Small Animal Critical Care Medicine [2 ed.] 9781455703067

Table of contents :
Small Animal Critical Care Medicine
Copyright page
Contributors
Preface
Acknowledgments
Dedication
Reference Ranges
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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F
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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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iv

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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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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PART XII  •  INTRAABDOMINAL DISORDERS

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