Effect of High-Dose Baclofen on Agitation-Related Events Among Patients With Unhealthy Alcohol Use Receiving Mechanical Ventilation: A Randomized Clinical Trial

Abstract

Importance: Unhealthy alcohol use can lead to agitation in the intensive care unit (ICU).

Objective: To assess whether high-dose baclofen reduces agitation-related events compared with placebo in patients with unhealthy alcohol use receiving mechanical ventilation.

Design, settings, and participants: This phase 3, double-blind, placebo-controlled, randomized clinical trial conducted in 18 ICUs in France recruited adults receiving mechanical ventilation who met criteria for unhealthy alcohol use. Patients were enrolled from June 2016 to February 2018; the last follow-up was in May 2019.

Interventions: Baclofen (n = 159), adjusted from 50 to 150 mg per day based on estimated glomerular filtration rate, or placebo (n = 155) during mechanical ventilation up to a maximum of 15 days before gradual dose reduction over 3 to 6 days.

Main outcomes and measures: The primary end point was the percentage of patients with at least 1 agitation-related event over the treatment period. Secondary outcomes included duration of mechanical ventilation, length of ICU stay, and 28-day mortality.

Results: Among 314 patients who were randomized (mean age, 57 years; 60 [17.2%] women), 313 (99.7%) completed the trial. There was a statistically significant decrease in the percentage of patients who experienced at least 1 agitation-related event in the baclofen group vs the placebo group (31 [19.7%] vs 46 [29.7%]; difference, -9.93% [95% CI, -19.45% to -0.42%]; adjusted odds ratio, 0.59 [95% CI, 0.35-0.99]). Of 18 prespecified secondary end points, 14 were not significantly different. Compared with the placebo group, the baclofen group had a significantly longer median length of mechanical ventilation (9 vs 8 days; difference, 2.00 [95% CI, 0.00-3.00]; hazard ratio [HR] for extubation, 0.76 [95% CI, 0.60-0.97]) and stay in the ICU (14 vs 11 days; difference, 2.00 [95% CI, 0.00-4.00]; HR for discharge, 0.70 [95% CI, 0.54-0.90]). At 28 days, there was no significant difference in mortality in the baclofen vs placebo group (25.3% vs 21.6%; adjusted odds ratio, 1.24 [95% CI, 0.72-2.13]). Delayed awakening (no eye opening at 72 hours after cessation of sedatives and analgesics) occurred in 14 patients (8.9%) in the baclofen group vs 3 (1.9%) in the placebo group.

Conclusions and relevance: Among patients with unhealthy alcohol use receiving mechanical ventilation, treatment with high-dose baclofen, compared with placebo, resulted in a statistically significant reduction in agitation-related events. However, considering the modest effect and the totality of findings for the secondary end points and adverse events, further research is needed to determine the possible role of baclofen in this setting and to potentially optimize dosing.

Trial registration: ClinicalTrials.gov Identifier: NCT02723383.

Figure 1.. Flow of Participants in a Study of the Effect of High-Dose Baclofen on Agitation-Related Events Among Patients With Unhealthy Alcohol Use Receiving Mechanical Ventilation

^aEligibility criteria were modified after the inclusion of the first 5 patients: the upper age limit was increased from 70 to 80 years and the expected duration of mechanical ventilation was decreased from 48 to 24 hours. ^bThe National Institute on Alcohol Abuse and Alcoholism (NIAAA) threshold is defined as consumption of more than 14 units per week for men and 7 units per week for women or men older than 65 years. One alcoholic drink (unit) is defined as 1 drink that contains approximately 12 to 14 g of pure alcohol (12 ounces of beer, 5 ounces of wine, or 1.5 ounces of 80-proof liquor). ^cAccording to French law. ^dThe per-protocol analysis excluded patients who received less than 100% of the protocol-specified dose (ie, incomplete treatment): 1 patient who withdrew consent, 2 with overestimation of alcohol intake (ie, did not meet inclusion criteria), and 1 included twice for 2 different admissions in the intensive care unit (ICU).

Figure 2.. Primary and Per-Protocol Analyses in a Study of the Effect of High-Dose Baclofen on Agitation-Related Events Among Patients With Unhealthy Alcohol Use Receiving Mechanical Ventilation

Trend lines were truncated when observations fell below 20%. Between-group differences were tested using Fine-Gray regression considering death as competing event for agitation. When baclofen was compared with placebo, the hazard ratio (HR) for agitation was 0.62 ([95% CI, 0.40-0.96]; P = .03) in the primary analysis and 0.36 ([95% CI, 0.17-0.79]; P = .01) in the per-protocol analysis. A hazard ratio less than 1 indicates that the probability of agitation was lower in the baclofen group at all times.