Netherlands Journal of Critical Care

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Netherlands Journal of Critical Care Accepted January 2013 review The pharmacologic treatment of alcohol withdrawal syndrome in the ICU D.P.F. van Nunen, D.H.T. Tjan Department of Intensive Care, Gelderse Vallei Hospital Ede, The Netherlands Correspondence DHT Tjan – e-mail: TjanD@zgv.nl Keywords - Alcohol withdrawal syndrome, delirium tremens, withdrawal seizures, benzodiazepines, anticonvulsants, gamma-hydroxybutyrate, α2-agonists, antipsychotics Abstract Alcohol withdrawal syndrome (AWS) presents a significant problem among new admissions to the intensive care unit. In patients with a history of alcohol abuse, AWS manifests itself with symptoms of autonomic hyperactivity, tremors, hallucinations, agitation, anxiety, and seizures. Progression of AWS, called delirium tremens (DT), is associated with increased mortality. Traditionally, AWS is treated with benzodiazepines which have a well-established record for reducing symptoms of withdrawal and provide adequate control of both seizures and DT. However, the side-effects of benzodiazepines have prompted the introduction of alternative agents. Anticonvulsants and gamma-hydroxybutyrate do suppress symptoms of AWS, but their effectiveness in the prevention of seizures and DT is doubtful. Ethanol results in less sedation than benzodiazepines, although the evidence for its role in AWS remains limited. Alpha-2 agonists are potent against symptoms of noradrenergic overdrive and are suitable as adjuvants to benzodiazepines. Antipsychotics have no demonstrable effectiveness in AWS and may even be harmful. symptoms are usually mild, 5-10% of alcohol-dependent patients 7 develop a severe dysautonomic and encephalopathic state known as ‘delirium tremens’ (DT) after 48-72 hours of abstinence 8,9 . In this progression of alcohol withdrawal syndrome (AWS) the autonomic disarray is further exacerbated and the patient’s cognition and level of consciousness can change within a short period of time. DT is associated with a mortality rate of 5% which is attributable to complications of its clinical symptomatology like coronary spasms, arrhythmias and myocardial infarction 8 . The natural course of AWS is a gradual lessening of symptoms 72 hours after its onset 9,10 . However, given the high mortality and morbidity, early treatment of AWS is warranted. Since the first clinical descriptions of the syndrome in the nineteenth century, many pharmacologic and therapeutic treatments have been published in medical journals 11 . Reviews of this body of literature are few and inconsistent. The objective of this review is to examine the evidence supporting the popular pharmacologic treatment options for AWS. The subsequent discussion is based on a systematic search of the electronic literature database MEDLINE (PubMed). For each Introduction The incidence of alcohol dependence and associated disorders is high amongst ICU patients. Although there are no epidemiological data for the Netherlands, in the United States between 10% and 33% of patients admitted to the ICU suffer from alcohol dependence 1 . According to the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) alcohol dependence is formally defined as a maladaptive pattern of alcohol use resulting in clinical impairment or stress as manifested by the development of tolerance and withdrawal, unsuccessful efforts to abstain, consumption of ever greater quantities and the involvement of a considerable amount of time that limits other activities 2 . Symptoms of alcohol withdrawal may occur in up to 91% of alcohol-dependent patients after acute abstinence 3,4 . The syndrome of alcoholic withdrawal consists of signs and symptoms (see table 1 2 ) developing in alcohol-dependent individuals within 6 to 48 hours after their last intake of alcohol or reduction in intake 5,6 . Although these Table 1. DSM-IV-TR Alcohol withdrawal – diagnostic criteria 2 A. Cessation of (or reduction in) alcohol use that has been heavy and prolonged B. Two (or more) of the following, developing within several hours to a few days after Criterion A - Autonomic hyperactivity (e.g., sweating or pulse rate greater than 100) - Increased hand tremor - Insomnia - Nausea or vomiting - Transient visual, tactile, or auditory hallucinations or illusions - Psychomotor agitation - Anxiety - Grand mal seizures C. Clinically significant distress or impairment in social, occupational, or other important areas of functioning D. The symptoms are not due to a general medical condition and are not better accounted for another mental disorder 12 Neth j crit care – volume 17 – no 1 – february 2013
Netherlands Journal of Critical Care The pharmacologic treatment of alcohol withdrawal syndrome in the ICU pharmacologic agent a search query was composed of synonyms for the respective agent in combination with ‘alcoholwithdrawal’, ‘AWS’, ‘delirium tremens’ and ‘DT’. The search results were filtered for relevant meta- analyses, trials, cohort studies and case series. Previous reviews describing a segment of the literature were also consulted. The resulting review is structured as follows. First, the pathophysiology of alcohol dependency and withdrawal is elucidated. Second, the method of diagnosing AWS is discussed. Third, the evidence supporting the popular pharmacotherapies is presented. The fourth and final section summarizes and concludes. Pathophysiology Alcohol or ethanol influences multiple stages of the neurotransmission cascade in the central nervous system. Genetic, pharmacological and electrophysiological studies have demonstrated that alcohol modifies synaptic transmission by altering neuronal excitability through an interaction with ligand and voltage-gated ion channels. The sedative effects of alcohol are principally thought to be the result of its interference with two neurotransmission systems. At low concentrations (< 100 mg/dl) alcohol enhances transmission of gamma-aminobutyric acid (GABA), by promoting chloride conductance through the GABAA-receptor. At higher concentrations (> 250 mg/dl) alcohol works directly on the GABAA-receptor and causes a prolonged opening of its chloride channel that is independent of the neurotransmitter GABA. This second mechanism makes alcohol toxic in overdose. A prolonged opening of the chloride channel causes excessive influx of chloride into neurons of the respiratory system resulting in respiratory depression 10,12 . Continued exposure to alcohol leads to tolerance with downregulation of GABAA-receptors. Besides reinforcing the inhibitory effects of GABA, alcohol tempers excitatory neurotransmission mediated by glutamate. This neurotransmitter binds N-methyl-D-aspartate (NMDA)-receptors resulting in a calcium influx depolarizing the neuron. One of the results of NMDA stimulation is an enhancement of signal transmission between neurons called long-term potentiation which underlies learning and the development of memory. Alcohol serves as a blocker of the NMDA-receptors inhibiting this process and contributing to amnesia and depression of cerebral function. Over time the brain’s reaction is to increase the number of NMDA-receptors which allow normal functioning in the presence of alcohol, the formation of tolerance 10,12 . In AWS, GABA neurotransmission is decreased while glutamatergic neurotransmission is increased resulting in a state of heightened excitability. Furthermore, the increased sympathetic activity is due to an overstimulation of noradrenergic neurons following increased glutamate function and the loss of noradrenergic autoinhibition 12 . The hallucinations experienced during withdrawal are caused by an enhanced dopaminergic transmission following disinhibition of dopaminergic neurons through reduced GABAergic activity 10 . Research has shown that the increased susceptibility to seizures seen in patients is likely to have its origin in the deep layers of the superior colliculus where NMDA-receptor mediated excitation is no longer chronically suppressed by alcohol 13 . Diagnosis AWS should be considered as a diagnosis of exclusion. If the patient’s history and physical findings prompt clinical suspicion then alternative etiologies must be ruled out, such as infection (meningitis), head trauma (intracerebral hemorrhage), epilepsy, electrolyte or metabolic disturbances, hepatic failure, intoxication or withdrawal from other substances. The formal diagnostic criteria are listed in table 1. The clinical spectrum varies from uncomplicated withdrawal syndrome with patients having a clear sensorium with signs of autonomic hyperactivity and increased sympathetic stimulation. Worsening of the symptoms can result in hallucinations and progression to DT with or without seizures. When the history on alcohol consumption is unavailable or unreliable, biomarkers such as gammaglutamyl transferase (GGT) and carbohydrate-deficient transferrin (CDT) may provide clues for chronic alcohol overuse with combined sensitivities of 81-90% and specificities of 63-95% 14 . Ethanol levels on admission have no predictive value for AWS 15 . After the diagnosis of AWS hs been made, the severity of symptoms can be quantified by the Clinical Institute Withdrawal Assessment Scale for Alcohol (CIWA-Ar) 16,19 . Treatment Without therapy the symptoms of alcohol withdrawal are expected to reach their peak 72 hours after the last ingestion of alcohol and generally resolve within four days after this moment 9,12 . In most cases the symptoms are relatively mild and no pharmacotherapeutic management is required. However, in manifest AWS treatment is indicated to avoid DT or seizures. The pharmacotherapeutic management of AWS entails the substitution of a long-acting agent for alcohol and subsequently to taper its dosage over time 17 . Historically, many different classes of drugs have been tried in the management of AWS. This section provides an overview of the primary pharmacologic agents. The discussion of supportive measures is beyond the scope of this article. Benzodiazepines Benzodiazepines have been the mainstay of pharmacotherapeutic treatment of AWS and the prevention of secondary seizures since 1969 18 . Benzodiazepines produce their effect by increasing the affinity of GABAA-receptors for the neurotransmitter GABA. This results in a greater influx of calcium into the neuron which inhibits neurotransmission. In this way benzodiazepines serve as a direct substitute for the GABA-modulating effects of alcohol 7 . The evidence supporting the use of benzodiazepines in AWS is relatively solid with three good quality meta-analyses independently concluding benzodiazepines to be the preferred treatment. Mayo-Smith 19 conducted a meta-analysis of six prospective, placebocontrolled trials from the 1960s to 1980s involving three Neth j crit care – volume 17 – no 1 – february 2013 13
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