The Clinical Picture
When managing a patient with chronic alcohol abuse who is beginning to withdraw, expect the unexpected.
Justine S. Gortney, PharmD, BCPS
Assistant Professor, Director of Assessment, Division of Pharmacy, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI
Joshua N. Raub, PharmD, BCPS
Clinical Pharmacist Specialist in Internal Medicine, Assistant Program Director, Pharmacy Practice, Detroit Receiving Hospital, Detroit, MI
Pragnesh Patel, MD
Assistant Professsor, Wayne State School of Medicine, Division of Geriatrics, University Health Center, Detroit Receiving Hospital, Detroit, MI
Lianne Kokoska, PharmD
United Physicians, Detroit, MI
Mae Hannawa, PharmD
Clinical Pharmacist, Detroit Receiving Hospital, Detroit, MI
Amy Argyris, PharmD, BCPS
Clinical Pharmacist Specialist in Internal Medicine, Harper University Hospital, Detroit, MI
Address: Justine S. Gortney, PharmD, BCPS, Department of Pharmacy Practice, Wayne State College of Pharmacy and Health Sciences, 259 Mack Avenue, Suite 2190, Detroit, MI 48201; e-mail: firstname.lastname@example.org
ABSTRACTThe authors provide a critical review focusing on pharmacotherapy of alcohol withdrawal syndrome in hospitalized patients who are not critically ill. They outline recommendations for patient assessment and monitoring.
Deprived of alcohol while in the hospital, up to 80% of patients who are alcohol-dependent risk developing alcohol withdrawal syndrome,1 a potentially life-threatening condition. Clinicians should anticipate the syndrome and be ready to treat and prevent its complications.
Because alcoholism is common, nearly every provider will encounter its complications and withdrawal symptoms. Each year, an estimated 1.2 million hospital admissions are related to alcohol abuse, and about 500,000 episodes of withdrawal symptoms are severe enough to require clinical attention.1–3 Nearly 50% of patients with alcohol withdrawal syndrome are middle-class, highly functional individuals, making withdrawal difficult to recognize.1
While acute trauma patients or those with alcohol withdrawal delirium are often admitted directly to an intensive care unit (ICU), many others are at risk for or develop alcohol withdrawal syndrome and are managed initially or wholly on the acute medical unit. While specific statistics have not been published on non-ICU patients with alcohol withdrawal syndrome, they are an important group of patients who need to be well managed to prevent the progression of alcohol withdrawal syndrome to alcohol withdrawal delirium, alcohol withdrawal-induced seizure, and other complications.
This article reviews how to identify and manage alcohol withdrawal symptoms in noncritical, acutely ill medical patients, with practical recommendations for diagnosis and management.
CAN LEAD TO DELIRIUM TREMENS
In people who are physiologically dependent on alcohol, symptoms of withdrawal usually occur after abrupt cessation.4 If not addressed early in the hospitalization, alcohol withdrawal syndrome can progress to alcohol withdrawal delirium (also known as delirium tremens or DTs), in which the mortality rate is 5% to 10%.5,6 Potential mechanisms of DTs include increased dopamine release and dopamine receptor activity, hypersensitivity to N-methyl-d-aspartate, and reduced levels of gamma-aminobutyric acid (GABA).7
Long-term changes are thought to occur in neurons after repeated detoxification from alcohol, a phenomenon called “kindling.” After each detoxification, alcohol craving and obsessive thoughts increase,8 and subsequent episodes of alcohol withdrawal tend to be progressively worse.
Alcohol withdrawal syndrome encompasses a spectrum of symptoms and conditions, from minor (eg, insomnia, tremulousness) to severe (seizures, DTs).2 The symptoms typically depend on the amount of alcohol consumed, the time since the last drink, and the number of previous detoxifications.9
The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,1 states that to establish a diagnosis of alcohol withdrawal syndrome, a patient must meet four criteria:
Some of the symptoms described in the second criterion above can occur while the patient still has a measurable blood alcohol level, usually within 6 hours of cessation of drinking.10 Table 1 describes the timetable of onset of symptoms and their severity.2
While the progression of the symptoms described above is commonly used for medical inpatients, the timeline may be different in an elderly patient. Compared with younger patients, elderly patients may have higher blood alcohol concentrations owing to lower total body water, so small amounts of alcohol can produce significant effects.11,12 Brower et al12 found that elderly patients experienced more withdrawal symptoms, especially cognitive impairment, weakness, and high blood pressure, and for 3 days longer.
In the elderly, alcohol may have a greater impact on the central nervous system because of increased permeability of the blood-brain barrier. And importantly, elderly patients tend to have more concomitant diseases and take more medications, all of which can affect alcohol metabolism.
ASSESSMENT SCALES FOR ALCOHOL WITHDRAWAL SYNDROME
A number of clinical scales for evaluating alcohol withdrawal have been developed. Early ones such as the 30-item Total Severity Assessment (TSA) scale and the 11-item Selected Severity Assessment (SSA) scale were limited because they were extremely detailed, burdensome to nursing staff to administer, and contained items such as daily “sleep disturbances” that were not acute enough to meet specific monitoring needs or to guide drug therapy.13,14
The Clinical Institute Withdrawal Assessment for alcohol (CIWA-A) scale, with 15 items, was derived from the SSA scale and includes acute items for assessment as often as every half-hour.15
The CIWA-Ar scale (Table 2) was developed from the CIWA-A scale by Sullivan et al.15 Using both observation and interview, it focuses on 10 areas: nausea and vomiting, tremor, paroxysmal sweats, anxiety, agitation, headache, disorientation, tactile disturbances, auditory disturbances, and visual disturbances. Scores can range from 0 to 67; a higher score indicates worse withdrawal symptoms and outcomes and therefore necessitates escalation of treatment.
The CIWA-Ar scale is now the one most commonly used in clinical trials16–20 and, we believe, in practice. Other scales, including the CIWA-AD and the Alcohol Withdrawal Scale have been validated but are not widely used in practice.14,21
BASELINE ASSESSMENT AND EARLY SUPPORTIVE CARE
A thorough history and physical examination should be performed on admission in patients known to be or suspected of being alcohol-dependent to assess the patient’s affected body systems. The time elapsed since the patient’s last alcohol drink helps predict the onset of withdrawal complications.
Baseline laboratory tests for most patients with suspected alcohol withdrawal syndrome should include a basic blood chemistry panel, complete blood cell count, and possibly an alcohol and toxicology screen, depending on the patient’s history and presentation.
Hydration and nutritional support are important in patients presenting with alcohol withdrawal syndrome. Severe disturbances in electrolytes can lead to serious complications, including cardiac arrhythmia. Close monitoring and electrolyte replacement as needed are recommended for hospitalized alcoholic patients and should follow hospital protocols.22
Thiamine and folic acid status deserve special attention, since long-standing malnutrition is common in alcoholic patients. Thiamine deficiency can result in Wernicke encephalopathy and Korsakoff syndrome, characterized by delirium, ataxia, vision changes, and amnesia. Alcohol withdrawal guidelines recommend giving thiamine intravenously for the first 2 to 5 days after admission.23 In addition, thiamine must be given before any intravenous glucose product, as thiamine is a cofactor in carbohydrate metabolism.23 Folic acid should also be supplemented, as chronic deficiencies may lead to megaloblastic or macrocytic anemia.
Most patients with a CIWA-Ar score ≥ 8 benefit from benzodiazepine therapy
CIWA-Ar scale. To provide consistent monitoring and ongoing treatment, clinicians and institutions are encouraged to use a simple assessment scale that detects and quantifies alcohol withdrawal syndrome and that can be used for reassessment after an intervention.21 The CIWA-Ar scale should be used to facilitate “symptom-triggered therapy” in which, depending on the score, the patient receives pharmacologic treatment followed by a scheduled reevaluation.23,24 Most patients with a CIWA-Ar score of 8 or higher benefit from benzodiazepine therapy.16,18,19
PRIMARY DRUG THERAPIES FOR MEDICAL INPATIENTS
Benzodiazepines are the first-line agents recommended for preventing and treating alcohol withdrawal syndrome.23 Their various pharmacokinetic profiles, wide therapeutic indices, and safety compared with older sedative hypnotics make them the preferred class.23,25 No single benzodiazepine is preferred over the others for treating alcohol withdrawal syndrome: studies have shown benefits using short-acting, intermediate-acting, and long-acting agents. The choice of drug is variable and patient-specific.16,18,26
Benzodiazepines promote and enhance binding of the inhibitory neurotransmitter GABA to GABAA receptors in the central nervous system.27 As a class, benzodiazepines are all structurally related and produce the same effects—namely, sedation, hypnosis, decreased anxiety, muscle relaxation, anterograde amnesia, and anticonvulsant activity.27
The most studied benzodiazepines for treating and preventing alcohol withdrawal syndrome are chlordiazepoxide, oxazepam, and lorazepam,16–20 whereas diazepam was used in older studies.23
Diazepam and chlordiazepoxide are metabolized by oxidation, each sharing the long-acting active metabolite desmethyldiazepam (half-life 72 hours), and short-acting metabolite oxazepam (half-life 8 hours).27 In addition, the parent drugs also have varying pharmacokinetic profiles: diazepam has a half-life of more than 30 hours and chlordiazepoxide a half-life of about 8 hours. Chlordiazepoxide and diazepam’s combination of both long- and short-acting benzodiazepine activity provides long-term efficacy in attenuating withdrawal symptoms, but chlordiazepoxide’s shorter parent half-life allows more frequent dosing.
Lorazepam (half-life 10–20 hours) and oxazepam (half-life 5–20 hours) undergo glucuronide conjugation and do not have metabolites.27,28 Table 3 provides a pharmacokinetic summary.27,28
Various dosage regimens are used in giving benzodiazepines, the most common being symptom-triggered therapy, governed by assessment scales, and scheduled around-the-clock therapy.29 Current evidence supports symptom-triggered therapy in most inpatients who are not critically ill, as it can reduce both benzodiazepine use and adverse drug events and can reduce the length of stay.16,19
Most inpatient trials of symptom-triggered therapy (Table 4)3,16–20 used the CIWA-Ar scale for monitoring. In some of the studies, benzodiazepines were given if the score was 8 or higher, but others used cut points as high as 15 or higher. Doses:
After each dose, patients were reevaluated at intervals of 30 minutes to 8 hours.
Most of these trials showed no difference in rates of adverse drug events such as seizures, hallucinations, and lethargy with symptom-triggered therapy compared with scheduled therapy.16,18,20 They also found either no difference in the incidence of delirium tremens, or a lower incidence of delirium tremens with symptom-triggered therapy than with scheduled therapy.16–18,20
Weaver et al19 found no difference in length of stay between scheduled therapy and symptom-triggered therapy, but Saitz et al16 reported a median benzodiazepine treatment duration of 9 hours with symptom-triggered therapy vs 68 hours with fixed dosing. Thus, the study by Saitz et al suggests that hospitalization might be shorter with symptom-triggered therapy.
Many of the trials had notable limitations related to the diversity of patients enrolled and the protocols for both symptom-triggered therapy and fixed dosing. Some trials enrolled only inpatients in detoxification programs; others focused on inpatients with acute medical illness. The inpatient alcohol treatment trials16,18 excluded medically ill patients and those with concurrent psychiatric illness,16,18 and one excluded patients with seizures.16 One of the inpatient alcohol treatment program trials16 excluded patients on beta-blockers or clonidine because of concern that these drugs could mask withdrawal symptoms, whereas trials in medically ill patients allowed these same drugs.17,19,20
Most of the patients were men (approximately 75%, but ranging from 74% to 100%), and therefore the study results may not be as applicable to women.16–20 Most participants were middle-aged, with average ages in all studies between 46 and 55. Finally, the studies used a wide range of medications and dosing, with patient monitoring intervals ranging from every 30 minutes to every 8 hours.16–20
In a 2010 Cochrane analysis, Amato et al29 concluded that the limited evidence available favors symptom-triggered regimens over fixed-dosing regimens, but that differences in isolated trials should be interpreted very cautiously.
Aside from the lack of evidence to support its use in alcohol withdrawal syndrome, prescribing oral ethanol to alcoholic patients clearly poses an ethical dilemma. However, giving ethanol intravenously has been studied, mostly in surgical trauma patients.30
Early reports described giving intravenous ethanol on a gram-to-gram basis to match the patient’s consumption before admission to prevent alcohol withdrawal syndrome. But later studies reported prevention of alcohol withdrawal syndrome with very small amounts of intravenous ethanol.30,31 While clinical trials have been limited to ICU patients, ethanol infusion at an initial rate of 2.5 to 5 g per hour and titrated up to 10 g per hour has appeared to be safe and effective for preventing alcohol withdrawal syndrome.30,31 The initial infusion rate of 2.5 to 5 g per hour is equivalent to 4 to 10 alcoholic beverages per 24 hours.
Nevertheless, ethanol infusion carries the potential for toxicities (eg, gastric irritation, precipitation of acute hepatic failure, hypoglycemia, pancreatitis, bone marrow suppression, prolonged wound healing) and drug interactions (eg, with anticoagulants and anticonvulsants). Thus, ethanol is neither widely used nor recommended.25,31
When managing a patient with chronic alcohol abuse who is beginning to withdraw, expect the unexpected.
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