Arch Intern Med. The authors have no relevant financial interest in this article. Evidence suggests that appropriate care improves mortality, but systematic reviews are unavailable. Statistically significant differences among various benzodiazepines and barbiturates were not found. No deaths were reported in patients from trials using benzodiazepines or barbiturates.
Adequate doses should be used to maintain light somnolence for the duration of delirium. Coupled with comprehensive supportive medical care, this approach is highly effective in preventing morbidity and mortality. Withdrawal signs and symptoms are usually minor, but they can be considerable and even fatal.
Alcohol withdrawal delirium AWDcommonly known as delirium tremens or "DTs," is the most serious manifestation of alcohol withdrawal syndrome. Current diagnostic criteria for AWD include disturbance of consciousness, change in cognition or perceptual disturbance developing in a short period, and the emergence of symptoms during or shortly after withdrawal from heavy alcohol intake Table 1.
Alcohol withdrawal delirium usually lasts 48 to 72 hours, but there have been case reports 6 - 8 of much longer duration. Given the seriousness of Medicine da delirium tremens and the apparent value of appropriate treatment in preventing morbidity and mortality, the development of an evidence-based guideline would have widespread utility. The purpose of this guideline, therefore, is to assist physicians and other health care professionals in providing appropriate treatment for all patients with AWD.
This guideline does not address the management of uncomplicated alcohol withdrawal syndrome or the prevention of AWD as these topics are covered in a previously published guideline.
A working group was appointed that included individuals with training in internal medicine, family practice, medicine da delirium tremens, and pharmacology and individuals involved in primary care medicine, addiction medicine, and research on alcohol withdrawal.
The primary outcomes considered by medicine da delirium tremens working group included 1 mortality rate, 2 duration of delirium, 3 time required for control of agitation, 4 adequate control of delirium, 5 treatment complications, and 6 medicine da delirium tremens. Acquisition costs were determined by averaging wholesale prices listed in the Red Book. The options considered for managing AWD included pharmacologic and nonpharmacologic strategies.
Any pharmacologic agent that has been studied in the medicine da delirium tremens of AWD was considered. Nonpharmacologic strategies included the choice of the setting for treatment, evaluation, monitoring, and supportive and psychosocial care.
Articles were selected if they involved human subjects and included new clinical data on the management of AWD ranging from a single case report to a prospective medicine da delirium tremens trial.
References from the selected articles, including those from beforefrom review articles, and from textbooks were also examined and included when appropriate. Members of the working group, using a structured data collection form, abstracted all articles meeting the initial inclusion criteria.
Articles identified as prospective controlled trials with patients meeting explicit inclusion criteria, including the basic elements of the DSM-IV criteria for AWD, underwent further independent review by a second member, with abstraction of data for meta-analysis. Medicine da delirium tremens differences of interpretation were resolved by consensus. Meta-analysis was performed when possible using the logit method.
Recommendations based on the evidence were drafted and graded according to a published system Table 2. In such areas, the level of evidence supporting these considerations was identified.
In formulating recommendations, greater weight was given to studies with higher grades of evidence, as defined in Table 2. When no evidence from controlled studies was available, expert opinion was considered. Among outcomes, greatest value was given to patient safety, followed by patient comfort, and then cost. Given the seriousness of the outcomes involved, it was believed that there would be little medicine da delirium tremens no variation in patient preference for treatment and that patients would prefer improved medical outcomes decreased mortality, shorter duration of medicine da delirium tremens, etc.
The draft guideline was sent for review to first authors of articles from the past 10 years that met the inclusion criteria and to representatives of organizations of medical interest drawn from the list published by the American Medical Association for whom this guideline may have been of interest. The American Society of Addiction Medicine Board of Directors approved the final version in Octoberwith review and revision scheduled for Novemberunless new information warrants revision before then.
Forty-three articles were identified as having original data, including medicine da delirium tremens prospective controlled trials. In the following subsections, data are reviewed according to the specific intervention studied.
No controlled trials comparing sedative-hypnotic agents with placebo in treating AWD were identified. However, 5 controlled trials 13 - 17 compared sedative-hypnotic agents and neuroleptic drugs in reducing mortality with AWD Table 3.
Meta-analysis indicated that sedative-hypnotic use is more effective than neuroleptic use in reducing mortality from AWD, with a summary relative risk of mortality with neuroleptic treatment compared with sedative-hypnotic treatment of 6. The effectiveness of different sedative-hypnotic agents diazepam, chlordiazepoxide, pentobarbital, paraldehyde, and barbital in reducing mortality with AWD was evaluated in 5 controlled trials Table 3.
The small number of deaths in these trials, however, limits the power to detect differences in this outcome.
Table 4 summarizes the results of prospective trials evaluating different agents in reducing the duration of AWD. Three of 4 trials 131417 comparing sedative-hypnotic agents with neuroleptic agents demonstrated that the former are superior to the latter in reducing the duration of AWD.
In the fourth trial, 16 there was insufficient data in the original article to calculate P values. Differences among sedative-hypnotic agents in reducing duration of AWD were medicine da delirium tremens demonstrated. Only 2 studies were identified that considered the time required to control agitation. In a study 19 comparing rectal paraldehyde use with intravenous IV diazepam use, the time to achieve adequate sedation, defined as the patient being quiet but awake, was significantly shorter with diazepam 1.
General pharmacokinetic studies have shown that oral diazepam has slightly shorter times to onset and to peak action than other benzodiazepines. Peak action of IV benzodiazepines is 5 to 15 minutes. However, continuous infusion has not been directly compared with intermittent dosing in any study. In the study 19 comparing rectal paraldehyde use and IV diazepam administration, satisfactory control of agitation was achieved in all 17 patients in the diazepam arm but in only 12 of 17 in the paraldehyde arm.
In a large, multicenter Veterans Affairs study, 17 there were no significant differences in achieving adequate control of delirium, but the medicine da delirium tremens of failure was low. Two of 46 patients taking perphenazine and 1 of 41 taking pentobarbital were "unresponsive to treatment" with their assigned medication. Studies have demonstrated that the required dose of medication can vary substantially among patients and within the same patient over time. In one study, 19 the doses for initial calming ranged from 15 to mg of diazepam.
In one published case, 28 the patient required mg of midazolam in a day period. Although studies medicine da delirium tremens shown no difference in overall rates of achieving control of delirium among different sedative-hypnotic agents, case series describe patients whose agitation was refractory to even massive doses of benzodiazepines but then responded to pentobarbital 30 or IV infusions of propofol. Barbiturates and propofol act via a different set of receptors, and, thus, their addition could yield beneficial results.
Furthermore, propofol has additional effects on N -methyl- D -aspartate and glutamate receptors that also are believed to play a role in alcohol withdrawal symptoms. Thus, propofol may be able to modify withdrawal symptoms by a different pathway than benzodiazepines. In the study 19 comparing rectal paraldehyde use and IV diazepam use, 2 of 17 patients in the paraldehyde group developed respiratory arrest requiring resuscitation. In another study, 17 1 patient treated with pentobarbital developed lethargy progressing to coma.
In the remainder of the studies, significant complications related to treatment were not observed. Medicine da delirium tremens has also been demonstrated in patients undergoing alcohol withdrawal, but not in those with AWD, that shorter-acting agents have a higher incidence of rebound symptoms 32 and may be associated with the occurrence of withdrawal seizures if medicine da delirium tremens too rapidly.
Several case medicine da delirium tremens have reported on the use of other sedative-hypnotic agents in managing AWD, including chlormethiazole, 34 - 37 lorazepam, 3839 flunitrazepam, 40 pentobarbital, 41 propofol, 3142 - 45 and midazolam.
The shorter-acting agents—propofol, pentobarbital, lorazepam, and midazolam—were thought to be advantageous owing to ease of titration and lower risk of excess sedation. However, there are no controlled trials comparing short- and longer-acting agents in AWD. Costs can vary greatly depending on the selected drug and the route of administration.
Midazolam would need continuous infusion, with medicine da delirium tremens doses at 0. Some practitioners medicine da delirium tremens2946 have described the use of continuous infusion of short-acting benzodiazepines, such as lorazepam or midazolam.
Such infusions can require very large amounts of medication over several hours or days. No placebo-controlled trials of neuroleptic agents in AWD were identified. The trials reviewed earlier demonstrated medicine da delirium tremens neuroleptic drug therapy is inferior to sedative-hypnotic drug use in medicine da delirium tremens mortality and duration.
Nevertheless, neuroleptic agents, especially haloperidol, are commonly used with sedative-hypnotic drugs to calm patients with AWD. Chlorpromazine, promazine, and other low-potency typical antipsychotic agents have been reported 51 to have the greatest effect on lowering seizure threshold. Chlorpromazine and thioridazine are the most common offenders for causing hypotension, and thioridazine may also prolong the QTc interval, increasing risk for torsade de pointes and sudden death.
No studies were identified describing the use of newer "atypical" antipsychotic agents, such as risperidone, olanzapine, and quetiapine, for AWD.
These agents are at least as efficacious as typical antipsychotic agents for other indications and have a preferable adverse effect profile. Low serum magnesium levels have repeatedly been reported 56 - 59 in patients with AWD. It has been suggested that magnesium administration reduces neuromuscular activity.
However, its use has not been evaluated in controlled trials in AWD. Although there have been small case series medicine da delirium tremens administration of alcohol for the prevention and treatment of withdrawal symptoms, there are no controlled trials evaluating its use in the prevention or treatment of AWD.
Ethyl alcohol is known to have the potential for several adverse effects, including hepatic, gastrointestinal, hematologic, and neurologic toxic effects. Patients with alcohol dependence are often thiamine deficient, and it has been reported 5759 that patients with AWD have even more substantial deficiencies. Thiamine deficiency is associated with Wernicke encephalopathy and Wernicke-Korsakoff syndrome. Thiamine administration has a low risk of adverse effects and can prevent the development of these conditions.
In particular, thiamine should be given before administration of IV fluids containing glucose, as the IV administration of glucose may precipitate acute thiamine deficiency. Several articles describe the use of various other agents medicine da delirium tremens managing AWD, including carbamazepine, 61 dexamethasone, 62 physostigmine, 63 5-hydroxytrytophan, 64 and bromperidol. In addition, although studies of other agents medicine da delirium tremens agents, clonidine, etc in managing alcohol withdrawal without delirium have been published, no evidence regarding their effectiveness in AWD has been identified.
No controlled studies of nonpharmacologic interventions were identified in the literature search. However, the literature includes recommendations from clinical experts on general management of AWD. A comprehensive history, physical examination, and thorough diagnostic evaluation are always recommended in view of the known morbidity and mortality of AWD and the frequent occurrence of associated medical illnesses.
Lumbar punctures have been recommended in febrile patients when there are no contraindications. The initial therapeutic goal in patients with AWD is control of agitation, the symptom that should trigger use of the medication regimens described in this guideline. Rapid and adequate control of agitation reduces the incidence of clinically important adverse events.
Sedative-hypnotic drugs are recommended as the primary agents for managing AWD grade A recommendation. These drugs reduce mortality, reduce the duration of symptoms, and are associated with fewer complications compared with neuroleptic agents in controlled trials. Current evidence does not clearly indicate that a specific sedative-hypnotic agent is superior to others or that switching from one to another is helpful. Examples of commonly used regimens are shown in the Box.