Ethanol withdrawal is a complex disease state. Two of the main players are GABA (an inhibitory neurotransmitter) and glutamate (an excitatory transmitter that can act on NMDA receptors). Simplistically, chronic ethanol use leads to a down-regulation of GABA receptors and an up-regulation in glutaminergic receptors, such as NMDA. When ethanol is abruptly discontinued, we are left with a largely excitatory state with less ability for GABA-mediated inhibition and more capacity for NMDA/glutamate-mediated excitation. While much of the treatment of severe ethanol withdrawal is focused on GABA, there are agents, such as phenobarbital and propofol, that can suppress the glutaminergic response. Ketamine seems like it should confer benefit, as well, due to its NMDA antagonist properties. Until recently there was only one clinical study using ketamine for severe ethanol withdrawal.1 Now there are three.2,3
In this post, we will review the body of evidence for ketamine in severe ethanol withdrawal and explain its potential application to clinical practice.
The First Ketamine Study in 2015
Annals of Pharmacotherapy journal 1
- Methodology: Retrospective study
- Study population: 23 adult patients administered ketamine specifically for ethanol withdrawal
- Mean time to initiation of ketamine from first treatment of ethanol withdrawal: 33.6 hrs
- Total duration of ketamine treatment: 55.8 hrs
- Median ketamine infusion rate: 0.20 mg/kg/hr
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Results:
- No change in sedation or alcohol withdrawal scores within 6 hours of ketamine initiation
- Less benzodiazepines: Median change in benzodiazepine requirements at 12 and 24 hrs post-ketamine initiation were -40.0 and -13.3 mg, respectively
- Complications: One documented adverse reaction of oversedation, requiring dose reduction
- Author conclusion: Ketamine appears to reduce benzodiazepine requirements and is well tolerated at low doses
The Second Ketamine Study in 2018
Critical Care Medicine journal 2
- Methodology: Retrospective observational cohort study where a guideline was instituted incorporating ketamine with benzodiazepines (or phenobarbital) for severe ethanol withdrawal
- Study population: 63 ICU patients with delirium tremens (DTs) diagnosed by a board-certified medical toxicologist (29 patients pre-guideline, 34 patients post-guideline)
- Median duration of ketamine treatment: 47 hrs
- Mean ketamine infusion rate: 0.19 mg/kg/hr (19 patients received a loading dose)
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Results: Ketamine associated with –
- Decreased ICU length of stay by 3 days (95% CI, -5.58 to -0.089)
- Decreased likelihood of intubation compared to pre-guideline (odds ratio, 0.14, p < 0.01)
- Less benzodiazepines: Mean dose (diazepam equivalent): 2,525 mg pre-guideline vs. 1,508 mg post-guideline (p = 0.02)
- More pronounced difference in the subgroup of 32 intubated patients: 3,016 mg vs. 833 mg (p = 0.01)
- Complications: One documented adverse reaction of oversedation, requiring dose reduction
The Third Ketamine Study in 2018
Journal of Medical Toxicology 3
- Methodology: Retrospective study
- Study population: 30 ICU patients with severe ethanol withdrawal receiving ketamine in addition to benzodiazepines and/or phenobarbital
- Mean time to initiation of ketamine from initiation of lorazepam infusion: 41.4 hrs
- Median duration of ketamine treatment: 54 hrs
- Mean initial ketamine infusion rate: 0.75 mg/kg/hr (average max daily infusion 1.6 mg/kg/hr)
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Results: Ketamine associated with –
- Less benzodiazepines: Lorazepam infusion decreased by 4 mg/hr in at 24 hr (p = 0.01) after ketamine infusion
- Initial symptom control within 1 hour of ketamine initiation in all 30 patients
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Complications:
- 2 patients experienced hypertension (0 had tachycardia) related to ketamine
- 6 patients intubated after ketamine initiation (2 for escalating symptoms despite ketamine)
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Thoughts:
- This study used much higher doses of ketamine compared to the other two. Even so, 6 patients ultimately were intubated after ketamine initiation (2 for worsening withdrawal).
- Is a reduction of lorazepam infusion by 4 mg/hr (from ~14 mg/hr to ~10 mg/hr) over 24 hours clinically significant?
- The authors report that initial symptom control was obtained within 1 hour of ketamine infusion initiation for all 30 patients. Yet, many remained on infusions (lorazepam, ketamine, or both) for up to 3 more days. Some institutions do not use benzodiazepine infusions and instead opt for symptom-triggered bolus therapy.
Application to Clinical Practice
- Ketamine has the potential to serve as a great partner to our GABA agents in the management of severe ethanol withdrawal. Unlike dexmedetomidine, which does not target the underlying pathophysiology (and has been extensively covered on the ALiEM blog), ketamine does attack part of the root cause. Therefore, a reduction in benzodiazepines may be an appropriate endpoint with ketamine (but not for dexmedetomidine).
- All 3 published studies were retrospective and not controlled. This needs to be taken into account when considering ketamine. However, the 2018 Pizon study reported on meaningful, patient-oriented outcomes like ICU length of stay and intubations. While well-designed trials are needed, ketamine seemed to be effective with few reported adverse effects in both studies.
- The infusion rate used in two studies was approximately 0.2 mg/kg/hr and seems to be a good place to start if considering ketamine for this indication. A bolus up to 0.3 mg/kg may be considered for some patients. The 2018 Shah study used a much higher infusion rate.
I am excited to see more ketamine literature coming out for severe ethanol withdrawal. The mechanism makes sense, the results thus far look promising, and this clinical entity can present a significant management challenge. More options in the armamentarium are always welcome. For now, ketamine may be considered as an adjunct to GABA agents in the management of severe ethanol withdrawal and DTs.
Teaching Point (and a plea from toxicologists): The term ‘DTs’ is often incorrectly used interchangeably with ‘ethanol withdrawal.’ While DTs is a severe manifestation of ethanol withdrawal, not all ethanol withdrawal is DTs (think ‘every square is a rectangle, but not every rectangle is a square’).
Further Reading
Handout from my 2018 American Academy of Emergency Medicine Scientific Assembly talk on Beyond Benzos for Severe Ethanol Withdrawal [PDF] and my general treatment algorithm
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