Management of Dysregulated Immune Response in the Critically Ill

Foreword
Preface
Contents
Contributors
I: The Host Immune Response
1: Phenotypes
1.1 Introduction: The Critically Ill, a Heterogeneous Population
1.2 Subphenotypes Identified in Critically Ill Patients
1.2.1 Sepsis
1.2.2 Acute Respiratory Distress Syndrome
1.2.3 Acute Kidney Injury
1.2.4 Implications of Identified Subphenotypes
1.3 The Immune Response in Subphenotypes
1.3.1 Innate Immune Response
1.3.2 Adaptive Immune Response
1.3.3 Implications of the Immune Response in Subphenotypes
1.3.4 Unique or Generalizable?
1.4 Future Challenges
References
2: The Dysregulated Host Response
2.1 Introduction
2.2 The Inflammatory Response in Severe Infection
2.3 The Immune Depression in Sepsis (Early and Late Phase)
2.3.1 The Immune Phases
2.3.2 The “Downregulation” of Monocyte/Macrophages
2.3.3 The Immunodepression and Adaptive Immunity
2.3.4 The Proteomic Consequences
2.4 The Role of Cellular Metabolism
2.4.1 The Aerobic Glycolysis or “Warburg Effect” (. Fig. 2.2 [57])
2.4.2 The Hypoxia-Inducible Factor (HIF)
2.4.3 The Regulation of the Immune Response by mTOR [68]
2.4.4 The Combination of Mediated mTOR and HIF-1α Aerobic Glycolysis: A Basis for Trained Immunity [3, 5] (. Fig. 2.4)
2.4.5 The Liaison Between Metabolic Shift Modifications and Functions of Immune Cells
Conclusion and Road Map for the Future
References
3: What Is Cytokine Storm?
3.1 Introduction
3.2 Pathophysiology of CS
3.3 Inflammation Due to Sepsis
3.4 Hypercytokinemia in Sepsis
3.5 Hypercytokinemia in Post-cardiac Arrest Syndrome
3.6 Endotoxin-Induced CS
3.7 CS After Splenectomy
3.8 Invasive Meningococcal Disease (IMD)
3.9 COVID-19
3.10 Iatrogenic CS
3.11 After the Storm
3.12 Summary
References
4: Hemophagocytic Lymphohistiocytosis
4.1 Introduction
4.2 Types
4.3 Epidemiology
4.4 Triggers and Underlying Conditions
4.5 Pathobiology
4.6 Clinical Presentation
4.7 Diagnosis
4.8 Treatment
4.9 Macrophage activation syndrome (MAS-HLH)
4.10 HLH and Sepsis
4.11 Prognosis
4.12 Summary
References
5: Extracorporeal Circulation-Related Immune Response
5.1 Introduction
5.2 Extracorporeal Circulations in ICU Practice
5.2.1 Renal Replacement Therapy
5.2.2 ECMO
5.3 Extracorporeal Circulation-Related Immune Response and the Clinical Implications
5.3.1 Contact and Complement System
Contact System
Complement System
5.3.2 Inflammatory Cytokine and Chemokine Response
5.3.3 Leukocytes
Impact on the Innate Immune Leukocytes: Neutrophils and Monocytes
Impact on Neutrophil Phenotype and Function
Impact on Monocyte Phenotype and Function
Impact on the Adaptive Immune Leukocytes: T and B Lymphocytes
Impact on T and B Lymphocyte Phenotype and Function
5.4 Causes of Extracorporeal Circulation-Related Immune Response
5.4.1 RRT and ECMO Technology (ECC Circuit Designs and Materials)
Blood Pumps
Membranes
RRT Filter Membranes
ECMO Membrane Oxygenator
5.4.2 Non-physiological Conditions
5.5 Priorities for Future Research: Potential Therapeutic Interventions in ECC-Associated Immune Response
5.5.1 Knowing the Technological Disparities
5.5.2 Understanding Factors Contributing to RRT- and  ECMO-Related Immune Modulation
5.5.3 Potential Interventions and Targets for RRT- and  ECMO-Related Immune Modulation
References
6: Septic Shock
6.1 Introduction
6.2 Of Infection, Mediators, and Vasodilation
6.3 Parameters of Tissue Perfusion in Early Resuscitation
6.3.1 Blood Pressure
6.3.2 Lactate Levels
6.3.3 Central Venous Oxygen Saturation (ScvO2)
6.3.4 Central Venous to Arterial PCO2 Difference (dPCO2)
6.3.5 Peripheral Perfusion
6.3.6 Holistic Approach
6.4 On the Use of Fluids
6.4.1 The Physiology
6.4.2 On the Volume of Fluids
6.5 On the Use of Vasoactive Medication
6.5.1 Vasopressors
Norepinephrine
Vasopressin
Phenylephrine
Other
Vasoplegia in the Context of Decreased Vasoresponsiveness
6.5.2 Inodilators
Dobutamine
Use of Alternative Inotropes
6.5.3 Mitigating the Adrenergic Response
References
II: Assessing Dysregulated Immune Response at the Bedside
7: Pro- and Anti-inflammatory Biomarkers
7.1 Introduction
7.2 Pro- and Anti-inflammatory Biomarkers
7.3 Separating Pro- and Anti-inflammatory Biomarkers?
7.4 Combining Cytokine Levels?
7.5 Clinical Applications of Biomarkers
References
8: How to Interpret Procalcitonin?
8.1 Introduction
8.2 Evidence Regarding PCT-Guided Antibiotic Stewardship
8.3 Practical Considerations for Use of PCT
8.4 Limitations of Procalcitonin
References
9: Assessment of the  Macro- and Microcirculation
9.1 Introduction
9.2 Coupling Macro- and Microcirculation: Monitoring Peripheral Perfusion in Critically Ill Patients
9.2.1 Role of Blood Lactate
9.3 Clinical Assessment of Peripheral Perfusion
9.3.1 Role of the Capillary Refill Time
9.4 Peripheral Perfusion Assessed by Skin Functional and Clinical Assessment
9.4.1 Skin Temperature and Mottling
9.5 Optical Monitoring
9.5.1 Peripheral Perfusion Index
9.5.2 Near-infrared Spectroscopy
9.5.3 Assessment of Microvascular Perfusion
References
III: Dysregulated Immune Response and Organ Dysfunction
10: Management of Dysregulated Immune Response in the Critically Ill: Heart and Circulation
10.1 Inflammation in Cardiovascular Diseases
10.1.1 The Central Role of Cytokines in Inflammation During Cardiovascular Diseases
10.1.2 The Pivotal and Critical Role of NLRP3 Inflammasome in Acute Myocardial Infarction (AMI)
10.2 Inflammation in Septic Cardiomyopathy
10.3 Inflammation and Cardiac Arrhythmias
10.4 Inflammation in Acute Heart Failure and Cardiogenic Shock
10.5 Inflammation and Vascular System
10.5.1 Endothelial Dysfunction
10.5.2 Glycocalyx Breakdown
10.5.3 Junction Protein Dysregulation
10.6 Long-Term Impact of Critical Care on Cardiovascular Health: Immune Scar
10.7 Therapeutic Approach of Inflammation During CVD
10.7.1 Anakinra
10.7.2 Colchicine
Anti-inflammatory Mechanisms
Therapeutic Benefits
10.7.3 Steroids
Conclusion
References
11: Brain
11.1 Introduction
11.2 Epidemiology
11.3 Pathophysiology
11.4 Biomarkers to Measure Neuroinflammation
11.5 Neuroinflammation in Systemic Inflammatory Conditions
11.6 Future Perspectives
References
12: Dysregulated Immune Response and Kidney Dysfunction
12.1 Introduction
12.2 Normal Physiology
12.3 Acute Kidney Injury
12.3.1 Endothelial Dysfunction
12.3.2 Microcirculatory Dysfunction
12.3.3 Tubular Cell Injury
12.3.4 Intrarenal Inflammation
12.4 Additional Factors Contributing to Inflammation in AKI
12.4.1 Haemodynamic Instability
12.4.2 Renal Venous Congestion
12.4.3 Tubular Obstruction
12.4.4 Hypersensitivity Immune Reactions
12.5 AKI Sub-types
12.6 Organ Crosstalk
12.7 Renal Repair/Progression
12.8 Management
References
13: Dysregulated Immune Response and Organ Dysfunction: Liver
13.1 Introduction
13.2 Immune Competent Cells of the Liver and Their Function
13.2.1 Hepatic Lymphocytes
13.2.2 Myeloid Cells in the Liver
13.2.3 Liver Sinusoidal Endothelial Cells
13.2.4 Hepatic Stellate Cells
13.2.5 Hepatocytes
13.3 Liver Impairment in Patients with Critical Illness
13.4 The Liver in Systemic Inflammation and Sepsis
13.5 Management of Liver Failure in Critical Illness
13.6 Targeting Immune Dysregulation in Liver Disease
References
14: Hemostasis
14.1 Introduction
14.2 The Pathophysiology of Inflammation-Induced Coagulopathy
14.2.1 Normal Hemostasis
14.2.2 Inflammation-Induced Alterations in the Coagulation System
14.3 Specific Forms of Inflammation-Induced Coagulopathy
14.3.1 Disseminated Intravascular Coagulation
14.3.2 Sepsis-Induced Coagulopathy (SIC)
14.3.3 Malignancy-Associated DIC
14.3.4 Obstetric Associated DIC
14.3.5 COVID-Associated Coagulopathy: An Exception to this Chapter
14.3.6 Trauma-Induced Coagulopathy (TIC)
14.4 Diagnosis of Inflammation-Induced Coagulopathy
14.4.1 Disseminated Intravascular Coagulation
14.5 Viscoelastic Tests in the Diagnosis of Inflammation-Induced Coagulopathy
14.6 Clinical Consequences of Inflammation-Induced Coagulopathy
14.6.1 Risk of Bleeding: Incidence and Risk Factors
14.6.2 Risk of Thromboembolic Events: Incidence and Risk Factors
14.6.3 Organ Failure
14.6.4 Mortality
14.7 Prevention of Bleeding in Inflammation-Induced Coagulopathic Patients
14.7.1 Prophylactic Platelet Transfusion
14.7.2 Prophylactic Plasma Transfusion
14.7.3 Tranexamic Acid
14.7.4 Prevention of Bleeding in Coagulopathic Patients Undergoing an Invasive Procedure
14.7.5 Treatment of Bleeding in Inflammation-Induced Coagulopathic Patients
14.8 Clinical Management of Risk of Thrombosis
14.8.1 Pharmacological Thromboprophylaxis
14.8.2 Type of Pharmacological Thromboprophylaxis
14.9 Management of Patients with DIC
14.9.1 Anticoagulant Treatment of (Micro)thrombotic Events
14.9.2 Substitution of Anticoagulant Proteins
14.10 Treatment of Thrombosis in Inflammation-Induced Coagulopathy
References
15: Dysregulated Immune Response and Organ Dysfunction: The Muscles
15.1 Introduction
15.2 Critical Illness-Associated Muscle Wasting
15.3 Muscle Metabolism and Mitochondrial Dysfunction in Critical Illness
15.4 Immune Dysfunction in Critical Illness
15.4.1 Persistent Inflammation, Immunosuppression, and Catabolism Syndrome
15.4.2 Intramuscular Inflammation, Mitochondrial Dysfunction, and Myocyte Necrosis
Systemic Inflammation as a Cause for Necrosis
Mitochondrial Dysfunction as a Cause of Myocyte Necrosis
15.4.3 So Which Mechanism Predominates?
References
IV: Modulating the Immune Response
16: The Role of Steroids
16.1 Introduction
16.2 Pathophysiology of Sepsis Relevant to Corticosteroids
16.3 Should Glucocorticoids Be Used in Sepsis?
16.4 When and How to Administer Glucocorticoids in Septic Shock
16.4.1 When Should Steroids Be Administrated in Septic Shock?
16.4.2 What Dose of Steroids Should Be Administered?
16.4.3 Should Fludrocortisone Be Associated with Hydrocortisone?
16.4.4 What Is the Optimal Duration of Glucocorticoid Administration?
16.4.5 Should Glucocorticoids Be Tapered Off?
16.4.6 What Are the Main Side Effects of Steroids?
16.4.7 Should Other Conditions Be Treated by Glucocorticoids in the ICU?
16.4.8 Can Glucocorticoid Treatment Be Personalized in Sepsis?
References
17: Anti-cytokine Therapy in Critical Illness: Is There a Role?
17.1 Introduction
17.2 Cytokines in the Regulation of a Systemic Response to Danger: A Historical Perspective
17.2.1 Cytokines and Hormones: How Do They Differ?
17.2.2 Cytokines: An Evolving Understanding
17.2.3 How Do Cytokines Alter Cellular Functioning?
17.3 Cytokine-Targeted Therapy in Chronic Inflammatory Diseases
17.3.1 Rheumatoid Arthritis
17.3.2 Other Autoimmune Disorders
17.3.3 Inflammatory Bowel Disease
17.3.4 Oncology
17.3.5 Other Diseases
17.4 Targeting Cytokines in Acute Inflammatory Diseases
17.4.1 Preclinical Insights
17.4.2 Insights from Clinical Trials in COVID-19
17.5 Cytokine-Targeted Therapy in Sepsis
17.5.1 The Story So Far
17.6 Why Have Clinical Trials of Anti-cytokine Therapy for Sepsis Been So Disappointing?
17.6.1 Sepsis Is Intrinsically Heterogeneous
17.6.2 The Innate Immune Response Is Vital to Effective Anti-infectious Host Defense
17.6.3 The Host Innate Immune Response Is Biologically Redundant
17.6.4 Preliminary Evaluation of Potential Strategies Is Often Inadequate
17.6.5 Mortality Endpoints Are Insensitive to Potential Benefits
17.6.6 Timing, Dose, and Duration of Treatment Are Poorly Understood
17.6.7 The Study Model Is Ill-Adapted to Understand the Reasons for Failure
17.6.8 Sepsis Lacks Effective Systems for Staging and Stratification
References
18: Extracorporeal Cytokine Removal
18.1 Introduction
18.2 High-Flux and High-Cutoff Hemofilters
18.3 Adsorptive Hemofilters
18.4 Dedicated Hemoadsorption Columns
18.5 Combined Plasma Filtration and Adsorption or Therapeutic Plasma Exchange
18.6 Summary
References