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Original Investigation
February 23, 2021

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

Author Affiliations
  • 1Centre Hospitalo-Universitaire de Nantes, Service d’Anesthésie Réanimation Chirurgicale, France
  • 2Centre Hospitalo-Universitaire de Nantes, Service de Médecine Intensive Réanimation, France
  • 3Centre Hospitalo-Universitaire de Rennes, Service de Médecine Intensive Réanimation, France
  • 4Centre Hospitalier Départemental Vendée, Service de Médecine Intensive Réanimation, La Roche-Sur-Yon, France
  • 5Centre Hospitalier Général de Saint-Nazaire, Service de Médecine Intensive Réanimation, France
  • 6Centre Hospitalo-Universitaire de Montpellier, Service de Médecine-Intensive Réanimation, France
  • 7Centre Hospitalo-Universitaire de Tours, Service d’Anesthésie-Réanimation, France
  • 8Centre Hospitalo-Universitaire de Montpellier, Service d’Anesthésie-Réanimation, France
  • 9Centre Hospitalo-Universitaire de Nantes, Service Pharmacie, France
  • 10Centre Hospitalo-Universitaire de Nantes, Service de Pharmacologie Clinique, France
  • 11Centre Hospitalo-Universitaire de Nantes, Plateforme de Méthodologie et Biostatistique, France
  • 12Université de Nantes, INSERM, SPHERE U1246, France
JAMA. 2021;325(8):732-741. doi:10.1001/jama.2021.0658
Key Points

Question  Among critically ill patients with unhealthy alcohol use who are receiving mechanical ventilation, is high-dose baclofen effective in preventing agitation-related events?

Findings  In this randomized clinical trial that included 314 patients, the percentage of patients with an agitation-related event was 19.7% in the baclofen group and 29.7% in the placebo group, a difference that was statistically significant.

Meaning  Although high-dose baclofen significantly reduced agitation-related events, further research is needed to determine the possible role of baclofen for patients receiving mechanical ventilation with unhealthy alcohol use, considering the modest effect and the totality of findings for the secondary end points and adverse events.

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

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