Although there has been extensive research on pharmacological interventions aimed at ameliorating withdrawal, the studies are widely dispersed in the medical literature, involve few subjects, and are often of uncertain methodological quality. Recommendations from authoritative sources vary widely, with recommendations for drugs that have never been tested in clinical trials or for approaches that result in the administration of unnecessary medication [23,55]. Most studies have failed to use an international scale to quantify AWS [41,55]. In certain studies, even the differentiation among autonomic signs, hallucinations, and the delirious state is missing [23,55]. In many studies, there are too few patients to detect differences among different regimens [23,55].
Notwithstanding, the following evidence-based practice guidelines were developed for nonsurgical patients . Benzodiazepines are suitable drugs for alcohol withdrawal. The choice among different drugs should be guided by duration of action, rapidity of onset, and cost. Because withdrawal severity varies greatly and the amount of medication needed to control symptoms can also vary significantly, AWS cannot be adequately treated by a fixed standardized dose for all patients. Treatment should allow for a degree of individualization so that patients can receive large amounts of medication rapidly if needed [55,63]. Individual treatment should be based on withdrawal severity as measured by withdrawal scales, comorbid illness, and history of withdrawal seizures. Trials comparing different benzodiazepines have demonstrated that all seem similarly effective in reducing signs and symptoms. There is some evidence that longer-acting drugs such as diazepam may be more effective in preventing seizures . There are few data on the comparative efficacy of benzodiazepines in reducing delirium . Pharmacological and clinical experience suggests that longer-acting benzodiazepines can pose a risk of excess sedation in selected groups, including the elderly and those with marked liver disease . Longer-acting benzodiazepines, however, contribute to an overall smoother withdrawal course with less breakthrough or rebound symptoms . Certain benzodiazepines have a higher liability for abuse, and the cost of these drugs varies considerably . beta-adrenergic blockers, clonidine, and neuroleptic drugs may be used as adjunctive therapy but are not recommended as monotherapy . To prevent Wernicke's encephalopathy, thiamine may be administered to all patients with alcohol dependence at the initial examination .
These guidelines have limited applicability to surgical and ICU patients because, in these situations, withdrawal severity not only varies greatly, but is usually increased. In addition, the amount of medication needed to control symptoms may be increased in individual patients by up to 100-fold compared with psychiatric patients admitted for ethanol detoxification (Table 3 and Table 4) [39,55,64-67]. Of 672 centers performing therapy for AWS in surgical patients, 64% use drug combinations [56,67]. The reasons for the discrepancies in the dose and number of detoxifying drugs in surgical and ICU patients are poorly understood. Transmitter imbalances (e.g., in endorphin and noradrenergic systems) may be more pronounced because of trauma, pain, and stress . We investigated the three most popular current regimens for AWS (benzodiazepine/haloperidol, benzodiazepine/clonidine, and chlormethiazole/haloperidol) in ICU patients after trauma (Table 4) . The intercurrent complications, but not the duration of ICU treatment, differed among the groups. The incidence of pneumonia was increased in the chlormethiazole/haloperidol group (68% vs 40% in the flunitrazepam/clonidine group and 53% in the flunitrazepam/haloperidol group), whereas cardiac complications were significantly increased in the flunitrazepam/clonidine group (59% vs 17% in the flunitrazepam/haloperidol group and 18% in the chlormethiazole/haloperidol group) . The major side effects of chlormethiazole are bronchial hypersecretion and respiratory depression; therefore, many patients require mechanical ventilation . Clonidine and haloperidol may lead to QT-interval prolongation, which may induce life-threatening arrhythmias [39,56,65,70]. Clonidine may not be the drug of choice for patients with increased intracranial pressure because alpha2-agonists can decrease cerebral blood flow and increase cerebral vascular resistance [71,72]. This was also found in experimental settings after hypoxia and may lead to insufficient cerebral tissue oxygenation .
To prevent the recurrence of withdrawal symptoms and secondary withdrawal from drugs, it is essential to gradually reduce the therapy [69,73]. A more symptom-oriented approach may decrease the medication requirement and the duration of treatment. The benefits of a symptom-triggered therapy with chlordiazepoxide have been shown in in-patient detoxification , but this requires extensive staff training. When no such training is available, an acceptable alternative is the use of fixed-schedule therapy, with the provision of additional medication when symptoms are not controlled . Because haloperidol or clonidine decreases seizure thresholds, the administration of a benzodiazepine (alternatively chlormethiazole) should be considered for every patient [39,55,69]. A summary concentrating on the evaluation of treatment is given in the guidelines developed by the Plinius Major Society .
Although pharmacological inhibitors of the NMDA transmitter system or anti-sense oligonucleotide-induced reduction of nitric oxide (NO) synthase produce beneficial effects , NMDA antagonists (including phencyclidine) have reinforcing and synergistic effects with drugs of abuse , which suggests that chronic co-administration of NMDA receptor antagonists could make certain drugs more addictive. In addition, such compounds (e.g., ketamine, a noncompetitive antagonist of the NMDA receptor) may have deleterious effects due to a reduced seizure threshold . The only indication for ketamine would be obstructive lung disease in patients with AWS pretreated with benzodiazepines and with no signs of autonomic hyperactivity. As adjunctive therapy, the dose is 0.4-1.0 mg [center dot] kg-1 [center dot] h-1 IV
Drugs that act on GABA receptors or that modulate GABA function, such as benzodiazepines and gamma-hydroxybutyric acid [76-78], are also abused [73,79]. gamma-Hydroxybutyric acid is a potent growth hormone releaser used by bodybuilders and athletes. Propofol acts on a subunit of the GABA receptor ionophore complex . The outstanding characteristic of propofol is its rapid penetration into the central nervous system and its rapid elimination kinetics . It can be used as an additive to reduce AWS symptoms overnight and leave the patient more alert during daytime. It can also be useful in refractory delirium tremens .
Ethanol consumption alters neuroendocrine and immune functions in both adults and the fetus. In animal studies, abnormal hypothalamic-pituitary-adrenal axis functions have been linked to the development of inflammation and infection . Surgery or trauma adds to the ethanol-induced immune suppression , possibly by down-regulating T-cell-mediated responses, delayed type hypersensitivity, interleukin (IL)-2 expression, initial tumor necrosis factor (TNF) and interferon production, and cytolytic activity [82-84]. We found significantly decreased levels of the proinflammatory cytokines TNF-alpha, IL-1, IL-6, and IL-8 in septic shock patients with a history of chronic alcohol use compared with those in nonalcoholics . More extensive research concerning the actions of alcohol on the neuroendocrine-immune axis should lead to the development of therapies aimed at alleviating aberrant immune system functions in these patients .
In the literature on AWS, there is repeated emphasis on performing a thorough preanesthesia assessment in patients with suspected chronic alcohol use. Because these patients are difficult to diagnose and to treat in surgical settings if complications arise, a multimodal approach is highly recommended . Ideally, AWS should be prevented by adequate prophylaxis. If AWS develops after surgery or trauma, immediate therapy is required. The symptoms of AWS can be controlled using the combination of a benzodiazepine (in Europe, also chlormethiazole) with haloperidol or clonidine. The drug regimens must be individualized and symptom-oriented to treat hallucinations and autonomic signs. Dosages are generally larger than those in detoxification units. Other approaches to modulate the neuroendocrine-immune axis in patients with an increased risk of postoperative infectious complications look promising but await controlled trials.
We are most grateful to Professor Christoph Stein for his critical review of this manuscript.
1. Lieber CS. Medical disorders of alcoholism. N Engl J Med 1995;333:1058-65.
2. Williams GD, Stinson FS, Lane JD, et al. Apparent per capita alcohol consumption: national, state and regional trends, 1977-94. National Institute on Alcohol Abuse and Alcoholism, 1996:3-6.
3. Gomberg ESL. Women and alcohol: use and abuse. J Nerv Ment Dis 1993;181:211-9.
4. Firshein J. Alcohol-treatment programmes are comparable [letter]. Lancet 1997;349:40.
5. Andreason S, Allebeck P. Hospital admission for somatic careamon young men: the role of alcohol. Br J Addict 1990;85:935-41.
6. Moore RD, Bone LR, Geller G, et al. Prevalence, detection and treatment of alcoholism in hospitalized patients. JAMA 1989;261:403-7.
7. Smith-Warner SA, Spiegelman D, Yaun SS, et al. Alcohol and breast cancer in women: a pooled analysis of cohort studies. JAMA 1998;279:535-40.
8. Seitz HK, Simanowski UA. Ethanol and carcinogenesis of the alimentary tract. Alcohol Clin Exp Res 1986;10(Suppl):33S-40S.
9. Vokes EE, Weichselbaum RR, Lippman S, Ki Hong W. Head and neck cancer. N Engl J Med 1993;328:184-94.
10. Spies C, Spies KP, Zinke S, et al. Alcoholism and carcinoma change the intracellular pH and activate the platelet Na+/H+-exchange
in men. Alcohol Clin Exp Res 1997;21:1653-60.
11. Gentilello LM, Donovan DM, Dunn CW, Rivara FP. Alcohol interventions in trauma centers. JAMA 1995;274:1043-8.
12. Soderstrom CA, Dischinger PC, Smith CS, et al. Psychoactive substance dependence among trauma center patients. JAMA 1992;267:2756-9.
13. Herve C, Gaillard M, Roujas F, Huguenard P. Alcoholism in polytrauma. J Trauma 1986;26:1123-6.
14. Spies C, Neuner B, Neumann T, et al. Intercurrent complications in chronic alcoholics admitted to the intensive care unit following trauma. Intensive Care Med 1996;22:286-93.
15. Spies C, Nordmann A, Brummer G, et al. Intensive care unit stay is prolonged in chronic alcoholic men following tumor resection of the upper digestive tract. Acta Anaesthesiol Scand 1996;40:649-56.
16. Jensen NH, Dragsted L, Christensen JK, et al. Severity of illness and outcome in alcoholic patients in the intensive care unit. Intensive Care Med 1988;15:19-22.
17. Jurkovich G, Rivara FP, Gurney JG, et al. The effect of acute intoxication and chronic alcohol abuse on outcome from trauma. JAMA 1993;270:51-6.
18. Tonnesen H, Petersen K, Hojgaard L, et al. Postoperative morbidity among symptom-free alcohol misusers. Lancet 1992;340:334-40.
19. American Psychiatric Association. DSM-IV options book. Washington, DC: American Psychiatric Association, 1991.
20. World Health Organization. The ICD-10 classification of mental and behavioural disorders: clinical descriptions and diagnostic guidelines. Geneva: World Health Organization, 1992.
21. Hall W, Zador D. The alcohol withdrawal syndrome. Lancet 1997;349:1897-900.
22. Plinius Secundus C. Naturalis historia. Book XIV, chapter 22(28).
23. The Plinius Major Society. Guidelines on evaluation of treatment of alcohol dependence. Alcoholism 1994;30(Suppl):1-83.
24. Hoffman PL, Tabakoff B. Alcohol dependence: a commentary on mechanisms. Alcohol Alcohol 1996;31:333-40.
25. Dodd P. Neural mechanisms of adaptation in chronic ethanol exposure and alcoholism. Alcohol Clin Exp Res 1996;20:151A-6A.
26. Ortiz J, Fitzgerald LW, Charlton M, et al. Biochemical actions of chronic ethanol exposure in the mesolimbic dopamine system. Synapse 1995;21:289-98.
27. Nestler EJ, Aghajanian GK. Molecular and cellular basis of addition. Science 1997;278:58-63.
28. Klinker JF, Lichtenberg-Kraak B, Damm H, et al. Activation of pertussis toxin-sensitive G-proteins in membranes of SH-SY5Y human neuroblastoma cells and bovine transducin by ethanol. Neurosci Lett 1996;213:25-8.
29. Crews FT, Morrow AL, Criswell H, Breese G. Effects of ethanol on ion channels. Int Rev Neurobiol 1996;39:283-367.
30. Ryabinin AE, Criado JR, Henriksen SJ, et al. Differential sensitivity of c-Fos expression in hippocampus and other brain regions to moderate and low doses of ethanol. Mol Psychiatry 1997;2:32-43.
31. Boyadjieva N, Reddy BV, Sarkar DK. Forskolin delays the ethanol-induced desensitization of hypothalamic beta-endorphin neurons in primary cultures. Alcohol Clin Exp Res 1997;21:477-82.
32. Rommelspacher H, Schmidt LG, Helmchen H. Pathobiochemie und Pharmakotherapie des Alkoholentzugssyndroms. Nervenarzt 1991;62:649-57.
33. Pich EM, Lorang M, Yeganeh M, et al. Increase of extracellular corticotropin-releasing factor-like immunoreactivity levels in the amygdala of awake rats during restraint stress and ethanol withdrawal as measured by microdialysis. J Neurosci 1995;15:5439-47.
34. Boyadjieva N, Sarkar DK. Effects of chronic alcohol on beta-endorphin secretion from hypothalamic neurons in primary cultures: evidence for alcohol tolerance, withdrawal, and sensitization responses. Alcohol Clin Exp Res 1994;18:1497-501.
35. Marchesi C, Chiodera P, Ampollini P, et al. Beta-endorphin, adrenocorticotropic hormone and cortisol secretion in abstinent alcoholics. Psychiatry Res 1997;72:187-94.
36. Brown ME, Anton RF, Malcolm R, Ballenger JC. Alcohol detoxification and withdrawal seizures: clinical support for a kindling hypothesis. Biol Psychiatry 1988;23:507-14.
37. Becker HC, Diaz-Granados JL, Weathersby RT. Repeated ethanol withdrawal experience increases the severity and duration of subsequent withdrawal seizures in mice. Alcohol 1997;14:319-26.
38. Vescovi PP, Coiro V. Persistence of defective serotonergic and GABAergic controls of growth hormone secretion in long-term abstinent alcoholics. Alcohol Alcohol 1997;32:85-90.
39. Spies C, Rommelspacher H, Schaffartzik W. Chronic alcoholics: high risk patients in intensive care units. In: Vincent JL, ed. Yearbook of intensive care medicine. Berlin: Springer, 1995:777-88.
40. Foy A, Kay J. The incidence of alcohol-related problems and the risk of alcohol withdrawal in a general hospital population. Drug Alcohol Rev 1995;14:49-54.
41. 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;84:1353-7.
42. Moller HJ, Angermund, et al. Pravalenzraten von Alcoholismus an einem chirurgischen Allgemeinkrankenhaus: empirische Untersuchungen mit dem Munchener-Alkoholismus-Test. Suchtgefahren 1987;33:199-202.
43. Ewing JA. Detecting alcoholism: the CAGE Questionnaire. JAMA 1984;252:1905-7.
44. Buchsbaum DG, Buchanan RG, Centor RM, et al. Screening for alcohol abuse using CAGE scores and likelihood ratios. Ann Intern Med 1991;115:774-7.
45. Sillanaukee P. Laboratory markers of alcohol abuse. Alcohol Alcohol 1996;31:613-6.
46. Stibler H. Carbohydrate-deficient transferrin in serum: a new marker of harmful alcohol consumption reviewed. Clin Chem 1991;37:2029-37.
47. Spies C, Emadi A, Neumann T, et al. Relevance of carbohydrate-deficient transferrin as a predictor of alcoholism in intensive care patients following trauma. J Trauma 1995;39:742-8.
48. Spies CD, KiBner M, Pragst F, et al. Elevated carbohydrate deficient transferrin predicts prolonged intensive care unit stay in traumatized men. Alcohol Alcohol 1998;33:661-9.
49. Spies C, von Winterfeld A, Muller C, et al. Reliability of carbohydrate deficient transferrin to detect chronic alcohol misuse in carcinoma patients. Eur Addict Res 1996;2:156-62.
50. Spies C, Rommelspacher H, Schnapper C, et al. beta-carbolines in chronic alcoholics undergoing elective tumor resection. Alcohol Clin Exp Res 1995;19:969-76.
51. Spies C, Rommelspacher H, Winkler T, et al. beta-carbolines in chronic alcoholics following trauma. Addict Biol 1996;1:93-103.
52. Spies CD, Herpell J, Beck O, et al. The preoperative urinary ratio of 5-hydroxytryptophol to 5-hydroxyindol-3-acetic acid in surgical patients with chronic alcohol misuse. Alcohol 1999;17:19-27.
53. Ueshima Y, Tsutsumi M, Takase S, et al. Acetaminophen metabolism in patients with different cytochrome P-4502E1. Alcohol Clin Exp Res 1996;20:25A-8A.
54. Wandel C, Neff S, Keppler G, et al. The relationship between cytochrome P4502E1 activity and plasma fluoride levels after sevoflurane anesthesia in humans. Anesth Analg 1997;85:924-30.
55. Mayo-Smith MF for the American Society of Addiction Medicine Working Group on Pharmacological Management of Alcohol Withdrawal. Pharmacological management of alcohol withdrawal. JAMA 1997;278:144-51.
56. Imdahl H, Imdahl A. Prophylaxis and therapy of alcoholic delirium tremens in surgery: analysis of questionnaire inquiry. Aktuelle Chir 1992;27:139-43.
57. Spies C, Dubisz N, Funk W, et al. Prophylaxis of alcohol withdrawal syndrome in alcohol dependent patients admitted to the intensive care unit following tumour resection. Br J Anaesth 1995;75:734-9.
58. Hansbrough JF, Zapata-Sirvent RL, Carroll WJ, et al. Administration of intravenous alcohol for the prevention of withdrawal in alcoholic burn patients. Am J Surg 1984;148:266-9.
59. Glickman L, Herbsman H. Delirium tremens in surgical patients. Surgery 1968;64:882-90.
60. Gower WE, Kersten H. Prevention of alcohol withdrawal symptoms in surgical patients. Surg Gynecol Obst 1980;151:382-4.
61. Craft PP, Foil MB, Cunningham PRG, et al. Intravenous ethanol for alcohol detoxification in trauma patients. South Med J 1994;87:47-54.
62. Mendenhall CL, Theus SA, Roselle GA, et al. Biphasic in vivo immune function after low-versus high-dose alcohol consumption. Alcohol 1997;14:255-60.
63. Saitz R, Mayo-Smith MF, Roberts MS, et al. Individualized treatment for alcohol withdrawal: a randomized double-blind controlled trial. JAMA 1994;272:519-23.
64. Nolop KB, Natow A. Unprecedented sedative requirements during delirium tremens. Crit Care Med 1985;13:246-7.
65. Metzger E, Friedman R. Prolongation of the corrected QT and torsades de pointes cardiac arrhythmia associated with intravenous haloperidol in the medically ill. J Clin Psychopharmacol 1993;13:128-32.
66. Schinzel H, Weilemann LS, Swars H, et al. Experiences in treatment of acute alcohol withdrawal syndrome with clonidine in an intensive care unit. Intensivmedizin 1993;30:79-83.
67. Pycha R, Miller C, Barnas C, et al. Intravenous flunitrazepam in the treatment of alcohol withdrawal delirium. Alcohol Clin Exp Res 1993;17:753-7.
68. Linnoila M, Mefford I, Nutt D, Adinoff B. Alcohol withdrawal and noradrenergic function. Ann Intern Med 1987;107:875-89.
69. Spies C, Dubisz N, Neumann T, et al. Therapy of alcohol withdrawal syndrome in intensive care patients following trauma: results of a prospective, randomized trial. Crit Care Med 1996;24:414-22.
70. Rettmar K, Stierle U, Muhl E, et al. Sinus bradycardia, prolonged QT-interval, and ventricular defibrillation under haloperidol- and clonidine-therapy in alcohol withdrawal syndrome. Intensivmedizin 1992;29:178-83.
71. Lee H-W, Caldwell JE, Dodson B, et al. The effect of clonidine on cerebral blood flow velocity, carbon dioxide cerebral vasoreactivity, and response to increased arterial pressure in human volunteers. Anesthesiology 1997;87:553-8.
72. McPherson RW, Koehler RC, Kirsch JR, Traystman RJ. Intraventricular dexmedetomidine decreases cerebral blood flow during normoxia and hypoxia in dogs. Anesth Analg 1997;84:139-47.
73. Strang J. Intravenous and other novel abuses of benzodiazepines: the opening of Pandora's box? Br J Addict 1992;87:1373-5.
74. Carlezon WA Jr, Wise RA. Rewarding actions of phencyclidine and related drugs in nucleus accumbens shell and frontal cortex. J Neurosci 1996;16:3112-22.
75. Mirski MA, Muffelman B, Ulatowski JA, Hanley DF. Sedation for the critically ill neurologic patient. Crit Care Med 1995;23:2038-53.
76. Gallimberti L, Ferri M, Santo D, et al. Gamma-hydroxybutyric acid in the treatment of alcohol dependence: a double-blind study. Alcohol Clin Exp Res 1992;16:673-6.
77. Lenzenhuber E, Muller C, Rommelspacher H, Spies C. Gamma-hydroxybutyrate for therapy of alcohol withdrawal syndrome in intensive care patients. Anaesthesist. In press.
78. Spies C, Morciniec P, Lenzenhuber E, et al. beta-carbolines in alcohol dependent intensive care patients after elective tumour resection in prophylactics and therapy of alcohol withdrawal syndrome: comparison of two regimens including flunitrazepam and gamma-hydroxybutyrate. Addict Biol 1998;3:281-94.
79. Thomas G, Bonnner S, Gascoigne A. Coma induced by abuse of gamma-hydroxybutyrate (GBH or liquid ecstasy): a case report. BMJ 1997;314:35-6.
80. Coomes TR, Smith SW. Successful use of propofol in refractory delirium tremens. Ann Emerg Med 1997;30:825-8.
81. Sarkar D. Neuroendocrine-immune axis of alcoholics. Alcohol Clin Exp Res 1996;20:256A-9A.
82. Szabo G, Mandrekar P, Verma B, et al. Acute ethanol consumption synergizes with trauma to increase monocyte tumor necrosis factor a production late postinjury. J Clin Immunol 1994;14:340-52.
83. Hammer JH, Nielson HJ, Moesgaard F, Kehlet H. Duration of postoperative immunosuppression measured by repeated delayed hypersensitivity (DTH) skin tests. Eur Surg Res 1992;24:133-7.
84. Tonnesen H. The alcohol patient at surgery. Alcohol Alcohol. In press.
85. Spies CD, Handrock C, Sanft C, et al. Immune modulation differs between chronic alcoholics and non-alcoholics in the course of sepsis [abstract]. Crit Care Med 1997;25:A123.
86. Kehlet H. Multimodal approach to control postoperative pathophysiology and rehabilitation. Br J Anaesth 1997;78:606-17.