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April - 2021


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Effect of High-Dose Baclofen on Agitation-Related Events Among Patients With Unhealthy Alcohol Use Receiving Mechanical Ventilation

M Vourch, C Garret, A Gacouin, et al for the BACLOREA Study Group JAMA, 2021, 325(8):732-741


What pharmacological agents are effective for the prevention and management of alcohol withdrawal related delirium and agitation in the ICU? 

The BACLOREA study provides new evidence for this area, with an RCT of baclofen (γ-aminobutyric acid type B receptor agonist that may decrease or suppress alcohol craving

in patients with alcohol use disorder) vs placebo in critically ill patients with unhealthy alcohol use receiving mechanical ventilation. 

Wha did they do;

  • Mulitcenter, double-blind, placebo controlled, RCT in 18 French medical and surgical ICUs
  • 314 adult patients, expected to require MV >24hrs, who had NIAAA criteria for unhealthy alcohol use (>14 units/week), with wide range exclusions
  • Randomised to Baclofen (50-150mg daily depending eGFR, to day 15 or extubation/tracheostomy)
  • Standard care included nursing led sedation protocol target to RASS -2 to +1 unless deep sedation prescribed. 
  • Agitation assessed using Riker Sedation Agitation Scale, and Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar) used for withdrawal assessment after extubation
  • Sample sized based on baseline agitation related events in ICU of 31% in low-risk users and 42% in unhealthy alcohol users, with 314 patients needed to detect 15% reduction with 5% alpha and 80% power. 

What did they find;

  • 14% of patients with MV>24 hrs had unhealthy alcohol use, 314 randomised 
  • About 80% men, age 57 years
  • Primary outcome of percentage of patients with an agitation-related event over treatment period was significant - 19.7% (baclofen) vs 29.7% (placebo), diff -9.9%(95% CI -19.5 to -0.4%), adj OR 0.58. (95% CI 0.34-0.98)
  • Secondary outcomes 
    • D28 after randomisation, % patients with at least 1 agitation related event did not differ significantly (28% vs 35%, -7%, 95% CI -17% to +3%, adj OR 0.72, 95% CI 0.45-1.17).
    • D28 after randomisation total number of agitation events was lower in Baclofen group adj RR, 0.63 [95% CI, 0.46-0.85]
    • No difference in sedative use, although patients spent significantly more time with RASS score between 1 and 3 (ie, deep sedation) by day 28 in the baclofen group (mean of 7.0 vs 4.6 days; diff, 2.44 [95%CI, 1.08-3.80])
    • No difference in reintubation, tracheostomy, ICU acquired infections. 
    • Baclofen group had fewer VFDs (median 14 vs 19 days; difference, –2 [95% CI, –4 to 0.])
    • Baclofen had significantly longer median duration of mechanical ventilation (9.0 vs 8.0 days; difference, 2.00 [95%CI, 0.00 to 3.00]; adjusted HR for extubation, 0.76 [95% CI, 0.60-0.97]) and stay in the ICU (14.0 vs 11.0 days; difference, 2.00 [95% CI, 0.00-4.00]; adjusted HR for ICU discharge, 0.70 [95% CI, 0.54-0.90]).

This study reports high-dose baclofen significantly reduced agitation-related events in adult patients with unhealthy alcohol use requiring mechanical ventilation. However this benefit must be considered in the light of secondary outcomes of deeper sedation, longer duration of mechanical ventilation and prolonged ICU care. 



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.


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