Assessing risk of respiratory depression following initial phenobarbital loading for severe alcohol withdrawal syndrome

Abstract

Severe alcohol withdrawal syndrome is a common cause of intensive care unit admission [1]. First-line treatment usually involves benzodiazepines [2], but phenobarbital has resurfaced as an alternative, with its use increasing across hospitals [3]. Prior evidence suggests phenobarbital may reduce the likelihood of mechanical ventilation and possibly shorten hospital length of stay [3]. Despite this, concerns about respiratory depression have limited its administration to emergency departments and ICUs [4]. Patients are often initially managed on hospital wards with benzodiazepines or transferred to an ICU for phenobarbital loading, even though the actual risk of acute respiratory compromise in this setting has not been well described. We sought to share our experience with phenobarbital loading and to examine how often respiratory deterioration occurred in the 24 h that followed, the period of highest exposure and therefore greatest potential risk.

Beginning in mid-2021, our center in the Bronx implemented a protocol that included phenobarbital for selected cases of alcohol withdrawal. Over the following two and a half years, 82 patients received a phenobarbital load, defined as a dose of at least 7 mg/kg. Twenty-five were already receiving invasive mechanical ventilation at the time of administration, leaving 57 who were not ventilated and who form the basis of this report. Of these, 50 patients (87.7%) required no respiratory support at baseline, 4 (7.0%) were receiving oxygen via nasal cannula or facemask, and 3 (5.3%) were on non-invasive support. The subsequent 24 h were examined for any increase in respiratory support, ranging from new oxygen supplementation to intubation.

Six patients (10.5%) experienced an escalation of respiratory support within 24 h of phenobarbital loading [Fig. 1]. Five were intubated within the first six hours and one at nine hours. Three of the intubations were due to persistent withdrawal symptoms that remained uncontrolled, one was for seizures, and one was for gastrointestinal bleeding requiring endoscopy. Only a single patient appeared to experience a respiratory event plausibly related to phenobarbital. This individual had already aspirated during a seizure and required high oxygen support before receiving the medication. They had also received levetiracetam and benzodiazepines in the hours prior. After the load, worsening hypoxia and hypercapnia necessitated intubation. Another patient required 2 L nasal cannula after the load, but this was attributed to pleural effusion rather than sedative effect. Notably, all patients who required increased support had received phenobarbital doses between 9.5 and 14.2 mg/kg, whereas those who remained stable received doses spanning 7.1 to 28.6 mg/kg, with an average of 14.7 mg/kg.

Fig. 1

Chart representing respiratory support at time of phenobarbital and in 6-hour blocks thereafter up to 24 h. NIV = Noninvasive ventilation. NRB = Nonrebreather mask. NC = nasal cannula. RA = Room Air. AUD = alcohol use disorder. PMH = past medical history

Full size image

These observations suggest that the risk of acute respiratory compromise attributable to phenobarbital loading is low. While six patients ultimately required intubation, most cases reflected the underlying severity of withdrawal or other complications rather than the medication itself. The single case that might be linked to phenobarbital occurred in a patient with multiple predisposing factors, including aspiration and concurrent sedative administration. The data therefore support the idea that phenobarbital loading could be performed more widely on hospital wards, provided patients are appropriately selected and monitored. Broader use in these settings could preserve ICU capacity and reduce costs without sacrificing safety.

There are important caveats. Despite recommendations to minimize benzodiazepine use after phenobarbital loading, some patients received them, introducing a potential confounder. In one case, lorazepam was administered for seizures prior to intubation, and hypoxia likely resulted from aspiration rather than drug effect. Phenobarbital dosing was not entirely uniform across patients, and practice varied between emergency physicians and critical care teams. The retrospective nature of this experience, the modest sample size, and the single-center setting all limit the ability to generalize. Nevertheless, the data come from a large, urban health system with a diverse patient population, making them relevant to many real-world hospital environments.

The management of severe alcohol withdrawal continues to evolve, and phenobarbital has become an increasingly attractive option given its predictable pharmacology and potential to reduce reliance on escalating benzodiazepine dosing. Our experience indicates that when phenobarbital is used for loading, acute respiratory decompensation is uncommon. The majority of patients tolerated the medication well, including those who received relatively high doses, and the events that did occur were largely attributable to the natural history of alcohol withdrawal or other medical complications. Expanding the use of phenobarbital loading to general wards, with careful attention to patient selection, could help streamline care, conserve ICU resources, and lower hospital costs. Further prospective evaluations will be important, but our findings provide reassurance that with appropriate safeguards, phenobarbital loading need not be restricted to the ICU.

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

SAWS:

Severe alcohol withdrawal syndrome

ICU:

Intensive care unit

ED:

Emergency department

NIV:

Noninvasive ventilation

NRB:

Nonrebreather mask

NC:

Nasal cannula

RA:

Room air

AUD:

Alcohol use disorder

PMH:

Past medical history

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Authors and Affiliations

1. Division of Pulmonary Medicine, Montefiore Medical Center, 111 E 210th St, Bronx , 10467, NY, United States

   Amy Suhotliv & Daniel G. Fein

2. Division of Critical Care Medicine, Montefiore Medical Center, 111 E 210th St, Bronx, 10467, NY, United States

   Amy Suhotliv, Alexander Miller, Amira Mohamed, Daniel G. Fein, Ari Moskowitz & Veronika Blinder

3. Division of Internal Medicine, Montefiore Medical Center, 111 E 210th St, Bronx, 10467, NY, United States

   Jovanpreet Singh, Kristine Torres-Lockhart & Maria Sanchez Carriel

Authors

1. Amy SuhotlivView author publications

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2. Alexander MillerView author publications

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3. Jovanpreet SinghView author publications

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4. Kristine Torres-LockhartView author publications

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5. Maria Sanchez CarrielView author publications

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6. Amira MohamedView author publications

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7. Daniel G. FeinView author publications

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8. Ari MoskowitzView author publications

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9. Veronika BlinderView author publications

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Contributions

AS was a major contributor in writing the manuscript, analyzing and interpreting the data. VB contributed to the conception and design of the work, writing and editing the manuscript, analyzing and interpreting the data. AMoskowitz contributed to the conception and design of the work, contributed to writing and editing the manuscript. JS, KTL, MSC, AMiller helped acquire and analyze the data. AMohamed, DFein helped edit the manuscript and contributed to the design of the work. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Veronika Blinder.

Ethics approval and consent to participate

This study was approved by Einstein IRB under a waiver of informed consent.

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Not applicable.

Competing interests

The authors declare no competing interests.

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Suhotliv, A., Miller, A., Singh, J. et al. Assessing risk of respiratory depression following initial phenobarbital loading for severe alcohol withdrawal syndrome. Crit Care 29, 397 (2025). https://doi.org/10.1186/s13054-025-05661-8

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• Received: 15 August 2025

• Accepted: 09 September 2025

• Published: 25 September 2025

• DOI: https://doi.org/10.1186/s13054-025-05661-8

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Keywords

• Phenobarbital
• Severe alcohol withdrawal syndrome
• Risk of respiratory depression