SEDCOM: Dexmedetomidine vs Midazolam for Sedation (2009)

“In mechanically ventilated medical and surgical ICU patients, dexmedetomidine was as effective as midazolam in maintaining light to moderate sedation, with a lower prevalence of delirium and a shorter time to extubation.”

— The SEDCOM Study Group

1. Publication Details

  • Trial Title: Dexmedetomidine vs Midazolam for Sedation of Critically Ill Patients: A Randomized Trial.
  • Citation: Riker RR, Shehabi Y, Bokesch PM, et al; SEDCOM (Safety and Efficacy of Dexmedetomidine Compared With Midazolam) Study Group. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA. 2009;301(5):489-499. doi:10.1001/jama.2009.56
  • Published: February 4, 2009, in The Journal of the American Medical Association (JAMA).
  • Author: Richard R. Riker, MD.
  • Funding: Hospira Inc.

2. Keywords

Critical Illness, Mechanical Ventilation, Sedation, Delirium, Dexmedetomidine, Midazolam, Intensive Care Unit.

3. The Clinical Question

In mechanically ventilated adult ICU patients requiring sedation for more than 24 hours (Population), is dexmedetomidine (Intervention) as effective as midazolam (Comparison) at maintaining the desired level of sedation and does it improve clinical outcomes like delirium and time to extubation (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Sedation is essential for the management of mechanically ventilated patients. Benzodiazepines like midazolam were the standard of care but were known to be associated with prolonged sedation and an increased risk of delirium, which is linked to worse patient outcomes.
  • Knowledge Gap: Dexmedetomidine, a selective alpha-2 agonist, offers a unique mechanism of sedation that does not cause respiratory depression and was hypothesized to be delirium-sparing. A large, robust trial was needed to compare it directly against the standard of care, midazolam.
  • Proposed Hypothesis: The authors hypothesized that dexmedetomidine would be non-inferior to midazolam for maintaining the target sedation level and superior in reducing the prevalence of delirium.

5. Study Design and Methods

  • Design: A prospective, randomized, double-blind, multicenter trial.
  • Setting: 68 centers in five countries.
  • Trial Period: Enrollment between March 2005 and July 2007.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) who were mechanically ventilated and anticipated to require sedation for >24 hours.
    • Exclusion Criteria: Severe neurologic disorders, severe hepatic impairment, recent cardiac surgery, pregnancy, or significant uncorrected hemodynamic instability.
  • Intervention: Continuous intravenous infusion of dexmedetomidine (0.2-1.5 µg/kg/h).
  • Control: Continuous intravenous infusion of midazolam (0.02-0.1 mg/kg/h).
  • Management Common to Both Groups: All patients were managed to a target sedation level of -3 to 0 on the Richmond Agitation-Sedation Scale (RASS). Open-label fentanyl was used for analgesia, and haloperidol was used for delirium treatment. Daily sedation interruptions were performed. Delirium was assessed daily using the Confusion Assessment Method for the ICU (CAM-ICU).
  • Power and Sample Size: The trial was powered for non-inferiority for the primary outcome, requiring approximately 366 patients for the final analysis.
  • Outcomes:
    • Primary Outcome: The percentage of time that patients were within the target sedation range (RASS -3 to 0).
    • Secondary Outcomes: Prevalence and duration of delirium, time to extubation, ICU length of stay, and incidence of adverse events.

6. Key Results

  • Enrollment and Baseline: 375 patients underwent randomization, with 366 included in the final analysis (244 dexmedetomidine, 122 midazolam). Baseline characteristics were well-matched.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: Dexmedetomidine was non-inferior to midazolam for the percentage of time within the target sedation range (median, 75% vs 75%; P = .72).
  • Secondary Outcomes:
    • Patients in the dexmedetomidine group had a lower prevalence of delirium (54% vs 76.6%; P < .001).
    • The median time to extubation was shorter in the dexmedetomidine group (3.7 days vs 5.6 days; P = .01).
    • There was no significant difference in ICU length of stay.
  • Adverse Events: Hypotension (20.6% vs 11.6%) and bradycardia (14.2% vs 5.2%) were more common with dexmedetomidine. Tachycardia was more common in the midazolam group (25.4% vs 44.3%).

7. Medical Statistics

  • Analysis Principle: An intention-to-treat analysis was performed.
  • Statistical Tests Used: The primary outcome was assessed for non-inferiority. Secondary outcomes were compared using appropriate parametric and non-parametric tests (e.g., Wilcoxon rank-sum, chi-square).
  • Primary Outcome Analysis: The percentage of time at target sedation was calculated for each patient and compared between groups to test for non-inferiority.
  • Key Statistic(s) Reported (for Delirium): Prevalence of delirium: 54% in the dexmedetomidine group vs. 76.6% in the midazolam group; P < .001.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of <.001 indicates a highly statistically significant difference in the prevalence of delirium between the two groups, making it very unlikely the finding was due to chance.
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR) for Delirium: 22.6% (76.6% – 54%).
    • Number Needed to Treat (NNT) to Prevent one case of Delirium: Approximately 4.4 (1 / 0.226). Treating about 4 to 5 patients with dexmedetomidine instead of midazolam would prevent one patient from developing delirium.
  • Subgroup Analyses: No major subgroup analyses were reported that altered the main conclusions.

8. Strengths of the Study

  • Study Design and Conduct: The randomized, double-blind design is the gold standard for minimizing bias.
  • Generalizability: The multicenter and international nature of the trial increases its external validity.
  • Patient-Centered Outcomes: The study focused on delirium and time to extubation, which are highly relevant clinical outcomes.
  • Standardized Assessments: Use of validated tools for sedation (RASS) and delirium (CAM-ICU) assessment adds rigor to the results.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was funded by the manufacturer of dexmedetomidine, which introduces a potential for bias.
  • External Validity (Generalizability): The exclusion of patients with severe neurologic or hepatic impairment may limit generalizability to these specific populations.
  • Other: The study was not powered to detect a difference in mortality.

10. Conclusion of the Authors

“Among critically ill, mechanically ventilated patients, dexmedetomidine was noninferior to midazolam for achieving light to moderate sedation. Dexmedetomidine was associated with a lower prevalence of delirium and a shorter time to extubation, but also with a higher incidence of bradycardia.”

11. To Summarize

  • Impact on Current Practice: This was a practice-changing trial that provided strong evidence that a non-benzodiazepine sedative (dexmedetomidine) was as effective for sedation as the standard of care (midazolam) while significantly reducing delirium and hastening extubation. It was a cornerstone study in the movement to reduce benzodiazepine use in the ICU.
  • Specific Recommendations:
    • Patient Selection: Mechanically ventilated adult patients in the ICU who require light to moderate sedation.
    • Actionable Intervention: Use a dexmedetomidine-based sedation strategy as a primary alternative to a midazolam-based strategy.
    • Expected Benefit: Reduced incidence of delirium and shorter duration of mechanical ventilation.
  • What This Trial Does NOT Mean: This trial does not mean dexmedetomidine is superior for all sedation goals. It is not necessarily the ideal agent for deep sedation or in patients where bradycardia or hypotension would be particularly dangerous.
  • Implementation Caveats: Clinicians must monitor for and be prepared to manage the known side effects of dexmedetomidine, primarily bradycardia and hypotension.

12. Context and Related Studies

  • Building on Previous Evidence: This trial directly challenged the long-standing practice of using benzodiazepines as first-line sedatives in the ICU.
  • Influence on Subsequent Research: The SEDCOM trial was highly influential and paved the way for further investigation into benzodiazepine-sparing sedation strategies. It was followed by trials like SPICE III (2019), which further explored the role of dexmedetomidine in a very large population, confirming its safety but not showing a mortality benefit with very early administration.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The optimal sedation strategy for patients requiring deep sedation remains an area of active research. The impact of dexmedetomidine on long-term cognitive outcomes requires further study.
  • Future Directions: Future research will likely focus on personalizing sedation strategies based on patient characteristics and underlying illness, as well as comparing different non-benzodiazepine agents.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The question was highly relevant, addressing the significant clinical problems of sedation management and delirium in the ICU.
  • Methods: The study’s double-blind, randomized, multicenter design was methodologically strong. The choice of midazolam as a comparator was appropriate as it was a global standard of care.
  • Results: The trial successfully demonstrated non-inferiority for its primary sedation endpoint and showed clinically important and statistically significant benefits in the key secondary outcomes of delirium and time to extubation.
  • Conclusions and Applicability: The authors’ conclusions are strongly supported by the data. The results are broadly applicable to the general population of mechanically ventilated ICU patients requiring light to moderate sedation. This trial provided compelling evidence to change practice and prioritize non-benzodiazepine sedatives.

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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