You are working an evening shift during your first year as an Emergency Medicine resident. A new patient shows up on the board. You briefly check his information, and you learn that he is a 32-year-old male with history of alcohol abuse coming into the Emergency Department for anxiety and tremors.
Triage note says in bold: “last drink 50 hours ago.” The patient is tachycardic, hypertensive, and mildly tachypneic.
You go to see the patient and based on the information you got, you diagnose him with alcohol withdrawal syndrome complicated by withdrawal delirium (delirium tremens). Good! You have a clinical diagnosis, but what does this patient need for workup and management?
Pathophysiology
There are two different ethanol action in the central nervous system (CNS) that lead to symptoms of alcohol withdrawal. Overall, alcohol is a central nervous system depressant. It simultaneously increases inhibitory tone via modulation of GABA activity and decreases excitatory tone via modulation of excitatory amino acid activity. In a patient with alcohol abuse disorder, only a constant presence of alcohol keeps the necessary homeostasis. Sudden cessation unmasks the adaptive responses to chronic ethanol use, resulting in overactivity of the central nervous system.
Gamma-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain. Highly specific binding sites for ethanol are found on the GABA receptor complex. Chronic ethanol use induces GABA receptor insensitivity to GABA resulting in a need for a stronger inhibitory stimulus to maintain a constant inhibitory tone. As alcohol tolerance develops, the individual retains arousal at alcohol concentrations that would normally produce lethargy or even coma in people who do not have alcohol use disorder. Sudden cessation of alcohol intake or a reduction from chronically elevated concentrations results in decreased inhibitory tone due to the lack of inhibitory effects of ethanol.
Glutamate is one of the major excitatory amino acids. When glutamate binds to the N-methyl-D-aspartate (NMDA) receptor, calcium influx leads to neuronal excitation by binding to the glycine receptor on the NMDA complex. Ethanol inhibits glutamate-induced excitation. Adaption occurs by increasing the number of glutamate receptors in an attempt to maintain a normal state of arousal.
Differential Diagnosis
Alcohol withdrawal remains a clinical diagnosis. The severity of presentation can be assessed using a clinical assessment scale called Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) that can be found on MD Calc.
In some cases, several additional tests might be needed to rule out other conditions that mimic or coexist with alcohol withdrawal syndrome. This is especially true when the patient has altered mental status and fever. Conditions such as infection (e.g., meningitis), trauma (e.g., intracranial hemorrhage), metabolic abnormalities, drug overdose, hepatic failure, and gastrointestinal bleeding can mimic or coexist with alcohol withdrawal. Also, it is of marked importance to try to understand why the patient stopped consuming alcohol. If you establish that he wanted to get sober, that is great, you or the admitting team can help setting up rehab for him after the acute problems are controlled. However, you should get suspicious if there is not a clear cause for the abrupt cessation of alcohol intake since it could be an acute condition being masked by the withdrawal syndrome.
Initial workup might include:
Supportive Care
As important as proving control of the patient’s withdrawal symptoms is to provide high-quality supportive care, which includes:
Symptomatic Treatment
The basis for the treatment of alcohol withdrawal is CNS depressants, such as benzodiazepines, with a treatment goal of Richmond Agitation and Sedation Scale (RASS) -1 and HR < 110. No single drug benzodiazepine is superior to another. A common treatment strategy is to use a benzodiazepine of choice and give escalating doses until symptomatic control or until you reach criteria for refractory alcohol withdrawal.
Refractory Withdrawal Delirium
Some patients have refractory delirium tremens (DT) despite treatment with high-dose benzodiazepines. Refractory DT is not clearly defined. It may be present if symptoms of severe withdrawal are not controlled adequately after the IV administration of more than 50 mg of diazepam or 10 mg of lorazepam during the first hour of treatment, or 200 mg of diazepam or 40 mg of lorazepam during the initial three to four hours of treatment. In such cases, as with any dangerous toxicologic disorder, you should obtain assistance from a medical toxicologist or poison control center. In case you diagnose your patient with alcohol withdrawal refractory to benzodiazepine treatment, you should have a few other options in your treatment arsenal.
Phenobarbital
There are case reports of up to 2000 mg of Phenobarbital administered orally or intravenously on the first day in patients with alcohol withdrawal delirium. Consider giving phenobarbital 130 to 260 mg IV, repeated every 15 to 20 minutes, until symptoms are controlled. Also, you can consider administering Phenobarbital earlier in the disease course. A randomized trial of 102 patients presenting to the emergency department with acute alcohol withdrawal, those treated with lorazepam and a single dose of Phenobarbital had substantially lower ICU admission rates compared with those treated with lorazepam alone (8 versus 25 percent).
Dexmetomedine
Another adjunctive medication for alcohol withdrawal is dexmedetomidine, an α2-adrenergic agonist that is used to provoke a state in which the patient is sedated but arousable, with a decreased sympathetic tone. Doses up to 0.7 μg per kilogram per hour have been administered in patients who do not have a good response to benzodiazepines. Heart block is a contraindication to this drug since it can cause bradycardia. In case it is given, blood pressure and heart rate must be closely monitored.
Propofol and Intubation
In patients who do not have a response to high doses of benzodiazepines (especially patients who are intubated), propofol may be administered to reach symptomatic control.
Further Reading
- Schuckit, MA. “Recognition and Management of Withdrawal Delirium (Delirium Tremens)”, N Engl J Med 2014; 371:2109-2113
- Hoffman, RS and Weinhouse, GL. “Management of moderate and severe alcohol withdrawal syndromes”, UpToDate, Dec 18, 2018. Available at https://www.uptodate.com/contents/management-of-moderate-and-severe-alcohol-withdrawal-syndromes
- Weingart, S. “EMCrit Podcast 11 – Delirium Tremens”, EMCrit RACC, Sep 29, 2009. Available at https://emcrit.org/emcrit/delirium-tremens/
References
- Isbell H, Fraser HF, Wilker A, et al. An experimental study of the etiology of rum fits and delirium tremens. Q J Stud Alcohol 1955; 16:1.
- Mihic SJ, Ye Q, Wick MJ, et al. Sites of alcohol and volatile anaesthetic action on GABA(A) and glycine receptors. Nature 1997; 389:385.
- Morrow AL, Suzdak PD, Karanian JW, Paul SM. Chronic ethanol administration alters gamma-aminobutyric acid, pentobarbital and ethanol-mediated 36Cl- uptake in cerebral cortical synaptoneurosomes. J Pharmacol Exp Ther 1988; 246:158.
- Hoffman PL, Grant KA, Snell LD, et al. NMDA receptors: role in ethanol withdrawal seizures. Ann N Y Acad Sci 1992; 654:52.
- Hecksel KA, Bostwick JM, Jaeger TM, Cha SS. Inappropriate use of symptom-triggered therapy for alcohol withdrawal in the general hospital. Mayo Clin Proc 2008; 83:274.
- Hack JB, Hoffman RS. Thiamine before glucose to prevent Wernicke encephalopathy: examining the conventional wisdom. JAMA 1998; 279:583.
- Hoffman RS, Goldfrank LR. The poisoned patient with altered consciousness. Controversies in the use of a ‘coma cocktail’. JAMA 1995; 274:562.
- Hoffman RS, Goldfrank LR. Ethanol-associated metabolic disorders. Emerg Med Clin North Am 1989; 7:943.
- Mainerova B, Prasko J, Latalova K, et al. Alcohol withdrawal delirium — diagnosis, course and treatment. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2013;157:1-9
- Mayo-Smith MF, Beecher LH, Fischer TL, et al. Management of alcohol withdrawal delirium: an evidence-based practice guideline. Arch Intern Med 2004;164:1405-1412
- Amato L, Minozzi S, Vecchi S, Davoli M. Benzodiazepines for alcohol withdrawal. Cochrane Database Syst Rev2010;3:CD005063-CD005063
- Hjermø I, Anderson JE, Fink-Jensen A, Allerup P, Ulrichsen J. Phenobarbital versus diazepam for delirium tremens — a retrospective study. Dan Med Bull 2010;57:A4169-A4169
- DeCarolis DD, Rice KL, Ho L, Willenbring ML, Cassaro S. Symptom-driven lorazepam protocol for treatment of severe alcohol withdrawal delirium in the intensive care unit. Pharmacotherapy 2007;27:510-518
- DeBellis R, Smith BS, Choi S, Malloy M. Management of delirium tremens. J Intensive Care Med 2005;20:164-173
- Cagetti E, Liang J, Spigelman I, Olsen RW. Withdrawal from chronic intermittent ethanol treatment changes subunit composition, reduces synaptic function, and decreases behavioral responses to positive allosteric modulators of GABAA receptors. Mol Pharmacol 2003; 63:53.
- Nolop KB, Natow A. Unprecedented sedative requirements during delirium tremens. Crit Care Med 1985; 13:246.
- Hack JB, Hoffmann RS, Nelson LS. Resistant alcohol withdrawal: does an unexpectedly large sedative requirement identify these patients early? J Med Toxicol 2006; 2:55.
- Rosenson J, Clements C, Simon B, et al. Phenobarbital for acute alcohol withdrawal: a prospective randomized double-blind placebo-controlled study. J Emerg Med 2013; 44:592.
- Rayner SG, Weinert CR, Peng H, Jepsen S, Broccard AF. Dexmedetomidine as adjunct treatment for severe alcohol withdrawal in the ICU. Ann Intensive Care 2012;2:12-12
- Muzyk AJ, Fowler JA, Norwood DK, Chilipko A. Role of α2-agonists in the treatment of acute alcohol withdrawal. Ann Pharmacother 2011;45:649-657
- Thomson AD, Cook CCH, Touquet R, Henry JA. The Royal College of Physicians report on alcohol: guidelines for managing Wernicke’s encephalopathy in the accident and emergency department. Alcohol Alcohol 2002;37:513-521
- Koethe D, Juelicher A, Nolden BM, et al. Oxcarbazepine — efficacy and tolerability during treatment of alcohol withdrawal: a double-blind, randomized, placebo-controlled multicenter pilot study. Alcohol Clin Exp Res 2007;31:1188-1194
