SEPSISPAM

Published

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.
PubMed • Full text • PDF

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 may theoretically improve end-organ perfusion, especially for those with chronic hypertension.

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)

• 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. 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<

Funding

• French Ministry of Health
• Authors with multiple financial disclosures