SedationBarbiturates for the treatment of alcohol withdrawal syndrome: A systematic review of clinical trials☆
Introduction
Approximately 15% to 20% of hospitalized patients and 50% of trauma patients suffer from alcohol use disorders [1], [2]. Many of these patients manifest signs and symptoms of alcohol withdrawal syndrome (AWS) when their alcohol consumption is abruptly stopped or significantly reduced [3], [4]. Patients with AWS exhibit a wide array of symptoms including tremor, tachycardia, nausea, insomnia, agitation, hallucination, diaphoresis, or tonic-clonic seizures [3], [4]. Alcohol withdrawal delirium, also known as delirium tremens (DTs), is the most severe manifestation of AWS. It is characterized by a fluctuating mental state marked by disturbances of attention and awareness, disorientation, diminished responsiveness, hallucinations, or delusions combined with alcohol withdrawal symptoms [3], [5]. About 5% of hospitalized patients with AWS will progress to DTs typically 48 to 72 hours after alcohol cessation [4], [6]. The serious complications of AWS such as alcohol withdrawal delirium and seizures often lead to intensive care unit (ICU) admission, prolonged hospital and ICU stay and increased mortality ranging from 5 to 15% [4], [5], [6], [7].
Benzodiazepines (BZDs) have been a mainstay of therapy for prevention and treatment of AWS [2], [4], [6], [7]. However, there are limited data available on whether BZDs have definite superiority in managing AWS and its complications when compared with other agents [3]. In addition, some patients with severe AWS may not respond to high doses of BZDs, as they develop tolerance over time due to the γ-aminobutyric acid (GABA) receptor desensitization [4], [6], [8]. Benzodiazepine-refractory (or resistant) withdrawal symptoms may be described as uncontrolled agitated states despite of the need for > 40 mg of lorazepam (LZP) in the first 3 to 4 hours, but it has not been well defined in the current literature [4], [9]. Patients with BZD-refractory withdrawal symptoms are more likely to require continuous BZD infusion, which may result in a higher rate of mechanical ventilation and longer ICU and hospital stays [4], [6].
Recently, there has been growing interest in the use of dexmedetomidine as adjunctive therapy to BZDs for the treatment of AWS. Dexmedetomidine, a presynaptic α2-receptor agonist, could be an attractive option particularly in severe AWS patients experiencing respiratory depression from BZD therapy since it dose not cause respiratory depression [10]. Studies have suggested that dexmedetomidine as an adjunct in AWS may decrease alcohol withdrawal symptoms and benzodiazepine use, thereby potentially preventing mechanical ventilation [11], [12]. However, it should be noted that clinical outcome data of dexmedetomidine in AWS were very limited to a handful of case reports/series and observational studies and one small prospective controlled trial [10], [11], [12], [13], [14]. Additionally, dexmedetomidine therapy is more costly and resource-intensive than other alternatives. As a result, the clinical impact of dexmedetomidine in AWS still remains unclear.
Previous studies have demonstrated the use of barbiturates, GABA receptor agonists similar to BZDs, as an adjunctive to BZD therapy may be effective and safe in severe AWS refractory to BZD [15], [16]. Of interest, in such patients, phenobarbital (PB) may play a role in reducing the need for ICU admission as well as mechanical ventilation [15], [16], [17]. Intravenous (IV) PB in particular has great potential in the treatment of severe AWS for the following reasons: (1) An IV formulation of PB can be especially useful when treating patients with acute AWS or DT compared to oral drugs, (2) IV PB can suppress acute withdrawal symptoms quickly due to its rapid onset of action (approximately 5 minutes) (3) Patients are less likely to require subsequent oral PB for AWS because PB concentrations gradually decline following iv injections due to its long duration of action (a half-life of 53-140 hours), and (4) From a safety standpoint, PB doses used for the treatment of hypnosedative withdrawal do not produce prominent central nervous system (CNS) depression [18], [19], [20]. Therefore, we conducted a systematic review of the current literature to assess the efficacy and safety of barbiturates with or without BZDs versus BZDs for the treatment of AWS in the acute setting. Additionally, the secondary objective was to evaluate the clinical utility and potential of PB in terms of preventing or reducing ICU admission as well as mechanical ventilation in patients developing acute AWS.
Section snippets
Data sources
We developed a comprehensive list of keywords to identify all relevant studies for inclusion, which included alcohol withdrawal syndrome, alcoholism, alcohol dependence, delirium tremens, barbiturates, and benzodiazepine. A literature search was performed using MEDLINE (1946-July 2015), EMBASE (1947-July 2015), and the Cochrane Library (1992-July 2015). Additionally, a manual review of citations from retrieved articles was performed to capture relevant studies that are not indexed in the
Results
Our initial screen of titles and abstracts resulted in a total of 98 studies, out of which 29 citations possibly eligible by inspection of abstracts were retrieved for full-text review (Figure). Ultimately, eight articles were retained for final inclusion; however, following the quality appraisal process, one study was excluded from our systematic review due to its small and unbalanced sample size between groups (pre-guideline group, n = 30 vs post-guideline group, n = 3) [22]. A summary of
Discussion
A total of 7 studies evaluating the use of barbiturates versus BZDs in the treatment of AWS were included in our analysis. We identified that there is little high-quality evidence available at this time; however, most of studies have a sample size greater than 100 patients and quality ratings using the MMAT of all seven studies were 50 % or higher. Of note, none of these studies demonstrated inferiority of barbiturates to BZDs in the management of AWS. Furthermore, overall safety profiles of
Conclusions
Although current clinical applications of this systematic analysis may be limited due to a paucity of evidence from randomized control trials, it is still notable that the use of PB seems particularly promising in its attempt to reduce the need for ICU admission or mechanical ventilation for the treatment of acute AWS. Based on our findings, for the treatment of AWS, we would not recommend PB as the initial agent in place of BZD; however, it is reasonable to use PB as an adjunct to a BZD-based
Acknowledgments
The authors would like to acknowledge Eugenia Liu, Information Service Librarian at WNE for her invaluable assistance in conducting literature searches. We would also like to thank Deborah Beagle, Interlibrary Loan Librarian at WNE for her help in locating and retrieving articles.
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Conflict of interest statement: All authors have no financial interest to declare in relation to the subject matter of this manuscript.
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