What common features are shared among various forms of shock?

1. What common features are shared among various forms of shock? Anthony F. Suffredini M.D. Critical Care Medicine Department National Institutes of Health Bethesda, MD, USA

2. Reduced Tissue Perfusion Common Shock Syndromes Hypovolemic Shock Severe hemorrhage Extensive trauma Burns Gastrointestinal loss Cardiogenic Shock Myocardial infarction Mechanical complications Extrinsic compression Outflow obstruction Septic Shock Severe infection with systemic inflammation

3. Acute Mortality of Shock Syndromes N Eng J Med 2001; 344:699 JAMA 2002; 288: 862 JAMA 2005; 294:448 Circulation 2005; 112: 1992 N Engl J Med 1994; 331:1105 J Trauma 1998; 45:545

4. Common Features of Shock Syndromes • Clinical signs • Histopathology • Mechanisms of cell injury • Systemic inflammation • Immunosuppression

5. Common Nonspecific Clinical Signs of Shock Syndromes • Hypotension • Rapid, weak pulse • Decreased skin perfusion • Pallor, cold, cyanosis, mottling • Early sepsis warm, flushed • Late sepsis cool extremities • Altered sensorium • Urine output low or absent

6. Arterial / arteriolar constriction Pulm cap press Cardiac output Syst vasc res Capillary flow Hemodynamic Profiles Hypovolemic Cardiogenic Septic Low resistance High resistance

7. Shock and Myocardial Depression Ann Intern Med 1984; 100:483 Circulation 2005; 112:1992 J Trauma 1998; 45: 470

8. Are there common histopathologic patterns associated with tissue hypoperfusion and shock?

9. Myocardium Lung Coagulative necrosis Contraction bands Edema Neutrophil infiltrate Diffuse alveolar damage Exudate, atelectasis Edema Hyaline membrane Histopathology of Tissue Hypoperfusion Associated with Shock Robbins & Cotran Pathologic Basis of Disease: 2005

10. Liver Small Intestine Mucosal infarction Hemorrhagic mucosa Epithelium absent Centrilobular hemorrhagic necrosis Nutmeg appearance Histopathology of Tissue Hypoperfusion Associated with Shock Robbins & Cotran Pathologic Basis of Disease: 2005

11. Brain Brain Bland infarct Punctate hemorrhages Eosinophilia and shrinkage of neurons Neutrophil infiltration Histopathology of Tissue Hypoperfusion Associated with Shock Robbins & Cotran Pathologic Basis of Disease: 2005

12. Kidney Pancreas Tubular cells, necrotic Detached from basement membrane Swollen, vacuolated Fat necrosis Parenchymal necrosis Histopathology of Tissue Hypoperfusion Associated with Shock Robbins & Cotran Pathologic Basis of Disease: 2005

13. Incidence of Ischemic Histopathology in Patients Dying with Shock McGovern VJ, Pathol Annu 1984;19:15

14. Tissue and Cell Hypoperfusion What are the mechanisms that contribute to cell injury?

15. Loss of selective membrane permeability Mitochondrial dysfunction Mechanisms Underlying Cell Injury from Ischemia

16. Anaerobic glycolysis Detachment of ribosomes Na pump Glycogen pH Protein synthesis Influx of Ca2+ H20, and Na+ Efflux of K+ ER swelling Cell swelling Blebs Lipid deposition Clumping chromatin Functional and Morphologic Consequences of Decreased ATP During Cell Injury Ischemia Oxidative Phosphorylation ATP

17. Mitochondrial Dysfunction in Cell Injury Increased cytosolic Ca2+, oxidative stress, lipid peroxidation Cytochromec and other pro-apoptotic proteins Mitochondrial PermeabilityTransition Robbins & Cotran Pathologic Basis of Disease: 2005 Apoptosis

18. Extracellular Ca2+ Mitochondrial Ca2+ Endoplasmic Reticulum Ca2+ Cytosolic Ca2+ Phospholipase Protease Endonuclease ATPase Disruption of membrane and cytoskeleton proteins Chromatin damage ATP Phospholipids Membrane Damage Role of Increased Cytosolic Calcium in Cell injury

19. Triggers Inflammatory cytokines Cell damage Redox-sensitive signaling pathways Defective host defenses Antioxidant Defenses Enzymatic systems Catalase, SOD Glutathione peroxidase Non-enzymatic systems Glutathione Vitamins (A, C, E) Cell death Hypoperfusion and Oxidative Stress Endogenous Sources Mitochondria Peroxisomes Lipoxygenases NADPH oxidase Cytochrome p450 Reactive Oxygen Species

20. Summary of Mechanisms of Cell Injury and Hypoperfusion • Cell and tissue damage depend in part on the • duration and severity of injury • pre-existing state of cell • ability to adapt to injurious stimuli • Hypoperfusion compromises • Aerobic respiration and energy production • Cell membrane integrity • Protein synthesis • Genetic integrity

21. Does systemic inflammation occur in all shock syndromes?

22. IL-6 (pg/mL) Controls SS and MOF CS and OF CS and MOF Cardiogenic Shock Septic Shock Geppert A, Crit Care Med 2002; 30:1987 TNF and IL-6: Septic vs Cardiogenic Shock TNF (pg/mL) IL-6 (pg/mL) N = 29 Controls Cardiogenic Shock Septic Shock deWerra I, Crit Care Med 1997; 25:607

23. TNF and IL-6: Septic vs Hemorrhagic Shock Martin C, Crit Care Med 1997; 25:1813

24. TNF (pg/ml) sTNFR1 (ng/ml) sTNFR2 (ng/ml) TNF, sTNFR1 and sTNFR2 after Trauma N = 47 ISS median 32.5 (17-61) Spielmann S, Acta Anaesthesiol Scand 2001: 45:364

25. Summary of Systemic Inflammation Associated with Shock Syndromes • Systemic inflammation is present in varying degrees in all shock syndromes • Increased leuckocytes, CRP, cytokines, other biomarkers • Septic shock has higher levels of cytokines and inflammatory biomarkers than either hemorrhagic or cardiogenicshock • Magnitude of biomarker elevation may be associated with new infection or severity of organ failure

26. Are all shock syndromes associated with immunosuppression?

27. E. Coli stimulation of whole blood N = 10 / group S. aureus stimulation of whole blood N = 10 / group 8 2.5 7 2 TNF (ng/ml) TNF (ng/ml) 6 5 1.5 4 1 3 2 0.5 1 Septic Shock Septic Shock Control Control 0 0 Cardiogenic Shock Cardiogenic Shock Pneumonia Pneumonia Suppressed Whole Blood TNF Production in Septic and Cardiogenic Shock De Were I, Swiss Med Wkly 2001; 131:35

28. Healthy controls n = 10 LPS stimulated whole blood TNF (U/ml) Trauma patients n = 18 Days After Injury ISS 24 (17 - 45) Suppressed Whole Blood TNF Production after Severe Blunt Trauma Majetschak M, J Trauma 1997; 43:880

29. Summary of Immunosuppression Associated with Shock Syndromes • Circulating leukocytes from patients with septic, cardiogenic or traumatic shock have impaired cytokine responses to microbial products • Mechanisms associated with depressed host responses include: • Circulating molecules • anti-inflammatory cytokines, hormones, catecholamines, ubiquitin • Altered cell phenotypes

30. Summary of Common Features Among Shock Syndromes • Fundamentally different etiologies underlie shock associated with severe infections, myocardial infarction or hypovolemia • Common elements that link the morbid events of these syndromes are hypotension and decreased tissue perfusion

31. Summary of Common Features Among Shock Syndromes • Hypoperfusion leads to cell injury and organ dysfunction due to alterations in cell permeability and mitochondrial energy production • Systemic inflammation and impaired host immune responses occur in all three shock syndromes • While shock resuscitation is directed at improving tissue hypoperfusion, definitive therapy requires syndrome-specific interventions