MENDS2: Dexmedetomidine vs. Propofol in Sepsis (2016)

“Among critically ill adults with sepsis undergoing mechanical ventilation, sedation with dexmedetomidine, compared with propofol, did not result in a statistically significant difference in 90-day mortality.”

  • The MENDS2 Study Investigators

1. Publication Details

  • Trial Title: Dexmedetomidine vs Propofol for Sedation in Mechanically Ventilated Adults With Sepsis
  • Citation: Hughes CG, Mailloux PT, Devlin JW, et al. Dexmedetomidine or Propofol for Sedation in Mechanically Ventilated Adults with Sepsis. N Engl J Med. 2021;384(15):1424-1436. DOI: 10.1056/NEJMoa2024922. Note: The definitive MENDS2 publication was in 2021.
  • Published: April 15, 2021, in The New England Journal of Medicine
  • Author: Christopher G. Hughes, M.D., M.S.
  • Funding: The National Heart, Lung, and Blood Institute (NHLBI).

2. Keywords

  • Sepsis, Sedation, Delirium, Dexmedetomidine, Propofol, Mechanical Ventilation, Randomized Controlled Trial

3. The Clinical Question

  • In critically ill adults with sepsis requiring mechanical ventilation (Population), does a strategy of sedation with dexmedetomidine (Intervention) compared to a strategy of sedation with propofol (Comparison) affect 90-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: The original MENDS trial (2007) showed that dexmedetomidine was superior to the benzodiazepine lorazepam in reducing delirium in septic patients. This contributed to a major shift away from benzodiazepine-based sedation. Propofol, a non-benzodiazepine sedative, became a common alternative.
  • Knowledge Gap: While dexmedetomidine was known to be less deliriogenic than benzodiazepines, it was unknown if it held any advantage over propofol, another commonly used non-benzodiazepine sedative. A large, definitive trial was needed to compare these two agents head-to-head.
  • Proposed Hypothesis: The authors hypothesized that sedation with dexmedetomidine would be superior to sedation with propofol in reducing 90-day mortality.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, double-blind, controlled trial (used to test the effectiveness of interventions).
  • Setting: 13 tertiary care medical centers in the United States.
  • Trial Period: Enrollment ran from October 2012 to May 2018.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) with sepsis and respiratory failure who were receiving mechanical ventilation and were expected to require sedation for at least 72 hours.
    • Exclusion Criteria: Included severe neurologic injury, pregnancy, and contraindications to either study drug (e.g., severe bradycardia for dexmedetomidine).
  • Intervention: Patients received a continuous intravenous infusion of dexmedetomidine.
  • Control: Patients received a continuous intravenous infusion of propofol.
  • Management Common to Both Groups: Both groups were managed with a protocol targeting a light level of sedation (RASS -2 to +1). Both also received fentanyl for analgesia and had daily sedation interruptions.
  • Power and Sample Size: The authors calculated that a sample size of 420 patients would provide 80% power to detect a 10% absolute difference in 90-day mortality. (Power is a study’s ability to find a real difference between treatments if one truly exists; 80% is the standard accepted level for clinical trials).
  • Outcomes:
    • Primary Outcome: 90-day all-cause mortality.
    • Secondary Outcomes: Included days free of delirium and coma, ventilator-free days, and 28-day mortality.

6. Key Results

  • Enrollment and Baseline: 422 patients were randomized (214 to dexmedetomidine and 208 to propofol). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in 90-day mortality. 74 of 214 patients (35%) in the dexmedetomidine group died, compared with 74 of 208 patients (36%) in the propofol group (p=0.88).
  • Secondary Outcomes: There were no significant differences between the groups in the number of days free of delirium and coma, ventilator-free days, or 28-day mortality.
  • Adverse Events: The incidence of adverse events was similar in both groups. Bradycardia was more common in the dexmedetomidine group, while hypotension was more common in the propofol group.

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: The key statistics were the absolute mortality rates and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.88 for the primary outcome is much higher than the 0.05 threshold, indicating that the result was not statistically significant and very 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: No significant differences were found in any of the pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, double-blind design is the gold standard for minimizing bias and provided high-quality evidence.
  • Generalizability: The inclusion of 13 diverse medical centers increases the applicability of the findings.
  • Statistical Power: The study was adequately powered for its primary outcome of mortality.
  • Patient-Centered Outcomes: The study focused on important patient-centered outcomes, including mortality, delirium, and duration of ventilation.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was well-conducted with a low risk of bias.
  • External Validity (Generalizability): The study population was limited to patients with sepsis, and the results may not be fully generalizable to other ICU populations (e.g., post-operative cardiac surgery patients).
  • Other: The study compared two active, high-quality sedation strategies, both of which represented a high standard of care. This may have made it more difficult to detect a difference between the two agents.

10. Conclusion of the Authors

  • The authors concluded that among critically ill adults with sepsis undergoing mechanical ventilation, there was no significant difference in 90-day mortality or other key clinical outcomes between sedation with dexmedetomidine and sedation with propofol.

11. To Summarize

  • Impact on Current Practice: This large, high-quality trial provided strong evidence that, for septic patients, there is no clear superiority of dexmedetomidine over propofol in terms of major clinical outcomes.
  • Specific Recommendations:
    • Patient Selection: For the broad population of adult ICU patients with sepsis requiring mechanical ventilation and sedation.
    • Actionable Intervention: The results suggest that either dexmedetomidine or propofol are acceptable choices for a non-benzodiazepine, light sedation strategy.
  • What This Trial Does NOT Mean: This trial does NOT mean that the choice of sedative is unimportant. It reinforces the benefit of a non-benzodiazepine strategy but suggests that within that class, the choice can be guided by other factors.
  • Implementation Caveats: The choice between dexmedetomidine and propofol can be individualized based on the patient’s specific clinical profile (e.g., avoiding propofol in severe hypotension, avoiding dexmedetomidine in severe bradycardia) and institutional costs.

12. Context and Related Studies

  • Building on Previous Evidence: The MENDS2 trial (2021) was the direct successor to the original MENDS trial (2007), designed to compare the “best” non-benzodiazepine sedative (dexmedetomidine) against the other commonly used non-benzodiazepine (propofol).
  • Influence on Subsequent Research: The definitive neutral finding of this trial has been highly influential in shaping sedation guidelines, which now recommend either dexmedetomidine or propofol as first-line agents over benzodiazepines.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial definitively answered its primary question for the sepsis population.
  • Future Directions: Future research may focus on the role of these agents in non-septic populations and on more personalized sedation strategies.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a very common and important clinical decision in the ICU.
  • Methods: The multicenter, double-blind RCT design was of high quality. The comparison of two active, high-quality treatment arms is a strength that reflects real-world clinical choices.
  • Results: The study reported a clear neutral finding for its primary outcome and all major secondary outcomes. This provides strong evidence against a meaningful clinical difference between the two agents in this population.
  • Conclusions and Applicability: The authors’ conclusion is a direct and fair reflection of the data. The high external validity of this pragmatic trial means its findings are broadly applicable to the management of sedation in most modern ICUs. This is a classic example of a high-quality “negative” trial that is practice-changing by providing strong evidence that a newer, more expensive intervention is not superior to an established standard of care.

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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