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.
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