Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials.

CONTEXT 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. DESIGN, SETTING, AND PATIENTS 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). INTERVENTIONS Sedation with dexmedetomidine, midazolam, or propofol; daily sedation stops; and spontaneous breathing trials. MAIN OUTCOME MEASURES 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. TRIAL REGISTRATION clinicaltrials.gov Identifiers: NCT00481312, NCT00479661.

[1]  G. Harlow,et al.  A Protocol of No Sedation for Critically Ill Patients Receiving Mechanical Ventilation: A Randomised Trial , 2011 .

[2]  G. Bernard,et al.  Delirium as a predictor of long-term cognitive impairment in survivors of critical illness , 2010, Critical care medicine.

[3]  Peter N. Murakami,et al.  Cognitive improvement during continuous sedation in critically ill, awake and responsive patients: the Acute Neurological ICU Sedation Trial (ANIST) , 2010, Intensive Care Medicine.

[4]  K. Ho,et al.  Use of dexmedetomidine as a sedative and analgesic agent in critically ill adult patients: a meta-analysis , 2010, Intensive Care Medicine.

[5]  R. Balk.  Early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomised controlled trial , 2010 .

[6]  J. Devlin,et al.  Incidence of propofol-related infusion syndrome in critically ill adults: a prospective, multicenter study , 2009, Critical care.

[7]  E. Ely,et al.  Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. , 2009, JAMA.

[8]  J. Barker.  Effect of Sedation With Dexmedetomidine vs Lorazepam on Acute Brain Dysfunction in Mechanically Ventilated Patients: The MENDS Randomized Controlled Trial , 2009 .

[9]  E. Ruokonen,et al.  Dexmedetomidine versus propofol/midazolam for long-term sedation during mechanical ventilation , 2009, Intensive Care Medicine.

[10]  G. Bernard,et al.  Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial , 2008, The Lancet.

[11]  M. Meade,et al.  A multicenter survey of Ontario intensive care unit nurses regarding the use of sedatives and analgesics for adults receiving mechanical ventilation. , 2007, Journal of critical care.

[12]  J. Payen,et al.  Current Practices in Sedation and Analgesia for Mechanically Ventilated Critically Ill Patients: A Prospective Multicenter Patient-based Study , 2007, Anesthesiology.

[13]  R. Griffiths,et al.  Precipitants of post-traumatic stress disorder following intensive care: a hypothesis generating study of diversity in care , 2007, Intensive Care Medicine.

[14]  Lorazepam Is an Independent Risk Factor for Transitioning to Delirium in Intensive Care Unit Patients , 2007 .

[15]  Jesse B. Hall,et al.  A randomized trial of intermittent lorazepam versus propofol with daily interruption in mechanically ventilated patients* , 2006, Critical care medicine.

[16]  G. Bernard,et al.  Lorazepam Is an Independent Risk Factor for Transitioning to Delirium in Intensive Care Unit Patients , 2006, Anesthesiology.

[17]  M. Danhof,et al.  Population pharmacodynamic modelling of lorazepam- and midazolam-induced sedation upon long-term continuous infusion in critically ill patients , 2006, European Journal of Clinical Pharmacology.

[18]  J. Vincent,et al.  The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure , 1996, Intensive Care Medicine.

[19]  Jesse B. Hall,et al.  The long-term psychological effects of daily sedative interruption on critically ill patients. , 2003, American journal of respiratory and critical care medicine.

[20]  C. Sessler,et al.  The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients. , 2002, American journal of respiratory and critical care medicine.

[21]  G. Bernard,et al.  Delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU). , 2001, JAMA.

[22]  S L Shafer,et al.  Propofol Dosing Regimens for ICU Sedation Based upon an Integrated Pharmacokinetic– Pharmacodynamic Model , 2001, Anesthesiology.

[23]  J. Kress,et al.  Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. , 2000, The New England journal of medicine.

[24]  G Sherman,et al.  Effect of a nursing-implemented sedation protocol on the duration of mechanical ventilation. , 1999, Critical care medicine.

[25]  M. Sydow,et al.  Sedation for the critically ill , 1999, Intensive Care Medicine.

[26]  G Sherman,et al.  The use of continuous i.v. sedation is associated with prolongation of mechanical ventilation. , 1998, Chest.