Bradley J. Phillips, MD Burn-Trauma-ICU Adults & Pediatrics

1. Bradley J. Phillips, MDBurn-Trauma-ICUAdults & Pediatrics SIRS & Sepsis: what are we doing and why ?

2. “Sepsis” the difference between infectionandinflammation • We must try to differentiate between the two… If we consider signs of inflammation (fever, leukocytosis) as actual evidence of infection, we clinically fuse two distinct entities…leading to the possibility of errors in decision-making and potentially, altering outcome-events.

3. The Inflammatory Response • Complex series initiated by an insult to the host • Microbial invasion • Physical trauma • Burns • Chemical irritants • Purpose is to protect the host 200 yrs ago, John Hunter pointed out that this response can actually injure the host

4. Inflammation: Protection vs. Injury Marino, 2nd ed.

5. Clinical Syndromes The relationship between infection, inflammation, and organ injury • Fever + Leukocytosis = SIRS • SIRS + Infection = Sepsis • Sepsis + Multiorgan Dysfunction = Severe Sepsis • Severe Sepsis + Refractory hypotension = Septic Shock [ACCP/ SCCM]

6. SIRS: definition ACCP/SCCM Consensus Conference on Sepsis & Organ Failure. (Chest 92;101:1644-1655.)

7. SIRS • In one study of 170 patients in a SICU, 93% satisfied the criteria for SIRS. [Pittet et al. ICMed 95;21:302-309] • Of those with SIRS, infection is identified in only 25 – 50% of patients. [Pittet et al. ICMed 95;21:302-309] [Rangel et al. JAMA 95;273:117-123]

8. Multiple Organ Dysfunction Syndrome • Triggering Insult… • Activated neutrophils in the circulating stream • Endothelial activation and expression of adhesion molecules • Once adherent, the neutrophils release their granular contents • Proteolytic enzymes • Oxygen metabolites damages the endothelium (which directly decreases thrombomodulin levels), permitting infiltration of the tissue parenchyma with the plasma contents and inflammatory mediators, leading to organ dysfunction

9. MODS Organ SystemClinical Syndrome Lungs ARDS Kidneys ATN / ARF Heart Hyperdynamic Hypotension Central nervous system Metabolic Encephalopathy Peripheral nervous system ICU Polyneuropathy Coagulation system DIC GI Tract Gastroparesis / Ileus Liver Noninfectious Hepatitis Adrenal glands Acute Adrenal Insufficiency

10. MODS: mortality directly related to the number of organs that fail

11. Severe Sepsis & Septic Shock Both of these are conditions in which multiorgan dysfunction is due to INFECTION • The only difference between these two is the presence of volume-resistant hypotension in septic shock… • The tendency to develop one (or both) of these conditions is NOT a function of the organism involved in the actual infectious process…but rather, the degree of HOST RESPONSE.

12. Nosocomial Septicemia: ICU Patients Pittet D et al. [JAMA 94;271:1598-1601]

13. Hemodynamics in Sepsis (1) • Early Stages • Hypovolemia • Relative - venous pooling • Absolute – transudation of fluid • Hypodynamic state • Low cardiac output due to BOTH systolic & diastolic impairment • Intrinsic decrease in contractile function • Though the mechanism has yet to be understood • Mysterious “myocardial depressant factor”

14. Hemodynamics in Sepsis (2) “but I thought sepsis was a hyperdynamic process…” • It is, early on – but only AFTER intravascular volume has been restored • The subsequent increase in Cardiac Output is due to a reflexive tachycardia NOT an actual increase in stroke volume • Late stages: sepsis becomes a hypodynamic state • Due to a reduced blood flow & peripheral vasoconstriction

15. Oxygen Transport in Sepsis (1) • Severe sepsis & septic shock are classically characterized by a defect in the peripheral extraction of oxygen “ OXYGEN DEBT ” • As peripheral blood flow decreases, the normal ability to extract molecular oxygen is impaired leading to a decrease in VO2 This cellular hypoxia decreases pyruvate metabolism and leads to anaerobic conversion of glucose to lactate in an attempt to salvage energetic losses

16. Oxygen Transport in Sepsis (2) Cellular Conservation of Glucose

17. Why is sepsis “so critical” ? The current rate of death from Severe Sepsis ranges from 30 – 50 %. • In the U.S., there are ~ 750,000 cases of sepsis each year. • Of these, at least, 225,000 are fatal. [NEJM 2001;344(10)]

18. Sepsis: how should we treat it ? (1) Mainstay of Early Treatment: Aggressive Volume Infusion • Crystalloid vs. Colloid ? • Tx of Hypoalbuminemia ? • End-point of volume infusions (what numbers are right ?) • CVP or Swan ? • Role of Vasotonics to treat associated hypotension ? • Dopamine, Levophed, Neo…

19. Sepsis: how should we treat it ? (2) Oxygen Transport: is there a role for the transport variables ? • Target parameters ? • Normal whole-body oxygen uptake… (VO2 > 100) • Supranormal delivery approach…(DO2 > 600, VO2 > 170) • Supply-dependence ? • Role of dobutamine ? is the treatment of “septic shock” similar to “major resuscitation”

20. Resuscitation Efforts: Patient Scenarios • 76 yr. old Female • 36 % TBSA Burn: 2nd / 3rd Degree with Inhalation • Caught in a Housefire - carried out by Firefighters • Medical Hx: “Hypertension” • Intubated/Supportive Ventilation • Hyperdynamic Protocols Initiated • 42 Hours Post-Admission: coded • Autopsy: Acute MI with Rupture of Left Ventricle (Phillips, Matthews, Schiller, Malone, & Shoemaker. in press)

21. Hemodynamic Parameters

22. Relationship:Serum Lactate & Cardiac Index

23. Patient Scenarios (2) • 42 yr. old Female • 30 % TBSA, 3rd Degree Burn • Barbecue Gas-Explosion • Compartment Syndrome to Right U.E. • Followed with Tissue Pressures • 8 hours after injury, required escharotomy • Resuscitated without event • Survived injury - transferred to E.C.F. (Phillips, Matthews, Schiller, Malone, & Shoemaker. in press)

24. Serum Lactate & Cardiac Index

25. Patient Scenarios (3) • 60 yr. old Male • 35 % TBSA Burn, 3rd Degree • Seized and fell into a bonfire • Compartment Syndrome to Right Upper Extremity • E.D. Fasciotomy (by phone) • 20 hour-delayed presentation to Burn Center • Shock State - Rhabdomyolysis/ATN • Unresponsive to Resuscitative Efforts • Eventual End-organ Collapse (Phillips, Matthews, Schiller, Malone, & Shoemaker. in press)

26. VO2 & DO2 vs. Time

27. Gastric Tonometry: pH(a)vs. pH(R)

28. Serum Lactate & Cardiac Index

29. so, even with all that information & all those tools, we still can’t treat sepsis…???there must be a way - other options ? Critical Care Medicine Boston Medical Center

30. Sepsis: how should we treat it ? (3) Empiric Antibiotics • Yes or No ? • Which antimicrobial agents should be used… • Early stages ? • Late-stages ? • Given that “septic shock”, by definition carries evidence of multiorgan dysfunction, how should we dose the antibiotics • would this have any effect on subsequent organ failure ? • What is the expected course & rationale management for “empiric” treatment…when, if ever, do we stop the antibiotics ?

31. Sepsis: how should we treat it ? (4) Steroids • 1960’s: High-dose steroids directly employed • American Infectious Disease Society: • “steroids should be avoided in patients with sepsis” Any new studies or approaches ?

32. Sepsis: Treatment Arms Marino, 2nd ed.

33. Sepsis: novel ideas (1) Anti-Inflammatory Antibodies • Anti-endotoxin antibody • Anti-TNF antibody • Anti-IL1 antibody • Large clinical studies have not shown a benefit… • McCloskey et al. Ann Intern Med 94;121:1-5 • Abraham et al. JAMA 95;273:934-941 • Fischer et al. JAMA 94; 271:1836-1843.

34. Sepsis: novel ideas (2) Antioxidant Therapy • Academically, seems to be a sound approach to limit metabolite-induced organ injury • PROBLEM: very little clinical science or investigation… • IV N-acetylcysteine may help with A.R.D.S….but confirmation is needed on a large-scale basis

35. Anti-oxidant Therapy Selenium (glu. Peroxidase) Glutathione (acts via reduction) N-acetylcysteine (a glutahione analog) Vit. E (blocks lipid peroxidation) Vit. C (pro-oxidant to maintain iron as Fe(II) Aminosteroids (? lipid peroxidation)

36. Sepsis: novel ideas (3) Activated Protein C APC, an endogenous protein that promotes fibrinolysis, is an important modulator of the coagulation and inflammation associated with severe sepsis. APC is converted from its inactive precursor, protein C, by thrombin coupled to thrombomodulin. The conversion of protein C to APC may be impaired during sepsis as a result of down-regulation of thrombomodulin by inflammatory cytokines. [NEJM 2001;344(10)]

37. Sepsis: novel ideas (4) Activated Protein C Reduced levels of protein C are found in the majority of patients with sepsis and are associated with an increased risk of death [NEJM 2001;344(10)]

38. Activated Protein C: PROWESS 19.4% decrease in the R.R. of death 6.1% decrease in the A.R. of death [NEJM 2001;344(10)]

39. APC: PROWESS Risks vs. Benefit [NEJM 2001;344(10)]

40. APC: “Economic Evaluation” Can we afford to treat ? Can we afford NOT to treat ? NEJM 2002;347(13)

41. Mortality Rates as a Baseline The clinical utility of APACHE Scores…and do we track it ?

42. SEPSIS in the Year 2002 what should we be doing & why ?

43. SEPSIS: A Targeted Approach Severe Sepsis -----------------------Septic Shock Aggressive Volume & Tissue Perfusion Antioxidants Antibiotics APC Toxic Metabolites Active Infection Inflammatory Response Circulatory Stasis

44. SIRS & SEPSIS what should we be doing & why ? Shriners Hospital for Children UTMB