Alcohol Withdrawal: An Old Challenge in a New Millennium
Special Feature
Alcohol Withdrawal: An Old Challenge in a New Millennium
By Richard J. Hamilton, MD, FAAEM, ABMT
A patient in alcohol withdrawal can be the most challenging patient in your emergency center. Alcohol use and its medical complications have been part of human disease for centuries. In 1900, patients generally died of untreated alcohol withdrawal. Even today, the challenge to prevent morbidity and mortality remain. Emergency physicians must be aware of the essential components of pathophysiology, the spectrum of symptoms, principles of safe and effective treatment, and pitfalls in clinical management. Once these are mastered, the alcohol withdrawal patient will get the rapid evaluation and stabilization that is necessary, and morbidity and mortality from this condition will be minimized.
Every withdrawal patient shares the following characteristics: 1) a state of physiologic adaptation to a drug or toxin, the continuous presence of which prevents physiologic derangement; and 2) decreasing concentrations of that substance. This is in contradistinction to simple tolerance. Tolerance to a drug or toxin is a simple physiologic adaptation that requires higher doses to get a predetermined response. So while the alcoholic may have tolerance (larger quantities of alcohol are required to produce inebriation), not every alcoholic may experience withdrawal. This distinction is important. Alcohol withdrawal patients require a drug which has activity at the gamma hydroxy butyrate receptor (GABA) to maintain the central nervous system (CNS) inhibitory control needed to function normally.
Ethanol, while having no direct binding site to GABA, acts to cross-couple membrane proteins. The GABA receptor functions by modulating a chloride channel in the core of its five subunits. This cross-coupling is enough to effect a change in membrane conductance that is clinically indistinguishable from other GABA agonists such as benzodiazepines and barbiturates. Although the exact mechanism is unknown, it is clear that chronic ethanol ingestion affects expression and function of GABA receptors and their binding of the neurotransmitter GABA. Without GABA—the main inhibitory neurotransmitter in the CNS—the patient has unmodulated CNS excitation and sympathetic stimulation.
The constellation of symptoms that constitute alcohol withdrawal are still best described in the original work of Victor and Adams.1 Patients usually present with a generalized tonic-clonic seizure. The post-ictal phase is usually brief. The patient then appears to be at baseline. These seizures are often mistaken for epilepsy, and many alcoholics are mistakenly worked up and placed on phenytoin maintenance. However, it can be difficult to distinguish between an alcohol withdrawal seizure and an acquired seizure disorder in the face of a history of repeated falls and head trauma, and the diagnosis of acquired epilepsy usually remains with the patient.
In time, the patient progresses to symptoms of CNS irritability and autonomic dysfunction characterized by sympathetic stimulation. The patient often becomes agitated and behaviorally difficult. The heart rate increases. Fever, diaphoresis, mydriasis, and mild hypertension are also present. A fine-amplitude tremor of the hand and tongue is a typical characteristic. Formication, or the sensation of ants crawling on the skin, often promotes repeated scratching and leads to excoriations. Disorders of thought, anxiety, agitation, and labile mood also manifest to varying degrees. Visual hallucinations are often present. If untreated or under-treated, the CNS excitation of these patients progresses to uncontrollable agitation, seizures, involuntary tremor, hyperthermia, rhabdomyolysis, and death.
Until 30 years ago, the mortality of alcohol withdrawal was as high as 30%.2 The cause was generally from improper supportive care, failure to identify comorbid conditions such as infections, and the use of phenothiazines for sedation, which of course impaired temperature regulation and exacerbated tachycardia. Attention to control of temperature, appropriate hydration, and monitoring of hemodynamics are essential. However, complacency regarding co-existing infections such as meningitis and pneumonia leads to poor outcomes, even today. Remember, the alcohol-dependent patient generally does not stop drinking unless unable, and becoming ill with an infection, confinement, or other condition is often the first step.
The classic alcohol withdrawal patient is usually in his or her middle 30s, a continuous (as opposed to binge) drinker, and male. However, patients of all ages can present with alcohol withdrawal—highly functional patients admitted for elective surgery, elderly patients who are hospitalized for falls and fractures—any patient who cannot maintain the alcohol level he or she requires.
The workup of the alcohol withdrawal patient should include a chest radiograph, complete blood count, serum electrolytes, calcium, magnesium, phosphorous, and urinalysis. If the patient has demonstrated his or her first alcohol withdrawal seizure, then a head CT should be obtained. All patients with a clouded sensorium or depressed level of consciousness should undergo cerebrospinal fluid analysis via lumbar puncture.
Note that the term "delirium tremens" (DTs) is often used inappropriately in an attempt to "stage" the patient (i.e., "impending DTs," "mild DTs," and ultimately "florid DTs"). This terminology is of no clinical or predictive value. Alcohol withdrawal is a neurologic condition with a continuum of symptoms ultimately leading to DTs. This latter term is best reserved for the patient with altered sensorium and autonomic instability. All phases of alcohol withdrawal, from mere anxiousness and tremor to obtundation with fever, require aggressive therapy.
A good outcome starts with good supportive care. All patients should receive intravenous hydration to achieve appropriate urine output and prevent rhabdomyolysis. Supplemental glucose is important to support the active CNS metabolism. Supplemental thiamine ensures appropriate transport of glucose into the CNS and corrects omnipresent nutritional deficiencies. Folate and multivitamins are also indicated. Magnesium should be supplemented when deficiencies are identified or considered. Cooling measures should be aggressive. Patients should be placed in protective physical restraints until chemical restraints, and more importantly, appropriate sedation, are administered.
Benzodiazepines revolutionized the treatment of alcohol withdrawal. They can effectively restore the inhibitory tone of the CNS. These drugs have very wide margins of safety and can be used in repetitive doses to a desired clinical effect. They are a vast improvement over the generation of sedatives before them, such as paraldehyde, chloral hydrate, etc. The use of intravenous alcohol leads to ketoacidosis and is not appropriate therapy.
It is important to realize that the goal of pharmacological management of the alcohol withdrawal patient is not just to quiet or control the patient. Experimental evidence supports the theory that patients who experience withdrawal symptoms will experience progressive worsening of symptoms with each subsequent withdrawal episode. This phenomenon, known as the "kindling hypothesis," prompts aggressive management of even minor symptoms with liberal use of benzodiazepines.3
The variety of benzodiazepines often presents a difficult choice for clinicians, and normally comfort in prescribing habits is achieved with only one or two drugs. It is my recommendation that diazepam be used for all alcohol withdrawal patients. Diazepam is metabolized to a number of active drugs that have half-lives on the order of 100 hours, a characteristic useful for tapering. Other drugs, such as lorazepam, do not share this characteristic and require frequent redosing. Intravenous drips require increased nursing vigilance and add to the risk of iatrogenic complications. Chlordiazepoxide has traditionally been used for alcohol withdrawal in an outpatient setting via the oral route. It has active metabolites, but is of limited usefulness via any parenteral route. Other benzodiazepines are employed, but none have any advantage over diazepam.
A number of controlled studies also demonstrate that diazepam should be administered in loading fashion when the patient presents to the emergency center.4,5 The end point is sustained reversal of autonomic exacerbations such as tachycardia, fever, tremor, and induction of a calm sleep. Concerns regarding airway compromise mean the emergency physician is the clinician most appropriately trained for safe, effective management. This "loading" dose approach results in less total administered drug when compared to the "symptom-triggered therapy" approach. In the latter, patients are quieted with periodic doses of benzodiazepines. The net effect is that the patient remains intermittently agitated, and the potential for morbidity increases. The least successful technique is the use of a fixed dosing regimen, which leads to insufficient doses when the patient is most ill and unnecessary doses when the condition is nearly resolved. This latter problem leads to oversedation and unresponsiveness—often in poorly monitored settings such as after transfer to a medical floor or psychiatric facility. Thus, diazepam should be given as a 10-20 mg bolus and repeated every 15 minutes to the above-mentioned end point in the emergency center. Then the patient should be assessed for the necessary level of care in the hospital.
Recent studies suggest that there are some patients who may not respond to even large doses of diazepam or other benzodiazepines, even in gram quantities. At that dose, the propylene glycol used as an excipient can cause acidosis and toxic alcohol symptoms. Because the GABA chloride channel can be activated without fail by barbiturates, the use of intravenous phenobarbital has met with success in refractory cases (up to 15 mg/kg total to effect). My suggestion for patients who exceed 200 mg of diazepam and are still agitated but at increased risk for airway compromise is to intubate the patient using a short acting barbiturate as an induction agent and start the patient on a pentobarbital drip (100 mg per hour titrated to effect). Gradually decrease this after 24 hours and maintain the infusion to clinical effect.
The use of antihypertensive agents, phenothiazines, neuroleptics, and sedative hypnotics (other than benzodiazepines and barbiturates) is soundly discouraged. Clonidine and beta-adrenergic antagonists will block the peripheral manifestations of alcohol withdrawal and leave the patient to suffer the CNS manifestations of withdrawal, such as anxiety, agitation, and delirium.
Not all patients are so ill as to require intensive care and inpatient hospitalization. Patients with appropriate outpatient support may be treated with tapering doses of oral diazepam until they reach an addiction specialist.
Chronic alcohol use leads to tolerance and dependence, which can lead to withdrawal in a wide variety of clinical settings. Emergency physicians should be thorough in their evaluation of these patients, administer benzodiazepines or barbiturates in an aggressive manner with appropriate consideration for airway control, and initiate fluid, metabolic, and nutritional resuscitation of these patients. In the 21st century, we expect no one to die from appropriately managed alcohol withdrawal.
References
1. Victor M, Adams RD. The effect of alcohol on the nervous system. Res Publ Assoc Res Nerv Ment Dis 1953;32:526-573.
2. Thomas DW, Freedman DX. Treatment of alcohol withdrawal syndrome: Comparison of promazine and paraldehyde. JAMA 1964;188:316-318.
3. Booth BM, Blow FC. The kindling hypothesis: Further evidence from a U.S. national study of alcoholic men. Alcohol Alcoholism 1993;28:593-598.
4. Saitz R, et al. Individualized treatment for alcohol withdrawal. A randomized double-blind controlled trial. JAMA 1994;272:519-523.
5. Wasilewski D, et al. Assessment of diazepam loading dose therapy of delirium tremens. Alcohol 1996; 31:273-278.
Reasonable pharmacotherapy for ethanol withdrawal includes all of the following except:
a. diazepam.
b. phenobarbital for benzodiazepine failures.
c. clonidine drip for benzodiazepine failures.
d. pentobarbital drip for intubated patients failing benzodiazepines.
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