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Management of Sepsis


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Management of Sepsis

  1. 1. Management of Sepsis Luca Bigatello, MD Director, Surgical ICU, Massachusetts General Hospital Associate Professor of Anesthesia, Harvard Medical School
  2. 2. Definitions <ul><li>Sepsis : proven or suspected infection, with a systemic response (fever, tachycardia, tachypnea, leukocytosis) </li></ul><ul><li>Severe sepsis : sepsis, with organ dysfunction </li></ul><ul><li>Septic shock : severe sepsis, with hypotension despite adequate fluid resuscitation </li></ul>Bone et al ., Crit Care Med ‘92 SCCM/ etc ., Crit Care Med ‘03
  3. 3. Sepsis & Septic Shock <ul><li>750,000 septic ICU pts. per year </li></ul><ul><li>> 200,000 die, slightly more than all deaths from acute coronary syndromes </li></ul><ul><li>Leading cause of death in ICU pts. </li></ul>Hotchkiss & Karl, NEJM ‘03
  4. 4. <ul><li>Early intervention: </li></ul><ul><ul><li>early and appropriate use of abx. </li></ul></ul><ul><ul><li>early goal- directed therapy </li></ul></ul><ul><li>Corticosteroids </li></ul><ul><li>Tight BS control </li></ul><ul><li>r-aPC </li></ul><ul><li>Vasopressors, inotropes </li></ul><ul><li>Blood products administration </li></ul><ul><li>Lung- protective ventilation for ALI/ARDS </li></ul><ul><li>Targeted sedation / daily wakeups </li></ul><ul><li>VAP, DVT, PE, stress ulcer prophylaxis </li></ul><ul><li>Renal replacement therapy </li></ul><ul><li>Consideration for limitation of support </li></ul>20 Societies- CCM ’08;36:296
  5. 5. Early Antibiotic Therapy <ul><li>Evidence not strong, but it seems common sense </li></ul><ul><li>Prioritization and implementation may be the hurdles </li></ul>Kumar et al ., CCM ’06;34:1589 <ul><li>Retrospective review of 2,700 pts. with SS </li></ul><ul><ul><li>80% received effective abx. after onset of hypotension </li></ul></ul><ul><ul><li>Significant effect of timing on survival rate </li></ul></ul><ul><li>Start appropriate abx. ASAP, after cultures </li></ul>
  6. 6. Early Goal-Directed Therapy: RCT <ul><li>260 septic pts. in ER: </li></ul><ul><li>6 hrs. of early goals: </li></ul><ul><ul><li>MAP  65, CVP  10, U.O.  0.5 ml/kg/h, ScvO 2  70% </li></ul></ul><ul><ul><li>Volume, vasopressors, transfusions </li></ul></ul>Rivers et al ., NEJM ’01;345:1368 <ul><li>Goal-directed arm, @ 6 hs.: </li></ul><ul><ul><li> BP, ScvO 2 </li></ul></ul><ul><ul><li>more fluids, red cells, inotropy </li></ul></ul><ul><ul><li>goals achieved 94- 99 % of pts. </li></ul></ul><ul><li>Goal-directed arm, @ 72 hs.: </li></ul><ul><ul><li> BP, ScvO 2 ,  HR, lactate, BE </li></ul></ul><ul><ul><li>less fluids, vasopressors, red cells, MV, PA lines </li></ul></ul><ul><ul><li>30% mortality, vs . 46% in controls </li></ul></ul>
  7. 7. <ul><li>Concern: just a study of adequate resuscitation? </li></ul><ul><ul><li>the study goals are not that unusual. … </li></ul></ul><ul><ul><li>ScvO 2 on admission was 49%!!! </li></ul></ul><ul><li>Merit: importance of timely , protocolized resuscitation of the patient in septic shock (and, probably, of other forms of shock: resuscitation of the trauma patient) </li></ul>Comments Rivers et al ., NEJM ’01;345:1368
  8. 8. Does it Change Practice in the ICU? <ul><li>Is this ICU/OR- appropriate evidence? </li></ul><ul><ul><li>ICU pts. are seldom severely under-resuscitated </li></ul></ul><ul><ul><ul><li>Hayes et al ., Gattinoni et al . (NEJM ’94, ‘95) could not achieve CO/CVP/WP goals in ~ 50% of their ICU pts.! </li></ul></ul></ul><ul><ul><li>How to deal with contrasting evidence/goals? </li></ul></ul><ul><ul><ul><li>the TRICC study limits transfusions NEJM ’99;340:409 </li></ul></ul></ul><ul><ul><ul><li>the ARDS- NET limits fluid NEJM ‘06;354:2564 </li></ul></ul></ul>Rivers et al ., NEJM ’01;345:1368
  9. 9. A Word of Caution on ScvO 2 <ul><li>How accurately does ScvO 2 estimate SvO 2 ? </li></ul><ul><li>Inconsistently: generally ScvO 2 is a little higher, trends seem OK, not in cardiogenic shock … </li></ul>Chawla et al ., Chest ’04, Dueck et al ., Anesthesiology ’05 Reinhardt et al ., ICM ’04, Scheinman et al ., Circulation ‘69
  10. 10. Steroids in Septic Shock <ul><li>Old ways: high dose treatment </li></ul>30 mg/kg MP x 4 doses No diff. in death, prevention or reversal of shock MP: higher death in pts with  ’d Crea., from infection
  11. 11. Relative Adrenal Deficiency in Septic Shock (SS) <ul><li>Low cortisol ( stim. test ) levels in SS pts. is associated with an increased mortality Rothwell et al ., Lancet ’91 </li></ul><ul><li>‘ Functional hypoadrenalism ’ Baldwin & Allo, Arch Surg ‘93 </li></ul><ul><li>Hydrocortisone, 50 mg x 1 decreased the need for vasopressors Annane et al ., Br J Clin Pharm ’98 </li></ul><ul><ul><ul><ul><ul><li> Bellissant et al ., Clin Pharm Ther ‘00 </li></ul></ul></ul></ul></ul><ul><li>Hydrocortisone, 100 mg tid x 5 d. reversed SS, improved survival Bollaert et al ., CCM ‘98 </li></ul>
  12. 12. 76% of pts. were non-responders! <ul><li>300 pts. with SS , mechanically ventilated </li></ul><ul><ul><li>Hydrocortisone, 50 mg. q 6 hs. + Fludro. 50  g q day x 7 d. </li></ul></ul><ul><ul><li>Placebo </li></ul></ul><ul><ul><li>ACTH - stim </li></ul></ul>Annane et al ., JAMA ’02;288:862 <ul><li>Non-responders : 53% mortality Hydrocort., vs . 63% mortality controls </li></ul><ul><li>Responders : Hydrocort. had slightly increased mortality </li></ul>
  13. 13. Comments <ul><li>Barely significant…… </li></ul><ul><li>Unusually high incidence of ‘relative insufficiency’ </li></ul><ul><li>Very high severity of illness </li></ul><ul><li>Or was it the Etomidate ?? </li></ul><ul><li>ACTH- stim test : </li></ul><ul><ul><li>Diagnostic criteria not well validated Annane et al ., CCM ‘06 </li></ul></ul><ul><ul><li>Repeated stim- gives different results Loisa et al ., A&A ‘05 </li></ul></ul><ul><ul><li>Bound vs . free cortisol Hamrahian et al ., NEJM ’04 </li></ul></ul>Annane et al ., JAMA ’02;288:862
  14. 14. <ul><li>500 pts. in 52 European ICUs, from 4/’02 to 11/’05 </li></ul><ul><li>Septic shock, with standard in./ex. criteria </li></ul><ul><li>Hydrocortisone: 50 mg q 6 hs. x 5 days, q 12 hs. x 3 days, q 24 hs. x 3 days, vs. placebo </li></ul>CORTICUS, NEJM ’08;358:111
  15. 15. CORTICUS…….. N=251 Steroids N=248 Placebo 28-day Mortality
  16. 16. Stim - test, non-responders (~51%) Stim - test, responders (~47%) P=0.8 P=1.0 28-day Mortality <ul><li>Shock reversal was faster in the steroids group </li></ul><ul><li>There were more episodes of superinfection and of new sepsis and septic shock in the steroids group </li></ul>
  17. 17. So, Who Should Get Steroids? <ul><li>Forget the ACTH Stim - test </li></ul><ul><li>Severe shock, unresponsive to Levophed, Vasopressin? </li></ul><ul><li>Kind of …..‘last resort’? </li></ul><ul><li>‘ Last resorts’ generally do not work, that’s why they are last resort </li></ul><ul><li>We may have heard the last of steroids </li></ul><ul><li>We said that 20 years ago </li></ul>Guidelines, 20 Societies- CCM ’08;36:296
  18. 18. Tight Glucose Control- I > 5 days <ul><li> ’ d rate of bacteremia </li></ul><ul><li> ’ d renal failure </li></ul><ul><li> ’ d transfusion requirement </li></ul><ul><li> ’ d critical illness polyneuropathy </li></ul><ul><li>34% decrease in-hospital mortality </li></ul><ul><li>Greatest reduction in mortality in pts. with severe sepsis </li></ul><ul><li>1,500 surgical ICU pts. (60% cardiac): 80 - 110 mg/dl vs. < 180 </li></ul><ul><li>Results: </li></ul>Van den Berghe et al ., NEJM ’01;345:1359
  19. 19. <ul><li>Rationale? </li></ul><ul><ul><li>ICU pts. develop a ‘diabetic’ state- may predispose to infection , critical illness polineuropathy </li></ul></ul><ul><ul><li>Benefit in diabetic pts., renal transplant pts., post- MI, and neurologic injury </li></ul></ul><ul><li>The study: </li></ul><ul><ul><li>A single center, non- blinded, mainly cardiac surgery pts., with a 200 - 300 g /24hs. glucose load </li></ul></ul>Van den Berghe et al ., NEJM ’01;345:1359 Langouche et al ., J Clin Invest ’05;115:2277 Angus & Abraham, AJRCCM ’05;172:1358 Comments
  20. 20. Aftermath <ul><li>Everybody wrote their own insulin protocol </li></ul><ul><li>Every Society, Department, Agency, QI initiative, QA group, ICU, Division, PACU, Operating Room, Committee…. either wrote or recommended an insulin protocol </li></ul>
  21. 21. Tight Glucose Control- II <ul><li>Intensive Insulin Therapy- II: </li></ul><ul><ul><li>1,200 MICU pts. projected stay  3 d. </li></ul></ul><ul><ul><li>APACHE II: 23 (vs. 9 in study I) </li></ul></ul><ul><ul><li>BUN & Crea.: 67-68 / 1.2- 1.3 </li></ul></ul>Van den Berghe et al ., NEJM’06;354:449 <ul><li>Overall: no effect </li></ul><ul><li> 3 d. in ICU: 10%  survival </li></ul><ul><li>< 3 days: slight  survival </li></ul><ul><li>Hypoglycemia : </li></ul><ul><li>19% in IIT, vs. 3% </li></ul><ul><li>BG during hypoglycemia: 32  6 </li></ul><ul><li>Independent predictor of mortality </li></ul>
  22. 22. <ul><li>German RCT 2x2 design of resuscitation of pts. with severe sepsis and septic shock </li></ul><ul><li>Interrupted at planned safety analysis- 488 pts. </li></ul><ul><li>Significantly higher incidence of hypoglycemic events, (17 vs. 4%) and of serious adverse events (11 vs. 5%), with no difference in survival and # of organ failures </li></ul><ul><li>Comment : very similar results to Van den Berge- II…. </li></ul>Tight Glucose Control- III VISEP, NEJM ’08;358:125
  23. 23. Tight Glucose Control- IV, V…. GLUCONTROL, in press……. <ul><li>Belgian RCT  3,000 pt., interrupted at 1 st interim </li></ul><ul><li>Hypoglycemia was frequent, and possibly harmful </li></ul>NICE-SUGAR, ongoing….. <ul><li>From down-and-under  5,000 pt., through 1 st interim... </li></ul>
  24. 24. <ul><li>Goals: </li></ul><ul><ul><li>To reach glycemic control in a reasonable time </li></ul></ul><ul><ul><li>Using a reliable method to measure blood glucose </li></ul></ul><ul><ul><li>To limit the incidence of hypoglycemia. Which means….. c an’t be too tight!!! </li></ul></ul><ul><ul><li>Simple, least prone to errors, reasonable nursing time </li></ul></ul>Insulin Infusion Protocols Wilson et al., Diabetes Care 2007;30:1005
  25. 25. So, Who Should Get…. How Tight …? <ul><li>Critically ill patients who are in the ICU for more than three- five days? (We are not good at predicting) </li></ul><ul><li>How about in the OR? Why……? </li></ul><ul><li>Definitely , the benefit will be seen only in highly- skilled, intensive nursing Units </li></ul><ul><li>Monitor glu. q 1-2 hs. till stable, watch low levels with point-of-care testing </li></ul><ul><li>Following initial stabilization, aim at glu. < 150 mg/dL using a validated protocol </li></ul>Guidelines, 20 Societies- CCM ’08;36:296
  26. 26. Vasopressin <ul><li>Some patients with longstanding septic shock have lower plasma V. concentration than pts. with other forms of shock </li></ul><ul><li>The administration of a low dose of V. increased plasma levels and decreased the need for catecholamines </li></ul>Landry et al ., Circulation ‘97
  27. 27. Vasopressin Holmes et al ., Int. Care M. ’97 Patel et al ., Anesthesiology ’02 Dunser et al ., Circulation ‘04
  28. 28. Vasopressin- Concerns <ul><li>Is it safe? </li></ul><ul><ul><li>Decreased splanchnic perfusion in pts. with septic shock? van Haren et al ., Chest ’03 </li></ul></ul><ul><ul><li>Decreased mesenteric and renal blood flow at slightly higher doses? Malay et al ., CCM ‘04 </li></ul></ul>
  29. 29. <ul><li>A low-dose of Vaso. in addition to Norepi. in 800 pts. w/ septic shock </li></ul><ul><li>Results : </li></ul><ul><ul><li>No effect on any outcome measure </li></ul></ul><ul><ul><li>Benefit in patients with less severe shock: ??!?- this was NOT the hypothesis </li></ul></ul>VASST, NEJM ’08;358:877
  30. 30. <ul><li>You don’t have to use it for pts. in septic shock if you don’t want to </li></ul><ul><li>If you do use it, a low dose (0.03 - 0.04 U./ min) does not seem harmful, is cheap, and it will decreases the need for Norepi. </li></ul>So, Who Should Get Vaso.? Guidelines, 20 Societies- CCM ’08;36:296
  31. 31. r-Human Activated Protein C for Severe Sepsis PROWESS, NEJM ‘01 <ul><li>Endogenous APC has multiple anti- injury activities </li></ul><ul><li>Low APC levels in sepsis, related to mortality </li></ul>
  32. 32. r-aPC for Severe Sepsis Angus et al ., CCM ‘04 PROWESS, NEJM ‘01 <ul><li>The strongest effect was seen in pts. with severe shock- APACHE II > 24 </li></ul>2% 3.5% bleeding 31% 25% mortality placebo rAPC 1700 pts .
  33. 33. r-aPC for Less- Severe Sepsis <ul><li>2,640 adult pts. with ‘less severe sepsis’, e.g., APACHE II < 25, or single organ failure </li></ul><ul><li>Enrollment terminated for futility . However: </li></ul><ul><li>Slightly higher mortality in r-APC pts.: </li></ul><ul><ul><li>APACHE II  25 </li></ul></ul><ul><ul><li>Single organ failure </li></ul></ul><ul><ul><li>Recent surgery </li></ul></ul><ul><li>Significantly higher incidence of bleeding in r-APC </li></ul>Abraham et al ., NEJM ’05;353:1332
  34. 34. r-aPC in Kids <ul><li>477 pedi. pts. (0 - 17 y.) with sepsis- induced cardiovascular and respirator failure </li></ul><ul><li>No difference in mortality and organ failure score </li></ul><ul><li>Numerically (not statistically) higher incidence of CNS bleeds </li></ul>Nadel et al., Lancet 2007;369:836-43
  35. 35. So, Who Should Get r-a PC? <ul><li>Only severely ill patients (APACHE II  25) have a proven (??) benefit </li></ul><ul><li>Hemorrhagic complications are real </li></ul><ul><li>$ 5,000 - 8,000 per four- day course </li></ul><ul><li>New trial requested to Lilly by the FDA: stay tuned </li></ul>
  36. 36. Conclusions <ul><li>Sepsis is the #1 killer of ICU patients </li></ul><ul><li>Early, appropriate interventions increase survival </li></ul><ul><li>New treatments are proposed at high pace. The recent developments around corticosteroids, tight blood sugar control, and vasopressin, underline the need for rigorous design and evaluation of clinical trials </li></ul>
  37. 37. Quantifying the Impact <ul><li>Absolute risk reduction, number needed to treat </li></ul><ul><ul><li>ARR = decrease in mortality; NNT = 1/ARR </li></ul></ul><ul><ul><li>Early goal directed therapy: 20%  5 </li></ul></ul><ul><ul><li>Low V T for ALI/ARDS: 9%  11 </li></ul></ul><ul><ul><li>Steroids in septic shock: 13%  7 </li></ul></ul><ul><ul><li>A- PC in septic shock: 6%  16 </li></ul></ul><ul><ul><li>…… if you believe the study </li></ul></ul>