SEPSISPAM: High vs Low MAP Targets in Septic Shock (2014)

“Targeting a mean arterial pressure of 80 to 85 mm Hg, as compared with 65 to 70 mm Hg, in patients with septic shock did not result in a significant difference in 28-day mortality.”

— The SEPSISPAM Investigators

1. Publication Details

  • Trial Title: High versus Low Blood-Pressure Target in Patients with Septic Shock.
  • Citation: Asfar P, Meziani F, Hamel JF, et al; SEPSISPAM Investigators. High versus low blood-pressure target in patients with septic shock. N Engl J Med. 2014;370(17):1583-1593. doi:10.1056/NEJMoa1312173.
  • Published: April 24, 2014, in The New England Journal of Medicine.
  • Author: Pierre Asfar, M.D., Ph.D.
  • Funding: French Ministry of Health.

2. Keywords

Septic Shock, Blood Pressure, Mean Arterial Pressure (MAP), Vasopressors, Norepinephrine, Acute Kidney Injury.

3. The Clinical Question

In adult patients with septic shock requiring vasopressors (Population), does targeting a high mean arterial pressure (MAP) of 80-85 mmHg (Intervention) compared to a low MAP target of 65-70 mmHg (Comparison) reduce 28-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Septic shock is characterized by hypotension and organ hypoperfusion. Vasopressors are used to raise the mean arterial pressure (MAP) to improve organ perfusion. Surviving Sepsis Campaign guidelines recommended a target MAP of at least 65 mmHg, but the optimal target was unknown, with many clinicians aiming for higher targets.
  • Knowledge Gap: It was unclear whether targeting a higher MAP provided additional benefit in terms of organ perfusion and survival, or if it simply led to increased vasopressor doses and associated adverse effects.
  • Proposed Hypothesis: The authors hypothesized that targeting a high MAP (80-85 mmHg) would lead to a reduction in mortality at day 28 compared to targeting a low MAP (65-70 mmHg).

5. Study Design and Methods

  • Design: A prospective, multicenter, open-label, randomized, controlled trial.
  • Setting: 29 intensive care units (ICUs) in France.
  • Trial Period: Enrollment from March 2010 to December 2012.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) with septic shock requiring norepinephrine at a dose of at least 0.1 µg/kg/min to maintain a MAP of ≥65 mmHg.
    • Exclusion Criteria: Pregnancy, recent MI, active bleeding, severe pulmonary hypertension, and expected death within 24 hours.
  • Intervention: Norepinephrine (and other vasopressors) titrated to maintain a MAP of 80 to 85 mmHg for up to 5 days.
  • Control: Norepinephrine (and other vasopressors) titrated to maintain a MAP of 65 to 70 mmHg for up to 5 days.
  • Management Common to Both Groups: All other aspects of septic shock management, including fluid resuscitation, antibiotics, and source control, were guided by the 2008 Surviving Sepsis Campaign guidelines.
  • Power and Sample Size: The authors calculated that a sample size of 776 patients would provide 80% power to detect an absolute risk reduction of 10 percentage points in 28-day mortality.
  • Outcomes:
    • Primary Outcome: All-cause mortality at 28 days.
    • Secondary Outcomes: 90-day mortality, organ-failure-free days, ICU and hospital length of stay, and incidence of new acute kidney injury (AKI).

6. Key Results

  • Enrollment and Baseline: 776 patients were randomized (388 to the high-target group, 388 to the low-target group). The groups were well-matched at baseline, although about 44% of patients in both groups had a history of chronic hypertension.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in 28-day mortality between the high-target and low-target groups (36.6% vs 34.0%; P=0.44).
  • Secondary Outcomes: There was no significant difference in 90-day mortality. However, in the pre-specified subgroup of patients with a history of chronic hypertension, those in the high-target group had a lower incidence of new AKI and required less renal-replacement therapy.
  • Adverse Events: The incidence of newly diagnosed atrial fibrillation was significantly higher in the high-target group (6.7% vs 2.8%; P=0.02). Patients in the high-target group received higher cumulative doses of norepinephrine.

7. Medical Statistics

  • Analysis Principle: An intention-to-treat analysis was performed.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test. A Cox proportional-hazards model was used for time-to-event analyses.
  • Primary Outcome Analysis: The proportion of deaths at day 28 was compared between the two groups.
  • Key Statistic(s) Reported: Hazard Ratio (HR) for death at 28 days: 1.07 (95% CI, 0.84 to 1.38; P=0.57).
  • Interpretation of Key Statistic(s):
    • Hazard Ratio (HR): An HR of 1.07 suggests a slightly higher hazard of death in the high-target group, but this was not statistically significant.
    • Confidence Interval (CI): The 95% CI widely crosses 1.0, indicating no significant difference between the groups.
    • P-value: The p-value of 0.57 is well above the 0.05 threshold, confirming the lack of a statistically significant difference in the primary outcome.
  • Clinical Impact Measures: Not applicable for the primary outcome as no benefit was shown.
  • Subgroup Analyses: A key pre-specified subgroup analysis of patients with chronic arterial hypertension (n=340) showed that those in the high-target group had a significantly lower incidence of doubling of creatinine or need for renal-replacement therapy (38.6% vs 52.0%; P=0.01).

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, controlled design provided high-quality evidence on a fundamental question in septic shock management.
  • Generalizability: The inclusion of 29 centers increases the applicability of the findings.
  • Important Subgroup: The pre-specified analysis of patients with chronic hypertension was a major strength, generating a clinically important hypothesis.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was open-label (unblinded), which could have introduced performance bias, although the primary outcome of mortality is objective and less susceptible to this.
  • External Validity (Generalizability): The results may not apply to patients with septic shock who do not require at least 0.1 µg/kg/min of norepinephrine.
  • Other: The study may have been underpowered to detect a smaller, but still potentially important, difference in mortality.

10. Conclusion of the Authors

“Targeting a mean arterial pressure of 80 to 85 mm Hg, as compared with 65 to 70 mm Hg, conferred no survival benefit in the overall population of patients with septic shock. However, a high-target MAP was associated with a reduced need for renal-replacement therapy in the subgroup of patients with chronic hypertension.”

11. To Summarize

  • Impact on Current Practice: This trial provided strong evidence against the routine practice of targeting a high MAP for all patients in septic shock. It reinforced a MAP target of 65-70 mmHg as a safe and appropriate initial goal for most patients, while also suggesting a more individualized approach may be beneficial for patients with chronic hypertension.
  • Specific Recommendations:
    • Patient Selection: For the general population of adults with septic shock, a MAP target of 65-70 mmHg is appropriate.
    • Actionable Intervention: For patients with a history of chronic hypertension, consider targeting a higher MAP of 80-85 mmHg to potentially reduce the risk of AKI, while being mindful of the increased risk of arrhythmia.
    • Expected Benefit: No mortality benefit overall. Potential for renal protection in patients with chronic hypertension.
  • What This Trial Does NOT Mean: This trial does not mean a MAP of 65 mmHg is a rigid, one-size-fits-all target. Clinical judgment and other markers of perfusion should still be used to individualize care.
  • Implementation Caveats: Targeting a higher MAP requires higher vasopressor doses and is associated with an increased risk of atrial fibrillation.

12. Context and Related Studies

  • Building on Previous Evidence: This trial was the first large RCT to directly compare two different MAP targets, providing much-needed evidence to guide a very common ICU intervention.
  • Influence on Subsequent Research: The findings of SEPSISPAM, particularly the subgroup analysis, have spurred further research into personalized hemodynamic targets. It was a key predecessor to the 65 Trial (2020), which studied older patients and also supported a more permissive approach to blood pressure, finding no benefit with a MAP target of 60-65 mmHg compared to usual care.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The main unresolved question is whether the potential renal benefit of a higher MAP target in patients with chronic hypertension translates into improved long-term outcomes. The optimal MAP target in this specific subgroup needs confirmation.
  • Future Directions: Future research is focused on using more advanced hemodynamic monitoring and other biomarkers of perfusion to individualize blood pressure targets beyond just a history of chronic hypertension.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant and addressed a fundamental, unresolved issue in the management of septic shock.
  • Methods: The multicenter RCT design was appropriate. The open-label nature is a limitation, but the primary outcome of mortality is objective. The pre-specified subgroup analysis was a key strength.
  • Results: The trial had a clear negative result for its primary outcome. The subgroup finding of renal protection in patients with chronic hypertension is a strong, hypothesis-generating signal that has influenced practice, despite not being the primary endpoint.
  • Conclusions and Applicability: The authors’ conclusion is a fair representation of the data. The results are highly applicable, providing reassurance that a standard MAP target of 65-70 mmHg is safe for most patients, while also providing a rationale for considering a higher target in a specific, common subgroup of patients.

16. Disclaimer and Contact

This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.

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