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Management of Sepsis
 

Management of Sepsis

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Management of Sepsis Management of Sepsis Presentation Transcript

  • Management of Sepsis Luca Bigatello, MD Director, Surgical ICU, Massachusetts General Hospital Associate Professor of Anesthesia, Harvard Medical School
  • 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
  • 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
    • 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
  • 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
  • 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
    • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
    • 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
  • CORTICUS…….. N=251 Steroids N=248 Placebo 28-day Mortality
  • 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
  • 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
  • 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
    • 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
  • 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/
  • 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
    • 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
  • 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...
    • 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
  • 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
  • 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
  • Vasopressin Holmes et al ., Int. Care M. ’97 Patel et al ., Anesthesiology ’02 Dunser et al ., Circulation ‘04
  • 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
    • 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
    • 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
  • 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
  • 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 .
  • 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
  • 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
  • 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
  • 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
  • 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