Elsevier

Drug and Alcohol Dependence

Volume 154, 1 September 2015, Pages 296-299
Drug and Alcohol Dependence

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Management of benzodiazepine-resistant alcohol withdrawal across a healthcare system: Benzodiazepine dose-escalation with or without propofol

https://doi.org/10.1016/j.drugalcdep.2015.07.005Get rights and content

Highlights

  • Limited evidence supports use of propofol for management of alcohol withdrawal.

  • Examined differences in outcomes between benzodiazepine dose-escalation and propofol.

  • Propofol associated with increased clinical care including length of stay.

  • Propofol associated with increased risk of adverse reactions, including hypotension.

Abstract

Background

Severe cases of alcohol withdrawal syndrome (AWS) may not resolve despite escalating doses of benzodiazepines (BZDs). Benzodiazepine-resistant alcohol withdrawal (RAW) is a subset of severe alcohol withdrawal defined by the requirement of ≥40 mg of diazepam administered within one hour. Use of adjunct agents, such as propofol, may be beneficial to minimize BZD adverse effects and improve symptom control. While limited evidence suggests propofol as an effective adjunct in AWS through improved sedation, evidence is currently lacking for the addition of only propofol to BZDs for management of RAW.

Methods

Retrospective review of adult patients from January, 2009 to March, 2012 with RAW. Patients were categorized into BZD dose-escalation only or BZD plus propofol. The primary endpoint was time to resolution of AWS. Secondary endpoints included safety outcomes associated with medication use.

Results

Of 1083 patients with severe AWS, 66 RAW patients (n = 33 BZD only, n = 33 BZD plus propofol) met inclusion. Median time to AWS resolution was 5.0 and 7.0 days for BZD only vs. BZD plus propofol (p = 0.025). Duration of mechanical ventilation, ICU and hospital length of stay were significantly higher with propofol (p = 0.017, <0.001 and <0.001, respectively). Ten patients required intervention for management of propofol-induced adverse reactions.

Conclusions

The addition of propofol for RAW treatment is associated with significant increases in clinical care. While randomized, prospective evaluations are necessary to determine the cause of this association, our data suggests use of adjunctive propofol therapy in RAW is associated with longer and more complicated hospital admissions.

Introduction

Alcohol withdrawal syndrome (AWS) occurs in patients due to cessation of alcohol, which is an agonist of γ-aminobutyric acid (GABA), an inhibitory neurotransmitter (Bayard et al., 2004). Alcohol-induced alterations of GABA and upregulation of the excitatory neurotransmitter N-methyl-d-aspartase (NMDA) results in associated withdrawal symptoms (Sarff and Gold, 2010). Benzodiazepines (BZDs) often serve as first-line therapy as they target the GABA-A receptor, which mediates the primary GABA effects of ethanol in the body (Brathen et al., 2005, Mayo-Smith et al., 2004, Nakagawa and Iwasaki, 1995). Despite escalating doses of BZDs, a subset of patients do not adequately respond (Gold et al., 2007, Hack et al., 2006). Benzodiazepine-resistant alcohol withdrawal (RAW) is defined as the requirement of ≥40 mg of diazepam (or equivalent) administered within one hour (Hack et al., 2006).

The use of agents that target another binding site of the GABA receptor or other modes of action may be beneficial in RAW patients (Liang et al., 2009, Radel and Goldman, 2001, Wong et al., 2015). Propofol has GABA-agonist activity at an alternative GABA receptor binding site, antagonizes NMDA, and has a relatively short duration of action allowing for ease in titration (Liang et al., 2009). Studies evaluating propofol for management of AWS initiated propofol after patients received significant amounts of BZDs, with variable effectiveness ranging from no benefit to effective management of agitation (Coomes and Smith, 1997, Hughes et al., 2014, Lizotte et al., 2014, Lorentzen et al., 2014, Sohraby et al., 2014). Other adjunct agents were allowed in these studies, including antipsychotics and phenobarbital, which may confound the effects of propofol alone on studied outcomes.

The purpose of this study is to describe the clinical characteristics of dose escalation of BZDs alone (BZDO) compared to BZDs plus propofol (PRO) in a RAW population, as evidence currently is lacking for the addition of only propofol without other adjunctive agents to BZDs for management of RAW. The primary endpoint was the time to resolution of AWS, with secondary endpoints including safety outcomes associated with medication use.

Section snippets

Patient population and setting

A retrospective cohort of adult patients were identified via International Classification of Diseases, Ninth Revision (ICD-9) codes with severe alcohol withdrawal (291.0, 291.2, 291.3, 291.81, 303.01, 303.91) from January, 2009 to March, 2012 in the University of Pittsburgh Medical Center health system.

From this population, a chart review using an electronic health record (Cerner Powerchart®, Kansas City, MO) was conducted to identify patients who met RAW criteria (requirement of ≥40 mg of

Patients

Of 1083 records reviewed of patients with ICD-9 codes for severe alcohol withdrawal, a total of 66 (6.1%) patients met eligibility. Patients were excluded due to lack of BZD-qualifying dosing for RAW (n = 834), receiving their RAW-designating dose for other indications, (n = 65), use of additional adjunctive agents for management of AWS (n = 106), or lack of BZD dose-escalation in the BZDO group (n = 12). Baseline demographics are provided in Table 1. There were differences at baseline between the

Discussion

In this retrospective description of patients with RAW, the addition of propofol to BZDs was associated with decreased short-term BZD requirements, consistent with the literature (Sohraby et al., 2014). We found that there was a significant increase in clinical care, as shown by worsening clinical outcomes and increased need for airway protection in these patients. This association may be reflective of indication bias in the PRO group as propofol, given its respiratory depressant effects,

Role of funding source

Nothing declared.

Contributors

Drs. Benedict and Kane-Gill have been supported by an investigator-initiated grant from Hospira, Inc. within the past five years. Study conception and design: Benedict, Kane-Gill, Lohr, Wong. Acquisition of data: Lohr, Wong. Analysis and interpretation of data: Benedict, Kane-Gill, Lohr, Pizon, Wong. Drafting of manuscript: Benedict, Kane-Gill, Lohr, Pizon, Wong. Critical revision: Benedict, Kane-Gill, Lohr, Pizon, Wong. All authors have read and approve of the submission to Drug and Alcohol

Conflict of interest

No conflict declared.

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    Supplementary material can be found by accessing the online version of this paper at http://dx.doi.org/10.1016/j.drugalcdep.2015.07.005

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