MENDS: Dexmedetomidine vs. Lorazepam for Sedation in Sepsis (2008)

“Among mechanically ventilated patients with sepsis, a strategy of sedation with dexmedetomidine resulted in more days alive without delirium or coma and a lower prevalence of delirium as compared with a strategy of sedation with lorazepam.”

  • The MENDS Study Investigators

1. Publication Details

  • Trial Title: Effect of Dexmedetomidine vs Lorazepam on Outcome in Patients With Sepsis: The MENDS Randomized Trial
  • Citation: Pandharipande PP, Pun BT, Herr DL, et al. Effect of dexmedetomidine vs lorazepam on outcome in patients with sepsis: the MENDS randomized trial. JAMA. 2007;298(22):2644-2653. DOI: 10.1001/jama.298.22.2644
  • Published: December 12, 2007, in The Journal of the American Medical Association (JAMA)
  • Author: Pratik P. Pandharipande, M.D., M.S.C.I.
  • Funding: Hospira Inc; United States National Institutes of Health (NIH).

2. Keywords

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

3. The Clinical Question

  • In mechanically ventilated adult patients with sepsis (Population), does a strategy of sedation with dexmedetomidine (Intervention) compared to a strategy of sedation with lorazepam (Comparison) increase the number of days alive without delirium or coma (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Delirium is a common and serious form of organ dysfunction in the ICU, associated with worse long-term outcomes. Benzodiazepines like lorazepam, the standard sedatives at the time, were known to be a major risk factor for the development of delirium.
  • Knowledge Gap: Dexmedetomidine, a newer sedative agent acting on alpha-2 receptors, was hypothesized to provide effective sedation with less risk of delirium compared to benzodiazepines. However, there was no high-quality evidence from a randomized controlled trial to support this.
  • Proposed Hypothesis: The authors hypothesized that sedation with dexmedetomidine would be superior to sedation with lorazepam in increasing the number of days alive without delirium or coma.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, double-blind, controlled trial (used to test the effectiveness of interventions).
  • Setting: 2 tertiary care medical ICUs in the United States.
  • Trial Period: Enrollment ran from August 2004 to August 2006.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) with sepsis 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.
  • Intervention: Patients received a continuous intravenous infusion of dexmedetomidine.
  • Control: Patients received a continuous intravenous infusion of lorazepam.
  • Management Common to Both Groups: Both groups were managed with a protocol targeting a light level of sedation (RASS 0 to -1). Both also received fentanyl for analgesia.
  • Power and Sample Size: The authors calculated that a sample size of 100 patients would provide 80% power to detect a 2.5-day difference in the primary outcome. (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: The number of days alive without delirium or coma during the 14-day study period.
    • Secondary Outcomes: Included ventilator-free days, length of ICU stay, and 28-day mortality.

6. Key Results

  • Enrollment and Baseline: 103 patients were randomized (51 to dexmedetomidine and 52 to lorazepam). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: Patients in the dexmedetomidine group had significantly more days alive without delirium or coma: a median of 7.0 days in the dexmedetomidine group vs. 3.0 days in the lorazepam group (p=0.01).
  • Secondary Outcomes: There were no significant differences between the groups in 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, but rarely required intervention.

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 Wilcoxon rank-sum test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the median number of days alive without delirium or coma between the two groups.
  • Key Statistic(s) Reported: The key statistics were the median values for the primary outcome and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.01 for the primary outcome is well below the 0.05 threshold, indicating that the observed difference is statistically significant and unlikely to be due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures:
    • Difference in Medians: The median number of days alive without delirium or coma was 4 days longer in the dexmedetomidine group. This represents a large, clinically meaningful benefit.
  • Subgroup Analyses: Not a major feature of this publication.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, double-blind design is the gold standard for minimizing bias.
  • Generalizability: The inclusion of patients from two different academic centers increases the applicability of the findings.
  • Patient-Centered Outcomes: The primary outcome, a composite of delirium-free and coma-free days, is a robust and highly relevant patient-centered endpoint.

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 or trauma patients).
  • Other: The trial was relatively small and was not powered to detect a difference in mortality.

10. Conclusion of the Authors

  • The authors concluded that in mechanically ventilated patients with sepsis, sedation with dexmedetomidine resulted in more days alive without delirium or coma than sedation with lorazepam.

11. To Summarize

  • Impact on Current Practice: This was a landmark trial that provided the first strong, randomized evidence that the choice of sedative agent can have a major impact on delirium. It was a key driver in the paradigm shift away from routine benzodiazepine-based sedation and towards a benzodiazepine-sparing approach.
  • Specific Recommendations:
    • Patient Selection: For adult patients with sepsis requiring mechanical ventilation and sedation.
    • Actionable Intervention: Dexmedetomidine should be considered as a primary sedative agent over benzodiazepines like lorazepam to reduce the burden of delirium.
  • What This Trial Does NOT Mean: This trial does NOT mean that dexmedetomidine is a perfect sedative for all patients. It can cause bradycardia and hypotension.
  • Implementation Caveats: The key takeaway is the importance of avoiding benzodiazepines when possible. The choice of sedative should be individualized based on the patient’s hemodynamic profile and sedation goals.

12. Context and Related Studies

  • Building on Previous Evidence: The MENDS trial (2007) was designed to test the hypothesis that a targeted, non-benzodiazepine sedative could improve delirium outcomes, a concept that grew out of earlier trials like Kress et al. (2000) which highlighted the harms of over-sedation.
  • Influence on Subsequent Research: The definitive positive result of this trial has been highly influential in shaping international sedation guidelines (e.g., the PADIS guidelines), which now strongly recommend a benzodiazepine-sparing approach. It also led to the design of the larger MENDS2 trial (2016) to confirm these findings in a broader ICU population.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The key unresolved question was whether the benefits of dexmedetomidine over benzodiazepines would hold true in a larger, more heterogeneous population of critically ill patients beyond those with sepsis.
  • Future Directions: The MENDS2 trial was the direct successor to this study, designed to answer the question of efficacy in a broader mixed medical-surgical ICU population.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a very common and serious complication of critical illness with a novel therapeutic strategy.
  • Methods: The multicenter, double-blind RCT design was of high quality. The use of a validated delirium assessment tool and a patient-centered primary outcome were major strengths.
  • Results: The study reported a statistically significant and clinically profound benefit for its primary outcome. The finding of no difference in mortality was expected, as the trial was not powered for this endpoint.
  • Conclusions and Applicability: The authors’ conclusion is strongly supported by the data. Despite its relatively small size, the trial was highly influential due to its rigorous design and the large, clinically important effect size. Its findings are broadly applicable to the management of sedation in septic 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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