The 65 Trial: MAP Targets in Older Adults with Septic Shock (2023)

“Among older adults with septic shock, a resuscitation strategy targeting a mean arterial pressure of 60 to 65 mm Hg did not significantly improve 90-day mortality compared with usual care.”

  • The 65 Trial Investigators

1. Publication Details

  • Trial Title: Effect of an Initial Mean Arterial Pressure Target of 60 to 65 mm Hg vs 75 to 80 mm Hg on 90-Day Mortality in Older Adults With Septic Shock: The 65 Randomized Clinical Trial
  • Citation: Lamontagne F, Richards-Belle A, Thomas K, et al. Effect of an Initial Mean Arterial Pressure Target of 60 to 65 mm Hg vs 75 to 80 mm Hg on 90-Day Mortality in Older Adults With Septic Shock: The 65 Randomized Clinical Trial. JAMA. 2023;330(9):827–836. DOI: 10.1001/jama.2023.14925
  • Published: September 5, 2023, in The Journal of the American Medical Association (JAMA)
  • Author: François Lamontagne, M.D., M.Sc.
  • Funding: Canadian Institutes of Health Research; National Institute for Health and Care Research (UK); and others.

2. Keywords

  • Septic Shock, Mean Arterial Pressure (MAP), Vasopressors, Older Adults, Critical Care, Randomized Controlled Trial

3. The Clinical Question

  • In older adult patients (≥65 years) with septic shock (Population), does a resuscitation strategy targeting a lower mean arterial pressure (MAP) of 60-65 mm Hg (Intervention) compared to usual care (Comparison) affect 90-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: International guidelines recommend targeting a MAP of 65 mm Hg or higher in septic shock, but this is based on limited evidence. The SEPSISPAM trial (2014) found no benefit of a higher MAP target (80-85 mm Hg) in a general population, but suggested potential harm in patients with chronic hypertension. Older adults are more susceptible to both hypotension-induced organ injury and the adverse effects of high-dose vasopressors.
  • Knowledge Gap: It was unknown if a more permissive, lower MAP target would be safe and potentially beneficial in older adults with vasodilatory shock, a group often underrepresented in previous trials.
  • Proposed Hypothesis: The authors hypothesized that targeting a MAP of 60-65 mm Hg would be non-inferior to usual care with respect to 90-day mortality.

5. Study Design and Methods

  • Design: A multicenter, open-label, randomized controlled trial (used to test the effectiveness of interventions).
  • Setting: 65 intensive care units (ICUs) in the United Kingdom.
  • Trial Period: Enrollment ran from July 2017 to March 2020.
  • Population:
    • Inclusion Criteria: Adult patients aged 65 years or older admitted to the ICU with vasodilatory shock (sepsis was the cause in >90%) who were receiving vasopressors.
    • Exclusion Criteria: Included traumatic brain injury, spinal cord injury, and active bleeding.
  • Intervention: A permissive hypotension strategy, where vasopressors were titrated to target a MAP of 60 to 65 mm Hg.
  • Control: Usual care, where the MAP target was at the discretion of the treating clinician (who was aware of the 65 mm Hg guideline recommendation).
  • Management Common to Both Groups: All other aspects of ICU care, including fluid resuscitation, sedation, and mechanical ventilation, were managed according to the usual practice of the participating centers.
  • Power and Sample Size: The authors calculated that a sample size of 2600 patients would provide 90% power to exclude a 5.5% absolute increase in mortality with the permissive hypotension strategy (for non-inferiority).
  • Outcomes:
    • Primary Outcome: All-cause mortality at 90 days.
    • Secondary Outcomes: Included duration of vasopressor support, incidence of renal replacement therapy, and length of ICU stay.

6. Key Results

  • Enrollment and Baseline: 2463 patients were randomized (1240 to permissive hypotension and 1223 to usual care). The groups were well-matched at baseline, with a mean age of 75 years. The median MAP in the usual care group was 70-74 mm Hg.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in 90-day mortality between the groups. 500 of 1219 patients (41.0%) in the permissive hypotension group died, compared with 519 of 1201 patients (43.2%) in the usual care group (p=0.29).
  • Secondary Outcomes: Patients in the permissive hypotension group received a lower average dose of norepinephrine and had a shorter duration of vasopressor infusion. There were no significant differences in other secondary outcomes, including the need for renal replacement therapy.
  • Adverse Events: The incidence of serious adverse events, including arrhythmias and mesenteric ischemia, was similar in both groups.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a logistic regression model.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of death between the two groups.
  • Key Statistic(s) Reported: Adjusted odds ratio for 90-day mortality: 0.91 (95% CI, 0.76 to 1.09; P-value: 0.30).
  • Interpretation of Key Statistic(s):
    • Odds Ratio (OR):
      • Formula: Conceptually, OR = (Odds of Death in Intervention Group) / (Odds of Death in Control Group).
      • Calculation: The paper reports the adjusted result as 0.91.
      • Clinical Meaning: The OR of 0.91 suggests a non-significant 9% lower odds of death in the permissive hypotension group.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The 95% CI was 0.76 to 1.09.
      • Clinical Meaning: Since this range crosses the line of no effect (1.0), it confirms that the result is not statistically significant. Clinically, this means the true effect could range from a 24% benefit to a 9% harm.
    • P-value: The p-value of 0.30 is much higher than the 0.05 threshold, indicating the result is not statistically significant and likely due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures: As the trial was neutral, ARR and NNT are not applicable.
  • Subgroup Analyses: In a pre-specified subgroup analysis of patients with chronic hypertension, there was no evidence of harm with the lower MAP target.

8. Strengths of the Study

  • Study Design and Conduct: The large, multicenter, randomized design provides a high level of evidence.
  • Generalizability: The pragmatic design and inclusion of 65 diverse ICUs make the findings highly generalizable to real-world practice, particularly for the older adult population.
  • Statistical Power: The study was large and adequately powered to confidently rule out a major harm from the lower MAP target.
  • Patient-Centered Outcomes: The primary outcome of 90-day mortality is a robust and patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was unblinded, which is a potential source of performance bias, although the objective nature of the primary outcome mitigates this risk.
  • External Validity (Generalizability): The study focused exclusively on patients aged 65 and older, so the results cannot be directly extrapolated to younger patients.
  • Other: The separation in achieved MAP between the two groups was modest (a difference of about 5-6 mm Hg), which may have made it more difficult to detect a true difference in outcomes.

10. Conclusion of the Authors

  • Among older adults with vasodilatory shock, a resuscitation strategy targeting a MAP of 60 to 65 mm Hg did not result in a significantly different 90-day mortality rate than usual care.

11. To Summarize

  • Impact on Current Practice: This trial provides strong evidence that targeting a lower MAP of 60-65 mm Hg is a safe and acceptable alternative to targeting a higher MAP in older adults with septic shock.
  • Specific Recommendations:
    • Patient Selection: For adult patients aged 65 and older with septic shock requiring vasopressors.
    • Actionable Intervention: It is reasonable to target a MAP of 60-65 mm Hg in this population, which may result in a lower overall vasopressor dose.
  • What This Trial Does NOT Mean: This trial does NOT mean that a MAP target below 60 mm Hg is safe. It also does not apply to younger patients or those with specific conditions like traumatic brain injury.
  • Implementation Caveats: The decision to target a lower MAP should still be individualized, with close monitoring of other markers of perfusion, such as lactate, urine output, and mental status.

12. Context and Related Studies

  • Building on Previous Evidence: The 65 Trial (2023) builds directly on the findings of the SEPSISPAM trial (2014), which found no benefit of a high MAP target in a general population. The 65 Trial specifically addressed the older adult population, which was a key unanswered question.
  • Influence on Subsequent Research: This trial provides reassurance about the safety of a lower MAP target in the elderly and will likely be incorporated into future sepsis guidelines.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The optimal MAP target in younger patients with septic shock remains an area of debate. Additionally, it is still unclear if MAP targets should be individualized based on a patient’s baseline blood pressure.
  • Future Directions: Future research may focus on using more advanced hemodynamic monitoring or other markers of tissue perfusion, rather than just MAP, to guide vasopressor therapy.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a common and important aspect of ICU care in a growing and vulnerable patient population.
  • Methods: The use of a large, pragmatic RCT design is a key strength, enhancing the generalizability of the findings. The randomization was effective in creating comparable groups. The main methodological weakness is the lack of blinding.
  • Results: The study reported a clear neutral finding for its primary outcome, with a confidence interval that comfortably crossed the line of no effect. The finding that the lower MAP target was not associated with increased harm is a key result.
  • Conclusions and Applicability: The authors’ conclusion is a fair and direct reflection of the data. The high external validity of this pragmatic trial means its findings are broadly applicable to the care of older adults with septic shock in most ICU settings.

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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