(1) Winthrop University Hospital, Department of Surgery, Division of Trauma & Critical Care, Mineola, New York
* Corresponding author Email: firstname.lastname@example.org
Alcohol abuse continues to be a global problem. Here the four stages and pathogenesis of alcohol withdrawal syndrome are reviewed. The pharmacotherapy of the patient includes benzodiazepines, propofol, barbituates, dexmedetomidine, beta-blockers and phenothiazines. The author’s pharmacological protocol for alcohol withdrawal syndrome is included.
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 centres[6,7].
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[9,10] and an almost three times higher incidence of healthcare-associated infections.
Complications of chronic alcohol consumption
The gold standard for the diagnosis of alcohol withdrawal syndrome (AWS) is the
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. While some patients may linearly progress through these stages, others may progress more rapidly. The author has seen patients in the postoperative period immediately after general anaesthesia for surgery present in delirium tremens with no manifestation of progression through the lower stages.
Stages of alcohol withdrawal
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.
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 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[20,21]. 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.
In less severe cases of AWS, benzodiazepine can be administered via the oral route. However, for alcohol withdrawal severe enough to require admission to the critical care setting, the parenteral route is chosen. In some cases, it can be intermittently given as a bolus, although some patients may require a continuous infusion of the medication. With a prolonged infusion of the sedative, mechanical ventilation is necessary, which prolongs the length of stay in the ICU, and has the known complication of ventilator-associated pneumonia (VAP) and prolonged coma even with cessation of benzodiazepine. When the duration of benzodiazepine infusion in the critical care setting exceeds seven days, a benzodiazepine withdrawal syndrome has also been described.
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 symptoms. 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.
There are sporadic reports of AWS patients being benzodiazepine resistant and requiring extremely high doses of these agents for a prolonged time to control their symptoms[29,30,31,32]. While these patients can be managed using benzodiazepine as monotherapy, it can only be done at supratherapeutic doses, which have a propensity to accumulate, and then require a significantly prolonged wean. This often precipitates unnecessary neurologic workup, including brain imaging and prolonged mechanical ventilation. Clinicians often turn to additional agents to avoid supratherapeutic benzodiazepines and the predictable sequelae.
Intravenous ethanol, while still used in some centres, is not currently favoured by many clinicians and offers no advantages over benzodiazepine. It is generally reserved for use in overdoses of methanol, isopropanol or ethylene glycol.
Barbiturates can be a reasonable agent in the setting of a severe AWS. Advantages include low cost and long half-life which can provide longer term saturation of the GABA receptors, resulting in less symptoms including agitation. A disadvantage of barbiturates is the lack of a reversal agent in case of an overdose. Phenobarbital has been used in emergency department settings as a sole agent for mild to moderate cases of alcohol withdrawal. In ICUs, barbiturates often get added to benzodiazepine in resistant cases. In a study by Gold et al., with a protocol of escalating doses of phenobarbital and diazepam, there was a trend towards less days of mechanical ventilation, less nosocomial pneumonia and a reduced ICU length of stay.
Another agent used in case of benzodiazepine-resistant patients with AWS is propofol. It is an intravenous sedative commonly used in critical care settings for sedation via continuous infusion. Its mechanism of action is also on the GABA receptor. Propofol has the advantage of a shorter half-life and rapid wakeup when stopped; the disadvantage is propofol infusion syndrome, particularly with longer usage at higher doses. It is hypothesised that the propofol is synergistic with benzodiazepine, thereby avoiding the toxic effects of monotherapy with a high-dose benzodiazepine approach. There is limited experience to this approach[37,38], although the most resistant AWS do respond to this strategy in the author’s experience. The major drawback of propofol for AWS is that it requires mechanical ventilation, so its use should be reserved for the more severe end of the spectrum.
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 <24 h. While there have been isolated case reports of dexmedetomidine being used for AWS with good results, retrospective data has recently been published[40,41,42]. Dexmedetomidine may be used as an adjunctive agent in conjunction with benzodiazepine for AWS, and it may shorten the ICU length of stay and avoid intubation. The maximum approved infusion dose of dexmedetomidine is 0.7 mcg/ kg/h, although some patients may benefit from higher doses (up to 1.4 mcg/kg/h). The patients who respond well to dexmedetomidine can be transitioned to a clonidine patch as their symptoms stabilise.
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 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.
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.
Critical care treatment of alcohol withdrawal syndrome
AWS, alcohol withdrawal syndrome; CIWA-A, Clinical Institute Withdrawal Assessment for Alcohol; GABA, gamma aminobutyric acid; ICU, intensive care unit; VAP, ventilator-associated pneumonia.
All authors contributed to the conception, design, and preparation of the manuscript, as well as read and approved the final manuscript.
All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.
Complications of chronic alcohol consumption
|Shortened life span|
|Increased risk of malignancy: gastric, oesophageal, pancreatic, breast|
|Peptic ulcer disease|
|Male: erectile dysfunction, gynaecomastia|
|Female: infertility, abnormal uterine bleeding|
|Impaired iron metabolism|
|Bone marrow suppression|
|Beer Drinker’s hyponatremia|
Stages of alcohol withdrawal
|Increased sympathetic outflow with an increase in circulating catecholamines with symptoms including diaphoresis, nausea, vomiting, anxiety, tremor and agitation.|
|Visual and tactile are common and auditory is unusual. The hallucination of ants crawling on skin is classically described.|
|Alcohol withdrawal seizures.|
|Delirium that is in combination with autonomic hyperactivity and alcohol hallucinosis.|
Critical care treatment of alcohol withdrawal syndrome
|•||Lorazepam 2 mg intravenously every 6 h|
|•||Dexmedetomidine up to 1.4 mcg/kg/h intravenously titrated to RASS* = 0 (tolerate −1 to +1) (apply clonidine patch 0.1 to 0.2 mg/day before stopping infusion)|
|•||Intubate patient and mechanical ventilation|
|•||Lorazepam at 0.5 to 2 mg/h continuous intravenous infusion|
|•||Propofol continuous infusion|
|•||Phenobarbital in escalating intravenous bolus doses (65 mg, 130 mg, 260 mg)|
|•||Lopressor 2.5 mg to 5 mg every 6 h intravenously for hypertension or sinus tachycardia >120 beats/min.|
|•||Haloperidol 2.5 mg to 10 mg every 6 h intravenously, and as needed for control of agitation.|
* RASS, Richmond Agitation–Sedation Scale