Risk Factors for Respiratory Depression Associated With Phenobarbital in Alcohol Withdrawal Syndrome

Introduction: Phenobarbital (PHB) has demonstrated safety and efficacy for alcohol withdrawal syndrome (AWS) management, particularly compared to benzodiazepines. However, limited data exist on specific risk factors for PHB-associated respiratory depression in AWS. The purpose of this study was to identify risk factors associated with sedation-related respiratory depression following PHB use in patients with AWS.


Methods: This single-center retrospective study included adults (≥18 years) who received at least one complete loading dose of PHB for AWS between January and December 2023 at a tertiary academic medical center. The primary outcome was respiratory support escalation within 24 hours of initial PHB administration, defined as increased oxygen requirements, initiation of non-invasive ventilation, or mechanical ventilation. Univariate and multivariate logistic regression analyses were performed to identify predictors, including age, sex, baseline respiratory conditions, hepatic dysfunction, PHB loading dose strategy, and use of concomitant sedating medications such as benzodiazepines and opioids administered before or after PHB.


Results: Among 180 patients included in the analysis, respiratory support escalation occurred in 33 patients (18.3%). Most escalations involved progression from room air to nasal cannula (n=27, 77%), followed by nasal cannula to BiPAP (n=15, 8.6%), BiPAP to mechanical ventilation (n=10, 5.7%), and direct escalation to mechanical ventilation (n=5, 2.9%). Baseline respiratory dysfunction was present in 46 patients (25.5%). After multivariate analysis, baseline hypoxia or hypercapnia was the strongest predictor of respiratory depression (aOR 3.44, p=0.005). Higher total PHB dose per kilogram (kg) ideal body weight was associated with lower odds of respiratory depression (aOR 0.86 per miligram/kg increase, p=0.019).


Conclusions: Baseline respiratory dysfunction, especially hypoxia or hypercapnia, was the strongest predictor of respiratory support needs after PHB administration. Although 18.3% of patients required escalation, most cases were limited to nasal cannula use (77%, n=25), suggesting mild severity. Future studies should aim to validate these findings prospectively and explore strategies to minimize respiratory complications with PHB.