EARN CATEGORY I CME CREDIT by reading this article and the article beginning on page 40 and successfully
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● Describe the supposed mechanism of action of alcohol withdrawal● List the signs and symptoms associated with alcohol withdrawal● Discuss the steps in evaluating the hospitalized patient with suspected alcohol withdrawal● Outline treatment goals related to supportive care, pharmacologic choices, and posthospital therapy Managing alcohol withdrawalin hospitalized patients Therapy includes benzodiazepines to reduce withdrawal symptoms and prevent delirium.
Symptom-driven protocols may be more beneficial than scheduled-dosing plans.
Zachary Hartsell, MPAS, PA-C; Jennifer Drost, MMSc, PA-C;
James A. Wilkens, MD; Adriane I. Budavari, MD

Alcohol is currently the second most abused drug in the United States and is abused by up to 9%of the population.1,2 Approximately 11 to 15million people report heavy alcohol intake, andthe costs of medical complications related to alcohol abuse in the United States are estimated to be almost$100 billion per year.2 Although many definitions of alco-holism exist, the National Institute on Alcohol Abuse andAlcoholism (NIAAA) classifies women who consume morethan 7 drinks per week and men who consume more than 14drinks per week as being at high-risk of progressing to alco-holism. More than 4 drinks a day is considered heavy alcoholuse for women, more than 5 drinks a day for men.3 Heavy alcohol users are at risk for withdrawal symptoms, with hospitalized patients who abuse alcohol at greatest risk.
Some reports suggest that at least 25% of general medical inpa-tients have alcohol use disorders.4 In trauma patients, the rateis much higher, with alcohol dependence or abuse present in25% to 47% of these patients.5 In a study of 242 trauma pa-tients admitted to a suburban US hospital, 43% were found to have elevated blood alcohol levels and 33% were legally intoxi-cated.5 The incidence of patients with alcohol withdrawal syn- drome is projected to be nearly 2 million per year, with morethan 500,000 per year having withdrawal symptoms severeenough to require pharmacologic treatment.6 Even though alcohol withdrawal is a common inpatient disorder, studies suggest that many hospitalized patients arenot receiving appropriate diagnosis or treatment. Bostwickand colleagues found that in an urban Level I trauma center,approximately 75% of alcohol abusers were identified.7 Despite this, only 43% of these patients had withdrawal pro- 20 JAAPA • SEPTEMBER 2007 20(9)
phylaxis ordered, and only 38% were monitored for alcohol by mild autonomic hyperactivity, manifesting as tremulous- withdrawal signs and symptoms.7 This article reviews the ness, mild anxiety, tachycardia, hypertension, GI upset, in- pathophysiology of alcohol withdrawal, describes how to somnia, and vivid dreams. Since the signs and symptoms evaluate and monitor patients potentially suffering from this of alcohol withdrawal are quite nonspecific at this stage, the condition, and suggests treatment strategies.
diagnosis can often be missed. Symptoms of minor with-drawal typically resolve spontaneously in 24 to 48 hours, PATHOPHYSIOLOGY
Although the exact mechanism of action for alcohol with- Major withdrawal Major withdrawal syndromes tend to
drawal is unknown, the GABA inhibition theory is the most occur approximately 48 to 72 hours after the last drink.
widely accepted. Alcohol enhances the inhibitory chloride They include alcoholic hallucinosis, alcohol seizures, and influx mediated by gamma-aminobutyric acid alpha (GABA- A), resulting in clinical sedation. With chronic alcohol use, First characterized in 1989, alcoholic hallucinosis occurs in tolerance develops and GABA receptor function is down- an estimated 10% to 25% of hospitalized alcoholics.9-11 Hallu- regulated. Alcohol also inhibits the excitatory N-methyl-D- cinations can be tactile, visual, or auditory, but patients with aspartate (NMDA) receptor, thus diminishing the excitatory alcoholic hallucinosis—unlike those with DTs—maintain a effects of glutamate and, over time, increasing neuroexcitato- clear sensorium.6 Although definite risk factors for alcoholic ry tone. Finally, alcohol causes alpha2-receptors to inhibit hallucinosis have not been identified, a study of 643 patients norepinephrine release. As a result, when alcohol is abruptly in a Veterans Affairs drug and alcohol treatment center found withdrawn, the unopposed hyperexcitable neurons cause the that those who developed alcoholic hallucinosis were younger at the onset of their alcoholism and tended to be heavier Another key pathophysiologic concept in alcohol with- drinkers than alcohol abusers who did not.11 drawal is the phenomenon of kindling. Kindling begins as a Alcoholic seizures occur in up to 10% of patients suffering single electrical stimulus initially causing no overt clinical alcohol withdrawal. They tend to occur 24 hours after the manifestations but eventually results in the appearance of last drink but can occur even while alcohol is still measurable abnormal behavior (such as seizures) when the stimulus is in the blood. Alcoholic seizures are single, short, generalized administered repeatedly. Applied to alcoholism, kindling tonic-clonic seizures that can recur successively but rarely explains why each episode of alcohol withdrawal appears to progress to status epilepticus.9 Status epilepticus, focal seizures increase patients’ risk of withdrawal symptoms. Chronic or seizures associated with fever or known head trauma, and alcoholics typically experience progressively shorter intervals seizures starting after the patient becomes delirious are not between their last drink and onset of symptoms, as well as typical of alcohol withdrawal and require further workup. progressive worsening of symptoms during each subsequent DTs is considered the end point of the alcohol withdrawal spectrum and represents a medical emergency. DTs occurs inapproximately 5% of patients with alcohol withdrawal.6 CLINICAL PRESENTATION
Symptoms typically start 48 to 72 hours after the last drink The signs and symptoms of alcohol withdrawal fall along a and include confusion, disorientation, impaired attention, spectrum, ranging from mild and self-limiting to life-threaten- severe autonomic activity, and hallucinations. A history of ing (see Figure 1, page 22). Importantly, these signs and DTs, a long history of sustained drinking, age greater than symptoms should be attributed to alcohol withdrawal only 65 years, concurrent medical comorbidities, and seizure after other medical conditions are considered and ruled out.
activity during the present admission are risk factors. Earlier Minor withdrawal The manifestations of mild alcohol with-
studies found mortality in patients with DTs to be as high drawal typically start between 5 and 10 hours after the last as 20% even with treatment, but more recently mortality is drink. This early stage of alcohol withdrawal is characterized cited at about 1%, with death generally occurring from KEY POINTS
■ Early identification of patients who are experiencing an alcohol withdrawal syndrome includes recognizing the spectrum of withdrawal indicators and monitoring carefully for signs and symptoms. With appropriate treatment, the risk of complications from alcohol ●●●●● Interpersonal & communication skills withdrawal is significantly lessened.
■ Benzodiazepines are the drug of choice for the treatment of most patients who have alcohol ■ Studies suggest that use of a symptom-triggered dosing protocol may reduce treatment times for patients with alcohol withdrawal syndrome.
■ In addition to recognizing alcohol withdrawal, clinicians should take the time to screen ●● Practice-based learning and improvement patients for alcohol abuse. Proper identification can ensure appropriate outpatient follow-up.
SEPTEMBER 2007 20(9) • JAAPA 21
CME Alcohol withdrawal
arrhythmias or concomitant illnesses. When DTs is unrecog- the current status of the patient with respect to alcohol with- nized and untreated, mortality can exceed 35%.12 drawal syndrome. The CAGE questions are designed to elic-it information about alcohol abuse in hopes of identifying EVALUATING THE PATIENT
patients most at risk for withdrawal; therefore it is most The first step in evaluating the hospitalized patient with sus- appropriate to use during the admission interview, before the pected alcohol withdrawal is ruling out other medical condi- tions that could be causing the signs and symptoms. When Laboratory results that may indicate alcohol abuse include
alcohol withdrawal remains likely, key historical information elevations in mean corpuscular volume (MCV), gamma- includes total duration of alcohol use, daily quantity of alco- glutamyl transpeptidase (GGT), and liver transaminases.
hol ingestion, elapsed time since last drink, history of alcohol Elevated liver transaminases with the pattern of AST being withdrawal syndromes, abuse of other substances, and histo- more than 2 times higher than ALT is the most common lab- ry of major medical and/or psychiatric conditions. The physi- oratory finding in patients who abuse alcohol. One study cal examination should not only focus on identifying the noted this finding in 83% of patients admitted with alcoholic signs and symptoms of alcohol withdrawal but should also hepatitis.15 Additionally, this pattern is generally not seen in attempt to uncover any signs of complicating medical condi- other forms of liver disease.15 GGT is commonly measured tions—including (but not limited to) arrhythmias, heart fail- to determine chronic alcohol use but has a sensitivity of only ure, liver disease, pancreatitis, or infections.
30% to 40%.15 GGT can be elevated in patients with nonal- Once alcohol withdrawal syndrome has been diagnosed, coholic forms of liver disease or in those taking certain med- the severity of the episode should be determined since severi- ications. An elevated MCV is an index of RBC size. MCV ty will guide further therapy. Although most patients under- increases with excessive alcohol intake after 4 to 8 weeks.
going alcohol withdrawal need close observation, some war- The mechanism of the elevation in chronic alcoholism is rant admission to an ICU. These include patients with unknown, but the elevation is found in 90% of alcoholics.
advanced age; hemodynamic instability; hyperthermia (per- Patients who binge drink or who have started drinking heav- sistent temperature higher than 39°C/103°F); a severe elec- ily only recently (within 90 days) may have normal-size trolyte disturbance or acid-base disorder; moderate to severe RBCs.16 In more recent studies, elevations in carbohydrate- cardiac, pulmonary, or renal disease; active infection; rhab- deficient transferrin level was shown to be a more sensitive domyolysis (as evidenced by an elevated creatine kinase and specific biologic marker for detecting alcohol abuse, but [CK] level combined with a normal CKMB/troponin level); testing for this is impractical in the hospital setting.17 Prevention—that is, trying to identify which patients are at
high risk for alcohol withdrawal before they become sympto- In patients with suspected active alcohol withdrawal, the matic—is considered the best practice. Although patients may Clinical Institute Withdrawal Assessment for Alcohol scale, be reluctant to discuss their drinking, the interview remains revised (CIWA-Ar), is the best tool to determine severity and the most reliable and accurate means of assessing alcohol to guide therapeutic intervention (see Figure 2, page 24). The intake and determining who is at risk for withdrawal. CIWA-Ar is well-validated and has high reproducibility and Although validated only in the outpatient setting, the CAGE questionnaire can also be a useful interview tool for The CIWA-Ar was created to assess and guide treatment assessing inpatients suspected of alcohol abuse. It is com- of acute alcohol withdrawal. It also has utility in triage. For example, patients with a CIWA-Ar score of less than 10 can • Have you ever felt the need to Cut down on drinking?
be observed and in some cases may be treated as outpatients, • Have you ever felt Annoyed by criticism of your drinking?
as long as they have a stable living situation with close follow- • Have you ever felt Guilty about your drinking?
up and no history of relapses or major comorbid mental or • Have you ever taken a morning Eye opener?
medical illness.19 Patients with a CIWA-Ar score greater than The CAGE questionnaire has an overall sensitivity of 85% 10 should be admitted for inpatient treatment and close ob- and a specificity of 89%; with three positive answers, its sen- servation. Patients with a CIWA-Ar score greater than 15 sitivity is 100%.14 The main disadvantage of the CAGE is will need initiation of treatment with benzodiazepines. After that it does not distinguish between past and present alcohol being used as a triaging tool, the CIWA-Ar can be used to use, and it therefore does not provide any information about guide therapy and monitor for worsening of the withdrawal.18 FIGURE 1. The spectrum of alcohol withdrawal syndrome
22 JAAPA • SEPTEMBER 2007 20(9)
Unfortunately, few clinicians report routinely using the based on the score. In the 117 patients studied, symptom- CAGE questionnaire or the CIWA-Ar with patients. Accord- triggered dosing showed no difference in comfort levels.
ing to Friedmann and colleagues, although most clinicians However, the mean duration of treatment was shorter in the ask patients if they consume alcohol, only 13% report using group treated in response to symptoms (20 hours vs 63 a validated screening tool such as the CAGE.20 In addition, hours), and there was a marked decrease in the mean quanti- the CIWA-Ar is rather labor-intensive, requiring high levels ty of medication administered (37 mg vs 231 mg). There was of nursing care to administer effectively. However, without no difference in complications between the two groups.25 validated tools, diagnoses of alcoholism and alcohol with- IV ethanol (IVE) historically was used for the treatment drawal are delayed, as are necessary treatments.
and prevention of alcohol withdrawal. Discussion of its usewas confined to case reports, whose authors felt IVE to be TREATMENT
less sedating than benzodiazepines.26 A 2004 review of anec- Treatment goals for alcohol withdrawal syndrome include dotal reports of IVE in critically ill patients with alcohol with- alleviating symptoms, preventing progression to DTs, control- drawal similarly found no evidence to support its use.27 This ling underlying comorbidities, and initiating rehabilitation.9 conclusion is a result of IVE’s inconsistent pharmacokinetic Supportive care Treating a patient in alcohol withdrawal
profile, relatively narrow therapeutic index, and enhance- includes providing a quiet environment with supervision and ment of drug interactions secondary to hepatic metabolism.27 precautions against falls. Electrolyte abnormalities should becorrected, but routine administration of magnesium has notproved effective.21 Similarly, IV fluids should be reserved for patients with signs of excess fluid loss. Finally, a daily multi- vitamin (orally if possible) and thiamine (100 mg by conven-tion) are generally recommended, though formal evidence to support these interventions is lacking. A recent Cochranesystematic review found insufficient evidence from random-ized controlled trials to guide clinicians in the optimal dose, Adjunct medications Benzodiazepines are considered first-
route, frequency, or duration of thiamine for prophylaxis line therapy for alcohol withdrawal syndrome, and adjunct against or treatment of Wernicke-Korsakoff syndrome.22 medication should be used only in conjunction with benzodi- Pharmacologic therapy Pharmacologic treatment of alcohol
azepines. Beta-blockers and alpha-blockers have been tradi- withdrawal centers upon using medications that are cross- tionally used in the management of alcohol withdrawal, par- tolerant with alcohol. Benzodiazepines are considered first-line ticularly to treat hypertension. The purpose of beta-blockade therapy. Their mechanism of action is to enhance the depres- in alcohol withdrawal is to reduce the result of increased car- sant neurotransmitter GABA and replace the effects of alco- diac autonomicity, including arrhythmias and increased car- hol. A review of 57 trials with a total of 4,051 patients found diac output. Adjunctive therapy with beta-blockers should be that the risk of alcohol withdrawal seizure was reduced with considered in patients with known coronary artery disease.
the use of benzodiazepines compared with placebo.23 Al- Alpha-blockers, such as clonidine, work similarly to decrease though no specific benzodiazepine has been shown to be sympathetic tone and affect mainly the alpha-receptors.24 superior to another, certain agents are recommended, based Historically, anticonvulsants have been widely used to con- largely on their pharmacokinetics. For example, long-acting trol alcohol withdrawal symptoms (particularly seizures).
agents such as diazepam and chlordiazepoxide effectively pre- Carbamazepine is used widely throughout Europe for outpa- vent rebound symptoms. In patients who are elderly, have tient treatment of alcohol withdrawal. It appears to suppress hepatic disease, or are critically ill, intermediate-acting agents the kindling effect and to decrease the craving for alcohol like lorazepam or oxazepam are preferred to prevent overse- after withdrawal.9 A 2005 review of 48 studies found the use dation. Lorazepam and diazepam are available for oral, IV, of anticonvulsants controversial. Because of the heterogeneity and IM administration, whereas chlordiazepoxide and oxaze- of agents available and the limited studies performed, no rec- pam have only oral formulations.24 Clonazepam, temazepam, ommendation could be made on their use for alcohol with- drawal. When compared to benzodiazepines, anticonvulsants Fixed-dose versus symptom-triggered regimens An influ-
had equal efficacy in preventing seizures but a worse side ential randomized controlled trial by Daeppen and colleagues effect profile.28 Additionally, studies have shown no effect on inspired a major change in how benzodiazepines are admin- istered to hospitalized patients experiencing alcohol with- Neuroleptics are often used to treat agitation and hallucina- drawal syndrome. This study compared symptom-triggered tions in alcohol withdrawal syndrome. In 2004, Mayo-Smith benzodiazepine therapy (administering a dose in response to and colleagues published a meta-analysis of nine prospective symptoms) versus fixed-dose (administering a fixed dose at controlled trials which culminated in the formation of an standard intervals regardless of symptoms) therapy. The evidence-based practice guideline for the management of CIWA-Ar was used to measure the severity of the withdraw- alcohol withdrawal delirium.29 They suggested that sedative- al, and an appropriate dose of benzodiazepine was given hypnotics are more effective than neuroleptic agents in reduc- SEPTEMBER 2007 20(9) • JAAPA 23
CME Alcohol withdrawal
FIGURE 2. Clinical Institute Withdrawal Assessment for Alcohol Scale
Patient ________________________________________________________________ Date _____________________ Time __________________ Pulse or heart rate, taken for 1 min ________________________________________ Blood pressure______________________________________ Ask: “Do you feel sick to your stomach? that is disturbing to you? Are you seeing Do not rate for dizziness or lightheaded- 1 Barely perceptible sweating, palms moist Rater’s initials _______________________ Adapted from Sullivan JT, Sykora K, Schneiderman J, et al. Assessment of alcohol withdrawal: the revised Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWA-Ar). Br J Addict. 1989;84:1353-1357.
24 JAAPA • SEPTEMBER 2007 20(9)
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SEPTEMBER 2007 20(9) • JAAPA 25


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