Alcohol withdrawal syndromes in the critically ill

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1 Page 1 of 5 Biomedical JP DeMuro 1 * Alcohol withdrawal syndromes in the critically ill Abstract Introduction 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, barbiturates, dexmedetomidine, betablockers and phenothiazines. The author s pharmacological protocol for alcohol withdrawal syndrome is included. Conclusion The pharmacological strategy needs to match the severity the patient is experiencing. 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 * Corresponding author jdemuro@winthrop.org 1 Winthrop University Hospital, Department of Surgery, Division of Trauma & Critical Care, Mineola, New York 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. The aim of this critical review is to discuss alcohol withdrawal syndromes in the critically ill. Discussion The author has referenced some of its own studies in this review. These referenced studies have been conducted in accordance with the Declaration of Helsinki (1964) and the protocols of these studies have been approved by the relevant ethics committees related to the institution in which they were performed. All human subjects, in these referenced studies, gave informed consent to participate in these studies. 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. 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

2 Page 2 of 5 Table 1. Complica ons of chronic alcohol consump on. Systemic Shortened life span Immunosupression Increased risk of malignancy: gastric, oesophageal, pancreatic, breast Cardiovascular Alcoholic cardiomyopathy Gastrointestinal Hepatic cirrhosis Peptic ulcer disease Pancreatitis Genita 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 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 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 Compe ng interests: none declared. Conflict of interests: none declared.

3 Page 3 of 5 Table 2. Stages of alcohol withdrawal 45. (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. 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 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. Beta-blockers 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

4 Page 4 of 5 Table 3. Cri cal 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. 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. 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. References 1. Management of substance abuse: alcohol. World Health Organization (WHO). Available from: int/substance_abuse/facts/alcohol/en/ index.html#, accessed Dec 26, Lieber CS. Medical disorders of alcoholism. New Engl J Med Oct;333(16): 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; NSDUH series H-36, HHS publication SMA 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 Aug;91(2): Baldwin WA, Rosenfeld BA, Breslow MJ, Buchman TG, Deutschman CS, Moore RD. Substance abuse-related admissions to adult intensive. Care Chest Jan;103(1): Lukan JK, Reed DN, Looney SW, Spain DA, Blondell RD. Risk factors for delirium tremens in trauma patients. J Trauma Nov;53(5): De Wit M, Jones DG, Sessler CN, Zilberberg MD, Weaver MF. Alcohol-use disorders in the critically ill. Chest Oct;138(4): Marik P, Mohedin B. Alcohol-related admissions to an inner city hospital intensive care unit. Alcohol & Alcoholism Jul;31(4): 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 Aug;155(15): De Roux A, Cavalcanti M, Marcos MA, Garcia E, Ewig S, Mensa J, et al. Impact of alcohol abuse in the etiology and severity of community and severity of community-acquired pneumonia. Chest Oct;129(5): De 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 Aug;215(2): First MB. Diagnostic and statistical manual-text revision (DSM-IV-TR, 2000). Washington DC: American Psychiatric Association; Al-Sanouri I, Dikin M, Soubani AO. Critical care aspects of alcohol abuse. South Med J Mar;98(3): Foy A, Kay J, Taylor A. The course of alcohol withdrawal in a general hospital. Q J Med Apr;90(4): Bayard M, McIntyre J, Hill KR,Woodside J. Alcohol withdrawal syndrome. Am Fam Physician Mar;69(6): Hoffman PL, Tabakoff B. Alcohol dependence: a commentary on mechanisms. Alcohol Alcohol Jul;31(4): Littleton J. Neurochemical mechanisms underlying alcohol withdrawal. Alcohol Health Res World. 1998;22 (1): Fuller RK, Gordis E. Refining the treatment of alcohol withdrawal. JAMA Aug;272(7): 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): Mayo-Smith MF, Beecher LH, Fischer TL, Gorelick DA, Guillaume JL, Hill A, et al. Management of alcohol withdrawal delirium: an evidence-based practice guideline. Arch Intern Med Jul;164(13): Mayo-Smith MF. Pharmacological management of alcohol withdrawal. A meta-analysis and evidence based guideline. JAMA Jul;278(2): Bird RD, Makela EH. Alcohol withdrawal: what is the benzodiazepine of choice? Ann Pharmacother Jan;28(1): Guglielminotti J, Maury E, Alzieu M,Delhotal Landes B, Becquemont L, Guidet B, et al. Prolonged sedation requiringmechanical ventilation and continuous flumazenil infusion after routine doses of clorazepam for alcohol withdrawal syndrome. Intensive Care Med Dec;25(12): 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 Apr;26(4): Daeppen JB, Gache P, Landry U, Sekera E, Schweizer V, Gloor S, et al. Symptom-triggered vs fixed-schedule Compe ng interests: none declared. Conflict of interests: none declared.

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