For citation purposes: DeMuro JP. Alcohol withdrawal syndromes in the critically ill. OA Alcohol 2013 Feb 01;1(1):1.

Critical review

 
Biomedical

Alcohol withdrawal syndromes in the critically ill

JP DeMuro1,*
 

Authors affiliations

(1) Winthrop University Hospital, Department of Surgery, Division of Trauma & Critical Care, Mineola, New York

* Corresponding author Email: jdemuro@winthrop.org

Abstract

Alcohol abuse continues to be a global problem. Here the four stages and pathogenesis of alcohol withdrawal syndrome are reviewed. The pharmacotherapy of the patient includes benzodiazepines, propofol, barbituates, dexmedetomidine, beta-blockers and phenothiazines. The author’s pharmacological protocol for alcohol withdrawal syndrome is included.

Introduction

Alcohol abuse is a common problem globally, and it is estimated to result in 2.5 million deaths annually[1]. Of the drugs of abuse, alcohol is the most common[2], with an estimated 18.3 million individuals dependent on it in the United States[3]. Alcohol abuse has a prevalence of 22.4% in a hospitalised general medical population[4]. In one analysis, alcohol-related admissions accounted for 9% of admissions to a population of mixed medical intensive care unit (ICU) and surgical ICU patients; in addition these patients accounted for 13% of total ICU costs[5]. One population with a particularly high rate of alcohol abuse are trauma patients, with estimates of prevalence ranging from 31% to 70% across centres[6,7].

Alcohol-related complications in the ICU affect nearly every organ system (Table 1). Alcohol abuse in patients is associated with increased length of stay[8], outpatient pneumonia[9,10] and an almost three times higher incidence of healthcare-associated infections[11].

Table 1

Complications of chronic alcohol consumption

Diagnosis

The gold standard for the diagnosis of alcohol withdrawal syndrome (AWS) is the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition[12]. It requires that a patient’s alcohol usage is heavy and prolonged, there is a cessation in alcohol intake and also that there is no other general condition that better accounts for the diagnosis. There should also be a manifestation of symptoms with two or more of the following: autonomic hyperactivity, increase in hand tremors, insomnia, nausea or vomiting, transient hallucinations, psychomotor agitation, anxiety or grand mal seizures. Finally, the symptoms should cause significant distress and interfere with important areas of functioning.

AWS has four clinical stages: (1) autonomic hyperactivity, (2) hallucinations, (3) neuronal excitation and (4) delirium tremens (Table 2)[13]. Patients generally start the withdrawal process at 5 h, with hallucinations at 24 h, and delirium at 48 h; it is rare for this to persist for more than 120 h[14]. While some patients may linearly progress through these stages, others may progress more rapidly. The author has seen patients in the postoperative period immediately after general anaesthesia for surgery present in delirium tremens with no manifestation of progression through the lower stages.

Table 2

Stages of alcohol withdrawal[45]

Pathophysiology

AWS is the result of a disruption of the delicate neurochemical balance that is controlled via inhibitory and excitatory neurotransmitters. The principal inhibitory neurotransmitter is gamma aminobutyric acid (GABA), which exerts its effect on the GABA-A neuroreceptor[15]. A principal excitatory transmitter is glutamate, which affects the N-methyl-D-aspartate neuroreceptor. With chronic alcohol exposure, the brain has a tolerance to the effects of the alcohol due to down-regulation of the GABA-A receptor over time[16]. This down-regulation may occur by modification of the GABA-A receptor in the alpha 1 subunit to make the receptor less susceptible to the effects of alcohol exposure[17].

Pharmacological treatment

The severity of the symptoms of AWS should direct the appropriate pharmacotherapeutic interventions. The patient’s comorbidities, other active diagnoses as well as exposure to any other drug of abuse should also be factored into the development of their treatment plan.

Benzodiazepines

Benzodiazepines have historically been the mainstay pharmacologic intervention of AWS[18]; they are generally considered to be the ‘gold standard’ treatment[19]. It has been shown that sedative-hypnotic agents such as benzodiazepines, in comparison with other agents, reduce mortality and control the symptoms of AWS[20,21]. All benzodiazepines have the same mechanism of action on the GABA receptor. Several agents have been used for AWS including chlordiazepoxide, lorazepam, valium, oxazepam and midazolam. Lorazepam is suggested as the benzodiazepine of choice for AWS due to its intermediate half-life, which balances a smooth withdrawal, with the potential for delayed metabolism in those with impaired hepatic function such as geriatric or cirrhotic patients[22].

In less severe cases of AWS, benzodiazepine can be administered via the oral route. However, for alcohol withdrawal severe enough to require admission to the critical care setting, the parenteral route is chosen. In some cases, it can be intermittently given as a bolus, although some patients may require a continuous infusion of the medication. With a prolonged infusion of the sedative, mechanical ventilation is necessary, which prolongs the length of stay in the ICU, and has the known complication of ventilator-associated pneumonia (VAP) and prolonged coma even with cessation of benzodiazepine[23]. When the duration of benzodiazepine infusion in the critical care setting exceeds seven days, a benzodiazepine withdrawal syndrome has also been described[24].

Benzodiazepines were traditionally administered to AWS patients in a fixed dose regimen. There has now been over two decades of experience accumulated with the use of on demand or ‘symptom-triggered’ dosing of benzodiazepines for AWS treatment[25]. This method of symptom-triggered dosing relies on the Clinical Institute Withdrawal Assessment for Alcohol [CIWA-A or CIWA-Ar (revised)]. In studies, the symptom-triggered dosing method results in both a decrease in the amount of benzodiazepines administered and a shortened duration of withdrawal symptoms[26]. While the symptom-triggered approach has these advantages, there is quite limited experience of the use of this approach in critical care settings[27], and it has not shown the same benefit across all studies[28].

Benzodiazepine resistance

There are sporadic reports of AWS patients being benzodiazepine resistant and requiring extremely high doses of these agents for a prolonged time to control their symptoms[29,30,31,32]. While these patients can be managed using benzodiazepine as monotherapy, it can only be done at supratherapeutic doses, which have a propensity to accumulate, and then require a significantly prolonged wean. This often precipitates unnecessary neurologic workup, including brain imaging and prolonged mechanical ventilation. Clinicians often turn to additional agents to avoid supratherapeutic benzodiazepines and the predictable sequelae.

Intravenous ethanol, while still used in some centres, is not currently favoured by many clinicians and offers no advantages over benzodiazepine[33]. It is generally reserved for use in overdoses of methanol, isopropanol or ethylene glycol[34].

Barbiturates can be a reasonable agent in the setting of a severe AWS. Advantages include low cost and long half-life which can provide longer term saturation of the GABA receptors, resulting in less symptoms including agitation. A disadvantage of barbiturates is the lack of a reversal agent in case of an overdose. Phenobarbital has been used in emergency department settings as a sole agent for mild to moderate cases of alcohol withdrawal[35]. In ICUs, barbiturates often get added to benzodiazepine in resistant cases. In a study by Gold et al., with a protocol of escalating doses of phenobarbital and diazepam, there was a trend towards less days of mechanical ventilation, less nosocomial pneumonia and a reduced ICU length of stay[36].

Another agent used in case of benzodiazepine-resistant patients with AWS is propofol. It is an intravenous sedative commonly used in critical care settings for sedation via continuous infusion. Its mechanism of action is also on the GABA receptor. Propofol has the advantage of a shorter half-life and rapid wakeup when stopped; the disadvantage is propofol infusion syndrome, particularly with longer usage at higher doses. It is hypothesised that the propofol is synergistic with benzodiazepine, thereby avoiding the toxic effects of monotherapy with a high-dose benzodiazepine approach. There is limited experience to this approach[37,38], although the most resistant AWS do respond to this strategy in the author’s experience. The major drawback of propofol for AWS is that it requires mechanical ventilation, so its use should be reserved for the more severe end of the spectrum.

Adjunctive agents

The alpha-2-agonist, clonidine, has traditionally been used to blunt the sympathomimetic effects of AWS[39]. This has been done outside critical care settings. While intravenous clonidine is available in Europe, it is not currently available for use in the United States. This has resulted in intensivists to turn to dexmedetomidine, a drug derived from clonidine. Dexmedetomidine is not FDA-approved for AWS, but rather for procedural conscious sedation and sedation for mechanical ventilation <24 h. While there have been isolated case reports of dexmedetomidine being used for AWS with good results, retrospective data has recently been published[40,41,42]. Dexmedetomidine may be used as an adjunctive agent in conjunction with benzodiazepine for AWS, and it may shorten the ICU length of stay and avoid intubation. The maximum approved infusion dose of dexmedetomidine is 0.7 mcg/ kg/h, although some patients may benefit from higher doses (up to 1.4 mcg/kg/h). The patients who respond well to dexmedetomidine can be transitioned to a clonidine patch as their symptoms stabilise.

Beta-blockers

Beta-blockers have been used as an adjunctive agent in AWS. Given the sympathetic outflow associated with autonomic hyperactivity, betablockers are a direct antagonist. This medication can be administered either orally or intravenously, and it serves to normalise tachycardia and hypertension in non-agitated patients that are otherwise comfortable. In a randomised trial by Gottlieb, atenolol in patients with AWS served to make a more rapid resolution of their vital sign abnormalities and clinical signs such as tremor[43]. Betablockers serve an important role as part of a multimodal pharmacological plan, but they should never be used without a GABA agent.

Haloperidol

Haloperidol is a phenothiazine that is commonly prescribed in ICUs for acute agitation. It has the benefit of haemodynamic neutrality, and the possible complications of an elevation in the QTc interval and tardive dyskinesia. While haloperidol is an adjunctive agent in AWS setting, it is particularly useful for the symptoms related to delirium[44].

Conclusion

AWS continues to challenge clinicians in critical care settings. Keys to good outcomes in this area include early recognition of the disorder and rapid implementation of appropriate pharmacologic treatment. The range of symptoms represents a spectrum; the pharmacologic strategy needs to match the severity that the patient is experiencing. While some patients have a good therapeutic response to a single benzodiazepine agent, more severe cases may require a multimodality therapy. The current protocol used at our institution is presented in Table 3. With a stepwise protocol-driven plan, intubation and mechanical ventilation can be avoided except in the more severe cases, contributing to better outcomes in terms of length of stay and VAP.

Table 3

Critical care treatment of alcohol withdrawal syndrome

Abbreviations list

AWS, alcohol withdrawal syndrome; CIWA-A, Clinical Institute Withdrawal Assessment for Alcohol; GABA, gamma aminobutyric acid; ICU, intensive care unit; VAP, ventilator-associated pneumonia.

Authors contribution

All authors contributed to the conception, design, and preparation of the manuscript, as well as read and approved the final manuscript.

Competing interests

None declared.

Conflict of interests

None declared.

A.M.E

All authors abide by the Association for Medical Ethics (AME) ethical rules of disclosure.

References

  • 1. . Management of substance abuse: alcohol.. World Health Organization (WHO). Available from: http://www.who.int/substance_abuse/facts/alcohol/en/index.html#. accessed Dec 26, 2012.
  • 2. Lieber CS . Medical disorders of alcoholism.. New Engl J Med. 1995 Oct;333(16):1058-65.
  • 3. . Substance Abuse and Mental Health Services Administration. Results from the 2008 National Survey on Drug Use and Health: National Findings. Rockville MD: Office of Applied Studies 2009;NSDUH series H-36, HHS publication SMA 09-4434.
  • 4. Umbricht-Schneiter A, Santora P, Moore RD. Alcohol abuse: comparison of two methods for assessing its prevalence and associated morbidity in hospitalized patients.. Am J Med. 1991 Aug;91(2):110-8.
  • 5. Baldwin WA, Rosenfeld BA, Breslow MJ, Buchman TG, Deutschman CS, Moore RD. Substance abuse-related admissions to adult intensive.. Care Chest. 1993 Jan;103(1):21-25.
  • 6. Lukan JK, Reed DN, Looney SW, Spain DA, Blondell RD. Risk factors for delirium tremens in trauma patients.. J Trauma. 2002 Nov;53(5):901-6.
  • 7. De Wit M, Jones DG, Sessler CN, Zilberberg MD, Weaver MF. Alcohol-use disorders in the critically ill.. Chest. 2012 Oct;138(4):994-1003.
  • 8. Marik P, Mohedin B. Alcohol-related admissions to an inner city hospital intensive care unit.. Alcohol & Alcoholism. 1996 Jul;31(4):393-6.
  • 9. Fernandez-Sola J, Junque A, Estruch R, Monforte R, Torres A, Urbano-Marquez A. High alcohol intake as a risk and prognostic factor for community-acquired pneumonia.. Arch Intern Med. 1995 Aug;155(15):1649-54.
  • 10. De Roux A, Cavalcanti M, Marcos MA, Garcia E, Ewig S, Mensa J. Impact of alcohol abuse in the etiology and severity of community and severity of community-acquired pneumonia.. Chest. 2006 Oct;129(5):1219-25.
  • 11. Wit M, Goldberg S, Hussein E, Neifeld J. Health care-associated infections in surgical patients undergoing elective surgery: are alcohol use disorders a risk factor?.. J Am Coll Surg. 2012 Aug;215(2):229-36.
  • 12. First MB . Diagnostic and statistical manual-text revision (DSM-IV-TR, 2000).. Washington DC: American Psychiatric Association; 2000.
  • 13. Al-Sanouri I, Dikin M, Soubani AO. Critical care aspects of alcohol abuse.. South Med J. 2005 Mar;98(3):372-81.
  • 14. Foy A, Kay J, Taylor A. The course of alcohol withdrawal in a general hospital.. Q J Med. 1997 Apr;90(4):253-61.
  • 15. Bayard M, McIntyre J, Hill KR, Wood-side J. Alcohol withdrawal syndrome.. Am Fam Physician. 2004 Mar;69(6):1443-50.
  • 16. Hoffman PL, Tabakoff B. Alcohol dependence: a commentary on mechanisms.. Alcohol Alcohol. 1996 Jul;31(4):333-40.
  • 17. Littleton J . Neurochemical mechanisms underlying alcohol withdrawal.. Alcohol Health Res World. 1998;22(1):13-24.
  • 18. Fuller RK, Gordis E. Refining the treatment of alcohol withdrawal.. JAMA. 1994 Aug;272(7):557-8.
  • 19. Worner TM . Propranolol versus diazepam in the management of the acute alcohol withdrawal syndrome: doubleblind controlled trial.. Am J Drug Alcohol Abuse. 1994;20(1):115-24.
  • 20. Mayo-Smith MF, Beecher LH, Fischer TL, Gorelick DA, Guillaume JL, Hill A. Management of alcohol withdrawal delirium: an evidence-based practice guideline.. Arch Intern Med. 2004 Jul;164(13):1405-12.
  • 21. Mayo-Smith MF . Pharmacological management of alcohol withdrawal. A meta-analysis and evidence based guideline.. JAMA. 1997 Jul;278(2):144-51.
  • 22. Bird RD, Makela EH. Alcohol withdrawal: what is the benzodiazepine of choice?.. Ann Pharmacother. 1994 Jan;28(1):67-71.
  • 23. Guglielminotti J, Maury E, Alzieu M, Alzieu M, Landes B, DelhotalLandes B, Becquemont L, Becquemont L, Guidet B, Offenstadt G. Prolonged sedation requiring mechanical ventilation and continuous flumazenil infusion after routine doses of clorazepam for alcohol withdrawal syndrome.. Intensive Care Med. 1999 Dec;25(12):1435-6.
  • 24. Cammarano WB, Pittet JF, Weitz S, Schlobohm RM, Marks JD. Acute withdrawal syndrome related to the administration of analgesic and sedative medications in adult intensive care unit patients.. Critical Care Med. 1998 Apr;26(4):676-84.
  • 25. Daeppen JB, Gache P, Landry U, Sekera E, Schweizer V, Gloor S. Symptom-triggered vs fixed-schedule doses of benzodiazepine for alcohol withdrawal.. Arch Intern Med. 2002 May;162(10):1117-21.
  • 26. Saitz R, Mayo-Smith MF, Roberts MS, Redmond HA, Bernard DR, Calkins DR. Individualized treatment for alcohol withdrawal. A randomized double blind trial.. JAMA. 1994 Aug;272(7):519-23.
  • 27. Spies CD, Otter HE, Huske B, Sinha P, Neumann T, Rettig J. Alcohol withdrawal severity is decreased by symptom-orientated adjusted bolus therapy in the ICU.. Intensive Care Med. 2003 Dec;29(12):230-8.
  • 28. Maldonado JR, Nguyen LH, Schader EM, Brooks JO. Benzodiazepine loading versus symptom-triggered treatment of alcohol withdrawal: a prospective, randomized clinical trial.. Gen Hosp Psychiatry. 2012 Dec;34(6):611-7.
  • 29. Hayes PC, Faestel PM, Shimamoto PL, Holland C. Alcohol withdrawal requiring massive prolonged benzodiazepine infusion.. Mil Med. 2007 May;172(5):556-9.
  • 30. Kunkel EJ, Rodgers C, DeMaria PA, Holleran D, Zaimes J, Gray C. Use of high dose benzodiazepines in alcohol and sedative withdrawal delirium.. Gen Hosp Psychiatry. 1997 Jul;19(4):286-93.
  • 31. Wolf KM, Shaughnessy AF, Middleton DB. Prolonged delirium tremens requiring massive doses of medication.. J Am Board Fam Pract. 1993 Sep;6(5):502-4.
  • 32. Kahn DR, Barnhorst AV, Bourgeois JA. A case of alcohol withdrawal requiring 1,600 mg of lorazepam in 24 hours.. CNS Spectr. 2009 Jul;14(7):385-9.
  • 33. Weinberg JA, Magnotti LJ, Fischer PE, Edwards NM, Schroeppel T, Fabian TC. Comparison of intravenous ethanol versus diazepam for alcohol withdrawal prophylaxis in the trauma ICU: results of a randomized trial.. J Trauma. 2008 Jan;64(1):99-104.
  • 34. de Wit M, Jones DG, Sessler CN, Zilber-berg MD, Weaver MF. Alcohol-use disorders in the critically ill patient.. Chest. 2010 Oct;138(4):994-1003.
  • 35. Hendey GW, Dery RA, Barnes RL, Snowden B, Mentler P. A prospective, randomized, trial of phenobarbital versus benzodiazepines for acute alcohol withdrawal.. Am J Em Med. 2011 May;29(4):382-5.
  • 36. Gold JA, Rimal B, Nolan A, Nelson LS. A strategy of escalating doses of benzodiazepines and Phenobarbital administration reduces the need for mechanical ventilation in delirium tremens.. Crit Care Med. 2007 Mar;35(3):724-30.
  • 37. Subramanian K, Gowda RM, Jani K, Zewedie W, Ute R. Propofol combined with lorazepam for severe poly substance misuse and withdrawal states in intensive care: a case series and review.. Emerg Med J. 2004 Sep;21(5):632-4.
  • 38. McCowan C, Marik P. Refractory delirium tremens treated with propofol: a case series.. Crit Care Med. 2000 Jun;28(6):1781-4.
  • 39. Muzyk AJ, Fowler JA, Norwood DK, Chilipko A. Role of α2-agonists in the treatment of acute alcohol withdrawal.. Ann Pharmacother. 2011 May;45(5):649-57.
  • 40. DeMuro JP, Botros D, Wirkowski E, Hanna AF. Use of dexmedetomidine for the treatment of alcohol withdrawal syndrome in critically ill patients: A Retrospective Case Series.. J Anesth. 2012 Aug;26(4):601-5.
  • 41. 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 May;2(1):12.
  • 42. Tolonen J, Rossinen J, Alho H, Harjola VP. Dexmedetomidine in addition to benzodiazepine-based sedation in patients with alcohol withdrawal delirium.. Eur J Emerg Med. 2012 Dec 7;[Epub ahead of print].
  • 43. Gottlieb LD . The role of beta blockers in alcohol withdrawal syndrome.. Postgrad Med. 1988 Feb;Spec No:169-74.
  • 44. Lansford CD, Guerriero CH, Kocan MJ, Turley R, Groves MW, Bahl V. Improved outcomes in patients with head and neck cancer using a standardized care protocol for postoperative alcohol withdrawal.. Arch Otolaryngol Head Neck Surg. 2008 Aug;134(8):865-72.
  • 45. Sarff M, Gold JA. Alcohol withdrawal syndromes in the intensive care unit.. Crit Care Med. 2010 Sep;38(Suppl 9):S494-S501.
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Complications of chronic alcohol consumption

Systemic
  Shortened life span
  Immunosupression
  Increased risk of malignancy: gastric, oesophageal, pancreatic, breast
Cardiovascular
  Alcoholic cardiomyopathy
Gastrointestinal
  Hepatic cirrhosis
  Peptic ulcer disease
  Pancreatitis
Genital
  Male: erectile dysfunction, gynaecomastia
  Female: infertility, abnormal uterine bleeding
Haematologic
  Impaired iron metabolism
  Megaloblastic anaemia
  Bone marrow suppression
Musculoskeletal
  Osteoporosis
Neurological
  Intracranial haemorrhage
  Wernicke-Korsakoff syndrome
  Peripheral neuropathy
Renal
  Beer Drinker’s hyponatremia
  Hypophosphatemia
  Hypomagnesemia
  Hypocalcaemia
  Nephromegaly

Stages of alcohol withdrawal45

(1) Autonomic hyperactivity
Increased sympathetic outflow with an increase in circulating catecholamines with symptoms including diaphoresis, nausea, vomiting, anxiety, tremor and agitation.
(2) Hallucinations
Visual and tactile are common and auditory is unusual. The hallucination of ants crawling on skin is classically described.
(3) Neuronal excitation
Alcohol withdrawal seizures.
(4) Delirium tremens
Delirium that is in combination with autonomic hyperactivity and alcohol hallucinosis.

Critical care treatment of alcohol withdrawal syndrome

Lorazepam 2 mg intravenously every 6 h
Dexmedetomidine up to 1.4 mcg/kg/h intravenously titrated to RASS* = 0 (tolerate −1 to +1) (apply clonidine patch 0.1 to 0.2 mg/day before stopping infusion)
Intubate patient and mechanical ventilation
Lorazepam at 0.5 to 2 mg/h continuous intravenous infusion
Propofol continuous infusion
Phenobarbital in escalating intravenous bolus doses (65 mg, 130 mg, 260 mg)
Adjunctive agents:
Lopressor 2.5 mg to 5 mg every 6 h intravenously for hypertension or sinus tachycardia >120 beats/min.
Haloperidol 2.5 mg to 10 mg every 6 h intravenously, and as needed for control of agitation.

* RASS, Richmond Agitation–Sedation Scale

Keywords