Dexmedetomidine vs Midazolam for Sedation of Critically Ill Patients

1. Dexmedetomidine vs Midazolam for Sedation of Critically Ill Patients A Randomized Trial Journal Club 09/01/11 JAMA, February 4, 2009—Vol 301, No. 5 489

2. Introduction • GABA Rc agonists (including propofol and benzodiazepines) have been the most common sedative for ICU patients • Well-known hazards associated with prolonged use of GABA agonists • Few investigations of ICU sedation have compared these agents to other drug classes

3. Dexmedetomidine • Sedation and anxiolysis via receptors within the locus ceruleus, analgesia via receptors in the spinal cord • Specific and selective activation of postsynaptic alpha2-adrenoreceptors • No significant respiratory depression

4. Methods

5. Hypothesis A sedation strategy using dexmedetomidine would result in im- proved outcomes in mechanically ventilated, critically ill medical and surgical ICU patients compared with the standard GABA agonist midazolam

6. Study Design • This prospective • Double-blind • Except the investigative pharmacist at each site • Randomized trial • 2:1 to receive vs Midazolam • ICUs at 68 centers • 5 countries • Between March 2005 and August 2007

7. Patients • 18 years or older • Intubated and MV • < than 96 hours prior to start of study drug • An anticipated ventilation and sedation duration of at least 3 more days • Exclusion criteria

8. Study Drug Administration • Sedatives used before Stopped • RASS target range of −2 to +1 • Optional blinded loading doses • Up to 1 μg/kg dexmedetomidine or 0.05 mg/kg midazolam • Maintenance infusion • 0.8 μg/kg per hour for dexmedetomidine • 0.06 mg/kg per hour for midazolam • Study drug was stopped

9. Other Drugs • Open-label midazolam bolus • 0.01 to 0.05 mg/kg at 10- to 15-minute • Fentanyl bolus doses (0.5-1.0 μg/kg) • PRN every 15 minutes • IV haloperidol for treatment of agitation or delirium • 1 to 5 mg/10-20 min PRN

10. The Primary End Point • The primary end point was the per- centage of time within the target seda- tion range (RASS score −2 to +1) during the double-blind treatment period. Total time within the target RASS range X 100 Time remained in the treatment period A correlation between the assessments, a multivariate analysis was performed using a generalized estimating equation

11. Secondary End Points • Prevalence and duration of delirium • Use of fentanyl and open-label midazolam • Delirium free days were calculated as days alive and free of delirium during study drug exposure • During the arousal assessment Confusion Assessment Method for the ICU (CAM-ICU) • Duration of mechanical ventilation • Length of stay in the ICU

12. Safety End Points • Laboratory test results • Vital signs • Electrocardiogram findings • Physical examination findings • Withdrawal related events • Adverse events

13. Statistical Analysis • Sample Size Determination • 250 patients randomized to dexmedetomidine and 125 to midazolam would have 96% power at an alpha of 05 to detect a 7.4% difference in efficacy for the primary outcome • Delirium and use of rescue medications were performed using the Fisher exact test • Delirium free days, duration of study drug, and doses of rescue medications were performed using the Mann-Whitney test • Time to extubation and length of ICU stay were calculated using Kaplan- Meier

14. A secondary analysis was conducted on the entire intent-to-treat population • Long-term use” subgroup • Sites enrolling 5 patients or more

15. Results

16. Baseline Demographics

17. Study Drug Administration The mean (SD) maintenance infusion dose • 0.83(0.37)μg/kg/h for dexmedetomidine • 0.056 (0.028)mg/kg/hour for midazolam Optional loading doses • 20/244 dexmedetomidine (8.2%) • 9/122 midazolam (7.4%) Open-label midazolam • 153/244[63%] vs 60/122 [49%]; P=.02

18. Efficacy Analyses

19. Extubation and Intensive Care Unit (ICU) Length of Stay

20. Effect of dexmedetomidine delirium as measured by GEE 24.9% reduction (95% CI, 16% to 34% P.001) CAM-ICU–negative: 15.4% decrease (95% CI, 2% to 29%; P=.02), with a delirium prevalence of 32.9% (25/76) dexmedetomidine patients vs 55.0% (22/40) in midazolam patients (P=.03) The composite nursing assessment score for patient communication, cooperation, and tolerance of the ventilator was higher for dexmedetomidine patients (21.2 [SD, 7.4] vs 19.0 [SD, 6.9]; P=.001) Delirium and Nursing Assessments

21. Long-term Use and Subpopulations • Intent-to-treat population • Time in target (75.4% vs 73.3%) • 24.9% Delirium reduction • Time to extubation , ICU length of stay • “long-term use” population • Time inthe target (80.8% vs 81% ) • 24% Delirium reduction

22. Stopped study drug because of adverse events 16.4%vs 13.1% P=.44 Adverse events related to treatment 40.6% vs 28.7% P=.03 12/244) required an intervention for bradycardia Safety

23. Conclusions • The primary outcome for this investigation, time in the target sedation range, was not different between groups • Patients treated with dexmedetomidine developed delirium more than 20% less often than patients treated with midazolam • Incorporated new standard elements for ICU sedation • Light-to moderate sedation target (RASS score−2 to 1) • delirium assessment • Study drug titration or interruption every 4 hours • Daily arousal assessment • Reductions in ventilator time

24. Limitations • The primary analysis targeted patients treated with study drug, rather than the usual intent-to treat • Midazolam was selected as the comparator medication • Many centers in this study enrolled few patients, raising concern for potential bias • Exclusion patients requiring renal replacement therapy