1. Multiple Organ Dysfunction Syndrome Presented By: Chaitra M Soumya Ray Moderated By: Dr. Anjolie Chabra www.anaesthesia.co.inanaesthesia.co.in@gmail.com

2. Introduction • MODS is a leading cause of morbidity and mortality in the ICU • Characterization of MODS as a single pathologic entity has been difficult • It is not clear whether MODS is a single pathologic process with highly variable clinical expression or a limited phenotypic expression of large number of divergent processes. • Advances in the support of vital organ functions made possible the identification of disorders with inflammatory basis involving different organ systems.

3. Introduction • A clear understanding of the mechanisms leading to organ dysfunction can help transform critical illness from a standoff to an eminently treatable condition • Clinical trials of treatments are difficult because of the heterogenity of patient population

4. Definitions ACCP-SCCM Consensus Conference, 1991 • Septicemia: Presence of microbes or their toxins in blood • SIRS: Two or more of the following conditions: • Fever >38C or hypothermia< 36C • Tachypnea • Tachycardia • Leukocytosis or leukopenia, or 10% bands • Sepsis: SIRS that has proven or suspected microbial etiology

5. Definitions ACCP-SCCM Consensus Conference, 1991 • Sepsis syndrome (severe sepsis): Sepsis with one or more signs of organ dysfunction • Cardiovascular • Renal • Respiratory • Hematologic • Unexplained metabolic acidosis • Adequate fluid resuscitation (PCWP>12mmHG) • Septic shock: Sepsis with hypotension, for atleast one hour, despite adequate fluid resuscitation or need for vasopressors, to maintain systolic B.P > 90mmHg or MAP – 70 mmHg

6. Definitions ACCP-SCCM Consensus Conference, 1991 • Refractory septic shock: Septic shock lasting for > 1hr and not responding to fluid resuscitation or pressor administration • MODS: Dysfunction of more than one organ requiring intervention to maintain homeostasis…

7. SCCM/ESICM/ACCP/ATS/SISInternational Sepsis Definitions Conference, 2001 * * *

8. * * * * SCCM/ESICM/ACCP/ATS/SISInternational Sepsis Definitions Conference, 2001

9. SCCM/ESICM/ACCP/ATS/SISInternational Sepsis Definitions Conference, 2001 * * * * *

10. The PIRO System of staging sepsis

12. Pathophysiology of sepsis/MODS

13. Canonical model of sepsisFrom Brunn and Platt, Trends Mol Med, 2006

14. Drawbacks of the canonical model • LPS is not detected in all patients with sepsis • LPS does not predict severity or outcome of SIRS/sepsis • Sepsis and SIRS have similar clinical presentation • Sepsis complicates gram+ve and fungal infections (where LPS is not involved) • Agents that block LPS do not improve outcome of sepsis • “Something other than LPS or PAMPs probably causes SIRS”

15. New model for sepsis/SIRSFrom Brunn and Platt, Trends Mol Med, 2006

16. Some endogenous activators of Toll-like receptors

17. Etiology • Infection • Trauma • Ischemia • Burns • Cancer • Pancreatitis • Transplantation • Pulmonary embolism • Ruptured/dissecting aneurysm • Post-CPB • Cardiac tamponade • Anaphylaxis

18. New model for sepsis/SIRS

19. Microbial invasion of bloodstream is not essential for development of severe sepsis • Blood cultures are positive in only 20-40 % of cases with severe sepsis, and 40-70% of cases of septic shock • Local inflammation can also elicit distant organ dysfunction and hypotension

20. Role of endothelium

21. Role of endothelium, cont’d E selectin,metalloproteinases,IL-8,ICAM,VCAM Vacuolisation, disintegration, apoptosis • Procoagulation (inhibition of thrombomodulin, Protein C, Protein S) • Loss of vasomotor tone • Increased permeability [thrombin,tnf] • Microvascular occlusion • Hypoxia • Organ dysfunction

22. Link between endothelial cell dysfunction and MODS • Endothelium is differentially regulated in time and space • Available data suggests – vascular beds regulated in different ways in organs • Changes in sepsis – initiate and perpetuate site specific inflammation and endothelial dysfunction

23. Link between endothelial cells, neutrophils and MODS

24. Cytokine code for septic shock and MODS Tracy et al, Trends Mol Med 2005 • TNF-α is necessary and sufficient for septic shock • But antibodies against TNF-α can worsen outcome in severe sepsis (Escandary et al, J Immunol, 1992) • High mobility group box 1 (HMGB1) mediates MODS

25. Cytokine code for septic shock and MODS Tracy et al, Trends Mol Med 2005 TNF HMGB1 IL-1 days hours

26. Role of gastrointestinal tractHassoun et al, Shock, 2001

27. Cellular hibernation(Hotchkiss et al, NEJM, 2003) • Degree of organ dysfunction – does not correlate with microscopic histopathogic findings in autopsy studies • Cells – relatively well preserved in contrast to degree of dysfunction • Cell stunning/hibernation therefore is proposed to occur. • Basic housekeeping functions preserved

28. Emerging concept of immune response in sepsis(Hotchkiss et al, NEJM, 2003)

29. Interventions that have improved mortality • Activated Protein C • Low dose glucocorticoids • Intensive insulin therapy • Early goal directed therapy

30. Therapeutic targets

31. Therapeutic challenges • Timing • Complexity of host-response • Usage of interventions with wider therapeutic net • Target non-redundant sites • Implications for clinical trails of drugs

32. Physiological consequences • Increased O2 demand • Altered O2 transport • Altered O2 extraction

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