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 cynthiaturner.com) |
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.
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.
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.