Emerging Principles in Intensive Care- a 2020 Precis

Table of contents :
Table of Contents
Chapter 1: Genomics in Intensive Care 11
Transcriptomics 13
Epigenetics 14
Chapter 2: Respiratory Care 16
A. Respiratory Monitoring 17
Pulse Oximetry 19
Interpretation of ABG 24
B. Respiratory Diseases 26
Community Acquired Pneumonia 27
Hospital/ ventilator Acquired Pneumonia 30
Acute Respiratory Distress Syndrome 35
C. Lung Imaging 39
Lung Ultrasound 40
CT Scan 46
Pulmonary Perfusion Measurement 48
CT Perfusion 49
Dual Energy Computer Tomography- DECT 52
Positron Emission Tomography- PET 55
Electrical Impedance Tomography- EIT 56
D. Respiratory Management 60
Airway Management 61
Strategies to minimize aerosolization 81
Aerosolization therapy 82
Non-Invasive Respiratory Support 84
CPAP therapy 86
Head Helmets 87
High Flow Nasal Cannula- HFNC 89
Mechanical Ventilation 93
Nero-Muscular Blocking Agents 133
Humidification 134
Extra-Corporeal Therapies 137
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Table of Contents
Chapter 3: Neuro- Critical Care 151
Disorders of Consciousness 152
Status Epilepticus 158
Primary and Secondary Injury 160
ICP Management 162
Invasive ICP Monitoring 163
SIBICC Algorithm 163
Patient tailored ICP threshold 171
Traumatic Brain Injury 172
Management 183
Cervical Spine Clearance 189
Rapid Ultrasound for the Brain 191
Approach to Brain Ultrasound 191
Neuro-Monitoring 195
Cerebral Physiology and Metabolism 195
Critical Neuro worsening 196
Automated Pupillometry 197
Cerebral Autoregulation 199
Multi Modality Monitoring- MMM 206
Electro-Physiological Monitoring 208
Optimal Cerebral Perfusion Pressure 221
Brain Oxygen Monitoring 228
Cerebral Microdialysis 233
Chapter 4: Renal Critical Care 241
Acute Kidney Injury 242
Renal Replacement Therapy 252
Acute Renal Replacement Therapy 242
Intermittent Hemo-Dialysis 253
SLED/EDD 254
CRRT 255
Dialy-trauma 256
Fluid Therapy 257
Four Phases of Shock 258
Dose of Fluid Therapy 259
Cardiac Output Monitoring 261
Fluid Management in Polytrauma 263
Fluids Therapy in Renal Failure 265
Rules for Fluid Prescription 266
Chapter 5: Cardio-Vascular Critical Care 271
Atrial Fibrillation 272
Hemodynamic Management 276
Fluid Responsiveness 276
Vasopressor Therapy 278
Septic Shock 280
Circulatory Failure 287
Cardiogenic Shock 292
Revascularization 294
Ventricular Assist Devices 295
V A ECMO 302
Post Cardiac Arrest Management 307
Chapter 6: Sepsis 311
Blood Purification 315
Chapter 7: Tissue Monitoring 320
Mitochondrial Physiology 321
Assessment of Tissue Hypoxia 324
Monitoring Microcirculation 326
Measuring Capillary leak 327
Measuring Tissue RBC Perfusion 330
Measuring Convection 333
Measuring Diffusion Capacity 339
Tissue CO2 Monitoring 342
Monitoring Peripheral Perfusion 344

Citation preview

Emerging Principles in Intensive Care - a 2020 Precis

Ramakanth Pata, MD Swathi Patha, MD

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PREFACE

This book encompasses the evolving concepts in intensive care medicine for the year 2020. Leaving the nitty gritty of the major trials aside, only the intended principles derived from these studies with a touch of the current standard of care clinical practice guidelines are included. The details of these studies are referenced as ‘further reading’ at the end of each chapter. In text references and indexing was purposefully avoided to minimize distraction while reading the content. Although the essence of the book is presented as an authoritarian style, the reader should recognize that these concepts may still be naive. Lastly medicine is an ever changing field. Clinical plan depends on circumstances, expertise and experience. I do not take any responsibility for the clinical plan that is formulated based on the concepts derived from this book. In the spirit of furthering the science of medicine, I whole heartedly support FOAM (Free open access meducation). Please feel free to email me at [email protected].

Ramakanth Pata, MD

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Table of Contents Chapter 1: Genomics in Intensive Care

11

Transcriptomics

13

Epigenetics

14

Chapter 2: Respiratory Care

16

A. Respiratory Monitoring

17

Pulse Oximetry

19

Interpretation of ABG

24

B. Respiratory Diseases

26

Community Acquired Pneumonia

27

Hospital/ ventilator Acquired Pneumonia

30

Acute Respiratory Distress Syndrome

35

C. Lung Imaging

39

Lung Ultrasound

40

CT Scan

46

Pulmonary Perfusion Measurement

48

CT Perfusion

49

Dual Energy Computer Tomography- DECT

52

Positron Emission Tomography- PET

55

Electrical Impedance Tomography- EIT

56

D. Respiratory Management

60

Airway Management

61

Strategies to minimize aerosolization

81

Aerosolization therapy

82

Non-Invasive Respiratory Support

84

CPAP therapy

86

Head Helmets

87

High Flow Nasal Cannula- HFNC

89

Mechanical Ventilation

93

Nero-Muscular Blocking Agents

133

Humidification

134

Extra-Corporeal Therapies

137

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Table of Contents Chapter 3: Neuro- Critical Care

151

Disorders of Consciousness

152

Status Epilepticus

158

Primary and Secondary Injury

160

ICP Management

162

Invasive ICP Monitoring

163

SIBICC Algorithm

163

Patient tailored ICP threshold

171

Traumatic Brain Injury

172

Management

183

Cervical Spine Clearance

189

Rapid Ultrasound for the Brain Approach to Brain Ultrasound Neuro-Monitoring

191 191 195

Cerebral Physiology and Metabolism

195

Critical Neuro worsening

196

Automated Pupillometry

197

Cerebral Autoregulation

199

Multi Modality Monitoring- MMM

206

Electro-Physiological Monitoring

208

Optimal Cerebral Perfusion Pressure

221

Brain Oxygen Monitoring

228

Cerebral Microdialysis

233

Chapter 4: Renal Critical Care

241

Acute Kidney Injury

242

Renal Replacement Therapy

252

Acute Renal Replacement Therapy

242

Intermittent Hemo-Dialysis

253

SLED/EDD

254

CRRT

255

Dialy-trauma

256

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Table of Contents Fluid Therapy

257

Four Phases of Shock

258

Dose of Fluid Therapy

259

Cardiac Output Monitoring

261

Fluid Management in Polytrauma

263

Fluids Therapy in Renal Failure

265

Rules for Fluid Prescription

266

Chapter 5: Cardio-Vascular Critical Care

271

Atrial Fibrillation

272

Hemodynamic Management

276

Fluid Responsiveness

276

Vasopressor Therapy

278

Septic Shock Circulatory Failure Cardiogenic Shock

280 287 292

Revascularization

294

Ventricular Assist Devices

295

V A ECMO

302

Post Cardiac Arrest Management

307

Chapter 6: Sepsis Blood Purification Chapter 7: Tissue Monitoring

311 315 320

Mitochondrial Physiology

321

Assessment of Tissue Hypoxia

324

Monitoring Microcirculation

326

Measuring Capillary leak

327

Measuring Tissue RBC Perfusion

330

Measuring Convection

333

Measuring Diffusion Capacity

339

Tissue CO2 Monitoring

342

Monitoring Peripheral Perfusion

344

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Chapter 1: Genomics in Intensive Care

Chapter 1: Genomics in Intensive Care

11

Transcriptomics

13

Epigenetics

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Chapter 1: Genomics in Intensive Care Definitions Genetics is the study of heredity. Genomics is the study of genes, their functions and related techniques. The main difference is that genetics scrutinizes the functioning and composition of the single gene whereas genomics addresses all genes and their inter relationships in order to identify their combined influence on the growth and development of the organism. Molecular biology studies the composition, structure and interactions of cellular molecules such as nucleic acids and proteins that carry out the biological processes essential for the cells functions and maintenance. Molecular biology is inter related to genomics. Genomics deal with genes, molecular biology deals with proteins from the genes, biochemistry deals with the function of these proteins. Phenotype is defined as an observed trait. Genotype is the genetic information defining the phenotype. Alleles is the alternative forms of a gene or a genetic maker, one or more variants of a gene. Various denominators can be used to describe an allele. For example: DNA sequence: Polymorphisms Combination genetic markers: Haplotype Functional: Wild type versus disease causing Parenteral origin: Maternal or paternal Haplotype is a group of genes with in an organism that was inherited together from a single parent. Polymorphism is a genetic variant where the rarer allele in a population occurs with a frequency > 1%, independent of the functional or pathogenic relevance of this alteration. SNP or Single nucleotide polymorphism is where the alleles vary within one single nucleotide base. Mutation is the occurrence of a change in genomic sequence or the resultant change itself e.g. disease causing genetic variants. The central dogma of gene expression includes transcription (DNA -> RNA), translation (RNA -> expressed protein) and posttranslational modification (expressed protein -> modified protein). Nucleosome is a structure formed after DNA is coiled around histones.

Genomics in Sepsis Genes may have an influence of susceptibility of the host to infection, mounted immune response and the outcome including mortality. For Example: 11

X chromosomal TLR7 abnormalities are associated with impaired type I and II IFN responses. TLR7 (cell endosomes) are a part of innate immune system to clear virus by inducing pro-inflammatory cytokines and interferons. TLR: Toll like receptors.

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Transcriptomics: Study of transcription and RNA. This is based on the assumption that the amount of mRNA for any gene is reflective of its impact on the cell function. Technique of transcriptomics primarily involves RNA sequence capture of mature messenger RNA (mRNA) while targeting the characteristic poly-A tail of m RNA. The study of the transcriptome, which is a complete set of RNA transcripts that are produced by the genome, under specific circumstances or in a specific cell using high throughput methods such as micro array analysis or next generation sequencing. Comparison of transcriptomes allows the identification of genes that are differentially expressed in distinct cell populations, or in response to different treatments. For example: 1 Gene expression has been used to differentiate between bacterial and viral pneumonia on day 1. 2 Patients with sepsis have been classified according to their blood genomic endotype (MARS type 1, 2, 3 and 4) that seem to predict mortality consistently. 3 Bacterial sepsis based on transcriptomic have been classified in to 3 subtypes that include a) coagulopathic (high mortality), b) adaptive (low mortality) c) Inflammopathic.

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Epigenetics: All other things that influence between DNA and protein are classified under epigenetics. These can be classified based on the "step of gene expression" that they influence. At the level of Transcription: Gene copy number Promotor activity Repression/Attenuation Histone modification Induction DNA methylation Chromatic remodeling At the level of Translation: mRNA life time Codon usage tRNA levels Ribosome binding Alternative Splicing RNA interference At the level of protein expression/post translational modification: Protein turn over Chemical modification such as phosphorylation Inhibition Allosteric change Non coding genome generates vast number of ncRNAs (ncRNA=non coding RNA) with diverse structures. Three classes are under investigation for diagnostic and therapeutic purposes. 1400 microRNAs (grouped in to 63 families) 16,000 long non coding RNAs (Several classes) Circular RNAs (unknown number) Epigenetics may have played a role in co-morbidities such as cardiovascular disease, diabetes, auto immune and sepsis, cancer (DNA in cancer cells regularly have different methylation pattern to the hosts normal cell). Other relevant fields of genomics include pharmacogenetics, pathogen genetics and mitochondrial genes that may have relevance in intensive care approaches including therapy.

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Further Reading Scicluna BP, van Vught LA, Zwinderman AH, Wiewel MA, Davenport EE, Burnham KL, Nürnberg P, Schultz MJ, Horn J, Cremer OL, Bonten MJ, Hinds CJ, Wong HR, Knight JC, van der Poll T; MARS consortium. Classification of patients with sepsis according to blood genomic endotype: a prospective cohort study. Lancet Respir Med. 2017 Oct; 5(10):816-826. doi: 10.1016/S2213-2600(17)30294-1. Epub 2017 Aug 29. PMID: 28864056. Sweeney TE, Azad TD, Donato M, et al. Unsupervised Analysis of Transcriptomics in Bacterial Sepsis across Multiple Datasets Reveals Three Robust Clusters. Crit Care Med. 2018; 46(6):915-925. doi:10.1097/CCM.0000000000003084.

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Chapter 2: Respiratory Care Chapter 2: Respiratory Care A. Respiratory Monitoring

16 17

Pulse Oximetry

19

Interpretation of ABG

24

B. Respiratory Diseases

26

Community Acquired Pneumonia

27

Hospital/ ventilator Acquired Pneumonia

30

Acute Respiratory Distress Syndrome

35

C. Lung Imaging

39

Lung Ultrasound

40

CT Scan

46

Pulmonary Perfusion Measurement

48

CT Perfusion

49

Dual Energy Computer Tomography- DECT

52

Positron Emission Tomography- PET

55

Electrical Impedance Tomography- EIT

56

D. Respiratory Management

60

Airway Management

61

Strategies to minimize aerosolization

81

Aerosolization therapy

82

Non-Invasive Respiratory Support

84

CPAP therapy

86

Head Helmets

87

High Flow Nasal Cannula- HFNC

89

Mechanical Ventilation

93

Nero-Muscular Blocking Agents

133

Humidification

134

Extra-Corporeal Therapies

137

A. Respiratory Monitoring

Pulse Oximetry Invented by Takuo Aoyagi. Pulse oximetry is used in monitoring: SpO2 (ambulatory, home, continuous monitoring) Pulse Rate Peripheral Perfusion Index (PI) Pulse/Pleth variability index (PVI) Changes in the Hemoglobin. Closed loop system to titrate O2 flow to target SpO2. Track changes in the BP

Perfusion Index (PI): Perfusion index is the relative strength of the pulsatile signal from pulse oximetry. It has been considered as a reliable indicator of peripheral perfusion. PI is derived as a ratio of pulsatile signal (AC) to the nonpulsatile signal (DC) times 100, and is expressed as a percent.

Figure demonstrating the calculation of Perfusion index

Determinants of Perfusion index include: Vascular tone 19

Sympathetic activity Blood flow or stroke volume If the vascular tone does not change i.e. in a short period of time, changes in PI should reflect changes in stroke volume. Extrapolating this concept to the passive leg rising (PLR) test for fluid responsiveness, PI can be employed as a surrogate of cardiac output when passive leg rising test is performed. A cut off of PLR induced increase in PI > or = 9% can be considered as a fluid responder. Similarly changes in PI due to lung recruitment maneuver (LRM) can also be used to predict fluid responsiveness in mechanically ventilated patients. This is based on the premise that fluid responders who are mechanically ventilated, demonstrate a drop in stroke volume (> 30%) during a lung recruitment maneuver. Lung recruitment maneuver: Airway pressure of 30 cm H20 applied for 30 secs, if stroke volume drops by 30% is a sign of fluid responsiveness. Similarly, if perfusion index drops by 26% is a sign of fluid responder. Fluid responder based on PI: PLR induced increase by 9% or LRM decrease by 26%.

Pleth Variability index: Pleth Variability Index (PVi) is a noninvasive technique of measuring fluid responsiveness. This technique is based on the respiratory variations of the plethysmography. Higher variability is associated with fluid responsiveness and preload dependence. Although many factors influence the index, it has been proposed as a measure of fluid responsiveness in adult patients on mechanical ventilation. This dynamic index can range from 0 – 100. It is analogous to Pulse pressure variation. In a spontaneously breathing patient, pulses paradoxus is present and with increasing respiratory effort, the amplitude fluctuates even more. Thus PVI in a spontaneously breathing patient can be used as a marker of respiratory distress in acute respiratory failure. Rather, excessive variation in the plethysmography waveform during spontaneous ventilation is an important sign of upper airway obstruction. Oximetry detected pulsus paradoxus has been proposed to predict severity in pediatric asthma patients. It has been observed that drop in delta esophageal pressure in a patient on NIV can predict NIV success. Extrapolating this concept, it can be safely assumed that PVI can be thus used as a variable to predict NIV success.

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Figure: PVI

Figure: Demonstrating the equation for PVI

Closed loop system to titrate O2 flow to target SpO2: Continuous monitoring by pulse oximetry connected to a closed loop system to titrate Oxygen flow to a target SpO2 has been shown to decrease the total amount of O2 administration, decrease length of hospital stay and increase the time the patient is above target SpO2.

Track changes in the BP: The pulse waveform is continuously analyzed by morphological feature extraction and machine learning to generate Systolic, mean and diastolic blood pressure.

Oxygenation Reserve Index The Oxygen Reserve Index (ORI) is a pulse oximeter based index that ranges from 1 to 0 as PaO2 decreases from about 200 to 80 mm Hg. This is measured by optically detecting changes in SvO2 after SaO2 saturates to the maximum. ORI has been proposed as a tool to detect impending desaturation by a median time of around 30 seconds, so that corrective actions can be initiated early.

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Figure: Relation of SpO2 and ORI to PaO2.

Figure: Time line of ORI alarm that can be observed earlier than the alarm of Spo2.

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Conclusion: Pulse oximetry is useful at: Home: to trigger hospitalization without delay. Ambulatory monitoring: wireless wearable connected to smartphone and command center Self-monitoring twice a day with a miniaturized pulse oximeter. Wards: continuous monitoring wired or wireless. For early detection of clinical deterioration Closed loop system for O2 administration. SpO2 remains input variable. Monitoring of respiratory effort (PVI) to detect need for intubation early enough. ICU: Can be employed for rational fluid management in addition to above Changes in PI during preload modifying maneuver.

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Interpretation of ABG Measured parameters: pH, PaCO2, PaO2 Calculated parameters: HCO3, Base excess/deficit, SaO2. SaO2 – It is usually calculated unless a co-oximetry is obtained, in which it is measured. PaO2 is helpful in determination of Oxygen diffusion or shunt. pH and CO2 are valuable in assessing ventilation and presence of acidosis/alkalosis. Base deficit/Excess: Difference between measured serum bicarbonate level and normal value of 27 (bicarbonate and carbonic acid). It is a non-respiratory reflection of acid-base status. Normal Values include: PH: 7.35 - 7.45 PaO2: 75-100 mm HG; 10-13.3 Kpa PaCO2: 35-45 mm HG; 4.7-6.0 Kpa HCO3: 22- 26 meq/L Base excess/ deficit: -4 to + 2 SaO2: 95 – 100%. NB: ABG can be abnormal even if pH is 7.40.

Rules of compensation: in sequence For every 10mm HG (1.33 Kpa) change in PaCO2, pH will change by 0.08. - Acute respiratory For every 10 meq/L change in base (not due to base changes related to PaCO2), pH will change by 0.15. For example: pH is 7.25, pCO2 is 66. Determine pH change, 7.40-7.25 = 0.15, PaCO2 change = 66-40=26. Expected change in pH only due to change in CO2 is 26/10 * 0.08 = 0.208 approx. 0.21. pH due to CO2 should have been 7.19. Hence respiratory acidosis with metabolic component. Metabolic related pH is therefore 7.25-7.19 = 0.06. This will be equivalent to base excess of 0.06 * 10/0.15 = 4mEQ of base excess. ABG can also determine the type and duration of the event such as Cardiac arrest by looking at the rise in PaCO2. Following are the normal values for the rise in PaCO2.

Rise in PaCO2 if no ventilation: 1. Awake patient with normal metabolic state: 6-7 mm HG/min (6.5) equivalent to 0.8 Kpa. 2. Anesthetized patient: 3.5 mm HG/min (3.5) 3. Brain death: 1.5-2.5 mm HG/min (2.5) 4. Cardiac arrest: 1-2 mm HG/min (1.5).

In metabolic disorders, look at the AG. AG: Na – Cl + HCO3. Normal = 3-11 meq/L. Principle anion in AG is albumin. Corrected AG: AG + 2.5 (4 – serum Albumin).

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Information from PaO2: A-a gradient or PaO2/FiO2 ratio determines the VQ mismatch and Shunt. A-a gradient = PAO2 [(760=47) * FiO2 – PaCO2/0.8)] - PaO2. Normal is 10-20 mm HG (Higher in range as we age). PaO2/FiO2 ratio < 285 is consistent with significant diffusion issue.

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B. Respiratory Diseases

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Community Acquired Pneumonia Management of severe CAP: 1. Early recognition of severe illness and pathogen diagnosis 2. Proper site of care: Use ATS severe CAP tool to identify if patients require ICU care

Figure: Criteria to define Severe CAP 3. Severity assessment and biomarkers 4. Supportive care: Oxygen therapy Delayed intubation is a risk for worse outcome in CAP including mortality For PF ratio < 300, consider HFNC if no immediate need for intubation. HFNC lowers mortality and decreases the need for intubation 5. Proper antibiotic selection: Beta lactam/Macrolide for all (adding Macrolide better favorable than FQs) Plus PES coverage if >/= 2 risk factors (Risk based therapy) PES pathogens: Pseudomonas aeruginosa, ESBL Enterobacteriaceae, MRSA Oseltamivir without steroids for influenza NB: Macrolide addition had the best benefit in Pneumococcal CAP with high CRP. Not all Macrolides have seen the same benefit. Azithromycin is probably the safest macrolide in terms of cardiac events (? Related to fluid volume).

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Risk Factors for PES pathogens: Systemic antibiotics in the past 3-6 months Hospitalization for> 2 days in the past 90 days Gastric acid suppression therapy Hemodialysis Immune suppression therapy Home wound care Chronic lung disease (COPD, bronchiectasis, tracheostomy) Poor functional status (Barthel’s index < 50, need for tube feeding, not ambulatory) Previous colonization/ infection (MRSA, Pseudomonas, PES pathogens) Recurrent skin infection Residence in a long term care facility 6. Adjunctive therapy (Steroids, IVIG): Steroids for severe CAP with high inflammation

Role of endogenous Steroids in Pneumonia: Immunopathogenesis in Pneumonia: Alarm phase: Resident immune cells (fibroblasts, mast cells, Macrophages) are activated by PAMP and DAMPs (Pathogen and damage associated molecular patterns) releasing inflammatory mediators. Mobilization phase: Corticosteroids are immediately released to regulate the inflammatory responses by inhibiting selectin and ICAM, P CAM, prevent tethering, coning and transmigration of circulating immune cells. Resolution phase: In the resolution phase ( a few days later) , glucocorticoids activate macrophages to Macrophage type 2C for removing apoptotic debris in addition to releasing anti-inflammatory mediators like IL-10 and TGF-b. Wound healing phase: Glucocorticoids regulate reepithelization, collagen deposition and angiogenesis (VGF) during the wound healing phase.

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Effect of Glucocorticoids on Immune cells: Glucocorticoids reprogram the genes rather than simply suppressing the mediator release. Glucocorticoids upregulate genes favoring innate immunity and suppress adaptive immunity. Innate immunity: Inflammation: Complement, cytokines, chemokines, enzymatic mediators Innate recognition: Scavenger system, Integrin, Apoptosis Adaptive immunity: Humoral, cellular immunity, Antigen presentation. Glucocorticoids cause polarization of T cells mediators. They inhibit Th1 and TH17 cells, They favoring Th2 and Treg cells. No effect on TH9 cells

Beneficial effect of exogenous steroid administration in Pneumonia: Recover sooner by 2 days, shorten hospital stay by 3 days – hasten clinical cure Steroids decrease the need for mechanical ventilation – hasten respiratory failure Reduced vasopressor need, decreased SOFA score (organ dysfunction) - resolution of shock Improved survival. Improve short and long term all-cause mortality in CAP When not to consider Steroids: Steroids in Influenza increase mortality and hospital acquired infection, delay clearance of virus Avoid steroids if contraindicated (DM needing insulin therapy, Major GI bleed in last 3 months) Then choose patients with the following categories: Community acquired pneumonia related septic shock / ARDS (Greater benefit in sickest patients) CRP > 15 mg/dl or 150 mg/L Steroid administration: Start as early as possible. 0.5 mg/kg/12hrs of Methylprednisolone or equivalent for 5 days.

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Hospital Acquired / Ventilator Associated Pneumonia HAP is a new pneumonia verified by the presence of new pulmonary infiltrate on imaging that develops more than 48 hours after admission in non-intubated patients. VAP is a new pneumonia that develops after 48 hours of endotracheal intubation, whether the patient is currently intubated or not. The term "HCAP (Health care associated Pneumonia)" has been eliminated as the criteria for HCAP did not reliably correlate with the presence of MDR organisms, nor did the mortality rates when corrected for patient’s age and comorbidities.

Risk Factors: Any factor that increases the risk of aspiration increases the risk for HAP/VAP. These include: Age Recent surgery Admission for neurologic causes Admission for cardiovascular failure Accumulation of Purulent mucous may increase the risk of VAP: Accumulation of purulent mucous along with epithelial cell damage is responsible for nosocomial pneumonia. Change in microbiome may also increase the risk for VAP. The risk factors for accumulation of purulent secretions include: Poor chest physiotherapy Poor oral care Oropharyngeal colonization Sedation/Delirium

Etiology: Coinfection s with viruses and bacteria is possible. Viruses: 20%. Most common include RSV, parainfluenza and rhinovirus. MDR organisms include MRSA and multi drug resistant Pseudomonas aeruginosa. Risk factors for MDR organisms include: Intravenous antibiotic use in the last 90 days Cystic fibrosis and bronchiectasis Septic shock or ARDS Renal replacement therapy At least 5 days of hospitalization

Diagnosis: Requires all of the following criteria 30

New lung infiltrate in chest imaging Respiratory decline Fever Nonproductive cough Absence of a new infiltrate significantly lowers the probability of VAP and alternative diagnosis such as pulmonary embolism should be sought.

Diagnostic tests: 1. Blood cultures: 25% of VAP, bacteremia is reflective of secondary non pulmonary source. If blood cultures are positive for Candida or Enterococcus, think of Catheter related Blood stream infection, as these organisms are not known to cause Pneumonia. 2. High quality Noninvasive Sputum culture: High quality is defined as few or no squamous epithelial cells on gram stain. 3. Semi-quantitative endotracheal aspirates should be preferred if sputum samples cannot be obtained , as quantitative testing may falsely be unremarkable if antibiotics have already been started before sample collection and erroneously trigger the cessation of appropriate therapy. Even Invasive sampling such as bronchoscopy and blind bronchial sampling (mini BAL) has not been associated with improvement in mortality rate, ICU length of stay and duration of mechanical ventilation. 4. Invasive sampling should be obtained (because of higher diagnostic yield) in Immunocompromised patient Continued decline despite antibiotics and negative noninvasive evaluation Positive invasive sampling for VAP = high cellularity (> 400,000 cells/ml), PMN > 50% in BAL. Can discontinue antibiotics if final BAL culture < 10 ^4 CFU/ml, though it must be remembered that the yield of bronchoscopic cultures dramatically decrease after 72 hours of antibiotic exposure. 5. PCR testing: can be considered to diagnose pathogens to guide antibiotic stewardship. In the context of HAP ( not VAP) , a negative nasal swab for MRSA might confidently guide to discontinue anti MRSA agents especially in patient population with MRSA prevalence of 10%, because of high negative predictive value. However it lacks sensitivity and specificity for VAP. A respiratory viral panel is also pcr based nasopharyngeal swab should be used during the influenza season to identify viral causes, for which antibiotic therapy is not essential. 6. Procalcitonin: Any infectious pneumonia can elevate serum Procalcitonin. Typical bacteria have higher procalcitonin levels than atypical bacteria or viruses. This is because cytokines associated with bacterial infections enhance procalcitonin release, whereas interferons associated with viral infections inhibit procalcitonin release. Elevated Procalcitonin in a patient with PCR proven viral infection such as influenza can suggest bacterial superinfection and may merit continuation of antibiotic therapy .A low positive or negative procalcitonin level in a patient with PCR proven viral infection may lend confidence for the diagnosis of viral HCAP/VAP and can consider safe discontinuation of antibiotics .A negative procalcitonin in a patient with clinical history suggesting alternative causes of respiratory decline or marked improve31

ment with diuresis may also indicates towards safe discontinuation of antibiotics. 7. Analysis of subglottic secretions Oropharyngeal secretions accumulate in the subglottic area above the cuff of ET tube. These particles may slide down in to trachea via microscopic channels in the cuff first causing colonization of distal airways – Sub glottic colonization.

Intermittent subglottic secretion drainage seems to decrease the incidence of VAP. Diagnosis by microbiology of samples (Sputum analysis, endotracheal aspirate, fiber optic bronchoscopic aspirate, BAL). Subglottic secretions culture are also accurate in identifying ET aspirates with excellent sensitivity and good negative predictivity. Subglottic cultures may not be inferior to ET aspirate in predicting BAL results in case of Ventilator associated Pneumonia. Furthermore, culturing subglottic secretions may prevent aerosolization of samples obtained via other sampling techniques if the patient required closed infection control measures.

Management: 1. When to start antibiotic therapy: Not all need immediate therapy Immediate antibiotics (Clinical strategy) should be considered in patients satisfying both of the following two criteria (diagnostic criteria and risk factor criteria). Diagnostic criteria: fever, productive cough/Secretions and leukocytosis Risk Factor criteria: Hemodynamic and respiratory instability, immunocompromised, unable to have lower respiratory samples. Culture based antibiotic initiation (bacteriologic strategy) in all others. In this strategy, antibiotics are held until all quantitative cultures of lower respiratory tract samples confirm a diagnosis of HAP/VAP.

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2. What to start: If risk factors for MDR organisms are present, it is reasonable to start antibiotics accordingly. MRSA antibiotics: vancomycin or linezolid Consider Anti MRSA if: Recently received intravenous antibiotics in the last 90 days Hospitalized in a unit with 20% or more of MRSA prevalence / unknown High mortality risk Pseudomonas aeruginosa: Piperacillin-tazobactam, cefepime, levofloxacin, imipenem, meropenem Consider two anti-pseudomonal drugs if: Recently received intravenous antibiotics Placement in ICU, where 10% of isolates are resistant gram negatives Presence of pseudomonas bacteremia High risk of death Despite the purported role of aspiration, empiric anaerobic coverage is not always indicated as after 48 hours of hospitalization, the bacterial colonization of oropharynx and ET tube evolves form streptococcal and anaerobic species to a predominant gram negative nosocomial flora. Inhaled antibiotics: If pathogens are susceptible to aminoglycosides or polymyxins, inhaled aminoglycosides or colistin can be considered in conjunction with intravenous formulation as inhaled antibiotics achieve higher target site concentration and less nephrotoxic although adjunctive inhaled antibiotics have not been demonstrated to affect overall mortality in VAP. Final regimen should include coverage for oral and enteric flora including gram negative and anaerobic bacteria even if sputum culture demonstrate only 1 pathogen , as HAP/VAP are considered inherently polymicrobial given the aspiration as risk factors. 3. How long to treat: Uncomplicated HAP/VAP: 7 days. Longer course, not much difference in outcomes (mortality, ventilator days, failure) Complicated HAP/VAP: e.g. if empyema, bacteremia, pathogens such as Pseudomonas, Acinetobacter Consider for 2 weeks, as there is risk of relapse.

Prevention: 1. Preventing colonization and Aspiration: Regular oral care (good oral cleanse, electric tooth brushing) Not necessarily chlorhexidine (to be decided on case by case basis) Assessment the need for PPI and histamine 2 receptor blocker Early identification and Rx of dysphagia in elderly, recent stroke and surgical procedures Head of bed elevation > 30 degrees 33

Once daily respiratory therapy driven weaning attempts Change from nasogastric to oro-gastric tube if feasible Maintain tracheal cuff pressure Eliminating non-essential tracheal suction Avoiding gastric over distension 2. Microbiome management: Probiotics have theoretical benefit, however evidence is lacking Selective digestive decontamination with topical antiseptic enterally for 5 days. (This has been shown to decrease mortality and decreased acquisition of MDR organisms, although a theoretical risk of Clostridiodes difficile). 3. Infection Control: Vaccinations in general population decreases the transmission of microorganisms Respiratory hygiene measures such as hand washing, mask for coughing patients Routine Cleaning or single use stethoscope and procedural equipment Universal gown glove contact isolation

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Acute Respiratory Distress Syndrome ARDS is a syndrome and not a disease. Acute hypoxemic respiratory failure is a type of respiratory failure with hypoxia. One subset of this hypoxic respiratory failure with certain characteristics has been termed ARDS. For example, a unilateral pneumonia may cause acute hypoxic respiratory failure, but according to Berlin definition, this would not be classified as ARDS despite the severe hypoxia. However the outcome and mortality is proportional to the number of quadrants involved whether it is ARDS or hypoxic respiratory failure. If adjusted for the area involved, then the mortality remains the same whether it is referred to as acute hypoxic respiratory failure or ARDS. ARDS may be more of conceptual definition than of clinical importance.

Concept of Berlin definition

NB: Unilateral opacity is not considered ARDS. Compliance criteria was removed in the Berlin definition. The morphological hall mark in ARDS is "diffuse alveolar damage”:a k a Pneumolysis Lesional pulmonary edema, PMN inflammation Hyaline membrane Intra alveolar hemorrhage. However there is discrepancy between Berlin definition and pathological co-relation. Not all ARDS have diffuse alveolar damage. Not all diffuse alveolar damage fit in to the criteria of ARDS. In addition, not all ARDS are same. Many different phenotypes with different responses to a particular treatment exist. Multiple causes of ARDS exists right that includes malaria, Wegener's granulomatosis etc.

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Concept of Phenotypes Despite the different phenotypes, mortality is higher in patients with both endothelial (high D dimer) and alveolar (low compliance) damage than either one. Recently described phenotypes include type L and type H. For the same degree of hypoxia, it may be possible that different ARDS can have totally different compliance. Hence it may be that compliance does not co-relate well with the severity of hypoxia. However decreased compliance is associated with increased mortality. These different phenotypes of L and H may be secondary to loss of lung vasomotor tone (loss of hypoxic pulmonary vasoconstriction) in the L type. Type L: Low elastance (high compliance), Low V Q ratio, Low lung weight, Low lung recruitability. Type H: High elastance (low compliance), High Right to left shunt (Qs/Qt), High weight, High recruitability. Patients often transition between the phenotypes and hence close monitoring and vigilance should be exercised. This is because the ventilator adjustments may be different in different phenotypes. For example in L type , where the compliance is often good at > 50 ml/CM H2O, intubation may be considered in the presence of high work of breathing , not for improving gas exchange , but to prevent PSILI. Hence mechanical ventilator settings may be slightly different. Tidal volume need not be limited to 6 ml/kg, although higher Vt may be injuries Respiratory rate < 20 /min High levels of PEEP (> 10 cm H2O) are not useful if high compliance and increased dead space Prone position can be considered to redistribute the blood flow.

Concept of Shrinking Baby Lung In terms of respiratory mechanics, ARDS lungs have been classically referred to as "Shrinking baby" lung that is a hall mark of VILI – the VILI vortex.

Figure: Evolving concept of the “baby lung” of ARDS. Initial interpretation of the supine CT images suggested a fixed anatomical location (left panel). Subsequently, the shifting of the aerated compartment by prone repositioning demonstrated its lack of structurally fixed location, functional nature, and responsiveness to changes in transpulmonary pressure (middle panel). The vulnerability of aerated lung units to pro36

gressively concentrating power that injures and promotes dropout of lung units from the functional compartment over time is implicit in the current “dynamic” model of the shrinking baby lung (right panel) Downward spiral of progressive lung shrinkage has been termed as VILI vortex. Progressive stress loading leads to unit drop out increasing the ventilation load. This increases specific power causing intolerable fibril strain further worsening stress loading. This has been called VILI vortex. Decreasing the transpulmonary pressure should be the goal to deescalate VILI vortex. This can be achieved either by invasive or noninvasive O2 therapy.

Concept of inflammatory Sub phenotypes in ARDS: Hyper inflammatory ARDS ( Type 2 ) : elevated IL-6 , IL-8 Hypo inflammatory ARDS (Type 1): decreased levels of inflammatory cytokines. Hyper inflammatory ARDS has better response to higher PEEP. Hypo inflammatory ARDS has higher mortality, higher organ dysfunction and higher duration of ventilator days if higher PEEP is used. Hence hyper inflammatory phenotype may benefit from higher PEEP and hypo inflammatory phenotype benefits from lower PEEP.

Treatment: 1. No drug has shown to be beneficial. Because ARDS is a syndrome and not a disease. Survival rates depend on identifying the cause and correcting it. 2. Protective lung ventilation should be applied during spontaneous as well as controlled i.e. NIV and invasive. This is applicable both in sick and as well as healthy lungs (even without ARDS). Although focal lung pathology may tolerate tidal volume up to 8 ml/kg and a lower PEEP without consequences. Intubation must be considered in patients with high work of breathing. 3. Tailored approach to the level of severity in ARDS according to PF ratio. PF ratio < 300: Vt < 6ml/kg PBW, Pplat < 30 cm H2O, PEEP > 5 cm H2O PF ratio < 200: Higher level of PEEP PF ratio < 150: Neuromuscular blockers < 48hrs, Prone positioning > 12-16 hours PF ratio < 80: Discuss V V ECMO. This tailored approach may be valid in ARDS with lower compliance which is characterized by high lung recruitability, high elastance (Type H). 4. Application of Prone position during mechanical ventilation may make the lungs more recruitable.

Prone position in spontaneous/ NIV Ventilation: Rationale: Spontaneous ventilation in ARDS can predispose to SILI, Mechanical ventilation to VILI Prone position in spontaneous breathing may minimize drive (decreased RR) and hence SILI. Prone position may improve hypoxia in patients with elevated shunt fraction minimizing the need for intubation and there by minimizes VILI. 37

Selecting patients: In patients with high compliance and high shunt with moderate respiratory failure. PF ratio: 100-200 Use Helmet/ CPAP/ HFNC/ NIV as adjunctive Rx. Follow up: All patients who receive prone position during spontaneous ventilation/ NIV must be closely monitored for 1 hour. If the SpO2 >/=95%, continued vigilance may be exercised. If SpO2 < 95%, intubation may be considered based on clinical circumstance.

Prognosis: PEEP induced O2 improvement predicts survival. If no response to PEEP, the mortality is higher. Having alveolar inflammation (decreased compliance) and endothelial involvement (D-dimers) seems to have worse outcomes compared with either one. Elevated d-dimers increases Ventilatory ratio, which is a proxy of dead space fraction. Elevated D dimers indicates microvascular thrombosis and endotheliopathy. Discordance between decreased compliance and level of hypoxemia indicates either "loss of hypoxic Vasoconstriction" or increased dead space. This is when D-dimers be considered in ARDS with discordant hypoxia. Markov Chain model for predicting the outcome of ARDS related to Certain Viral Pneumonia demonstrated that the following parameters were important in escalating the transition of care in terms of escalating O2 requirements such as NIV to invasive, invasive to ECMO. CRP > 150 SAPS score > 25 SOFA score > 4

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C. Lung imaging

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Lung Ultrasound Ultrasound of the lung is done at the following points defined in the BLUE protocol. The BLUE protocol.

Figure: The BLUE protocol of lung ultrasound. Two hands are placed this way (size equivalent to the patient’s hands, upper hand touching the clavicle, thumbs excluded) correspond to the location of the lung, and allow three standardized points to be defined. The upper-BLUE-point is the middle of the upper hand. The lower-BLUE-point is the middle of the lower palm. The PLAPS-point is defined by the intersection of: a horizontal line at the level of the lower BLUE-point; a vertical line at the posterior axillary line. Small probes, such as this Japanese micro convex one , allows positioning posterior to this line as far as possible in supine patients, providing more sensitive detection of posterolateral alveolar or pleural syndromes (PLAPS). The diaphragm is usually at the lower end of the lower hand.

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Lung Ultrasound reveals the following patterns. 1. A-line: bilateral A lines is called A profile.

2. B lines: Comet rockets. Bilateral B lines = B profile: Correlates with GGOs on CT scan

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3. AB profile: Combination of A and B

4. C-profile: anterior consolidation

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5. PLAPS (Posterior lateral alveolar) point: Consolidation or pleural effusion

6. Thickened Pleural line: indicates Sub pleural consolidation.

Figure: Lung ultrasound shows pleural line thickening or course, sub pleural lung consolidation with air bronchograms (the area within the white circle, echogenic bright lines or bright spots within the region are air bronchograms), interstitial syndrome and disappearing A-lines. B: Chest x -ray shows grade II respiratory distress syndrome.

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Figure: White lung and numerous B-lines were predominant features. Increased density and distribution of B-lines were associated with deterioration in clinical signs.

Figure: Small sub pleural consolidations with disruption of the pleural line

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Algorithm for Lung Ultrasound: In addition to BLUE protocol, it is recommended to look at the pleural line, not to miss Sub pleural consolidation, as BLUE protocol may diagnose bilateral pneumonia as pulmonary edema.

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CT scan: CT has revolutionized the understanding of ARDS. What was considered a homogenous lung by anteroposterior radiography appeared non-homogenous. CT revealed areas of normally aerated, collapsed and hyper-inflated lung revealing heterogeneity of lung units resulting in a revolutionary concept of baby lung in ARDS. Therefore a famous quote in ARDS is - "lungs are not stiff, but small". It has also been observed that the degree of aeration is directly related to the ratio of tidal volume to EELV. This is the same concept of driving pressure. Aerated/non aerated α TV/EELV

Uses of CT scan in ARDS: 1: Currently CT of the lungs can estimate the weight of lungs that correlate with the severity of ARDS. Weight can increase to 3 times in ARDS. Normal weight of lungs is 800 g. In typical ARDS it may increase to up to 1900 g depending on the phenotype. 2: Can quantitate the morph functional effects of PEEP-degree of collapse and hyperinflation, degree of recruitment. (Compliance is proportional to normally aerated lung) 3: Can classify ARDS patients in to recruitable versus non recruitable. In fact recruitable patients present with severe impairment in gas exchange. Application of PEEP reverses collapse and there by classifies a patient in to recruiter. 4: Can delineate the beneficial effect of prone position.

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Figure: CT scan demonstrating the effect of PEEP. To classify them as low recruitability or high lung recruitability.

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Pulmonary Perfusion Measurement Delineating pulmonary perfusion is important as it represents heart lung interactions, which have major effects on general hemodynamics. Some of these major hemodynamic changes include Increase in pulmonary vascular resistance: decreases cardiac output Increased right ventricular afterload Decreased left ventricular preload Decreased Venous return to heart: decreased right ventricular preload Imaging modalities that measure lung perfusion include: Conventional Scintigraphy Single photon emission computer tomography (SPECT) Positron Emission tomography (PET) Perfusion CT scan Dual Energy computer tomography Electrical Impedance tomography Lung Ultrasound Fluorescent Microspheres Pulmonary perfusion and aeration analysis may also aid in Ventilation perfusion matching, which is a key determinant in pulmonary gas exchange. Atelectasis: results in shunt VQ mismatch: increase in functional dead space

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CT Perfusion: Regional perfusion in the lung is affected by the status of hypoxic pulmonary vasoconstriction, airway pressures and posture. Molecular mechanisms that determine perfusion include vasoconstriction, endothelial swelling, obstruction and collapse of vessels (due to increase in lung weight). All these culminate in to areas of high VQ, low VQ and shunt. Non-dependent areas: VQ ratio > 1, increase in functional dead space Dependent areas: VQ < 1, atelectasis and therefore shunt

Figure: Color-maps, showing distribution of perfusion throughout and axial slice of lung in patients with ARDS. Spectrum changing from blue to red indicates increasing perfusion.

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Regional perfusion is mainly distributed in the dependent regions where atelectasis or consolidation is concentrated. Perfusion is altered by application of PEEP.

Increase in PEEP increases the perfusion in the dependent parts of the lung. If the lung is not recruited, then increase in PEEP, although increases perfusion may not translate in to increase in Oxygenation. Changing from controlled ventilation to assisted ventilation such as PSV, the perfusion may be redirected to the non dependent regions of the lung. Prone position can cause homogenous distribution of both Ventilation and perfusion. Redistribution of either ventilation or perfusion can also happen that can be easily guessed by looking at the blood gases. By Proning, if Increase in PaO2 , No change in PaCO2 , then Only flow diversion without recruitment (no redistribution of ventilation) Increase in PaO2 , Decrease in PaCO2 , then flow diversion with recruitment (redistribution of ventilation)

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In Summary, CMV without PEEP: Non dependent regions: High Ventilation, Low perfusion (Alveolar Inflation) Mid Zone: Ventilation = Perfusion (Small airway collapse) Dependent regions: Low Ventilation, High Perfusion (Alveolar collapse) CMV with PEEP: Non dependent regions: Low Ventilation, Low Perfusion (Still Alveolar inflation) Mid Zone: Ventilation = Perfusion (Small Airway collapse) Dependent regions: High Ventilation, High perfusion (Alveolar collapse, reduced shunt) Assisted MV: Recruitment, No perfusion redistribution Non dependent regions: Low Ventilation, Low Perfusion Mid Zone: Ventilation = Perfusion (Small airway collapse) Dependent regions: High Ventilation, High Perfusion Assisted MC: No Recruitment, Perfusion redistribution Non dependent regions: High Ventilation, High Perfusion Mid Zone: Ventilation = Perfusion (Small airway collapse) Dependent regions: Low Ventilation, Low Perfusion. It must be remembered that an increase in oxygenation by application of PEEP or Proning may simply because of change in regional perfusion and not necessarily due to recruitment.

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Dual Energy Computer Tomography (DECT) Dual-energy computed tomography (CT) is a technique that combines the high spatial resolution of standard CT with improved contrast resolution, reduce artifact, and separate materials of different atomic weights and energy-based attenuation through post processing.

Figure: Axial (A), coronal (B), and left sagittal (C) dual-energy computed tomography (CT) iodine maps show the occluded left pulmonary artery and corresponding perfusion defect color-coded blue, demonstrating perfusion/ventilation mismatch, a typical finding of pulmonary embolism in perfusion/ventilation scintigraphy.

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Figure: Dual energy computer tomography demonstrating the predominant dependent regions of perfusion. ARDS can have perfusion defects secondary to micro thrombi.

Figure: Axial monoenergetic CT image (A, lung window): CT pattern associating central ground glass opacities and peripheral areas of consolidation. Iodine color overlay on axial CT image (B, mediastinal window): heterogeneity of iodine map with high iodine concentrations in consolidations, and left mediobasal segment hypoperfusion (dotted line), secondary to the thrombosis of corresponding segmental pulmonary artery (white arrow). 53

Typical ARDS findings on DECT include: 1 Distribution of non-aerated lung tissue in the dependent regions 2 Percent distribution of pulmonary blood volume follows a non-gravitation gradient , low VQ 3 Percentage of perfusion defects in the non-aerated lung tissue increases from non dependent to dependent lung regions. 4 Higher shunt in non-aerated lung regions. Predictors of mortality in ARDS detected via DECT include: Lower Gas Volume Lower normally aerated lung tissue Higher total lung mass More blood volume distributed in poorly aerated tissue (low VQ) Larger amount of perfusion defects in poorly and non-aerated lung regions. Poor alveolar recruitment with higher PEEP

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PET scan: Regional distribution of FDG signal can be analyzed using a PET scan and see if the avid uptake is coupled to a CT appearance or not. It has been observed that "uncoupled" were more severe than "Coupled" lesion.

(A) 18-FDG distribution parallels that of the opacities detected on CT. (B) intense 18-FDG uptake can be observed in normally aerated regions (square 1), while activity is lower in the dorsal, ‘non-aerated’ regions of both lungs

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Electrical Impedance tomography: Electrical impedance tomography (EIT) can be used to estimate alveolar collapse and hyper distension at the bedside with a very good precision. This has been validated with the CT image findings. Typically in a decremental PEEP trial, the nondependent over distension that is evident at higher PEEP may disappear and dependent atelectasis appear at lower PEEP. This change in pattern of compliance can be detected by EIT using an algorithmic analysis of pixel density.

Figure demonstrating EIT and the percentage of collapsed and hyper distended units during a decremental PEEP trial. The left column of EIT images demonstrate nondependent white pixels at PEEP of 23 suggestive of over distension. As the PEEP is lowered, the over distension disappears. On the right column of EIT images, as the PEEP is lowered, the dependent blue shadows appear and progressively increase suggestive of dependent atelectasis. The graph illustrates the percent of collapsed and over distension at each level of PEEP. Please note that the X axis denotes the decremental PEEP trial. In this graph, the optimal PEEP would be around 16, the crossing point at which it is the lowest collapse and lowest hyper distention. This would correspond to an end expiratory transpulmonary pressure of 3. Thus by balancing the risk of hyper distention with minimal collapse, it is possible to determine best possible PEEP with optimal recruitment in a patient with ARDS using EIT. Thus EIT is one of the methods to titrate PEEP by obtaining best possible pixel compliance. The advantages of EIT over CT scan is that there are no arbitrary thresholds to define a pixel unlike Hounsfield units of CT scan. Another advantage is EIT is not biased by baseline densities.

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Figure: EIT acquisition .Electrode belt is encircled around the chest of the patient and EIT images are obtained. EIT can be performed at the bed side.

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Figure: EIT is interpreted in terms of pixel compliance. NB: It must be remembered that a healthy mammal across any species has the best compliance with end expiratory transpulmonary pressure around 3. Higher or lower than that decreases compliance. Therefore EIT can be used to titrate PEEP such that end expiratory transpulmonary pressure of 2-3 such that pixel compliance is the highest. This would correspond to the crossover point. Thus, it can be said that EIT can provide information similar to that of esophageal balloon, in that PEEP can be titrated to obtain end expiratory transpulmonary pressure of 2-3 cm H20.

EIT in obese patients: Obesity can present challenges in the management of ARDS due to airway closure. There is direct correlation between BMI and end expiratory esophageal pressure (Pleural pressure). Optimal PEEP in these population can be difficult to determine and increases with increasing BMI. Some methods to derive optimal PEEP include: 1

Regression equation : Optimal PEEP = (0.34 * BMI) + 2.16

2

Esophageal balloon to target end expiratory transpulmonary pressure of 2-3, by titrating PEEP.

3

Use of Electrical Impedance tomography to determine the PEEP at crossover point.

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EIT for lung perfusion: Regional lung perfusion can be estimated by EIT after saline injection. EIT can thus be utilized even to calculate V Q ratio.

Figure: EIT to calculate V Q ratio. EIT can be used to evaluate regional lung perfusion and compare the status of perfusion to ventilation. Cardiac output may be obtained via thermodilution. Thus when ventilation and perfusion images are superimposed , a pure blue segment would mean dead space , a pure reddish area would mean shunt and the remaining green area would mean VQ matched area. EIT can then be used to titrate optimal PEEP and also can evaluate the utility of prone position to optimize VQ match. EIT can also be used to detect pulmonary embolism via VQ mismatch and consequent shunt due to divergent overflow via non embolic areas. This has been correlated with CT angiogram.

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D. Respiratory Management

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Airway Management in the ICU Airway management is the first step in the resuscitation of a critically ill patient. The information presented here is presented in detail for the sake of perusal and it the most fundamental skill for an intensivist. Goals of Airway management are: Provide an un-obstructed airway or maintain airway patency. Supplement Oxygen as needed.

Airway Obstruction: Airway obstruction can be caused by structural alteration from the mouth to the end of tracheobronchial tree. It can be detected by "Look, listen and feel" approach. Look for signs of respiratory distress Listen for bilateral breath entry Feel for gas flow at nose and mouth It is important to distinguish complete versus partial obstruction. Complete obstruction is characterized by silent chest and paradoxical see saw movement of chest and abdomen. This can be accompanied by cyanosis and accessory muscle use. Partial obstruction has much more broader presentation and usually characterized by tachypnea, agitation and increased work of breathing. Increased work of breathing can be manifested by use of accessory muscles, tracheal tug, and recession of chest wall and if not managed in time can lead to exhaustion. It is important to recognize certain subtle or unique signs that suggest probability of partial obstruction like change in voice, snoring, inability to swallow or any visible swelling near the airway. The quality and phase of obstructive sounds may help in localizing the site of obstruction. Stertor: Pharyngeal obstruction (snoring noise) Inspiratory stridor: Laryngeal obstruction Expiratory stridor: Tracheobronchial obstruction Biphasic stridor: glottic or subglottic obstruction.

Difficult Airway Assessment: Many different definitions exist: "Difficulty in face mask ventilation/ endotracheal intubation by trained clinician experiences". "Difficulty with rescue airway techniques in critically ill patients”. Rescue techniques include: Insertion of Supra glottic airway device Achieving Front of Neck Access- FONA

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In critically ill patients, one must be aware of "physiologically difficult airway" than a technically difficult airway. A physiologically difficult airway is the physiological derangement associated with airway management that may lead to potential harm. Airway management in the ICU consists of series of successive rescue techniques and anticipation of difficulties must be assessed at each technique. These include Endotracheal intubation Rescue face mask oxygenation Rescue Supraglottic airway device insertion Rescue FONA Physiological stability during airway management Avoidance of pulmonary aspiration. Assessment of difficulty airway: includes Clinical assessment Advanced assessment

Clinical Assessment: Difficulty Endotracheal Intubation: Direct laryngoscopy with endotracheal intubation requires Adequate Mouth opening Adequate head extension Adequate neck flexion Assessment is done in successions: 1.Limited mouth opening can be seen in trismus ( dental abscess) , Temporomandibular dysfunction , post radiotherapy fibrosis , rheumatoid arthritis , facial burns , scleroderma , certain airway syndromes .

Figure: Lady with Trismus, characterized by limited mouth opening. Causes include dental abscess, tetanus (lock jaw). Similarly fibrosis of soft tissue around mouth such as post radiotherapy, scleroderma and joint pathology of TMJ as in rheumatoid arthritis or TMJ dysfunction can result in limited mouth 62

opening. Congenital syndromes associated with difficult intubation include: Anatomical site

Related syndromes

Nasopharynx

Mucopolysaccharidoses

Oral cavity/oropharynx (macroglossia)

Trisomy 21 Beckwith–Wiedemann syndrome Mucopolysaccharidoses

Mandible/maxilla (retrognathia, micrognathia, mandibular hypoplasia or dysplasia)

Pierre Robin sequence Treacher Collins syndrome Goldenhar syndrome Apert syndrome

Pharynx/larynx

Trisomy 21

Trachea

Trisomy 21 Mucopolysaccharidoses

Cervical spine

Trisomy 21 Klippel–Feil syndrome Goldenhar syndrome

2. Airway pathology and certain medical conditions should be reviewed. These include epiglottitis, laryngeal edema, lingual tonsil hyperplasia, Ludwig’s angina, obesity, and advanced pregnancy- third trimester, Marfans syndrome and Acromegaly.

Figure: demonstrating enlarged epiglottis and aryepiglottic folds. 63

Figure demonstrating the degrees of laryngeal edema. The severe the edema, more difficult is intubation.

Figure revealing high arched palate, which may contribute to difficulty intubation. High arched palate can be seen in Crouzon syndrome, Downs’s syndrome, Alpert syndrome, Ehler-Danlos syndrome and Marfans syndrome. Of note, even chronic thumb sucking can result in high arched palate. 3. Immobility of Cervical Spine should be checked for. Conditions that may impair cervical spine movement include Spinal immobilization, cervical spondylosis, ankylosing spondylitis, post radiation fibrosis, Klippel Feil abnormalities of cervical spine.

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Figure: Klippel-Feil syndrome, characterized by short neck, low hairline at the back of the head, and restricted movement of the upper spine due to congenital fusion of cervical vertebrae.

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4. Thyromental distance < 6.5 cm or Thyromental height < 50 mm is associated with difficulty intubation.

Figure: demonstrating the technique of measuring Thyromental distance.

Figure: Technique of measurement of Thyromental height.

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5. Sterno mental distance < 12.5 cm is associated with difficulty intubation.

Figure: demonstrating the technique to measure Sternomental distance. 6. Cervical Spine instability: Seen in Spine trauma, Rheumatoid arthritis, Trisomy 21. Manual inline spinal immobilization is employed during airway management.

Figure demonstrating the application of MILS- Manual inline Spinal immobilization during intubation.

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Scores to predict difficulty intubation: No score has been proven to have high discriminatory power to predict difficult intubation. Three scores that are popular include The modified Mallampati classification The Wilson score The MACOCHA score. Modified Mallampati Classification: Patient is asked to maximally open mouth and protrude tongue and the oropharynx is visualized.

Figure demonstrating the four different classes of Mallampati. Class III and IV are associated with difficulty intubation.

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The Wilson Score: Five anatomical features are scored from 0-2 to a total maximum of 10. The higher the score, more difficult is the intubation.

Figure: Wilson score. Anatomical features include: obesity, head and neck movement, jaw movement, receding mandible, buck teeth.

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The MACOCHA score: A summed score of seven clinical features has been validated in predicting difficult intubation in critically ill patients.

Figure: MACOCHA score components.

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Figure: Proposed airway algorithm for intubation based on MACOCHA score.

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Difficulty Mask Ventilation: Mask Ventilation should be the next step as rescue measure for difficulty intubation. Predictors of difficult mask ventilation include: "Mnemonic: OBESE MAN R.J.M" O: Obesity B: Beard E: Elderly S: Snorer E: Edentulous MAN: Male gender R: Radiotherapy to Neck J: Limited Jaw protrusion M: Modified Mallampati Class 3 or 4 Radiotherapy results in non-compliant fibrotic tissue and is considered as the most significant predictor of almost impossible mask ventilation.

Difficulty Supra glottic airway (SGA) insertion: If the Mask ventilation is not possible and endotracheal intubation has failed, the next best rescue technique is Supraglottic airway device insertion. Supraglottic airway devices, as the name suggests is an airway device that seal around the top of glottis. Cricoid force must be removed for optimal positioning of SGA. Some Supraglottic airway devices include: Laryngeal Mask airway (2nd generation ones have gastric decompression, facilitate intubation via fiber optic scope.

Figure: Laryngeal mask airway

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Figure: "Intubating LMA”

Figure: Combitube. Combitube has two balloons, two lumens, two ventilation ports

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Figure: Placement of Combitube

Figure: Kings Laryngeal tube. King LT: design almost similar to Combitube.

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Predictors of difficulty SGA include: Mnemonic: SGA S: Short Thyromental distance, limited neck movement G: Gender, male gender A: Age > 45 years. Difficulty Front of Neck Access (FONA): Causes include Obesity (bec. of overlying adipose tissue , impalpable landmarks) , previous radiotherapy , previous surgery for example tracheostomy , neck masses such as thyroid tumor , goiter, limited neck extension , fixed neck flexion , reduced Sternomental distance.

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Advanced airway assessment technique: 1. Flexible Nasendoscopy 2. Ultrasound 3. Computer tomogram 4. Magnetic resonance imaging Flexible Nasendoscopy:

It is quick test that can be performed for endoscopic examination of the airway up to the level of larynx. It can identify intra-luminal cause of airway obstruction and also dynamic respi-phasic variations in the airway. However, it must be remembered, that it does not predict the ease of intubation by direct laryngoscopy. Ultrasound: Ultrasound can be employed for wide areas of airway assessment. It can be used to identify larynx, cricothyroid membrane, trachea, detecting esophageal intubation. Most often it is used to identify cricothyroid membrane and locate blood vessels for FONA. A linear high-frequency transducer is used to scan the structures of the upper airway. A strong hyperechoic line indicates tissue-air border and everything beyond this line is an artifact. Until this interface, soft tissues from skin to anterior luminal surface of airway from mouth to mid trachea can be visualized.

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Figure: Curved low-frequency transducer. Green: mentum of mandible, Purple: muscles of floor of mouth. Orange: Hyoid bone. Red: dorsal surface of tongue.

Figure: A transverse midline scan over the thyroid cartilage. Green: thyroid cartilage, Red: anterior commissure. Orange: vocal cords, Yellow: Arytenoids.

Figure: A linear high-frequency transducer placed in the midsagittal plane. Green: thyroid cartilage, RED: cricothyroid membrane, Dark Blue: cricoid cartilage, light blue: tracheal rings, Orange: Air-tissue border, Brown: Isthmus of thyroid gland.

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Transverse scan just above supra sternal notch. Light blue: anterior part of tracheal cartilage, Purple: Esophagus, Red: carotid artery. Computer tomography: Can be performed supine, if not possible in lateral position. Useful for identification of extrinsic compression, intrathoracic lesions and laryngeal trauma. In addition, 3D reconstruction can be done for "virtual endoscopy".

Figure: reconstruction of CT scans can be done to create Virtual endoscopy.

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MRI: Although cannot be suited in an urgent situation, as there is a need to lie flat for prolonged periods of time, it is an excellent tool for soft tissue imaging. It cannot be emphasized that airway may be inaccessible due to receiver coils.

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Tracheostomy: Tracheostomy is performed usually at 10-14 days of mechanical ventilation. Earlier tracheostomy is performed in some conditions such as TBI, trauma and neurologic conditions (MG). Indications: Facilitate prolonged Mechanical Ventilation, facilitates weaning Bypass Upper airway obstruction e.g.: Sleep Apnea, tumor Maintain patent airway in severe head and neck injury/ surgery Airway anomalies Secretion removal esp. with weak cough and thick secretions Recurrent aspiration Patient selection: Stable Cardiopulmonary and hemodynamics No significant extra pulmonary multi organ dysfunction. No anticipated need for proning No significant coagulopathy Technique: Percutaneous / Open surgical / Hybrid

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Strategies to minimize aerosolization during standard ICU care: Minimize ventilator disconnection Use of cuffed non fenestrated tube Use of inline suction Cuff should remain inflated, checked Q12hrs, maintained at 20-30 cm H2O or above P peak. Minimize number of leak tests, avoid water filled cuffs Use a simple HME filter (adequate humidification, no aerosols generated)

Fig: HME filter Strategies to minimize aerosolization during tracheostomy: Reduced PEEP at 2-3 cm H2O, FiO2 @ 0.9 -1.0 Use HEPA filters / Negative pressure room, HME filter Flow interruption after tracheal incision for dilator and cannula insertion Use of appropriate DPI (Facial mask, goggles, N 95, gloves, hemo repellant gowns) Consider tracheostomy at day 10 of mechanical ventilation Use Ultrasound to assess the point of entry Deep sedation and neuromuscular blockers be used to minimize cough and agitation Apnea challenge test before procedure – to mimic apnea Apnea challenge test: Discontinue PEEP, withhold Ventilation Increase FiO2 to prevent desaturation, Observe for 30s to 1 min Pack the oropharynx and hypopharynx. Suction tip may be placed in the mouth to decrease aerosolization of secretion when ETT is pulled back Place moist gauze/sponge around guidewire, during dilation and neck stoma Alternatively, bronchoscope is placed alongside the ETT while advancing the ETT below the intended stomal point of entry If open tracheostomy: use apnea during ETT manipulation and incision. Minimize diathermy and suction Place Petroleum gauze dressing at the fresh stoma until it heals (Prevents air leak) Apnea be done at any step of open ventilator period. Trach tube be secured with trach collar, not any sutures NB: Various periods of Apnea are encountered during tracheostomy. These include: When bronchoscopy adapter is added to the circuit Inserting bronchoscope in to ETT When ETT is pulled back with cuff deflation Introducer needle, Angio catheter, dilation and tracheostomy tube insertion until closed circuit connection Removal of ETT from oropharynx. 81

Aerosolized Therapy Aerosolized antibiotics for pneumonia should be used only as an adjunctive therapy, not as stand alone. Examples include: Aerosolized Amikacin for MDR Gm negatives such as P.Aeruginosa, A.Baumanii. Aerosolized Vancomycin for MRSA. Doses used in studies: Amikacin 300-400 mg / Fosfomycin 120 mg BID for 7-10 Advantages/ disadvantages of Aerosolized antibiotics: Less systemic antibiotics therapy More de-escalation Less incidence of resistance Adverse effect may include bronchospasm No reduction in mortality, severity index.

Optimizing aerosol delivery of antibiotics in ventilated patients: 1

Remove HME filter and turn of heated humidifier. If delivery time > 30 min, add humidification.

2

Limit Inspiratory flow turbulence : if to be used in an "Non synchronized fashion" Use controlled mode of ventilation and not assist mode. Hence may require sedation. Tidal volume of 7-9 ml/kg, Constant inspiratory flow < 30 L/min, Minute volume < 6 L/min, RR = 12/min I: E ratio = 1:1 End Inspiratory pause: 20% of duty cycle, 50% duty cycle

3

Nebulized dose = Systemic IV dose + extra pulmonary deposition (tubing , expiratory filter)

4

Ultrasonic or vibrating plate nebulizers preferred to Jet nebulizers. Ultrasonic Nebulizers may heat the antibiotic Vibrating plate nebulizer can synchronize with inspiration. Place vibrating plate in inspiratory limb before the Y connector and ETT tip.

NB: There are three types of nebulizers. These include Ultrasonic, Jet and Vibrating Mesh. Ultrasonic nebulizer generates aerosols by high frequency piezo electric crystal in drug solution. It is placed in the circuit 15 – 40 cm upstream of Y connector. It leaves behind medium residual. However it may overheat the drug solution. Jet Nebulizer works by venturi effect on the compressed air. Placed 15 – 40 cm upstream of Y connector. Jet nebulizer can leave large residual and may interfere with ventilator. Least preferred, although the most common.

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Vibrating mesh nebulizer generates aerosol by high frequency mesh vibration in drug solution. This can run continuous or can be actuated by breath (Non-synchronized versus synchronized). It is placed just proximal to Y connector or distal to Y connector with breath actuated system. Generates < 5 u particles and 60% of the drug reaches patient leaving behind the least amount of residual. It does not heat the drug. Probably the only disadvantage is that it may take longer time to deliver the full dose. Most preferred.

Figure: Location of nebulizer for aerosol therapy.

Principles in Prescription of aerosolized therapy: Add Inhaled to systemic antibiotics for Gm Negative Pneumonia due to MDR pathogens, sensitive only to polymyxins and aminoglycosides. Use adjunctive inhaled Colistin for Acinetobacter sensitive only to colistin. Similar for Carbapenem resistant organisms. Prefer inhaled Colistin to inhaled Polymyxin B. Should not be used routinely, but only when the infection is refractory and organisms are only sensitive to poorly penetrating antibiotics such as aminoglycosides and colistin. Might be useful in moderately ill population such as APACHE score of 10-25. May have a role as monotherapy in Ventilator associated tracheobronchitis (VAT)

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Non Invasive Respiratory Support Noninvasive respiratory support is superior to standard oxygen and if successful decreases mortality and the need for intubation in hypoxic respiratory failure. It is better avoided in patients with PF ratio < 150. However, the patient requires close vigilance as there is risk of failure and delayed intubation leading to mortality. In addition, less control on ventilatory pattern and effort causing VILI due to excess tidal volumes and pressures. Advantages of NIV: Avoids the need for sedation Conscious and co-operative Reduced self-induced lung injury compared to O2 cannula Nurse –patient ratio (low intensity nursing) Equipment is cheaper and readily available Disadvantages of NIV: Limited compliance in using the technique, patients may be claustrophobic Pressure ulcers Risk of gastric insufflation/ vomiting Increased self-induced lung injury if excessive TV compared to invasive mechanical ventilation Might require very high O2 flow causing infrastructure failure (O2 hungry) Generate infectious aerosols. Conditions that are known to benefit from NIV: Immunocompromised patients Heart failure Acute exacerbation of COPD Post-operative patients Contraindications to Non Invasive techniques: Severe ARDS PF ratio < 150 Presence of Multi organ dysfunction/ Shock Higher Severity Scores High respiratory drive or work of breathing: consider intubation to decrease P-SILI. High work of breathing can be detected by either clinically – Phasic (not tonic) contraction on palpation of sternomastoid or esophageal manometry NIV failure may be seen in moderate to severe ARDS and high mortality has been demonstrated to independently co-relate with NIV failure. Other predictors of NIV failure may include HACOR score, poor sleep, hemodynamic instability and high tidal volumes > 9.5 ml/kg.

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HACOR Score: A HACOR score >5 at 1hour of NIV highlights patients with a >80% risk of NIV failure regardless of diagnosis, age, and disease severity.

Figure: HACOR Score. Heart Rate, Acidosis, Conscious, Oxygenation, RR Risk of infectious aerosolization: In terms of environmental contamination, the level of protection is: Head helmets > CPAP with good interface > High flow nasal cannula (similar to standard O2 therapy). HEPA anti-viral filter can be connected to outlet of Helmet. NB: NIV along with chest physiotherapy are droplet generating procedures, not aerosol. Droplets are defined as > 10 um and fall out with in 1 m. Exposure risk is thus 1 meter radius around the patient.

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CPAP Rx: Can be considered as one of the therapies in acute respiratory failure. If carefully applied, it decreases the need for mechanical Ventilation. Close follow up is essential as some patients may eventually need intubation and in these cases, delayed intubations have been linked to mortality. Also, some patients may exhibit excessive tidal volumes due to high drive. This may generate high transpulmonary pressure leading to P-SILI. Markers predicting CPAP failure in ARDS: Following markers if elevated have been correlated with CPAP failure. These include: Inflammatory markers: CRP Ventricular dysfunction: BNP Pulmonary Micro thrombi: D-dimers Organ dysfunction including RRT and vasopressor use. Cell Stress marker: LDH Some CPAP devices are said to be Oxygen hungry with possible risk of compromising hospital supply. CPAP may be modified to prevent environmental contamination and decrease Overall Oxygen use. One such device is "UCL Ventura CPAP".

Figure: Proprietary CPAP device schema

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Head Helmets Indications: Head helmets may be considered for hypoxic respiratory failure with PF ratio > 150, with similar indications such as for CPAP/Bipap. It decreases the need for intubation. The principle behind treating hypoxic failure is to increase "mean airway pressure". CPAP via any technique can be considered. It is better avoided in hypercapnia failure. It does not outperform traditional mask for hypercapnic failure. The principle behind treating hypercapnic failure is to decrease fatigue via assisting "work of breathing". PSV: Face mask has to be considered.

Figure: Head Helmets: Schematic Head helmet and CPAP There is a gas inlet and outlet. The gas inlet receives fresh gas flow of Oxygen gas mixture. A simple PEEP valve can be attached to the outlet to deliver CPAP. Advantages of the helmet is that it is more tolerant than traditional BIPAP and furthermore it does not require electricity, however "bias flow" in the helmet must be at least 40 L/min to flushing out the exhaled gas to prevent rebreathing. It has all similar beneficial effects of NIV. It must be remembered not to connect head helmets to ventilator for CPAP, rather the best way to generate CPAP in head helmets is via using PEEP valve. Rather head helmets have been purported to deliver stable PEEP levels. Head Helmet for PSV Ventilator can be connected to head helmet to deliver PSV, however this use must be discouraged as helmet has slower reaction because of large volume, hence possibility of asynchrony. Because of limited fresh gas flow when connected to ventilator, CO2 rebreathing may be present. It must be realized that connecting ventilator to head helmets display huge tidal volumes of around 1600 ml or so, as this measured tidal volume accommodates for the helmet volume. 87

Head helmet and High flow Nasal Cannula

Figure: HFNC has been combined with Helmet CPAP. One innovative consideration is to combine Helmet CPAP and HFNC. With the combination technique, the breathing frequency was significantly lower compared to either technique alone. It is interesting to know that although temperature inside the helmet increased, fog effect was not observed.

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High Flow Nasal Cannula Four important features of HFNC include Accurate FiO2 delivery Provides small amounts of positive airway pressure at end expiration Washes out pharyngeal dead space Warm and humidified gas. HFNC delivers the set fraction of inspired oxygen (FiO2) by reducing the entrainment of room air thereby preventing the dilution of inspired gas. In addition, HFNC provides very high flow rates that match the excessive flow demand when the patients are in distress. At 50 l/min, HFNC has been experimentally observed to create maximal expiratory nasopharyngeal pressures of 5 cm H20. It has been proposed that every 10 liters increase in flow would create 1 cm H20 at the end of expiration. This positive pressure may reduce atelectasis and contribute to alveolar recruitment. Increasing flow rates increases end expiratory lung volume and decreases esophageal pressure time product, decreases work of breathing, improvement in P/F ratio. EELV has been correlated to FRC, which is considered as an Oxygen reservoir of the body. High flows of inspired gas up to 60 l/min can be given. Full humidification at 37 C, 100% of RH (relative humidity) of 44 mg H20/L can be achieved. This decreases interface discomfort, dryness symptoms at 24 hours, when compared to venturi mask after extubation. Best comfort is with flow of 60 L/min at 31 C. The effect of HFNC on P-SILI may be mixed, as it depends on transpulmonary pressure. HFNC may not decrease mortality in acute hypoxic respiratory failure, rather it may decrease the need for intubation. Indications for HFNC: Hypoxemic normocapnic respiratory failure, Weaning after extubation. Prevents re-intubation almost similar to NIV. Palliative care Support during Rapid sequence Intubation Hypercapnic respiratory failure in a sub set of patients

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Figure: Role of HFNC in ARDS HFNC and NIV have been proposed to have role in ARDS. This is one of the recommended algorithms for the management of ARDS and defines the role of HFNC. It is important to note that evaluation is done every one hour to either augment or continue the respiratory care. P/F ratio > 300: Standard O2 therapy P/F ratio < 150: Endotracheal intubation P/F ratio 150-300: HFNC then NIV. Monitoring the Patient on HFNC: An index to predict outcome of HFNC was proposed that combines Respiratory rate and Oxygenation. ROX = (SpO2/FiO2 in %) /RR. ROX: Respiratory rate and Oxygenation index. ROX score > 4.88 predicted success of HFNC.

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Monitoring the patient on NIV: 1. HACOR score > 5 predicts NIV failure. HACOR=Heart rate, Acidosis, Consciousness, Oxygenation, Respiratory Rate 2. Tidal Volume > 9.5 ml/kg of PBW increases the risk of NIV failure. Indicates very high drive. This leads to P-SILI. 3. It has been observed that drop in delta esophageal pressure in a patient on NIV can predict NIV success. Extrapolating this concept, it can be safely assumed that PVI can be thus used as a variable to predict NIV success.

Figure: Parameters for HACOR score While the patient is being monitored on HFNC or NIV, if any of following indication is met, intubation should be considered. Indications of Intubation in ARDS: Patient in severe respiratory distress P/F ratio < 150 Deterioration of Neurological status Hemodynamic instability.

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Role of HFNC post extubation: In low risk of extubation failure: consider HFNC or NIV In high risk of extubation failure: esp. if hypercarbia, consider NIV alternating with HFNC. Role of HFNC in Hypercapnia: HFNC is proposed to wash out nasopharyngeal dead space. As the flow rates increases, dead space decreases and there by decreases rebreathing CO2. HFNC decreases neuroventilatory drive and work of breathing (PTP: Pressure time product) in a COPD patient post extubation. Another consideration is to combine HFNC with CPAP.

Figure: HFNC has been combined with Helmet CPAP. One innovative consideration is to combine Helmet CPAP and HFNC. With the combination technique, the breathing frequency was significantly lower compared to either technique alone. It is interesting to know that although temperature inside the helmet increased, fog effect was not observed.

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Mechanical Ventilation Micromechanical causes of tissue injury: Cumulative injurious strain is believed to be responsible for causing VILI. This strain can be monitored by calculating either Ventilatory power or driving pressure. Low ventilatory power or low driving pressure seems to be lung protective, which translates to low tidal volumes, low plateau pressure in a "modified open lung approach". Determinants of tissue injury include: 1. Driving Pressure Damage from a given driving pressure depends on effective lung unit compliance and resulting expansion. For the same driving and plateau pressures: Compliant lung: attains large volume, high energy input - Overstretched Non complaint lung: attains small volume, low energy input – tolerated strain. 2. Frequency: AKA respiratory rate. If the cycle strain > threshold, frequency and duration may become important determinants of lung injury. At the micro mechanical level, this progressively damaging process is referred to as "accelerated sequential failure". 3. Rate of pressure conversion during the expiratory side. Many mechanisms exist for the power amplification and there by injuring the lung. These mechanisms are collectively referred to as "micromechanics". Some of these include: Reduced ventilating capacity of the "baby lung" Geometric power focusing by asymmetry Flow dependent viscoelastic drag Sequential loading by drop out of parallel stress bearing elements in extracellular matrix Mechano-signaling between interstitium and cellular interior via integrin. Reduced Ventilatory capacity of Baby Lung: Because ARDS lung is compared to that of a baby lung, rather an absolute mechanical power threshold to determine lung strain, it may be prudent to consider mechanical power relative to the "baby lung". It has also been observed that, at a constant tidal volume, size and strain of the individual lung units of the baby lung change with advancing injury – this has been referred to as "Shrinking baby lung". Unlike pressure alone, the shrinking baby lung concentrates power. However, not all units behave similarly. Some baby lung units (embedded among damaged units) may not be that vulnerable as injury advances. Rather, because of less intrinsic compliance, they may not be overstretched and damaging level of strain may not be reached and therefore in fact protected.

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Figure: The mechanism of how shrinking baby lung concentrates power and there by accelerating lung injury. Geometric focusing and Viscoelastic drag: Because of the heterogeneity of the intrinsic compliance of lung, a force that is applied does not result in uniform distribution of the mechanical power, but rather certain areas receive more impact and others less. This is called "Geometric focusing". In addition, the effect of how fast this stretch is applied also is a determinant of micromechanics. A slow but similar stretch may have different impact than a fast with similar stretch. This rate of fastness of a stretch is called as "Viscoelastic drag". Sequential loading of interstitial stress bearing elements: The interstitium is multi fibrillar and there is heterogeneity in the tolerance levels of the interstitium to an applied stretch. Some stress bearing elements are weaker that others and are subjected to higher effective local stresses resulting in "repeated microfractures". Because these fractured fibrils cannot take up their share of load, the other fibrils must tolerate the extra burden, leading to further susceptibility. This shared stress progressively increases strain at individual unit causing drop out and sequential failure. This process is referred to as "sequential loading by drop out". Several indices have been proposed as bedside markers for development of VILI. These include: Plateau pressure Driving pressure Mechanical power = step wise increase in mortality Respiratory rate Driving pressure * RR Driving pressure squared to 2 * RR: probably the best index = linear relation PfP index = PaO2/FiO2 /PEEP PEEP = U shaped relationship

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Monitoring Driving Pressure, RR and mechanical Power: Of all the parameters, driving pressure is the best predictor of survival. Driving pressure rather has been experimentally shown to co-relate with histology (e.g. inflammation and fibrosis). The higher the driving pressure, the worse is the histological grade. Low tidal volume ventilation is considered protective only because of low driving pressure. Probably, low tidal volume ventilation with similar driving pressure may have same consequences of high tidal volume with similar driving pressure. It should however be recognized that both PEEP level and tidal volume are co-determinants of driving pressure. The best predictor of mortality is driving pressure squared * RR. Mechanical power of ventilation is associated with mortality in critically ill patients. The higher the mechanical power, the worse is the outcome, although the correlation is not that strong as that of driving pressure versus mortality. This may be because unlike the thermodynamic system, biological systems are much more complex and correlation may not be linear. MP > 18 J/min was associated with increased mortality. The equation for calculation of mechanical power is given below.

Components of mechanical power include: Dynamic: ΔP * Vt/2 Static: PEEP * Vt Resistive: Flow * R * Vt From the above equation, it can be assumed that mechanical power incorporates almost all components of monitoring armamentarium regarding ventilation such as RR, PEEP, tidal volume, driving pressure and plateau pressure. Of all these components, only driving pressure and respiratory rate seems to have signif95

icant impact on survival. Monitoring driving pressure and Respiratory rate is all is needed at bedside to predict prognosis. The effect size of driving pressure is 4 times the effect size of respiratory rate. Therefore, it is worth decreasing driving pressure (by decreasing tidal volume) at the expense of increasing respiratory rate at the same Isocapnic conditions. Each patient has an optimum RR in which minimal driving pressure to be attained. The ideal RR is usually above 35 breaths/min in severe ARDS (35-65/min) Consider extreme reductions in tidal volume especially when compliance is low (< 6 ml/kg).In high compliance, Vt > 6 ml/kg to improve synchrony might be beneficial without VILI risk. The equation of Mechanical power can be simplified as: MP (J/min) = 0.008 * Vt * RR * (Ppeak – ½ Δ P)

Figure: Representing the sub components of mechanical power required to overcome elastic, resistive work in different ventilatory modes.

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Setting PEEP while Medicine based Evidence: - Personalizing targets Atelectasis by itself may not be harmful, but its effect on baby lung are. Atelectasis causes alveolar injury in non-atelectatic lung regions. PEEP is applied to recruit the atelectatic lung and at the same time to prevent over distention of non-atelectatic lung regions. Finding this optimal PEEP can be challenging and requires continuous monitoring. Furthermore, sub phenotype of ARDS may have different therapeutic response to PEEP. Hyper inflammatory phenotype (type 2 ARDS) may have beneficial response to PEEP than hypo inflammatory ARDS (type 1 ARDS). Some methods to define optimal PEEP include: 1 Pre-defined range in an individual patient 2 To limit escalation of PEEP until plateau pressure limit is reached (28-30 cm H2O) 3 PEEP- FIO2 table (higher versus lower) may be the best way to look for recruitment if no advanced techniques available 4 Recruitment to inflation ratio 5 Transpulmonary pressure limit (using esophageal pressure) 6 Decremental PEEP titration to dynamic compliance (open lung strategy) 7 Decremental steps to titrate to EIT 8 Dynamic testing

Figure: Lower and Higher PEEP FiO2 table Stair case recruitment with decremental PEEP trial (Open lung approach) had higher mortality compared to other techniques of setting PEEP. Airway Closure might occur in ARDS. PEEP should be set above the closing pressure. Setting PEEP below the AOP (Airway occlusion pressure) may increase the risk of VILI including bronchiolar damage generated by repeated opening and closing of distal airways. Furthermore, there is a risk of denitrogenation atelectasis.

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Effects of PEEP: Lung recruitment with higher PEEP improves mortality in moderate – severe ARDS. Successful lung recruitment is good, but increased PEEP without recruitment may be bad due to over distension of alveoli and can cause heart compression. In less complex patients, PEEP- FiO2 table should be used first. If already on high PEEP, check for R/I ratio to ensure recruitment In Severe ARDS – decremental PEEP trial using compliance or Pes. Always assess PEEP response with O2 and hemodynamics

Open lung approach for high PEEP: In an open lung approach, atelectasis is defined as areas of lung recruited when pressure > 35 cm H20, whereas consolidation is defined as no recruitment with pressures > 35. Atelectasis/ consolidation determines PEEP required for recruitment. High PEEP minimizes atelectrauma Low PEEP minimizes Volutrauma. Hence higher PEEP may be useful in patients with homogenous atelectasis with less risk of Volutrauma. Open lung approach with high PEEP is probably useful in post-op cardiac patients or obese patients (with potential for recruitment) and PF ratio < 250. However even pressures of 20 is almost similar to holding the lung expanded at the level of total lung capacity, which may be injurious. Furthermore, at the same driving pressure, higher PEEP has higher mechanical power. If open lung approach is used, EIT should be employed to monitor the dynamic recruitment.

PEEP in Prone position: It has been well established that the lung densities and perfusion in ARDS predominantly prefer the dependent regions, whereas aeration in the nondependent areas. In Supine position: Transpulmonary pressure (Ptp < Pao) = atelectasis In Prone position: Transpulmonary pressure > Pao = Ventilation Prone position: 1 2 3 4 5 6 7

Decreases Pleural pressure gradient and attains a more homogenous distribution of transpulmonary pressure. Reduces lung stress and strain in ARDS (decreased elastance of chest wall and increased compliance). Minimizes Ventilator induced lung injury. Augments tidal recruitment Decreases hyperinflation in lobar/focal ARDS than diffuse ARDS (Similar to effect of PEEP) Allows reduction in PEEP and FiO2. Minimizes PEEP induced hyperinflation Improves VQ match

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PEEP in prone position can be set either according to "low PEEP/FiO2" table or by end expiratory esophageal pressure (EEO + 3cm H2O). By these methods, PEEP was found to be similar in supine or prone position, just that oxygenation improved and elastance decreased. If PEEP was set according to driving pressure, the set PEEP was found to be lower in prone position than supine position, although there may not be any change in oxygenation status. In conclusion, 1 2 3 4 5 6

The oxygenation response to prone positioning depends on PEEP titration technique No improvement in oxygenation in prone when using transpulmonary pressure to set PEEP. Prone position could enhance lung protection independently from PEEP titration technique and from oxygenation response. Oxygenation response to prone depends on PEEP titration techniques. Prone and PEEP independently improve lung compliance Intra-abdominal hypertension increased the PEEP needed for the best lung compliance, however does not affect response to PEEP in prone position.

Strategies to improve survival in severe ARDS: Prone position with low-moderate PEEP- first choice Supine and high PEEP (< 15 cm H20)-second choice Combination of Prone and high PEEP-third choice Minimal PEEP for minimal SaO2 (99-92% = PaO2 of 55-80); less right ventricular impairment.

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Protective Ventilation in non-ARDS: less is more. The following guidelines are applicable only to non-ARDS patients. LIPS score > 4 predicts hospital mortality and survival in ICU. LIPS: Lung Injury Prediction Score. LIPS score is used to identify "non-ARDS" patient who are at risk of ARDS.

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Setting the tidal volume: An initial tidal volume of 6-10 ml/kg/PBW can be considered and then the tidal volume is adjusted as tolerated depending on the sedation requirements and PaCO2. Lower tidal volume (4-6 ml/kg PBW) if tolerated with less sedation and assisted breathing. If not higher tidal volumes (8-10 ml/kg PBW) and assisted breathing with less sedation. Lower tidal volume (6 ml/kg): is associated with High respiratory rate, if hypercapnia Longer mechanical ventilation Higher frequency of delirium No difference in P/F ratio. These complications were lower in intermediate tidal volume (9 ml/kg)

Setting the PEEP: Initial setting of PEEP of 5 cm H20. High PEEP: associated with No change in duration of MV Lower rates of ARDS. It is recommended to set PEEP minimal to target SaO2 of 88-92 % or PaO2 of 55-80 mm HG. This would also minimize right ventricular impairment. Goal in non ARDS is to ventilate the aerated lung gently and resting the atelectatic lung. Hence the phrase "less is more". No recruitment maneuver.

Plateau Pressure: aim for Pplat < 18 cm H20. Driving Pressure: aim for driving pressure < 13 cm H20. Directly associated with mortality. Lowest is better.

Mechanical Power: measured in joules/min. It is the energy load per min imposed on respiratory system. MP (J/min): 0.098 * Vt * (Ppeak-½ ΔP) *RR ΔP: driving pressure. It was observed that there were different parameters associated with increased mortality. These include: Higher Vt and driving pressure. Higher MP even at low Vt and low driving pressure Higher respiratory rate Hence, it can be concluded that any component in the equation of mechanical power can contribute to the mortality including RR. Aim for mechanical power < 17 J/min with the maximum limit of 20 J/min. MP can be easily decreased by going low on RR up to maintain pH > 7.25.

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Protective Ventilation in Obese Patients: Obesity classification: Class 1: BMI 30-34.9 kg/m2 Class 2: BMI 35-39.9 Class 3: BMI >/= 40 kg/m2. Class 3 Obesity frequently develop: Intraoperative desaturation (Rx: recruitment maneuver, increase FiO2) Intraoperative hypotension (Rx: Fluids, Vasoactive drugs) Postoperative Pulmonary complications - Acute respiratory failure and the need for mechanical ventilation. NB: Recruitment maneuver by bag squeeze was associated with higher postoperative pulmonary complications Anesthesia and paralysis is associated with reduction in lung volume by dependent atelectasis and nonaerated tissue. In obesity, this is aggravated even resulting in some loss of compliance and gas exchange. The elevated intraabdominal pressure translates to intrapleural pressure and there by squeezing alveoli in the dependent regions and promotes airway closure in the mid parts of the lungs. Application of PEEP and recruitment maneuver can minimize the wide regional variations in transpulmonary pressures, minimizing the airway closure and atelectasis. Because transpulmonary pressure is dependent on the BMI, sometimes PEEP of 20 may be required to make transpulmonary pressures positive of 2-4 in the dependent parts of lungs. PEEP application: Can decrease the driving pressure / stress index by opening the atelectatic areas Also, excessive PEEP can increase driving pressure by over distending the non-dependent regions. Hence the best PEEP is when there is a lowest driving pressure of the U shaped relationship. Current guidelines for Protective mechanical Ventilation during General Anesthesia: Low tidal volume – 7 ml/kg PBW Low PEEP: 5 cm of H2O No recruitment maneuver (RM) as a routine P Plat < 17 cm H2O, (< 22 in Obese) Driving Pressure < 13 cm H2O (< 18 in obese) If SaO2 < 92%, increase FiO2 up to 90%. If persistent SaO2 < 92%, RM and increase PEEP

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Protective Ventilation in ARDS and Obese patients: Driving pressure is associated with mortality in non-obese patients with ARDS, however this relationship is not found in obesity. Higher PEEP may be beneficial. Prone position improves gas exchange and survival in obese than in non-obese ARDS patients. ISTART Protocol for Ventilating Obese patients:

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Mechanical Ventilation in Brain injury patients: Lung and the brain: A dangerous cross talk Brain injury promotes lung injury and conversely lung injury promotes brain injury.

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Some concerns of this cross talk: 1 2 3

Acute intracranial hypertension increases EVLW (extra vascular lung water) both in healthy and ARDS lungs. VILI promotes Brain injury ( C fos positive cells in central amygdala; C fos : marker of neuronal injury) Peripheral organ dysfunction is associated with worse outcome in brain injury patients.

Some concerns of Protective ventilation in brain injury patients: 1 2

Low tidal volume causes Permissive hypercapnia can increase ICP High PEEP or recruitment maneuver Increased intrathoracic pressure can increase ICP

Effect of PEEP on cerebral physiology: How PEEP increases CBV and ICP PEEP -> Increased Intrathoracic pressure -> Raised CVP -> Waterfall effect or if CVP > ICP: = impaired venous return. NB: Waterfall effect or "Starling Resister effect" wherein, subsequent to collapse, the flow through the tube becomes independent of the downstream pressure. Starling effect occurs at the level of collapsing veins and non-collapsible sagittal sinus. PEEP -> alveolar hyperventilation, increased PaCO2 -> cerebral vasodilation -> increased arterial inflow PEEP ->high intrathoracic pressure ->decreased venous return (preload) -> decreased MAP/CPP.

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In the presence of intact autoregulation, decreased MAP can cause cerebral vasodilation, increased CBV and ICP. If Cerebral autoregulation is impaired, decreased MAP leads to arterial collapse (? ischemia), decreased CBV and decreased ICP. NB: PEEP was observed to decrease MAP/CPP in patients with normal lung compliance. However, in patients with low lung compliance, PEEP had no effect on MAP/CPP. Hemodynamic impact of PEEP is attenuated in patients with decreased lung compliance. If cerebral autoregulation is intact, PEEP may not have significant impact on ICP, PBO2, CBF, however decreased MAP may cause cerebral vasodilation. However in patients with brain injury, cerebral autoregulation is narrowed and right shifted. If cerebral auto regulated is disrupted, PEEP although decreased MAP, CBF and PBO2, did not have any effect on ICP. Some conflicting ventilatory paradigms: Brain directed strategy

Lung protective ventilation

Optimize O2 delivery

Optimize O2 delivery

Control PaCO2 ( higher tidal volume and Ve)

Avoid Over distension, Volutrauma, hence lower TV

Minimize potential effects of PEEP

Avoid cyclical collapse, atelectrauma, higher PEEP

Aim : to avoid increase in ICP and optimize CBF Aim to prevent VILI In summary, effect of altering airway pressure on the brain depends on: Respiratory mechanics: lung/chest wall compliance Decreased lung compliance: no effect on ICP Normal lung compliance: increased ICP Lung recruitability: If lung recruitable: No effect on ICP If lung not recruitable: increased ICP Cerebral autoregulation: Intact: If MAP is decreased results in increased ICP Disrupted: If MAP is decreased, decreased ICP, but may increase cerebral ischemia Baseline ICP and cerebral compliance High cerebral compliance: no increase in ICP Low Cerebral compliance: increased ICP The Final Verdict: Lung protective strategies should be considered in patients who are mechanically ventilated and have acute brain injury without significant elevation in intracranial pressure. Even in patients with significant ICP elevation, lung protective strategy should be considered in patients with ARDS with ICP monitoring / neuromonitoring and adjusting the ventilator parameters accordingly. So, MV in brain injury is not so different from general population, but neuromonitoring should be employed and ventilator settings adjusted to prevent ICP rise. 106

Ventilator targets in only ARDS: PaO2: 55-80 PaCO2: any value as long as pH > 7.25 (permissive hypercapnia) Ventilatory targets in acute brain injury: PaO2: > 75 mm HG PaCO2: Normocapnia. PaCO2 < 30 mm HG is not recommended for the fear of cerebral ischemia Ventilatory targets in ARDS + Brain Injury: PaO2: > 75 mm HG PaCO2: Either aim for Normocapnia or Neuromonitoring and pH. Setting Tidal volume: An initial tidal volume of 6-9 ml/kg PBW should be considered, target Plateau Pressure < 30 cm H2O. Adjust tidal volume according to driving pressure and plateau pressure RR can be increased initially to prevent hypercapnia Setting PEEP: PEEP improves systemic oxygenation and therefore cerebral oxygenation. PEEP also prevents cyclic recruitment and derecruitment, this cyclic trauma may be transmitted to brain. ZEEP is not recommended, set the PEEP as it would have been set in a typical ARDS patients. PEEP should be adjusted by monitoring both cerebral and lung compliance (moderate PEEP may be safe) Because hyperinflation can cause hypercapnia and impair venous return, it should be minimized Ensure adequate filling pressure to avoid decrease in MAP Head of Bed should be elevated to diminish effect of intrathoracic pressure on Brain Follow ICP closely or neuromonitoring Monitor PaCO2 and EtCO2. Prone position: Consider prone position in patients with ARDS and brain injury without ICP elevation. Prone position may increase ICP, if considered neuromonitoring should be employed Recruitment maneuvers: Can be considered in patients with ARDS and brain injury without ICP elevation. RM can increase ICP, hence if employed, must be guided by neuromonitoring ECMO: Can be considered if the patient qualifies, as a rescue therapy. Heparin dose must be adjusted increased risk of bleeding.

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Figure: Ventilation strategies and targets in brain injury and ARDS One another strategy is to perform Brain and Lung US, the so called "brain protective recruitment strategy".

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ARDS acute respiratory distress syndrome, LUS lung ultrasound, BUS brain ultrasound, PEEP positive end expiratory pressure, PI middle cerebral artery pulsatility index, Vd middle cerebral artery diastolic arterial flow velocity, FV flow velocity; ONSD optic nerve sheath diameter, MAP mean systemic arterial pressure, ICP intracranial pressure, BGA blood gas analysis, TBI traumatic brain injury, ECCOR extracorporeal CO2 removal, vvECMO veno-venous extracorporeal membrane oxygenation, EEG electroencephalography, CRS respiratory system compliance, ΔP driving pressure, CapVol volumetric capnometry, SpO2 arterial oxygen saturation

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Lung ultrasound–Brain ultrasound (LUS–BUS) combined respiratory and neurological monitoring in patients with TBI and ARDS. Four step approach is proposed: LUS-BUS Step 1—Lung Ultrasound of ventral and dorsal chest areas to differentiate: ARDS with focal/patchy morphology (with less recruitment potential and greater risk of anterior lung over distention). ARDS with diffuse, more homogenous, morphology (amenable to successful recruitment at higher PEEP levels). Step 2—Perform Brain ultrasound. Medical therapy is instituted if elevated ICP to reduce the negative impact of the ventilatory maneuvers on the brain. Step 3—Perform Recruitment maneuver while simultaneously monitoring lung and Brain parameters. Monitoring lung: Driving pressure, Static compliance, volumetric capnogram, SpO2, lung aeration score Monitoring Brain: Pulsatility index, Diastolic arterial flow velocity, Optic nerve sheath diameter Step 4—Assess the final effect of PEEP and RM on gas exchange, hemodynamics, ICP.

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Spontaneous Assisted Ventilation / Assisted Spontaneous Breathing ASB: Spontaneous assisted ventilation has the following advantages and should be practiced whenever feasible. Decreased intrathoracic pressure, therefore more stable hemodynamics Better V Q matching due to better distribution of ventilation.  Increased variability of ventilation and lung protection Prevents disuse atrophy of respiratory muscles Less need for sedation and decreases delirium. Disadvantages of spontaneous assisted ventilation: High incidence of Patient ventilator asynchronies Diaphragmatic dysfunction – Over or under assistance High respiratory drive, less control of ventilator pattern and effort, excessive Vt and Pressures High incidence of Ventilator induced lung injury NB: The intra-alveolar pressure is more negative in a pressure support ventilation than a controlled ventilation for the same transpulmonary pressure and the distending trans-alveolar pressure. Targets during Assisted Spontaneous Breathing: Optimization of O2 delivery, organ perfusion = Normal lactate, normal SvO2. Adequate gas exchange: normal pH, PaO2 higher than controlled ventilation, PaCO2 regulated by patient. Avoidance of dyssynchrony, control VT and RR (although difficult to control) to minimize VILI Avoidance of excessive muscular fatigue / over assistance – titrate sedation Avoidance of excessive metabolic needs. Monitoring during Assisted Spontaneous Breathing: Respiratory drive: Breath pattern, P0.1, EAdi Effort, P musc:Δ Pes, PMI, Δ CVP, Pocc VILI: Vt, P Plat, Crs, Pocc Muscle Strength: NIF Pt-Vent Synchrony: Vent Waveforms, Pes, EAdi Diaphragm function: Echo

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P0.1 - The airway occlusion pressure: it is the negative deflection of airway pressure during the first 100 msec of the spontaneous breath of an occluded airway. It is not related to the muscular force. It is related only to the drive of the patient. P0.1 is linearly correlated with the Work of breathing and therefore O2 consumption of respiratory muscles. P0.1 < 2: Scare effort P0.1 > 4: Intense effort Target P0.1: 2-4.

Figure: The airway pressure is measured at 100 msec after end expiratory occlusion. This is referred to as P0.1. (I.e. at 0.1 part of 1 sec). The target P0.1 should be around 1-3.5 cm H20. The amount of max pressure dropped I, recorded as Pocc, from which Predicted Pmusc and Predicted dynamic transpulmonary pressure can be calculated by formula. The same expiratory hold can help in differentiating reverse triggering versus double triggering.

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Figure: End expiratory hold to calculate Pocc and to differentiate reverse versus double triggering. Representative tracings showing a) the airway occlusion maneuver in a spontaneously breathing patient at rest, and b) two patients with double triggering; one resulting from reverse triggering and the other resulting from a dissociation between neural and mechanical inspiratory time. Airway pressure (Paw), flow, esophageal pressure (Pes), and transpulmonary pressure (PL) were recorded during the expiratory occlusion maneuver. Pocc represents the inspiratory swing in airway pressure against an occluded airway. ∆Pes represents the dynamic esophageal pressure inspiratory swing. The dynamic transpulmonary driving pressure (∆PL, dyn) represents the dynamic mechanical stress applied to the lung during inspiration. By applying previously validated correction factors, clinicians can use Pocc to estimate respiratory muscle effort (Pmus) and ∆PL, dyn. In panel b, during the expiratory hold, there is no respiratory effort from the patient with reverse triggering, signifying that the double triggering is occurring in the absence of spontaneous respiratory drive. Conversely, an inspiratory effort can be seen during the hold in the other patients’ tracing.

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Pmus: Estimation of patient inspiratory effort

Figure to calculate P musc: Three different modalities of muscular pressure (Pmus) calculation 1.Pes-based method : Esophageal pressure (Pes) is measured during tidal ventilation by an esophageal balloon, and Pmus is calculated as the instant-by-instant difference between Pes and the chest-wall elastic recoil curve (equal to the instant-by-instant product of the tidal volume and chest-wall elastance, derived during the phase of controlled mechanical ventilation). 2. EAdi-based Method: Electromyography (EMG) of the diaphragm is continuously recorded through a dedicated nasogastric balloon, sampling crural diaphragm electrical activity (EAdi). Then, during a brief occlusion maneuver, the ratio between airway pressure (Paw) drops (which, in absence of flow, is equal to Pmus) and the corresponding EAdi signal (which is the electrical activity that the diaphragm requires to generate Pmus) is calculated. This index, the Pmus/EAdi Index (PEI), indicates how much cm H2O of pressure the diaphragm can produce for every V of electrical activity and is stable within any patient at different levels of inspiratory effort, which thus allows reliably conversion of the V of electrical activity into cm H2O of Pmus. Finally, during tidal ventilation, EAdi is instant by instant converted in Pmus calculated as the product of EAdi and the corresponding PEI. PEI: Pmus/EAdi, or Pmus: EAdi * PEI/1.5

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3. Surface EMG-based method: Electrical Activity of the diaphragm is continuously recorded trough a couple of surface electrodes positioned at the lower costal margin, bilaterally on the midclavicular line, sampling costal diaphragm electrical activity (surface EAdi). With the same procedure of EAdi, Pmus/ surface EAdi is calculated and during tidal ventilation it is used for the instant-by-instant conversion of surface EAdi in Pmus. Inspiratory swings of CVP: The inspiratory swings of CVP has linear relationship with swings in esophageal pressure, bot during ZEEP or PEEP. P plat: Can be monitored even during Spontaneous assisted breathing (Pressure support or NAVA) provided the inspiratory muscles are relaxed. For this, end inspiratory occlusion (inspiratory hold) is done and P plat recorded. This P plat has similar significance to that obtained during controlled ventilation. In fact driving pressure and compliance can also be calculated and interpreted. Muscle strength: Can be measured by Maximum Inspiratory pressure (MIP) or Negative inspiratory force (NIF). Diaphragmatic Ultrasound: Can be used as an indicator of respiratory effort in critically ill patients on mechanical ventilation. No relationship is found between diaphragm excursion and PTPes (Pressure time product) or TF (thickening fraction) or work of breathing. However Thickening fraction is significantly correlated with diaphragm and esophageal PTP during tidal breathing, inspiratory effort, and driving pressure.

Figure: Calculating thickening fraction

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Figure: Diaphragm excursion Predicted P mus by End – Expiratory exclusion maneuver: Perform 3 single breath end expiratory airway occlusions to measure Δ Pocc every 4-8 hours. Estimate P mus. Predicted P mus = (-0.7) * Δ Pocc. If Δ Pocc is < 0 cm H2O, then estimate Δ Pl (transpulmonary pressure) Predicted Δ Pl = (Peak Paw – PEEP) - 0.6 * Δ Pocc. If Predicted P mus > 13-15 cm H20 or Predicted Δ Pl >/= 16-17 cm H2O; consider Pes/ sedation/ adjust ventilator If Predicted P mus < 13-15 cm H20 or Predicted Δ Pl < 16-17 cm H2O; target is achieved

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Driving pressure during assisted ventilation: Driving pressure is defined as the ratio of tidal volume to compliance. Compliance is the ratio of tidal volume to Pplat-PEEP. Thus, Driving pressure = Pplat- PEEP. If esophageal pressure is available, driving pressure = Pplat – Esophageal pressure. NB: The esophageal pressure, even if it’s negative has to be included in the equation with the appropriate sign. It must be realized that plateau pressure may remain same across different patient, but driving pressures may be different depending on the level of PEEP applied. As compliance is the best proxy for lung size, monitoring and adjusting ventilatory parameters by monitoring driving pressure can personalize the application of amount of tidal volume to an individual patient. During assisted ventilation/ PSV, negative pressure swings happen may remain occult if only airway pressures are monitored. The positive pressures generated by ventilator may be buffered by the negative pressure swings due to spontaneous effort. There are two methods to circumvent this issue: 1 Monitoring esophageal pressure , looking for negative pressure swings 2 Monitoring Pplat after end inspiratory hold. End inspiratory hold is presumed to cause relaxation of inspiratory muscles and thus would remove the effect of negative pressure swings on monitoring respiratory mechanics. Driving pressure is then calculated. This is the same reason for plateau pressure being higher than peak pressure. Occasionally, patient may sense closure of expiratory valve with end inspiratory hold, which may lead to "non-readable measurements", as plateau may not be achieved and airway pressures keep rising. Driving pressure is independently associated with outcome. Driving pressure during assisted ventilation has same effect as during controlled ventilation, except that Pplat is measured differently. NB: Airway closure have been observed to occur in ARDS. Measurement of airway pressure at end expiration may thus lead to inappropriate estimation of driving pressure.

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Transpulmonary Pressure: Benefits of PEEP depends on recruitability. If increasing PEEP increases Pplateau and driving pressure, it indicates non recruitability and in such an instance, PEEP may do more harm than good. Therefore it is important to identify those subset of patients who have recruitable lungs, where PEEP would have a beneficial effect. One such method to identify recruitability is by means of Transpulmonary pressure. Transpulmonary pressure can be considered as a distending pressure of the lung. Transpulmonary pressure (Pl) = Pairway – Ppleural. Ppleural is estimated via esophageal pressure. Pl < 0 = atelectasis. Mechanical ventilation (PEEP) guided by esophageal pressure or transpulmonary pressure improves mortality compared to empiric low PEEP and has similar outcomes to empiric high PEEP. Esophageal pressure guided PEEP might have significantly more beneficial effect on patients with lower APACHE score, there by signifying its positive impact if the patient had more lung involvement ( ARDS attributable risk) than dysfunction of other organs. Thus Pes guided PEEP improves survival when risk of death is mostly due to ARDS. During assisted spontaneous breathing, because of the negative swings in pleural pressure, the airway pressure may seem to be relative "safe”, although transpulmonary pressures are high and may cause VILI. Clinically, Transpulmonary pressure is used in the following settings 1 PEEP can be increased such that end expiratory transpulmonary pressure is 0 or positive ( not negative) 2 End Inspiratory transpulmonary pressure > 10 indicates lung with impaired respiratory mechanics.

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Recruitment: ARDS human lungs have different degrees of lung recruitability. The percentage of potentially recruitable lung is extremely variable and is strongly associated with response to PEEP. Recruitment maneuver is found to be useful in a subset of ARDS patients that include: Post-operative cardiac patient with severe hypoxia Super obese patients Recruitable lungs Methods to identify recruitable lungs: 1

CT chest can help in identifying recruitability, however application at the bed side may be limited.

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Electrical Impedance tomography (EIT) plethysmography can help identify lung recruitability especially during incremental and decremental maneuvers. If the calculated compliance increases, it is called Recruitment. If the compliance decreases, it referred to as over distension. Rather, regional ventilation displayed by EIT acts as an incentive to decrease PEEP.

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Bed side measurement of FRC by N2 wash out/ wash in technique, but this requires metabolic stability. Volume and concentration of Nitrogen captured, change in Oxygen concentration observed while calculating change in nitrogen. By metabolic monitoring, FRC is calculated. FRC: VN2/N2%Start – N2%end N2% = 1- EtO2- EtCO2 VN2 = Vti * N2%in – Vte*N2%out N2%in = 1- FiO2 N2%out = 1-EtO2-EtCO2. Recruitment is then estimated based on calculating Strain at High and Low PEEP Strain High PEEP = (EELV at high PEEP – FRC) / (FRC + Rec) Strain Low PEEP = (EELV at low PEEP- FRC) / FRC

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PV curve method: Plot pressure volume curve first with low flow inflation at ZEEP (Zero end expiratory pressure) and then repeat the measurements at PEEP with long expiration to ZEEP. The EELV (End Expiratory lung volume) is calculated. Expired Volume – Vt = Increase in EELV induced by PEEP.

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Figure: Measuring recruitment using pressure-volume curve 5

Assess for Recruitment to Inflation ratio. (R/I maneuver)

Set the mode to Volume assist control mode. Pplat is measured using a 0.3 sec inspiratory pause rather than manual inspiratory pause. Manual inspiratory pause that is too long may erroneously decrease P plat. Decrease the respiratory rate to 6-8/min (to ensure complete exhalation when PEEP will be dropped). Record the exhaled volume at the initial high PEEP. Now Drop the PEEP by 10 cm H20 at once (not gradual) and record the exhaled volume and Pplat (aka end inspiratory pressure). By a proprietary algorithm (https://crec.coemv.ca/), a ratio is generated. This denomination is actually the ratio of compliance of lung to that of respiratory system. A ratio > or = 0.5 indicates more potential for lung recruitment with respect to inflation. Caveat:High PEEP for this maneuver should be at least 5 cm above airway occlusion pressure as long as Pplat < 30 cm H20.

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Nota bene: Airway opening pressure : Set the mode to SIMV with PS. Slow inflation maneuver : Decrease the rate to 5/min , PEEP to 5 cm H20, adjust inspiratory time until flow is 5l/min or adjust flow to 5l/min, tidal volume to 6 ml/kg of PBW, Square wave, 100% rise. Record or freeze the graph of Pressure time scalar. If there is no inflection point, there is no airway closure. The presence of inflection point indicates airway closure. Inflection point is recorded as the pressure at the inflection. Compliance can be calculated by the ratio of tidal volume at the inflection point to delta P (P inflection – PEEP). Concept of Recruitment to Inflation ratio: Ratio of compliance of recruitment to compliance of inflation. R/I ratio = C rec / Crs. R/I ratio > 0.5 = High recruiters R/I ratio < 0.5 = Low recruiters Compliance of Recruitment: C-rec: delta Volume due to recruitment/ delta Pressure due to recruitment C rec: Δ Vrec / (PEEP high – AOP) Compliance of inflation: C baby: delta volume due to inflation/ delta Pressure due to inflation. Crs: At PEEP low or above AOP.

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Patient self-inflicted lung injury (P-SILI): Definition: Negative pressure swings associated with spontaneous efforts can worsen lung function in a patient with severe lung injury. This has been called Patient self-inflicted lung injury. Hence the need to monitor respiratory efforts. Mechanism: Lung edema due to capillary leak leads to impaired gas exchange and abnormal lung mechanics. This causes augmented respiratory drive. This augmented respiratory drive is associated with: a b c d e

Increased swings in esophageal pressure- dyssynchrony , double triggering Increased minute ventilation and direct over distention injury Increased pendelluft Decreased alveolar pressure due to expiratory muscle activation and decreased EELV Increased lung perfusion

All these mechanisms can worsen inflammation and further augment lung injury. Pendelluft: Also referred to as "air swinging". This is a phenomenon of transient air movement with-in the lung from one region to another region without change in tidal volume. This happens because of heterogeneity in lung stretch kinetics i.e. time constant inequalities in injured lung. Pendelluft seems to more often happen during the early part of inflation. Spontaneous efforts during mechanical ventilation may further augment pendelluft there by over-stretching certain areas and under expanding others.

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Critical illness associated diaphragm weakness: This can be secondary to Ventilator associated diaphragmatic dysfunction (diaphragmatic myotrauma) or deranged physiology due to critical illness. Ventilator induced diaphragm dysfunction: Diaphragm thickness rapidly changes during mechanical ventilation. In majority of the patients have decline in thickness and in minority, the diaphragm actually thickens (due to load related injury). Both decrease and increase in thickness from baseline was associated with delayed liberation from ventilation. These changes in muscle architecture has been labeled "Diaphragm myotrauma". Mechanisms: 1

Insufficient unloading /under-assistance: Also referred to excessive muscle loading. This is secondary to increased neural drive and associated high diaphragm activity. This leads to sarcomere disruption, contractile fatigue and diaphragmatic injury. Causes include acute respiratory failure of any cause and associated inappropriate efforts.

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Excessive unloading / Over-assistance: Similar to disuse atrophy or insufficient muscle loading. This is secondary to decreased neural drive and associated low diaphragm activity. This leads to diaphragmatic atrophy (myofibril damage) by decreased protein synthesis and increased protein degradation by ubiquitin proteasome and caspase calpain pathways. Causes include excessive assistance from mechanical ventilation and sedation. This is the most common mechanism.

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Eccentric contraction: Can result due to patient ventilator dyssynchrony causing maldistribution of forces of contraction causing myotrauma. E.g.: Reverse triggering.

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End expiratory shortening: Maintaining a muscle at shortened length for period of time results in sarcomere drop out.

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Metabolic stress: This could be related to oxidative stress of sepsis and de-nutrition associated with critical illness. Sepsis seems to predominantly affect diaphragm than any other muscle in the body (e.g. Psoas muscle).

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Figure: Mechanisms of diaphragmatic myotrauma.

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Reverse Triggering: This is considered as a form of neuromechanical coupling, where by mechanical ventilation induces a triggered breath. That is, diaphragmatic contraction occurs after a mechanical breath that can be identified by the negative pressure swing of esophageal pressure or electrical activity of diaphragm after the flow of positive pressure breath. This has been referred to as reverse triggering as a spontaneous breath is triggered after a mechanical breath. Occasionally, this can also present as Double Cycling. Patient would receive twice the tidal volume. If the spontaneous breath is triggered during expiration, then this may lead to eccentric contractions and diaphragmatic myotrauma. High incidence is seen around 24 hours after intubation, almost ubiquitously, in sedated patients. Most breaths represent small efforts. Higher efforts increase the risk of double cycling and breath stacking. Risk factors include: Smaller tidal volumes (viz ARDS) Transitioning state from deep sedation to resumption of spontaneous breathing. (Assist control)

Figure: Reverse triggering in a patient ventilated with assist volume control ventilation. Esophageal pressure (Pes) decrease reveals patient inspiratory efforts (blue line) after every mechanical inflation in 1:1 relationship. Indirect evidence of patient inspiratory activity during mechanical inflation is the flow distortion (grey shaded area) and the disappearance (blue arrows) of plateau airway pressure (Paw) in the flowtime and Paw-time waveform, respectively. In this patient, a reverse triggered breath was strong enough to trigger the ventilator at the end of the mechanical inspiration, causing breath stacking (red shaded area). Inflated tidal volume (V T) during breath stacking increased from 444 ml to 800 ml (double arrow). Reverse triggering thus can cause double triggering. Although, presence of air leak should be ruled out.

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Figure : End expiratory hold to calculate P musc and to differentiate reverse triggering and double triggering .Representative tracings showing a) the airway occlusion maneuver in a spontaneously breathing patient at rest, and b) two patients with double triggering; one resulting from reverse triggering and the other resulting from a dissociation between neural and mechanical inspiratory time. Airway pressure (Paw), flow, esophageal pressure (Pes), and transpulmonary pressure (PL) were recorded during the expiratory occlusion maneuver. Pocc represents the inspiratory swing in airway pressure against an occluded airway. ∆Pes represents the dynamic esophageal pressure inspiratory swing. The dynamic transpulmonary driving pressure (∆PL, dyn) represents the dynamic mechanical stress applied to the lung during inspiration. By applying previously validated correction factors, clinicians can use Pocc to estimate respiratory muscle effort (Pmus) and ∆PL, dyn. In panel b, during the expiratory hold, there is no respiratory effort from the patient with reverse triggering, signifying that the double triggering is occurring in the absence of spontaneous respiratory drive. Conversely, an inspiratory effort can be seen during the hold in the other patients’ tracing. 126

  Figure: Monitoring spontaneous efforts during assisted ventilation via esophageal pressure. Over-assistance: Positive esophageal pressure curve during assisted ventilation. Under-assistance: Deep negative esophageal pressure during spontaneous efforts Eccentric myotrauma: patient ventilator dyssynchrony. Figure: Monitoring spontaneous efforts during assisted ventilation via esophageal pressure. Over-assistance: Positive esophageal pressure curve during assisted ventilation. Under-assistance: Deep negative esophageal pressure during spontaneous efforts Eccentric myotrauma: patient ventilator dyssynchrony. Outcomes: Diaphragmatic myo-trauma has been associated with prolonged ventilation and poor outcomes. Hence, Monitoring spontaneous efforts or diaphragmatic activity during assisted mechanical ventilation may protect not only lung, but also diaphragm.

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Diaphragm activity/ Spontaneous efforts can be monitored by 1. Esophageal pressure monitoring: The more negative, the more spontaneous efforts 2. Measuring electrical activity (EAdi) in a paralyzed patient. EaDi > 7 uvolts corresponds to roughly 15% of thickening fraction. It has been observed that it may take 24-48 hours for diaphragm to recover from sedation and paralysis. 3. Airway Occlusion pressure (P0.1): P0.1 is the monitoring tool for respiratory drive which closely reflect effort. High drive is > 3.5 cm H2O. (High effort) Ex: Over assistance or over sedated. Low drive is < 1 cm H2O. (Low effort) Ex: Under assistance Target P 0.1 should be between 1-3.5 cm H20. Some studies quote 2-4. P0.1 co-relates well with pressure time product. 4.Dynamic transpulmonary driving pressure. The airway is occluded at the start of effort and the negative pressure swings in airway pressure is monitored. The more the negative pressure swing that is generated, the more is the effort.

Figure: Monitoring airway occlusion pressure at 100 msec. The airway pressure is measured at 100 msec after end expiratory occlusion. This is referred to as P0.1. (I.e. at 0.1 part of 1 sec). The target P0.1 should be around 1-3.5 cm H20.

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Figure: Detecting high respiratory drive by dynamic transpulmonary driving pressure Representative tracings obtained during the airway occlusion maneuver. Flow, airway pressure (Paw), esophageal pressure (Pes), and diaphragm electrical activity (Edi) were recorded while a one-way end-expiratory occlusion permitting expiratory flow but not inspiratory flow (black arrow) was applied at a random interval. Transpulmonary pressure (PL), obtained by digital subtraction of Pes from Paw, and signifies the dynamic stress applied to the lung. Chest wall elastic recoil pressure (ΔPcw) was estimated by multiplying tidal volume by predicted chest wall elastance. Inspiratory effort was quantified by the peak inspiratory muscle pressure, Pmus, estimated as the difference between ΔPcw and ΔPes (baseline Pmus is 0 cm H2O by definition). Note that peak Edi did not differ between occluded and non-occluded breaths.

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Treatment/Prevention: Concept of diaphragm protective ventilation: As elucidated above, both insufficient and excessive diaphragm activity has been associated with diaphragmatic myotrauma and prolonged ventilator dependence. Mechanical ventilator parameters may have to be adjusted such that diaphragm is optimally assisted – diaphragm protective ventilation. 1 Mechanical ventilation parameters have to optimized by adjusting peak inspiratory flow , support level , PEEP , FiO2 2 Switch to Proportional mode (technology to assist physiology): Driving pressure are typically measured breath to breath. 3 Adjust sedation accordingly. All these adjustments optimize the 'dose of ventilatory support' to aim for normal work of breathing. Too low dose would cause respiratory distress. Too high dose would result in VILI, VALI and VIDD. Integrating all the ventilator parameters to optimally assist both the lung and diaphragm so called "Lung and diaphragm protective ventilation" is a complicated task and should be individualized. Targeted respiratory monitoring by esophageal manometry, airway occlusion pressure (P0.1- that is a representative of respiratory drive), expiratory occlusion pressure (POCC- obtained after end expiratory hold) and titrating accordingly might fine tune the dose of ventilator delivered. In circumstances, where it is not possible to deliver both lung and diaphragm protective ventilation due to competing mechanisms , then protecting the lung should be prioritized over diaphragm. VILI: Ventilator induced lung injury VALI: Ventilator associated lung injury VIDD: Ventilator induced diaphragmatic dysfunction. An Ideal mechanical ventilator should be able to Monitor lung volumes, enable Electrical Impedance tomography, diaphragm EMG Enable all modes such as PAV+, NAVA, Smart Care, and ASV/Intellivent. Smart monitoring and analysis to minimize lung and diaphragm injury, to enhance synchrony. For example: Smartcare is an automated weaning process from mechanical ventilation that adjusts pressure support according to patient’s effort that enables synchrony and optimizes ventilatory dose.

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Ventilator Weaning: Myocardial Ischemia during weaning: Spontaneous ventilation is considered as an exercise and is associated with not only increased O2 consumption, but causes diversion of cardiac output to respiratory muscles leading to tissue hypoxia (decreased supply). In addition, weaning is associated with increased sympathetic tone resulting in increased preload due to venoconstriction, tachycardia, and diastolic alteration. All these mechanisms lead to imbalance in myocardial O2 supply and demand. This has been labeled "Weaning induced cardiac ischemia"WICI. WICI can lead to WIPO (weaning induced pulmonary edema) by causing systolic - diastolic dysfunction and impair ventricular coupling (esp. in COPD). Patient can have either WICI or WIPO and only a few have both. Systolic dysfunction: Increase in PAOP and LVEDVI. Diastolic dysfunction: Increase in PAOP and no increase in LVEDVI. WIPO during SBT can be diagnosed by observing the increase in ratio of E/Ea. and E/A at the end of SBT, rise of NT-proBNP and increase in plasma protein concentration at the end of weaning ~ 2 hours. Increase in plasma protein is also called as "protedemia". Protedemia occurs probably due to the filtration of plasma to the alveolar compartment. WIPO was associated with weaning failure. Dx criteria for WIPO: All events occurring at the end of SBT (2/3 criteria) TTE: E/A > 0.95, E/e > 8.5 Increase BNP >/= 48 ng/l or increase NT-proBNP >/= 21 ng/l Increase in Protedemia >/= 6%. Dx criteria for WICI: ST segment monitoring of 12 derivations with standard definitions. ESC 2012: ST elevation in two contiguous leads; >/=0.10 mV in all leads other than V2-V3 >/=0.15 mV in V2-V3 in women >/=0.20 mV in V2-V3 in Men 40 years or older >/=0.25 mV in V2-V3 in Men < 40 years ST depression >/= 0.05 mV in two contiguous leads AHS 2013: ST elevation or depression >/= 0.10mV in two contiguous leads. Troponins did not change in WICI probably due to half -life. Myoglobin may be a better marker. N.B: Risk factors for WICI: Intubation for cardiac arrest is the predominant risk factor. Chronic ischemic heart disease was not associated with increased risk of WICI. WICI can be managed conservatively or aggressively depending on the cardiac pathology.

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Causes of hemodynamic impairment : Mechanical ventilation settings – PEEP, recruitment maneuver Hypercapnia Associated Septic shock Positive pressure of mechanical ventilation: Decreases RV preload (decreased venous return): increased overall RV pressure, but decreased transmural Increased RV afterload: increased pulmonary artery systolic and mean pressures May cause Acute Cor pulmonale in 50% of ARDS: Paradoxical septal motion or D shaped LV on bed side Echocardiogram. The intensity and incidence of acute Cor pulmonale increases in proportion to the severity of ARDS. Mortality is higher in patients with Cor pulmonale. High PEEP can contribute to Cor pulmonale, more so in Open lung approach for recruitment. The hemodynamic effects disappear immediately after being done with the recruitment maneuver and setting the best PEEP. Recruitment maneuver also decreases systolic function of LV, but again the effect wanes off once the maneuver is done and best PEEP set. This effect on LV could be due to decrease in coronary perfusion pressure. Therefore the hemodynamic effect of recruitment maneuver can be considered as only transient. Poor tolerance is defined as > 15% change in blood pressure and most commonly seen in ARDS patients with poor lung compliance (< 20 ml/cm H2O). Hemodynamic Management during Mechanical Ventilation: Hemodynamic management should be personalized as much as possible given the different phenotypes of ARDS. Certain different phenotype features include whether it is Pulmonary or extra pulmonary, bilateral or bi-basal, degree of inflammation, presence of shock of hypovolemia, Nitric oxide responders, and history of pulmonary cardiac disease, responder to PEEP or recruitment maneuver, presence of Cor pulmonale. Avoid hypovolemia and prevent hypervolemia. Cumulative fluid balance predicts mortality and increases time on mechanical ventilation in ARDS patients. Norepinephrine may improve RV systolic function. Hence considered vasopressor of choice in cor pulmonale in ARDS. As far as hemodynamics are concerned , opening the lung before applying high PEEP may be associated with better hemodynamic profile with only trivial perturbation.

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Neuro Muscular blocking agents NMBA may be administered as intermittent boluses or continuous infusion. Its use should be considered in adult patients with sepsis induced ARDS and PF ratio < 150 especially complicated by excessive airway pressures and asynchrony. Consider using NMBA < 48 hours. Advantages and disadvantages of NMBAs Improve chest wall compliance , Reduces the need for deep sedation Reduce airway pressure, Provide recruitment maneuver (decrease barotrauma ), Decrease respiratory drive high respiratory drive = P0.1 > 3.5 cm H2O, may harm by high transpulmonary pressure- SILI Limit respiratory dyssynchrony (In the event of persistent dyssynchrony , continuous infusion may be preferable) NMBA increases the risk if ICU- acquired weakness, hence shorter duration. Examples include : Cis-atracurium at 37.5 mg/h for 48 hours. Summary : 1.Protective Mechanical Ventilation : Vt < 6 ml/kg PBW Plateau Pressure < 30 cm H2O. Driving Pressure < 15 cm H2O Short term paralysis in severe ARDS esp in asynchrony

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Humidification Spontaneously breathing patients , a typical oropharynx temperature is 30-32 with a humidity of 29-35 g.m3. HME : Results in passive humidification . This is the first choice for humidification in mechanically ventilated patients. It should be placed close to the patient .Prevents aerosolization of infectious particles, but prone to blockade. May require changing frequently . Typically changed in 24 –168 hours ( 7 days ..!). It has been demonstrated that , there is no loss of humidifying performance , no increase in circuit colonization , no increase in VAP with the use of HME.

Figure : HME However , HME may increase compliance, increase resistance , increase plateau pressure , increased dead space Vd/Vt and increased work of breathing. Airway occlusion is a feared complication , hence should be changed Q24-48hrs in an ideal setting. Hygroscopic filters are best in terms of humidification , however there is increased risk of pneumonia . As time passes , it becomes wet and decreases the efficiency. Large pore hygroscopic filters are less efficient bacterial filters , but more efficient humidifiers than hydrophobic HMEs. Hygroscopic HMEs may be better for long term ventilation due to reduced incidence of airway occlusion. Hydrophobic filters has reduced incidence of pneumonia , but more frequently get blocked. Pleated hydrophobic filters screen as much as 99.9977% of viral /bacterial organisms , but have higher resistance ( thick secretions, endotracheal tube occlusions ). Electrostatic filters can have enhanced viral and bacterial filtration. The advantage of an electrostatic filter id requiring less material to trap pathogens which reduces resistance to flow. The electrostatic filter is not an HME, but only a filter. It is important to differentiate HME and bacterial/viral filters. Some of them are hybrid ( HMEF).

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Figure : expiratory filter Ideally , an hygroscopic filter should be placed on catheter mount ( for preserving humidification) and an electrostatic filter placed on the expiratory port ( filtering microorganisms). Most expiratory filters are tested using a bacteriophage whose size is 0.027um and most of them have efficacy of 99.99%. This may be important in pandemics such as COVID. COVID virus is 0.05-0.1 um. Heated humidifier ( wet circuit): Results in active humidification. Not the first preferred mode of humidification. Possibly , more circuit colonization was demonstrated . Some of them are servo controlled dual limb heated circuits with or without water traps. Removing water traps dramatically reduced the incidence of VAP even when compared to HME. These are designed so that exhaled humidity diffuses through the wall of the expiratory limb. End expiratory filter can be attached. The electrostatic filter media is also hydrophobic to reduce the absorption of water. Filters have double wall to provide additional insulation aimed at reducing condensation formation with in them. Another advantage of heated humidification is the decrease in cast formation and decreased plugging which is observed in dry circuit. Heated humidification is the best way to humidify during HFOV.

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Figure : Dual limb heated humidification

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Extracorporeal Therapies Mortality in ARDS is dependent on the dose of mechanical ventilation. The more energy of mechanical ventilation transmitted to the lungs , higher is the risk of VILI . Concept of Baby lung has demonstrated that "Vt/Baby lung" ratio is directly related to the development of VILI. Predictors of VILI include: Driving pressure > 14 -15 cm H2O. Respiratory rate (independently association): 3% increase in additional breath/min Mechanical power > 17 J/min Rationale for high flow V V ECMO : To decrease the intensity of mechanical ventilation for lung protection To allow the lungs to rest for healing Consider V V ECMO if refractory hypoxemia , high driving pressures , respiratory acidosis despite conventional lung protective measures ( higher PEEP , prone positioning) . Extracorporeal techniques aims to decrease the dose of mechanical ventilation. For example , it is estimated that a typical ECMO would decrease mean mechanical power by 75%, as ECMO allows for decreasing tidal volume , RR and driving pressure. This has even been demonstrated by reduction in inflammatory cytokines concentration in BAL fluid and plasma (bio trauma). ECMO conceptually can be though to minimize Volutrauma, barotrauma, atelectrauma , bio trauma and myotrauma. Advantages of extracorporeal techniques include :

Figure : Physiological mechanisms of benefit of ECLS Less Hypoxia : Decreased tissue hypoxia, decreased neurocognitive and psychiatric sequel. Less Hypercarbia : Decreased RV afterload , increased Cardiac output, decreased mortality Decreased intensity of mechanical ventilation : Decreased VILI- trauma 137

Less diaphragmatic myotrauma : accelerated weaning . To replace pulmonary function, allows lung to rest and heal ECMO should be started early for maximizing the benefit. The longer the duration of mechanical ventilation prior to ECMO, lesser is the beneficial outcome. ECMO versus ECCO2R . The essential difference between ECMO and ECCO2R is the blood flow . As the blood flow increases , the oxygenation is supported. At an approximate estimate , 1 L of blood flow would supply around 75 ml of Oxygen/ min . At this level of blood flow , it can be called as "Mini-ECMO" or "high efficiency ECCO2R". Oxygenation : Determinants of "Oxygen transfer" in ECMO : ECMO blood flow ( Qecmo) : directly proportional Membrane oxygenator characteristics Pressure gradient between sweep gas and pre-oxygenator blood. An ECMO blood flow rate of > 4 l/min may be required for adequate oxygenation in severe ARDS. NB : An increase in Cardiac Output with constant ECMO flows may decrease systemic Oxygenation as the ECMO efflux is relatively decreased compared to native venous return. Aiming for Qecmo/Cardiac Output > 60% seems to be adequate in most patients. Qecmo/Q > 60%. In case of refractory hypoxemia, after checking for cannulas and circuits, short acting beta blockers can be used to decrease Qe:Qs ratio ( Qextracorporeal to Q systemic flow), but may worsen cardiac output . Packed cell transfusion, paralysis, prone positioning and hypothermia may also increase Oxygen delivery. Recirculation : the oxygenated blood that has been reinfused is withdrawn through the drainage cannula before it can circulate in the lungs. This can be minimized by femoro-jugular cannulation or proper position of jugular dual lumen catheter esp. if right ventricular failure of ARDS.

Carbon dioxide clearance : Determinants of CO2 removal : CO2 content of blood ( PvCO2) Artificial lung surface area Sweep gas flow ECMO blood flow . Blood flow rates of 1-3 L may be sufficient to fully remove the entire CO2 production . This is because of increased CO2 solubility and greater CO2 than O2 for a given volume of blood.( esp. at physiological levels) Sweep gas flow can be increased to 10-12 L/min for increasing CO2 removal.

138

Parameter

ECCO2R

ECMO

Blood flow

0.3 L/min

4- 5L/min

Indications

For Lung Protection; Moderate ARDS

For Lung protection Oxygenation ; Severe ARDS

Catheter size

15-18Fr for dual lumen jugular

27-31Fr for Dual lumen jugular ECMO 23-29Fr for Full VV ECMO ( Vf-Vj or Vf-Vf)

Full flow ECMO may not be achievable with dual lumen jugular ECMO due to the shared lumen. For refractory hypoxia : VV ECMO is the choice as rescue therapy For Cardiac failure : VA ECMO is the choice of ECLS To minimize VILI : ECCO2R. ECCO2R should not be used for refractory hypoxemia. ECMO in Hypoxic Respiratory Failure : Choice is the V V ECMO Indications based on EOLIA criteria which is : Refractory hypoxemia despite lung protective ventilation : any one PF ratio < 50 mm HG with FiO2 >/= 0.80 for 3 hours PF ratio < 80 mm HG with FiO2 >/= 0.80 for > 6 hours. PH < 7.25 and PaCO2 >/= 60 for 6 hours Refractory hypoxia: Despite potential use of inhaled NO, recruitment maneuvers , prone position, almitrine infusion, HFO ventilation ( choice depends on subset of population). If ARDS : prone position , paralytics and high PEEP strategy must be tried before considering ECMO. " The three Ps before Puncture". Lung protective ventilation : Pplat /= 7-10 days Pregnancy Weight > 1kg/cm ( BMI > 45kg/m2) Chronic respiratory insufficiency (Rx with O2 therapy or NIV), Cirrhosis Cardiac failure requiring VA ECMO History of HIT, contraindication to anticoagulation, massive intracranial hemorrhage Metastatic Malignancy or hematological disease with survival < 5 years Moribund patient with SAPS II > 90 139

Non drug –induced coma following cardiac arrest or prolonged cardiac arrest Irreversible neurological injury , severe anoxic brain injury Decision to withdraw or withhold life sustaining therapies Expected difficulty in obtaining vascular access for ECMO Bone marrow transplant Salvage/ Rescue ECMO : ECMO applied when there is severe right heart failure or other severe decompensation should be avoided because of high mortality. NB : Isolated kidney injury is not a contraindication for ECMO. Rather CVVH can be coupled with ECMO. A typical course and targets during ECMO : Initial phase : Qecmo > 4l/min + ultra protective mechanical ventilation. Stabilization Phase : Monitor anticoagulation , infections, adjustment in antibiotics dosage, checking cannulas and blood gas. Ultra protective Ventilation , early physical rehabilitation. Rehabilitation phase : Target is to maintain spontaneous activity , but not excessive drive. Excessive drive may be controlled by increasing sweep gas flow that lowers PaCO2. Weaning phase : FiO2 < 60% , Sweep gas flow < 8 L/min, Vt > 4.5 ml/kg PBW Pplat 60 mm HG, SaO2>90%, FiO2 < 60% PaCO2 < 50 , pH > 7.36, RR /= 10 CM H20. (guided by transpulmonary pressure or EIT) Respiratory rate < 10-15 breaths/min ( may require sedation and NM blockers) PCV allows for early detection of recovery by observing increase in tidal volume FiO2 : 0.3- 0.5 In BIPAP/APRV : Phigh < 24 cm , Plow > 10 , RR < 10-20/min Proning while on ECMO may enhance early weaning from VV ECMO and increases survival.

142

ECCO2R : It is an extracorporeal technique similar to ECMO , but aimed only to remove CO2 , with much level of complexity than that is required in ECMO – a concept of lung dialysis. ECCO2R in ARDS:

Figure : Schema for ECCO2R. Configurations a Minimally invasive veno-venous ECCO2R system with a single venous vascular access through a double-lumen cannula that can be inserted in the internal jugular / femoral vein. b Pumpless arterio-venous ECCO2R system with the placement of the membrane in the circuit connecting the femoral artery with the contralateral vein. VVECO2R is preferable to AV ECCO2R. Patient need not be intubated for ECCO2R. The principle of using ECCO2R in ARDS is not only to relieve hypercarbia , but rather to decrease the intensity of mechanical ventilation in ARDS, thereby decreasing lung stress and strain. A blood flow of 400-1000ml/min can remove 20-70% of total CO2 production. ECCO2R enables to deliver even ultraprotective lung ventilation, as in some patients , it has been observed that even lower tidal volumes such as 6 ml/kg still resulted in overinflation of aerated lungs ( tidal hyperinflation). Ultralow tidal volumes such as 4 ml/kg may risk hypercarbia and acidosis. By application of extracorporeal techniques ,there is decrease in tidal volume , plateau pressure , respiratory rate and driving pressure. This minimizes volutrauma, barotrauma , atelectrauma and biotrauma. Based on this , the indication of the use of ECCO2R is not necessarily patients with elevated PaCO2. The degree of CO2 removal is primarily determined by the degree of alveolar dead space. 143

Probably patients with higher alveolar dead space, lower respiratory system compliance might potentially benefit from ECCO2R. Potential indications : Rescue therapy for acute hypercapnic respiratory failure after failed or contraindicated NIV Primary therapy for acute hypercapnic respiratory failure Respiratory dialysis in chronic hypercapnic respiratory failure Ultra-lung protective ventilation in ARDS/ARF Facilitate protective spontaneous breathing in ARDS/ARF Adverse effects of ECCO2R : Mechanical : Membrane Clotting , pump malfunction, Catheter displacement Brain hemorrhage Pneumothorax Infectious complications Hematologic : Thrombocytopenia , hemolysis , hypofibrinogenemia, bleeding Low flow devices at 300-500 ml/min ( low CO2 extraction) has higher cannula , bleeding , hemolysis and higher membrane clotting. High flow devices at 800-1000ml/min ( high CO2 extraction) has higher membrane complications and lower membrane clotting. Thrombosis and hemolysis are more frequent in low flow ECMO and ECCO2R. NB : Hemolysis generates cell free Hemoglobin which may in fact potentiate acute lung injury. Rather Haptoglobin 2 variant was proposed to increase susceptibility to ARDS during sepsis. Selecting patients : Because of high rates of adverse effects , ECCO2R should be considered only when benefits outweigh the risks. Probably patient who fulfill all the following criteria might benefit : Higher alveolar dead space fraction Lower respiratory system compliance Adjustments in mechanical ventilator have been exhausted In the above circumstances , ECCO2R may be considered. However the benefits appeared to skew only with relatively higher blood flow rates of at least 1-1.5 L/min ( high device performance) , which should actually be termed as "Mini-ECMO", as high efficiency ECCO2R involves using full ECMO circuits at lower flows. These low flows may require higher anticoagulation. Largest benefit even in ECMO was seen in patients with hypercarbia and less severe hypoxia than patients with severest hypoxia.

144

Brain Injury in ECMO : Neurological injury during ECMO may impact long term outcome. Patients with neurological complications are more likely to be discharged to long term facility than home, higher length of stay in ICU and hospital. It also increases mortality. Higher in VA ECMO. Highest if ECPR Complications include : Hypoxic Ischemic Injury Ischemic Stroke Brain hemorrhage : ICH, SAH , microbleeds, petechial hemorrhages Diffuse Cerebral Edema Risk Factors : Patient related (age, Cardiovascular risk factors, chronic cardiomyopathy, arrhythmia) Critical illness (Pre ECMO cardiac arrest, Hypoxia, Hypoperfusion, sepsis, DIC) ECMO related: Altered CBF, Platelet activation, Acquired VWF disease, Anticoagulation Jugular vein Obstruction (return cannula) Indications of ECMO Central cannulation and thrombocytosis were independent risk factors for Ischemic neurological complications. Female gender , central cannulation and thrombocytopenia were independent risk factors for hemorrhagic complications. Interestingly , early changes in PaCO2 ( both hypo and hyper capnia) after cannulation was associated with increased neurologic complications. This may be related to cerebral vasoconstriction , neuronal excitability and metabolic demand. Neurological complications may be reduced by avoiding a rapid decrease in PaCO2 . Aim to decrease PaCO2 < 20 mm HG /h over the first 24 hours of ECMO. Monitoring Brain during ECMO : FOUR Score gives a greater neurological detail than GCS including brain stem reflexes , breathing patterns and the ability to recognize different stages of herniation. Automated pupillometry with Neurological pupil index identifies patients at high risk for neurological complications. EEG : Standard EEG (background abnormalities : background reactivity for noise or painful stimulus , discontinuous background) and continuous EEG (loss of Sleep transients: spindles and K complexes) are associated with unfavorable neurological outcome. Early lower background EEG frequency is associated with increased mortality at 28 days. Cerebral NIRS (Near Infrared spectroscopy) can predict acute cerebral complications from VA ECMO. 145

Blood biomarkers of astrocytic injury ( S100B protein levels) , Neuronal injury (Neuron specific enolase), GFAP is associated with higher neurological complications. Prevention : AT ECMO onset , optimize cerebral perfusion, avoid abrupt drops in PaCO2. Early assessment of neurological status Multimodal monitoring Non-invasive bed side evaluation using EEG, Cerebral Oximetry , Blood biomarkers Repeat brain imaging Use lower anticoagulation targets (anti Xa : 0.2 - 0.3) Higher transfusion threshold (platelets > 100,000/mm3 ; FFP to maintain INR < 1.5) Optimize ECMO weaning process.

146

Further Reading Diaphragmatic myotrauma: a mediator of prolonged ventilation and poor patient outcomes in acute respiratory failure. Goligher, Ewan C et al. The Lancet Respiratory Medicine, Volume 7, Issue 1, 90 - 98 . https://www.masimo.co.uk/ori/ Szmuk P, Steiner JW, Olomu PN, Ploski RP, Sessler DI, Ezri T. Oxygen Reserve Index: A Novel Noninvasive Measure of Oxygen Reserve--A Pilot Study. Anesthesiology. 2016 Apr;124(4):779-84. doi: 10.1097/ALN.0000000000001009. PMID: 26978143. Brodie D, Slutsky AS, Combes A. Extracorporeal Life Support for Adults With Respiratory Failure and Related Indications: A Review. JAMA. 2019;322(6):557–568. doi:10.1001/jama.2019.9302 Le Guennec, L., Cholet, C., Huang, F. et al. Ischemic and hemorrhagic brain injury during venoarterialextracorporeal membrane oxygenation. Ann. Intensive Care 8, 129 (2018). https://doi.org/10.1186/ s13613-018-0475-6 Magalhaes, E., Reuter, J., Wanono, R. et al. Early EEG for Prognostication Under Venoarterial Extracorporeal Membrane Oxygenation. Neurocrit Care (2020). https://doi.org/10.1007/s12028-020-01066-3 Cho SM, Farrokh S, Whitman G, Bleck TP, Geocadin RG. Neurocritical Care for Extracorporeal Membrane Oxygenation Patients. Crit Care Med. 2019 Dec;47(12):1773-1781. doi: 10.1097/ CCM.0000000000004060. PMID: 31599814. Cavayas YA, Munshi L, Del Sorbo L, Fan E. The Early Change in PaCO2 after Extracorporeal Membrane Oxygenation Initiation Is Associated with Neurological Complications. Am J Respir Crit Care Med. 2020 Jun 15;201(12):1525-1535. doi: 10.1164/rccm.202001-0023OC. PMID: 32251606. Cho, Sung-Min DO1–3; Geocadin, Romergryko G. MD1–3; Caturegli, Giorgio MD1–3; Chan, Vanessa BS4; White, Bartholomew MD4; Dodd-o, Jeffrey MD5; Kim, Bo Soo MD5; Sussman, Marc MD5; Choi, Chun Woo MD5; Whitman, Glenn MD5; Chen, Liam L. MD, PhD4 Understanding Characteristics of Acute Brain Injury in Adult Extracorporeal Membrane Oxygenation: An Autopsy Study*, Critical Care Medicine: June 2020 - Volume 48 - Issue 6 - p e532-e536 doi: 10.1097/CCM.0000000000004289 Sepsis Is Associated with a Preferential Diaphragmatic Atrophy: A Critically Ill Patient Study Using Tridimensional Computed Tomography. Boris Jung, Stephanie Nougaret, Matthieu Conseil, Yannaël Coisel, Emmanuel Futier, Gerald Chanques, Nicolas Molinari, Alain Lacampagne, Stefan Matecki, Samir Jaber;Anesthesiology 2014; 120:1182–1191 doi: https://doi.org/10.1097/ALN.0000000000000201 The airway occlusion pressure (P0.1) to monitor respiratory drive during mechanical ventilation: increasing awareness of a not so new problem. Irene Telias, Felipe Damiani, Laurent Brochard in Intensive Care Medicine( 2018). Bertoni M, Telias I, Urner M, et al. A novel non-invasive method to detect excessively high respiratory effort and dynamic transpulmonary driving pressure during mechanical ventilation. Crit Care. 2019;23(1):346. Published 2019 Nov 6. doi:10.1186/s13054-019-2617-0.

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Talmor D, Sarge T, O'Donnell CR, Ritz R, Malhotra A, Lisbon A, Loring SH. Esophageal and transpulmonary pressures in acute respiratory failure. Crit Care Med. 2006 May;34(5):1389-94. doi: 10.1097/01.CCM.0000215515.49001.A2. PMID: 16540960; PMCID: PMC2278169. Turbil E, Galerneau LM, Terzi N, Schwebel C, Argaud L, Guérin C. Positive-end expiratory pressure titration and transpulmonary pressure: the EPVENT 2 trial. J Thorac Dis. 2019;11(Suppl 15):S2012S2017. doi:10.21037/jtd.2019.06.34. Regional Ventilation Displayed by Electrical Impedance Tomography as an Incentive to Decrease Positive End-Expiratory Pressure.Takeshi Yoshida 1,2,3*, , Thomas Piraino 2,3*, , Cristhiano A. S. Lima 4, , Brian P. Kavanagh 5†, , Marcelo B. P. Amato 6, , and Laurent Brochard . https://doi.org/10.1164/rccm.201904-0797LE PubMed: 31225973 Chen, Lu & Sorbo, Lorenzo & Grieco, Domenico Luca & Junhasavasdikul, Detajin & Rittayamai, Nuttapol & Soliman, Ibrahim & Sklar, Michael & Rauseo, Michela & Ferguson, Niall & Fan, Eddy & Richard, Jean-Christophe & Brochard, Laurent. (2019). Potential for Lung Recruitment Estimated by the Recruitment-to-Inflation Ratio in Acute Respiratory Distress Syndrome. American Journal of Respiratory and Critical Care Medicine. 201. 10.1164/rccm.201902-0334OC. Dianti, J., Bertoni, M. & Goligher, E.C. Monitoring patient–ventilator interaction by an end-expiratory occlusion maneuver. Intensive Care Med (2020). https://doi.org/10.1007/s00134-020-06167-3 Bellani, Giacomo MD, PhD1,2; Mauri, Tommaso MD1,2; Coppadoro, Andrea MD1,2; Grasselli, Giacomo MD2; Patroniti, Nicolò MD1,2; Spadaro, Savino MD2; Sala, Vittoria MD1,2; Foti, Giuseppe MD2; Pesenti, Antonio MD1,2 Estimation of Patient’s Inspiratory Effort From the Electrical Activity of the Diaphragm*, Critical Care Medicine: June 2013 - Volume 41 - Issue 6 - p 1483-1491 doi: 10.1097/ CCM.0b013e31827caba0 . Cardenas, Letícia & Santana, Pauliane & Caruso, Pedro & Carvalho, Carlos & Albuquerque, André. (2018). Diaphragmatic Ultrasound Correlates with Inspiratory Muscle Strength and Pulmonary Function in Healthy Subjects. Ultrasound in Medicine & Biology. 44. 10.1016/j.ultrasmedbio.2017.11.020. Blankman, P., Hasan, D., Erik, G.J. et al. Detection of ‘best’ positive end-expiratory pressure derived from electrical impedance tomography parameters during a decremental positive end-expiratory pressure trial. Crit Care 18, R95 (2014). https://doi.org/10.1186/cc13866. Holanda, Marcelo & Sousa, Nathalia & Melo, Luana & Marinho, Liégina & Ribeiro, Helder & Troncon, Luiz & Bastos, Vasco & Santos, Armênio & Siqueira, Rodrigo. (2018). Helping students to understand physiological aspects of regional distribution of ventilation in humans: a experience from the electrical impedance tomography. Advances in physiology education. 42. 655-660. 10.1152/advan.00086.2018. Suffredini DA, Allison MG. A Rationale for Use of High Flow Nasal Cannula for Select Patients With Suspected or Confirmed Severe Acute Respiratory Syndrome Coronavirus-2 Infection. Journal of Intensive Care Medicine. September 2020. doi:10.1177/0885066620956630. Demoule, A., Hill, N. & Navalesi, P. Can we prevent intubation in patients with ARDS?. Intensive Care Med 42, 768–771 (2016). https://doi.org/10.1007/s00134-016-4323-6. 148

Hill NS, Ruthazer R. Predicting Outcomes of High-Flow Nasal Cannula for Acute Respiratory Distress Syndrome. An Index that ROX. Am J Respir Crit Care Med. 2019;199(11):1300-1302. doi:10.1164/ rccm.201901-0079ED. Di mussi, R., Spadaro, S., Stripoli, T. et al. High-flow nasal cannula oxygen therapy decreases postextubation neuroventilatory drive and work of breathing in patients with chronic obstructive pulmonary disease. Crit Care 22, 180 (2018). https://doi.org/10.1186/s13054-018-2107-9 Accuracy of pleth variability index to predict fluid responsiveness in mechanically ventilated patients: a systematic review and meta-analysis.Chu H, Wang Y, Sun Y, Wang G. J Clin Monit Comput. 2016 Jun;30(3):265-74. doi: 10.1007/s10877-015-9742-3. Epub 2015 Aug 5. Review. PubMed PMID: 26242233. G Krishnan S, Wong HC, Ganapathy S, et alOximetry-detected pulsus paradoxus predicts for severity in paediatric asthma. Archives of Disease in Childhood 2020;105:533-538. Beurton A, Teboul JL, Gavelli F, et al. The effects of passive leg raising may be detected by the plethysmographic oxygen saturation signal in critically ill patients. Crit Care. 2019;23(1):19. Published 2019 Jan 18. doi:10.1186/s13054-019-2306-z. Kristensen MS, Teoh WH. Ultrasound of the neck for airway management. In: Laursen CB, Rahman NM, Volpicelli G, eds. Thoracic Ultrasound (ERS Monograph). Sheffield, European Respiratory Society, 2018; pp. 172–183 [doi.org/10.1183/2312508X.10007517]. Bauman ZM, Gassner MY, Coughlin MA, Mahan M, Watras J. Lung Injury Prediction Score Is Useful in Predicting Acute Respiratory Distress Syndrome and Mortality in Surgical Critical Care Patients. Crit Care Res Pract. 2015;2015:157408. doi:10.1155/2015/157408 Zolfaghari, Parjam & Wyncoll, Duncan. (2011). The tracheal tube: Gateway to ventilator-associated pneumonia. Critical care (London, England). 15. 310. 10.1186/cc10352. Peh WM, Ting Chan SK, Lee YL, Gare PS, Ho VK. Lung ultrasound in a Singapore COVID-19 intensive care unit patient and a review of its potential clinical utility in pandemic. J Ultrason. 2020;20(81):e154e158. doi:10.15557/JoU.2020.0025 https://covid19research.uclb.com/product/ucl-cpap Dakin J, Jones AT, Hansell DM, Hoffman EA, Evans TW. Changes in lung composition and regional perfusion and tissue distribution in patients with ARDS. Respirology. 2011;16(8):1265-1272. doi:10.1111/ j.1440-1843.2011.02048. Musch G, Bellani G, Vidal Melo MF, et al. Relation between shunt, aeration, and perfusion in experimental acute lung injury. Am J Respir Crit Care Med. 2008;177(3):292-300. doi:10.1164/rccm.200703484OC. Long Jiang Zhang, MD, PhD , Chang Sheng Zhou, BS , and Guang Ming Lu, MD Dual Energy Computed Tomography Demonstrated Lung Ventilation/Perfusion Mismatch in a 19-Year– Old Patient With Pulmonary Embolism.

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Franck Grillet, Andreas Busse-Coté, Paul Calame, Julien Behr, Eric Delabrousse, Sébastien Aubry. COVID-19 pneumonia: microvascular disease revealed on pulmonary dual-energy computed tomography angiography Gattinoni, L., Meissner, K. & Marini, J.J. The baby lung and the COVID-19 era. Intensive Care Med 46, 1438–1440 (2020). https://doi.org/10.1007/s00134-020-06103-5. Frisvold, Shirin & Robba, Chiara & Guérin, Claude. (2019). What respiratory targets should be recommended in patients with brain injury and respiratory failure?. Intensive Care Medicine. 45. 10.1007/ s00134-019-05556-7. Corradi F, Robba C, Tavazzi G, Via G. Combined lung and brain ultrasonography for an individualized "brain-protective ventilation strategy" in neurocritical care patients with challenging ventilation needs. Crit Ultrasound J. 2018;10(1):24. Published 2018 Sep 17. doi:10.1186/s13089-018-0105-4 Morales-Quinteros, L., Del Sorbo, L. & Artigas, A. Extracorporeal carbon dioxide removal for acute hypercapnic respiratory failure. Ann. Intensive Care 9, 79 (2019). https://doi.org/10.1186/s13613-019-05516 Anita Rae Modi, Christopher S. Kovacs.Hospital-acquired and ventilator-associated pneumonia: Diagnosis, management, and prevention . Cleveland Clinic Journal of Medicine October 2020, 87 (10) 633-639; DOI: https://doi.org/10.3949/ccjm.87a.19117.

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Chapter 3: Neuro Critical Care Chapter 3: Neuro- Critical Care

151

Disorders of Consciousness

152

Status Epilepticus

158

Primary and Secondary Injury

160

ICP Management

162

Invasive ICP Monitoring

163

SIBICC Algorithm

163

Patient tailored ICP threshold

171

Traumatic Brain Injury

172

Management

183

Cervical Spine Clearance

189

Rapid Ultrasound for the Brain Approach to Brain Ultrasound Neuro-Monitoring

191 191 195

Cerebral Physiology and Metabolism

195

Critical Neuro worsening

196

Automated Pupillometry

197

Cerebral Autoregulation

199

Multi Modality Monitoring- MMM

206

Electro-Physiological Monitoring

208

Optimal Cerebral Perfusion Pressure

221

Brain Oxygen Monitoring

228

Cerebral Microdialysis

233

151

Disorders of Consciousness Consciousness is defined as awareness of self and environment. It is also described as a subjective experience and self-report of mental representations. Impairment of consciousness is frequent during sleep , anesthesia and brain injury. Neuroanatomical basis of consciousness : Ascending arousal system of brain stem connections to cortex Mesocircuit of Basal ganglia connections to cortex Thalamo cortical connections Cortex itself ( Mathematically conceptualized by global workspace theory) Etiology of Unconsciousness : Supratentorial Structural lesions Infratentorial structural lesions Metabolic/Nonstructural pathology Psychogenic Differential is broad with diversity of causes even within a single etiology. For example , a patient with TBI may have cerebral edema in addition to SAH or epidural hematoma coupled with diffuse axonal injury. Consciousness in ICU patients frequently fluctuate resulting in delirium. Patients may recover from initial insult or may succumb to secondary complications , medical complications ( E.g : Pulmonary embolism) , medication adverse effect and metabolic confounders.

Assessment of Unconsciousness : Glasgow Coma Scale (GCS) FOUR score ( Full Outline of Unresponsiveness) 60 sec test for Attention COMA recovery Scale : the gold standard , comprehensive

Figure : Comparison of GCS and FOUR score 152

Figure : Components of FOUR score.

153

Figure : Coma Recovery Scale – Revised .

154

Behavioral classification of disorders of consciousness

Figure : Disorders of consciousness in terms of cognitive and motor function domain. MCS can be classified in to MCS+ or MCS -.

155

Behavioral State

Motor function

Cognitive Function

Coma

Reflexes

0

Vegetative State- VS

Reflexes- Non reflexive

+

Minimally Conscious State MCS MCS+ / MCS-

MCS- : Non reflexive MCS+ : Responds to command

++

Emergence

Communicative

+++

Communicative

+++

Recovered

Communicative

++++

Cognitive Motor Disassociation –CMD

Reflexes

++++

Locked In Syndrome- LIS

People in Coma , Vegetative State and MCS can have CMD . CMD ultimately might recover. Management : ABC : Airway , breathing and circulation History and Neuro exam to identify the most likely category ( structural –any compression or metabolic or psychogenic ) Targeted therapies early ( if necessary , involve Neuro surgeon) Standardized Emergency Neurological Life Support – ENLS Recovery from Unconsciousness depends on: Patient factors : Age , comorbidity , environment Injury : Mechanism , location , extent Time to treatment , time to injury Best Exam . However clinical prognostication is poor and methods to go beyond traditional behavioral assessments are encouraged. These include : Resting Measures : Structural Imaging Resting EEG , Resting State MRI Perturbation , passive tasks Long latency EPs, ERP TMS , TMS-EEG co registration (PCI), Somatosensory evoked CI Perturbation , active tasks Functional MRI-motor imagery paradigm Functional EEG-motor imagery paradigm Response of biomarkers to interventions Amantadine Electrical/Ultrasound stimulation 156

Figure : Functional MRI ( fMRI) - Motor Activation Paradigm After motor and spatial imagery tasks , activation of supplementary motor area (yellow) and of the parahippocampal gyrus (blue-green)can be seen in healthy subjects (A) and UWS (B). UWS shows significant activation in the supplementary motor area (yellow) after the motor imagery task, similar to the one found in healthy subjects. EEG : Motor activation paradigm EEG is recorded when the patient is asked to obey commands. With the use of machine learning algorithms , EEG data that is acquired is processed and analyzed. With the use of fMRI /EEG , a subset of patients "cognitive motor disassociation-CMD" can be identified , whose motor disability does not match cognitive capacity. Cognition seems to be better than motor expression. It has been estimated that 15% of unconscious patients have CMD. It is important to identify patients with CMD , because they are much more likely to have good functional outcome (GOSE > 3) GOSE: Glasgow Outcome Scale Extended. Advanced therapeutics : on a case by case basis Medications : Amantadine , Zolpidem Direct Thalamic Stimulation , Vagal Nerve Stimulation Focused Ultrasound

157

Status Epilepticus Status Epilepticus (SE) is a seizure lasting > 5 minutes . SE is considered as a brain emergency and therefore urgent treatment is needed. Delay in treatment either due to improper dosing or sequence of drugs is associated with poor outcome. Rapid treatment with benzodiazepines should be considered in the pre-hospital setting as the safe time limits of seizure activity is in the order of minutes . Type of SE

t1

t2

Tonic Clonic SE

5 min

30 min

Focal seizures with impaired consciousness

10 min

> 60 min

Absent Status Epilepticus

10-15 min

Unknown

Table: Significant time interval limits after seizure and possible consequences if not acted up on immediately. t1 is the time limit when a seizure is likely to be prolonged leading to continuous seizure activity and t2 is the time limit when a seizure may cause long term consequences(including neuronal injury, neuronal death, alteration of neuronal networks and functional deficits) Prehospital Rx : Treatment should be considered in the pre-hospital setting if Seizures > 5 min or repeated seizures. Medications include Diazepam 5 mg IVP or Lorazepam 2 mg IVP . Midazolam 10 mg IM Can be repeat one more time if needed. IM Midazolam seems to have shorter administration time when compared to the IV formulations however the latency periods are similar due to slow intramuscular absorption. For intramuscular route , consider 10 mg of midazolam if > 40 kg. If 13-40 kg : 5 mg midazolam. For children , midazolam can be dosed from 2-4 mg IM. Emergency room Rx : Drug of choice is Lorazepam 0.1 mg/kg IVP ( best efficacy) For BDZ failure : either one can be considered . Similar overall safety profile Fos-phenytoin 20 mg /kg ( Max of 1500mg - max assumed to be 75 kg) Valproate 40 mg/kg ( Max of 3000 mg) Levetiracetam 60 mg/kg ( Max of 4500 mg). If the patient is not improving in an hour, consider short term continuous EEG monitoring . There are rapid EEG systems available to monitor the electrical activity. Rapid EEG should be done to make sure if seizures are stopped. 158

Figure : Ceribell’s portable EEG helping to detect seizures. The belt (headband) is placed around the forehead and EEG recorded. It takes around 5-10 min in getting in the EEG done. If the patient still has Status epilepticus , it is termed Refractory Status Epilepticus. Consider any of the following approach. Repeat IV bolus of AED ( Fos-phenytoin, Levetiracetam, Valproate) Continuous infusions of AED : Midazolam 0.1 mg/kg followed by 0.05 - 3 mg/kg/hr Propofol 50-150 mcg/kg/min infusion Pentobarbital 15-20 mg/kg IV followed by 1-10 mg/kg/hr Ketamine 0.3-7.5 mg/kg/hr infusion Mortality is high in Super refractory status epilepticus , however good outcomes have been reported in some survivors.

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Primary and Secondary Injury Primary Injury : Primary injury arises from external physical forces applied to head . These include : Skull fractures Hematomas and Contusions Deformation and Destruction of Brain tissue Axonal injury Treatment of Primary Injury is Neuro surgery / Observation.

Secondary Injury : Secondary injury develops over time with activation of multiple molecular and cellular pathways . Main mechanisms include : Release of excitatory neurotransmitters Altered cellular permeability Mitochondrial dysfunction ->Apoptosis Cytotoxic , vasogenic edema BBB disruption Disturbed Autoregulation Secondary brain injury can be minimized by Multi modal monitoring and optimizing the physiological parameters . Physiological parameters that are usually targeted ( in general) include : SpO2 > /= 90% PaO2 > 100 mm HG PaCO2 35-45 mm HG SBP >/= 100 mm HG PH : 7.35 - 7.45 ICP < 20 PbtO2 >/= 15 mm HG CPP >/= 60 mm HG Temp : 36 – 38.3 C Glucose 80-180 mg/dl Plasma Sodium : 135-145 – if using hypertonic saline (145-160) INR /= 75 X 10 ^3/mm3 Hb >/= 8 gm/dl Resuscitation preferences : Fluids or Vasopressors CBF = k X CPP X d^4 / 8lv CBF is dependent on the CPP . CPP is like the driving pressure ( MAP – ICP) 160

Vasopressors increases perfusion pressure by increasing MAP. Nor epinephrine: Both Alpha and beta. First choice. Phenyl ephrine : only alpha Milrinone : Inodilator increases CBF The effect of vasopressor is dependent on the intactness of cerebral autoregulation , whether vasopressors relatively increase MAP or ICP. Hence "MAP challenge" should be considered. In patients with intact autoregulation, increase in MAP causes vasoconstriction and hence ICP goes down. The discordance of MAP and ICP indicates intact autoregulation. On the contrary , if ICP goes up with the increase in MAP , it is referred to as "Pressure passive" and indicated disrupted autoregulation. The goal of using vasopressors in SAH is to increase rCBF (regional) and increase PbtO2 (induced hypertension-H), while fluids have no effect on rCBF and decrease PbtO2.(hypervolemia-hemodilution;HH) Hence there was a paradigm shift in treating SAH from HHH therapy to HNT Rx. HHH : Hypertension , hypervolemia , hemodilution HNT : Hypertension , Normovolemia , Transfusion . The limitation of using vasopressors is "pressure induced diuresis", a vicious cycle Pressors -> increased Sodium loss ->H2O reabsorption (SIADH) ->decreased plasma Na, Osm causing brain edema , that would increase the need for further vasopressors. Vasopressors are preferred way to increase MAP whereas fluids are given to alter the tonicity and volume status of the patient. Isotonic ( NaCl, Balanced crystalloids) or hypertonic ( NaCl, Mannitol , NaLac) are the preferred type of fluids. Hypertonic fluids may be preferred as the total amount of volume given is reduced and furthermore it may counteract some aspects of pressure induced diuresis.

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ICP management ICP spikes may be associated with Signs of herniation : Change in pupillometer parameters Change in GCS motor score Change in ICP waveform Cushing's response Signs of Ischemia : Drop in pbtO2 < 15 ( when CPP is dropped) Decrease in SjvO2 Increase in lactate/pyruvate ratio Increase EEG

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Invasive ICP Monitoring: Invasive ICP monitoring performed by Intensivists decreases the time to placement of catheter without the increase in complication rate when compared with procedures done by neuro surgeons. The amount of time gain may translate in to improved outcomes by reducing the time and dose of intracranial hypertension . ( time lost is brain lost). Intraparenchymal ICP monitoring can be done at bedside. Techniques : External Ventricular drainage ( EVD) : Requires Operating room. Intraparenchymal ICP Monitor : less complications when using "twist drill craniostomy". Can be done at bedside.

Figure : different techniques of Intracranial pressure monitoring . ICP > 20 mm HG is associated with poor outcomes as per the epidemiological data , however aggressive therapy need not be initiated at this level, as epidemiological threshold is not necessarily the same as clinical threshold. ICP > 22 mm HG is considered currently as the threshold for initiating ICP reducing therapy.

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ICP management -SIBICC ICP Algorithm : SIBICC = Seattle International Severe traumatic brain Injury Consensus Conference It is recommended to monitor both ICP and PbtO2 in patients suspected of having elevated ICP to understand physiology and guide therapy. Repeated physical exam, repeat CT scan to re-evaluate pathology , reconsider surgical options should be incorporated in the daily care of these patients ( inter tier recommendations ). There are many therapeutic strategies to decrease ICP, but some of which come with risks. ICP reducing therapies with no risk : Head Up at 30 Mechanical ventilation Conventional temperature management 35-37 Sedation ICP reducing therapies with intermediate risk Osmolar therapy CSF drainage Hyperventilation ICP reducing therapies with high risk : Barbiturate coma Primary decompression Secondary decompression – late; Lowers mortality ICP reducing therapies with very high risk : Worse outcomes Secondary decompression – early Hypothermia < 35 (Prophylactic or therapeutic). Because certain therapies come with very high risk , it is important to formulate a therapeutic strategy for CP reduction via tiered approach based on the risk benefit considerations. One of these tiered approaches is the SIBICC algorithm. It should be emphasized that this is a guideline based on expert consensus and should not be used to replace clinical judgement. Lowest possible tier must be used . There is no rank order with in the tier and all modalities in a given tier need not be exhausted before moving on to the next tier. If it is considered advantageous , tier can be skipped when advancing treatment. Any sign of "critical neuroworsening" may require hyperosmolar bolus or hyperventilation while simultaneously investigating the cause with imaging or other modalities.

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Tiered Approach to ICP management : Tier 0 : Standard Measures ( Before ICP and PbtO2 monitoring ) . Basic severe TBI care. Endotracheal intubation and mechanical Ventilation Serial evaluation of neurological status including pupillary reactivity Head of bed elevation 30-40 degree Analgesia to aim for Pain ( not to aim at ICP or PbtO2) Sedation to prevent ventilator asynchrony or agitation ( not to aim for ICP or PbtO2) Core temperature < 38 C Central line , End tidal CO2, Arterial line with continuous blood pressure Anti-Seizure prophylaxis for 1 week unless ongoing need CPP >/= 60 mm HG Hb > 7 gm/dl, SpO2 >/= 94% Avoid Hyponatremia Optimize Venous return ( Head in midline , not too tight cervical collar) Consider ICP monitoring and PbtO2 ( brain tissue O2) Normal/target ICP < 22 mm HG Normal/target PbtO2 > 20 and < 50 mm HG. Classify patients in the following groups A, B, C and D .

Figure : Classify patients in A/B/C/D based on ICP and PbtO2 Type A reflects normal values for both monitors and does not require treatment. Type B involves ICP elevation but normal brain oxygen values Type C patients have hypoxic brains but normal ICP Type D patients have both brain hypoxia and ICP elevation.

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Type B patients ( Elevated ICP , normal Brain tissue Oxygenation ) : Tier 1: Hyperosmolar therapy and CSF diversion (in summary) Maintain CPP = 60-70 mm HG Increase analgesia and sedation to lower ICP PaCO2 at lower normal : 35-38 mm HG/ 4.7-5.1 Kpa Mannitol intermittent bolus @ 0.25 - 1 g/kg ( keep Osmolality < 320 mosm/L) Hypertonic Saline intermittent bolus ( Keep Na < 155 mEQ/L, Osmolarity < 320 mosm/L) CSF drainage if EVD in situ and consider placement of EVD if needed Consider EEG monitoring If ICP elevation is refractory , consider Tier 2 : Paralysis , MAP challenge ( summary) Mild hypocapnia ( PaCO2 32-35 mm HG/ 4.3 - 4.7 kPa) Neuro muscular paralysis if it lowers ICP MAP challenge to test for intactness of autoregulation. Raise CPP with fluids , vasopressors , inotropes to lower ICP if autoregulation is intact. Paralytic challenge : A trial dose of NM paralytic agent is given to see if it lowers ICP. Only if efficacy is demonstrated , continuous infusion is planned. MAP Challenge : Assess cerebral autoregulation and guide MAP and CPP goals in individual patients. Sedation should not be adjusted during this maneuver. The vasopressor or inotrope is increased by 100 mm HG for not more than 20 min, while parameters such as ICP , MAP , CPP and PbtO2 are monitored before and after the challenge. Cautious application of MAP challenge is recommended as the status of cerebral autoregulation may not be stable. If ICP is decreased or pbtO2 is increased as a response to increase in MAP/CPP, it means autoregulation is intact. If ICP is still elevated , consider Tier 3 : Rescue Rx . Secondary decompressive Craniectomy or Clot evacuation, Mild hypothermia (35-36 C) using active cooling measures Hyperventilation PaCO2 30-32 mm HG/ 4.0-4.3 kPa Barbiturate (thiopentone or pentobarbital) coma- titrate to ICP control If efficacious. Don't exceed Barbiturate dose that cause burst suppression, avoid hypotension with Barbiturates. If no effect of barbiturate is demonstrated on ICP , it should be discontinued. Type C patients ( Hypoxic brain , normal ICP) Tier 1 : Perfusion and Oxygen ( summary) CPP 60-70 mm HG Increase CPP to maximum of 70 mm HG with fluids, vasopressors or inotropes PaCO2 > 35 mm HG/ 4.7 Kpa 166

Further increase PaO2 by increasing FiO2 to 60% Consider EEG monitoring If brain is still hypoxic , then consider , Tier 2 : Paralytic and MAP challenge Ventilator management to increase PaO2 to 150 mm HG/ 20 Kpa Decrease ICP to < 22 mm HG , Consider CSF drainage Sedation , paralytic challenge to see for increase in PbtO2 MAP challenge and to increase CPP by fluids , vasopressors and inotropes If brain is still hypoxic , then consider , Tier 3 : Rescue hypercapnia and transfusion Increase PaCO2 to 45-50 mm HG/ 6.0-6.7 Kpa ( avoid increase In ICP) Consider Normobaric hyperoxia ( PaO2 > 150 mm HG / 20 Kpa) Consider PRBC if Hb < 9 gm/dl Type D patient ( Hypoxic brain , Elevated ICP) Tier 1 : Combined type B and C Tier 2 : Combined type B and C Tier 3 : Combined type B and C Certain therapeutic measures have not been recommended . These are not to be used . These include : Non bolus continuous infusion of Mannitol Scheduled infusion of Hyperosmolar agents ( Q4-6 hrs) Lumbar CSF drainage Furosemide, routine use of steroids Routine therapeutic hypothermia ( < 35 C) due to systemic complications High dose Propofol to attempt Burst suppression PaCO2 < 30 mm HG/4.0 Kpa CPP > 90 mm HG Hypercarbia especially in type D Hypothermia or barbiturate for low PbtO2 unless otherwise indicated.

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ICP reducing maneuvers and associated dangers : Recommended monitoring Treatment

Rx of Deranged Physiology

Dangers with maneuvers Additional monitor

CPP augmentation

Insufficient brain perfu- Cardiopulmonary complision cations Worsening of brain edema

Echocardiogram Swan Ganz, PICCO CBF , PbtO2 Autoregulation

Sedation

CMRO2 Seizure

Prolonged MV, LOS Failure to detect Neuro change Propofol infusion syndrome

CT , EEG Microdialysis PbtO2

CSF drainage

Monro-Kellie

Midline shift Infection

CT, pbtO2 Liquor examination

Osmolar therapy

Edema

Sodium balance Fluid balance

Electrolytes , Renal function test pbtO2

Hypocapnia

Cerebral blood volume

Ischemia

pbtO2

Barbiturates

Deep Metabolic Suppression

Cardio Vascular Instability EEG, CT Infection Microdialysis, PbtO2

Secondary decompressive craniectomy

Herniation

Bleeding Infection Trephynoid Syndrome Misappropriate therapy

CT , Microdialysis PbtO2, pupillometry Goals of care

Hypothermia < 35

Presumed neuroprotection

Worse outcomes

Reserved for extreme cases

Hypertonic Fluids: Hypertonic fluids are superior to colloids or isotonic fluids in systemic and Cerebral osmotic derived volume reduction. Osmolarity of hypertonic fluid is the primary determinant of efficacy. Infusion of Hypertonic fluids are associated with improved hemodynamics, reducing the total amount of volume required in addition to less tissue edema . There is robust evidence of hypertonic fluids being used as acute resuscitative fluid, although less evidence for chronic intravascular expansion efficacy. For example : To replenish 1 L of plasma loss in a 70 kg person : it requires 14 L of D5W ( free water) : As it moves in all of the water compartments (42/3) 168

4.7 L of 0.9% NS : As it is confined to only Extracellular compartment (14/3) 1L of 3% NS ( Stays totally with in the compartment) 0.5 L of 7.5% NS ( Pulls water from other compartment) NB : Total body water content = 60% of 70 kg = 42 L ( Intracellular of 28 L + Extracellular of 14 L) Extracellular of 14 L = Intravascular of 3L + Extravascular of 11L. Total blood volume = 70 ml/kg = Intravascular of 3L + RBC volume of 2 L

Some salient features of hypertonic fluids : Hypertonic saline may also additionally have immunosuppressive benefits in critically ill patients , by mitigating inflammatory cascade (Neutrophil response is delayed in hypertonic medium). Coagulation may be deranged only if the concentration exceeds 7.5% with prolongation of R , K times and decreased Alpha angle, LY 30. Renal diuretic action of hypertonic saline is dependent on it tonicity. Chronic hypertonic state ( > 1-2 days) with may cause cell to synthesize organic osmolytes (amino acids , methylamines , polyols) as a protective reflex to maintain cell volume. The synthesis of non-perturbing organic osmolytes require gene translation and accumulates over days. Similarly the down regulation may be slow. However prolonged use of hypertonic saline has been safely demonstrated in critically ill patients as long as the weaning was gradual to prevent rebound. Adverse effects of Hypertonic Saline : Congestive Heart Failure Metabolic acidosis Electrolyte disturbance Hypokalemia Coagulopathy (inhibits clot formation and lysis) CPM Decreased CSF resorption Adverse effects of Mannitol : Hypovolemia Hypotension Congestive Heart Failure Acute renal failure Electrolyte Depletion Hyperkalemia Hyponatremia Rebound Intracranial Hypertension The infusion of hypertonic fluids may reduce the severity of Uncal herniation. There is definite reduction in cerebral water reduction and ICP. Hypertonic fluids include either Mannitol or Hypertonic saline and both have similar efficacy when compared to their equi-osmolar quantities. The effects of Mannitol may be transient and can have rebound effects with ICP going above baseline , 169

whereas hypertonic saline may have more sustained effect. This is because Mannitol may sequester in to the brain tissue at disrupted BBB locations , while the circulating Mannitol is excreted , causing the osmotic gradient to reverse, whereas hypertonic saline tend to equilateral across the membrane. Characteristics of cerebral vasculature also enhance the action of hyperosmolar agents as the histological attributes of Blood brain barrier is different than a traditional capillary endothelial barrier at Viscera. Visceral Capillary Endothelium Type of Junction Pore Size Ion Permeability

Blood Brain Barrier

Fenestrated Junction

Tight Junction

65 A

7A

Permeable

Impermeable

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Patient tailored ICP threshold It was observed in a study that the outcomes were similar when ICP is monitored or not (with only guesstimates based on imaging and clinical examination).In another study , ICP cutoff for worse outcomes for all patients was 35 mm HG , and only 61% had worse outcomes when the ICP cut off of 30 mm HG was used. The ICP cut off ranged from 22 – 36 for different CT classifications. It may be inappropriate to set a single target ICP , as higher values may be tolerated in certain CT classifications. ICP spikes associated with signs of neuro deterioration may be more useful than a single digital reading. This lead to a hypothesis that there may not be an actual critical ICP threshold with the acknowledgment that higher or trending upward of ICP is worse. ICP threshold like the MAP may have to be individualized or even semi quantitative noninvasive measures such as ONSD that reflect the trend in ICP may suffice whether to institute a higher tier approach or the trajectory is reassuring. It is recommended not to use a crisis approach ( to just react to ICP crisis) , but a tailored and protocolized approach (tiered therapy).

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Traumatic Brain Injury Globally, the incidence of TBI is increasing. The incidence of TBI has shifted from young population involving high speed trauma to elderly with comorbidities involving incidental falls. TBI should not be viewed as an event, but as a progressive and chronic disease with life time consequences. Precision approach to the treatment requires more accurate disease phenotyping. Recent advances in genomics , neuroimaging and biomarkers may be applied for disease phenotyping. TBI is a dynamic pathophysiological process that starts from the moment of impact.

Subtypes of TBI : Diffuse Injury : Concussion Diffuse axonal injury Blast Abusive head trauma/Shaken baby syndrome Focal : Contusion Penetrating Epidural hematoma Subdural hematoma Intraparenchymal hematoma Sub arachnoid hemorrhage Intraventricular hemorrhage

Risk stratification in TBI :

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Diagnosis CT imaging : Technical aspects : Acquired in axial images with bone and soft tissue window Axial slices must be 3-4 mm in diameter. Aneurysms < 3 mm may be missed 10-20% of the time. CTA and Vasospasm : The gold standard for diagnosis of vasospasm is catheter angiography. There is usually a concordance between catheter angiography and CTA for "no spasm" or "severe spasm" and CTA is adequate if the patient is symptomatic. However the accuracy using CTA for mild and moderate spasm is only modest. Furthermore , concordance between CTA and catheter angiography is greater for proximal than for distal vessels. CTA and CTP may be compared to further detect vasospasm and can guide therapeutic strategy such as hemodynamic augmentation to improve blood flow. CTP is used to evaluate infarct core versus penumbra. It shows areas of reduced blood flow in a patient with vasospasm. It can also demonstrate the presence or absence of autoregulation. The penumbra is considered to have reduced CBF , normal or elevated CBV due to cerebral autoregulatory response and elevated MTT.

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Figure : Core infarct

Figure : Ischemic Penumbra

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Contrast versus Non contrast CT scan Consider Non contrast CT scan for anatomical intracranial injury Hemorrhage Hydrocephalus Contusion Mass effect, shifts Ischemia- infarction Shear Injury Diffuse Axonal Injury Consider Contrast enhanced CT scan for : Medium to large vascular abnormalities (not typically aneurysms) Masses Blood brain barrier disruption Infection Chronic effects of hemorrhage Indications of CT scan : PECARN rule for children TBI in patients on anticoagulants or has bleeding disorder GCS < 13 Canadian CT head rule High risk for Neurosurgical intervention Medium risk for brain injury High risk for Neurosurgical Intervention : GCS < 15 at 2 hours after injury Suspected open or depressed skull fracture Any sign of basal skull fracture Two or more episodes of vomiting Age >/= 65 years Medium risk for Brain injury Amnesia before impact of 30 min or more Dangerous mechanism Biomarkers concentration (Serum GFAP , UCH-L1) may predicts the absence of intracranial injury and might help in clinical decision whether CT is indicated or not. Even if the initial CT is negative , elevated biomarkers might predict MRI abnormality and future neurosurgical intervention.. Analysis of GFAP concentration with in 24 hours of injury might improve detection of TBI and help identify patients who may require subsequent MRI and follow up. Negative predictive value of combination of Serum GFAP and UCH-L1 is nearly 100%. Currently these tests are available as POC. Blood biomarkers are probably sufficiently sensitive to safely exclude the need for neuroimaging in many mild TBI patients and to indicate MRI scans for some who would otherwise not have been imaged.

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Figure : PECARN rules for children: (a) younger than 2 years, (b) aged 2 years and older

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CT scan and hemorrhage Sensitivity for detecting intracerebral hemorrhage on a CT scan is nearly 100%. Hence CT scan is usually the first investigation to consider to rule out hemorrhage. Hounsfield Units (HU) of blood depends on protein concentration (I.e. hemoglobin or hematocrit- HCT). Grey matter : 37-41 HU White Matter : 30-34 HU Acute blood with HCT of 45% : 56 HU (Blood is hyperdense to grey matter) Acute blood may appear Isodense if : Hence can be missed Anemic patients ( Hb < 8-10 g/dl) Coagulopathy Hyperacute stage – blood has not clotted yet As occasionally , CT scan may miss Isodense appearing hemorrhage , it is important to recognize those patients who are at high risk of Intracranial hemorrhage. Clinical Prediction of Intracranial hemorrhage : GCS < 8 Loss of consciousness and skull fracture Persistent drowsiness Children with refractory vomiting ICP > 25 . CT – differentiating fractures from other normal structures (vessels and suture lines) Attribute

Fracture

Vessel

Suture

Wall Margins

Sharp, Imperceptible

Thick , Sclerotic

Imperceptible (child) Fused (adults)

Course

Non branching

Branching

May branch

Appearance

Linear

May curve

Zigzag (child)

Thickness

Varies , often < 2mm

>2mm

< 2mm

Location

Point of impact

Some characteristic

Characteristic

Skull layers

Inner and Outer

One, usually inner

Inner and Outer

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CT findings of elevated ICP : Midline shift > 5 mm Lateral ventricle ( LV) asymmetry Trapped lateral Ventricle Effacement of Cisterns (esp perimesencephalic) Ratio of frontal horn diameter to internal diameter Optic nerve sheath diameter (ONSD) > 6-7 mm CT scan and herniation : Herniation may result in duret hemorrhages and compression of posterior cerebral artery compression causing infarction.

Figure : Large left hemispheric and parafalcine subdural hematoma (short black arrows ) Midline shift (long black arrows) . Uncal (long white arrow ) Duret hemorrhage in the paramedian midbrain (short white arrow) Downward brainstem herniation has leads to Duret hemorrhages

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CT brain in TBI is usually evaluated by Marshall or Rotterdam classification. The presence of compressed basal cisterns or midline shift indicates elevated intracranial pressure.

Figure : Marshall Classification of TBI . Mean ICP values in diffuse TBI cannot be predicted by Marshall CT scan classification.

Figure : Rotterdam classification of TBI 180

TBI phenotype by CT scan :

Figure : TBI phenotypes based on CT scan. CT scans of 6 patients classified as severe TBI with GCS score of 8. EDH : Epidural hematoma, contusions and parenchymal hematomas (Contusion/Hematoma), DAI: diffuse axonal injury ,SDH :subdural hematoma , SAH/IVH : subarachnoid hemorrhage and intraventricular hemorrhage (SAH/IVH), and diffuse brain swelling . Epidural hematoma : Does not cross suture lines Subdural hematoma : Crosses suture lines CT brain is good at defining brain swelling ( ICP risk) and planning surgery for Space occupying lesion. However CT may miss "prognosis defining lesions" that do not increase ICP such as brainstem injury or diffuse axonal injury. These lesions have outcome impact independent of ICP and its control. ICP management may not benefit these patients. It is important to differentiate two groups of patients based on elevated ICP is whether a cause of poor outcome ( ICP Rx would help) or elevated ICP is simply a marker/ consequence of devastating injury and not the cause ( ICP Rx may not modify outcome). This categorization may be better achieved by MRI ( esp SWI). However elevated ICP patients may be too unstable to be transported to MRI suite. Furthermore MRI in everyone is logistically challenging at this moment . Hence , it is essential to identify those subset of patients who would benefit from early MRI. Advanced modes in MRI such as DTI may be considered in patients who do not regain consciousness with unexplainable defects in CT . MRI detects more Contusions and TAI. CT detects more SAH and EDH. Detection of CT negative, MR positive lesions with the use of biomarkers could possibly identify patients less likely to benefit from aggressive ICP management . 181

Some of the blood biomarkers include : S100B NSE GFAP UCH-L1 Tau NFL

Figure : Biomarkers and their origin. Markers of neuronal body injury: NSE , UCHL1 Markers of Axonal Injury : NFL , MBP Markers of dendritic injury : Tau Markers of Astrocyte Injury : S100B, GFAP. Cell free DNA is a market of site specific structural damage However it has been observed that in diffuse axonal injury , all biomarkers including GFAP are markedly elevated. Degree of GFAP elevation has been linked to the CT severity of TBI.Elevation in plasma GFAP concentration has been associated with MRI positive , CT negative findings in TBI. In patients with TBI , CT negative , but elevated GFAP may be considered as "Diffuse DAI" and may benefit from MRI .

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Management : ABC / ENLS Primary injury and prevention of secondary injury Surgery : to be considered if Extra axial mass lesion > 1 cm thick Midline shift > 5 mm ICH > 3 cm in diameter Midline shift < 5 mm , but ICP > 20 mm HG Penetrating injury Compound depressed skull fracture Intracranial hypertension refractory to medical management . Type of surgery : Craniotomy for focal lesions e.g SDH with midline shift Decompressive craniectomy e.g : salt and pepper contusions. Surgery may be futile in a patient with multiple contusions in white matter and diffuse cerebral swelling or in patients with herniation or in victims of gun shot with trans ventricular wound depending on clinical circumstance .

ICP management: ICP/CPP monitoring reduces in-hospital and 2 week mortality. Target Systolic blood pressure >/= 100 mm HG if patient is 50-69 years old Target Systolic blood pressure >/= 110 mm HG if patient is 15 –49 years or > 70 years Rx ICP if > 22 mm HG , target CPP for survival/favorable outcomes is 60-70 mm HG Minimal optimal CPP (60/70 mm HG) depends on autoregulatory status. Deaths directly attributable to TBI are due to refractory intracranial hypertension. Escalating therapies for ICP management are applied , but come with side effects. These therapies are usually applied in the form of tiers and goal directed therapeutic strategies with SIBICC protocol. It is important to differentiate two groups of patients based on elevated ICP is whether a cause of poor outcome ( ICP Rx would help) or elevated ICP is simply a marker of poor outcome and not the cause ( ICP Rx may not modify outcome). Some of these include : Optimizing CPP , PaO2 and PaCO2 Hyperosmolar therapy Deepening sedation or analgesia Rescue - Barbiturate coma or hypothermia ( occasionally to achieve burst suppression) Late rescue Decompressive craniectomy (risk of severe disability) Rescue therapies increase survival by 20%.

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Ordering a Second CT scan : Repeat CT head should be obtained in those patients at risk of evolution of intracranial pathology. These include : Prehospital anticoagulants , high dose antiplatelets or coagulopathy Low dose Aspirin may not require routine repeat CT GCS 24 hours , INS < 1.5 , PTT < 40 , No coagulopathy , Fibrinogen > 1.0, platelets > 100, not on anticoagulant medications ) High risk patients : Avoid pharmacological anticoagulation. Some consider pharmacological prophylaxis starting at 4-7 days in severe TBI with stable CT/ neuro findings. Low Risk TBI -> Apply Sequential Compression devices (SCDs) -> Repeat Head CT in 6-24 hours. If Repeat CT head is stable and GCS motor score is stable : Start VTE PPx pharmacologic. If Repeat CT or Neuro exam unstable , Repeat CT in Q48hrs. Third CT scan and Neuro exam is stable : Start VTE PPx pharmacologic Third CT scan or GCS is unstable , B/L lower extremity doppler Q7 days. If positive – IVC filter. Severity based anticoagulation : Mild to moderate TBI : Start Anticoagulation PPx after stable CT in 24-72 hours Severe TBI : one of the following IPC (Intermittent pneumatic compression) , Pharmacological start by day 7 Pharmacological start 3-4 days after TBI only after CT is stable NB : Anticoagulation prophylaxis is safe to start on the first post-operative day (24 hours later) after elective neurosurgery, although not in TBI. 188

Cervical Spine Clearance : Modern CT seems to be adequate for cervical spine clearance. Negative predictive value is 100% with both sensitivity and specificity > 99.9%. The negative likelihood ratio of unstable cervical injury after a negative CT scan is < 0.001. MRI can be considered as the ultimate test for detecting spine injuries but usually is not required for clearance. MRI may be used for surgical planning however. NEXUS criteria / Canadian cervical spine rule can be used to determine if CT imaging of cervical spine is required or not. NEXUS : National emergency X radiography utilization study. When a significant mechanism of Injury is present , a cervical spine is determined to be stable if : There is no posterior midline cervical tenderness There is no evidence of intoxication Patient is alert, Oriented *4(time, place, person and event) There is no focal neurological deficit There is no painful distracting injury (long bone fracture) While CT is the appropriate technique for the urgent detection of hematomas and contusions in the cerebral hemispheres, it is much less effective at documenting diffuse injury and posterior fossa lesions and is therefore partially predictive of outcome. Current stratification for Outcome includes age initial GCS pupillary reactivity CT possibly blood biomarkers Patient with apparently favorable outcomes, including those with mild TBI may show persistent, subtle but clinically significant deficits. Outcome prediction models : These are not sufficient for "treatment limiting clinical decisions" and to be used only for risk adjustment, quality assurance and clinical trials.

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IMPACT TBI score : Predicts 6 months functional outcome after TBI Employed for patients with head injury and GCS 24 mm HG , however there may not be linear correlation with increased ICP.

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Intracranial pressure measurement : Measured in three different ways using ultrasound 1. Arterious Transcranial doppler : PI and FVd formula

Figure : Noninvasive ICP measurement ICP plateau waves can be reliably replicated by different TCD-based nICP methods. nICP_BB (mmHg) :based on a black-box mathematical model nICP_FVd (mmHg) : based on the diastolic cerebral blood flow velocity. nICP_CrCP (mmHg) : based on the concept of critical closing pressure. nICP_PI (mmHg):based on the pulsatility index. R, correlation coefficient in the time domain between direct ICP and nICP. 193

2.Venous TCD 3.Optic Nerve Sheath Diameter ( ONSD) : The increased intracranial pressure is transmitted to the elastic membrane located behind the retina in the optic nerve, which increases the diameter of the optic nerve. Measuring the diameter of optic nerve sheath using a linear probe with probe frequency > 7.5 Hz, thermal index > 1, mechanical index < 0.3 can detect intracranial hypertension. With this probe characteristics , it is easy to differentiate the sheath and the nerve. The ONSD makes a qualitative assessment of elevated intracranial pressure and the value may not correlate with the number of intracranial pressure ( no quantitative information obtained). NICP (ONSD) = 4.7 X ONSD – 12.35 (mm HG) NICP : Noninvasive ICP measured by ONSD Cardiac Arrest : Cerebral edema post cardiac arrest is related to worse outcomes. Detection of edema by CT scan may be difficult occasionally especially in the early periods . Insertion of ICP catheter is also not routine in post cardiac arrest phase . Brain ultrasound in this setting may be extremely useful to detect elevated ICP.

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Neuromonitoring Cerebral Physiology and metabolism: Aerobic metabolism : 38 ATP for 1 mol of glucose ( 90% in brain) Anaerobic metabolism : 2 ATP for 1 mol of glucose (10% in brain) CMRG- Glucose consumption : 31 mmol /100 gm/min or 0.325 umol/g/min O2 consumption : 160 mmol /100gm/min or 1.5umol/g/min or 3.4 ml/100g/min AVDO2 : 6.5 ml/dl O2ER : 35% CMRL : 0.02umol/g/min Cerebral blood flow is constant @ 50 ml/100gm/min Brain weight is 1-2% of total body weight Cerebral blood flow is 20% of cardiac output. Brain performance is highly sensitive to any decrease in Oxygen supply. A reduction in plasma Oxygen pressure to 65 mm HG : impaired ability to perform complex tasks 55 mm HG : Impaired short term memory < 35 mm HG : loss of consciousness At high altitudes or other oxygen depleted environments , cognitive and motor performances are impaired while performing relatively simple tasks. Hyperbaric Oxygen or hyperoxia may be associated with improved cognition, but comes with many adverse effects such as increased pulmonary toxicity, increased vasoconstriction, decreased cardiac output, reduced coronary blood flow and increased free radical mediated damage to various organs. Effect of hyperoxia is time sensitive. It may that hyperoxia during the ischemic phase may be beneficial , but not during the reperfusion phase.

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Critical Neuroworsening / Clinical monitoring : Spontaneous decrease in GCS score of >/= 1 point compared with previous New decrease in pupillary reactivity New pupillary asymmetry or bilateral mydriasis New focal motor deficit Herniation syndrome Cushing's triad Any sign of Critical neuro worsening requires either an empiric treatment such as hyperosmolar bolus or hyperventilation and investing the cause by considering emergent imaging or other techniques.

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Automated Pupillometry : Automated pupillometry should routinely employed in neuro-intensive setting.

Automated Pupillometry is useful in neurointensive care and the information obtained can be used to : Estimate the severity of injury ( brain stem function, cortical function) Adjust sedation and analgesia Direct certain diagnostic tests Give specific therapies such as to monitor the effect of Osmotherapy on brain edema Predict increase risk of delirium Neuro prognostication. Automated Pupillometry allows quantitative analysis of pupil function and is more precise than a clinician's appraisal. It has improved detection of anisocoria over clinicians judgement. Automated pupillometry also gives additional information viz latency, constriction velocity , peak constriction, pupillary escape , dilation velocity, time to peak constriction etc. It gives a quantitative estimation of pupil size and degree of response similar to a vital sign. In cases of elevated ICP , reduction in constriction velocity (CV) occurs far before anisocoria develops , suggesting a very early subtle sign of possible herniation. Also reduced constriction velocity of pupil at day 3 was associated with increased likelihood of ICU delirium and may have an adjunctive role of estimating cortical function , other than EEG. . Automated pupillometry (Constriction Velocity : significant change is defined by 20%) has been correlated with the findings of EEG or may identify patients who would benefit from EEG monitoring in the ICU. Thus it may be interesting to identify those patients at risk of delirium by automated pupillometry.

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Sedation and analgesia does affect the pupillometry variables. Propofol Pupillometry Reduced pupil size Reduced CV Decreased PLR

Fentanyl

Inhaled anesthetics

Dexmedetomidine

Increased dilation latency to pain

Pupillary dilatation Reduced/abolished PLR (pupil light reflex)

Slightly increase of PLR, reduced pupillary dilatation

To minimize the confounding effects of sedation and analgesia on the pupil size , many different indices have been proposed that are based on proprietary algorithms. These include : Neurological Pupil Index (NPI) Pupil reactivity assessment scale which goes from 0 to 5. NPI > 3 : trend towards normal pupillary response NPI < 3 : trend towards weaker pupillary response. NPI < 3 for longer duration on repeated assessments are associated with poor outcomes (GOS scale) NPI < 3 may indicate near future delayed cerebral ischemia in sub arachnoid hemorrhage. NPI trajectory on repeated measurements predict outcome in patients on VA ECMO. NPI has been used for prognostication in cardiac arrest patients, better than standard PLR . NPI in cardiac arrest : NPI 0.3 or positive co-relation: Disturbed pressure reactivity Setting the calculation window to 6-8 hours provides enough data to capture the CPP-opt curve and yet it is short enough to provide feedback for titrating the blood pressure.

Figure : Time trends and scatter plots with regression lines for ICP and ABP . A : Denotes Good pressure reactivity , B : Disturbed Pressure reactivity .

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Figure : Example of a 4 hour epoch of multimodality monitoring signals in TBI. Top panel : CPP Second Panel : PRx over 4 hour period ( 0600 to 1000) Third Panel : Risk chart . PRX > 0.3 indicates disturbed autoregulation when CPP < 60 ( twice in the chart) Bottom panel : CPP plotted against PRx and a polynomial curve is drawn. Minimum of curve is 65 mm HG , which therefore is the optimal CPP at time point 10:00. PRX detects the lower limit of autoregulation and optimal CPP(CPP-opt).Lowest PRx values corresponding to the strongest autoregulation level. Rates of favorable outcome reaches maximum when CPP is close to optimal CPP. Lower CPPs increase mortality , higher CPPs increase severe disability. CPP-diff = CPP – CPP opt CPP diff : negative = Increase mortality CPP diff : positive = Increase disability Pressure reactivity index has been co-related with : PET-CBF derived autoregulation Cerebral metabolic rate for O2 Transcranial doppler related Dynamic autoregulation index Outcome/ Mortality in TBI. Similarly other indices have been proposed ( considered as PRx clones) . These include Pulse amplitude index (PAx; correlation between pulse amplitude of ICP [AMP] and MAP) RAC (correlation between AMP and cerebral perfusion pressure [CPP])

Cerebral Oximetry Index ( COX) : ICP slow waves can be replicated with NIRS based measurements of blood volume. IT has been observed that coherence between blood volume and ICP is high at slow wave frequency. Cerebral oximetry index (COx) was calculated as a moving, linear correlation coefficient between slow waves of arterial blood 226

pressure and cerebral oximetry measured with near-infrared spectroscopy. ABP opt can be calculated.

Figure : Lowest COx defines Optimal MAP. COx increases if MAP moves away from optimal MAP. Here the Optimal MAP is 80mm HG (black arrows) .

Total Hemoglobin reactivity ( THx) : Total hemoglobin reactivity index (THx) is derived from near-infrared spectroscopy (NIRS) to assess cerebral vasoreactivity non-invasively. THx is calculated as correlation coefficient with arterial blood pressure (ABP).THx can be used as a noninvasive measure for PRx, but only during phases with sufficient slow wave power in the input signal. Furthermore , PRx is a global measure, whereas THx is a local measure.

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Brain Oxygen monitoring : Brain injury is not just associated with CPP-ICP paradigm , but much more happens at the cellular level with microvascular ischemia and mitochondrial dysfunction. Rather changes in biochemistry such as lactate /pyruvate ratio, glutamate levels precedes the increase in ICP. Brain hypoxia can occur without the decrease in perfusion ( "diffusion hypoxia for the brain"). It has been observed that 30% of the patients suffer from brain hypoxia despite adequate cerebral perfusion pressure after resuscitation in TBI. Factors that influence brain oxygen : Brain Oxygen measures the interaction between O2 content , CBF and CMRO2. Significantly , it measures the interaction of CBF and AVDO2, but however it should not considered as a measure of blood flow alone, it includes the effect of respiration such as PF ratio, blood transfusion. Systemic Factors : ABP, ICP , PaO2, PaCO2, pH , Temperature Blood Hb content , P50 , viscosity and Hematocrit Local factors : O2 consumption of neurons and glial cells O2 diffusion conditions/gradients in tissue Number of perfused capillaries per tissue volume Length and diameter of perfused capillaries Capillary perfusion rate and micro flow pattern Hb O2 release in microcirculation The effect of ICP on pbtO2 is not always consistent. With increasing ICP, pbtO2 may increase. Further increases in ICP may actually lower pbtO2. It may be such that there is always a particular CPP and ICP at which pbtO2 is optimal in a given clinical circumstance. PbtO2 decreases with shivering , probably explaining only a modest and humble (or rather no effect) effect of hypothermia. Blood transfusion does not necessarily increase PbtO2 , in some cases excessive blood transfusion may even decrease pbtO2. Techniques to monitor Brain O2: Positron Emission Tomography (gold standard) Magnetic resonance Spectroscopy SjO2 ( Jugular O2 saturation via retrograde jugular catheters) AVDO2 at Jugular level Near Infra-red Spectroscopy – NIRS Partial pressure of brain tissue Oxygen : Licox ( Integra Neuroscience) Neurotrend (Codman) Oxford Optronix Raumodic ( Muchberg,Germany) Foxy-ptiO2 (Ocean optics –Dunodin,FL,USA) "PO2-100DW" ( IsInter Medical Co Ltd ,Nagoya, Japan)

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Figure : Fluid-attenuated inversion recovery (FLAIR), cerebral blood flow (CBF), oxygen extraction fraction (OEF), ischemic brain volume (IBV), 18F-FMISO trapping rate (k3)-Fluorine 18 labeled Fluoromisonidazole , and hypoxic brain volume (HBV) . CPP was 80 mm HG, ICP of 21 mm HG. The FLAIR image : hemorrhagic contusions with surrounding vasogenic edema in bilateral frontal and right temporal regions. High signal consistent with injury are seen in left thalamus and bilateral occipital regions. Thin subdural hematomas at the right cortex and left frontal region. Frontal regions have low CBF , but increased K3 in the absence of increased OEF consistent with conventional macrovascular ischemia. The HBV (100 mL) in this patient had a mean CBF of 14 mL/100 mL/min; cerebral blood volume (CBV): 2.1 mL/100 mL; cerebral oxygen metabolism, 27 μmol/100 mL/min; OEF, 35%. These values does not match the region of brain within the IBV (149 mL), with a mean CBF of 15 mL/ 100 mL/min; CBV: 3.4 mL/100 mL; CMRO2, 63 μmol/100 mL/min; OEF, 88%.

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The volume of overlap between these 2 tissues classes in this patient is 10 mL.

Licox ( Integra Neuroscience) :

Figure : Licox monitor for PbtO2. It has a triple lumen durable probe that measures ICP , brain temperature and pbtO2 in the interstitial space. Near zero drift occurs at low pbtO2. It integrates a smart card specific for each system and therefore calibration takes only 5 seconds. The LCD display can be slaved to HP monitor and data acquisition system. It measures the interaction between O2 content , CBF and CMRO2. Significantly , it measures the interaction of CBF and AVDO2, but however it should not considered as a measure of blood flow alone, it include the effect of respiration. Normal pbtO2 > 30 mm HG Treat if < 20 mm HG Ischemia < 15 mm HG Cell death < 5 mm HG. It is essential to perform a CT scan after the placement of pbtO2 probe to check for the positioning. The data that is interpreted depends on the site of lesion and position of probe. Probe located in white matter has correlated with global oxygenation, even though it is designed for local tissue oxygenation.

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Figure : A, Digital subtraction angiography (DSA) showing the tip of the Licox monitor in the ACA-MCA watershed territory. B, Reconstructed sagittal CTA showing the intraparenchymal location and depth of the fiberoptic Licox cable tip. Therapies to treat low pbtO2 : 1. Adjust ventilatory parameters to increase PaO2. 2. Increase FiO2 ( up to 60%) , increase PEEP 3. Transient hyperoxia with FiO2 at 100% 4. Augment CPP(colloid bolus, neosynephrine, dopamine ) 5. Pharmacological sedation,analgesia (Propofol, midazolam, opioids) 6. Head position, avoid turning 7. Ventriculostomy – continuous or intermittent drainage 8. Blood transfusion 9. NM paralysis (Pancuronium , vecuronium) 10. Ventilator rate to manipulate PaCO2 11. Pulmonary toilet to improve PF ratio.

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Recommendations : Systemic Pulse Oximetry : In all patients End tidal CO2 , ABG : Mechanical Ventilated patients Brain O2 monitor ( PbtO2 or SjvO2) : Patients at risk of cerebral ischemia/ hypoxia PbtO2 : Brain tissue Oxygen SjvO2 : Jugular bulb Oximetry PbtO2 or SjvO2 may be monitored at a location , that depends on the type and severity of lesion. The data derived from PbtO2 or SjvO2 may be employed for modifying therapeutic strategy. In addition , it can guide prognostication . Low PbtO2 has been associated with unfavorable outcome. Therapies modified based on pbtO2 also have been associated with improved outcomes. Anemia with brain hypoxia is also associated with worse 30 day outcomes. While low PbtO2 and SjvO2 desaturation is associated with unfavorable outcome , other modalities and clinical parameters in conjunction with brain O2 should be used for accurate prognostication. For example , combining the following three parameters may have superior prognostication. Marshall CT score APACHE II PbtO2.

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Cerebral microdialysis It is a technique to look at the metabolic environment of the brain tissue . It gives information regarding the levels of glucose , lactate, pyruvate , L/P ( lactate pyruvate) ratio at the level of tissue I.e brain. O2 and CO2 targets : Definitions : Hypoxia : Low tissue O2 , low PbtO2. < 20 mm HG Hypoxemia : Low blood O2 , low PaO2, < 60 mm HG Hyperoxia : High inspired O2 , high FiO2, > 60% Hyperoxemia : High blood O2, high PaO2 , > 150 mm HG Hypercapnia : High PaCO2, > 45 mm HG Hypocapnia : Low PaCO2, < 35 mm HG

Figure : Effect of PO2 and PCO2 on cerebral blood flow. Cerebral vasodilation occurs in response to increase in PaCO2 or decrease in PaO2. ( increased ICP) CO2 reactivity zone is the range of PaCO2 at which cerebral vessels react maximum to the level of PaCO2. CO2 reactivity zone is 20-60 mm HG.

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In Neuro- ICU , the targets may be different : PaO2 : 80-100 mm HG (Avoid PaO2 < 70 , PaO2 > 150 mm HG) PaCO2 : If ICP normal : 36-40 mm HG, If ICP elevated : 30-35 mm HG Combined ICP and PbtO2 monitoring . Hyperoxia with PaO2 > 300 mm HG is associated with worse outcome in post cardiac arrest , sepsis, TBI or stroke. (Reperfusion injury) . Moderate Hyperoxemia with hyperoxia ( PaO2 150-300, FiO2 < 60%) may be associated with a better functional outcome ( Glasgow Outcome Scale – Extended ; GOSE score). This could be because of improvement in oxidative metabolism as demonstrated by reduction in lactatepyruvate ratio for this level of hypoxemia. ( via cerebral microdialysis). Lowering CO2 , decreases ICP via cerebral vasoconstriction, but too much can result in cerebral ischemia. The best way to monitor the response to PaCO2 is to look at PbtO2 , which is a direct surrogate marker of cerebral blood flow. PaCO2 < 30 and > 49 mm HG is associated with worse outcomes. Optimal target may be 30-35 mm HG and the upper limit can be extended up to 49 mm HG with Neuro monitoring ( PbtO2).

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Further Reading Godoy, Daniel & Seifi, Ali & Garza, David & Lubillo-Montenegro, Santiago & Murillo-Cabezas, Francisco. (2017). Hyperventilation Therapy for Control of Posttraumatic Intracranial Hypertension. Frontiers in Neurology. 8. 10.3389/fneur.2017.00250. https://icmplus.neurosurg.cam.ac.uk/home/applications/tcd-nicp/non-invasive-intracranial-pressure-monitoring/ Robba, C., Goffi, A., Geeraerts, T. et al. Brain ultrasonography: methodology, basic and advanced principles and clinical applications. A narrative review. Intensive Care Med 45, 913–927 (2019). https:// doi.org/10.1007/s00134-019-05610-4 Di Battista AP, Buonora JE, Rhind SG, et al. Blood Biomarkers in Moderate-To-Severe Traumatic Brain Injury: Potential Utility of a Multi-Marker Approach in Characterizing Outcome. Front Neurol. 2015;6:110. Published 2015 May 26. doi:10.3389/fneur.2015.00110 Favre E, Bernini A, Morelli P, Pasquier J, Miroz JP, Abed-Maillard S, Ben-Hamouda N, Oddo M. Neuromonitoring of delirium with quantitative pupillometry in sedated mechanically ventilated critically ill patients. Crit Care. 2020 Feb 24;24(1):66. doi: 10.1186/s13054-020-2796-8. PMID: 32093710; PMCID: PMC7041194. Scales DC, Riva-Cambrin J, Wells D, Athaide V, Granton JT, Detsky AS. Prophylactic anticoagulation to prevent venous thromboembolism in traumatic intracranial hemorrhage: a decision analysis. Crit Care. 2010;14(2):R72. doi:10.1186/cc8980 Margolick J, Dandurand C, Duncan K, Chen W, Evans DC, Sekhon MS, Garraway N, Griesdale DEG, Gooderham P, Hameed SM. A Systematic Review of the Risks and Benefits of Venous Thromboembolism Prophylaxis in Traumatic Brain Injury. Can J Neurol Sci. 2018 Jul;45(4):432-444. doi: 10.1017/ cjn.2017.275. Epub 2018 Jun 13. PMID: 29895339. https://radiopaedia.org/articles/ct-perfusion-in-ischaemic-stroke?lang=us Kim JJ, Gean AD. Imaging for the diagnosis and management of traumatic brain injury. Neurotherapeutics. 2011 Jan;8(1):39-53. doi: 10.1007/s13311-010-0003-3. PMID: 21274684; PMCID: PMC3026928. https://en.wikipedia.org/wiki/Diffuse_axonal_injury https://radiopaedia.org/articles/traumatic-subarachnoid-haemorrhage-1?lang=us. Lorton, Fleur & Poullaouec, C. & Legallais, E. & Simon-Pimmel, J. & Chêne, M. & Leroy, H. & Roy, M. & Launay, Elise & Gras-Le Guen, Christèle. (2016). Validation of the PECARN clinical decision rule for children with minor head trauma: A French multicenter prospective study. Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine. 24. 98. 10.1186/s13049-016-0287-3. Durham SR, Clancy RR, Leuthardt E, Sun P, Kamerling S, Dominguez T, Duhaime AC. CHOP Infant Coma Scale ("Infant Face Scale"): a novel coma scale for children less than two years of age. J Neurotrauma. 2000 Sep;17(9):729-37. doi: 10.1089/neu.2000.17.729. PMID: 11011813. 235

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Vincent, Jean-Louis & Taccone, Fabio & He, Xinrong. (2017). Harmful Effects of Hyperoxia in Postcardiac Arrest, Sepsis, Traumatic Brain Injury, or Stroke: The Importance of Individualized Oxygen Therapy in Critically Ill Patients. Canadian Respiratory Journal. 2017. 1-7. 10.1155/2017/2834956. Ó Briain D, Nickson C, Pilcher DV, Udy AA. Early Hyperoxia in Patients with Traumatic Brain Injury Admitted to Intensive Care in Australia and New Zealand: A Retrospective Multicenter Cohort Study. Neurocrit Care. 2018 Dec;29(3):443-451. doi: 10.1007/s12028-018-0553-5. PMID: 29949002. Pires PW, Dams Ramos CM, Matin N and Dorrance AM (2013). The effects of hypertension on the cerebral circulation. Am. J. Physiol. Heart. Circ. Physiol. 304: 1598–1614, https://icmplus.neurosurg.cam.ac.uk/home/applications/tcd-nicp/transcranial-doppler-assessment-cerebral-autoregulation/ Lavinio A, Ene-Iordache B, Nodari I, Girardini A, Cagnazzi E, Rasulo F, Smielewski P, Czosnyka M, Latronico N. Cerebrovascular reactivity and autonomic drive following traumatic brain injury. Acta Neurochir Suppl. 2008;102:3-7. doi: 10.1007/978-3-211-85578-2_1. PMID: 19388278. Young AMH, Donnelly J, Czosnyka M, Jalloh I, Liu X, et al. (2016) Continuous Multimodality Monitoring in Children after Traumatic Brain Injury—Preliminary Experience. PLOS ONE 11(3): e0148817. https://doi.org/10.1371/journal.pone.0148817

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Chapter 4: Renal Critical Care Chapter 4: Renal Critical Care

241

Acute Kidney Injury

242

Renal Replacement Therapy

252

Acute Renal Replacement Therapy

242

Intermittent Hemo-Dialysis

253

SLED/EDD

254

CRRT

255

Dialy-trauma

256

Fluid Therapy

257

Four Phases of Shock

258

Dose of Fluid Therapy

259

Cardiac Output Monitoring

261

Fluid Management in Polytrauma

263

Fluids Therapy in Renal Failure

265

Rules for Fluid Prescription

266

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Acute Kidney Injury Epidemiology : 20% of hospital admissions develop AKI, of which 1-2% require RRT. Definition : Acute Kidney Injury (AKI): Injury or overt dysfunction < 7 days Acute kidney disease (AKD) : dysfunction for 7-90 days Chronic Kidney disease (CKD) : dysfunction > 90 days Risk Factors : Isovolumic hemodilution : Positive fluid balance (either crystalloid or albumin) has been associated with Acute kidney injury. Fluid administration may improve MAP and thereby increase renal blood flow , but the oxygen availability in the cortex of kidney at microvascular level is decreased. Even fluid resuscitation following hemorrhagic shock causes vascular injury indicated by increase in sialic acid levels (endothelial marker). Anemia ( Hb < 7.4 gm/dl) at ICU stay is associated with AKI. Renal cortex is extremely vulnerable to anemia . At HCT of < 10 , the renal oxygen consumption dependent on the blood flow unlike in the heart , where this threshold is 9 , and intestine at 17. High Salt intake : High Salt intake ( > 12 g/day) may induce decrease in microvascular density , increase in transcapillary escape rate ( increased microvascular permeability) even without affecting macrohemodynamics. These microvascular changes may precede the development of hypertension. Similar effects are seen with excessive normal saline and hypertonic saline. 1L of NS contains 9 gm of sodium chloride. Fluids decrease Oxygen transport capacity , salt causes endothelial injury and vascular barrier dysfunction, both leading to AKI. Anti-inflammatory resuscitation fluids It is plausible that addition of N acetyl cysteine to the resuscitation fluids may decrease the risk of AKI. Staging and Diagnosis of AKI : Increase in SCr by >/= 0.3 ,g/dl (26.5 umol/L) with in 48 hours Increase in SCr to > 1.5 times baseline ; presumed to have occurred in prior 7 days Urine volume < 0.5 ml/kg/hr for 6 hours.

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Serum Creatinine has low sensitivity as it is elevated if 50% of nephron function is lost. Urine Output has low specificity as it is influenced by several factors. With the increasing recognition that AKI is a progressive pathophysiological disorder , "subclinical AKI" precedes the development of AKI as defined by KDIGO criteria. Biomarkers may identify golden hours prior to diagnosis and may aid in risk assessment with the notion that early intervention changes the course of disease. Elevated biomarker levels despite normal serum Creatinine is associated with increased mortality indicating damage and not just functional deterioration of the nephrons affects the outcome. Biomarkers ( Urinary) may be used to guide intervention to prevent AKI especially after major cardiac and abdominal surgery. Thus biomarkers may be exploited to diagnose subclinical injury , to predict who might benefit from early initiation of RRT, early and late prognostication including "renal non recovery" . Biomarkers allow clearer identification of high risk patients and different AKI sub phenotypes and have a potential to improve management of AKI.

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Biomarkers in Acute Kidney Injury can be either classified according to the site of injury they reflect or according to the clinical utility and significant. According to the site of Injury : Markers of Glomerular function : Cystatin C RBP Hepcidin Cathepsin Proenkephalin Markers of inflammation and repair : thin segment of Loop Calprotectin HGF IL-1b Markers of cell stress : tubules and thick segment of Loop IGFBP7 TIMP-2 Markers of tubular damage : NAG α/π GST GGT NGAL KIM-1 RBP L-FABP Α1/β2 microglobulin Netrin-1 Hsp72 According to the clinical Utility : Damage Biomarkers : Should be used early to identify Subclinical AKI (affects clinical outcome) KIM-1 NGAL TIMP2/IGFBP7 Functional/Stress Biomarkers : Should be used later for Risk stratification Creatinine Urine Output Cystatin C

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Creatinine : Pancreas, Liver and Kidney generate Creatine from Arginine + Glyc via an intermediate molecule- guanidinoacetate (glycocyamine) . Creatine is converted in the skeletal muscle to phosphocreatine and creatinine. Creatinine clearance is achieved via glomerular filtration and some tubular secretion. ( Creatinine is not reabsorbed by the tubule). Generation of creatinine depends on muscle bulk and Liver function and hence should not be considered as Renal specific. NGAL : Neutrophil gelatinase associated lipocalin . Can be measured both in plasma and Urine. Plasma NGAL can predict kidney injury in ICU , post cardiac surgery. Plasma NGAL < 150 ng/ml can be used to exclude patients for RRT. However the performance of NGAL is better in patients with normal kidney function than in renal failure. TIMP2 * IGFBP7 (cell cycle arrest biomarkers) : Predicts AKI in next 48 hours in ICU. When measured 4 hours after cardiac surgery , it predicts AKI. Values < 0.3 rules out KDIGO stage 2/3 AKI with in 12hours Values > 2.0 diagnoses impending KDIGO 2/3 in the next 48 hours TIMP-2 :Tissue inhibitor metalloproteinase 2 IGFBP-7 : Insulin like growth factor binding protein –7 These biomarkers can predict the long term adverse outcomes .Chronic common conditions ( CKD, CHF) do not affect performance of cell cycle arrest biomarkers for risk stratification of acute kidney injury. Dickkopf –3 : Urinary DKK3 is an independent predictor for post-operative AKI and for subsequent loss of kidney function . CCL-14 : Elevated Urinary CCL-14 predicts persistent AKI and renal non recovery in critically ill patients with severe AKI. Biomarkers should be measured in a patient who is at risk for AKI akin to the concept of "renal angina", to help improve the utility of biomarkers. Caveat : Renal biomarkers should be interpreted similar to Troponin. The presence of risk factors and symptoms increase the positive predictive value of elevated troponin and so is the similar case with renal biomarkers. Hence the concept of Renal angina for risk profiling.

Effect of AKI on other organ function : "From AKI to Multiorgan dysfunction" There is significant interaction between systemic inflammation and renal tubular epithelial cells. Inflammation can result in tubular epithelial injury that activates WBCs and platelets further augment the inflammatory damage. This can have devastating consequences to Heart (apoptosis of cardiomyocytes) , Lung (increased aquaporin 5 expression) , Gut (increased channel inducing factor-CHIF,intestinal macrophages, increased K+ excretion), Brain (increased microglia, keratinocyte derived cytokines) Liver

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Possible mechanisms of distant organ injury following AKI include venous congestion, vascular permeability and apoptosis/necrosis. These mechanisms may be mediated via Cytokines/Chemokines IL-1,IL-6,TNF-a (Pro-inflammatory) IL-10 (Anti-inflammatory) Leucocyte Extravasation PMNs, Lymphocytes and Macrophages Oxidative Stress Superoxide dismutase , Malondialdehyde ,Glutathione depletion Sodium and Water dysregulation In fact , Cardio renal syndrome is a typical example of interdependency of function of one organ with the other. Type 1 Acute Cardiorenal Syndrome : Acute HF leading to AKI. This may be related to altered hemodynamics. Type 2 Chronic Cardiorenal syndrome : Chronic HF leading to progressive and permanent CKD. This may be secondary to accelerated renal cell apoptosis and replacement fibrosis. Type 3 acute Reno cardiac syndrome : AKI causing AHF. Here the salt and water imbalance coupled with uremia induced neuro hormonal dysregulation, sympathetic and RAAS activation may cause cellular apoptosis and cardiac hypertrophy/fibrosis. The mediator seems Galacetin-3. Elevated levels of Galectin 3 is associated with increased severity of AKI and its adverse impact on the heart. Galectin 3/cytokine pathway may play a significant role in type 3 cardiorenal syndrome. Type 4 Chronic Reno cardiac syndrome : CKD leading to chronic HF and CKD progression. Related to CKD induced myopathy. Type 5 Secondary Cardio Renal Syndrome : Systemic insult such as Sepsis or septic shock causing injury to both heart and kidney is a typical example. Microcirculatory dysfunction , altered innate and adaptive immune responders with cytokine release results in simultaneous organ injury.

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Lung Kidney Cross talk :

Figure : Lung Kidney Crosstalk. Ischemic re-perfusion renal injury can impact lung function even at cellular level by activating caspase pathway and expression of aquaporin. Vascular permeability is increased by activation of macrophages. Brain –Kidney Crosstalk : Main mechanisms of the cross talk are : Mechanism

Results

Impaired blood–brain barrier integrity

Alteration of essential amino acid concentrations, inflammatory mediators and organic osmolyte in the brain

Neurotransmitter derangement

Decreased cerebral norepinephrine, epinephrine and dopamine may lead to impaired locomotor activity

Trigger inflammatory cascade Three waves of danger signalling unleashing uric acid, Weibel– Palade bodies and high mobility group box 1 protein Acid–base disturbance

Activation of acid-sensing ion channels leading to cellular injury

Vasoregulation

Local vasodilatory effects as a result of cerebral oedema

Organic osmolyte and brain water disturbance

Increased intracellular idiogenic osmoles and brain water

Alteration of drug pharmacokinetics

Downregulation of organic acid transporters and organic cation transporters. Alteration of protein binding of drug Impaired renal and hepatic clearance of drug

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Kidney GUT cross talk : Kidney intestinal microbiota cross talk depends on microbe generated and kidney generated factors. Macrophages may play a key role. Bone marrow-kidney cross talk : AKI can affect levels of G CSF causing PMNs to infiltrate the bone marrow. The function of endothelial progenitor cells (EPC) and paracrine factors may be diminished Traditional indications of RRT : Oligo-anuria Refractory Severe Acidemia (pH < 7.15) Azotemia Refractory Severe Hyperkalemia Suspected Uremic Organ involvement Severe Dysnatremia ( Na > 160 or < 155 mmol/l) Hyperthermia ( Core temp > 39.5C) Clinically significant organ edema (Pulmonary edema resistant to diuretics) Drug overdose with dialyzable toxin Coagulopathy requiring large amounts of blood products in patients with high risk of ARDS Risks associated with RRT : 1. AKI is self-resolving depending on circumstances 2. Risks involved in RRT is related access, hemodynamic instability , electrolyte imbalance, arrhythmia and is dependent on dose , intensity and duration. 3. Dialysis by itself may not improve survival , recovery or functional status. NB: complications related to access is no different from that of traditional central venous and arterial access.

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Early accelerated initiation of RRT : Pros : Faster achievement of euvolemia. Possible to increase nutrition load Removal of toxic solutes Achievement of acid base homeostasis Prevention of over complications attributable to AKI May improve time to recover May reduced mortality Cons: Spontaneous recover of kidney function may occur even in severe AKI Higher Vascular access complications (hemorrhage, thrombosis, bacteremia) Higher complications : intradialytic hypotension, hypersensitivity to circuit Enhanced clearance of trace elements and antibiotics Extensive resource utilization Timing of RRT initiation : Timing of renal replacement therapy cannot be answered definitively. Too early intervention exposes the patients to an unnecessary risk of invasion , too late reduced benefit and risk irreversible organ failure. There is no difference in outcomes between early accelerated initiation of renal replacement therapy over standard traditional indications. When there is a concordance in decision between intensivist and nephrologist , early initiation improves survival. In the context of equipoise , early initiation may not benefit. Diuretic challenge : Diuretics do not affect outcome or the need for renal replacement therapy . However they convert from oliguric to non-oliguric which is easier to manage. Diuretic challenge (Furosemide 20-200 mg boluses) can be considered in an oliguric fluid overload patient and the urine output observed in 3-6 hours. If there is no satisfactory response , it is reasonable to consider extracorporeal therapy. Wait and See Approach : Also referred to as "Permissive hyper-uremia" Wait and See approach is defined as a strategy that involves postponing RRT in critically ill patients with severe AKI who have no life-threatening complications. Life threatening complications include severe hyperkalemia , severe metabolic acidosis and refractory pulmonary edema. The timing of RRT initiation does not affect survival (hospital mortality , ventilator free days)in critically ill patients with severe acute kidney injury in the absence of urgent indications for RRT. Delaying RRT initiation , with close patient monitoring , might lead to a reduced use of RRT, thereby saving health resources. "Wait and see" approach may be the new standard of care as it minimizes "Artificial Kidney induced kidney injury" AKIKI (similar to disuse atrophy) . AKIKI is a measure of dialysis dependency after ICU discharge . Wait and see approach is associated with more rapid renal function recovery .

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Measures to Prevent AKI : Adherence to bundles improve outcome especially in high risk population, that may be identified by biomarkers. (eg TIMP2 * IGFBP7 > 0.3). These include : Discontinuation of Nephrotoxic agents including ACE inhibitors Optimize volume status and perfusion pressure by protocolized hemodynamic resuscitation Consider functional hemodynamic monitoring Monitor Serum creatinine and Urine output Avoid hyperglycemia Consider alternative to radio contrast procedure An example of protocolized hemodynamic resuscitation : SVV > 12 : Crystalloid resuscitation with aliquots of 500-1000ml CI < 3l/min/m2 : Dobutamine or epinephrine MAP < 65 mm HG : Norepinephrine Monitor urine output and creatinine , glucose No medication has uniquely been demonstrated to prevent or treat AKI other than the above bundle. Outcomes in AKI : Recovery from AKI in the ICU is heterogeneous and the pattern of renal recovery influences resource utilization and mortality. A "stuttering course" of AKI significantly increases dialysis frequency , prolongs hospital and ICU length of stay and is found to be associated with increased mortality. Non recovery has worse outcomes. Patients with "stuttering course with no recovery" have higher ICU and In-hospital mortality. Phenotyping patients based on their recovery patterns may identify patients amenable to therapeutic intervention in addition to prognostication. Renal recovery patterns include : Early sustained reversal Late sustained reversal Relapse recovery Relapse and non-recovery Never reversed Many factors may influence the renal recovery patterns . These include : Age AKI especially Stage 3 and institution of dialysis Maximum SOFA score

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Prognostic significance of AKI natural history : Element of natural history

Short term outcome

Long term outcome

Timing of onset in ICU

Mortality

NA

Severity of Injury

Mortality

Mortality/CKD/Readmission

Duration of Injury

Mortality

Mortality

Recovery/transient injury

Survival

Survival

Recurrent episodes

NA

CKD

Fluid status

Mortality

CKD/mortality

Baseline GFR

Survival

ESRD

The mortality in AKI is more related to hyperkalemia, metabolic acidosis and cumulative fluid balance (>10%) than AKI itself . Probably this is the reason why permissive hyper-uremia with RRT only for emergency indications and aggressive RRT have similar outcomes.

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Renal replacement therapy Acute Renal replacement therapy in ICU : Many different modalities exist : These include Parameter

IRRT

Hybrid IRRT SLED/EDD/PIRRT

CRRT

PD

Duration in hours

4-6

6-16

24

24

Frequency

daily/alternate

daily/alternate

daily

daily

Solute transport

diffusion

diffusion/convection

diffusion/convection

diffusion

Blood flow ml/min

200-350

100-300

100-250

NA

Dialysate flow ml/min

300-800

200-300

0-50

25-40

Urea clearance ml/min

150-180

90-140

20-45

15-35

Access

Central Venous Dialysis catheter

Central venous Dialysis catheter

Central venous Dialysis catheter

Peritoneal catheter

Anticoagulation

Usually

Usually

Absolutely

No

Fluctuation of Osmotically active metabolites

++

+

Less , but occur No during Rx interruption

Fluctuations in fluid

++

+

Less, but occur No during Rx interruption

Effect on ICP in TBI

Increase

Potential increase

None

None

Effect on serum levels Major of renally cleared drugs

Some

Less

Less

Infection risk

Line infection bacteremia

Line infection bacteremia

Line infection bacteremia

Exit –site Tunnel Peritonitis

Provision of calories

No

No

No

Yes

Loss of nutrients

Yes

Yes

Yes

Yes

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Intermittent hemodialysis : Widely available Rapid correction of metabolic abnormalities Option of no anticoagulation Can cause hemodynamic instability

Strategies to improve hemodynamic tolerance of IRRT : Isovolemic initiation : Principle : Preserve intravascular volume and prevent relative or absolute hypovolemia Technique : Fill circuit with 0.9% Saline Reduced Dialysate temperature : Principle : Preserve vasomotor tone and prevent temperature induced decreases in systemic vascular resistance. Technique : Decrease dialysate temperature by 0.5 - 1.5 C Reduce Dialysate flow rate: Principle : Preserve plasma osmolality , promote vascular refill and prevent rapid shifts in plasma osmolality. Technique :decrease to 50-100 ml/min Dialysate Sodium profiling: Principle : Preserve plasma osmolality, promote vascular refill and prevent rapid shifts in plasma osmolality. Technique : Progressive increase in dialysate Sodium > 145 mmol/L Preferential Use of Bicarbonate buffer: Principle: Preserve myocardial contractility. Technique : Avoid acetate based dialysis buffer Maintain normal systemic Ionized Calcium: Principle : Preserve myocardial contractility and Vasomotor tone Technique : Maintain systemic Ca > 1.0 mmol/L Conservative Ultrafiltration: Principle : Preserve intravascular volume and prevent iatrogenic relative/ absolute hypovolemia Technique : Start with isolated dialysis , gentle ultrafiltration, extend treatment session to achieve fluid balance goals.

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SLED/EDD/PIRRT : SLED : Sustained low efficiency dialysis EDD: Extended daily dialysis PIRRT : Prolonged intermittent renal replacement therapy In all of the above modalities , the conventional hemodialysis technology is applied for prolonged periods so as to render the dialysis with more hemodynamic stability. It’s a kind of hybrid of IRRT and CRRT and can be considered as a "stretchy IRRT".

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CRRT : Continuous renal replacement therapy Offers greater hemodynamic stability than IRRT Lower risk of increased intracranial pressure Need for anticoagulation Labour/resource intensive High cost

Prescription pearls of CRRT Dose : 20-25 ml/kg/hr of effluent rate Anticoagulation of choice : Citrate prolongs filter life. Timing : early intervention not helpful. Apply RRT at traditional indications Fluid balance may be new target in CRRT : de-resuscitation Magnitude and duration of positive fluid balance is associated with mortality and use of loop diuretics may have beneficial effect in patients with positive fluid balance. Positive fluid balance has been associated with worse kidney outcomes. A negative (? Even) cumulative fluid balance has been co-related with survival. It has been observed that it takes median time of 21 hours from the onset of CRRT that the fluid balance becomes negative and 48 hours for the cumulative fluid balance to become negative. Net Ultrafiltration Rate ( NUF) : Total effluent rate - ( replacement fluid + spent dialysate) Fluid balance is best estimated by Net ultrafiltration rate ( NUF - the fluid removed/ hr with the machine). Too fast removal of fluid with high NUF rate can cause myocardial stunning (cardiac MRI) , which may be subclinical except for mild increases in vasopressor requirements. Furthermore , aggressive NUF has been associated with mortality (up to 1 year), increase in hypophosphatemia and delay renal recovery (dialysis dependence) . Hence like fluid resuscitation , fluid removal should be goal directed. Target NUF : 1.01 - 1.75 ml/kg/hr( for example in 80 kg man ; aim for < 140 mls/hr) . Rationale : Patients with critical illness with inflammation ( elevated CRP) may have capillary leakage of fluid and their intravascular refill rate may be 0 or even negative. A high NUF rate may cause intravascular volume depletion by removing fluid in addition to what is being lost via capillary leakage. This intravascular hypovolemia may cause organ injury. In contrast a low NUF may lead to persistent edema in recovery phase and delay recovery. Miscellaneous : CRRT may be chosen over standard intermittent RRT for hemodynamically unstable patients. It may be possible that IRRT as initial modality may increase the risk of dialysis dependency in future when compared to CRRT, which led to an erroneous belief that "IRRT is a nephrotoxin". CRRT is associated with decreased mortality and may be a preferred option for predominant fluid balance. At this time, there is no difference in outcome between continuous or intermittent renal replacement techniques, however weight gain of > 2 kgs between ICU admission and onset of RRT may predict dialysis dependency.

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Concept of Dialy-trauma: Akin to respiratory mechanics where high driving pressures were associated with volutrauma and barotrauma , high NUF has been termed "Dialy-trauma". Triad of Dialy trauma : positive Fluid balance , high NUF and hypophosphatemia.

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Fluids Fluids are drugs . Effects of fluid therapy : Fluid therapy influences Blood flow distribution pO2 Hb/Hct Volume status Blood sheer stress Autoregulation Viscosity/Coagulation Metabolic Inflammation. Caveat : 1 L of NS has 9gm of NaCl. This is equivalent to 50 bags of chips. 500 ml of fluids decrease HCT by about 8% , roughly by 1 gm/dl. Hence, fluids are better regarded as drugs that are not just innocent therapies, but with unrecognized adverse effects. "Fluid Overload" is a vague term denoting excess total body water content and may be associated with edema . However it does not refer to the intravascular fluid status. A patient with fluid overload may have hypovolemia. "Hypervolemia" indicates excess in circulating blood volume and may require fluid restriction strategy or even diuretics.

257

Four phases in the treatment of shock : SOSD

Figure : Phases in the treatment of shock In salvage phase : Low threshold for fluid administration. Fluid balance is usually positive . However avoid excessive fluid administration I.e no fluid is administered if no fluid responsiveness. In optimization phase : individualize therapy based on the following indications. Potential Indications of fluid therapy may be preferable based on dynamic variables .

Static Variables Arterial hypotension Tachycardia Oliguria Decreased skin perfusion, mottling, increased capillary refill time OPS , NIRS , hyperlactatemia ( altered microcirculation) Low SvO2, high PaCO2 gap Low cardiac output, low cardiac filling pressures, small cardiac chambers

Dynamic Variables Respiratory variation in IVC may be unreliable Trans esophageal echo guided SVC variability may be unreliable ( esp in sedated and paralyzed) On fully controlled mechanical ventilation ( deep sedation / paralyzed ) - in the OR( not in ICU) No major arrhythmia : PPV or SVV If spontaneous ventilation ( with or with-out mechanical Ventilator ) : in ICU Perform Fluid challenge Passive leg raising 258

Dose of fluid therapy : Liberal fluid administration results in major edema and need for RRT Restrictive fluid administration resulted in no edema , ? Sphlancnic ischemia , need for RRT. Patient may have edema , but hypovolemia may still exist ( relative hypovolemia) . This can happen because of vasodilation , decreased colloid osmotic pressure, altered vascular permeability. Aim of fluid therapy is to increase cardiac output and DO2 ultimately to improve tissue perfusion. At the same time , to minimize cardiac filling pressures and thus no increase in edema. When to consider Fluid challenge/ Fluid responsiveness / Preload responsiveness: 1.Fluid responsiveness is a normal phenomenon and hence if a patient is fluid responsive , that is not an automatic indication for fluid therapy . Fluid responsiveness does not necessarily mean hypovolemia . Hence it is imperative to evaluate objectively , whether the patient requires fluid or not . Because irrational administration of fluid may cause fluid overload leading to worse outcome. Preload responsive should be elicited only if cardiac output is low . Fluid overload can cause : Increased right Ventricular failure Hemodilution Increased lung water Increased abdominal pressure Decreased perfusion pressure gradient Cumulative positive fluid balance is an independent risk factor for mortality in Sepsis ARDS AKI Intra-Abdominal hypertension 2.In cases of obvious fluid losses , at the early phase of septic shock , predicting fluid responsiveness is obvious. 3.Because fluid overload is an independent risk factor for mortality in Sepsis , ARDS , AKI and intraabdominal hypertension , fluid responsiveness must be investigated in particular. Fluid loading is a fluid therapy given to a hypovolemic patient , but fluid challenge is a test to see if a patient would respond to fluid bolus or not , because of uncertainty in intravascular volume status. For example :A patient in traumatic shock or GI bleeding , consider fluid loading , where as a 85 y/o patient severe cardiomyopathy , consider fluid challenge. Response to fluid challenge can be classified either as fluid responder or non-responder. Fluid challenge has to pragmatically defined as too short time for a particular bolus might elicit a positive 259

test even in an euvolemic person ( false positive) and too long time might have too small effect ( false negative) . The valid dose of fluid challenge is 100-200ml in 5-10min of crystalloid. NB: 500 ml in 30 min is not a fluid challenge , it is a fluid bolus . For fluid challenge test to be effective , four items have to be defined in advance. (The TROL approach) Before the fluid challenge : T : Type of fluid : eg Ringers Lactate R : Rate of infusion : 200 ml in 10 min O : Clinical Objective : increase in CO or MAP L : Safety Limits : CVP max. During the fluid challenge : Do not change the dose of vasopressors Do not suction the trachea Do not stimulate the patient Do not touch the patient After the fluid challenge : Monitoring the response to this fluid is an important component. This test may have to be repeated depending on clinical circumstances. Fluid responder : Fluid challenge increases Cardiac Output , minimal increase in filling pressure Fluid Non responder : Fluid challenge does not increase cardiac Output , but filling pressure increases. Increases in cardiac output may increase in MAP and decrease heart rate , however in a vasodilatory state (high vascular compliance) , increased cardiac output need not translate to improvement in vital signs. Hence cardiac output monitoring seems prudent to look for fluid responsiveness during a fluid challenge.

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Methods for cardiac Output monitoring Thermodilution : Swan Ganz Catheter Transpulmonary dilution/Lithium dilution : PiCCO, Pulsion, LIDCO, Volume View , Edwards. Arterial Waveform analysis : PiCCO,LiDCO, Flotrac/Vigileo, Edwards, PRAM, Vytech Doppler : CardioQ, Deltex, Waki , USCOM Partial CO2 breathing : NICO , respironics Passive Leg raising and monitor change in CO ( not arterial pressure)

Figure : five rules of passive leg raising test. Rules of passive leg raising : PLR should be performed by adjusting the bed and not manually raising the patients legs. A PLR should start from the semi-recumbent and not the supine position B PLR effects must be assessed by direct measurement of cardiac output and not simply blood pressure as this maneuver is a stress inducing test C The technique used to measure cardiac output during PLR should be able to detect short term and transient changes as the PLR effect wane in 1 min. D CO should be measured before , during and after PLR when the patient has been moved back to to the semi-recumbent position in order to check if it returns to baseline. E Pain , cough , discomfort and awakening could provoke sympathetic stimulation and should not be interpreted as change in cardiac output.

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Bioimpedance / Bioreactance : NICOM, Cheetah Aortic Blood flow – The mini fluid challenge ( in the OR) 100 ml of HES/ crystalloid infused over 1 min Transthoracic echocardiogram : Use Velocity time integral Patient should be in Sinus rhythm Compare two exams before and after fluid challenge ( eg 500 ml) Each exam should have an average of three measurements

Stroke volume (SV) calculation. (a) Measurement of LV outflow tract diameter (LVOTD) using the parasternal long-axis view, and (b) use of pulsed Doppler for the measurement of velocity-time integral (VTI), as obtained in the 5-chamber apical view. Cardiac output (CO) = SV × HR; SV = VTI × LVOT area, where LVOT area =  πLVOT  diameter/22. Stroke volume increase by 10% or its equivalent ( VTI by 15%) is considered significant . If the stroke volume increases and filling pressure increase reasonably , then fluid is administered. If the stroke volume does not increase , filling pressures does not increase , search for concurrent losses. If the stroke volume does not increase , but filling pressures increase consider inotropes/ vasopressors If the stroke volume increases and filling pressures increase , consider inotropes/vasopressors De-escalation phase : Aim for negative fluid balance by diuretics or ultrafiltration. Passive leg raising test can be used to guide the amount and rate of fluid removal. If the PLR was negative before ultrafiltration , the probability of hypotension and hence volume depletion is low. Simply put , do not de-resuscitate a patient , if the patient is preload responsive. This is based on the premise that a patient with hypovolemia would have preload responsiveness and hence may succumb to hypotension , if the fluid is removed too much or too quickly. A patient with euvolemia should not be having preload responsiveness , if fluid needs to be removed.

262

Fluid Management in Polytrauma Damage control resuscitation The goal is to provide only interventions necessary to control hemorrhage to focus on reestablishing a survival physiologic status. It is intended to limit deleterious effects of hemodynamic instability , coagulopathy , hypothermia and acidosis. This strategy begins from ground zero to the emergency room and continues through the OR and in to the ICU. The three pillars of damage control resuscitation : a Permissive hypotension b Low volume of crystalloids c Early transfusion of blood products Permissive hypotension : Target Systolic BP 80-90 mm HG ( MAP of 50-60 mm HG) until major bleeding is stopped . MAP > /= 80 mm HG in patients with severe TBI ( GCS 1:1.5 decrease in mortality) Consider Fibrinogen concentrate if significant bleeding and fibrinogen deficiency Fibrinogen deficiency is either Plasma fibrinogen < 1.5 g/l or functional fibrinogen deficit Transfuse platelet to keep platelets above 50 ,000. Aim for platelet count > 100,000 if TBI or ongoing bleeding.

264

Fluid Management in renal failure Fluid overload is deleterious in patients with AKI and a risk factor for death. Rather failure to account for fluid overload delays recognition of AKI or its severity. It is recommended that creatinine should be corrected for fluid balance. Fluid overload is also an independent risk factor for sepsis after AKI. Furthermore , fluid overload impacts the ability to achieve appropriate antibiotic levels. Fluid overload : (Fluid in – Fluid Out) * 100 / weight in Kgs. Fluid overload is defined as > 10% increase in body weight. Corrected Creatinine = Serum Creat * Actual Volume of distribution / presumed volume of distribution. The goal of fluid removal in these patients with diuretics or RRT is to mobilize fluids from interstitial compartment without causing intravascular fluid depletion. This is sometimes difficult in sepsis patients due to the presence of inflammatory cytokines and low oncotic pressure , that make the vascular barrier leaky. Diuretics are not bad in Acute kidney injury and should be considered to treat fluid overload. Furosemide decreases Sodium transport in the loop of Henle, decreasing metabolic demand thereby decreasing the O2 requirements. ( pO2 in medulla of kidney in healthy is low : 10-20 mm Hg). High dose furosemide ( 25 mg/kg/day) in patients needing RRT has been shown to increase urine output , but no decrease in time on RRT with no significant complications. Furosemide stress test : This is test done to help risk stratify patients with AKI. It tests the ability of kidney to respond to diuretic akin to stress echocardiogram. Furosemide is administered to the patient at the dose of 1 – 1.5 mg/kg in patient without hypovolemia.

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Rules for fluid prescription 1. Clinical parameters including are not sensitive or specific enough to determine volume status in a patient unless extreme. Passive leg raising test does not reliably estimate volume status , but predicts fluid responsiveness. Similarly dynamic indices must be always considered to check for fluid responsiveness. When IV fluid infusion is prescribed , that prescription must be reevaluated several times a day. 2. Fluid bolus is defined as 4 ml/kg over 10-15 min. Fluid challenge is defined 1ml/kg over 5 min. Choice of fluid for fluid bolus is not Normal Saline , but Plasmalyte A or Ringers Acetate or Hartmanns solution ( RL). 1L of Gluc 5% expands volume only by 100 ml after 1 hour , hence cannot be used for fluid bolus. 1 L of NS bolus after 1 hour result in volume expansion by 250 ml. 3. For fluid maintenance , the best choice is Glucion 5% or Maintelyte 5% that is ready from the shelve, rather than a fluid composed in real time. Also maintenance fluids that are NOT recommended include Plasmalyte A , Normal Saline , Ringers Acetate , Hartmanns solution, Glucose in Saline , Volulyte 6%.Typically 1250 ml of fluid is required as maintenance in 24 hours. Sodium requirement is 1.0 meq/kg. Potassium requirement is 1.0 meq/kg. Glucose requirement is 1.0 - 1.5 g/kg. 4. Starch solutions , Albumin 4% should never be used . Albumin 20% can be used for deressucitation for fluid overload and presence of hypoalbuminemia. Some starch solutions include Volulyte / Voluven that contains 6% hydroxyethyl starch 130/0.4 in a balanced electrolyte solution. Parameter

Plasma

Voluven

Volulyte

Osmolarity (osm/L)

296

308

286.5

HCO3/Acetate

24

-

34

Sodium

142

154

137

Potassium

4.0

-

4.o

Calcium

2.5

-

-

Magnesium

1.0

-

-

Chloride

103

154

110

5. It is safe to give a balanced infusion fluid with potassium content of 5 meq/L to a patient with renal insufficiency and clearance of 25 ml/min. 6. Normal Saline (0.9%) contains 154 meq/l of sodium , equivalent to 3.5 gm of free sodium in 1L. (Recommended daily intake of sodium is 2.3 gm). Strong ion difference of NS is 0. Normal saline infusion can result in hyperchloremia , metabolic acidosis and hypernatremia.

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7. Plasmalyte contains : pH is 5.5 ( 4.0 to 8.0 , adjusted with HCl) Sodium gluconate : 502 mg Sodium acetate trihydrate : 368 mg Potassium chloride : 37 mg Magnesium chloride : 30 mg Sodium : 140 meq/L Potassium : 5 meq/L Magnesium : 3 meq/L Chloride : 98 meq/L Acetate : 27 meq/L Gluconate : 23 meq/L SID : 50 Osmolarity : 294 mosm/L Caloric content : 21 Kcal/L Glucose is absent in this fluid. 8. Maintelyte Solution of 1000 ml contains : pH : 4.5 to 6.5. Also referred to as GnaK 50 solution. Glucose ( as monohydrate ) :50 gm Sodium chloride : 1gm Sodium acetate trihydrate : 3.13 gm Potassium chloride : 1.5gm Magnesium Chloride hexahydrate : 0.30 gm Na : 40 mmol / l K: 20 mmol/L Mg : 1.5 mmol/L Acetate : 23 mmol/L Cl : 40 mmol/L Osmolarity : 402 mosm/L Calories : 200kcal/L 9. Glucion 5% fluid :PH : 4.0 to 5.2 Glucose Monohydrate 55 mg/ml Lactic Acid 0.54 mg/ml Magnesium Chloride Hexahydrate 0.54 mg/ml Potassium Hydrogen Phosphate 1.08 mg/ml Potassium Chloride 1 mg/ml Sodium Chloride 2 mg/ml Sodium Lactate 2.13 mg/ml Sodium: 54 mmol litre−1 Potassium: 26 mmol litre−1 Chloride: 55 mmol litre−1 Phosphate: 12.4 meq/L or 6.2 mmol litre−1 Magnesium : 2.6 mmol litre−1 Lactate: 25 mmol litre−1 Osmolarity 447 mOsm litre−1; Tonicity 169 mOsm/L Calories : 200 Kcal/L

267

Composition of regular crystalloid fluids

268

Further Reading http://www.sdfops.com/en-xinw6.htm Myatra SN, Prabu NR, Divatia JV, Monnet X, Kulkarni AP, Teboul JL. The Changes in Pulse Pressure Variation or Stroke Volume Variation After a "Tidal Volume Challenge" Reliably Predict Fluid Responsiveness During Low Tidal Volume Ventilation. Crit Care Med. 2017 Mar;45(3):415-421. doi: 10.1097/ CCM.0000000000002183. PMID: 27922879. Meersch, M., Schmidt, C., Hoffmeier, A. et al. Prevention of cardiac surgery-associated AKI by implementing the KDIGO guidelines in high risk patients identified by biomarkers: the PrevAKI randomized controlled trial. Intensive Care Med 43, 1551–1561 (2017). https://doi.org/10.1007/s00134-016-4670-3 Nongnuch, A., Panorchan, K. & Davenport, A. Brain–kidney crosstalk. Crit Care 18, 225 (2014). https:// doi.org/10.1186/cc13907 Ko GJ, Rabb H, Hassoun HT. Kidney-lung crosstalk in the critically ill patient. Blood Purif. 2009;28(2):75-83. doi:10.1159/000218087 Hoste, E., Bihorac, A., Al-Khafaji, A. et al. Identification and validation of biomarkers of persistent acute kidney injury: the RUBY study. Intensive Care Med 46, 943–953 (2020). https://doi.org/10.1007/s00134019-05919-0 Gaudry S, Hajage D, Benichou N, Chaïbi K, Barbar S, Zarbock A, Lumlertgul N, Wald R, Bagshaw SM, Srisawat N, Combes A, Geri G, Jamale T, Dechartres A, Quenot JP, Dreyfuss D. Delayed versus early initiation of renal replacement therapy for severe acute kidney injury: a systematic review and individual patient data meta-analysis of randomised clinical trials. Lancet. 2020 May 9;395(10235):1506-1515. doi: 10.1016/S0140-6736(20)30531-6. Epub 2020 Apr 23. PMID: 32334654. Smith OM, Wald R, Adhikari NK, Pope K, Weir MA, Bagshaw SM; Canadian Critical Care Trials Group. Standard versus accelerated initiation of renal replacement therapy in acute kidney injury (STARRTAKI): study protocol for a randomized controlled trial. Trials. 2013 Oct 5;14:320. doi: 10.1186/17456215-14-320. PMID: 24093950; PMCID: PMC3851593. Bagshaw, S.M., Darmon, M., Ostermann, M. et al. Current state of the art for renal replacement therapy in critically ill patients with acute kidney injury. Intensive Care Med 43, 841–854 (2017). https://doi.org/ 10.1007/s00134-017-4762-8 DiMauro S, Schon EA. Mitochondrial respiratory-chain diseases. N Engl J Med. 2003 Jun 26;348(26):2656-68. doi: 10.1056/NEJMra022567. PMID: 12826641. http://www.sliderbase.com/spitem-618-1.html Falk L, Hultman J, Broman LM. Extracorporeal Membrane Oxygenation for Septic Shock. Crit Care Med. 2019 Aug;47(8):1097-1105. doi: 10.1097/CCM.0000000000003819. PMID: 31162206.

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Muller, L., Louart, G., Bousquet, P. et al. The influence of the airway driving pressure on pulsed pressure variation as a predictor of fluid responsiveness. Intensive Care Med 36, 496–503 (2010). https://doi.org/ 10.1007/s00134-009-1686-y Gavelli F, Shi R, Teboul JL, Azzolina D, Monnet X. The end-expiratory occlusion test for detecting preload responsiveness: a systematic review and meta-analysis. Ann Intensive Care. 2020 May 24;10(1):65. doi: 10.1186/s13613-020-00682-8. PMID: 32449104; PMCID: PMC7246264. Jozwiak M, Depret F, Teboul JL, Alphonsine JE, Lai C, Richard C, Monnet X. Predicting Fluid Responsiveness in Critically Ill Patients by Using Combined End-Expiratory and End-Inspiratory Occlusions With Echocardiography. Crit Care Med. 2017 Nov;45(11):e1131-e1138. doi: 10.1097/ CCM.0000000000002704. PMID: 28857907. Silva S, Jozwiak M, Teboul JL, Persichini R, Richard C, Monnet X. End-expiratory occlusion test predicts preload responsiveness independently of positive end-expiratory pressure during acute respiratory distress syndrome. Crit Care Med. 2013 Jul;41(7):1692-701. doi: 10.1097/CCM.0b013e31828a2323. PMID: 23774335. Guérin L, Teboul JL, Persichini R, Dres M, Richard C, Monnet X. Effects of Passive Leg Raising And Volume Expansion On Mean Systemic Pressure And Venous Return in Shock in Humans. Intensive Care Med Exp. 2015;3(Suppl 1):A16. Published 2015 Oct 1. doi:10.1186/2197-425X-3-S1-A16 Monnet X, Osman D, Ridel C, Lamia B, Richard C, Teboul JL. Predicting volume responsiveness by using the end-expiratory occlusion in mechanically ventilated intensive care unit patients. Crit Care Med. 2009 Mar;37(3):951-6. doi: 10.1097/CCM.0b013e3181968fe1. PMID: 19237902. Monnet X, Bleibtreu A, Ferré A, Dres M, Gharbi R, Richard C, Teboul JL. Passive leg-raising and endexpiratory occlusion tests perform better than pulse pressure variation in patients with low respiratory system compliance. Crit Care Med. 2012 Jan;40(1):152-7. doi: 10.1097/CCM.0b013e31822f08d7. PMID: 21926581. Michard F, Chemla D, Teboul JL. Applicability of pulse pressure variation: how many shades of grey?. Crit Care. 2015;19(1):144. Published 2015 Mar 25. doi:10.1186/s13054-015-0869-x Ospina-Tascón, G.A., Hernandez, G., Alvarez, I. et al. Effects of very early start of norepinephrine in patients with septic shock: a propensity score-based analysis. Crit Care 24, 52 (2020). https://doi.org/ 10.1186/s13054-020-2756-3 Marik PE, Linde-Zwirble WT, Bittner EA, Sahatjian J, Hansell D. Fluid administration in severe sepsis and septic shock, patterns and outcomes: an analysis of a large national database. Intensive Care Med. 2017 May;43(5):625-632. doi: 10.1007/s00134-016-4675-y. Epub 2017 Jan 27. PMID: 28130687.

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Chapter 5: Cardio-vascular Critical Care Chapter 5: Cardio-Vascular Critical Care

271

Atrial Fibrillation

272

Hemodynamic Management

276

Fluid Responsiveness

276

Vasopressor Therapy

278

Septic Shock Circulatory Failure Cardiogenic Shock

280 287 292

Revascularization

294

Ventricular Assist Devices

295

V A ECMO

302

Post Cardiac Arrest Management

307

271

Atrial Fibrillation Atrial fibrillation is one of the important causes of exacerbation of heart failure and hemodynamic instability. It has been incorporated in the famous mnemonic of "CHAMP" in deciphering the precipitants for Heart failure . C : Coronary event H : Hypertensive events A : Arrhythmia M : Mechanical causes P: Pulmonary embolism In the ICU , atrial fibrillation is common in cardiac patients , post-operative ( both cardiac and non-cardiac settings) and in sepsis. DC cardioversion is the treatment of choice if atrial fibrillation is responsible for hemodynamic decompensation. In stable patients and if atrial fibrillation is an epiphenomenon as occurs in the ICU , rate control is the preferred choice. If the rate control cannot be achieved even after the combination of drugs , rhythm control may be attempted . Rate control can be achieved by beta blockers , NDCC ( Non-dihydropyridine calcium channel blockers) , digoxin and Amiodarone. Target ventricular rate < 110/min ( lenient rate control) . Adequate rate control increases the ease of rhythm control. At times , rate control alone spontaneously reverts the rhythm to sinus.

272

Rate control : Rate control remains the preferred strategy in critically ill patients with atrial fibrillation . The first drug of choice is beta blockers . NDCC and digoxin can be added to beta blockers if the target ventricular rate is not achieved . Amiodarone should be considered as the last choice. Other rate limiting anti-arrhythmic drugs such as dronedarone and sotalol should be regarded only for rhythm control and not rate control. Beta blocker challenge can be considered to see if the patient would respond to beta blockers or not in the ICU patients . Short acting beta blockers such as Landiolol infusion can be started and heart rate observed in two hours, as the dose is gradually increased. An adequate response is defined as 20% decrease in heart rate in 2 hours . If the response is not adequate , other drugs such as digoxin or Amiodarone may be considered. Amiodarone can also be considered , if hemodynamic instability is severe and EF is very low , where the beta blocker administration is thought to worsen the circulatory function. Choice of drugs for rate control can be extrapolated from the standard cardiology guidelines, the summary of which is provided below. If no co-morbidity / HTN/ HFpEF : First choice : Beta blockers Second choice : NDCC or digoxin . If HFrEF : LVEF < 40% First Choice : Beta-blockers Second choice : Digoxin or Amiodarone If Severe COPD/Asthma : high risk of bronchospasm First choice : NDCC Second choice : Digoxin If Pre-excited AF/Afl : First choice : Ablation. Can combine any of the above drugs . However betablockers and NDCC may increase the risk of bradycardia or asystole and hence should be monitored. Beta blockers may be avoided in severe COPD or Asthma. Amiodarone may be considered in HFrEF. The third choice remains CRT-P/CRT-D or pacemaker with AV nodal ablation. Betablockers: Beta blockers remain the drugs of choice for rate control strategy in patients with either preserved or reduced ejection fraction. The advantages of betablockers include : Anti-ischemic Antiarrhythmic Anti –hypertensive Improves the structure and function of left ventricle Inhibits cardiotoxicity of norepinephrine Suspends cardiac cell apoptosis Suspends platelet accumulation Inhibits thromboxane production Reduces mechanical stress on atherosclerotic plaque Anti-oxidant property 273

NB : Norepinephrine infusion has shown to induce IL-6 production in macrophages , thereby exhibitng pro-inflammatory and pro-atherosclerotic effect. Drug – beta blockers

T1/2

β1:β2 selectivity

Landiolol

4 min

255

Esmolol

9 min

33

Atenolol

6-9 hours

4.7

Metoprolol

3-4 hours

2.3

Propranolol

3-4 hours

-8.3

Labetolol

5.5 hours

-2.5 ( α blocker too)

Bisoprolol

9-12 hours

13.5

Comparison of intravenous beta blockers used in ICU Beta blockers Intra- Onset venous

t1/2

Duration

Cardio-selective β1:β2

Effect

Landiolol

1 min

4 min

15 min

255:1

More HR depression than BP

Esmolol

1-2 min

9 min

10-20 min

33:1

Decreased HR and BP

Metoprolol

20 min

180-420 min

300-480 min

2.3

Decreased HR and BP

Choice of beta blocker is Landiolol because of high selectivity and shorter duration of action. Landiolol infusion can be considered in Acute heart failure, Septic shock and Post-op cardiac and non cardiac surgery patients. Landiolol ( eg Rapibloc) : Fast acting beta blocker with limited effect on BP. No significant effect on inotropy. The drug undergoes hydrolysis by plasma esterases and Carboxylesterases, thus having a short half-life . Further it can be safely used in renal , liver , cardiac and pulmonary failure. It has limited tolerance and rebound effect. It might have anti-inflammatory properties against lipopolysaccharide . Landiolol infusion has been shown to reduce the levels of TNF , IL-6 and HMGB-1. The dose of Landiolol can vary from 0.1 ug/kg/min to 40ug/kg/min. The intravenous infusion should start from the lowest possible dose and escalated gradually especially in septic shock patients. Lowest possible doses should also be considered in patients with EF < 40% , CI < 2.5 ml/min/M2 or NYHA class III or IV. Occasionally , the dose of norepinephrine may have to be increased. The infusion of Landiolol should be limited to 24-48 hours.

274

Rhythm Control : Rhythm control should be attempted , if target rate cannot be achieved with reasonable drug combinations or if symptoms persists. The choice of drugs for rhythm control includes : Normal EF : Class IC / class III Antiarrhythmic drugs Reduced EF : Amiodarone

275

Hemodynamic management Fluid responsiveness : Dynamic variables are recommended over static variables to predict fluid responsiveness. Dynamic variables are those that can quantify the slope of Frank-starlings curve to define preload responsiveness. There are two categories of dynamic indices :

Heart lung interaction indices Respiratory variation of Stroke Volume ( PPV/SVV) End expiratory occlusion test Tidal volume challenge

Passive Leg raising test Heart lung interaction indices work on the premise that the more the stroke volume ( or cardiac output) changes with Mechanical ventilation , the more likely that the patient's heart is preload responsive. Respiratory Variation of Stroke Volume : High PPV/SVV indicates fluid responsiveness. Low PPV/SVV indicates preload unresponsiveness. False positives PPV test : Spontaneous breathing , Irregular heartbeats , increased abdominal pressure. (Arrhythmia and Abdominal pressure) False negative PPV test : Spontaneous breathing , Low HR/RR ratio, Low tidal volumes, open thorax (Low and low) Arrhythmia may result in false positive PPV/SVV as the variation of pulse pressure is mainly related to the irregularity of the cardiac diastole ,irrespective of the respiratory cycle. PPV/SVV accurately predicts fluid responsiveness in patients with left ventricular dysfunction and sinus rhythm. In cases of increased intraabdominal pressure , if the PPV threshold is increased , it may predict fluid responsiveness. The predictive value of PPV test in patients with low lung compliance is poor. ( PLR or EEO test must be considered). PPV in Right Ventricular dysfunction : In right ventricular failure , the right ventricular stroke volume is thought to be related more to its afterload than preload . Mechanical insufflation of lungs may increase transpulmonary pressure by compressing intra-alveolar micro vessels increasing the afterload of the right ventricle. This would translate in to low stroke volume from the right ventricle and heightened PPV/SVV. Thus a high PPV occurs despite fluid unresponsiveness resulting in false positive PPV. This mechanism may dominate if the tidal volumes are higher than 8 ml/kg.

276

End expiratory occlusion test : EEO End expiratory occlusion for 15 seconds would cause transient increase in venous return and preload. This increase in preload increases stroke volume only in preload responders. This can be detected by increase in CO . Significant increase in Cardiac output as measured by pulse contour analysis is 5%. The EEO test works in : Cases of inspiratory efforts with spontaneous breathing activity (while on mechanical ventilator) Patients with low lung compliance ( < 30 ml/cm H20) Patients with low tidal volume ( < 7 ml/kg) Works independent on the level of PEEP ( up to 14 cm H20) Limitations : Patients inspiratory efforts should lead to triggering the ventilator (occur in 20% of patients) Precise and real time CO measurement is mandatory (detecting 5% requires highly sensitive test such as pulse contour analysis or PICCO. NB: Echocardiography has poor precision with "least significant change" for Velocity-time integral (VTI, a surrogate of CO) is around 10%. If Echocardiography is used for predicting fluid responsiveness , then "Combined end expiratory and end inspiratory occlusions" must be performed , where the cut off value is 13%. Tidal Volume Challenge : Low tidal volume ventilation can have a false negative impact on PPV/SVV due to low driving pressure. Tidal volume challenge consists of a transient increase ( 1 min) in tidal volume from 6 to 8 ml/kg. PPV & SVV is estimated at 6 ml/kg and at 8 ml/kg of tidal volume . Then ΔPPV6-8 is calculated. ΔPPV 6-8 = PPV at 8 ml/kg TV – PPV at 6 ml/kg TV . Cut off is significant at 3.5 %. Delta PPV > 3.5 = Fluid responsiveness. The advantage of tidal volume challenge is the feasibility to continue low tidal volume ventilation ( except during the transient measurements) and the need for only arterial line. ( no need of CO monitoring ).

277

When to initiate Vasopressors : Mean systemic pressure (Psm) is defined as the venous pressure at which there is no venous return , as this pressure will be equivalent to right atrial pressure and hence no gradient. Mean systemic pressure is the upstream pressure for venous return and depends on blood volume and venous tone.Fluid infusion increases mean systemic pressure whether the patient is fluid responsive or not. This increase in mean systemic pressure translates to increase in Cardiac Output only in a fluid responder. Psm – CVP : Venous pressure gradient increases in fluid responders . This is because , cardiac output tends to decrease CVP. The Venous pressure gradient does not change in fluid non responder. The increase in Cardiac output decreases sympathetic tone and the increased flow triggers arteriolar NO secretion causing vasodilation ( "Flow dependent vasodilation"). Hence SVR decreases when CO increases after fluid therapy. MAP increases only if increase in CO exceeds the decrease in SVR. Vasopressors such as Nor epinephrine increases venous resistance and despite this , venous return increases through an increase in mean systemic pressure probably related to blood redistribution from unstressed to stressed volume. This may be advantageous because unstressed volume is abnormally increased during sepsis and can be overfilled further by fluid loading. Norepinephrine increases all markers of preload such as CVP , LVEDA , E wave and GEDV. Nor epinephrine increases CO in preload dependent patients. It reduces the degree of preload dependency or in other words, imposes a synergistic effect on volume expansion to a venous return.

278

Fluid Infusion in a fluid responder : Increases Psm Increases CO Decreases SVR MAP increases if CO increase > decrease in SVR MAP decreases if CO increase < decrease in SVR MAP remains the same if CO increase = SVR decrease . Adding Vasopressor such as Nor epinephrine : Increases Psm Increased venous return Increases CI Increase in SVR Increase in GEDVI Decreases PPV Increase in MAP. Hence it is recommended to initiate vasopressors very early in sepsis ( probably in the first 1 hour). Combination of fluids and vasopressors in sepsis increases mean systemic pressure, increases venous return and Cardiac output in preload dependent patients. Addition of norepinephrine increases SVR there by elevating MAP even further. The potential advantage of starting norepinephrine is limiting fluid overload and therefore tissue edema. It has been observed that patients who received > 6 liters of fluids the first day had higher mortality rate . Fluid infusions can cause hemodilution and limit oxygen delivery . Very early combination of fluid therapy and Nor epinephrine has been shown to improve outcomes with lower incidence of cardiogenic pulmonary edema and lower rates of new onset cardiac arrhythmia. Vasopressors should be started early in septic shock even before the completion of fluid resuscitation. This may be true in shocks with both hypovolemic and vasodilatory components such as Septic and hemorrhagic shock.

279

Septic Shock Shock is a clinical expression of circulatory failure that results in inadequate cellular oxygen utilization. Epidemiology of types of shock in Intensive Care : Distributive – Septic : 62% Distributive – Non septic : 4% Cardiogenic : 16% Hypovolemic : 16% Obstructive : 2% Main mechanisms of septic shock include: Vasoplegia Ventriculo-arterial decoupling Capillary leakage Micro circulatory dysfunction

Concept of Vasoplegia: Vasoplegia is considered to be the main pathophysiology in septic shock. Refractory vasodilatory shock is defined as impaired responsiveness to catecholamines. Mortality in refractory vasodilatory shock is up to 60%.Many mechanisms have been proposed to explain the refractory vasodilatory state . These include : 1. Overproduction of reactive oxygen species causing endothelial and mitochondrial dysfunction . 2. Circulating factors result in uncontrolled production of NO and PGI2muscle .Dysregulated nitric oxide metabolism can cause activation of ATP sensitive potassium channel resulting in membrane hyperpolarization and vascular smooth muscle relaxation. 3. Altered microcirculatory flow coupled with dysregulated mitochondrial respiration may lead to tissue hypoxia and acidosis that activate ATP sensitive potassium channel. 4. The presence of hyperglycemia , hypocalcemia and corticosteroid deficiency may impair the responsiveness to catecholamines. 5. Most septic patients can have Vasopressin and angiotensin II deficiency.

280

Ventriculo-arterial coupling : It describes the dynamic adaptation of the systolic function of each ventricle to the afterload. That is the mechanical contraction of the heart seems to adapt to the afterload of the vascular system to make the cardiac contraction efficient . The heart seems to pump blood in to the arterial circulation at a rate and at such volume that the arterial system is able to handle smoothly , so that cardiac energetics are optimal. If the heart is unable to adapt to a change in afterload , it has been called as Ventriculo-arterial decoupling and is often considered as a consequence ( perhaps even cause )of the "failing" heart . Ventriculo-arterial coupling can be detected by the ratio of arterial elastance to the ratio of ventricular elastance . Ventricular elastance : Also "End systolic pressure volume relationship". (Ees) Think of it like a intrinsic ionotropic state. Appreciation of pressure volume loop is helpful in understanding the concept of ventricular elastance. Normal Pressure Volume loop of left ventricle

Figure : Analysis of Pressure Volume Loops. The Theoretical Pressure-Volume Loop Shown Describes the Normal Cardiac Cycle. Following aortic valve (AV) closure (1), isovolemic contraction occurs (1 -2) as ventricular pressure decreases below atrial pressure. The duration of this phase is represented by Tau. The mitral valve (MV) then opens contemporaneously with atrial systole, filling the ventricle (2 -3). Systole then commences with isovolemic contraction (3 -4) until ventricular pressure exceeds diastolic arterial pressure, at which time the AV opens. Stroke volume is the difference between lines 1 -2 and 3 -4. Stroke work is the area within the 1 -2 -3 -4 curve. ESPVR has also been termed as Ees ( Ventricular elastance). The steeper the slope, the greater the contractility . Ees (mm Hg/ml) is a useful, load independent index of myocardial contractility and LV inotropic efficiency (end-systolic LV stiffness)

281

Arterial Elastance : Think of it like an afterload or the capability of the arterial vessels to increase pressure when LV stroke volume increases. Arterial elastance is the ratio of end systolic pressure and stroke volume. Ea = ESP/SV Efficiency of Ventriculo-arterial coupling : Ea/Ees ratio : 0.8 to 1.3 = Optimal efficiency ( normally elastance of LV equal to arterial elastance) Ea/Ees ratio > 1.3 = failing heart ( decrease in contractility , increase in arterial elastance) The concept of ventriculo-arterial coupling is important because ,when the ventriculo-arterial coupling ( VAC) is normal , the PV loop is such that the myocardial O2 consumption is optimized .

Concept of potential energy and Stroke work of left ventricle

Figure : Left ventricular pressure-volume curve. Myocardial energy is the sum of external work (namely, stroke work) and elastic potential energy . DBP diastolic blood pressure, EDP end diastolic pressure, EDPVR end-diastolic pressure-volume relationship, EDV end-diastolic volume, ESP end-systolic pressure, ESPVR end systolic pressure-volume relationship, PE potential energy, ESV end systolic volume, SBP systolic blood pressure, SV stroke volume, SW stroke work.

282

Pressure Volume Area (PVA ) = SW + PE. PVA strongly correlates linearly with myocardial oxygen consumption per beat ( MVO2) . Myocardial oxygen consumption is determined by Potential energy ( basal metabolism) Stroke work ( calcium cycling) Mechanical Work Increasing contractility increases myocardial O2 consumption by increasing stroke work. Energy transfer : The efficiency of energy transfer from the ventricle to the arterial system is represented by EW (external work) to PVA (pressure volume area)

Figure : Schematic of pressure-volume (P-V) relations of left ventricle (left panel) and P-V area (PVA) (right panel). Three P-V loops of ejecting contractions are shown in the left panel. The solid circles at the left upper corners of the loops are the end-systolic P-V points. The line through these points is the endsystolic P-V line, and its slope is Ees. Diastolic P-V curve consists of the diastolic segment of these P-V loops. Effective arterial elastance, Ea, is the slope of end-systolic pressure-stroke volume(P-SV) relation. The origin of the relation line, that is, its volume axis intercept, is a given end-diastolic volume. The stroke volume is represented on this ventricular volume axis as a distance to the left of this intercept. When the ventricle is coupled with the arterial system, the equilibrium is determined as the intersection between the arterial end-systolic P-SV line and the ventricular end-systolic P-V line. PVA is the area in the P-V diagram that is circumscribed by the end-systolic P-V line, the end-diastolic P-V relation curve, and the systolic segment of P-V trajectory (E-A-B-C-E, right panel). PVA consists of the external work (EW) performed during systole and the end-systolic elastic potential energy (PE) stored in the ventricular wall at end systole. EW is the area within the P-V loop trajectory (A-B-C-D-A), and PE is the area be tween end-systolic P-V line and end-diastolic P-V relation curve to the left of EW (E-C-D-E).

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Energy transfer efficiency = EW / PVA EW/PVA = 1/ [1+ (Ea/Ees)/2]. This formula implies that work efficiency is a function of basal ionotropic state ( Ees) and afterload ( Ea) . Any change in elastances of ventricle or arterial system can affect the myocardial O2 consumption and performance .

Figure : The rise in pressure within the arterial system with an increase in arterial volume (equals the decrease in ventricular volume). Compared with the healthy state (top panel), a decrease in ventricular elastance and an increase in arterial elastance mean that more energy is wasted on the PVA diagram. LV left ventricular, P-V pressure–volume. The management of critically ill patients with acutely altered hemodynamic states may benefit from the assessment of V A Coupling . Changing Ees , Ea or both leads to change in VAC and stroke volume . Bed side evaluation of Ea/Ees by echocardiography is one such tool .

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Figure : The left ventricular (LV) P-V loop. The P-V loop area is highlighted in blue. The slopes of LV elastance (Ees) and arterial elastance (Ea) are shown. ESV: end-systolic volume; ESP: end-systolic pressure; EDV: end-diastolic volume; EDP: end-systolic pressure.

Figure : Echocardiographic measurements of left ventricular (LV) time intervals ( left ) and LV ejection fraction (EF, right ). The white arrow indicates the beginning of the QRS complex, the dark blue arrows indicate the aortic valve opening and closure. The light blue lines show the time interval measurements. Since end-systolic arterial pressure occurs slightly after peak systolic pressure is achieved, Ea can be calculated as 0.9 × systolic arterial pressure/stroke volume, where 0.9 × systolic arterial pressure equals LVESP. A calculator is available to measure the ventricular and arterial elastance at the bed side by inputting the values such as Systolic BP , diastolic BP , Stroke Volume , Ejection fraction , pre-ejection time and total ejection time .

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VA coupling in Septic Shock : In Septic shock , cardiovascular efficiency is impaired, and the Ea/Ees becomes uncoupled (Ea/Ees > 1) due to increase in Ea ( norepinephrine induced vasoconstriction) and decrease in Ees ( reduced myocardial contractility). The cardiac energetics therefore are unfavorable and are often sacrificed to maintain tissue perfusion. Therapeutic approach with fluid administration, inotropes and vasoconstrictors aiming to normalize the coupling while maintaining tissue perfusion may be preferable. For example ,the use of levosimendan has been suggested for the treatment of myocardial dysfunction associated with septic shock by examining the myocardial energetics. VA coupling of right heart : RV V-A coupling expresses the optimal interaction between RV performance and function of the pulmonary vascular system. When Ees decreases (RV acute myocardial infarction, septic shock) or Ea increases (pulmonary hypertension, acute respiratory distress syndrome [ARDS]), the right side of the cardiovascular apparatus becomes uncoupled. In failing heart , Levosimendan seems to enhance coupling of the right ventricle and pulmonary arterial circulation. Rather one of the algorithm for management of cardiovascular failure included "The Beat Approach". Browse the heart ( by echocardiogram) Elastances ( both ventricular and arterial) Assess volume status ( by dynamic indices or PLR) Treat according to pathophysiologic approach Based on this approach : If PLR increases stroke volume : Give Volume If PLR does not result in significant increase in stroke volume : Look at VAC . VAC < 1 : Ees > 2 , Ea < 2 : Vasopressor ( goal is to increase arterial elastance) VAC < 1 : Ees < 2 , Ea /, 2 : inotrope . ( goal is to increase the inotropic state of heart) VAC > 1 : Ees < 2 , Ea > 2 : Inodilator ( increase inotropic state of heart , also vasodilation) VAC > 1 : Eea =2 , Ea >>2 : Vasodilation ( goal is to decrease arterial elastance)

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Circulatory failure Typical circulatory failure is characterized by Low MAP Low CO Low or high SVR High HR Low Urine Output Low SvcO2 / SVO2 Increased lactate Increased BNP Hemodynamic Monitoring is done by : Pulse contour analysis Thermodilution Bioimpedance Esophageal Doppler LIDCO In patients with circulatory failure, hemodynamic monitoring should be done to determine the predominant physiology. Establishing a blood pressure target is vital in designing a plan for hemodynamic management. Personalized Blood pressure targets : Critically ill patients are heterogenous and significant heterogeneity exists with in shock itself . Unique pathophysiology exists in an individual patient that depends on the etiology of shock, age , co-morbidities , organ specific vascular bed dynamics and pharmacogenomics. All these determine a particular target blood pressure for an individual patient. Probably not MAP , but MPP ( mean perfusion pressure ) should be the target. Some considerations : Increasing MAP beyond 65 has not been demonstrated to improve lactate clearance , urine output , capillary blood flow , pCO2 gap and mortality. Increasing MAP with norepinephrine has been demonstrated to increase cardiac index , heart rate , but no effect on lactate. Higher MAP does not necessarily mean better GI perfusion . Adding Vasopressin to norepinephrine increased the MAP , but decreased perfusion to stomach as measured by gastric tonometry, whereas methylene blue raised MAP, without compromising flow to the stomach. It must be appreciated that different vasopressors have different effects on gastrointestinal perfusion. Patient who had single nucleotide polymorphism (SNP) in the vasopressin receptor gene have more significant adverse effects , conforming that pharmacogenomics may play a role in response and adverse effects with an individual drug.

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Fluid boluses given for hypotension in critically ill patients has been shown to increase MAP modestly with a value of 7.8 mm HG, the effect lasting only for 1 hour. The blood pressure response to a fluid bolus is usually small and short lived. Higher MAP target ( 80-85 mm HG) in chronic hypertensives decreases adverse renal outcomes including RRT. Although there is no need to routinely target high MAP in patients with septic shock , in chronic hypertensives , high MAP may decrease the risk of AKI and need for RRT. However , higher MAP may be associated with more atrial fibrillation especially with nor epinephrine. It has also been observed that mean perfusion pressure ( MPP = MAP- CVP) in almost all critically ill patients is lower than MPP at pre-morbid level for the same mean arterial pressure. This lower MPP , called as "relative hypotension" may be a risk factor for adverse kidney related outcomes. It has been observed that for every 1 % of time weighted average MPP deficit , the odds of adverse kidney events ( MAKE-14 score) was more than 5.5 %. It may be prudent to target MAP ( rather even better MPP ) to pre-morbid level. Permissive hypotension in elderly with reduced exposure to vasopressor may have survival benefit . In elderly patients with no chronic hypertension or patients with cirrhosis , lower MAP target may be considered as long as adequacy of perfusion is monitored in important sites ( Brain , skin and kidney) . Vasopressor therapy : Vasopressor therapy should be started if MAP is below target and signs of hypoperfusion present despite fluid administration or in a vasoplegic state. One clue to the presence of vasoplegic state is diastolic blood pressure < 60 mm Hg. Vasopressor therapy may be started in conjunction with fluids if needed, not necessarily after fluid therapy. Vasopressors that cause increase in heart rate by 15% has been demonstrated to exhibit trend towards increase in mortality and those that decrease heart rate by 10-20% or neutral to heart rate shows trend towards decrease in mortality. Nor epinephrine is the drug of choice . Second vasopressor may be considered , if the dose of norepinephrine is maxed out ( e.g 30 ug/min or 0.25 ug/kg/min), although in some parts of world , there is no maximum dose of nor-epinephrine. Vasopressin is the second drug of choice and can be considered for escalating doses of nor-epinephrine. It is possible that very early use of Vasopressin might improve microcirculation and have beneficial effect on kidney outcomes especially if tachycardia. Survival benefit was demonstrated if vasopressin was added to nor epinephrine esp in lower severity of illness ( low APACHE scores) and less incidence of new onset atrial fibrillation in distributive shock. A third vasopressor is angiotensin II. Norepinephrine : High doses of nor-epinephrine has been linked to increased mortality by oxidative stress , immunomodulation and myocardial injury. Nor epinephrine has been shown to dysregulate immune responses and compromised host defense during sepsis unlike Vasopressin. Mechanism of action: NE stimulates Alpha receptor ( Gq family) - > *phospholipase C ( PIP2 + IP3) -> increases cytosolic Calcium -> Ca/ Calmodulin - > MLC kinase -> Actin/MLC kinase =contraction. Infact any increase in cytosolic Calcium increases calcium influx from ECF via VSCC( channel) Alpha receptor activation : increases Protein kinase C -> increased NF-kB -> pro inflammatory cytokine 288

gene transcription -> increased TNF a , IL-6 , IL-1 b. Beta receptor activation : Increased cAMP -> protein kinase A -> decreases NF-kB -> decreased pro inflammatory cytokine gene transcription -> decreased TNF-a , IL-6 and IL-1b and increased IL-10. Angiotensin : Mechanism of action : * AT1 receptors ( Gq) -> stimulates ( *) Rho A/Rho kinase-> inhibits MLC phosphatase , which indirectly stimulates MLC kinase -> actin/MLC-P = contraction . Metaraminol : May be given in peripheral line , however should not be considered as the first line. Methylene Blue : It is a vasopressor prescribed in refractory shock patients. Methylene blue infusion when added to norepinephrine does not cause decreased perfusion to the stomach unlike Vasopressin . Vasopressin :

Figure : Physiological effects of vasopressin. AVP Arginine Vasopressin, AQP2 Aquaporin 2. Vasopressin is synthesized in the hypothalamus and circulates along axons of magnocellular neurons to the post-pituitary gland. After stimulation, vasopressin is released into blood circulation, to 3 receptor subtypes. Binding on V1a receptors induces vascular smooth cell contraction in the periphery and on renal efferent arteriole and platelet aggregation. Vasopressin binding on renal V2 receptors causes aquaporin 2 recruitment, leading to water re-absorption and on extra-renal V2 receptors induces the release of coagulation factors. Binding on V1b receptors induces corticotropic axis stimulation and insulin secretion. During septic shock, vasopressin plasma level is low. Administration of vasopressin or its analogues induces a strong vasoconstriction, leading to an increase in blood pressure, and higher glomerular filtration rate. 289

Mechanism of Vasopressin : Vasopressin * V receptors ( Gq) -> * Phospholipase -> calcium/ calmodulin -> MLC kinase V1 receptor : Vasoconstriction V2 receptor : Water retention in kidney V3 ( V1b) receptor : stimulates endocrine cell to release ACTH and hence increases cortisol levels Indications of Vasopressin : Distributive shock Septic shock Vasoplegic shock after cardiac surgery Cardiogenic shock : Right ventricular failure , Aortic stenosis Hemorrhagic shock : patients receiving blood transfusion Vasopressin in septic shock :No effect on mortality ( or may be slight reduction in less severe critically ill patients with low APACHE II score) or serious adverse events . Fewer arrhythmia (atrial fibrillation) and more digital ischemia ( non-disabling) , mesentric ischemia ( measured by gastric tonometry) was noted. Vasopressin up to 0.03 u/min or epinephrine can be added to norepinephrine with the intent of rising MAP to target or to decrease the dose of Norepinephrine dosage. Vasopressin unlike norepinephrine does not dysregulate immune system. In addition , Vasopressin allows de-catecholaminisation during sepsis . This decreases many potential complications secondary to the use of catecholamines. Vasopressin deficiency has been documented in the late phase of septic shock. In summary Vasopressin is septic shock may reduce AF , AKI incidence , RRT and possibly mortality. Catecholamines use in sepsis is associated with : Myocardial injury Arrhythmia Impaired immune response Impaired splanchnic function Coagulopathy microcirculation Vasopressin in Vasoplegic shock after cardiac surgery : Vasopressin has higher survival rates , less severe complications including atrial fibrillation when compared to norepinephrine. Vasopressin in cardiac surgery , even when not in shock reduced many different peri-operative complications that include AKI , Vasodilatory shock , new onset tachyarrhythmia , mesenteric ischemia , digital ischemia , myocardial infarction , stroke , hyponatremia , water intoxication , hepatic insufficiency and right heart failure. Vasopressin in Cardiogenic shock : Because of lack of inotropy , vasopressin should not be used as a first line agent. Vasopressin may be advocated during right ventricular failure as it does not lead to increase in pulmonary arterial pressure, as there are no vasopressin receptors in pulmonary circulation. Also in shock caused by aortic stenosis , which is an afterload dependent state in which inopressor agents are not indicated if LVEF is preserved , Vasopressin may be considered. Vasopressin in Hemorrhagic trauma patients : Vasopressin at low doses such as 0.04U/min decreases the need for blood transfusion. 290

Terlipressin is vasopressin analogue with long half-life is not recommended due to serious adverse events. One of the protocol for septic shock / Pulmonary hypertension that is often used is exemplified by the following : Starting Vasopressors : Adequate fluid resuscitation : RL @ 30 mls/kg given in < 3 hours. Monitoring via PICCO/ US/ PLR. Start Noradrenaline . If dose of NA is 0.1 ug/kg/min : start steroids If dose of NA is > 0.25 ug/kg/min : do not increase further , go to step 2 if MAP not achieved Start Argipressine @ 0.01IU/min . Increase Q 15 min by 0.01 IU/min until target. Max is 0.03. Weaning Vasopressors : First lower Noradrenaline gradually until 0.1 mcg/kg/min. Continue Noradrenaline at 0.1 mcg/kg/min. Then go to Step 2 , if MAP is sufficient . Taper Argipressine . Decrease Q 60 min by 0.01 IU/min , until stop infusion . This slow weaning is because of "rebound hypotension" seen after interruption of Argipressine. If the patient goes in to hypotension , Argipressine is restarted or dose increased to 0.03 IU/min.

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Cardiogenic shock Recently, Society for Cardiovascular Angiography and Intervention (SCAI) has proposed five stages of cardiogenic shock.

Figure : SCAI stages of cardiogenic shock. SCAI : Society for Cardiovascular Angiography and Intervention

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Figure : clinical identification of SCAI stages Severe heart failure not only causes macro-circulatory dysfunction , but also can cause micro-circulatory dysfunction. Micro-circulatory dysfunction in patients with severe heart failure may present with four states of alterations . These include : Heterogeneity Hemodilution Constrictive tamponade Edema Heterogeneity : Heterogenous red blood cell ( RBC flow) , where flowing RBCs carry Oxygen and local stagnant RBCs both exist and correspondingly tissue cells receive oxygen or not. Hemodilution : A reduction in oxygen carrying capacity of the micro-circulation due to hemodilution Constrictive tamponade : Global stagnation in RBC flow in the microcirculation due to arterial vasoconstriction ( increased vascular resistance) and raised venous pressure. Edema : Increased Oxygen diffusion distances due to tissue edema. The amount of viable cardiomyocytes is reduced and therefore decreased contractility and increased LV end diastolic pressure and end diastolic volume. The goal of treatment is to protect the remaining cardiomyocytes by lowering the pressures , heart rate , reducing O2 consumption.

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Revascularization : Most patients who present with Cardiogenic shock have multi-vessel CAD. Nor-epinephrine is the vasopressor of choice over dopamine / adrenaline. Most mortality occurs in the first one month of presentation. Early revascularization reduces mortality. A culprit lesion is defined as the lesion involved in the initial AMI, and a non-culprit lesion as any lesion in the entire coronary tree outside the culprit lesion. Culprit lesions should satisfy at least 2 of the criteria of intraluminal filling defect, plaque ulceration, plaque irregularity, dissection, or impaired flow. Revascularization options include : Culprit lesion PCI only Culprit lesion PCI + staged Revascularization CABG Immediate MV-PCI ( Multi vessel PCI) Culprit lesion only reduces all-cause mortality and renal replacement therapy when compared to immediate multi-vessel PCI and this remains at least until 1 year. Staged revascularization may be considered if the patient with Angina Severe Disease Ongoing Ischemia The best option for cardiogenic shock may be "Culprit lesion PCI + staged revascularization" . The possible exceptions to this include : No identifiable culprit lesion > 1 culprit lesion High grade stenosis with reduced flow

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Ventricular assist devices (VAD) Different configurations exist : These include pulsatile, total artificial heart, rotatory ( axial and centrifugal)

Pulsatile : Physiology : Blood ejected by a mechanical pusher plate either pneumatically or electrically Examples : Berlin Heart Excor Heart Mate XVE Thoratec PVAD WorldHeart , Novacor Thoratec IVAD Abiomed AB 5000 Medos HIA WorldHeart , Heart Saver

Figure : First-generation LVAD. ( A ) Diagram of HeartMate I. ( B ) Chest radiograph of implanted HeartMate I.

TAH (Total artificial heart) : CardioWest Abiomed, AbioCor

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Rotary – Axial : Physiology : Blood propelled by impeller blades on a rotor, rotated parallel to blood flow producing a continuous or semi-pulsatile blood pressure wave. Examples include : Impella , Abiomed MicroMed De Backey Berlin Heart Incor Jarvik 2000 Heart Mate II

Figure : Heartmate II

Rotary- Centrifugal : Physiology : Blood propelled by centrifugal forced by a miniature / Paracorporeal device , in which the blood is spinned in a circular motion using a rotating disk producing continuous or semi-pulsatile blood pressure wave. Examples : Tandem Heart Heart Mate III VentraCor Terumo DuraHeart Arrow CorAide Levitronix (Centrimag) ECMO 296

Figure : HeartMate III (Miniatured Centrifugal device)

Figure : CentriMag (Levitronix, Zurich, Switzerland) temporary implantable VAD

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Hemodynamic Changes associated with Mechanical Circulatory devices. Continuous blood flow devices ( Rotary : Axial or centrifugal) : The hemodynamic changes can be described in terms of macro and micro hemodynamics. Macrohemodynamics : As the pump speed increases from Pump off to 12,000 rpm : Systolic pressure remains same Diastolic and hence mean blood pressure increases This reduces pulse pressure and pulsatility is therefore low. One of major complications of MCS without transpulmonary blood flow is LV stasis and thrombosis. This complication is detected early by advanced hemodynamic monitoring and hence should be employed. Rather , outside OR , MCS without transpulmonary blood flow is not helpful. There is no agreement on the optimal method of hemodynamic monitoring in assessing and treating patients in cardiogenic shock, including pulmonary artery catheterization. Patient monitoring at a minimum during MCS should include : ACT every 4-6 hours Echo every 8 hours (LV,RV,IVC, ? AR/MR, LV thrombus, cannula and Impella position) Free Hb daily Full labs daily Volume management Reduce catecholamines ECG, Oximetry, Urine output, Chest X ray Invasive blood pressure and ABG PA Catheter Vascular access sites Use of PA catheter in cardiogenic shock especially on mechanical circulatory support is independently associated with survival benefit, as it may not only define hemodynamic targets , but also warn the potential evolution of impending right heart failure. During MCS ( eg. Impella ) , depending on the flow , Ventricular Vascular uncoupling may lead to dampened aortic pulse wave configuration and hence pulse wave plethysmogram derived hemodynamic parameters ( PICCO) may not be relied up on. Similarly , thermodilution derived cardiac output is a poor surrogate of cardiac output when the patient is on ECMO rather than Impella. Cardiac power is the strongest hemodynamic correlate of mortality in cardiogenic shock .Cardiac Power Output (CPO) along with number of inotropes and lactate levels predict outcome including in hospital mortality. Increasing age and female gender are independently associated with lower cardiac power. CPO = MAP * CO / 451. Higher than 0.6 was associated with survival.

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PCWP and CVP indicates LAP and RAP which are surrogates of preloads, must be taken in to consideration during volume management. Pulmonary artery pulsatility index (PAPI) is helpful in determining right ventricular failure. PAPI = (PA sys – PA dia) /CVP or Pulmonary pulse pressure/ CVP Hemodynamic variable

No RVF

RVF

Severe RVF

CVP

/= 15 mm HG

CVP/PCW

0.8

PAPI

>/= 2

0.8 SVR < 1500 MAP >/= 70 . Indicators of right heart failure ( eg . In patients on Impella CP support ) High PCWP , High CVP Low- normal PA mean , Low MAP Low PAPI and Low CPO. In the presence of right heart failure in patients on Impella CP , consider VA ECMO , Impella 5.5 or Impella RP , that either support right heart or increase the flow.

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Microhemodynamics Correction of global hemodynamic parameters ( macro-circulation) by rotary VADs does not always cause a parallel improvement in microcirculatory perfusion of organs as it famously said the loss of hemodynamic coherence between macro and micro circulation. The disagreement between macro and micro circulation may determine the inefficiency of targeting higher Oxygen delivery. This may be because the factors that control blood flow in macro and microcirculation are entirely different . Macro-circulation

Micro-circulation

Blood flow ( MCS rpm)

Myogenic factors Strain and stress forces

Native heart ( small amount)

Metabolic factors pH,pCO2,Lac,K,pO2,NO,ATP

Preload

Hemorheology RBC flow and deformability

Afterload

Neuro-harmonal control

Table : Factors controlling macro and micro circulation Monitoring macro-circulation is not the same as monitoring micro-circulation. In addition , Implantation of VAD or mechanical circulatory support leads to a complex response in the recipient organism leading to microcirculatory dysfunction and multi organ failure . Major mechanisms of microcirculatory dysfunction includes : Inflammatory response Coagulation disorders Hemodilution Intravascular sludging Pulseless flow Increased Peripheral resistance Assessing tissue perfusion in patients on mechanical cardiac support is essential to avoid "Low Output Syndrome", which remains one of the leading causes of death after VAD implantation. Some surrogates for tissue perfusion include : Lactate/ SvO2 or ScVO2 PCO2 gap , PCO2/da-vO2 Mottling score, Capillary refill time Each of them has limitations , in addition , they do not provide direct visualization of microcirculation. Direct visualization of microcirculation can be assessed by handheld microscope (SDF device). Sublingual microscopy may reveal decrease in density of small vessels , sluggish or no blood flow. Micro-circulatory recruitment and hemodynamic coherence has been co-related with survival in patients on mechanical circulatory device. By side stream dark field imaging , it has been demonstrated that implantation of continuous mechanical circulatory devices in severe heart failure patient improves Perfused capillary density, Capillary red blood 300

cell velocity ,Tissue perfusion index (PCD x cRBCv) immediately and the benefit is sustained at least for 24 hours. Microcirculatory blood flow is extremely dependent on ECMO support in severe heart failure. High blood flows exhibit good hemodynamic coherence with recruitment. As the blood flow increases from 1 to 5 L/min , micro circulatory flow increases. Lower than optimal flows may have inefficiency of targeting higher Oxygen delivery. There is a growing trend towards the positive impact of pulsatile flow in terms of microcirculation based on the observation of different flow patterns generated using an LVAD. Pulsatile flow ( high shear stress) -> NO release -> recruitment of additional capillaries Semi-pulsatile flow ( medium shear stress) -> less intense release of NO -> less recruitment Non pulsatile ( low shear stress) -> less NO release -> even lesser recruitment of micro circulation The oscillatory shear stress in the microcirculation is responsible for the release of endothelium derived relaxing factors viz NO. Hence , improvement in microcirculation and tissue perfusion is expected if a pulsatile flow is added to rotary MCS. With the premise that ECMO would support systemic circulation and maintains hemodynamic stability , while providing gas exchange, where as IABP creates a pseudopulsatile blood flow which is converted in to surplus hemodynamic energy ( SHE) , the study of adding IABP to ECMO did not demonstrate any significant impact on microcirculatory parameters, however this may not be the ultimate conclusion as microcirculation was evaluated 6 days after MCS , by then microcirculation would have improved already. In addition , the continuous flow time ( IABP off) was very short and the baseline microcirculatory variables were in near normal range. Monitoring microcirculation coupled with systemic hemodynamics in patients on MCS may provide relevant information on tissue perfusion and may have prognostic significance. However there are limitations. Parameters obtained by hand held microscope have no clearly defined target values . Furthermore , there is limited availability of therapeutic interventions specifically targeting the microcirculation.

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V-A ECMO for refractory cardiogenic shock: VA ECMO supports both lungs and heart. However ECMO has differing response to different degrees of heart failure. VA ECMO does not unload the diseased heart. Major complication of ECMO is Left Ventricular stasis and thrombosis, that may be detected by advanced hemodynamic monitoring. As blood flow increases in ECMO : In case of Healthy Heart : Systolic wall stress decreases LVEDP increases End systolic volume decreases End diastolic volume decreases In case of Heart Failure : Systolic wall stress increases massively LVEDP increases Ens systolic volume decreases End diastolic volume decreases

Indications : 1. 2. 3. 4. 5. 6. 7. 8.

Escalating need for inotropes Deteriorating neurological status Evidence of rapid cardiac deterioration : Nausea, abdominal pain , altered conscious , skin mottling Tachycardia, rhythm disturbance , Ionic disturbance, acidosis Hepatic / renal failure Doppler Echocardiography with low CO ( Ao VTI < 7-8cm ) "Extremis" SCAI stage of cardiogenic shock esp after Acute MI, dilated cardiomyopathy ( bridge to transplant) , fulminant myocarditis , post cardiotomy patients . ( Cheaper , easier to set up , more versatile when compared to expensive implantable VADs) . 9. As a bridge to heart transplant . 10. ECMO for Septic shock and severe LV failure. (Sepsis induced cardiogenic shock) 11. Catastrophic Pulmonary embolism ( severe shock , inadequate perfusion , high lactate , peri-arrest). Other potential indications of ECMO in Pulmonary embolism include : As a part of resuscitation in cardiac arrest PE patients To stabilize severe hemodynamic compromise (before or after catheter or post-surgical embolectomy) Failed or contraindication to systemic thrombolysis Failed catheter based clot extraction As a definitive therapy until clot resolution (via heparin or endogenous.

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ECPR : ECMO for refractory cardiac arrest (Extracorporeal CPR) Younger patients ( upper age limit not established , ? < 70 years) Witnessed Cardiac arrest , no flow time < 5 minutes , bystander CPR Cardiac arrest of presumed cardiac origin ( initial shockable rhythm) Efficient CPR ensured , EtCO2 > 10 mm HG under CPR Collapse to ECMO time < 50-60 min.

Timing of ECMO : Early initiation may have a better outcome (with in 24hours of hypoperfusion) . Higher lactate levels at the initiation of ECMO portends a poor prognosis.

Configuration : Patient tailored Hybrid configuration had better hemodynamics than the traditional one. Traditional ECMO cannulation was associated with changes in patients' conditions or the occurrence of specific complications (i.e., cerebral hypoxia or left ventricular dilation) that require modifications in cannulation strategies or additional modification of ECMO. "Hybrid" approaches have been proposed such as the addition of a third or fourth ECMO cannula to improve venous drainage and/or optimize systemic hemodynamics/oxygenation, or the implementation of surgical or percutaneous unloading of the left ventricle (LV), to reduce cardiac dilation and pulmonary edema. At times , IABP or Impella , tandem heart may have to be added to VA ECMO. Some of the variations in hybrid configurations include :

Figure : Addition of other MCS to VA ECMO

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Figure : Different type of extracorporeal membrane oxygenation configurations in hybrid modes, apart from classic veno‐arterial or veno‐venous approach with single cannulas or double‐lumen cannulas. A: VenoVenous‐Arterial (VV‐A) ECMO with double venous cannulation in the right internal jugular and omolateral femoral vein up to the inferior vena cava for drainage and omolateral femoral artery cannulation for perfusion; B: VenoVenous‐Arterial (VV‐A) ECMO with double venous cannulation in the right femoral vein up to the inferior vena cava and controlateral femoral vein up to the iliac vein for drainage and right femoral artery cannulation for perfusion; C: Venovenovenous‐Arterial (VVV‐A) with double‐lumen cannula acting only as venous drainage and right femoral artery as perfusion; D: Venous‐ArterialVenous (V‐AV) ECMO with single venous drainage at the right femoral vein up to the inferior vena cava and right femoral artery and right internal jugular vein for perfusion; E: Veno‐ArteroVenous (V‐AV) ECMO with double‐lumen cannula acting as drainage and perfusion cannulas an right femoral artery as second perfusion cannula; F: VenoVenous‐ArteroVenous (VV‐AV) ECMO with double cannulation of the two femoral veins up to the inferior vena cava from the right side and iliac vein from the left as drainage, and right femoral artery as perfusion; G: VenoVenous‐ArteroVenous (VV‐AV) ECMO with right internal jugular vein and left femoral vein up to the omolateral iliac vein as drainage, and right femoral artery and inferior vena cava from the omolateral femoral vein as perfusion; H;VenoVenoVenous‐Arterial (VVV‐A) with triple venous drainage from the right internal jugular, omolateral femoral up to the inferior vena cava, and contralateral femoral vein up to the iliac vein as drainage, and right femoral artery as perfusion. 304

Cannulation: In addition to traditional arterial and venous cannula , pulmonary artery cannulation via percutaneous approach has been attempted to enhance ECMO management in acute cardiac failure. This pulmonary artery cannula can be used either to drain or to perfuse depending on the hemodyanmics.

Figure : Double‐lumen pulmonary artery cannula (ProtekDuo, TandemLife, CardiacAssist® Inc., Pittsburgh, Pennsylvania

Organizational Aspects : A dedicated ECMO team is associated with higher survival to explant and discharge, possibly because of optimal decision making. ECMO management / LV unloading : Hybrid approaches unload LV effectively and lowers mortality. Furthermore LV venting enhances ECMO weaning . More time on ECMO is associated with longer ICU stay. However addition of another MCS may be associated with more hemolysis.

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Complications : Cannula / Catheter related Surgical Site hemorrhage Limb Ischemia (Peripheral VA ECMO) - new cannulas may minimize Neurological injury Hemolysis Thrombocytopenia

Outcomes : ECMO has poor outcomes if multi organ failure at the time of ECMO institution. Independent predictors of ICU death determined at admission for fulminant myocarditis : SAPS II > 56 Troponin Ic > 12g/L . The early dynamic behavior of lactate has been linked to mortality in post cardiotomy patients ECMO support . Lactate clearance predicts survival.

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Post Cardiac Arrest – Cardiogenic shock Early arterial hypotension is common in the post cardiac arrest syndrome and associated with increased in-hospital mortality. Refractory circulatory dysfunction can culminate in to multi-organ failure , ultimately leading to death. Post resuscitation shock -> Acute renal failure -> Coagulopathy -> Hypoxic Hepatitis -> ARDS -> Death. Refractory shock itself can contribute to mortality in the early post cardiac arrest period, even before neurological prognostication. It has worse outcomes even in the long term. Post cardiac arrest related cardiogenic shock can have heightened long term all-cause mortality and major adverse cardiac events. Main mechanism of post resuscitation shock is myocardial dysfunction. It involves a complex interactive pathophysiology of post arrest myocardial dysfunction , splanchnic ischemia reperfusion and systemic inflammation. Post Cardiac arrest Myocardial dysfunction is usually a reversible systolic dysfunction that may take 3 – 6 months for recovery. It is thought to be secondary to drug toxicity ( epinephrine) , defibrillation , coronary occlusion , Ischemia-reperfusion and SIRS. Immediate PCI of the culprit lesion post cardiac arrest is associated with benefit. Best benefit ( 50% survival) is obtained if early revascularization is coupled with temporary mechanical assistance in severe cardiogenic shock. Post resuscitation disease after cardiac arrest is thought to be mimic sepsis in terms of pathogenesis hence it may be regarded "Sepsis like syndromes". The pathophysiology includes Ischemia reperfusion syndrome , inflammatory response , coagulopathy , circulatory failure , adrenal dysfunction. Vasoplegia could be secondary to Lipopolysaccharide/Endotoxin release from the GUT injury due to splanchnic hypoperfusion and is associated with elevated urinary IFABP and decreased plasma citrulline levels. Hemodialysis with high cut-off membrane during early periods of post-resuscitation shock , aimed to remove cytokines did not show any significant benefit in the outcomes including the hemodynamic derangement. The most important factor in determining the outcome in post cardiac arrest is the brain injury. The only therapeutic option that has been shown to improve neurological outcomes is the "targeted temperature management". MAP is higher and improved lactate clearance is seen when TTM is targeted at 36 C versus 33 C. It may be preferable to target to 36 C.

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Further Reading Hamzaoui, O., Georger, J., Monnet, X. et al. Early administration of norepinephrine increases cardiac preload and cardiac output in septic patients with life-threatening hypotension. Crit Care 14, R142 (2010). https://doi.org/10.1186/cc9207 Brasseur A, Scolletta S, Lorusso R, Taccone FS. Hybrid extracorporeal membrane oxygenation. J Thorac Dis. 2018 Mar;10(Suppl 5):S707-S715. doi: 10.21037/jtd.2018.03.84. PMID: 29732190; PMCID: PMC5911562. Lo Coco V, Lorusso R, Raffa GM, Malvindi PG, Pilato M, Martucci G, Arcadipane A, Zieliński K, Suwalski P, Kowalewski M. Clinical complications during veno-arterial extracorporeal membrane oxigenation in post-cardiotomy and non post-cardiotomy shock: still the achille's heel. J Thorac Dis. 2018 Dec;10(12):6993-7004. doi: 10.21037/jtd.2018.11.103. PMID: 30746245; PMCID: PMC6344687. Al-Fares AA, Randhawa VK, Englesakis M, McDonald MA, Nagpal AD, Estep JD, Soltesz EG, Fan E. Optimal Strategy and Timing of Left Ventricular Venting During Veno-Arterial Extracorporeal Life Support for Adults in Cardiogenic Shock: A Systematic Review and Meta-Analysis. Circ Heart Fail. 2019 Nov;12(11):e006486. doi: 10.1161/CIRCHEARTFAILURE.119.006486. Epub 2019 Nov 13. PMID: 31718322. Lorusso R, Raffa GM, Heuts S, Lo Coco V, Meani P, Natour E, Bidar E, Delnoij T, Loforte A. Pulmonary artery cannulation to enhance extracorporeal membrane oxygenation management in acute cardiac failure. Interact Cardiovasc Thorac Surg. 2020 Feb 1;30(2):215-222. doi: 10.1093/icvts/ivz245. PMID: 31665308. Mehta SR, Wood DA, Storey RF, Mehran R, Bainey KR, Nguyen H, Meeks B, Di Pasquale G, LópezSendón J, Faxon DP, Mauri L, Rao SV, Feldman L, Steg PG, Avezum Á, Sheth T, Pinilla-Echeverri N, Moreno R, Campo G, Wrigley B, Kedev S, Sutton A, Oliver R, Rodés-Cabau J, Stanković G, Welsh R, Lavi S, Cantor WJ, Wang J, Nakamya J, Bangdiwala SI, Cairns JA; COMPLETE Trial Steering Committee and Investigators. Complete Revascularization with Multivessel PCI for Myocardial Infarction. N Engl J Med. 2019 Oct 10;381(15):1411-1421. doi: 10.1056/NEJMoa1907775. Epub 2019 Sep 1. PMID: 31475795. Sorokin V, MacLaren G, Vidanapathirana PC, Delnoij T, Lorusso R. Choosing the appropriate configuration and cannulation strategies for extracorporeal membrane oxygenation: the potential dynamic process of organ support and importance of hybrid modes. Eur J Heart Fail. 2017 May;19 Suppl 2:75-83. doi: 10.1002/ejhf.849. PMID: 28470922. Fincke R, Hochman JS, Lowe AM, Menon V, Slater JN, Webb JG, LeJemtel TH, Cotter G; SHOCK Investigators. Cardiac power is the strongest hemodynamic correlate of mortality in cardiogenic shock: a report from the SHOCK trial registry. J Am Coll Cardiol. 2004 Jul 21;44(2):340-8. doi: 10.1016/ j.jacc.2004.03.060. PMID: 15261929. Li CL, Wang H, Jia M, Ma N, Meng X, Hou XT. The early dynamic behavior of lactate is linked to mortality in postcardiotomy patients with extracorporeal membrane oxygenation support: A retrospective observational study. J Thorac Cardiovasc Surg. 2015 May;149(5):1445-50. doi: 10.1016/j.jtcvs.2014.11.052. Epub 2014 Nov 24. PMID: 25534305. 308

Grand J, Hassager C, Skrifvars MB, et al. Haemodynamics and vasopressor support during prolonged targeted temperature management for 48 hours after out-of-hospital cardiac arrest: a post hoc substudy of a randomised clinical trial. European Heart Journal: Acute Cardiovascular Care. June 2020. doi:10.1177/2048872620934305 Geri G, Grimaldi D, Seguin T, Lamhaut L, Marin N, Chiche JD, Pène F, Bouglé A, Daviaud F, MorichauBeauchant T, Arnaout M, Champigneulle B, Zafrani L, Bourcier S, Nguyen YL, Charpentier J, Mira JP, Coste J, Vinsonneau C, Cariou A. Hemodynamic efficiency of hemodialysis treatment with high cut-off membrane during the early period of post-resuscitation shock: The HYPERDIA trial. Resuscitation. 2019 Jul;140:170-177. doi: 10.1016/j.resuscitation.2019.03.045. Epub 2019 Apr 8. PMID: 30974188. Grimaldi D, Sauneuf B, Guivarch E, Ricome S, Geri G, Charpentier J, Zuber B, Dumas F, Spaulding C, Mira JP, Cariou A. High Level of Endotoxemia Following Out-of-Hospital Cardiac Arrest Is Associated With Severity and Duration of Postcardiac Arrest Shock. Crit Care Med. 2015 Dec;43(12):2597-604. doi: 10.1097/CCM.0000000000001303. PMID: 26427593. Kilgannon JH, Roberts BW, Reihl LR, Chansky ME, Jones AE, Dellinger RP, Parrillo JE, Trzeciak S. Early arterial hypotension is common in the post-cardiac arrest syndrome and associated with increased in-hospital mortality. Resuscitation. 2008 Dec;79(3):410-6. doi: 10.1016/j.resuscitation.2008.07.019. Epub 2008 Nov 5. PMID: 18990478; PMCID: PMC2746417. Sanaiha Y, Ziaeian B, Antonios JW, Kavianpour B, Anousheh R, Benharash P. Intraaortic Balloon Pump vs Peripheral Ventricular Assist Device Use in the United States. Ann Thorac Surg. 2020 May 23:S00034975(20)30752-9. doi: 10.1016/j.athoracsur.2020.03.129. Epub ahead of print. PMID: 32454014. Vallabhajosyula S, Payne SR, Jentzer JC, Sangaralingham LR, Yao X, Kashani K, Shah ND, Prasad A, Dunlay SM. Long-Term Outcomes of Acute Myocardial Infarction With Concomitant Cardiogenic Shock and Cardiac Arrest. Am J Cardiol. 2020 Oct 15;133:15-22. doi: 10.1016/j.amjcard.2020.07.044. Epub 2020 Jul 28. PMID: 32811650. Yannopoulos D, Bartos JA, Raveendran G, Conterato M, Frascone RJ, Trembley A, John R, Connett J, Benditt DG, Lurie KG, Wilson RF, Aufderheide TP. Coronary Artery Disease in Patients With Out-ofHospital Refractory Ventricular Fibrillation Cardiac Arrest. J Am Coll Cardiol. 2017 Aug 29;70(9):11091117. doi: 10.1016/j.jacc.2017.06.059. PMID: 28838358. Laurent I, Monchi M, Chiche JD, Joly LM, Spaulding C, Bourgeois B, Cariou A, Rozenberg A, Carli P, Weber S, Dhainaut JF. Reversible myocardial dysfunction in survivors of out-of-hospital cardiac arrest. J Am Coll Cardiol. 2002 Dec 18;40(12):2110-6. doi: 10.1016/s0735-1097(02)02594-9. PMID: 12505221. Thiele H, Akin I, Sandri M, de Waha-Thiele S, Meyer-Saraei R, Fuernau G, Eitel I, Nordbeck P, Geisler T, Landmesser U, Skurk C, Fach A, Jobs A, Lapp H, Piek JJ, Noc M, Goslar T, Felix SB, Maier LS, Stepinska J, Oldroyd K, Serpytis P, Montalescot G, Barthelemy O, Huber K, Windecker S, Hunziker L, Savonitto S, Torremante P, Vrints C, Schneider S, Zeymer U, Desch S; CULPRIT-SHOCK Investigators. One-Year Outcomes after PCI Strategies in Cardiogenic Shock. N Engl J Med. 2018 Nov 1;379(18):16991710. doi: 10.1056/NEJMoa1808788. Epub 2018 Aug 25. PMID: 30145971.

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Petroni T, Harrois A, Amour J, Lebreton G, Brechot N, Tanaka S, Luyt CE, Trouillet JL, Chastre J, Leprince P, Duranteau J, Combes A. Intra-aortic balloon pump effects on macrocirculation and microcirculation in cardiogenic shock patients supported by venoarterial extracorporeal membrane oxygenation*. Crit Care Med. 2014 Sep;42(9):2075-82. doi: 10.1097/CCM.0000000000000410. PMID: 24810530. Myers TJ, Frazier OH, Mesina HS, Radovancevic B, Gregoric ID. Hemodynamics and patient safety during pump-off studies of an axial-flow left ventricular assist device. J Heart Lung Transplant. 2006 Apr;25(4):379-83. doi: 10.1016/j.healun.2005.11.459. PMID: 16563964. Akin S, Kara A, den Uil CA, Ince C. The response of the microcirculation to mechanical support of the heart in critical illness. Best Pract Res Clin Anaesthesiol. 2016 Dec;30(4):511-522. doi: 10.1016/ j.bpa.2016.10.001. Epub 2016 Oct 27. PMID: 27931654. https://www.medgadget.com/2007/08/heartmate_ii_shown_effective_in_waiting_translpant_candidates.html Baran, DA, Grines, CL, Bailey, S, et al. SCAI clinical expert consensus statement on the classification of cardiogenic shock. Catheter Cardiovasc Interv. 2019; 94: 29– 37. https://doi.org/10.1002/ccd.28329 Rodriguez LE, Suarez EE, Loebe M, Bruckner BA. General surgery considerations in the era of mechanical circulatory assist devices. Surg Clin North Am. 2013 Dec;93(6):1343-57. doi: 10.1016/ j.suc.2013.08.004. PMID: 24206855. Von Ruden SA, Murray MA, Grice JL, Proebstle AK, Kopacek KJ. The pharmacotherapy implications of ventricular assist device in the patient with end-stage heart failure. J Pharm Pract. 2012 Apr;25(2):232-49. doi: 10.1177/0897190011431635. PMID: 22392840. Vincent, Jean-Louis , De Backer, Daniel, Circulatory Shock, N Engl J Med 2013; 369:1726-1734, DOI: 10.1056/NEJMra1208943. Gaspar, Heloisa & Morhy, Samira. (2015). The Role of Focused Echocardiography in Pediatric Intensive Care: A Critical Appraisal. BioMed Research International. 2015. 1-7. 10.1155/2015/596451.

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Chapter 6: Sepsis Chapter 6: Sepsis Blood Purification

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Pathophysiology of sepsis Insult -> triggers -> sensors and effector cells -> mediators and biomarkers -> organ function -> outcome. Triggers: PAMPs: Pathogen associated molecular patterns (LPS, LTA, lipoproteins, peptidoglycans, bacterial DNA) DAMPs: Damage associated molecular patterns) Heat shock protein, HMG, DNA) Sensors and effector cells: Complex protein systems: Complement and Coagulation system Vascular and tissue cells: Endothelial, epithelial and adipose tissue Blood and lymphatic cells: Granulocytes, macrophages and monocytes, lymphocytes (T and B cells) Mediators and biomarkers: C3a, C5a, C5b-9, Protein C , aPTT, PT , Endothelial stress response (ELAM-1, ICAM-1, Selectins) , Acute phase reactants ( CRP, Procalcitonin) , Cytokines, chemokines, soluble receptors ( ILs, sTNF , TREM-1) , Cell surface markers ( CD48 , CD 64). Impact on Organ function: Brain (confusion, Encephalopathy ) , Lung (Respiratory distress, Acute lung injury) , Cardiovascular system (Shock) , Kidney (Oliguria, anuria) , Liver ( excretory and metabolic failure), GUT (loss of barrier function) , microcirculation (capillary leak ) Outcome: Outcome depends on effective source control. Source control can normalize biomarkers and resolution of organ dysfunction. Ineffective source control can cause multi organ dysfunction and death. Although the pathophysiology of sepsis is centered on high levels of pro-inflammatory mediators such as TNF, IL –6, complement activation, these cytokines are essential in fighting infections. Suppressed function or very low levels of these cytokines may succumb the host to infections. Nevertheless, high levels of IL-6 and IL-10 have been associated with mortality in patients with pneumonia. One intriguing approach in the interim to manage sepsis may be to minimize excessive cytokinemia.

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Pre hospital consideration: Early recognition of Sepsis may limit life threatening organ dysfunction due to a dysregulated host response to infection. It has been observed that antibiotics administered with in 1 hour of hypotension has 80% survival with each hour delay decreased absolute survival by 8%. Earlier fluid bolus may improve survival only in a subset of sepsis population, especially if fluid responsive and hypotension. Prehospital identification and treatment of sepsis is an opportunity, however, system barriers may delay delivery of time-sensitive sepsis treatments. Screening for Sepsis (out of hospital, ED or general hospital ward): Use qSOFA Respiratory rate >/= 22/min Altered mentation: GCS score Systolic Blood pressure 1 min) has been associated with poor outcomes that include: Myocardial injury Renal injury Stroke Mortality Real time monitoring is an excellent tool to determine stability at the current moment, but not good at predicting future instability. Certain algorithms utilizing integration of hemodynamic monitoring may aid in the prediction of hypotension early such as : Acumen Hypotension Prediction Index (HPI) Arterial waveform analysis has been utilized to derive certain cardiovascular parameters such as contractility, stroke volume, aortic impedance, afterload and vascular tone. Machine learning algorithm from arterial waveform analysis has been incorporated to derive a prediction model to predict hypotension in the next 5 – 17 min. Rather it has been validated that the higher the value of hypotension prediction index (from 0 to 100) , higher the event rate of future hypotension and shorter the time to hypotension. No other hemodynamic variables (CO, SV, MAP, Perfusion pressure, HR, SVV, Shock index) were able to predict hypotension. Hypotension prediction index has been extended to utilize non-invasive pulse plethysmogram. Further derivations of HPI (by software analysis) enables the clinician to choose volume, inotrope or vasopressor to manage this hypotension. For example: Volume necessity is determined by Pulse pressure variation, stroke volume variation Estimation of contractility: dP/dtmax. (Systolic contractility index) A measure of contractility is the maximum change in pressure over time (slope) in left ventricle. This is also known as dP/dtmax. Peripheral arterial waveform dP/dtmax mostly correlate with LV dP/dtmax. Dynamic arterial elastance: Eadyn= PPV/SVV. Dynamic arterial response predicts pressure response in preload responders. It is often referred to as "stroke volume variation of the pressure world". It is a measure of ventriculo-arterial coupling. Optimal cut-off for predicting MAP rise is about 1.0 (grey zone of 0.8-1.2).

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Figure: Systolic contractility index

Figure: dynamic arterial elastance Preemptive treatment derived from this index intraoperatively has been shown to significantly reduced complications. Hypotension prediction index has been incorporated in "early warning system" for Intraoperative purposes. One of the purported benefits of HPI is thought to change the current practice from reactive to proactive hemodynamic management.

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Blood Purification/ECOS in Sepsis: Cytosorb Minimizing excessive cytokinemia without totally suppressing them is one intriguing thought to minimize organ dysfunction in sepsis, while the effective source control takes its effect. Targets for extracorporeal blood purification: 1: Cytokine mediators (cytokines, LPS) 2: Protection of endothelium and maintaining microvascular function (coagulation, complement) 3: Protection of epithelium in the kidney and Liver (related to removal of PAMPs and DAMPs) 4: Reprogramming of the innate immune response through modulation of chemokine gradients. Many different potential extracorporeal techniques have been proposed. Hemoperfusion has the strongest benefit. Plasma exchange also may have a beneficial effect. These include: Convective therapies: Conventional CRRT High Volume Hemofiltration (HVHF) technique High Cut membrane technique Perfusion-Adsorption techniques: endotoxin removal PMX Cytosorb Hybrid therapy: CPFA (Coupled plasma filtration adsorption) Other Misc. techniques: Therapeutic Plasma exchange RAD: Renal tubule cell assist device SCD: Selective cytapheretic device. The performance of these modalities depend on many variables, which make each of them to be unique in their own way. Dose of Hemofiltration: Standard volume hemofiltration dose is 35 ml/kg/hr. (upper limit) High volume hemofiltration dose: 70 ml/kg/hr. (upper limit) Outcomes have been similar, but none of the studies measured levels of cytokines. Rather one study revealed that cytokine levels alone may not be the only determinant of the phenotype of a sepsis patient. Active Surface area: CRRT < 2 Sq.m (Square meters) Cytosorb Cartridge > 40,000 Sq.m

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Molecular weights: < 50 Daltons: Sodium (23), Phosphorus (31), Potassium (35) 50-100 Daltons: Urea (60), Phosphate (94) 100-500 Daltons: Creatinine (113), Uric acid (168), Glucose (180) 500-1000 Daltons: Aluminum desferroxamine complex (700) 1000-5000 Daltons: Vitamin B 12 (1350) 5000-10,000 Daltons: Insulin (5200) 10,000- 50,000 Daltons: Beta 2 microglobulin (11,800), IL-1b (18,000) IL-6 (28,000) 50,000-100,000 Daltons: TNF a (52,000), Albumin (55,000 – 60,000) Sepsis mediated biomarkers has the following molecular weight: IL-1b (18,000) IL-6 (28,000) TNF a (52,000) Traditional CRRT has cut off closer to 1500 Daltons, while Cytosorb has cut off 5000- 60,000 Daltons (560Kda), hence called "Cytokine sweet spot". Cytosorb is delivered as a cartridge containing 10 gm of material with 300-800 microns diameter. Each gram of material has a surface area of 850 Sq.m. Cytosorb is made of polystyrene divinyl benzene copolymer beads with a biocompatible coating. Prescription of Blood purification using Cytosorb with CVVH/CVVHD: Potential Indications: ARF, IL-6 > 1000 pg. /ml, PCT > 5 ng/l Pearls: CiCa anticoagulation, BF > 150 ml/min, 24hr/day, adsorber change daily Change adsorber < 24 hours if very high levels of IL-6/PCT (approx. 10,000) Prepare to reinstall Cytosorb therapy if 2nd septic hit occurs Cytosorb decreases levels of IL-6 and PCT significantly in approximately 24 hours Cytosorb use decreases the noradrenaline dose required. Cytosorb may decrease mortality in higher SOFA score, can be used as a rescue therapy Consider Cytosorb early in sufficiently sick septic patients Probably best benefit is seen in sepsis with high NE dose, High SOFA and High IL-6/PCT levels Cytosorb can be considered in rhabdomyolysis, Liver failure, and intoxications.

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Outcomes in sepsis: Mortality is directly related to SOFA score Maximum SOFA score

Mortality

0-6

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>90%

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Further Reading Vincent JL, Weil MH. Fluid challenge revisited. Crit Care Med. 2006 May;34(5):1333-7 Monnet, X., Cipriani, F., Camous, L. et al. The passive leg raising test to guide fluid removal in critically ill patients. Ann. Intensive Care 6, 46 (2016). https://doi.org/10.1186/s13613-016-0149-1 Teboul, J., Hamzaoui, O. & Monnet, X. SvO2 to monitor resuscitation of septic patients: let's just understand the basic physiology. Crit Care 15, 1005 (2011). https://doi.org/10.1186/cc10491 Boulain T, Garot D, Vignon P, Lascarrou JB, Desachy A, Botoc V, Follin A, Frat JP, Bellec F, Quenot JP, Mathonnet A, Dequin PF; Clinical Research in Intensive Care and Sepsis Group. Prevalence of low central venous oxygen saturation in the first hours of intensive care unit admission and associated mortality in septic shock patients: a prospective multicentre study. Crit Care. 2014 Nov 6;18(6):609. doi: 10.1186/ s13054-014-0609-7. PMID: 25529124; PMCID: PMC4265332. Monnet X, Julien F, Ait-Hamou N, Lequoy M, Gosset C, Jozwiak M, Persichini R, Anguel N, Richard C, Teboul JL. Lactate and venoarterial carbon dioxide difference/arterial-venous oxygen difference ratio, but not central venous oxygen saturation, predict increase in oxygen consumption in fluid responders. Crit Care Med. 2013 Jun;41(6):1412-20. doi: 10.1097/CCM.0b013e318275cece. PMID: 23442986. Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline JA; Emergency Medicine Shock Research Network (EMShockNet) Investigators. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA. 2010 Feb 24;303(8):739-46. doi: 10.1001/jama.2010.158. PMID: 20179283; PMCID: PMC2918907. Dres M, Monnet X, Teboul JL. Hemodynamic management of cardiovascular failure by using PCO(2) venous-arterial difference. J Clin Monit Comput. 2012 Oct;26(5):367-74. doi: 10.1007/s10877-012-9381-x. Epub 2012 Jul 25. PMID: 22828858. Yu M, Pei K, Moran S, Edwards KD, Domingo S, Steinemann S, Ghows M, Takiguchi S, Tan A, Lurie F, Takanishi D Jr. Shock. 2011 Mar;35(3):220-8. doi: 10.1097/SHK.0b013e3181fc9178. https://www.daxor.com/how-bva-100-works/ Fraser DD, Patterson EK, Slessarev M, Gill SE, Martin C, Daley M, Miller MR, Patel MA, Dos Santos CC, Bosma KJ, O'Gorman DB, Cepinskas G. Endothelial Injury and Glycocalyx Degradation in Critically Ill Coronavirus Disease 2019 Patients: Implications for Microvascular Platelet Aggregation. Crit Care Explor. 2020 Aug 24;2(9):e0194. doi: 10.1097/CCE.0000000000000194. PMID: 32904031; PMCID: PMC7449254. Demiselle, J., Fage, N., Radermacher, P. et al. Vasopressin and its analogues in shock states: a review. Ann. Intensive Care 10, 9 (2020). https://doi.org/10.1186/s13613-020-0628-2 Nagendran M, Russell JA, Walley KR, Brett SJ, Perkins GD, Hajjar L, Mason AJ, Ashby D, Gordon AC. Vasopressin in septic shock: an individual patient data meta-analysis of randomised controlled trials. Intensive Care Med. 2019 Jun;45(6):844-855. doi: 10.1007/s00134-019-05620-2. Epub 2019 May 6. PMID: 31062052. 319

Levy, Brunoa,b,c; Klein, Thomasa,b,c; Kimmoun, Antoinea,b,c Vasopressor use in cardiogenic shock, Current Opinion in Critical Care: August 2020 - Volume 26 - Issue 4 - p 411-416 doi: 10.1097/ MCC.0000000000000743 Sims CA, Holena D, Kim P, Pascual J, Smith B, Martin N, Seamon M, Shiroff A, Raza S, Kaplan L, Grill E, Zimmerman N, Mason C, Abella B, Reilly P. Effect of Low-Dose Supplementation of Arginine Vasopressin on Need for Blood Product Transfusions in Patients With Trauma and Hemorrhagic Shock: A Randomized Clinical Trial. JAMA Surg. 2019 Nov 1;154(11):994-1003. doi: 10.1001/jamasurg.2019.2884. PMID: 31461138; PMCID: PMC6714462. Corrêa TD, Jakob SM, Takala J. Arterial blood pressure targets in septic shock: is it time to move to an individualized approach?. Crit Care. 2015;19(1):264. Published 2015 Jun 18. doi:10.1186/s13054-0150958-x

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Chapter 7: Tissue monitoring Chapter 7: Tissue Monitoring

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Mitochondrial Physiology

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Assessment of Tissue Hypoxia

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Monitoring Microcirculation

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Measuring Capillary leak

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Measuring Tissue RBC Perfusion

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Measuring Convection

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Measuring Diffusion Capacity

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Tissue CO2 Monitoring

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Monitoring Peripheral Perfusion

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Mitochondrial Physiology Present in almost all cell types and is the primary provider of ATP and body heat. 90% of oxygen consumption is used by the mitochondria. Senescent mitochondria are degraded by fission and removed by mitophagy, swallowed by autophagosome. New mitochondria are generated by biogenesis.

Structure of mitochondria:

It consists of outer and inner mitochondrial membrane. The inner mitochondrial membrane is folded multiple times (known as cristae) to increase surface area and encompasses Matrix containing enzyme and proteins. The electron transport change with its respiratory enzyme complexes and ATP synthetase is located on inner mitochondrial membrane. Mitochondria has its own DNA with 37 genes. But most of the mitochondrial protein comes from nuclear encoded DNA.

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Figure: Biochemical pathways in mitochondria Cytosol: shown in blue, mitochondria in pink; Glycolysis happens in cytosol. Pyruvate goes in to mitochondria for Krebs cycle or it can be reversibly converted to lactate in the cytosol. Similarly Fatty acyl co A is transported in to mitochondria, with the help of carnitine participates in beta oxidation. NADH and FADH2 donate electrons to complex I and II respectively. Electrons pass through the ETC (electron transport chain) from I to IV via coenzyme Q and cytochrome C. Complex IV is also called as cytochrome Oxidase, which uses Oxygen. During the electron passage, the hydrogen is transported creating a proton gradient. Oxidative phosphorylation takes place with the return of hydrogen ion across inner membrane due to the gradient, generating ATP from ADP. ATP is then transported out of mitochondria. Oxygen is also utilized by coenzyme Q and complex I to generate Superoxide (free radicals) that have important role in cell signaling. During some disease processes, superoxide is generated in massive pathological quantities. . Proteins can pass through the mitochondrial membrane without generating ATP (uncoupling) generating heat. Total ATP generated is 9 X 10 ^20 mol/s or 65 kgs/day. One mole of glucose generates: 2 ATP from glycolysis 2 ATP from Krebs cycle 24-30 ATP from Oxidative phosphorylation 323

Functions of mitochondria include: Major source of free radicals in body Major target of Nitric Oxide (+ CO, H2S) Major role in triggering cell death Major role in intracellular calcium regulation Major site of action of hormones (e.g. thyroid hormones) Major site of production of hormones (e.g. cortisol) Major site of production of 1, 25 di-hydroxy vitamin D Major role in lipid metabolism Major role in immune function Most Cell types require Oxygen to function: Cardiomyocytes have 5000 mitochondria/ cell Hepatocytes have 2000 mitochondria/cell Neutrophils have relatively few mitochondria (predominantly relies on glycolysis) Only Erythrocytes lack mitochondria (totally relies on glycolysis) From lungs to tissues oxygen is carried by convection, from capillary to mitochondria by diffusion According to a pressure gradient. PO2 in artery is 13 Kpa, PO2 in mitochondria is 0.1-1 Kpa. Cytochrome oxidase can operate at very Oxygen concentration. Only when the partial pressure is < 0.1 Kpa, that’s when the activity of mitochondria starts dropping. Oxygen consumptive Processes are related to : Mitochondria coupled to ATP synthesis: 75-80% Mitochondria uncoupled: 15-20% (heat and ROS generation) Non mitochondrial: 5%

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Assessment of tissue hypoxia Two determinants of tissue hypoxia : Cardiac output ( preload and contractility) Perfusion pressure Markers of tissue hypoxia : SvO2/ ScVO2( Central venous/ mixed venous O2 saturation) Lactate PCO2 indices : PCO2 gap ( Venous- arterial CO2 gap) ScVO2 / SvO2 : Best indicator of DO2/VO2 adequacy Low SvO2 indicates either decreased O2 delivery or increased O2 consumption Decreased O2 delivery : Decreased Cardiac output , Hb and SaO2. Increased O2 consumption : Fever , Agitation Scenario : ScVO2 < 70% : Aim to normalize Hb and PaO2 and reassess ScVo2 < 70% , normal Hb , Normal PaO2 : Rx is increase in Cardiac Output If preload responsive : Consider volume expansion If decreased contractility : Consider Inotropes However , it has been found not to be helpful in septic shock, as level of critical O2 delivery increases, which means as soon as the DO2 decreases , O2 consumption decreases early ( secondary to microcirculatory abnormality) . SCVO2 remains normal in sepsis despite tissue hypoxia . In addition , true value of ScVO2 is only estimated by PAC. Lactate : In aerobic metabolism , oxidative phosphorylation stops and lactate production increases. Level of lactate has been co-related to the severity of hypoxia . Mortality increases when lactate levels > 2 m mol/L. It is a very sensitive test with no false negatives. However , there is a delay in change in the levels of lactate. It may take at least 6 hours for lactate levels to reflect optimization of tissue perfusion . False positive Lactate : here it may not reflect tissue hypoxia Renal failure Liver failure Myolysis ARDS Metformin Anti-HIV drugs Sodium Valproate

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Lactate and SCVO2 should be interpreted together . It is unclear if lactate guided strategy is superior or not to ScVo2 guided therapy. Scenario: A patient with cirrhosis is admitted to ICU with Ascites infection . Lactate is 6 mmol/l , ScVO2 = 45%. Rx : Although lactate may be considered secondary to cirrhosis , low SCVO2 suggest that the treatment is increase in Cardiac output. A patient admitted with Pneumonia . At admission , ScVO2 = 70% , lactate is 4 mmol/l . After 1l of fluid , ScVO2 = 70% , lactate is 2 mmol/L . It means patient has improved . As lactate kinetics takes time to measure adequacy of tissue perfusion , V-ACO2 gap has been proposed as an alternative variable for hemodynamic management. If Lactate >/= 1.7 mmol/L : look at pCO2 indices PCO2 gap : There is normally a difference between CO2 levels of venous and arterial system. The determinants of this gap are : Cardiac output ( CO2 is carried to the lungs) : If cardiac output is low , CO2 accumulates on the venous side , hence increased V-A gradient Metabolism and production of CO2 Aerobic origin of CO2 ( in proportional to O2 consumption) : decreases PCO2 gap Anerobic origin of CO2 ( CO2 production by acid buffering ) : increases PCO2 gap Hence there are two causes of elevated PCO2 gap : Decreased cardiac output and increased anerobic metabolism. To differentiate between the two , CO:O2 ratio can be used VCO2/VO2 is respiratory quotient . It is elevated in anerobic metabolism . VCO2/VO2 = CO* c ( V-A) CO2/CO* c (A-V) O2 = p(V-A) CO2/c(A-V) O2= PCO2 gap/O2 content gap. VCO2 : amount of Co2 produced VO2 : amount of O2 consumed CO : cardiac output , c = content In cases of anerobic metabolism = PCO2 gap/O2 content gap is elevated ( marker of anerobic metabolism) PCO2 gap indices are accurate and cause rapid changes after hemodynamic optimization . However , requires further validation. In summary, PCO2 gap >/= 1.8 mm HG/ml : consider increase in cardiac output 326

Monitoring Microcirculation

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Measuring Capillary leak Based on a principle of transudation of a tracer. Evans blue dye (EB): Introduced in 1915 to measure plasma/RBC volume, CO and Vascular permeability esp. of the blood brain barrier. With a molecular weight of 961 KDa and high water solubility, it strongly binds to albumin with 0.1 - 0.3 % free EB in the plasma. Eliminated from circulation by liver. The disadvantage with using EB is that it stains the tissues blue. Currently this technique has been replaced by radiolabeled albumin. Radiolabeled Albumin (Iodine 125 and 131): Introduced in 1946, it is currently approved by FDA for the use at bedside. In this technique, the albumin is labeled outside the body and then injected. A baseline sample of 5 ml blood is obtained with simultaneous measurement of HCT. Iodine 131 with albumin (5-30 microcuries) is injected in 1 minute. Mixing is allowed for 10 min and then subsequent blood samples are taken around at 10, 15,20 min and analyzed in semi-automated device. After 20-60 minutes, the report can be obtained after regression analysis.

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Figure: The human figures represent sequential calculated blood volumes at the recommended intervals for drawing blood samples after tracer injection. As the Volumex® tracer transudates from the intravascular to the extravascular space (depicted as the pink dots moving outside the red vein), the quantity of tracer decreases intravascularly implying a higher dilution factor and therefore higher blood volume. The red line represents is the regression calculation of the analyzed draws to time zero or time of injection, which indicates the level of true total intravascular blood volume. The red line is also a measure of albumin transudation, a measure of capillary permeability The report generates the following data: (Blood volume analysis) Total Blood Volume (TBV): Severe Excess (26.2%) indicates the need for diuresis. Red blood cell volume (RBCV): Moderate deficit of (- 23.3%) indicates the need for RBC. Normalized HCT (n HCT): low nHCT (30.7%) indicates true anemia and not related to dilution. Additional analysis includes Albumin transudation slope. A slightly elevated value (0.31%) is acceptable. Normal value is < 0.25%. The slope depends on the rate of disappearance of radioactivity which is a surrogate of capillary leak.

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It has been used in heart failure and critically ill patients with circulatory failure. Blood volume measurements may allow physicians to promptly treat physiologic disturbance (anemia, volume overload) in both red blood volume and plasma volume. Blood volume measurements have been purported to improve survival in critically ill patients predominantly by preventing multi-organ failure, as tissue edema in fluid overload is thought to be one of the key factors for multi-organ failure. A persistently elevated albumin transudation rate is associated with increased mortality. Based on one experiment, it was proved that endothelial barrier function was decreased in association with Diabetes and markers of platelet activation than inflammation especially in peritoneal dialysis patients. In some patients of sepsis with endothelial barrier dysfunction, glycocalyx degradation was demonstrated with heightened levels of sP-Selectin, Hyaluronic acid and Syndecan-1. The association of the transudation rate of the radiolabeled albumin is an element of the actual blood volume measurement and a surrogate for endothelial leakage.

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Measuring tissue RBC perfusion The ultimate purpose of the cardiovascular system is to provide the microcirculation with oxygen carrying red blood cells to provide tissue cells with oxygen needed to support oxidative phosphorylation. Shock is a state in which the circulation is unable to deliver sufficient oxygen to meet the demands of the tissues, resulting in cellular dysfunction. The physiological rationale for fluid administration or vasopressors in acute circulatory dysfunction is to improve tissue perfusion or microvascular blood flow. MAP measurement, lactate are a few surrogates of tissue perfusion, but they do not exactly measure the tissue RBC perfusion. Moreover, resuscitation may have stabilized shock in terms of optimizing macro hemodynamic variables, however there may be persistent tissue hypoperfusion (percentage of well perfused capillaries still remain low). Monitoring microcirculation is one direct way to measure tissue perfusion. Even subjective assessment of peripheral perfusion in critically ill patients by means of capillary refill and temperature may have a prognostic value to stratify patients in to unfavorable versus favorable evolution of SOFA score. Hence it is believed that objective assessment of perfusion by microcirculatory monitoring tools may provide a better insight in to the micro-hemodynamics of shock states. It enables the clinician to detect hemodynamic coherence between micro and macro-circulation. This may be important because, dobutamine in septic shock patients may increase cardiac index, but the proportion of well perfused capillaries may remain the same, where it would be considered futile or increasing MAP beyond 65 mm HG may not beneficially alter microcirculation in certain patients, as measured by capillary microvascular flow index. Rate limiting factors of Oxygen transport to the tissues depend on the blood flow in to the tissues (the Convection) and transport of Oxygen from RBC in functional capillaries to tissues cells (the diffusion) that depend on functional capillary density. For example: Heart failure or hypovolemia: Low convection (flow), normal diffusion Hemodilution: Normal convection, large diffusion distance. VO2 = D * A (CappO2 – mitpO2) / L VO2: Volume of Oxygen transported by diffusion D: diffusion constant A: Systemic capillary surface area CappO2: Capillary pO2 MitpO2: mitochondrial pO2 L: distance from RBC to mitochondria. In addition, fluid therapy can be fine-tuned to microcirculatory targets - "Microcirculatory guided fluid therapy".

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Figure: Microcirculatory-guided fluid therapy. To optimize the oxygen-carrying capacity of the microcirculation, optimization is required of the convective (sufficient flow) and diffusive capacity (optimal FCD to have short diffusion distances between the oxygen-carrying RBCs and the tissue cells). Observation of sublingual microcirculation using hand-held microscopy in states of hypovolemia identifies low convective flow (left), indicating the need for fluid administration. Microcirculatory fluid responsiveness indicates the success of fluid therapy by showing enhanced convective RBC flow. A reduction in FCD signals the occurrence of a type 2 microcirculatory alteration (right) and this indicates that too much fluid has been administered, causing increased diffusion distance between the RBCs and tissue cells reducing the oxygen transport capacity of the microcirculation. This approach provides a personalized physiologicalbased patient-centered fluid resuscitation strategy to optimize the oxygen-carrying capacity of the microcirculation. FCD = functional capillary density. Some technologies have allowed to calculate "micro tools" for automated quantification of capillary density and RBC velocities to generate validated histograms (e.g. handheld vital microscopy). It is available as point of care test.

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Some examples of Micro tools are capillary hematocrit and tRBCp Capillary hematocrit: It estimates the number of RBCs in a single capillary vessel, thus determining the O2 carrying capacity of that particular vessel. A software tool has been developed to quantify capillary hematocrit and microvascular hemodilution in sublingual dark field microscopy clips. It has been observed that volume expansion by colloid reduces capillary hematocrit in cardiac surgery patients, by expanding the distance between RBCs. Tissue RBC perfusion (tRBCp): Normalization of tissue perfusion and therefore optimizing Oxygen delivery is the ultimate end point for resuscitation of shock patients. A precise tissue perfusion parameter such as tissue RBC perfusion (tRBCp) that combines the convective and diffusive components of tissue perfusion may be an optimal target for resuscitation. This is important to monitor tRBCp, as traditional resuscitation targets in shock aim for increasing perfusion pressure this increase in perfusion pressure by fluid therapy may or may not translate in to increasing tissue RBC perfusion. It is probable that microcirculatory targets may be the standard of care in near future. Techniques to monitor microcirculation can be divided in to those: Measure convection / RBC flow in to the tissues Measure RBC- functional capillary density and there by diffusion capacity

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Measuring Convection: Laser Speckle Imaging: Sophisticated ways of measuring perfusion are by" laser speckle imaging”, that track the movement of RBC. An example of laser speckle imaging is "PeriCam PSI NR" is based on Laser Speckle contrast analysis (LASCA)

Figure: Laser Speckle Contrast imaging

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Figure: PeriCAM PSI NR

Figure: Measurement of perfusion by PeriCAM PSI NR

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Figure: Laser speckle imaging (LSI) perfusion maps before (A) and after (B-D) infusion of air bubble-enriched isotonic saline. The air bubbles first led to complete obstruction of the renal cortical artery (B, 7 s post-infusion) after which the bubbles gradually dissolved (C, 14 s post- infusion) until normal renal cortical perfusion was restored (D, 21 s post-infusion). Laser speckle imaging has also been used to monitor cortical microcirculatory flow induced by motor activity during awake craniotomy.

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Vevo LAZR X: This technology combines high frequency ultrasound and photoacoustic in to one platform for high resolution anatomical, functional and molecular imaging. It does not give any quantitative information regarding microcirculation, as the resolution is low (down to 30 um). RBCs are stimulated and the change in their acoustics properties are then captures with this instrument. Hence the information that is obtained is qualitative.

Figure: Vevo LAZR X

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Near Infrared Spectroscopy (NIRS): It looks at the level of oxygenation of the tissues. Has been employed for analysis of microcirculation during surgical reconstruction of tissues post burn injury etc.

Figure: Near infrared spectroscopy (NIRS) monitor in use. The probe is placed over the thenar eminence.

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Figure: (a) Typical StO 2 changes during arterial vascular occlusion test (VOT) in three cases. (b) Schematic illustration of the StO2 changes during VOT.

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Measuring functional capillary density / Diffusion capacity: Cytocam-IDF (Incident dark field illumination): measures convection and functional capillary density.

Figure: Cytocam-IDF It is a handheld video microscope for visualization of microcirculatory alterations, based on Incident Dark field technology enabling real-time observation of the human microcirculation. It generates a video of RBCs moving real time in the tissues. It is predominantly for visualization of micro- circulation of tissues in the orifices of human body and cutaneous surfaces. Additional software is used to analyze the images and determine microcirculatory parameters such as Total Vessel Density (TVD), Perfused Vessel Density (PVD), and Flow velocity by use of Space Time Diagrams, Microcirculatory Flow Index (MFI).

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Figure: Cytocam-IDF images of sublingual microcirculation-a visual representation of the increase of the TVD. Images of sublingual microcirculation video clips obtained from one patient on day 1 (T0), day 2 (T1), and day 3 (T2) after ICU discharge. The red lines indicate the vessels smaller than 25 um and represent the TVD within the entire image. This has been labelled "microcirculatory recruitment".

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Side Stream Dark field imaging: Second generation device

Figure: SDF imaging consists of a light guide surrounded by green light-emitting diodes (wavelength 530 nm) whose light penetrates the tissue and illuminates the microcirculation from within. The light is absorbed by hemoglobin of the red blood cells and scattered by leukocytes. A magnifying lens projects the image onto a video camera. Placed on organ surfaces, SDF imaging provides crisp images of the red blood cells and leukocytes flowing through the microcirculation. SDF (Side stream dark field) imaging device is used to analyze micro-circulation based on the following parameters: Perfused Capillary density (PCD) Capillary red blood cell Velocity (cRBCv) Tissue Perfusion index (TPI) = PCD x cRBCv.

Cytocam – IDF: It is a third generation device

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Tissue CO2 monitoring Measured by Gastric tonometry or sublingual capnometry Tissue CO2 is an index of circulatory flow to that particular tissue. Determinants of tissue CO2 includes: Tissue CO2 = PaCO2 + K (VCO2/Q). Increased tissue CO2 can occur: Increase in tissue metabolism (increased VCO2) Decrease in tissue blood flow (decreased Q) Tissue CO2 gradient = Tissue CO2 – PaCO2. If tissue CO2 gradient < 6 mm HG: indicates adequacy of O2 delivery to metabolism If tissue CO2 gradient > 6 mm HG: O2 delivery is sub-optimal to metabolic demand.

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Gastric tonometry:

Figure: Schematic diagram of gastric tonometry. Gastric tonometry measures the degree of blood flow to stomach and bowel. It measures partial pressure of a diffusible gas such as CO2 using a saline filled balloon attached to a specialized nasogastric tube. Modified Henderson-Hasselbalch equation is used to calculate the intramucosal pH (not the same as luminal pH). It may be accurate in determining tissue perfusion, but not necessarily tissue oxygenation.

Sublingual Capnometry (Exostat Medical Inc.) / Buccal Capnometry (Microtrend system) Sublingual / Buccal Capnometry has been proposed as a simple and non-invasive technique to quantify the severity of circulatory shock. A threshold of P (SL) CO2 of 70 mm HG has been proposed. A value < 70 mm HG predicted survival. PslCO2 gap has been inversely co-related to the percentage of well perfused capillaries. Buccal Capnometry measures PomCO2 (Om= oral mucosa).

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Monitoring peripheral perfusion (Skin and muscle vascular beds) Peripheral perfusion is among the first to deteriorate in circulatory shock and the last to be restored after resuscitation. Exploring peripheral perfusion could help detect occult tissue hypoperfusion during acute circulatory shock. Clinical assessment of peripheral perfusion: Capillary refill time Mottling Score Skin temperature Device related monitoring of peripheral perfusion: NIRS Peripheral perfusion index Skin laser Doppler- Skin blood flow Trans cutaneous PCO2 monitoring Skin blood flow (SBF): Measured by Skin laser Doppler (PeriFlux system 5000, Perimed). This is based on the principle of thermal Challenge. Here the Skin blood flow is measured at baseline temperature. Then a thermal challenge is applied and skin blood flow is again measured at 37C. Response to a thermal challenge is measured as Thermal challenge ratio: ΔSBF/ Δ T. Alteration in skin blood flow at the fingertip has been co-related to mortality in patients with circulatory shock and thermal challenge test has been co-related with mortality. Similarly studying the effect of fluid removal on peripheral perfusion such as finger skin blood flow during the "de-escalation" phase of circulatory shock (that aims for negative fluid balance) may limit overshoot hypovolemia. These changes in skin blood flow occur before tissue hypoperfusion (defined as drop in MAP or 10% increase in lactate at 6 hours). Thus resuscitation strategy may be fine-tuned to target peripheral perfusion.

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Handheld microscope / SDF device: A hand held microscope is used to visualize sublingual mucosa. The optical view of this SDF imaging is 0.94mm x 0.75mm.

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Summary of techniques that measure microcirculation

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Further Reading Van Haren FM, Pickkers P, Foudraine N, Heemskerk S, Sleigh J, van der Hoeven JG. The effects of methylene blue infusion on gastric tonometry and intestinal fatty acid binding protein levels in septic shock patients. J Crit Care. 2010 Jun;25(2):358.e1-7. doi: 10.1016/j.jcrc.2010.02.008. Epub 2010 Apr 8. PMID: 20381302. Glassford NJ, Eastwood GM, Bellomo R. Physiological changes after fluid bolus therapy in sepsis: a systematic review of contemporary data. Crit Care. 2014 Dec 27;18(6):696. doi: 10.1186/s13054-014-06965. PMID: 25673138; PMCID: PMC4331149. Asfar P, Meziani F, Hamel JF, Grelon F, Megarbane B, Anguel N, Mira JP, Dequin PF, Gergaud S, Weiss N, Legay F, Le Tulzo Y, Conrad M, Robert R, Gonzalez F, Guitton C, Tamion F, Tonnelier JM, Guezennec P, Van Der Linden T, Vieillard-Baron A, Mariotte E, Pradel G, Lesieur O, Ricard JD, Hervé F, du Cheyron D, Guerin C, Mercat A, Teboul JL, Radermacher P; SEPSISPAM Investigators. High versus low blood-pressure target in patients with septic shock. N Engl J Med. 2014 Apr 24;370(17):1583-93. doi: 10.1056/NEJMoa1312173. Epub 2014 Mar 18. PMID: 24635770. Lamontagne F, Richards-Belle A, Thomas K, Harrison DA, Sadique MZ, Grieve RD, Camsooksai J, Darnell R, Gordon AC, Henry D, Hudson N, Mason AJ, Saull M, Whitman C, Young JD, Rowan KM, Mouncey PR; 65 trial investigators. Effect of Reduced Exposure to Vasopressors on 90-Day Mortality in Older Critically Ill Patients With Vasodilatory Hypotension: A Randomized Clinical Trial. JAMA. 2020 Feb 12;323(10):938–49. doi: 10.1001/jama.2020.0930. Epub ahead of print. PMID: 32049269; PMCID: PMC7064880. Panwar R, Tarvade S, Lanyon N, Saxena M, Bush D, Hardie M, Attia J, Bellomo R, Van Haren F; REACT Shock Study Investigators and the ANZICS Clinical Trials Group. Relative Hypotension and Adverse Kidney-related Outcomes Among Critically Ill Patients with Shock- A Multicenter Prospective Cohort Study. Am J Respir Crit Care Med. 2020 Jul 2. doi: 10.1164/rccm.201912-2316OC. Epub ahead of print. PMID: 32614244. Vincent JL, De Backer D. Circulatory shock. N Engl J Med. 2013 Oct 31;369(18):1726-34. doi: 10.1056/NEJMra1208943. PMID: 24171518. Orabona, Rossana & Sciatti, Edoardo & Vizzardi, Enrico & Prefumo, Federico & Bonadei, Ivano & Valcamonico, Adriana & Metra, Marco & Lorusso, Roberto & Ghossein-Doha, Chahinda & Spaanderman, Marc & Frusca, Tiziana. (2018). Inappropriate left ventricular mass after preeclampsia: another piece of the puzzle Inappropriate LVM and PE. Hypertension Research. 42. 10.1038/s41440-018-0163-9. Walley, K.R. Left ventricular function: time-varying elastance and left ventricular aortic coupling. Crit Care 20, 270 (2016). https://doi.org/10.1186/s13054-016-1439-6. Guarracino, F., Baldassarri, R. & Pinsky, M.R. Ventriculo-arterial decoupling in acutely altered hemodynamic states. Crit Care 17, 213 (2013). https://doi.org/10.1186/cc12522 Guarracino F, Bertini P, Pinsky MR. Management of cardiovascular insufficiency in ICU: the BEAT approach. Minerva Anestesiol. 2020 Aug 4. doi: 10.23736/S0375-9393.20.14613-3. Epub ahead of print. PMID: 32755093. 348

Stolk, Roeland & van der Pasch, Eva & Naumann, Flavia & Schouwstra, Joost & Bressers, Steffi & Herwaarden, Teun & Gerretsen, Jelle & Schambergen, Roel & Ruth, Mike & Hoeven, Jg & Leeuwen, Henk & Pickkers, Peter & Kox, Matthijs. (2020). Norepinephrine Dysregulates the Immune Response and Compromises Host Defense During Sepsis. American Journal of Respiratory and Critical Care Medicine. 202. 10.1164/rccm.202002-0339OC. Russell JA. Vasopressin in septic shock: clinical equipoise mandates a time for restraint. Crit Care Med. 2003 Nov;31(11):2707-9. doi: 10.1097/01.CCM.0000092458.16716.EE. PMID: 14605551. De Backer D, Ospina-Tascon G, Salgado D, Favory R, Creteur J, Vincent JL. Monitoring the microcirculation in the critically ill patient: current methods and future approaches. Intensive Care Med. 2010 Nov;36(11):1813-25. doi: 10.1007/s00134-010-2005-3. Epub 2010 Aug 6. PMID: 20689916. Lima A, Jansen TC, van Bommel J, Ince C, Bakker J. The prognostic value of the subjective assessment of peripheral perfusion in critically ill patients. Crit Care Med. 2009 Mar;37(3):934-8. doi: 10.1097/ CCM.0b013e31819869db. PMID: 19237899. Ponticorvo, A., Dunn, A. K. How to Build a Laser Speckle Contrast Imaging (LSCI) System to Monitor Blood Flow. J. Vis. Exp. (45), e2004, doi:10.3791/2004 (2010). https://www.perimed-instruments.com/content/pericam-psi-nr/ Bezemer, Rick & Legrand, Matthieu & Klijn, Eva & Heger, Michal & Post, Ivo & Gulik, Thomas & Payen, Didier & Ince, Can. (2010). Real-time assessment of renal cortical microvascular perfusion heterogeneities using near-infrared laser speckle imaging. Optics express. 18. 15054-61. 10.1364/ OE.18.015054. www.visualsonics.com Lipcsey, M., Woinarski, N.C. & Bellomo, R. Near infrared spectroscopy (NIRS) of the thenar eminence in anesthesia and intensive care. Ann. Intensive Care 2, 11 (2012). https://doi.org/10.1186/2110-5820-2-11 Uz, Z., Ince, C., Guerci, P. et al. Recruitment of sublingual microcirculation using handheld incident dark field imaging as a routine measurement tool during the postoperative de-escalation phase—a pilot study in post ICU cardiac surgery patients. Perioper Med 7, 18 (2018). https://doi.org/10.1186/s13741-0180091-x Ince, C. Hemodynamic coherence and the rationale for monitoring the microcirculation. Crit Care 19, S8 (2015). https://doi.org/10.1186/cc14726 Hilty MP, Guerci P, Ince Y, Toraman F, Ince C. MicroTools enables automated quantification of capillary density and red blood cell velocity in handheld vital microscopy. Commun Biol. 2019;2:217. Published 2019 Jun 19. doi:10.1038/s42003-019-0473-8

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Considerations for Intensive care - a precis Demographics : Age, sex, ethnicity, height, weight, pregnant Co-morbidities : Chronic cardiac disease Arterial hypertension Chronic Pulmonary disease Asthma Chronic Kidney disease HIV Chronic Liver disease Chronic Neurological disorder (seizures, strokes) Diabetes Malignancies Immunosuppression DVT/PE Ambulatory Medications : Ace-inhibitors / ARBS Steroids Immunosuppression Antiplatelets/anticoagulation Vital signs/Labs : Temperature , White count ( Neutrophil , leucocyte) C- reactive protein Pro-calcitonin Ferritin High Sensitive troponin Fibrinogen APTT/PT D dimers Platelet count Complications during ICU stay : Cardiac arrhythmia Sepsis induced Cardiomyopathy Stress myocardiopathy Circulatory failure Myocarditis Pericardial effusion Pneumothorax Atelectasis Delirium Seizure Pressure sores ( facial in case of prone, back in case of supine) 353

Acute Kidney injury Accidental extubation Tube obstruction Hemorrhage: lines, GI, respiratory , CNS Thrombosis : DVT, PE, MI, Stroke, Limb Ischemia, line or filter clot Infections : Bacteremia, Respiratory , Abdominal , UTI , CNS , CLABSI Pathogens : Bacteria- MDR/XDR/PDR, Fungal Eg of MDR : MRSA, VRE, MDR-PA, CRE, ESBL, Acinetobacter Therapies during ICU stay Antibiotics, Antiviral, Antifungals Corticosteroids Gastric Ulcer PPx Vasopressors, inotropes, vasodilators Blood component therapy Beta blockers, CCBs, antiarrhythmatics Sedative- analgesics Fluids, Lasix , RRTs Neuro muscular blockers Respiratory support : NIV, MV , ECMO, prone Tracheostomy Physiotherapy including mobilization Mechanical Ventilation : Mode : VCV, PCV, BIPAP , APRV, PSV Tidal volume, FiO2, P/F ratio, PaCO2, Driving pressure DVT PPx or therapeutic anticoagulation : Heparin unfractionated or Calciparine Fondaparinux Enoxaparin/Dalteparin/Tinzaparin/Nadroparin Antiplatelet PPx : Aspirin/Clopidogrel/Ticlopidine Ticagrelor/Triflusal Bundled Care Appropriate Use of PPE including Hand hygiene Protective mechanical ventilation Minimal use of sedatives , choice of sedative Conservative fluid management strategy Avoidance of Nephrotoxic drug, adjust drug doses to renal function VTE prophylaxis Multidisciplinary rounds Checklists for prevention of ICU acquired complications Infection prevention bundles.

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