title: Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials.
abstract: BACKGROUND
  Long-term sedation with midazolam or propofol in intensive care units (ICUs) has serious adverse effects. Dexmedetomidine, an α(2)-agonist available for ICU sedation, may reduce the duration of mechanical ventilation and enhance patient comfort.
  
  
  OBJECTIVE
  To determine the efficacy of dexmedetomidine vs midazolam or propofol (preferred usual care) in maintaining sedation; reducing duration of mechanical ventilation; and improving patients' interaction with nursing care.
  
  
  METHODS
  Two phase 3 multicenter, randomized, double-blind trials carried out from 2007 to 2010. The MIDEX trial compared midazolam with dexmedetomidine in ICUs of 44 centers in 9 European countries; the PRODEX trial compared propofol with dexmedetomidine in 31 centers in 6 European countries and 2 centers in Russia. Included were adult ICU patients receiving mechanical ventilation who needed light to moderate sedation for more than 24 hours (midazolam, n = 251, vs dexmedetomidine, n = 249; propofol, n = 247, vs dexmedetomidine, n = 251).
  
  
  METHODS
  Sedation with dexmedetomidine, midazolam, or propofol; daily sedation stops; and spontaneous breathing trials.
  
  
  METHODS
  For each trial, we tested whether dexmedetomidine was noninferior to control with respect to proportion of time at target sedation level (measured by Richmond Agitation-Sedation Scale) and superior to control with respect to duration of mechanical ventilation. Secondary end points were patients' ability to communicate pain (measured using a visual analogue scale [VAS]) and length of ICU stay. Time at target sedation was analyzed in per-protocol population (midazolam, n = 233, vs dexmedetomidine, n = 227; propofol, n = 214, vs dexmedetomidine, n = 223).
  
  
  RESULTS
  Dexmedetomidine/midazolam ratio in time at target sedation was 1.07 (95% CI, 0.97-1.18) and dexmedetomidine/propofol, 1.00 (95% CI, 0.92-1.08). Median duration of mechanical ventilation appeared shorter with dexmedetomidine (123 hours [IQR, 67-337]) vs midazolam (164 hours [IQR, 92-380]; P = .03) but not with dexmedetomidine (97 hours [IQR, 45-257]) vs propofol (118 hours [IQR, 48-327]; P = .24). Patients' interaction (measured using VAS) was improved with dexmedetomidine (estimated score difference vs midazolam, 19.7 [95% CI, 15.2-24.2]; P < .001; and vs propofol, 11.2 [95% CI, 6.4-15.9]; P < .001). Length of ICU and hospital stay and mortality were similar. Dexmedetomidine vs midazolam patients had more hypotension (51/247 [20.6%] vs 29/250 [11.6%]; P = .007) and bradycardia (35/247 [14.2%] vs 13/250 [5.2%]; P < .001).
  
  
  CONCLUSIONS
  Among ICU patients receiving prolonged mechanical ventilation, dexmedetomidine was not inferior to midazolam and propofol in maintaining light to moderate sedation. Dexmedetomidine reduced duration of mechanical ventilation compared with midazolam and improved patients' ability to communicate pain compared with midazolam and propofol. More adverse effects were associated with dexmedetomidine.
  
  
  BACKGROUND
  clinicaltrials.gov Identifiers: NCT00481312, NCT00479661.
authors.affiliation: Department of Intensive Care Medicine, Bern University Hospital and University of Bern, Bern, Switzerland.
authors.forename: Stephan M
authors.initials: SM
authors.lastname: Jakob
authors.forename: Esko
authors.initials: E
authors.lastname: Ruokonen
authors.forename: R Michael
authors.initials: RM
authors.lastname: Grounds
authors.forename: Toni
authors.initials: T
authors.lastname: Sarapohja
authors.forename: Chris
authors.initials: C
authors.lastname: Garratt
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Pocock
authors.forename: J Raymond
authors.initials: JR
authors.lastname: Bratty
authors.forename: Jukka
authors.initials: J
authors.lastname: Takala
mesh_terms: D000368:Aged; D003142:Communication; D016292:Procedural Sedation / Q000145:classification / Q000379:methods*; D020927:Dexmedetomidine / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives / Q000009:adverse effects / Q000627:therapeutic use*; D007362:Intensive Care Units; D007902:Length of Stay; D008297:Male; D008874:Midazolam / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D009723:Nurse-Patient Relations; D010146:Pain; D010147:Pain Measurement; D015742:Propofol / Q000009:adverse effects / Q000627:therapeutic use*; D012121:Respiration, Artificial; D013997:Time Factors
chemical_list: D006993:Hypnotics and Sedatives; D020927:Dexmedetomidine; D008874:Midazolam; D015742:Propofol