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Management of Sepsis

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

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