SEPSISPAM

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Asfar P, et al. "High versus low blood-pressure target in patients with septic shock". The New England Journal of Medicine. 2014. 370(17):1583-1593.
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Clinical Question

For patients with septic shock, does treatment to a goal MAP of 80-85 mmHg reduce all-cause mortality at 28 days when compared to a goal MAP of 65-70 mmHg?

Bottom Line

For patients with septic shock, a goal MAP of 80-85 mmHg does not reduce all-cause mortality at 28 days when compared to a goal of 65-70 mmHg. The higher MAP goal was associated with reduction in rates of renal dysfunction for patients with a history of chronic hypertension.

Major Points

No large, randomized-controlled trial exist to support a MAP target in sepsis. A higher MAP goal than the current 65 mmHg as recommended by the Surviving Sepsis Campaign[1] may theoretically improve end-organ perfusion, especially for those with chronic hypertension.[2]

The 2014 Sepsis and Mean Arterial Pressure (SEPSISPAM) trial randomized 776 patients with septic shock to a goal MAP of 65-70 or 80-85 mmHg for up to 5 days through vasopressor administration. (Both groups' average achieved MAPs were about 5 mmHg above the target range after day 2.) There was no difference between the two groups for all-cause mortality at 28 or 90 days. Those with a history of chronic hypertension had less renal dysfunction with a higher MAP goal. The higher MAP goal was generally well tolerated, except for an increase in AF.

Guidelines

Surviving Sepsis Campaign severe sepsis and septic shock (2016, adapted)[3]

  • During the initial resuscitation, target MAP of 65 mm Hg in patients with septic shock needing vasopressors
  • Recommend norepinephrine as first-line vasopressor (strong recommendation, moderate quality of evidence)
    • Can add vasopressin up to 0.03 U/min (weak recommendation, moderate quality of evidence) or epinephrine (weak recommendation, low quality of evidence) to norepinephrine to achieve MAP targets
    • Can add vasopressin up to 0.03 U/min to decrease norepinephrine dose (weak recommendation, low quality of evidence)

Design

  • Multicenter, randomized, open label, controlled trial
  • N=776
    • MAP goal 65-70 mmHg (n=388)
    • MAP goal 80-85 mmHg (n=388)
  • Setting: 29 French centers
  • Enrollment: 2010-2011
  • Follow-up: 90 days
  • Analysis: Intention-to-treat
  • Primary outcomes: All-cause mortality at day 28

Population

Inclusion Criteria

  • Age ≥18 years with septic shock refractory to administration of 30 mL/kg NS or colloids or was deemed to have inadequate response on right-heart catheterization, pulse-pressure measurement, SV measurement, or echocardiography
    • Sepsis defined by ≥2 SIRS criteria, likely or proven infection, and ≥1 organ with new dysfunction
  • If requiring norepinephrine or epinephrine:
    • Minimum infusion rate of 0.1 ug/kg/min
    • Evaluation for enrollment within six hours of initiation of vasopressor therapy

Exclusion Criteria

  • Lack of competence and no legal guardian, incarceration, pregnancy, or other legal protection
  • No French health system affiliation
  • Recent participation in another study
  • Recent participation in an interventional study with a primary outcome of mortality
  • Investigator's decision to withhold resuscitation

Baseline Characteristics

From the MAP 65-70 mmHg group. Groups were similar.

  • Demographics: 65 years, male 64.4%
  • PMH: Ischemic heart disease 10.1%, HF 13.7%, COPD 12.1%, CKD 7.7% (ESRD on HD 3.1%), cirrhosis 7.2%, DM 23.2%, autoimmune disease or cancer 34.8%, chronic arterial hypertension
    • Recent surgery: Elective 1.3%, emergent 14.2%
  • Sepsis data:
    • Infection source: Lung 51.5%, abdomen 17.3, urinary tract 11.3%, other 18.8%
      • Community-acquired: 65.2%
    • Severity:
      • SAPS II score: 57.2 (out of 163, higher numbers indicate more severe disease)
      • SOFA score: 10.8 (out of 20, higher numbers indicate more organ dysfunction)
        • AKI: 48.7%
        • Requiring intubation: 73.7%
    • Other data on inclusion: MAP 73 mmHg, HR 103 BPM, pH 7.30, serum lactate 3.7 mmol/L, PaO2:FIO2 198 mmHg, creatinine 1.96 mg/dL, Hgb 10.3 g/dL
    • Initial therapy before inclusion: Fluids administered 2.9 L
      • Vasopressors (median dose): Norepinephrine 94.8% (0.35 ug/kg/min), epinephrine 5.2% (0.23 ug/kg/min), dobutamine 5.4%

Interventions

  • Randomization to a group with stratification by history of hypertension
    • MAP 65-70 mmHg - Lower MAP target
    • MAP 80-85 mmHg - Higher MAP target
      • MAP goal was reduced to 65-70 if adverse events related to elevated goal (i.e. clinically-relevant bleeding, MI, major ventricular arrhythmia, SVT that was poorly tolerated, mesenteric ischemia, or distal-limb ischemia)
  • Both groups maintained goal MAPS for up to 5 days or until weaned from vasopressors with subsequent BP goals directed by treating physician
  • Resuscitation per French guidelines
    • Norepinephrine administered preferentially (one center used epinephrine preferentially)
    • Decision for use of activated protein C and hydrocortisone use was left to the treating physician
  • Diuretics, NSAIDS, IV contrast, and nephrotoxic agents were disallowed except for extenuating circumstances
  • Initiation of RRT if ≥1 of the following present:
    • Anuria
    • Hyperkalemia with changes on EKG
    • "Pure" metabolic acidosis with pH <7.2
    • BUN >84 mg/dL
  • Sedation, analgesia, and muscle relaxants left to discretion of clinicians
    • Goal RASS target of -3 to 0

Outcomes

Presented as MAP 65-70 mmHg vs. MAP 80-85 mmHg. Some data and statistical analyses are inconsistently presented between the main text and supplementary appendix.[4] Conflicting data are extracted from the main text.

Primary Outcome

All-cause mortality at day 28
34.0% vs. 36.6% (HR for MAP 80-85 mmHg 1.07; 95% CI 0.84-1.38; P=0.57)

Secondary Outcomes

All-cause mortality at day 90
42.3% vs. 43.8% (HR for MAP 80-85 mmHg 1.04; 95% CI 0.83-1.30; P=0.74)
Survival or no organ support at day 28
62.1% vs. 60.6% (P=0.66)
Days free of organ support through day 28
Vasopressor: 18 vs. 16 days (P=0.03)
Mechanical ventilation: 16 vs. 15 days (P=0.21)
RRT: 21 vs. 19 days (P=0.36)
Change in renal SOFA score
Calculated as maximum score between days 1 and 7 minus inclusion SOFA score.
+1.0 vs. +0.8 (P=0.076)
No chronic hypertension: +0.9 vs. +0.9 (P=0.95)
Chronic hypertension: +1.1 vs. +0.7 (P=0.005)
Doubling of creatinine
41.6% vs. 38.6% (OR 0.88; 95% CI 0.66-1.17; P=0.42)
No chronic hypertension: 33.0% vs. 38.5% (P=0.32)
Chronic hypertension: 52.0% vs. 38.9% (P=0.02)
RRT through day 7
35.8% vs. 33.5% (P=0.50)
No chronic hypertension: 30.7% vs. 34.8% (P=0.36)
Chronic hypertension: 42.2% vs. 31.7% (OR 0.64; 95% CI 0.41-0.99; P=0.046)
Length of stay
ICU: 8 vs. 8 days (P=0.60)
Hospital: Not presented
SOFA score by day 7
Not presented

Additional Analyses

MAP during the 5 day period
Higher for the MAP 80-85 mmHg group (P=0.02; see Figure 2)
Survival at day 28 without organ support
Organ support includes vasopressors, mechanical ventilation, or RRT.
62.1% vs. 60.1% (P=0.66)
Administration of other therapeutics
Corticosteroids: 80.0% vs. 85.0%
Activated protein C: 6.8% vs. 7.5%
Cumulative measurements through day 5
Fluid intake: 10.0 vs. 10.5 L (P=0.89)
UOP: 6.7 vs. 6.9 L (P=0.87)
Fluid balance: +2.8 vs. +2.4 liters (P=0.74)

Adverse Events

Any
17.8% vs. 19.1% (P=0.64)
MI: 0.5% vs. 1.8% (P=0.18)
AF: 2.8% vs. 6.7% (P=0.02)
VF or V-tach: 3.9% vs. 5.7% (P=0.24)
Digital ischemia: 2.3% vs. 2.6% (P=0.82)
Mesenteric ischemia: 2.3% vs. 2.3% (P=1.00)
Bleeding: 10.8% vs. 8.0% (P=0.22)

Criticisms

  • Not blinded
  • Incomplete recording of inclusion variables like right-heart catheterization, pulse pressure measurement, SV measurement, and echocardiography
  • Underpowered secondary to lower than expected mortality
  • MAPs achieved tended to be above their goal ranges (70-75 and 85-90 mmHg)
  • Widespread corticosteroid use
  • Stroke was not measured, which is problematic given the rate of AF<[2]

Funding

  • French Ministry of Health
  • Authors with multiple financial disclosures

Further Reading

  1. Dellinger RP et al. "Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2012." Critical Care Medicine (2013) 41(2) 580-637.
  2. 2.0 2.1 Russell JA. "Editorial: Is there a good MAP for septic shock?" The New England Journal of Medicine. ePublished 2014-03-18. Accessed 2014-04-15.
  3. Rhodes A, et al. "Surviving Sepsis Campaign: International guidelines for management of sepsis and septic shock: 2016." Critical Care Medicine. 2017;45(3)1-67.
  4. Supplementary appendix