Dexmedetomidine vs Midazolam for Sedation of Critically Ill Patients

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Dexmedetomidine vs Midazolam for Sedation of
Critically Ill Patients

• A Randomized Trial
• Journal Club 09/01/11

JAMA, February 4, 2009Vol 301, No. 5 489
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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

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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

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Methods
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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

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Study Design

• This prospective
• Double-blind
• Except the investigative pharmacist at each site
• Randomized trial
• 21 to receive vs Midazolam
• ICUs at 68 centers
• 5 countries
• Between March 2005 and August 2007

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Patients

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

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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

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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

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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.

A correlation between the assessments, a
multivariate analysis was performed using a
generalized estimating equation
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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

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Safety End Points

• Laboratory test results
• Vital signs
• Electrocardiogram findings
• Physical examination findings
• Withdrawal related events
• Adverse events

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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

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

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Results
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Baseline Demographics
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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
• 153/24463 vs 60/122 49 P.02

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Efficacy Analyses
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Extubation and Intensive Care Unit (ICU) Length
of Stay
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Delirium and Nursing Assessments

• Effect of dexmedetomidine delirium as measured by
  GEE
• 24.9 reduction (95 CI, 16 to 34 P.001)
• CAM-ICUnegative 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)

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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

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Safety

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

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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

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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