MIDEX-PRODEX

MIDEX-PRODEX: Dexmedetomidine vs Midazolam or Propofol for Sedation During Prolonged Mechanical Ventilation: Two Randomized Controlled Trials

Jakob. JAMA 2012; 307:1151-1160. doi:10.1001/jama.2012.304.

Clinical Question

  • In adult intensive care patients requiring mechanical ventilation, is dexmedetomidine inferior to propofol or midazolam in achieving target sedation level?

Design

  • Parallel trial design, depending on the study centre’s usual practice
    • MIDEX: midazolam
    • PRODEX: propofol
  • Non-inferiority statistical design
  • ‘Double-dummy’ design with opaque syringe and giving set to mask propofol administration
  • Double blind design – study personnel and patients were unaware of the group allocation
  • Deemed non-inferior if the 95% confidence intervals for the dexmedetomidine to standard sedation ratio for the time within target RASS score did not cross 0.85 (i.e. 15% inferiority margin)
    • For 90% power a sample size of 450 in each trial was required
    • (RASS score is Richmond Agitation-Sedation Scale – see external links at bottom)

Setting

  • MIDEX: 44 centres in 9 European countries
  • PRODEX: 31 centres in 6 European countries and 2 in Russia
  • 2007 through 2010

Population

  • Inclusion: over 18 years; invasive mechanical ventilation; target RASS score 0 to -3 (light to moderate sedation); expected to require sedation for at least 24 hours; within 72 hours of ICU admission and within 48 hours of starting either midazolam or propofol
  • Exclusion: acute severe neurological disorder; MAP < 55 mmHg despite optimisation; heart rate < 50/min; AV conduction defects; recent use of alpha agonists or antagonists
  • MIDEX: 8301 ventilated patients screened of which 501 randomised
  • PRODEX: 11610 ventilated patients screened of which 500 randomised

Intervention

  • Dexmedetomidine 0.2-1.4 mcg/kg/hr

Control

  • MIDEX: midazolam 0.03-0.2 mg/kg/hr
  • PRODEX: propofol 0.3-4.0 mg/kg/hr

Outcome

In words

  • Primary outcome: non-inferiority of dexmedetomidine confirmed against both midazolam and propofol
    • Time at target sedation (RASS 0 to -3) without rescue medication was similar for midazolam vs dexmedetomidine and for propofol vs dexmedetomidine. Small differences were not significant and the 95% confidence intervals for the ratio did not cross 0.85.
    • Duration of mechanical ventilation was significantly shorter for dexmedetomidine compared to midazolam, but the slightly shorter duration for dexmedetomidine against propofol was not statistically significant.
  • Secondary outcome: superiority of dexmedetomidine was suggested but not confirmed statistically
    • Median length of stay in ICU was shorter for dexmedetomidine against both midazolam and propofol, but differences were not statistically significant.
    • The nurses’ assessment of patient arousal, cooperation and communication by visual analogue scale were higher (better) for dexmedetomidine against both midazolam and propofol.
  • Other data outcomes:
    • Mean sedation scores were higher for dexmedetomidine against both midazolam and propofol with statistical significance.

In numbers

 

Primary Outcome
Study Dexmedetomidine Usual Drug Estimated ratio 95% CI p
Time at target sedation without rescue medicine – proportion of total time
MIDEX 60.7% 56.6% 1.07 0.97 – 1.18 0.15
PRODEX 64.6% 64.7% 1.00 0.92 – 1.08 0.97
Median duration of MV (including NIV) – hours [IQR]
MIDEX 123 [67–337] 164 [92–380] 0.03
PRODEX 97 [45–257] 118 [48–327] 0.24
CI = confidence interval; p = p-value; MV = mechanical ventilation; NIV = non-invasive ventilation
Pre-defined Secondary Outcomes
Study Dexmedetomidine Usual Drug MD 95% CI p
Median length of ICU stay – hours [IQR]
MIDEX 211 [115–831] 243 [140–630] n/a 0.27
PRODEX 164 [90–480] 185 [93–520] n/a 0.54
Combined VAS (as mm out of 100) for nurses’ assessment of arousal, cooperation and communication
MIDEX 49.7 30.0 19.7
Favours dexmedetomidine
15.2 – 24.2 <0.001
PRODEX 51.3 40.1 11.2
Favours dexmedetomidine
6.4 – 15.9 <0.001
MD = mean difference; CI = confidence intervals; p = p-value; VAS = visual analogue scale

Authors’ Conclusions

  • Dexmedetomidine is non-inferior to midazolam and propofol for long-term mild to moderate sedation on intensive care.
  • It may reduce time to extubation and it does improve communication between staff and patients.

Strengths

  • Efficient use of parallel trial design
  • Clinically useful outcome measure
  • Independent statistical analysis helps toward preventing any bias from sponsoring manufacturer
  • Per-protocol analysis for non-inferiority primary outcome will prevent bias toward non-inferiority conclusion, whereas the intention-to-treat analysis for efficacy secondary outcomes prevent bias toward positive difference. This approach will limit the chance of false positive conclusions.
  • Extensive online publication of raw data

Weaknesses

  • Sponsored by manufacturer of dexmedetomidine with significant trial design, oversight and manuscript input
  • Recruitment rate averages 3 to 4 patients per year per centre! Was there selection bias?
  • Only short term measures of delirium and neurocognitive problems used
  • The finding that mean sedation scores were higher in patients managed with dexmedetomidine may be a confounding factor (by chance or by accidental unblinding) leading to a bias that favours dexmedetomidine. Alternatively, it may be a positive finding that sedation was easier to manage and titrate with dexmedetomidine.

The Bottom Line

  • This non-inferiority trial opens the door to using dexmedetomidine in intensive care, but further trials with longer-term neurocognitive follow-up and cost-analysis are required before it can be recommended as first-line.

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