950s and is defined as the amount of acid or base necessary to titrate 1 L of blood to a pH of 7.4 if PCO2 is held constant at 40 mm Hg.25,26 Because PCO2 is held constant, the BE is reflective of the nonrespiratory component of the organism’s buffer system. Tables 186-2 and 186-3 and Box 186-2 show the most common causes of metabolic acidosis and alkalosis, as well as relevant acid-base responses. The question remains as to whether cats typically have the expected ventilatory response to metabolic acidoses. There is experimental evidence to suggest that they do not.7

Number 4: Determine if there is one problem or many One of the biggest challenges when analyzing a blood gas measurement is to determine the primary disorder. A good rule of thumb is that the pH of the sample reflects the primary disorder. This sounds simple, but it becomes more and more complicated as compensation and multiple disturbances occur. Various acid-base disturbances may be present simultaneously, except for respiratory alkalosis and acidosis, which are mutually exclusive. Multiple primary disorders that change the pH in the same direction are readily apparent (see Table 186-2). Multiple primary disorders that change the pH in different directions may be distinguished from a single primary disorder with compensation by determining the expected compensation in PCO2, HCO3−, or pH and comparing it with the observed compensation (see Table 186-3). If the two are not equal, there are most likely multiple primary disorders.3,7-9

Anion gap

Although BE has been used in human medicine for many years as a bedside index of acid-base analysis it has several short comings. Chiefly, the buffer base nomogram from which the BE equation is derived was created by examining the behavior of blood in vitro; this tends to underestimate whole body buffering capacity. Secondly, this index is fairly insensitive for the detection of complex mixed acidbase disturbances; therefore concurrent but opposing disturbances

BOX 186-3 

Causes of Metabolic Acidosis in Dogs and Cats Based on the Anion Gap (AG) Approach7,29,30

Normal AG (Hyperchloremic) Diarrhea Dilutional acidosis (fluid administration with 0.9% NaCl) Renal tubular acidosis Carbonic anhydrase inhibitors Hypoadrenocorticism Ammonium chloride administration Cationic amino acid administration

Increased AG (Normochloremic) Lactic acidosis Diabetic ketoacidosis Uremic acidosis Hyperphosphatemia Intoxication Ethylene glycol Metaldehyde Salicylates

such as metabolic acidosis and alkalosis may actually be overlooked when this index is used.27 In the 1970s the anion gap approach for acid-base analysis was developed to address some of these concerns.28 As previously mentioned, [H+] in solution is provided by the dissociation of water into H+ and OH−, and the concentration of these two is determined by the concentration of all the other charged ions in the solution. By the law of electroneutrality, the concentration of positively charged ions (cations) in solution such as plasma is equal to the concentration of negatively charged ions (anions). The anion gap (AG) is calculated as the difference between all the major cations and anions:

AG = ([Na + ] + [K + ]) − ([Cl − ] + [HCO3 − ]) However, by the law of electroneutrality there should be no AG. It follows, therefore, that any apparent calculated AG must come from a difference in unmeasured cations and anions. Because changes in unmeasured cations of the magnitude necessary to increase the AG are incompatible with life,28 the AG is generally used as an index to estimate changes in the concentration of unmeasured anions. In healthy dogs and cats the AGs are approximately 12 to 24 mEq/L and 13 to 27 mEq/L, respectively,7 with the bulk of the unmeasured anions represented by plasma proteins (chiefly albumin), phosphate, and sulfate. Because increases in the AG are much more common than decreases, the AG is most commonly used as an aid in the differentiation of causes of metabolic acidoses. With organic acidosis (lactic acidosis, ketoacidosis, etc.), HCO3− is titrated from H+ ions of the fixed acids. Consequently, the [HCO3−] of the extracellular fluid should decrease, causing an increase in the AG. This is referred to as a normochloremic metabolic acidosis. In contrast, when HCO3− is lost, as with gastrointestinal loss or renal tubular acidosis, there is a concomitant Cl− retention; therefore the AG does not change. These types of metabolic acidoses are classified as normal AG or hyperchloremic metabolic acidoses. Box 186-3 shows causes of metabolic acidosis based on the AG approach. It is important to keep in mind, however, that because the bulk of the AG is comprised of the negative charge on plasma proteins and phosphates, changes in either of these parameters may have a significant impact on the calculated AG. In fact, the only clinically

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BOX 186-4 

Anion Gap (AG) Correction for Albumin and Phosphorus7,29

AGAlb adj = AG + 4.2(3.77 − [albumin measured in g/dl]) AGPhos adj = AG + 4.2(3.77 − [albumin measured in g/dl]) + (2.52 − 0.58 [phosphorus measured in mg/dl]) AGAlb adj, Anion gap adjusted for effect of abnormal serum albumin concentration; AGPhos adj anion gap adjusted for effect of abnormal serum phosphorus concentration.

relevant cause of a decrease in the AG is hypoalbuminemia.7 It is advisable to adjust the AG as shown in Box 186-4 any time either or both of these values lie outside the normal reference range.29

The Stewart approach (see Chapter 55)

In 1983 the mathematician-biophysicist Peter Stewart changed the face of modern acid-base assessment by asserting that, to determine the [H+] of extracellular fluid, it is necessary to ascertain the dissociation equilibriums for all fully dissociated and partially dissociated ionic compounds and apply three simple rules: (1) Electroneutrality: in aqueous solutions, the sum of all of the positively charged ions must equal the sum of all of the negatively charged ions. (2) Dissociation equilibrium: the dissociation equilibriums of all incompletely dissociated substances, as derived from the law of mass action, must be satisfied at all times. (3) Mass conservation: the amount of a substance remains constant unless it is added, removed, generated, or destroyed. Through a series of mathematically elegant although cumbersome equations, Stewart found that three independent variables fit these criteria: (1) strong ion difference; (2) the concentration of partially dissociated ions, weak acids, or buffer ions (Atotal); and (3) PCO2. In the Stewart approach, PCO2 also determines the respiratory component of acid-base abnormalities (as in the traditional Henderson-Hasselbalch approach); however, metabolic derangements are defined by changes in SID and Atotal. Strong Ion Difference.  By definition, a strong ion is any substance that is fully dissociated in plasma at body pH. In plasma the most important strong ions are Na+, K+, Cl−, Mg2+, Ca2+, lactate, β-hydroxybutyrate, acetoacetate, and sulfate. The strong ion difference (SID) is defined as the difference between strong cations and anions as follows:

SID = ([Na + ] + [K + ] + [Mg 2 + ] + [Ca 2 + ]) − ([Cl − ] + [A − ]) where [A−] is the concentration of unmeasured strong anions. This equation is considered the SID apparent (SIDapp). Under normal conditions the SIDapp of plasma is approximately 40 to 44 mEq/L. By the law of electroneutrality this charge is balanced by the net negative charge of weak acids, predominately HCO3− and Atotal, which consists of albumin, globulin, and phosphate.8 This is the SID effective (SIDeff ). Changes in SID occur by three basic mechanisms: (1) changes in free water content of plasma, (2) changes in [Cl−], and (3) changes in unmeasured strong anions [A−]−). Because Na+ and Cl− are quantitatively the most important strong ions clinically it is often acceptable to simplify the SIDapp as follows:

SIDapp = [Na + ] − [Cl − ] When SID is evaluated, chloride abnormalities must always be considered in relation to free water changes; therefore it is necessary to use corrected Cl values as follows:

[CL− ]corrected = [Cl − ] × ([Na + ]normal /[Na + ]measured )

Box 186-5 depicts the most common causes of changes in SID. An increase in SID correlates with metabolic alkalosis and a decrease in SID correlates with metabolic acidosis.7,30 Strong Ion Gap.  Although Stewart’s equations provide a very sound mechanistic explanation for plasma pH changes, they are too cumbersome (as previously mentioned) to be seen as clinically useful. Consequently, in the 1990s Figge et al developed a modification to the Stewart approach called the strong ion gap (SIG).7 Figge proposed that unmeasured strong ions could be determined by subtracting weak acids (buffer ions) from strong ions, or

SIDapp − SIDeff = [Na + ] + [K + ] + [Ca 2 + ] + [Mg 2 + ] − [Cl − ] − [A − ] − ([HCO3 − ] − [albumin] − [phosphate]) = SIG The advantage that this approach has over the AG is that it should not be affected by changes in albumin and phosphate concentration because both variables are considered in the calculation. Unfortunately, this formula is equally cumbersome and is not easily applicable to dogs and cats. However, through the work of Constable and McCullough31,32 and others a simplified SIG (SIGsimpl) was developed for dogs at a plasma pH of 7.4 and for cats at plasma pH of 7.35 as follows:

For dogs: SIGsimpl = [albumin measured in g/dl] × 4.9 − AG For cats: SIGsimpl = [albumin measured in g/dl] × 7.4 − AG As with the AG, hypophosphatemia may falsely elevate the SIGsimpl; therefore the AG should always be corrected for phosphate before calculating the SIGsimpl. The range of normal values for SIGsimpl is ±5 mEq/L. An increase in unmeasured strong anions or metabolic acidosis is indicated by a decrease in SIGsimpl. Clinically, an increase in SIGsimpl is rare but would be indicative of the presence of unmeasured strong cations and thus would produce a metabolic alkalosis. At this time, controlled studies in dogs and cats evaluating the SIGsimpl have yet to be published; however, studies in humans are very suggestive that SIGsimpl may be a valuable tool for evaluating acid-base balance in the critical care setting.33 Base Excess Modification.  Despite the pragmatism of Stewart’s mechanistic approach to acid-base physiology the practical application of strong ion equations to clinical situation continues to be debated, largely due to the fact that traditional indices of acid-base analysis such as standard base excess (SBE) have been available, are intuitively easy to understand, and, except for very ill patients, show good agreement with indices like the AG. In an effort to try to tackle these issues Fencl, Jabel, et al focused on the concept of improving upon SBE/BD by applying a series of corrective equations to the measured SBE/BD to account for some effects considered in Stewart approach, as shown in Table 55-1.34 Although base excess gap has not been validated for the dog and cat it is a simple, reasonable way to consider various metabolic components that may be contributing to a patient’s overall acid-base status.

Number 5: Determine how well the patient is oxygenating (see also Chapter 15) Oxygen is necessary for aerobic metabolism. Hypoxia occurs whenever oxygen levels in the blood are low enough to cause abnormal organ function. Hypoxemia occurs when oxygen levels in the blood are too low to meet metabolic demands.16 PaO2 is the partial pressure of oxygen dissolved in the arterial blood (plasma). It is the most common blood gas parameter used to monitor the progress of patients with respiratory disorders. Normal PaO2 values for dogs and cats breathing room air (21% O2) are shown in Table 186-1. A PaO2 of less than 80 mm Hg is considered hypoxemia.16 Although PaO2 is

CHAPTER 186  •  Blood Gas and Oximetry Monitoring

BOX 186-5 

Causes of Metabolically Induced Acid-Base Disorders Based on the Stewart Approach Hypochloremic alkalosis (decreased Cl−corr)

SID Acidosis (Decreased SID) Dilutional acidosis (decreased Na+)

• Gain of Na+ relative to C1− • Isotonic or hypertonic NaHCO3 administration • Loss of Cl− relative to Na+ • Vomiting of stomach contents • Use of thiazide or loop diuretics

• With hypovolemia • Vomiting • Diarrhea • Hypoadrenocorticism • Third-space loss • Diuretic administration • With normovolemia • Psychogenic polydipsia • Hypotonic fluid infusion • With hypervolemia • Severe liver disease • Congestive heart failure • Nephrotic syndrome

Atotal Acidosis (Increased Atotal) Hyperalbuminemia

• Water deprivation Hyperphosphatemia

Hyperchloremic acidosis (increased Cl−corr)

• Loss of Na+ relative to Cl− • Diarrhea • Gain of Cl− relative to Na+ • Fluid therapy (0.9% NaCl, 7.2% NaCl, KCl-supplementation) • Cl− retention • Renal failure • Hypoadrenocorticism Organic acidosis (increased unmeasured strong ions)

• Uremic acidosis, ketoacidosis, or lactic acidosis • Toxicities • Ethylene glycol • Salicylate SID Alkalosis (Increased SID) Concentration alkalosis (increased Na+)

• Pure water loss • Water deprivation • Diabetes insipidus • Hypotonic fluid loss • Vomiting • Nonoliguric renal failure • Postobstructive diuresis

• Translocation • Tumor cell lysis • Tissue trauma or rhabdomyolysis • Increased intake • Use of phosphate-containing enemas • Intravenous phosphate administration • Decreased loss • Renal failure • Urethral obstruction • Uroabdomen Atotal Alkalosis (Decreased Atotal) Hypoalbuminemia

• Decreased production • Chronic liver disease • Malnutrition or starvation • Acute response to inflammation • Extracorporeal loss • Protein-losing nephropathy • Protein-losing enteropathy • Sequestration • Inflammatory effusions • Vasculitis

Atotal, Concentration of partially dissociated ions, weak acids, and buffer ions; Cl−corr, corrected Cl− concentration based on changes in sodium (see text for details); SID, strong ion difference.

very useful and reliable, it is dependent on the alveolar partial pressure of oxygen (PAO2) according to the alveolar gas equation:

PAO2 = (PB − PH 2O)FiO2 −

PaCO2 R

where PB = the atmospheric pressure, PH2O = the partial pressure of water vapor in the air at a given atmospheric pressure, FiO2 = the fractional inspired concentration of oxygen, and R = the respiratory quotient that is the ratio of oxygen consumption to CO2 production (0.78 to 0.92 in dogs).35 In normal healthy lungs, oxygen diffuses readily from the lungs to the arterial circulation. The PaO2 should be within 10 mm Hg of the PAO2 in animals breathing room air and up to 100 mm Hg when the FiO2 is 100%. It is possible for healthy dogs living at high altitudes to have a PaO2 of 60 mm Hg (PAO2 and PaO2 are decreased at low atmospheric pressure). Similarly, a PaO2 reading of 100 mm Hg is not acceptable if a dog is anesthetized and breathing 100% oxygen (the PaO2 should be 500 mm Hg). The alveolar-arterial (A-a) gradient is calculated as a way to quantify the efficiency of gas exchange. At FiO2 concentrations of 21%, the A-a gradient is expected to be less than 10 mm Hg; however, at

O2 concentrations of 100% the A-a gradient can normally be up to 100 mm Hg.35,36 Consequently, the patient’s FiO2 must always be considered when evaluating the A-a gradient. The ratio of PaO2 to FiO2 is another index of oxygenation. Normal values for the PaO2:FiO2 (PF) ratio are greater than 400 mm Hg. Values below 300 mm Hg indicate severe defects of gas exchange. Values less than 200 mm Hg may indicate acute respiratory distress syndrome (ARDS; see Chapters 7 and 24).37 The PF ratio demonstrates some dependency on PaCO2, but this diminishes at an FiO2 above 50%, which is the point at which this ratio is most likely to be employed. The oxygen content in milliliters per deciliter (CaO2) is a calculated value that is included with many blood gas measurements. It is an assessment of the total amount of oxygen carried in the blood. It includes the oxygen dissolved in the plasma and bound to hemoglobin and is an important measure of the oxygen-carrying capacity of the blood, as follows:

CaO2 = (PaO2 × 0.003) + (1.34 × Hb × SaO2 ) where 0.003 = the solubility of oxygen in plasma, 1.34 = the amount of oxygen in milliliters that each gram of hemoglobin (Hb) can hold

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if it is 100% saturated with O2, and SaO2 = oxygen saturation. Normal CaO2 is 20 ml of O2 per deciliter of blood. SaO2 is a measure of the percentage of the heme groups in an arterial blood sample that are occupied by oxygen molecules as measured using a co-oximeter. The relationship between SaO2 and PaO2 is sigmoidal, with maximum saturation seen above a PaO2 of 100 mm Hg. Most blood gas analyzers do not measure SaO2 and instead calculate it using a nomogram derived from the oxygen dissociation curve. Under normal circumstances this has few drawbacks; however, if dysfunctional hemoglobin species (such as carboxyhemoglobin, methemoglobin, sulfhemoglobin, or carboxy sulfhemoglobin) or fetal hemoglobin are in circulation, it is important to measure oxygen saturation with a co-oximeter. These devices use four wavelengths of light passed through a blood sample to distinguish between oxygenated hemoglobin and the other types of hemoglobin that are not carrying oxygen or unable to contribute to gas exchange.3

Pulse oximetry

Pulse oximeters are bedside monitors that noninvasively measure the SpO2 rather than the SaO2 and take advantage of the simple principle used by co-oximeters: blood that is oxygenated is a different color than blood that is not well oxygenated. When light is transcutaneously passed through a tissue bed it is possible to determine the oxygen saturation within that tissue. Deoxygenated hemoglobin absorbs more red light, and oxygenated blood absorbs more infrared light. By using two wavelengths (940 and 660 nm), a high light transmittance speed, fast sample rate, and microprocessor that filters any nonpulsatile data as nonarterial blood flow, it is possible to build a pulse oximeter capable of providing a noninvasive measure of oxygenation.38 Pulse oximetry is useful for several reasons. It provides an inexpensive, noninvasive means of monitoring oxygenation that is well tolerated and reliable in dogs and cats when more invasive monitoring is either unwarranted, undesirable, impossible to perform, or some combination thereof.39-41 The machines are small, quiet, and portable and can be used for extended periods, and their readings may be used as an indirect measure of perfusion. Recently several studies have been published in human pediatrics as well as adult critical care medicine demonstrating the utility of the SpO2:FiO2 ratio (SF) as a reliable noninvasive surrogate marker for the PF ratio. In human medicine the SF ratio has been shown to be a valid diagnostic indicator for ARDS and acute lung injury (ALI); it is especially useful in evaluating the severity of the illness and predicting outcome. A recent pilot study in veterinary medicine suggested that in spontaneously breathing dogs that are not receiving supplemental oxygen, the SF and PF ratios show good correlation. The potential exists, therefore, that pulse oximetry may provide a noninvasive means of monitoring veterinary species that have ARDS/ ALI and other forms of respiratory failure.42 This concept requires further investigation. As with most screening equipment, there are drawbacks. Pulse oximetry probes typically perform well on the tongue, but this location can be difficult to use in a conscious patient. In cats in particular it may be difficult to obtain accurate readings.43 The probe may be placed on the shaved skin of the lip, pinna, toe web, flank, or tail, but many conscious patients will not readily tolerate it. Additionally, pulse oximetry readings can be affected by movement, bright overhead lights, vasoconstriction, dark skin pigment, hypothermia, and hypoperfusion. Abnormal hemoglobin also causes the machine to read inaccurately. Carboxyhemoglobin absorbs infrared light similarly to oxygenated hemoglobin and produces falsely high SpO2 readings. Methemoglobin, on the other hand, absorbs both wavelengths of light equally well. In the presence of this hemoglobin species the pulse oximeter defaults to a value of 85%, reading high or low depending on the patient’s actual saturation level.44 Most impor-

tantly, pulse oximetry gives little information about the efficiency of gas exchange. An SpO2 of 100% in a patient breathing pure oxygen (FiO2 of 100%) does not evaluate whether the patient’s PaO2 is 500 mm Hg or 100 mm Hg. It is more appropriate to perform arterial blood gas analysis anytime that precise information is needed regarding the patient’s oxygenation status.

Number 6: Look at the whole picture The final step in blood gas analysis is to fit the analysis to the patient. The clinician should make sure the conclusions fit the clinical picture. Regardless of the evaluation methods employed, the clinician must be sure that the conclusions drawn make sense. It is easy to become confused when one is learning acid-base physiology and acid-base analysis; several methods of analysis are possible. The main principles to keep in mind are the following: (1) Everything begins with the patient. (2) The clinician must begin an acid-base analysis with the method with which he or she is most familiar to determine the primary problem. (3) If the answer fits the clinical picture, it is most likely correct. (4) If the answer does not fit, or the therapy is unsuccessful, the clinician should look again using another method (see Chapters 54 and 55).

Venous Blood Gas Values Venous blood gas samples are often more simple to obtain than arterial blood gas samples. The PCO2 of venous blood is usually 4 to 6 mm Hg higher and the pH is usually 0.02 to 0.05 units lower than those of arterial blood. Venous blood gas samples are adequate for the clinical assessment of acid-base disorders in patients that are hemodynamically stable.15,45 Peripheral venous PO2 values are not representative of arterial oxygen values; however, the blood from veins in the tongue or the claw may be “arterialized” under certain conditions and used for this purpose.15,46-48 A venous PO2 of less than 30 mm Hg may suggest poor tissue oxygenation and should be investigated further.

REFERENCES 1. Rawson RE, Quinlan KM: Evaluation of a computer-based approach to teaching acid/base physiology, Adv Physiol Educ 26:85-97, 2002. 2. Muir WW, deMorais HSA: Acid-base balance: traditional and modified approaches. In Thurmon JC, Tranquilli WJ, Benson GJ, editors: Lumb and Jones’ veterinary anesthesia, ed 3, Baltimore, 1996, Williams & Wilkins. 3. Martin L: All you really need to know to interpret arterial blood gases, ed 2, Philadelphia, 1992, Williams & Wilkins. 4. DiBartola SP: Introduction to acid-base disorders. In DiBartola SP, editor: Fluid, electrolyte, and acid-base disorders in small animal practice, ed 4, St Louis, 2012, Saunders. 5. DiBartola SP: Metabolic acid-base disorders. In DiBartola SP, editor: Fluid, electrolyte, and acid-base disorders in small animal practice, ed 4, St Louis, 2012, Saunders. 6. Johnson RA, deMorais HA: Respiratory acid-base disorders. In DiBartola SP, editor: Fluid, electrolyte and acid-base disorders in small animal practice, ed 4, St Louis, 2012, Saunders. 7. deMorais HA, Leisewitz AL: Mixed acid-base disorders. In DiBartola SP, editor: Fluid, electrolyte, and acid-base disorders in small animal practice, ed 4, St Louis, 2012, Saunders. 8. deMorais HA, Constable PD: Strong ion approach to acid-base disorders. In DiBartola SP, editor: Fluid, electrolyte, and acid-base disorders in small animal practice, ed 4, St Louis, 2012, Saunders. 9. Rose BD, Post TW: Clinical physiology of acid-base and electrolytes disorders, ed 5, New York, 2001, McGraw-Hill. 10. Corey HE: Stewart and beyond: new models of acid-base balance, Kidney Int 64:777-787, 2003. 11. Matousek S, Handy J, Rees SE: Acid-base chemistry of plasma: consolidation of traditional and modern approaches from a mathematical and clinical perspective, J Clin Monit Comput 25:57-70, 2011.

CHAPTER 186  •  Blood Gas and Oximetry Monitoring 12. Siggaard-Andersen O: Sampling and storing of blood for determination of acid-base status, Scand J Clin Lab Invest 13:196-204, 1961. 13. Haskins SC: Sampling and storage of blood for pH and blood gas analysis, J Am Vet Med Assoc 170:429-433, 1977. 14. Murkin JM, Martzke JS, Buchan AM, et al: A randomized study of the influence of the perfusion technique and pH management strategy in the 316 patients undergoing coronary artery bypass surgery. II: Neurologic and cognitive outcomes, J Thorac Cardiovasc Surg 110(2):349-362, 1995. 15. Plessis AJ, Jonas RA, Wypij D, et al: Perioperative effects if alpha-stat versus pH-stat strategies for deep hypothermic cardiopulmonary bypass in infants, J Thorac Cardiovasc Surg 114(6):991-1000, 1997. 16. Haskins SC: Blood gases and acid-base balance: clinical interpretation and therapeutic implications. In Kirk RW, editor: Current veterinary therapy VIII, ed 8, Philadelphia, 1983, Saunders. 17. Ilkiw JE, Rose RJ, Martin ICE: A comparison of simultaneously collected arterial, mixed venous, jugular venous, and cephalic venous blood samples in the assessment of blood gas and acid-base status in dogs, J Vet Intern Med 5:294, 1991. 18. Guyton AC, Hall JE: Respiration. In Guyton AC, Hall JE, editors: Textbook of medical physiology, ed 9, Philadelphia, 1996, Harcourt Brace. 19. Jennings DB, Davidson JS: Acid-base and ventilatory adaptation in conscious dogs during chronic hypercapnia, Respir Physiol 58:377-393, 1984. 20. Szlyk PC, Jennings BD: Effects of hypercapnia on variability of normal respiratory behavior in awake cats, Am J Physiol 252:R538-R547, 1987. 21. Lemieux G, Lemieux C, Duplessis S, et al: Metabolic characteristics of cat kidney: failure to adapt to metabolic acidosis, Am J Physiol 259:R277R281, 1990. 22. deMorais HA, DiBartola SP: Ventilatory and metabolic compensation in dogs with acid-base disturbances, J Vet Emerg Crit Care 1:39-49, 1991. 23. Adrogue HJ, Brensilver J, Cohen J, et al: Influence of steady-state alterations in acid-base equilibrium on the fate of administered bicarbonate in the dog, J Clin Invest 71:867, 1983. 24. Cornlius LM, Rawlings CA: Arterial blood gas and acid base values in dogs with various diseases and signs of disease, J Am Vet Med Assoc 178:992, 1981. 25. Astrup P, Jorgensen K, Siggaard-Andersen O, et al: Acid-base metabolism: new approach, Lancet 1:1035, 1960. 26. Astrup P: New approach to acid-base metabolism, Clin Chem 7:1, 1961. 27. Muir WW, de Morais HAS: Acid-base and fluid therapy. In Grimm KA, Tranquilli WJ, Lamont LA, editors: Essentials of small animal anesthesia and analgesia, ed 2, West Sussex, UK, 2011, Wiley-Blackwell. 28. Oh MS, Carroll HJ: Current concept. The anion gap, N Engl J Med 297:814-817, 1977. 29. Figge J, Jabor T, Kazda A, et al: Anion gap and hypoalbuminemia, Crit Care Med 26(11):1807-1810, 1998. 30. Whitehair KJ, Haskins SC, Whitehair JG, et al: Clinical applications of quantitative acid-base chemistry, J Vet Intern Med 9:1-11, 1995.

31. McCullough SM, Constable PD: Calculation of the total plasma concentration of nonvolatile weak acids and the effective dissociation constant of nonvolatile buffers in plasma for use in the strong ion approach to acid-base balance in cats, Am J Vet Res 64:1047-1051, 2003. 32. Constable PD, Stampfli HR: Experimental determination of net protein charge and A(tot) and K(a) of nonvolatile buffers in canine plasma, J Vet Intern Med 19:507-514, 2005. 33. Funk GC, Doberer D, Sterz F, et al: The strong ion gap and outcome after cardiac arrest in patients treated with therapeutic hypothermia: a retrospective study, Intensive Care Med 35:232-239, 2009. 34. Fencl V, Jabor A, Kazda A, et al: Diagnosis of metabolic acid-base disturbances in critically ill patients, Am J Respir Crit Care Med 162:2246-2251, 2000. 35. Muggenburg BA, Mauderly JL: Cardiopulmonary function of awake, sedated, and anesthetized beagle dogs, J Appl Physiol 37(2):152-157, 1974. 36. Haskins SC: Interpretation of blood gas measurements. In King LG, editor: Textbook of respiratory disease in dogs and cats, ed 1, St Louis, 2004, Saunders. 37. Schuurmans Stekhoven JH, Kreuzer F: Alveolar-arterial O2 and CO2 pressure differences in the anesthetized, artificially ventilated dog, Respir Physiol 3:177-191, 1967. 38. Van Pelt DR, Wingfield WE, Wheeler SL, et al: Oxygen-tension based indices as predictors of survival in critically ill dogs: clinical observations and review, J Vet Emerg Crit Care 1(1):19-25, 1991. 39. Dorsch JA, Dorsch SE: Understanding anesthesia equipment, ed 4, Baltimore, 1999, Williams & Wilkins. 40. Fairman NB: Evaluation of pulse oximetry as a continuous monitoring technique in critically ill dogs in the small animal intensive care unit, J Vet Emerg Crit Care 2(2):50-55, 1992. 41. Hendricks JC, King LG: Practicality, usefulness, and limits of pulse oximetry in critical small animal patients, J Vet Emerg Crit Care 3(1):5-12, 1993. 42. Calabro JM, Prittie JE, Palma DA: Preliminary evaluation of the utility of comparing SpO2/FiO2 and PaO2/FiO2 ratios in dogs, J Vet Emerg Crit Care (San Antonio) 23(3):280-285, 2013. 43. Jacobson JD, Miller MW, Mathews NS, et al: Evaluation of accuracy of pulse oximetry in dogs, Am J Vet Res 53(4):537-540, 1992. 44. Barker SJ, Tremper KK, Hyatt J: Effects of methemoglobinemia on pulse oximetry and mixed venous oximetry, Anesthesiology 70:112-117, 1989. 45. Wingfield WE, Van Pelt DR, Hackett TB, et al: Usefulness of venous blood in estimating acid-base status in the seriously ill dog, J Vet Emerg Crit Care 4:23, 1994. 46. Solter PF, Haskins SC, Patz JD: Comparison of PO2, PCO2, and pH in blood collected from the femoral artery and a cut claw of cats, Am J Vet Res 49(11):1882-1883, 1988. 47. Quandt JE, Raffe MR, Polzin D, et al: Evaluation of toenail blood samples for blood gas analysis in the dog, Vet Surg 20(5):357-361, 1991. 48. Wagner AE, Muir WW: A comparison of arterial and lingual and venous blood gases in anesthetized dogs, J Vet Emerg Crit Care 1(1):14-18, 1991.

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CHAPTER 187  COLLOID OSMOTIC PRESSURE AND OSMOLALITY MONITORING Lori S. Waddell,

DVM, DACVECC

J v = K fc ([Pc − Pi ] − σ[π p − π i ])

KEY POINTS • Determination of colloid osmotic pressure (COP) can guide artificial colloid therapy in veterinary patients. • Estimation of COP via equations using the patient’s albumin and globulin concentrations are unreliable, particularly in critically ill patients that may have altered albumin/globulin ratios. • Direct measurement via a colloid osmometer is the only reliable way to monitor COP. • Maintenance of a goal COP of at least 15 mm Hg in whole blood for both dogs and cats reduces the risk of edema formation and secondary organ dysfunction associated with edema. • Plasma osmolality can be estimated from an equation or measured directly via a freezing point depression osmometer. • Diagnosis of an osmolal gap (measured plasma osmolality − estimated plasma osmolality) of more than 10 mOsm/kg indicates the presence of an unmeasured osmole(s), such as ethanol or ethylene glycol and its metabolites, and may be clinically useful in diagnosing these toxicities.

Colloid osmotic pressure (COP) is the physiochemical phenomenon that occurs when two solutions with different colloid concentrations are separated by a semipermeable membrane. Oncotic pressure is defined as the osmotic pressure exerted by colloids in solution, so the terms colloid osmotic pressure and oncotic pressure can be used interchangeably; colloid oncotic pressure, a commonly used misnomer, is redundant. The particles contributing to COP (and the particles that they may hold with them because of their electrical charge) do not pass readily through the semipermeable membrane. This is in contrast to small crystalloid particles such as electrolytes, glucose, and other metabolites, which do pass readily through the membrane. COP is determined using a patient’s blood sample and is referenced to normal saline rather than pure water because normal saline is more representative of the fluid in the interstitial space. COP should be thought of as the osmotic pressure exerted by plasma proteins and their associated electrolytes because the electrolytes contribute significantly to the COP. Albumin and its associated cations provide approximately 60% to 70% of the plasma oncotic pressure and globulins provide the remaining 30% to 40%. Osmolality is the concentration of osmotically active particles (solute) per kilogram of solution. The size and charge of the particles does not matter when determining the osmolality; only the number of particles in solution is relevant.

COLLOID OSMOTIC PRESSURE Starling’s Hypothesis Starling’s hypothesis states that fluid flux at the capillary level is controlled by a balance between hydrostatic pressure and osmotic pressure gradients between the capillaries and interstitial space. 978

where Jv = the net rate of capillary filtration; Kfc = the capillary filtration coefficient; Pc = capillary hydrostatic pressure; Pi = interstitial hydrostatic pressure; σ = the osmotic reflection coefficient; πp = plasma oncotic pressure; and πi = interstitial oncotic pressure. This equation shows the importance of plasma COP in maintaining a normal fluid balance between the intravascular space and the interstitial space (Figure 187-1). If the COP in the capillaries drops lower than the COP in the interstitium, fluid will move out of the vessels and edema formation will be favored. It is important to note that recent evidence has challenged the classic Starling-Landis principle and led to a revised Starling principle that uses the COP of the subglycocalyx space, rather than the COP of the interstitium, to describe fluid movement across some microvascular beds. The colloid osmotic pressure of the fluid in the subglycocalyx space can be substantially lower than that of the free interstitial fluid because of the combined effects of protein sieving by the endothelial glycocalyx and the convective flow of filtered fluid through the endothelial clefts. In addition, this space below the glycocalyx limits fluid reabsorption by the microvasculature.1 Of all the variables included in the equation above, only the COP and the capillary hydrostatic pressure can be manipulated clinically. Increasing capillary hydrostatic pressure by administering intravenous fluids tends to increase edema formation. By measuring a patient’s COP and using colloid fluid therapy to help maintain normal COP, one can reduce transvascular fluid efflux and the clinical problems associated with it, including interstitial edema and cavitary effusions (see Chapter 11).

Calculated versus Measured Values Equations have been developed to try to predict COP. In humans, the Landis-Pappenheimer equation can be used:

COP = 2.1P + 0.16P2 + 0.009P3 where P = plasma protein. Capillary

p

Pc Arteriole

Venule Pi

i

Interstitial space FIGURE 187-1  Starling’s hypothesis of fluid flux across the capillary membrane. Pc, Capillary hydrostatic pressure; Pi, interstitial hydrostatic pressure; πp, plasma oncotic pressure; πi, interstitial oncotic pressure.

CHAPTER 187  •  Colloid Osmotic Pressure and Osmolality Monitoring

This equation is unreliable in other species, including cats, dogs, cattle, and horses, because they have different albumin/globulin ratios. Species-specific equations have been derived1a but are not reliable in critically ill patients, in which protein concentrations (specifically the albumin/globulin ratio) may be altered.2 Unfortunately, these equations do not provide an alternative for direct measurement of COP because of the changes associated with illness. Although total solids certainly give an indication of hypoproteinemia and therefore a low COP, refractometry cannot accurately predict COP. Furthermore, once artificial colloids have been administered, the measurement of total solids via refractometry will be inaccurate. The artificial starches available in the United States have a refractometry reading of 4 to 4.2 mg/dl, so the patient’s total solids level will appear to approach this range, even if it is actually lower. The only way to predict COP accurately, particularly in critically ill patients and those receiving artificial colloids, is direct measurement via a colloid osmometer (Model 4420, Wescor, Logan, Utah).

Normal Colloid Osmotic Pressure Values Normal values for COP are species, sample, and laboratory dependent. Published normal values for plasma are 23 to 25 mm Hg for cats and 21 to 25 mm Hg for dogs.3 For whole blood, normal values are 24.7 ± 3.7 mm Hg for cats and 19.95 ± 2.1 for dogs.4 A recent study showed a significant difference between COP measured on whole blood and that measured on plasma in healthy dogs.5 The COP was slightly higher in whole blood (mean magnitude of 0.5 mm Hg) due to the presence of red blood cells, which make a minor contribution to the COP. However, the individual values obtained were all within the expected reference intervals, so either sample may be used clinically. It is recommended that clinicians use the same sample type for comparison in an individual patient.5 When whole blood is used for COP measurement, samples should be collected with lyophilized heparin, which is commonly available in green-top tubes. Slight variability does occur from one laboratory to another, so normal values should be established for each setting. Samples of plasma or serum that cannot be processed immediately may be frozen and later thawed for determination of COP with little effect on the accuracy of the values obtained. This practice was evaluated in the study mentioned earlier, which showed changes in frozen samples stored up to 7 days that were minor and would not affect clinical decision making.5 Whole blood samples can also be refrigerated and processed within 24 hours without any significant effect on the COP. Care should be taken to prevent hemolysis of the sample because free hemoglobin can increase COP. Dilution of the COP due to anticoagulants in the collection tube or syringe can occur; thus lyophilized heparin is preferred. It is provided in a dry form, has a high molecular weight, and is used in a very low concentration so it will have a minimal effect on COP.

Colloid Osmotic Pressure in Critically Ill Patients COP has been measured in whole blood in 124 critically ill cats and dogs. Mean values obtained were 13.9 ± 3.1 mm Hg (range, 7.6 to 23.8).6 The normal values for this laboratory were as listed earlier for whole blood. Critically ill cats and dogs can have substantial decreases in their COP values and may benefit greatly from COP monitoring and therapy aimed at correcting a low COP.

How Colloid Osmotic Pressure Is Measured The colloid osmometer determines the COP of a solution using a semipermeable membrane. The membrane has a uniform pore size that allows only molecules with a molecular weight of 30,000 Da or less to pass through, simulating the capillary endothelium in veterinary patients. This membrane separates two chambers, a reference chamber filled with 0.9% saline and a test chamber into which the

Colloid osmotic pressure

Colloid and saline solution

Test chamber

Saline solution

Reference chamber Semipermeable membrane

FIGURE 187-2  Measurement of colloid osmotic pressure in a colloid osmometer across a semipermeable membrane. The colloid in the patient’s blood sample, placed in the test chamber, cannot move across the semipermeable membrane. Water is therefore drawn across the membrane from the reference chamber. The difference in pressure is measured as the colloid osmotic pressure.

patient sample is injected. The sample tested can be serum, plasma, or whole blood (normal ranges vary slightly depending on which is used, as described earlier). The membrane is relatively impermeable to the proteins because of their large size. Water migrates from the reference chamber into the test chamber as a result of differences in the colloid concentration and COP (Figure 187-2). The COP as determined by the membrane depends not only on the colloid concentration but also on the GibbsDonnan effect, which takes into account the negative charge of the proteins. Electroneutrality must be maintained on each side of the membrane. The negative charge of the proteins causes retention of positively charged ions, primarily Na+, which increases the concentration of these normally diffusible ions in the test chamber. Because osmotic pressure is proportional to the number of molecules present, not the size of the molecules, the cations contribute significantly to the COP. The actual contribution of these ions to the COP can be determined by the square of the electrical charge carried by the colloid component. Because the total measured COP is determined by both the colloid and the associated positive ions, the COP is related nonlinearly to the colloid concentration. The charge of the proteins in a sample depends on the pH of the sample and the electrophoretic pattern of the proteins. These may be very abnormal in critically ill patients, which makes direct measurement of the COP all the more essential. After equilibrium has been established between the two chambers (within 30 to 90 seconds), a negative pressure gradient exists in the reference chamber. A sensing diaphragm next to the fluid in the reference chamber is attached to a pressure transducer. Minute pressure changes in the reference chamber are converted into alterations in electrical impedance, which is measured, amplified, then converted into a display on the osmometer that is reported in mm Hg.

Indications for Colloid Osmotic Pressure Measurement COP measurement should be part of routine monitoring in any patient receiving artificial colloids, in patients with edema, and in

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patients that are treated with aggressive crystalloid therapy or have low serum albumin concentration. Critically ill patients may have hypoalbuminemia and a decreased COP due to dilution from crystalloid therapy, decreased albumin production caused by anorexia and a shift to production of acute-phase proteins, and increased loss via blood loss, loss into effusions, or loss into the interstitium associated with increased vascular permeability. Monitoring of COP may help prevent edema formation in these patients by allowing the clinician to direct therapy toward correcting a low COP. Fortunately, COP measurement requires a very small sample of blood or serum (less than 0.5 ml). COP can change rapidly in patients receiving large amounts of crystalloid or colloid fluid therapy; therefore daily or twice-daily measurement often is indicated. In a recent study, healthy isoflurane-anesthetized dogs received lactated Ringer’s solution at a rate of 0, 10, 20, or 30 ml/kg/hr for 1 hour. In those given the solution at rates of 20 or 30 ml/kg/hr significant decreases in COP were measured at 30 and 60 minutes compared with baseline.7 Whether this information translates into predictable clinical sequelae is not well studied and most likely depends on other Starling’s forces. Edema of organs such as the heart (which causes increased ventricular stiffness and decreased end-diastolic volume, stroke volume, and cardiac output) and of the lungs (which causes interstitial edema and increased work of breathing) can lead to multiple organ dysfunction long before clinically appreciable peripheral edema is present. By correcting low COP in critically ill patients, some of these secondary problems that contribute to patient morbidity and mortality may be prevented. A low COP in a critically ill patient can and should be managed with administration of plasma, human or canine albumin solutions, or artificial colloids (e.g., hydroxyethyl starch solutions). In human patients, a lower COP has been associated with decreased survival, particularly before the use of artificial colloids became commonplace.8 In a later study, COP was not significantly different between survivors and nonsurvivors in patients with a critical illness of at least 7 days’ duration. In this study, however, artificial colloids could be used as directed by the patients’ physicians, and mean COP in all patients was 16.1 mm Hg.9 This maintained the COP value above the cutoff that had previously been associated with increased mortality. Further research may find that through management of a patient’s low COP with artificial colloids and albumin, this risk factor is eliminated in critically ill patients, and therefore the overall chance of survival is improved.

OSMOLALITY Definition Osmolality is the number of particles of solute per kilogram of solvent, and osmolarity is the number of particles of solute per liter of solvent. Both are purely dependent on the number of particles in solution; the particle size, shape, density, or electrical charge has no relevance. In body fluids, they are almost exactly equal because the solvent is primarily water, and 1 kg of water is equal to 1 L of water. Normal values for osmolality are 290 to 310 mOsm/kg in dogs and 290 to 330 mOsm/kg in cats.10

Determination of Osmolality Plasma osmolality can be estimated by using the following equation:

Calculated plasma osmolality = 2(Na + ) + (BUN ÷ 2.8) + (glucose ÷ 18) where BUN = blood urea nitrogen and Na+ = sodium concentration.11-13 The sodium concentration is multiplied by a factor of 2 to include the chloride and bicarbonate ions that are present to maintain

BOX 187-1 

Common Causes of Hyperosmolality in Small Animals

Effective Osmoles

Ineffective Osmoles

Sodium Glucose Mannitol Ketoacids Lactic acid Phosphates and sulfates (with renal failure) Radiopaque contrast solutions

Blood urea nitrogen Ethylene glycol and metabolites Ethanol and methanol Acetylsalicylic acid Isopropyl alcohol

electroneutrality. Concentrations of urea and glucose are measured in milligrams per deciliter and must be converted to millimoles per liter by the conversion factor of 2.8 for BUN and 18 for glucose. Common causes of increased calculated plasma osmolality include hypernatremia, hyperglycemia secondary to diabetes mellitus, and azotemia (Box 187-1; see later section on effective osmolality). The most common cause of decreased calculated plasma osmolality is hyponatremia (see Chapters 50). Serum osmolality can be determined indirectly by using a freezing point depression osmometer or determining the vapor point depression of the solution.10,12 Freezing point depression is the more common and accurate method because it measures volatile substances in solution (e.g., alcohol) that would be missed using the other method.11 For every 1 mol of nondissociating molecules dissolved in 1 kg (or 1 L) of water, the freezing point depression is decreased by 1.86°C. The osmolality of this solution would be 1 Osm/kg or 1000 mOsm/kg.10

Osmolal Gap The difference between the measured and calculated serum osmolality is referred to as the osmolal gap. Recent evidence has shown a nearly zero osmolal gap in dogs and cats (−5 to 2 with a median of −2 in dogs and −3 to 6 with a median of 2 in cats).12,13 A measured value that is more than 10 mOsm/kg higher than the calculated plasma value10 indicates that an unmeasured solute is present in a large amount in the plasma. This could be any solute that is not accounted for in the equation and can include lactic acid, sulfates, phosphates, acetylsalicylic acid, mannitol, ethylene glycol and its metabolites, ethanol, isopropyl alcohol, methanol, radiographic contrast solution, paraldehyde, sorbitol, glycerol, propylene glycol, or acetone (see Box 187-1).10,14 It has been reported that commercially available activated charcoal suspensions which contain propylene glycol or glycerol can cause increased serum osmolality in healthy dogs.15 This may result in difficulty in interpreting serum osmolality when evaluating for some toxins (e.g., ethylene glycol) if activated charcoal is administered before blood samples are obtained for measurement of serum osmolality. An increased osmolal gap can also occur with pseudohyponatremia secondary to hyperlipidemia, marked hyperglycemia, or hyperproteinemia.10,16 Newer methods of measuring plasma electrolytes with ion-selective electrodes have helped to circumvent this problem.

Effective Osmolality Because some molecules such as urea are freely diffusible across cell membranes, changes in their concentrations do not cause fluid shifts between the intracellular and extracellular compartments. Other molecules—most importantly sodium, but also glucose, chloride, and others—do not readily cross cell membranes and therefore cause

CHAPTER 187  •  Colloid Osmotic Pressure and Osmolality Monitoring

water movement. Effective osmolality, also known as tonicity, can be estimated as follows:

Calculated effective osmolality = 2(Na + ) + (glucose ÷ 18) This is the same as the previous equation for calculated plasma osmolality without BUN, which is an ineffective osmole. Tonicity is an important concept when comparing solutions. A solution is hypertonic if it contains a higher concentration of impermeant solutes than a reference solution and hypotonic if it contains a lower concentration of impermeant solutes. Solutions are isotonic if they have equal numbers of impermeant solutes. Effective osmolality is especially relevant when evaluating azotemic patients. With a very elevated BUN level, the calculated osmolality will be increased, but the effective osmolality or tonicity may be normal or even decreased. The calculated osmolality needs to be used to evaluate these patients; direct measurement of osmolality using the freezing point depression method cannot distinguish between effective and ineffective osmoles.10 Evaluation of osmolality, both calculated and measured, can be important for recognition and treatment of several clinical conditions, including sodium disorders, hyperglycemia, and certain toxicities (see Box 187-1). Therapy should be aimed at preventing rapid changes in osmolality because adverse reactions, especially neurologic, may result if the serum osmolality is changed abruptly (see Chapter 50 for more details).

Urine Osmolality Urine osmolality is the number of molecules (unaffected by the size of the molecules) per kilogram of water and must be measured by an osmometer. It is used to assess the concentrating ability of the kidney and should be interpreted along with the hydration and volume status of the patient. Urine specific gravity (USG) is more commonly used to assess renal concentrating ability because it is easier to measure (through the use of a hand-held refractometer). Specific gravity is a ratio of the density of a substance compared to water, so it is affected by the number of molecules and their molecular weights. Normally, the urine osmolality and USG are linearly correlated. If many high-molecular-weight molecules are present in the urine, USG will overestimate the urine solute concentration, whereas the urine osmolality remains accurate. Some of the molecules that can interfere with USG include albumin, synthetic colloids, and iohexal.17 Interpretation of urine osmolality requires knowledge of the hydration and intravascular volume status of the patient. This allows for differentiation of an appropriate versus an abnormal physiologic response of the kidneys. The urine osmolality is useful for differentiating sodium disorders, identifying the syndrome of inappropriate antidiuretic hormone (see Chapter 68), differentiating prerenal from renal causes of azotemia, and diagnosing diabetes insipidus.

REFERENCES 1. Levick JR, Michel CC: Microvascular fluid exchange and the revised Starling principle, Cardiovasc Res 87:198, 2010. 1a.  Brown SA, Dusza K, Boehmer J: Comparison of measured and calculated values for colloid osmotic pressure in hospitalized animals, Am J Vet Res 55:910, 1994. 2. Thomas LA, Brown SA: Relationship between colloid osmotic pressure and plasma protein concentration in cattle, horses, dogs, and cats, Am J Vet Res 53:2241, 1992. 3. Rudloff E, Kirby R: Colloid osmometry, Clin Tech Small Anim Pract 15:119, 2000. 4. Culp AM, Clay ME, Baylor IA, et al: Colloid osmotic pressure (COP) and total solid (TS) measurement in normal dogs and cats, Proceedings of the IVECCS, San Antonio, September 7-11, 1994 (abstract). 5. Odunayo A, Kerl ME: Comparison of whole blood and plasma colloid osmotic pressure in healthy dogs, J Vet Emerg Crit Care 21:236-241, 2011. 6. King LG, Culp AM, Clay ME, et al: Measurement of colloid osmotic pressure (COP) in a small animal intensive care unit, Proceedings of the IVECCS, San Antonio, September 7-11, 1994 (abstract). 7. Muir WW, Kijtawornrat A, Ueyama Y, et al: Effects of intravenous administration of lactated Ringer’s solution on hematologic, serum biochemical, rheological, hemodynamic, and renal measurements in healthy isofluraneanesthetized dogs, J Am Vet Med Assoc 239:630, 2011. 8. Weil MH, Henning RJ, Puri VK: Colloid oncotic pressure: clinical significance, Crit Care Med 7:113, 1979. 9. Blunt MC, Nicholson JP, Park GR: Serum albumin and colloid osmotic pressure in survivors and nonsurvivors of prolonged critical illness, Anaesthesia 53:755, 1998. 10. DiBartola SP: Disorders of sodium and water: hypernatremia and hyponatremia. In DiBartola SP, editor: Fluid, electrolyte and acid-base disorders in small animal practice, ed 4, St Louis, 2012, Saunders. 11. Barr JW, Pesillo-Crosby SA: Use of the advanced micro-osmometer model 3300 for determination of a normal osmolality and evaluation of different formulas for calculated osmolarity and osmole gap in adult dogs, J Vet Emerg Crit Care 18:270, 2008. 12. Dugger DT, Mellema MS, Hopper K, et al: Estimated osmolality of canine serum: a comparison of the clinical utility of several published formulae, J Vet Emerg Crit Care (in press). 13. Dugger DT, Epstein SE, Hopper K, et al: Comparative accuracy of several published formulae for the estimation of serum osmolality in cats, J Small Anim Pract 54(4):184-189, 2013. 14. Feldman BF, Rosenberg DP: Clinical use of anion gap and osmolal gap in veterinary medicine, J Am Vet Med Assoc 178:396, 1981. 15. Burkitt JM, Haskins SC, Aldrich J, et al: Effects of oral administration of a commercial activated charcoal suspension on serum osmolality and lactate concentration in the dog, J Vet Intern Med 19:683, 2005. 16. Wellman ML, DiBartola SP, Kohn CW: Applied physiology of body fluids in dogs and cats. In DiBartola SP, editor: Fluid, electrolyte and acid-base disorders in small animal practice, ed 4, St Louis, 2012, Saunders. 17. Smart L, Hopper K, Aldrich J, et al: The effect of hetastarch (670/0.75) on urine specific gravity and osmolality in the dog, J Vet Intern Med 23:388, 2009.

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CHAPTER 188  INTRAABDOMINAL PRESSURE MONITORING Guillaume L. Hoareau,

DrVet, DACVECC  •  Matthew

KEY POINTS • Abdominal perfusion pressure, the difference between the mean arterial pressure and the intraabdominal pressure (IAP), can be compromised with IAP elevations. • Intraabdominal hypertension predisposes patients to developing multiple organ dysfunction and failure. • Intraabdominal pressure can be dangerously elevated even in disease states that do not primarily involve the abdomen. • Measurement of IAP can be performed using simple, minimally invasive methods. • Trends are more useful than a single measurement in helping to assess organ perfusion and can assist in decision making.

Intraabdominal pressure (IAP) and intraabdominal hypertension (IAH) have been recognized in animals and humans for over 150 years.1,2 A discussion of IAP in pregnancy was published in 1913, and the effects of IAH on renal function in humans was described in 1947.3,4 One of the first published studies was undertaken simply to determine whether IAP was typically positive or negative in value and involved a series of varied procedures in different species.1 Original research into the physiologic effects of IAH was performed in several species once the normal IAP was established.2 These studies used inconsistent protocols, the findings were rarely confirmed independently, and the techniques used would be found unacceptable for technical and humane reasons today. Scientists believed it was important to establish the parameters at that time, though, because surgery and interventional medicine were evolving.

S. Mellema,

DVM, PhD, DACVECC

during their intensive care unit stay. Approximately 14% of these patients have IAP elevations severe enough to be diagnosed with ACS.7,8 Conzemius et al reported that in a series of 20 dogs with gross abdominal distention and gastric dilation/volvulus, pyometra, acute ascites, or diaphragmatic hernia the period prevalence of IAH was quite high if one applies the human diagnostic criteria (IAP > 12 mm Hg).9 All of the patients in this study had an IAP of 15 cm H20 (~11 mm Hg) or more. The prevalence of IAH and ACS in critically ill veterinary patients otherwise remains unknown.

RISK FACTORS Certain conditions have been associated with an increased risk of IAH in human patients. They are classified by the World Society of the Abdominal Compartment Syndrome as diseases that can lead to the following: (1) diminished abdominal wall compliance, (2) increased intraluminal content, (3) increased abdominal content, or (4) capillary leak syndrome.10 These same risk factors have been investigated in a series of canine patients.11 Those patients in which a known risk factor was identified had significantly higher IAP than dogs in the no-risk group, which suggests that these same risks factors are relevant to veterinary as well as human patients. Also, evidence from human studies suggest that physical examination is not always

Table 188-1  Interpretation of Intraabdominal Pressure (IAP) and Recommendations for Therapy Grade

IAP (cm H2O)

IAP (mm Hg)

I

16-20

12-15

Normovolemia should be ensured and the underlying disease should be pursued.

II

21-27

16-20

Volume resuscitation may be necessary, diagnostics to identify the cause should be instituted, and decompression might be considered.

III

28-34

21-25

Volume resuscitation may be necessary, diagnostics to identify the cause should be instituted, and decompression should be considered.

IV

>34

>25

Decompression is necessary to reverse organ damage and prevent further deterioration. Either paracentesis or surgical exploration is strongly recommended.

DEFINITIONS AND INCIDENCE Intraabdominal pressure refers simply to the pressure within the abdominal cavity, regardless of the actual reading. Intraabdominal hypertension is defined as a sustained or repeated pathologic elevation of IAP of more than 12 mm Hg.5,6 An IAH grading system has been proposed with severity graded on the basis of the magnitude of IAP elevation (Table 188-1). Abdominal compartment syndrome (ACS) is defined as a sustained increase in IAP of more than 20 mm Hg (with or without an APP < 60 mm Hg) that is associated with new organ dysfunction or failure.5,6 ACS is considered primary if the site of trauma or disease lies within the abdominal cavity (e.g., fractured liver or spleen, penetrating foreign body, peritonitis, neoplasia, hepatic abscess, pancreatitis) and secondary if the inciting disease is extraperitoneal in origin (e.g., burns or thoracic trauma, usually followed by massive fluid resuscitation or high-pressure mechanical ventilation). Prevalence studies have reported that approximately 32% to 51% of human intensive care patients experience IAH at some point 982

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CHAPTER 188  •  Intraabdominal Pressure Monitoring 12

a reliable tool to evaluate IAP. Clinicians are therefore encouraged to measure and monitor IAP in patients affected by diseases known to predispose to IAH, with or without evidence of IAH on physical examination.

PATHOPHYSIOLOGY Both primary and secondary ACS are associated with multiple organ dysfunction and a worsened prognosis.8,13-15 This is an important association because it is highly recommended that IAP be monitored in critically ill patients that do not have intraperitoneal disease. Resolution of the ACS can significantly improve outcome in patients without primary abdominal disease that develop multiple organ dysfunction.16,17 The effects of elevated IAP on organ function are well documented.18-21 Visceral perfusion, abdominal blood flow, central venous pressure (CVP), pulmonary pressures, cardiac output, and renal function are all adversely affected by an increasing IAP, and early changes can be seen when levels exceed 10 cm H2O. Much of the research documenting the systemic effects of ACS has been performed in dogs.21-27 Little clinical work in veterinary medicine has documented the effects of ACS in hospitalized patients; however, the disease processes in which it is recognized in humans exist in small animal patients, and the technology for monitoring and responding to changes are the same. Several comprehensive reviews of the subject have been published in the human medical literature.28-33 IAH has been documented in human patients with ruptured abdominal aortic aneurysm, abdominal hemorrhage from trauma, occluded mesenteric artery, ruptured or necrotic bowel, bile peritonitis,20 blunt trauma to any of the abdominal organs, gastric perforation, bladder rupture,31 and large abdominal mass.34 In many of these cases, there was a previous surgical procedure and the IAH mandated a reexploration of the abdomen. Fluid infusions and effusions in dogs,21 morbid obesity,35 the use of antishock trousers,36 and pregnancy in humans3 are also conditions that have been documented to increase IAP.

METHODS OF INTRAABDOMINAL PRESSURE MEASUREMENT IAP has been measured via catheters placed in the inferior vena cava, stomach,37,38 urinary bladder, and peritoneal cavity.39 The urinary bladder method is currently considered the gold standard by the World Society of the Abdominal Compartment Syndrome.10 Excluding gas in the intestinal tract, the abdominal contents are noncompressible, and thus the pressure at one point is equal to the pressures at all others in the steady state. Therefore bladder pressure measurements reflect the pressure in the abdomen as a whole. Such measurements are relatively simple to obtain in small animal patients and provide consistent, accurate measurements.39 A urethral catheter is inserted aseptically so that the tip is just inside the trigone of the urinary bladder. A Foley catheter is preferred to ensure that the fenestrations lie just inside the bladder. A sterile urine collection system is attached in the usual way, but two three-way stopcocks are placed in the system (Figure 188-1). A water manometer is attached to the upright stopcock port. A 35-ml to 60-ml syringe of 0.9% sodium chloride or a bag of 0.9% sodium chloride and an intravenous administration set are attached to the distal stopcock port for filling the manometer and infusing the bladder. The bladder is emptied and 0.5 to 1  ml/kg (maximum of 25  ml per patient) of sterile 0.9% sodium chloride is instilled to fill it slightly. This lessens the likelihood that the bladder wall will obstruct the catheter fenestrations. The system is zeroed to the patient’s midline at the symphysis pubis and the manometer is filled with isotonic saline. The stopcock is closed to the fluid source, so that the meniscus in the manometer can drop and equilibrate with the pressure in the urinary bladder. The difference between the reading at the meniscus and the zero point is the IAP. The patient should be laterally recumbent when measurements are obtained. Patient position affects measurement40 and should therefore be the same at each measurement. Endexpiratory readings are standard. Use of appropriate aseptic technique for placement and handling of the urethral catheter and the

48 46 44 42 40 38 36 34 32 30 28

d

26 24 22 20 18 16 14 12 10 08 06 04 02

b a

00

c

FIGURE 188-1  Setup for measurement of intraabdominal pressure via a urethral catheter. a, Urinary bladder; b, Foley catheter; c, three-way stopcock; d, water manometer; e, syringe filled with 0.9% NaCl. (Image courtesy John Doval.)

e

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BOX 188-1 

Factors Influencing Intraabdominal Pressure Readings

• Body positioning • Body condition • Pregnancy • Increased abdominal wall tone • Pain • Anxiety • External abdominal pressure application • Belly bandages • Volume of infusate measurement system prevents a urinary tract infection in an otherwise healthy dog.9 Normal IAP in dogs is 0 to 5 cm H2O. Healthy dogs undergoing elective abdominal surgery (ovariohysterectomy) had a postoperative IAP ranging from 0 to 15 cm H2O. No problems associated with IAH were observed.9 Normal IAP ranges from 4 to 8 cm H2O in sedated cats and 6 to 11 cm H2O in awake cats.41 Many factors can impact the measured value of IAP, and following a set protocol minimizes the potential for error. Factors influencing IAP are presented in Box 188-1. In patients at risk of (or suffering from) IAH, IAP should be monitored every 2 to 8 hours. IAP can be monitored more frequently if clinically indicated. In patients for which indwelling bladder catheter placement is not feasible or desirable, measurements made from a catheter tip located in the intraabdominal vena cava may be substituted. Acceptable agreement has been found between intravesicular and caudal vena cava pressures in at least one canine model.42 Vena cava access may be obtained by advancing a long catheter centrally from a pelvic limb peripheral vein (e.g., lateral saphenous) insertion site (see Chapter 195).

PHYSIOLOGIC EFFECTS OF INTRAABDOMINAL HYPERTENSION Hemodynamic Effects Abdominal perfusion pressure (APP) better estimates perfusion pressure to visceral organs than mean arterial pressure (MAP) alone. It is defined as MAP minus IAP. In humans, maintaining APP at or above 60 mm Hg has been associated with improved outcome in patients with IAH and ACS. APP has therefore been proposed as a resuscitation endpoint.5,6,43 Increases in IAP lead to elevations in CVP, pulmonary artery pressure, right atrial pressure, pulmonary capillary wedge pressure, MAP, and systemic vascular resistance.21,44,45 These changes are believed to develop in part because of catecholamine release and a subsequent shift of abdominal vascular volume into the thorax.44 Cardiac output may increase transiently with the initial increase in preload resulting from the vascular volume shift. Cardiac output then declines because venous return from the caudal part of the body is reduced and systemic vascular resistance is increased as a result of compression of the abdominal vasculature.25,26 In a porcine model, an IAP of 30 mm Hg for 4 hours was associated with a significant decrease in cardiac output.46 Interestingly, the elevation in IAP may be transmitted to the thoracic cavity and falsely elevate CVP measurements, providing the clinician with a false assessment of the patient’s intravascular status.47 In cases of IAH or ACS, CVP must therefore be interpreted with caution. Other advanced hemodynamic parameters (i.e., pulse pressure variation and global end-diastolic volume) proved more useful than CVP in predicting fluid responsiveness in a porcine model of IAH.48

BOX 188-2 

Abdominal Perfusion Pressure and Filtration Gradient Formulas

• Abdominal perfusion pressure = mean arterial pressure (MAP) − intraabdominal pressure (IAP)

• Filtration gradient = glomerular filtration pressure − proximal tubule pressure = MAP − IAP − IAP = MAP − 2IAP

When graded increases in IAP were tested in dogs and pigs, urine output decreased,4,27 and arterial and venous lactate levels increased.24 These effects are largely due to the reduction in cardiac output. Increasing vascular volume with intravenous fluid infusions improved the reduced cardiac output associated with IAH. Surgical decompression improved oxygenation, cardiac output, and atrial filling pressures within 15 minutes in human patients.19,49

Renal Effects Glomerular filtration rate and urine output were reduced in dogs with an IAP of 10 to 20 cm H2O. Oliguria and anuria developed in these dogs with moderate to severe IAH of 25 cm H2O or higher. The evidence suggests that this occurs because of reduced cardiac output and compression of the renal vasculature and parenchyma rather than a postrenal effect of pressure on the ureters.27 Urine production initially depends on the glomerular filtration gradient (Box 188-2). For the same change in IAP, urine production is reduced beyond the decrease due solely to reduction in APP.5,50 Porcine models of IAH demonstrated alteration in renal cortical blood flow51 and anuria at an IAP higher than 30 mm Hg.46 Azotemia develops secondary to decreased blood urea nitrogen and creatinine excretion. Patients with ACS consistently experience improved urine output and a reduction in azotemia very quickly after surgical decompression.4,9,19,27,52

Pulmonary and Thoracic Effects Pulmonary compliance is reduced with IAH.40,53 Greater pressure on the peritoneal side of the diaphragm impairs its ability to contract and generate adequate subatmospheric intrathoracic pressure.44 A small study in human patients with acute lung injury54 reported that a rise in IAP was associated with a decrease in the overall respiratory system compliance. Partition analysis showed that this was mostly the result of a decrease in chest wall compliance because pulmonary mechanics were unaltered. In mechanically ventilated pigs the negative hemodynamic effects of positive end-expiratory pressure combined with IAH led to a significant increase in blood lactate levels as well as markedly increased CVP, pulmonary capillary wedge pressure, and pulmonary artery pressure.24,55,56 IAP monitoring is a valuable tool in assessing the numerous factors contributing to changes in pulmonary and hemodynamic function. Patients undergoing mechanical ventilation that have concurrent abdominal disease may benefit from measurement of IAP. To allow the decrease in respiratory compliance to be taken into consideration, volume-controlled mechanical ventilation may be preferred in cases of IAH.56 Approximately 60% to 70% of the IAP is transmitted to the thoracic cavity as evidenced by a rise in esophageal pressure.57,58 Thus, when a lungprotective ventilator strategy is being considered, it has been suggested to use ΔPPlat, the difference between the plateau pressure (PPlat) and the IAP.59 Even with surgical decompression, human burn patients with ACS experienced more severe lung injury during the 3 days following the burn than those without ACS. This underscores the potential for IAH to trigger pulmonary damage.60 When pulmonary or cardiovascular parameters deteriorate, if IAH can be ruled out as a cause, the clinician’s focus can be better directed to the true cause of

CHAPTER 188  •  Intraabdominal Pressure Monitoring

deterioration. It has been suggested that elevated positive endexpiratory and peak inspiratory pressures may be the cause, rather than effect, of ACS. Regardless, both should improve with timely intervention when IAP exceeds 25 to 35 cm H2O.17

Central Nervous System Effects Intracranial pressure is increased with IAH.35,55,61 Pressure is transmitted from the abdomen to the thorax. Increased thoracic pressures and blood volume in the more compliant compartments reduce venous blood flow in the jugular system and, therefore, drainage from the head.62 This process has been implicated in the central nervous system abnormalities associated with morbid obesity as well as with iatrogenic pneumoperitoneum during laparoscopic procedures.63 Patients with IAH should be monitored carefully for signs of increasing intracranial pressure. These include obtundation, changes in and loss of cranial nerve reflexes, vomiting, and seizures.

Visceral Effects Hepatic, portal, intestinal, and gastric blood flow declined with an associated tissue acidosis in pigs with IAH.46,64-66 Bowel tissue oxygenation is reduced as measured at the terminal ileum.67 Laser Doppler microcirculation analysis in a pig model of IAP51 demonstrated a significant decrease in blood flow to the gastric mucosa, seromuscular layer of the small and large intestine, and renal cortex. Intestinal mucosal blood flow was less affected than blood flow to other layers. Decreased lymphatic drainage68 and venous return promotes interstitial edema in the viscera, which further promotes IAH. Bacterial translocation across the intestinal wall in association with reduced blood flow in ACS at pressures above 20 mm Hg has been documented in rats.69,70 In a rabbit model of IAH, an IAP above 20 mm Hg was associated with increased intestinal permeability to fluorescent probes as well as bacterial endotoxin. Translocation of bacteria to the mesenteric lymph nodes and liver was concurrently documented.71 Although bacterial translocation may predispose the patient to sepsis and its sequelae (i.e., systemic inflammatory response syndrome and multiple organ dysfunction syndrome),72 it is important to remember that it is also a physiologic process.73 Additionally, a porcine model showed that pigs subjected to hemorrhagic shock followed by fluid resuscitation and an IAP of 30 mm Hg did not demonstrate a higher rate of bacterial translocation than controls when polymerase chain reaction testing and culture were used to detect bacterial translocation.74 The link between IAH, ACS, and bacteremia and its association with the development of systemic inflammatory response syndrome and sepsis remains unclear.

Systemic Effects Several hormonal changes have been documented with IAH. An increase in plasma antidiuretic hormone levels occurred in dogs with externally applied abdominal pressures of 80 mm Hg. This increase was prevented by a prior intravenous infusion of 6% dextran at 8 to 10 ml/kg.23 Pigs had elevated plasma renin activity and aldosterone levels in response to IAH of 34 cm H2O.44 Decompression reversed the hormonal changes. In a pneumoperitoneum model, pigs had elevated levels of epinephrine and norepinephrine at an IAP of 27.2 cm H2O but not at an IAP of 13.6 cm H2O.75 This study did not measure hormone levels after decompression. These changes probably relate to reduced renal perfusion and the baroreceptor and renin-angiotensin responses to a perceived reduction in blood pressure or volume. Evidence regarding the involvement of IAH and systemic inflammation is growing. Studies in rats76 and pigs77 demonstrated a rise in levels of interleukin 1β, interleukin 6, and tumor necrosis factor α as well as lung injury following experimentally induced IAH. This demonstrates the potential for IAH and ACS to injure extraabdominal

organs and initiate multiple organ dysfunction syndrome. IAH promotes intraabdominal venous stasis, which is known to encourage thrombosis. The potential for thromboembolism at the time of decompression has been mentioned.59 To the authors’ knowledge there is no consensus guideline regarding anticoagulant therapy in patients with IAH or ACS. Blood flow to the rectus sheath muscles is reduced with IAH, and this may impair wound healing.78 Thus in postceliotomy patients both systemic and local effects of IAH may promote wound dehiscence and postsurgical complications.

GENERAL CONSIDERATIONS As a general rule, the following pressure guidelines may be used to assist in clinical decision making in response to elevations in IAP (see Table 188-1): If IAP is 10 to 20 cm H2O, normovolemia should be ensured and the underlying cause should be pursued. If IAP is 20 to 35 cm H2O, volume resuscitation may be necessary, diagnostic modalities to identify the cause should be instituted, and decompression should be considered. If IAP is higher than 35 cm H2O, decompression either by paracentesis or surgical exploration is strongly recommended. Consideration should be given to managing the patient as an open abdomen. Obviously the breadth of physiologic changes associated with IAH makes the condition a concern in any patient with multisystem disease. Patients with traumatic damage to more than one body cavity often have significant muscle and organ trauma. These patients would benefit from IAP monitoring because bowel ileus, organ ischemia, progressive abdominal hemorrhage, or other problems that are not readily apparent clinically may develop. Dogs with acute, severe pancreatitis can develop effusions and infections that could cause IAH and a rapid deterioration of their clinical status. IAP measurement provides another objective parameter to use in deciding if and when to perform a surgical exploration. Patients who have had major abdominal surgery may benefit from IAP measurement as a means of early identification of the need for follow-up procedures. For instance, increasing IAP in postoperative patients may indicate dehiscence of surgery sites or peritonitis from any source. If IAP is increasing and urine output is decreasing in spite of adequate fluid therapy, surgical intervention or paracentesis is indicated.18,19,79 IAP changes can aid in the assessment of the need for paracentesis in patients with severe ascites. Procedures such as therapeutic or diagnostic peritoneal lavage and peritoneal dialysis may be better managed if IAP is monitored in conjunction with monitoring of urine output and patient comfort. Other situations that can lead to IAH, ACS, and organ dysfunction include intraperitoneal therapies and diagnostic tests. Iatrogenic IAH is generated during diagnostic peritoneal lavage, intracavitary infusion of drugs such as analgesics and antineoplastic agents, and peritoneal dialysis. Patient discomfort and negative effects can be linked to the increased IAP associated with these procedures.80-82 The long-term effects are unknown, and there is some speculation that the length of time IAH is present can influence the degree of impairment and improvement with decompression.17 Short-term effects from iatrogenic IAH are more directly associated with patient comfort and quality of life.80 IAP is a valuable parameter to monitor in critically ill patients. Regardless of whether primary abdominal disease is present, IAP may rise in response to interventions and treatments and can ultimately result in multiple organ dysfunction and death. Controlled studies still need to be performed in the veterinary clinical setting to better assess which patients will benefit most from measurement of IAP and to establish more specific guidelines for action.

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ACKNOWLEDGMENT In the first edition of this text, this chapter was written by Dr. Sharon Drellich. Dr. Drellich was a highly skilled and well-respected veterinary criticalist who was taken from us at too young an age. She was also a cherished friend and resident-mate of one of the authors (MM). Although the current authors have agreed to update the chapter, the conceptual framework and starting point for this chapter were Sharon’s. The authors have elected to continue to have Sharon’s name listed as an author posthumously in honor of her memory and many contributions to the field.

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19. Cullen DJ, Coyle JP, Teplick R, et al: Cardiovascular, pulmonary, and renal effects of massively increased intra-abdominal pressure in critically ill patients, Crit Care Med 17:118-121, 1989. 20. Williams M, Simms HH: Abdominal compartment syndrome: case reports and implications for management in critically ill patients, Am Surg 63:555-558, 1997. 21. Barnes GE, Laine GA, Giam PY, et al: Cardiovascular responses to elevation of intra-abdominal hydrostatic pressure, Am J Physiol 248:R208-213, 1985. 22. Robotham JL, Wise RA, Bromberger-Barnea B: Effects of changes in abdominal pressure on left ventricular performance and regional blood flow, Crit Care Med 13:803-809, 1985. 23. Le Roith D, Bark H, Nyska M, et al: The effect of abdominal pressure on plasma antidiuretic hormone levels in the dog, J Surg Res 32:65-69, 1982. 24. Burchard KW, Ciombor DM, McLeod MK, et al: Positive end expiratory pressure with increased intra-abdominal pressure, Surg Gynecol Obstet 161:313-318, 1985. 25. Kashtan J, Green JF, Parsons EQ, et al: Hemodynamic effect of increased abdominal pressure, J Surg Res 30:249-255, 1981. 26. Ivankovich AD, Miletich DJ, Albrecht RF, et al: Cardiovascular effects of intraperitoneal insufflation with carbon dioxide and nitrous oxide in the dog, Anesthesiology 42:281-287, 1975. 27. Harman PK, Kron IL, McLachlan HD, et al: Elevated intra-abdominal pressure and renal function, Ann Surg 196:594-597, 1982. 28. Watson RA, Howdieshell TR: Abdominal compartment syndrome, South Med J 91:326-332, 1998. 29. Carr JA: Abdominal compartment syndrome: a decade of progress, J Am Coll Surg 216:135-146, 2013. 30. Malbrain ML, Cheatham ML: Definitions and pathophysiological implications of intra-abdominal hypertension and abdominal compartment syndrome, Am Surg 77(Suppl 1):S6-11, 2011. 31. Meldrum DR, Moore FA, Moore EE, et al: Prospective characterization and selective management of the abdominal compartment syndrome, Am J Surg 174:667-672, 1997; discussion 672-663. 32. Nathens AB, Brenneman FD, Boulanger BR: The abdominal compartment syndrome, Can J Surg 40:254-258, 1997. 33. Saggi BH, Sugerman HJ, Ivatury RR, et al: Abdominal compartment syndrome, J Trauma 45:597-609, 1998. 34. Celoria G, Steingrub J, Dawson JA, et al: Oliguria from high intraabdominal pressure secondary to ovarian mass, Crit Care Med 15:78-79, 1987. 35. Sugerman HJ, DeMaria EJ, Felton WL 3rd, et al: Increased intra-abdominal pressure and cardiac filling pressures in obesity-associated pseudotumor cerebri, Neurology 49:507-511, 1997. 36. Gaffney FA, Thal ER, Taylor WF, et al: Hemodynamic effects of Medical Anti-Shock Trousers (MAST garment), J Trauma 21:931-937, 1981. 37. Collee GG, Lomax DM, Ferguson C, et al: Bedside measurement of intraabdominal pressure (IAP) via an indwelling naso-gastric tube: clinical validation of the technique, Intensive Care Med 19:478-480, 1993. 38. Sugrue M, Buist MD, Lee A, et al: Intra-abdominal pressure measurement using a modified nasogastric tube: description and validation of a new technique, Intensive Care Med 20:588-590, 1994. 39. Iberti TJ, Kelly KM, Gentili DR, et al: A simple technique to accurately determine intra-abdominal pressure, Crit Care Med 15:1140-1142, 1987. 40. Obeid F, Saba A, Fath J, et al: Increases in intra-abdominal pressure affect pulmonary compliance, Arch Surg 130:544-547, 1995; discussion 547-548. 41. Rader RA, Johnson JA: Determination of normal intra-abdominal pressure using urinary bladder catheterization in clinically healthy cats, J Vet Emerg Crit Care 20:386-392, 2010. 42. Lacey SR, Bruce J, Brooks SP, et al: The relative merits of various methods of indirect measurement of intraabdominal pressure as a guide to closure of abdominal wall defects, J Pediatr Surg 22:1207-1211, 1987. 43. Cheatham ML, White MW, Sagraves SG, et al: Abdominal perfusion pressure: a superior parameter in the assessment of intra-abdominal hypertension, J Trauma 49:621-626, 2000; discussion 626-627. 44. Bloomfield GL, Blocher CR, Fakhry IF, et al: Elevated intra-abdominal pressure increases plasma renin activity and aldosterone levels, J Trauma 42:997-1004, 1997; discussion 1004-1005.

CHAPTER 188  •  Intraabdominal Pressure Monitoring 45. Moffa SM, Quinn JV, Slotman GJ: Hemodynamic effects of carbon dioxide pneumoperitoneum during mechanical ventilation and positive end-expiratory pressure, J Trauma 35:613-617, 1993; discussion 617-618. 46. Toens C, Schachtrupp A, Hoer J, et al: A porcine model of the abdominal compartment syndrome, Shock 18:316-321, 2002. 47. Schachtrupp A, Graf J, Tons C, et al: Intravascular volume depletion in a 24-hour porcine model of intra-abdominal hypertension, J Trauma 55:734-740, 2003. 48. Renner J, Gruenewald M, Quaden R, et al: Influence of increased intraabdominal pressure on fluid responsiveness predicted by pulse pressure variation and stroke volume variation in a porcine model, Crit Care Med 37:650-658, 2009. 49. Peng ZY, Critchley LA, Joynt GM, et al: Effects of norepinephrine during intra-abdominal hypertension on renal blood flow in bacteremic dogs, Crit Care Med 36:834-841, 2008. 50. Sugrue M, Jones F, Deane SA, et al: Intra-abdominal hypertension is an independent cause of postoperative renal impairment, Arch Surg 134:1082-1085, 1999. 51. Olofsson PH, Berg S, Ahn HC, et al: Gastrointestinal microcirculation and cardiopulmonary function during experimentally increased intraabdominal pressure, Crit Care Med 37:230-239, 2009. 52. Jacques T, Lee R: Improvement of renal function after relief of raised intra-abdominal pressure due to traumatic retroperitoneal haematoma, Anaesth Intensive Care 16:478-482, 1988. 53. Mutoh T, Lamm WJ, Embree LJ, et al: Abdominal distension alters regional pleural pressures and chest wall mechanics in pigs in vivo, J Appl Physiol 70:2611-2618, 1991. 54. Malbrain ML, Deeren DH, Nieuwendijk R, et al: Partitioning of respiratory mechanics in intra-abdominal hypertension, Intensive Care Med 29(Suppl 1):S1-213, 2003. 55. Bloomfield GL, Ridings PC, Blocher CR, et al: Effects of increased intraabdominal pressure upon intracranial and cerebral perfusion pressure before and after volume expansion, J Trauma 40:936-941, 1996. 56. Wauters J, Claus P, Brosens N, et al: Relationship between abdominal pressure, pulmonary compliance, and cardiac preload in a porcine model, Crit Care Res Pract 2012:763181, 2012. 57. Malbrain M: Effect of intra-abdominal pressure on pleural and filling pressures, Intensive Care Med 29:S73, 2003. 58. Quintel M, Pelosi P, Caironi P, et al: An increase of abdominal pressure increases pulmonary edema in oleic acid-induced lung injury, Am J Respir Crit Care Med 169:534-541, 2004. 59. Malbrain ML: Is it wise not to think about intraabdominal hypertension in the ICU? Curr Opin Crit Care 10:132-145, 2004. 60. Oda J, Yamashita K, Inoue T, et al: Acute lung injury and multiple organ dysfunction syndrome secondary to intra-abdominal hypertension and abdominal decompression in extensively burned patients, J Trauma 62:1365-1369, 2007. 61. Citerio G, Vascotto E, Villa F, et al: Induced abdominal compartment syndrome increases intracranial pressure in neurotrauma patients: a prospective study, Crit Care Med 29:1466-1471, 2001. 62. Bloomfield GL, Ridings PC, Blocher CR, et al: A proposed relationship between increased intra-abdominal, intrathoracic, and intracranial pressure, Crit Care Med 25:496-503, 1997. 63. Josephs LG, Este-McDonald JR, Birkett DH, et al: Diagnostic laparoscopy increases intracranial pressure, J Trauma 36:815-818, 1994.

64. Rasmussen IB, Berggren U, Arvidsson D, et al: Effects of pneumoperitoneum on splanchnic hemodynamics: an experimental study in pigs, Eur J Surg 161:819-826, 1995. 65. Diebel LN, Dulchavsky SA, Wilson RF: Effect of increased intra-abdominal pressure on mesenteric arterial and intestinal mucosal blood flow, J Trauma 33:45-48, 1992; discussion 48-49. 66. Diebel LN, Wilson RF, Dulchavsky SA, et al: Effect of increased intraabdominal pressure on hepatic arterial, portal venous, and hepatic microcirculatory blood flow, J Trauma 33:279-282, 1992; discussion 282-273. 67. Bongard F, Pianim N, Dubecz S, et al: Adverse consequences of increased intra-abdominal pressure on bowel tissue oxygen, J Trauma 39:519-524, 1995; discussion 524-515. 68. Moore-Olufemi SD, Xue H, Allen SJ, et al: Effects of primary and secondary intra-abdominal hypertension on mesenteric lymph flow: implications for the abdominal compartment syndrome, Shock 23:571575, 2005. 69. Diebel LN, Dulchavsky SA, Brown WJ: Splanchnic ischemia and bacterial translocation in the abdominal compartment syndrome, J Trauma 43:852-855, 1997. 70. Polat C, Aktepe OC, Akbulut G, et al: The effects of increased intraabdominal pressure on bacterial translocation, Yonsei Med J 44:259-264, 2003. 71. Cheng JT, Xiao GX, Xia PY, et al: Influence of intra-abdominal hypertension on the intestinal permeability and endotoxin/bacteria translocation in rabbits, Zhonghua Shao Shang Za Zhi 19:229-232, 2003. 72. Deitch EA, Rutan R, Waymack JP: Trauma, shock, and gut translocation, New Horiz 4:289-299, 1996. 73. MacFie J: Current status of bacterial translocation as a cause of surgical sepsis, Br Med Bull 71:1-11, 2004. 74. Doty JM, Oda J, Ivatury RR, et al: The effects of hemodynamic shock and increased intra-abdominal pressure on bacterial translocation, J Trauma 52:13-17, 2002. 75. Mikami O, Fujise K, Matsumoto S, et al: High intra-abdominal pressure increases plasma catecholamine concentrations during pneumoperitoneum for laparoscopic procedures, Arch Surg 133:39-43, 1998. 76. Rezende-Neto JB, Moore EE, Melo de Andrade MV, et al: Systemic inflammatory response secondary to abdominal compartment syndrome: stage for multiple organ failure, J Trauma 53:1121-1128, 2002. 77. Oda J, Ivatury RR, Blocher CR, et al: Amplified cytokine response and lung injury by sequential hemorrhagic shock and abdominal compartment syndrome in a laboratory model of ischemia-reperfusion, J Trauma 52:625-631, 2002. 78. Diebel L, Saxe J, Dulchavsky S: Effect of intra-abdominal pressure on abdominal wall blood flow, Am Surg 58:573-575, 1992. 79. Kron IL, Harman PK, Nolan SP: The measurement of intra-abdominal pressure as a criterion for abdominal re-exploration, Ann Surg 199:28-30, 1984. 80. Mahale AS, Katyal A, Khanna R: Complications of peritoneal dialysis related to increased intra-abdominal pressure, Adv Perit Dial 19:130-135, 2003. 81. Enoch C, Aslam N, Piraino B: Intra-abdominal pressure, peritoneal dialysis exchange volume, and tolerance in APD, Semin Dial 15:403-406, 2002. 82. Morris KP, Butt WW, Karl TR: Effect of peritoneal dialysis on intraabdominal pressure and cardio-respiratory function in infants following cardiac surgery, Cardiol Young 14:293-298, 2004.

987

CHAPTER 189  AFAST AND TFAST IN THE INTENSIVE CARE UNIT Søren R. Boysen,

DVM, DACVECC

KEY POINTS • The focused assessment with sonography for trauma (FAST) scan is not an extensive evaluation of all organs of the abdomen. • The objective of the FAST scan is to detect free fluid in less than 5 minutes. • Not all trauma-induced abdominal injury produces free fluid. • The ultrasound probe should be moved and fanned at each FAST site to increase the sensitivity for detecting smaller localized pockets of free fluid. • Serial FAST examinations may detect delayed fluid accumulations and can be used to monitor progression or resolution of free fluid accumulations over time. • Positive findings on FAST scan in trauma patients typically indicate blood; however, ascites, urine, bile, and other forms of peritonitis cannot be ruled out. • The FAST scan can be used to detect free fluid in nontrauma patients. • The FAST scan can be extended to include views of the pleural and pericardial space, termed thoracic focused assessment with sonography for trauma (TFAST). • TFAST is used to detect pericardial effusions, pleural effusions, and pneumothorax. • Pneumothorax can be sonographically detected only when pleural air is located directly beneath the ultrasound probe. • The glide sign may be difficult to detect in patients that are panting or have rapid shallow respirations.

In contrast to traditional extensive formal ultrasound examinations performed by radiologists and cardiologists, focused assessment with sonography for trauma (FAST) examinations are focused and limited studies performed as a point-of-care emergency procedure to answer specific clinical questions or to facilitate specific procedures (i.e., fluid collection). FAST examinations have become the standard of care in many emergency department and intensive care unit (ICU) settings because they are safe, noninvasive, rapid, repeatable, and portable, and can be performed at the time of initial triage during patient resuscitation.1,2 To date, veterinary FAST examinations have involved ultrasound evaluation of the pericardial, pleural, and abdominal spaces for the presence of free fluid, and evaluation of the pleural space for pneumothorax, particularly in patients with cardiovascular instability and those with trauma.1-3 When the sonographic examination is focused to answer specific questions, ultrasound can be rapidly and effectively used to diagnose and manage patients in the ICU with minimal formal training in the technology.1-3

TERMINOLOGY The terminology for focused emergency ultrasound examinations differs between human and veterinary medicine. As in the original canine veterinary study, human studies use the term FAST when 988

referring to emergency ultrasound examinations of the abdomen and extended or E-FAST when referring to a FAST examination that includes the thorax.1,4 To differentiate abdominal from thoracic FAST examinations in dogs and cats, the two are also referred to as abdominal focused assessment with sonography for trauma (AFAST) and thoracic focused assessment with sonography for trauma (TFAST), respectively.2,3 The AFAST examination in dogs is analogous to the FAST examination in humans, and the two terms are often used interchangeably in veterinary medicine. The TFAST examination in dogs is analogous to the E-FAST examination in humans. This chapter uses the terms AFAST and TFAST when referring to veterinary studies and FAST and E-FAST when referring to human studies.

OBJECTIVE OF FOCUSED ASSESSMENT WITH SONOGRAPHY FOR TRAUMA The objective of FAST examinations is to obtain an immediate answer to a clinically urgent question. FAST examinations are typically performed when obtaining immediate results can help guide resuscitative efforts or delaying the diagnosis can result in deterioration of the patient. Classical situations in which FAST examinations have clinical utility include the patient with cardiovascular instability or the patient in respiratory distress when the underlying cause is uncertain. The chance of ruling in or ruling out a specific pathologic condition is typically maximized by using the FAST examination to answer simple binary (yes-no) questions such as “Is fluid present in the abdomen?” or “Is air present in the pleural space?” It is important to stress that focused emergency ultrasound assessments are not intended to replace more extensive formal ultrasound examinations. AFAST and TFAST examinations should be considered complimentary diagnostic tests performed in the critically ill or unstable patient to provide timely diagnostic information and to help facilitate the use of emergency techniques.

ABDOMINAL FOCUSED ASSESSMENT WITH SONOGRAPHY FOR TRAUMA There are three applications of focused emergency ultrasound scanning that have been studied in dogs experiencing abdominal trauma: AFAST, serial AFAST, and abdominal fluid scoring.1,2 AFAST is a rapid and focused examination of four sites in the abdomen designed to quickly rule in or rule out the presence of free abdominal fluid (typically indicative of hemorrhage). It is not an extensive examination of all the internal abdominal organs and should easily be accomplished within 5 minutes.1,2 AFAST may be used as an extension of the initial triage examination in patients that have experienced trauma and in patients with cardiovascular instability in which the cause of shock is unknown. Although the use of AFAST is relatively novel in veterinary medicine, preliminary studies in dogs and cats show it to have clinical utility in diagnosing and managing trauma-induced intraabdominal injury.1,2 Although not specifically studied in veterinary medicine, application of the AFAST

CHAPTER 189  •  AFAST and TFAST in the Intensive Care Unit

FF

Aerated lung

Bladder

Liver

FIGURE 189-1  Subxiphoid view. The subxiphoid view detects free fluid (FF) between the liver lobes and between the liver and the diaphragm (white arrow). In this image free fluid appears as an anechoic triangle between liver lobes. The liver and lungs are separated from each other by the diaphragm. This view can also be used to image the pleural and pericardial spaces (see Figure 189.6).

examination to nontrauma patients for the detection of free fluid due to uroabdomen, nontraumatic hemoabdomen, hollow viscus perforation, and other forms of peritonitis seems reasonable. The use of serial AFAST examinations has been studied in dogs experiencing blunt abdominal injury and was found to detect changes in the quantity of fluid present in the abdomen over time, especially when combined with determination of abdominal fluid score (AFS).2 In addition, some dogs with negative results on the initial AFAST examination had positive findings on serial AFAST examinations, which suggests that AFAST has improved sensitivity and specificity for detecting free fluid after blunt trauma when performed serially— similar to what has been shown in people.2,5 This is particularly true for hollow organ injuries and injuries resulting in only small amounts of free fluid, which are easily missed on the initial AFAST examination.5 Recommendations regarding when the FAST examination should be repeated vary; however, most studies suggest repeating the FAST examination every 2 to 4 hours, or as needed when the patient’s condition is difficult to stabilize or deteriorates following initial stabilization.2,5 The AFS is a semiquantitative evaluation of the degree of free fluid (typically hemorrhage) present in the abdomen and is performed by recording the number of sites among the four standard views (see the later section on technique) in which free fluid is detected in the abdomen.2 It has been suggested that by serially tracking and recording the progression or resolution of intraabdominal hemorrhage, the AFS may help direct therapeutic clinical decisions when considered along with other clinical examination findings.2 Although the AFS has shown initial promise in the management of dogs experiencing blunt abdominal injury, a study in cats failed to demonstrate such findings.6 Further studies are needed to assess the value of AFS as an endpoint of resuscitation and its utility in directing fluid therapy or surgical intervention in dogs and cats.

AFAST Technique The AFAST examination involves visualizing the diaphragm, liver, gallbladder, spleen, kidneys, intestinal loops, and urinary bladder at four sites of the abdomen for the detection of free fluid. Free fluid tends to accumulate in the most dependent areas of the abdomen as anechoic triangles surrounded by organs (Figures 189-1 through 1894).1 The examination can be completed without clipping the fur and

FF

FIGURE 189-2  Bladder view. The midline view over the bladder detects fluid against the external wall of the urinary bladder. In this view free fluid (FF) appears as an anechoic triangular shape abutting the urinary bladder wall in the near and far fields of the image.

FF Spleen

FF

Left kidney

FIGURE 189-3  Left flank view. The left flank view evaluates the splenorenal region. In this image free fluid (FF) is seen between the spleen and the left kidney, outlining the borders of both organs.

FF

Right kidney

Liver FF FIGURE 189-4  Right flank view. The right flank view is used to assess the hepatorenal region. In the near field of this image free fluid (FF) is seen between the body wall, right kidney, and liver. A loop of intestine (white arrow) can be seen “floating” within the free fluid. In the far field free fluid is noted outlining the cranial pole of the right kidney.

989

990

PART XXI  •  MONITORING 0

3

Liver 1

2

GB

5

4 VW

FIGURE 189-5  Transducer placement for the abdominal focused assessment with sonography for trauma examination. The patient can be placed in left or right lateral recumbency. In this figure the patient is shown in left lateral recumbency. The transducer is centered at one of four locations and then moved at least 4 cm and fanned through at least 45 degrees in a cranial, caudal, left, and right direction (arrows). Longitudinal views should be used at each site, and if results are equivocal then a transverse view should also be used. The four sites are (1) the subxiphoid site with the head of the transducer tilted cranially and placed just caudal to the xiphoid process (the transducer often has to be applied with some force to obtain good images, particularly in large breed dogs and when the pleural and pericardial spaces are included); (2) the midline site with the transducer placed over the bladder; (3) the right flank site with the transducer placed over the hepatorenal region; and (4) the left flank site with the transducer placed over the splenorenal region.

with the application of alcohol at the probe-skin interface, although some clinicians prefer to shave a small 2 × 2-inch area of fur at each site and apply ultrasound gel at the probe-skin interface.1,2 The AFAST examination can be performed with the patient in right or left lateral recumbency depending on the preference of the sonographer, patient stability, and the position of the patient at presentation (animals brought in left lateral recumbency can be scanned in this position to minimize stress to the patient from movement or manipulation).1,2 If the animal is in sternal recumbency or is ambulatory, the examiner may choose right lateral recumbency if the volume status of the patient is to be evaluated echographically (e.g., using an echocardiography table) or if the left retroperitoneal space is to be evaluated in detail. Left lateral recumbency may be preferred if the right retroperitoneal space is to be evaluated. Concurrent traumatic injuries including flail chest, fractures, or spinal cord injury may also dictate the AFAST examination position. Dorsal recumbency is typically avoided because blunt trauma commonly causes thoracic injury, and pulmonary function may deteriorate when patients with significant thoracic injury are placed in dorsal recumbency. The four standard views of the AFAST examination are (1) the subxiphoid or diaphragmaticohepatic view to evaluate the hepatodiaphragmatic interface, gallbladder region, pericardial sac, and pleural spaces; (2) the left flank or splenorenal view to assess the splenorenal interface and areas between the spleen and body wall; (3) a midline bladder or cystocolic view to assess the apex of the bladder; and (4) the right flank or hepatorenal view to assess the hepatorenal interface and areas between the intestinal loops, right kidney, and body wall (Figure 189-5).1,2 The examination can be accomplished using only the longitudinal view at each site, although adding the transverse view is helpful if results of the longitudinal view are equivocal.1,2 The ultrasound probe should be moved a few inches in several directions at each site and fanned through an angle of 45 degrees until target organs are identified to allow a greater area to be evaluated for the presence of free fluid.1 The time to complete the examination in dogs is 3 to 6 minutes.1,2 The order in which elements of the examination are performed is unlikely to affect the examiner’s ability to detect free fluid, but all four sites of the abdomen should be included in the examination, particularly if the AFS is to be determined. The subxiphoid or diaphragmaticohepatic site is often the first site examined because it

*

PF 10

15

20

FIGURE 189-6  Subxiphoid view of the thoracic focused assessment with sonography for trauma examination. The subxiphoid view provides an excellent acoustic window into the thorax via the liver, gallbladder (GB), and diaphragm (large white arrow). When the image depth is increased, the subxiphoid view can be used to evaluate the pleural and pericardial spaces. In this image pleural fluid (PF) is detected as an anechoic, roughly triangular accumulation located between the diaphragm, pericardial sac (short white arrow), and lung lobes. Pericardial effusion (*) is also seen as an anechoic arciform band between the pericardial sac and the ventricular wall of the heart (VW).

allows identification of the gallbladder, which can then be used to adjust the ultrasound settings.1,2 Visualization of the gallbladder is accomplished by tilting and fanning the probe to the right of midline and adjusting the gain until the fluid-filled gallbladder appears anechoic. Increasing the ultrasound depth at the subxiphoid location allows the examiner to evaluate the thoracic cavity distal to the diaphragm as far as the level of the heart (Figure 189-6). This view of the thorax is part of the TFAST examination and may allow free fluid to be detected in the pleural and pericardial spaces (see the section on TFAST). The sensitivity and specificity for detecting free fluid in the pleural and pericardial spaces via the subxiphoid view has not been reported in dogs or cats. Evaluating the pleural and pericardial spaces via the subxiphoid view may add to the length of time needed to perform the AFAST examination.

Abdominal Fluid Score Technique Determining the AFS involves recording the number of sites (among the four standard views) in which free abdominal fluid is detected with the animal in lateral recumbency. Animals with an AFS of 0, 1, 2, 3, and 4 would show negative findings at all sites, positive results at one site, positive findings at any two sites, positive results at any three sites, and positive findings at all four sites, respectively.2 Serial AFAST examinations should be performed every 2 to 4 hours, or more frequently as dictated by clinical findings (e.g., difficulty stabilizing the patient’s condition or a deterioration in hemodynamic status).2,7 Studies evaluating AFS in dogs and cats examined patients in both right and left lateral recumbency; however, it is unknown if patient position with respect to organ injury affects the AFS score. Further studies investigating patient position in relation to AFS score in dogs and cats are warranted.

AFAST for Blunt Abdominal Trauma FAST examinations are very sensitive and specific for the detection of free abdominal fluid, even when performed by nonradiologists.8-10 When present, free fluid detected by AFAST in trauma patients is usually indicative of hemorrhage.1,2 However, trauma-induced abdominal free fluid may be caused by different intraabdominal

CHAPTER 189  •  AFAST and TFAST in the Intensive Care Unit

injuries, including urinary tract rupture, biliary tract rupture, and hollow viscus rupture, so abdominocentesis with fluid analysis (including cytologic examination) is recommended to confirm the diagnosis.1

AFAST for Penetrating Abdominal Trauma FAST examinations are less sensitive at detecting intraabdominal injury following penetrating trauma than following blunt trauma.1113 FAST examinations omit large portions of the abdomen and do not reliably exclude localized organ injury. Penetrating trauma often results in localized injury, which may not result in sonographically detectable fluid accumulation, particularly when bowel injury occurs. However, if FAST examination results are positive following penetrating abdominal injury, patients are usually referred for emergency exploratory laparotomy.11-13 Therefore a positive result on FAST examination can help guide clinical decision making in patients with penetrating abdominal injury, but a negative finding on FAST examination does not rule out intraabdominal injury.11,13 The sensitivity for detecting free fluid caused by penetrating trauma is improved when serial FAST examinations are performed 12 to 24 hours after the initial insult.5

AFAST for Determining the Cause of Intraabdominal Injury Despite having excellent sensitivity for the detection of free abdominal fluid, FAST is not as sensitive at localizing the site of injury responsible for free abdominal fluid accumulations. Human studies demonstrate that FAST has a limited role in the detection of solid organ injury, which requires greater expertise to detect and adds significantly to the time needed to perform a FAST examination.14-16 In human studies, the sensitivity for sonographic detection of hepatic and splenic injury (the two most common causes of intraperitoneal hemorrhage in small animals following blunt trauma)17,18 varies from 41% to 80% depending on the organ affected, the location of the lesion, organ size, and the presence of overlying bowel and gastrointestinal gas.14-16 The sensitivity and specificity of ultrasound for detecting solid organ injury in human trauma patients is much higher (96.4% and 98%, respectively) when contrast-enhanced ultrasound is used.19 Blunt trauma–induced retroperitoneal injury is also difficult to diagnose consistently during FAST examinations in people, with low sensitivity demonstrated in several studies.20,21 Although the sensitivity for detecting retroperitoneal injury is increased when FAST examinations are performed serially, missed injuries are still frequent. In human trauma cases with negative findings on FAST examination in which retroperitoneal or solid organ injury is still suspected, further testing including computed tomographic scanning is recommended.20-22 The ability of AFAST to detect trauma-induced retroperitoneal and solid organ injury in veterinary medicine, with or without contrast enhancement, has not yet been investigated.

THORACIC FOCUSED ASSESSMENT WITH SONOGRAPHY FOR TRAUMA TFAST is a rapid focused evaluation of the thorax.3 The objective of the TFAST examination is to rule in or out the presence of air or fluid in the pleural space, and to rule in or out the presence of fluid in the pericardial space.3 In a prospective study of dogs experiencing blunt and penetrating thoracic trauma, the TFAST examination was found to have a sensitivity and specificity for detecting pneumothorax of 78% and 93%, respectively, compared with thoracic radiographs.3 It should be noted that there were considerable differences in sensitivity when the examinations were performed by an experienced sonographer (95% sensitivity with >70 scans) compared with a novice sonog-

rapher (45% sensitivity with