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The Pharmacologic Treatment of Alcohol Withdrawal Syndrome in the ICU

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The Pharmacologic Treatment of Alcohol Withdrawal Syndrome in the ICU 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: [email protected] Keywords - Alcohol withdrawal syndrome, delirium tremens, withdrawal seizures, benzodiazepines, anticonvulsants, gamma-hydroxybutyrate, α2-agonists, antipsychotics Abstract symptoms are usually mild, 5-10% of alcohol-dependent patients7 Alcohol withdrawal syndrome (AWS) presents a significant problem develop a severe dysautonomic and encephalopathic state known as among new admissions to the intensive care unit. In patients with ‘delirium tremens’ (DT) after 48-72 hours of abstinence8,9. In this a history of alcohol abuse, AWS manifests itself with symptoms progression of alcohol withdrawal syndrome (AWS) the autonomic of autonomic hyperactivity, tremors, hallucinations, agitation, disarray is further exacerbated and the patient’s cognition and level anxiety, and seizures. Progression of AWS, called delirium tremens of consciousness can change within a short period of time. DT is (DT), is associated with increased mortality. Traditionally, AWS associated with a mortality rate of 5% which is attributable to is treated with benzodiazepines which have a well-established complications of its clinical symptomatology like coronary spasms, record for reducing symptoms of withdrawal and provide adequate arrhythmias and myocardial infarction8. control of both seizures and DT. However, the side-effects of The natural course of AWS is a gradual lessening of symptoms benzodiazepines have prompted the introduction of alternative 72 hours after its onset9,10. However, given the high mortality and agents. Anticonvulsants and gamma-hydroxybutyrate do suppress morbidity, early treatment of AWS is warranted. Since the first symptoms of AWS, but their effectiveness in the prevention of clinical descriptions of the syndrome in the nineteenth century, seizures and DT is doubtful. Ethanol results in less sedation many pharmacologic and therapeutic treatments have been than benzodiazepines, although the evidence for its role in AWS published in medical journals11. Reviews of this body of literature are remains limited. Alpha-2 agonists are potent against symptoms few and inconsistent. The objective of this review is to examine the of noradrenergic overdrive and are suitable as adjuvants to evidence supporting the popular pharmacologic treatment options benzodiazepines. Antipsychotics have no demonstrable effectiveness for AWS. The subsequent discussion is based on a systematic search in AWS and may even be harmful. of the electronic literature database MEDLINE (PubMed). For each Introduction The incidence of alcohol dependence and associated disorders is Table 1. DSM-IV-TR Alcohol withdrawal – diagnostic criteria2 high amongst ICU patients. Although there are no epidemiological data for the Netherlands, in the United States between 10% and 33% A. Cessation of (or reduction in) alcohol use that has been heavy and of patients admitted to the ICU suffer from alcohol dependence1. prolonged According to the fourth edition of the Diagnostic and Statistical B. Two (or more) of the following, developing within several hours to a few days after Criterion A Manual of Mental Disorders (DSM-IV) alcohol dependence is - Autonomic hyperactivity (e.g., sweating or pulse rate greater than 100) formally defined as a maladaptive pattern of alcohol use resulting - Increased hand tremor in clinical impairment or stress as manifested by the development - Insomnia of tolerance and withdrawal, unsuccessful efforts to abstain, - Nausea or vomiting consumption of ever greater quantities and the involvement of a - Transient visual, tactile, or auditory hallucinations or illusions considerable amount of time that limits other activities2. Symptoms - Psychomotor agitation - Anxiety of alcohol withdrawal may occur in up to 91% of alcohol-dependent - Grand mal seizures patients after acute abstinence3,4. The syndrome of alcoholic C. Clinically significant distress or impairment in social, occupational, or 2 withdrawal consists of signs and symptoms (see table 1 ) developing other important areas of functioning in alcohol-dependent individuals within 6 to 48 hours after their D. The symptoms are not due to a general medical condition and are not better accounted for another mental disorder last intake of alcohol or reduction in intake5,6. Although these 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 superior colliculus where NMDA-receptor mediated excitation is no for the respective agent in combination with ‘alcoholwithdrawal’, longer chronically suppressed by alcohol13. ‘AWS’, ‘delirium tremens’ and ‘DT’. The search results were filtered for relevant meta- analyses, trials, cohort studies and case series. Diagnosis Previous reviews describing a segment of the literature were also AWS should be considered as a diagnosis of exclusion. If the consulted. patient’s history and physical findings prompt clinical suspicion The resulting review is structured as follows. First, the pathophysiology then alternative etiologies must be ruled out, such as infection of alcohol dependency and withdrawal is elucidated. Second, (meningitis), head trauma (intracerebral hemorrhage), epilepsy, the method of diagnosing AWS is discussed. Third, the evidence electrolyte or metabolic disturbances, hepatic failure, intoxication supporting the popular pharmacotherapies is presented. The fourth or withdrawal from other substances. The formal diagnostic and final section summarizes and concludes. criteria are listed in table 1. The clinical spectrum varies from uncomplicated withdrawal syndrome with patients having a clear Pathophysiology sensorium with signs of autonomic hyperactivity and increased Alcohol or ethanol influences multiple stages of the neurotransmission sympathetic stimulation. Worsening of the symptoms can result cascade in the central nervous system. Genetic, pharmacological in hallucinations and progression to DT with or without seizures. and electrophysiological studies have demonstrated that alcohol When the history on alcohol consumption is unavailable or modifies synaptic transmission by altering neuronal excitability unreliable, biomarkers such as gammaglutamyl transferase (GGT) through an interaction with ligand and voltage-gated ion channels. and carbohydrate-deficient transferrin (CDT) may provide clues The sedative effects of alcohol are principally thought to be the for chronic alcohol overuse with combined sensitivities of 81-90% result of its interference with two neurotransmission systems. At and specificities of 63-95%14. Ethanol levels on admission have no low concentrations (< 100 mg/dl) alcohol enhances transmission predictive value for AWS15. of gamma-aminobutyric acid (GABA), by promoting chloride After the diagnosis of AWS hs been made, the severity of symptoms conductance through the GABAA-receptor. At higher concentrations can be quantified by the Clinical Institute Withdrawal Assessment (> 250 mg/dl) alcohol works directly on the GABAA-receptor and Scale for Alcohol (CIWA-Ar)16,19. causes a prolonged opening of its chloride channel that is independent of the neurotransmitter GABA. This second mechanism makes Treatment alcohol toxic in overdose. A prolonged opening of the chloride channel Without therapy the symptoms of alcohol withdrawal are expected causes excessive influx of chloride into neurons of the respiratory to reach their peak 72 hours after the last ingestion of alcohol system resulting in respiratory depression10,12. Continued exposure to and generally resolve within four days after this moment9,12. In alcohol leads to tolerance with downregulation of GABAA-receptors. most cases the symptoms are relatively mild and no pharmaco- Besides reinforcing the inhibitory effects of GABA, alcohol therapeutic management is required. However, in manifest AWS tempers excitatory neurotransmission mediated by glutamate. This treatment is indicated to avoid DT or seizures. The pharmaco- neurotransmitter binds N-methyl-D-aspartate (NMDA)-receptors therapeutic management of AWS entails the substitution of a resulting in a calcium influx depolarizing the neuron. One of the long-acting agent for alcohol and subsequently to taper its dosage results of NMDA stimulation is an enhancement of signal transmission over time17. Historically, many different classes of drugs have been between neurons called long-term potentiation which underlies tried in the management of AWS. This section provides an overview learning and the development of memory. Alcohol serves as a blocker of the primary pharmacologic agents. The discussion of supportive of the NMDA-receptors inhibiting this process and contributing to measures is beyond the scope of this article. amnesia and depression of cerebral function. Over time the brain’s reaction is to increase the number of NMDA-receptors which allow Benzodiazepines normal functioning in the presence of alcohol, the formation of Benzodiazepines have been the mainstay of pharmacotherapeutic tolerance10,12. treatment of AWS and the prevention of secondary seizures since In AWS, GABA neurotransmission is decreased while glutamatergic 196918. Benzodiazepines produce their effect by increasing
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