Wednesday, January 21, 2015

Hitting the bottle hard, beyond benzos for AWS.

Clinical Scenario:
It’s the age old story, chronic alcoholic evaluated for an unrelated issue, cleared from that issue only to now have developed alcohol withdrawal. The patient in question is a middle aged male with heavy alcohol use history who was transferred from another center for specialist evaluation. After being cleared by the consultant, he is now 24 hours from his last drink and looks decidedly not well. He is tremulous, tachycardic, anxious, and vomiting. You recognize his alcohol withdrawal, but despite treatment, he rapidly worsens requiring very high doses of benzodiazepines and an ICU admission. What adjunct therapies are available for severe alcohol withdrawal?

Synapse in AWS (© 2015 Cynthia Turner
Alcohol abuse is an exceedingly common problem and alcohol-related ED visits are encountered daily across the country.  Annually, around 500,000 episodes of acute alcohol withdrawal require treatment. The symptoms typically begin to manifest within hours to days after cessation of alcohol and typically peak at 2 – 3 days.  The clinical course of alcohol withdrawal varies widely among patients.  Chronic alcohol use leads to down-regulation of GABA receptors and up-regulation of NMDA glutamate receptors. Additionally, GABA receptor expression is suppressed. In the active drinker, this allows patients to maintain a normal level of consciousness despite blood alcohol levels that would incapacitate a nondrinker. Withdrawal is therefore, associated with a decrease in GABAergic activity and an increase in glutaminergic activity. The increase in excitatory activity and loss of inhibitory activity results in the symptom complex of alcohol withdrawal. Symptoms include autonomic hyperactivity, tremor, insomnia, nausea/vomiting, hallucinations (commonly visual or tactile in addition to auditory), psychomotor agitation, anxiety, generalized tonic-clonic seizures. Benzodiazepines are the standard of care for alcohol withdrawal. Adjunct therapies of old have targeted adrenergic symptoms, not so much the underlying disease. These include beta-blockers and calcium channel blockers. Other more targeted therapies like gabapentin are hindered by prolonged onset of action. Adjuncts that make a bit more sense pharmacologically and are gaining popularity include barbiturates, ketamine, and dexmedotomidine.  Let’s look at some of that data.

Literature Review:

Phenobarbital?! What is this the dark ages? Phenobarbital has a rapid onset and long duration of action, with a half-life of 80 – 120 hours. Barbiturates stimulate the GABA receptor and may augment the efficacy of benzodiazepines – so it makes sense.  A retrospective cohort study by J. Gold et al at Bellevue described success with an alcohol withdrawal treatment protocol that used phenobarbital as the primary adjunct. In this protocol, increasing bolus doses of benzodiazepines (in their case primarily diazepam) were given in a symptom-based manner. If symptoms were not controlled with these measures, phenobarbital was added to the mix. All of their patients were admitted to the ICU specifically for alcohol withdrawal. They found that their 24hour diazepam dose, maximum individual dose and use of phenobarbital increased after protocol initiation. With these increases, they also observed a reduction in the need for mechanical ventilation and non-significant trends towards improved ICU length of stay and nosocomial infections.

What about everyone’s favorite drug of the moment, ketamine? Well, it might be good for this too! (Is there anything it can’t do?) Ketamine is an NMDA antagonist. Remember that this is the other system that has been screwed up by chronic alcohol use. A pharm paper by Wong et al out of UPMC describes a retrospective review of patients treated in their ICU for alcohol withdrawal with ketamine. In their 23 cases, they found that after initiation of ketamine infusions, patients’ benzodiazepine requirement at 12 and 24 hours decreased. Sedation scores and alcohol withdrawal scores were stable despite the decrease in benzodiazepine administration. Their median infusion dose was 0.2mg/kg/hr and on average, was continued for just over 2 days. They do note that ketamine does increase heart rate and blood pressure, which can pose challenges in treatment titration.

Dexmedetomidine, a cousin to clonidine, has anesthetic, anxiolytic, analgesic and sympatholytic effects. A case series of 10 patients with severe alcohol withdrawal treated in the ICU with dexmedetomidine (J DeMuro et al) described improvements in vital signs but these improvements did not reach statistical significance. They noted no change in the rate of adverse events despite addition of dexmedetomidine to multiple other agents including bolus dose benzodiazepines, beta-blockers, antipyschotics and propofol. They also noted that dexmedetomidine allowed lower doses of other agents, thereby reducing the risk of respiratory depression with large doses of benzodiazepines, argue their authors. Additionally, they add to the literature that documents safe use of dexmedetomidine far past the FDA approved 24 hour window. The decreased need for benzodiazepines with dexmedetomidine use was echoed by S. Mueller et al. They performed a randomized, double-blind placebo controll trial comparing high dose dexmedetomidine, low dose dexmedetomidine, and placebo. They noted no difference in sedation scores despite greater reduction in benzodiazepine requirements in the dexemedetomidine group.

An important eye in the sky point to take away from a lot of this literature is don’t be stingy with the benzos. These folks have seriously mucked up their brain chemistry and may need an alarming amount of medication. Just taking the literature we’ve reviewed here, DeMuro describes benzodiazepine dosing in the 10 cases used in his series as 2mg lorazepam Q6hrs or 1mg midazolam Q4 hours and reports an average ICU LOS of 9.3 days. Compare that to the 24 hour totals in the Gold paper of over 500mg diazepam (around 50mg lorazepam) with their average ICU LOS of 3.21 days. Far from an apples to apples comparison, but a striking point.

Take home points:
So we end with another age old story. This time we answered the question we asked in the beginning only to find ourselves with more. Yes there are adjuncts to benzodiazepines that may improve clinically important outcomes like intubation, ICU length of stay, and complication rate. However, each of these has it’s own appeal and downsides, and there is no clear winner. So the next time you approach that patient with severe alcohol withdrawal, think back to some of this literature. Use strategies that have been shown to improve outcomes – symptom based and aggressive early benzodiazepine dosing. Beyond that, use of adjuncts looks like a good idea. Choosing a particular adjunct will likely be a multifactorial decision and include factors like availability, cost, and your own comfort with a particular agent. Plus, if your alcohol withdrawal patient is this sick, it might be time to call your friendly, neighborhood toxicologist.

Submitted by Sara Manning, PGY-3@EM_SaraM
Edited by Louis Jamtgaard, PGY-3 @Lgaard
Faculty reviewed by Evan Schwarz @TheSchwarziee 

DeMuro, JP et al, “Use of dexmedetomidine for the treatment of alcohol withdrawal syndrome in critically ill patients: a retrospective case series” 2012. Journal of Anesthesia. Vol. 26(4); pp. 601-605.
Gold, JA et al, “A strategy of escalating doses of benzodiazepines and phenobarbital administration reduces the need for mechanical ventilation in delirium tremens.” 2007. Critical Care Medicine. Vol. 35(3); pp. 724 – 730.
Goldfrank et al, Goldfranks Toxicologic Emergencies, 8ed. 2006. McGraw-Hill.
Mueller, SW et al, “A Randomized, Double-Blind, Placebo-Controlled Dose Range Study of Dexmedetomidine as Adjunctive Therapy for Alcohol Withdrawal.” 2014. Vol. 42; pp – 1131 – 1139.
Wong, A et al, “Evaluation of adjunctive ketamine to benzodiazepines for management of alcohol withdrawal syndrome.” 2015, Vol. 49(1)pp 14 – 19.

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