Benzodiazepine-Treated Patients Experienced Higher Mortality than Patients Managed Using Propofol
October 1, 2014
ABSTRACT & COMMENTARY
Benzodiazepine-Treated Patients Experienced Higher Mortality than Patients Managed Using Propofol
By Leslie A. Hoffman, RN, PhD
Professor Emeritus, Nursing and Clinical & Translational Science, University of Pittsburgh
SYNOPSIS: In a matched sample, patients managed using propofol experienced lower mortality, earlier discontinuation of mechanical ventilation, and earlier ICU discharge compared to those managed using benzodiazepines.
SOURCE: Lonardo NW, et al. Propofol is associated with favorable outcomes compared with benzodiazepines in ventilated intensive care unit patients. Am J Respir Crit Care Med 2014;189:1383-1394. Erratum in: Am J Respir Crit Care Med 2014;189:e70.
To provide comfort and reduce anxiety, patients are commonly managed with a continuous-infusion sedative during use of mechanical ventilation. Despite evidence of adverse outcomes when benzodiazepines are selected as the sedative agent, surveys suggest continued use. Various rationales have been offered to explain this finding, including criticism of the restrictive entry/exclusion criteria of a randomized controlled trial (RCT). To evaluate findings in an actual practice setting, the authors analyzed data from a large observational critical care database (Project IMPACT, Cerner Corp, Kansas City, MO). A total of 13,692 patients from 104 participating centers met inclusion criteria. Patients were included if they: 1) had a single ICU admission, 2) required mechanical ventilation for > 48 hours, and 3) were managed exclusively with a single, continuous infusion of propofol, midazolam, or lorazepam. Patients who received propofol were matched with those who received midazolam or lorazepam on 15 baseline covariates using propensity score matching techniques.
After 1:1 matching, there were 2250 propofol-treated patients who matched to midazolam-treated patients and 1054 propofol-treated patients who matched to lorazepam-treated patients. By ICU day 28, the cumulative incidence of death was 19.2% in propofol-treated patients compared with 28.0% in midazolam-treated patients (P < 0.001). For lorazepam, cumulative incidence of death was 19.1% in propofol-treated patients compared with 24.6% of lorazepam-treated patients (P < 0.0018). By ICU day 28, the cumulative incidence of being discharged from the ICU was 78.9% in propofol-treated patients compared with 69.5% of midazolam-treated patients (P < 0.001). Results were similar for lorazepam-treated patients. By ICU day 28, the cumulative incidence of being discharged from the ICU was 79.2% in propofol-treated patients vs 71.9% of lorazepam-treated patients (P < 0.001). By ventilator day 28, the cumulative incidence of ventilator discontinuation was 84.4% for propofol-treated patients, compared with 75.1% of midazolam-treated patients (P < 0.001). Over this same period, the cumulative incidence of ventilator removal was 84.3% in propofol-treated patients compared with 78.8% in lorazepam-treated patients (P < 0.001). There was also a higher rate of ventilator-associated pneumonia (VAP) in lorazepam-treated patients (12.7%) compared to propofol-treated patients (7.9%; P < 0.001).
COMMENTARY
A number of RCTs have compared propofol with benzodiazepines, with results that strongly suggest improved patient outcomes when benzodiazepines are not used as the sedative agent. In response, the Society of Critical Care Medicine updated its clinical practice guidelines to recommend a non-benzodiazepine (e.g., propofol or dexmedetomidine) as the preferred sedative, with the goal of reducing the incidence of delirium. Nevertheless, surveys continue to suggest that benzodiazepines are widely used.
One criticism of current evidence focuses on entry criteria used for RCTs, which are typically restrictive and therefore may not represent the full scope of patients who may require these drugs. In particular, RCTs may exclude patients with renal or liver dysfunction and hemodynamic instability. To provide evidence from a large critical care database without such restrictions, the authors matched patients who exclusively received propofol with those who exclusively received either lorazepam or midazolam on 15 baseline characteristics and examined differences in mortality, ICU length of stay, time required to ventilator weaning, and incidence of VAP. Results uniformly favored propofol.
Although speculative, due to the retrospective study design, these results likely relate to a higher incidence of delirium when benzodiazepines are used. Propofol has a shorter duration of action, a characteristic that may explain shorter time to awakening and earlier extubation. Earlier extubation, in turn, reduces the incidence of VAP. This study had many strengths, including a large population, accurately measured clinical variables, a large number of ICUs, and matching on a large set of baseline measures that included admission service, type of service (medical or surgical), and type of hospital. It provides additional evidence of the benefits of a strategy that avoids use of benzodiazepines.