Alcohol Withdrawal Syndromes

Alcohol Withdrawal Syndromes

Should You Treat This Patient s Alcohol Withdrawal With Benzodiazepines?! Meta-analysis of RCTs of benzodiazepines for the treatment of alcohol withdrawal! 11 RCTs identified, most involving small samples of patients (n=1286) and different outcome measures! 3 RCTs found that benzodiazepines were superior to placebo (OR = 3.3)! 2 studies that compared different benzodiazepines to each other did not show differences in efficacy Holbrook A., et al. Meta-analysis of benzodiazepine use in the treatment of acute alcohol withdrawal.

Options For Benzodiazepines! Diazepam usually favored b/c of fast onset of action and longer half life! Oral dosing works just as quickly as IV dosing! Longer half life may be harmful, particularly in elderly or those with severe liver disease! In those cases a shorter acting benzodiazepine like lorazepam should be used

Is it better to give PRN dosing or a standing dose of benzodiazepines?! Randomized, double blind, placebo controlled trial of 2 benzodiazepine strategies (PRN vs. fixed dose)! Enrolled patients admitted to an alcohol treatment inpt program, whose last drink was < 72 hours ago! Exclusion criteria included patients with major cognitive, psychiatric or medical comorbidity! All patients evaluated using the Clinical Institute Withdrawal Assessment for Alcohol scale! Fixed schedule: Oxazepam 30 mg q6hours for 1 day, then 15 mg q6 hours for 2 days. Medication could also be given based on CIWA-Ar score! Symptom triggered schedule: Matching placebo q6 hours for 3 days. Medication given based on CIWA-Ar score! Medication withdrawn if pt. became somnolent

! Results! 117 enrolled and followed to completion: 19 of these patients had a history of severe alcohol withdrawal (seizures, hallucinations, delirium tremens)! Patients in the symptom triggered group were! Less likely to be treated with any benzodiazepine! Received lower total doses of oxazepam! Had slightly higher CIWA Ar scores, possibly indicating more anxiety and discomfort! Had a higher level of physical functioning! Only 1 pt had a seizure, and there were no other major adverse events in either group! Symptom triggered treatment of ETOH withdrawal has been shown to reduce the amount and duration of benzodiazepine treatment Daeppen J, et al. Symptom-triggered vs. fixed schedule doses of benzodiazepine for alcohol withdrawal. Arch Intern Med 2002; 162: 1117-21

Are there other pharmacologic options for treating alcohol withdrawal?! Clonidine Benzodiazepine shown to be more effective! Carbamazepine - Benzodiazepine shown to be more effective! Beta blockers Propranolol was more effective that placebo at lowering heart rate, blood pressure and tremor but was less effective than a benzodiazepine in reducing anxiety, insomnia and nausea Holbrook A., et al. Meta-analysis of benzodiazepine use in the treatment of acute alcohol withdrawal. CMAJ 1999; 649-55

Should you give this patient thiamine? Folate? MVI? Magnesium?! Acute Wernicke s Encephalopathy! Confusion! Ophthalmoplegia / nystagmus! Ataxia! Early treatment with thiamine is key in preventing irreversible brain damage! Korsakoff psychosis! Chronic condition! Severe short term loss of memory! irreversible

! Systematic Review of clinical trials of thiamine for the prevention of Wernicke-Korsakoff syndrome! 2 RCTs were identified, and one was excluded due to small sample size! RCT compared 5 different dosages of IM thiamine (5-200 mg/day) given fro 2 days to pts admitted to an alcohol detoxification unit who did not have the triad of acute Wernicke s encephalopathy! Primary outcome was their performance on memory testing on day 3, given by a psychiatrist blinded to treatment allocation

! 169 participants were enrolled, but 43 did not complete treatment and assessment, and 19 were excluded b/c of imbalances in baseline characteristics! Pts in the 200 mg/day group performed significantly better than those in the 5 mg/day group! There were no other differences when the other doses were compared with 5 mg/day! The authors did not report on the incidence of confusion, nystagmus, opthalmoplegia or ataxia in these patients Day E, et al. Thiamine for Wernicke-Korsakoff syndrome in people at risk from alcohol abuse. Cochrane Database System Rev 2004, Issue 1. Art. No.: CD004033

! Although chronic alcohol abusers are frequently malnourished, there is no evidence to support routinely giving MVI or folate. While some may point out that these interventions are inexpensive and unlikely to cause harm, do not that giving the traditional banana bag (IV thiamine, folate, and MVI) is costly. If the patient is able to take oral medications, and the meds are given purely for prevention they should be given PO instead of IV! Unless the patient is found to have hypomagnesemia, there is no role for routine magnesium administration

Once the patient s withdrawal symptoms are controlled, do you need to taper him off his benzodiazepines?! If the patient has been treated with diazepam, one may stop the treatment without taper, allowing to active metabolites to auto taper. For shorter acting benzodiazepines, a quick taper over 2-3 days would probably suffice, but there are no controlled studies

Did this patient have an alcohol withdrawal seizure?! Given the patient s history of chronic alcohol abuse, his previous history of seizures, and his normal neuro exam, it is likely that this patient did have an alcohol withdrawal seizure! Alcohol withdrawal seizures usually present 7-48 hours after cessation of alcohol intake. Reduction of alcohol intake can also provoke a seizure, so the patient s positive BAL is still consistent with having an alcohol withdrawal seizure! Not that pure alcohol withdrawal seizures can be present without accompanying symptoms of alcohol withdrawal, such as tremor or tachycardia

Should you treat with benzodiazepines? If so, what dose?! Randomized, double-blind controlled trial of 2 mg IV lorazepam vs. placebo in patients brought the the ER with a single alcohol related seizure! Inclusion criteria: chronic alcohol abuse, witnessed generalized seizure, reported use of alcohol within the previous 72 hours! Exclusion criteria: alternative cause for seizures, required continued treatment for moderate to severe alcohol withdrawal! Outcomes:! development of a second seizure within 6 hours of drug administration.! Rehospitalization for seizures within 48 hours of discharge, using EMS data base

! 186 patients randomized. Lorazepam associated with:! Decrease in recurrent seizure within 6 hours! NNT 6, ARR 21%! Decrease in hospitalization rate! NNT 8, ARR 13%! Decrease in recurrent seizure after discharge from ER! NNT 8, ARR 13% D Onofrio G, et al. Lorazepam for the prevention of recurrent seizures related to alcohol. NEJM 1999; 340:915-9

What about phenytoin?! Phenytoin has not been shown to be effective in pure alcohol withdrawal seizures. However, many patients with chronic alcohol abuse have secondary causes for seizures, such as previous head trauma or stroke, and phenytoin can be useful in those instances

Does this patient need to be admitted to the hospital? What is the minimal amount of time he should be observed?! About 60% of patients have multiple seizures, but the interval from the first to the last seizure is less than 6 hours in 85% of patients. Status epilepticus is very rare in pure alcohol withdrawal.! In general, patients with alcohol withdrawal seizures need to be observed for a minimum of 6 hours D Onofrio G, et al. Lorazepam for the prevention of recurrent seizures related to alcohol. NEJM 1999; 340:915-9

Do you need to prescribed him a benzodiazepine taper?! Usually patients do not need to be given a taper after treatment of alcohol withdrawal seizure(s). A brief 2-3 day taper is often used but not proven to be necessary

Should you treat this patient with benzodiazepines?! The CIWA-Ar is not effective in this patient. It is only validated in patients whose last drink was < 72 hours ago. In addition, patients must be able to answer the questionnaire coherently, which the patient clearly cannot do

! Retrospective review of a sampling of medical and surgical inpatients who received symptom-triggered therapy (STT) for alcohol withdrawal, using the CIWA-Ar! Use of STT deemed appropriate if:! Medical record documented recent heavy alcohol consumption and a history of alcohol dependence or abuse and! Patients had the ability to communicate meaningfully with nursing staff! Primary outcomes! Incidence of inappropriate STT use! Adverse events associated with STT

! Only 48% of patients met both STT inclusion criteria. Of those who didn t! 14% were unable to communicate! 55% had no recent alcohol history! 31% met neither criterion! Post-operative patients had a 70% incidence of inappropriate use of STT! Limitations! Study was not powered to see if inappropriate use of STT led to more adverse outcomes. However, the same hospital published 4 earlier case reports of patients who experienced adverse outcomes, including death related to appropriate use of the CIWA-Ar Hecksel K, et al. Inappropriate use of symptom-triggered therapy for alcohol withdrawal in the general hospital. Mayo Clin Proc 2008; 83: 274-9

At this point, would you treat with! Delirium Tremens benzodiazepines?! Usually present 3 days to up to a week after cessation of alcohol intake, and the patient may be completely asymptomatic up until that point.! Delirium (disorientation, inability to attend to questions or tasks, hallucinations)! Tremors! Autonomic hyperactivity (tachycardia, hypertension, fever, sweating)! There are no RCTs comparing benzodiazepines to placebo in DT. However, the mortality of DTs has dropped from 15% in the older literature to 1%

! Systematic review of pharmacologic treatments for alcohol withdrawal delirium (delirium tremens)! Results! No RCTs comparing sedative hypnotic agents with placebo! 5 RCTs comparing sedative hypnotic agents to neuroleptics! Sedative hypnotics used in these trials were highly variable, including benzodiazepines, chloral hydrate, paraldehyde and barbiturates! Neuroleptic treatment associated with a higher mortality! Number of deaths in the sedative hypnotic group too small to evaluate the relative efficacy of each of these drugs! Sedative hypnotics associated with shorter duration of delirium compared to neuroleptics! 1 controlled study of propranolol found a higher incidence of delirium Mayo-Smith M, et al. for the Working Group on the Management of Alcohol Withdrawal Delirium, Practice Guidelines Committee, American Society of Addiction Medicine. Management of alcohol withdrawal delirium: an evidence based practice guideline. Arch Intern Med 2004; 164: 1405-12

! What concerns do you have about giving high doses of benzodiazepines?! Respiratory depression! Narcotics and sedative-hypnotics can be deadly! Turn off morphine PCA! Give pain meds cautiously! What is the maximum daily dosage of benzodiazepine?! The maximum dose is the amount required to sedate the patient without making him unconscious. In some instances, the patient may require intubation to protect his airway.! In the past, the most common cause of death due to DTs was cardiovascular collapse and arrhythmias! Is a continuous infusion of IV midazolam appropriate option for this patient?! Although IV midazolam should theoretically provide good treatment for his DTs, it has never been studied in a prospective fashion.! It is also much more expensive

! What other supportive measures should be provided?! Check and replete electrolytes! IV fluids to replace his insensible losses from fever and diaphoresis! ICU or step down for telemetry! IV thiamine

Are neuroleptics a useful adjunct for treating this patient s delirium?! There are no RCTs comparing sedative-hypnotics to placebo in DTs! There ARE RCTs comparing them to neuroleptics.! Neuroleptics have an associated higher mortality, prolong QT interval, lower the seizure threshold, and predispose to arrhythmias Mayo-Smith M, et al. for the Working Group on the Management of Alcohol Withdrawal Delirium, Practice Guidelines Committee, American Society of Addiction Medicine. Management of alcohol withdrawal delirium: an evidence based practice guideline. Arch Intern Med 2004; 164: 1405-12

Should you give a beta blocker to control this patient s heart rate?! Although propranolol reduces heart rate, hypertension and tremor, it has not been shown to improve mortality, and it may worsen the delirium. It also masks the autonomic signs of DTs, leading to underdosing of benzodiazepines! Consider using only if: history of CAD, arrhythmias such as atrial fibrillation, chest pain, or ischemic EKG changes Mayo-Smith M, et al. for the Working Group on the Management of Alcohol Withdrawal Delirium, Practice Guidelines Committee, American Society of Addiction Medicine. Management of alcohol withdrawal delirium: an evidence based practice guideline. Arch Intern Med 2004; 164: 1405-12