Impact of oversedation prevention in ventilated critically ill patients: a randomized trial-the AWARE study

Abstract

Background: Although oversedation has been associated with increased morbidity in ventilated critically ill patients, it is unclear whether prevention of oversedation improves mortality. We aimed to assess 90-day mortality in patients receiving a bundle of interventions to prevent oversedation as compared to usual care.

Methods: In this randomized multicentre trial, all adult patients requiring mechanical ventilation for more than 48 h were included. Two groups were compared: patients managed according to usual sedation practices (control), and patients receiving sedation according to an algorithm which provided a gradual multilevel response to pain, agitation, and ventilator dyssynchrony with no specific target to alter consciousness and no use of sedation scale and promoted the use of alternatives to continuous infusion of midazolam or propofol (intervention).

Results: Inclusions were stopped before reaching the planned enrolment. Between 2012 and 2014, 584 patients were included in the intervention group and 590 in the control group. Baseline characteristics were well balanced between groups. Although the use of midazolam and propofol was significantly lower in the intervention group, 90-day mortality was not significantly lower (39.4 vs. 44.2% in the control group, p = 0.09). There were no significant differences in 1-year mortality between the two groups. The time to first spontaneous breathing trial and time to successful extubation were significantly shorter in the intervention group than in the control group. These last results should be interpreted with precaution regarding the several limitations of the trial including the early termination.

Conclusions: This underpowered study of severely ill patients was unable to show that a strategy to prevent oversedation could significantly reduce mortality. Trial registration NCT01617265.

Keywords: Intensive care units; Mechanical ventilation; Mortality; Sedation; Weaning.

Fig. 1

Oversedation prevention (OSP) strategy was centred on patients’ level of agitation, ventilator dyssynchrony, and pain, assessed on a 4-level scale, with gradual on-demand responses, frequent reassessments, and promotion of alternatives to continuous around-the-clock infusion of intravenous hypnotics. These alternatives included frequent (every 6 h) intravenous hypnotic interruptions, intravenous boluses of hypnotics without continuous intravenous infusion, and the use of non-hypnotic drugs, including neuroleptics, hydroxyzine, and anxiolytic benzodiazepines. The choice of the non-hypnotic drugs and their route of administration (intravenous boluses or nasogastric tube) were left to the preference of the attending physician. There was no restriction for the use of morphinics and non-morphinic analgesics. Patient at Level 0, who showed no discomfort, received no treatment, or continuation of a successful level-1 therapeutic response (a). Patient at Level 1, with only moderate discomfort, pain, or anticipated procedural pain (b), received any form of analgesics as deemed necessary by the attending physician and/or non-hypnotic drugs as well as verbal reassurance and, if appropriate, changing of ventilator settings (c). Patients at Level 2, with severe agitation or ventilator dyssynchrony first received repeated intravenous boluses of either propofol or midazolam according to physician preferences, and, if discomfort persisted, 6-h continuous intravenous infusion of midazolam or propofol. This treatment was also applied in case of Level 1 therapy failure (which was maintained or stopped according to physician preference (d). Patients at Level 3, with ARDS and a PaO₂/FiO₂ ratio < 150 mmHg, were treated with a continuous intravenous infusion of midazolam or propofol, with neuromuscular blocking agents administered according to physician preference. This treatment was also applied in the case of Level 2 therapy failure

Fig. 2

Flowchart. ^aPatients lost to follow-up: imputation of missing data (alive vital status) was performed. OSP, oversedation prevention

Fig. 3

Cumulative incidence of deaths in the hospital. The cumulative incidence of hospital death did not differ significantly between the two groups (220 in oversedation prevention group vs. 253 in the control group): hazard ratio for the oversedation prevention group versus the control group, 0.85; 95% confidence interval, 0.71–1.01; p = 0.06. For the analysis of time from randomization to death in the hospital, alive hospital discharge was handled as a competing risk