Grand Rounds Review: Severe Alcohol Withdrawal

This morning, Dr. Matthew Leveno, director of the Parkland Medical ICU and youngest winner of the housestaff teaching award, gave an incredible grand rounds presentation about the history, pathophysiology, diagnosis, and management of severe alcohol withdrawal. Take a look below for some important information. 


Introduction

Alcohol abuse is a common problem globally, and it is estimated to result in 2.5 million deaths annually. Of the drugs of abuse, alcohol is the most common, with an estimated 18.3 million individuals dependent on it in the United States. Alcohol abuse has a prevalence of 22.4% in a hospitalised general medical population. In one analysis, alcohol-related admissions accounted for 9% of admissions to a population of mixed medical intensive care unit (ICU) and surgical ICU patients; in addition these patients accounted for 13% of total ICU costs. One population with a particularly high rate of alcohol abuse are trauma patients, with estimates of prevalence ranging from 31% to 70% across centers.

Alcohol-related complications in the ICU affect nearly every organ system (Table 1). Alcohol abuse in patients is associated with increased length of stay, outpatient pneumonia and an almost three times higher incidence of healthcare-associated infections.

Clinical Manifestations and Diagnosis

The gold standard for the diagnosis of alcohol withdrawal syndrome (AWS) is the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. It requires that a patient’s alcohol usage is heavy and prolonged, there is a cessation in alcohol intake and also that there is no other general condition that better accounts for the diagnosis.

 

AWS has four clinical stages: (1) autonomic hyperactivity, (2) hallucinations, (3) neuronal excitation and (4) delirium tremens (Table 2). Patients generally start the withdrawal process at 5 h, with hallucinations at 24 h, and delirium at 48 h; it is rare for this to persist for more than 120 h.

Pathophysiology

AWS is the result of a disruption of the delicate neurochemical balance that is controlled via inhibitory and excitatory neurotransmitters. The principal inhibitory neurotransmitter is gamma aminobutyric acid (GABA), which exerts its effect on the GABA-A neuroreceptor. A principal excitatory transmitter is glutamate, which affects the N-methyl-D-aspartate neuroreceptor. With chronic alcohol exposure, the brain has a tolerance to the effects of the alcohol due to down-regulation of the GABA-A receptor over time. This down-regulation may occur by modification of the GABA-A receptor in the alpha 1 subunit to make the receptor less susceptible to the effects of alcohol exposure.

Pharmacological treatment

The severity of the symptoms of AWS should direct the appropriate pharmacotherapeutic interventions. The patient’s comorbidities, other active diagnoses as well as exposure to any other drug of abuse should also be factored into the development of their treatment plan.

Benzodiazepines

Benzodiazepines have historically been the mainstay pharmacologic intervention of AWS; they are generally considered to be the ‘gold standard’ treatment. It has been shown that sedative-hypnotic agents such as benzodiazepines, in comparison with other agents, reduce mortality and control the symptoms of AWS. All benzodiazepines have the same mechanism of action on the GABA receptor. Several agents have been used for AWS including chlordiazepoxide, lorazepam, valium, oxazepam and midazolam. Lorazepam is suggested as the benzodiazepine of choice for AWS due to its intermediate half-life, which balances a smooth withdrawal, with the potential for delayed metabolism in those with impaired hepatic function such as geriatric or cirrhotic patients.

Benzodiazepines were traditionally administered to AWS patients in a fixed dose regimen. There has now been over two decades of experience accumulated with the use of on demand or ‘symptom-triggered’ dosing of benzodiazepines for AWS treatment. This method of symptom-triggered dosing relies on the Clinical Institute Withdrawal Assessment for Alcohol [CIWA-A or CIWA-Ar (revised)]. In studies, the symptom-triggered dosing method results in both a decrease in the amount of benzodiazepines administered and a shortened duration of withdrawal symptom. While the symptom-triggered approach has these advantages, there is quite limited experience of the use of this approach in critical care settings, and it has not shown the same benefit across all studies.

Adjunctive agents

The alpha-2-agonist, clonidine, has traditionally been used to blunt the sympathomimetic effects of AWS. This has been done outside critical care settings. While intravenous clonidine is available in Europe, it is not currently available for use in the United States. This has resulted in intensivists to turn to dexmedetomidine, a drug derived from clonidine. Dexmedetomidine is not FDA-approved for AWS, but rather for procedural conscious sedation and sedation for mechanical ventilation

Beta-blockers

Beta-blockers have been used as an adjunctive agent in AWS. Given the sympathetic outflow associated with autonomic hyperactivity, betablockers are a direct antagonist. This medication can be administered either orally or intravenously, and it serves to normalise tachycardia and hypertension in non-agitated patients that are otherwise comfortable. In a randomised trial by Gottlieb, atenolol in patients with AWS served to make a more rapid resolution of their vital sign abnormalities and clinical signs such as tremor. Betablockers serve an important role as part of a multimodal pharmacological plan, but they should never be used without a GABA agent.

Haloperidol

Haloperidol is a phenothiazine that is commonly prescribed in ICUs for acute agitation. It has the benefit of haemodynamic neutrality, and the possible complications of an elevation in the QTc interval and tardive dyskinesia. While haloperidol is an adjunctive agent in AWS setting, it is particularly useful for the symptoms related to delirium. Most frequently, it is used in patients with underlying psychiatric disorders. 

Conclusion

AWS continues to challenge clinicians in critical care settings. Keys to good outcomes in this area include early recognition of the disorder and rapid implementation of appropriate pharmacologic treatment. The range of symptoms represents a spectrum; the pharmacologic strategy needs to match the severity that the patient is experiencing. While some patients have a good therapeutic response to a single benzodiazepine agent, more severe cases may require a multimodality therapy. The current protocol used at our institution is presented in Table 3. With a stepwise protocol-driven plan, intubation and mechanical ventilation can be avoided except in the more severe cases, contributing to better outcomes in terms of length of stay and VAP. 


Modified from: DeMuro JP. Alcohol withdrawal syndromes in the critically ill. OA Alcohol 2013 Feb 01;1(1):1. Under the terms of the Creative Commons Attribution License (CC-BY).