Thank you. So just a little background about myself. So my name is Dipali Dixit. As it was mentioned, I am a clinical associate professor at Rutgers University, and I also have a practice site at Robert Wood Johnson University Hospital in New Brunswick. I'm already having technical difficulties. All right, so I have nothing to disclose, except I will say that it's not fair that I have to cover three drugs in 10 minutes, and Jeremiah had a whole 10 minutes to cover one drug. But other than that, I have nothing to disclose. Okay, with that, we'll go ahead and get started. So for the next 10 minutes, I will be discussing the emerging role of ketamine, dexamethamidine, and gabapentin for adjunctive therapy in the management of severe alcohol withdrawal. So first up is ketamine. Very popular ketamine, as we know, is an NMDA receptor antagonist with very favorable pharmacokinetic properties, such as it has a quick onset of action, as well as a short duration. Ketamine was approved in 1970s as an anesthetic, and it has continued to have a lot of interest in various different conditions, and it has been explored in many different conditions as well. To name a few, it's been looked at for pain syndromes, depression, PTSD, as well as substance use disorders. Ketamine may serve as an adjunct to benzos in alcohol withdrawal syndrome due to its effect on the NMDA receptor, and that it targets the underlying pathophysiology of withdrawal where we see an upregulation of NMDA. Believe it or not, benefits of ketamine in DTs goes as far back as 1970s. The authors in this particular study, not that it was specifically in the ICU, they used high doses, and it was deemed to be pretty safe. More recently, one of the first studies that actually evaluated the adjunct role of ketamine was published by Wong and colleague in 2015, and the objective of this study was to determine the safety and efficacy of ketamine in the management of alcohol withdrawal. This was a retrospective cohort study in adult patients that were initiated on ketamine at a dose listed there for you for the management of active DTs. There were only a total of 23 patients. Their primary outcome was to look at the change in benzo requirements at 12 and 24 hours post-ketamine initiation. With the results, ketamine was not shown to be a statistically significant difference in terms of reducing benzo requirements, and this was before and after ketamine infusion at 12 as well as 24 hours, and like I said, it wasn't statistically significant. Of note, the mean time to initiating ketamine was 33 hours. The authors simply concluded that ketamine may and appears to have a role for this particular disorder. In terms of ADEs, they did have two patients that ended up on a ventilator, and that was really because of over sedation. Next, a study was published in 2018 by Piteson and colleagues, and their objective was to also determine if treatment guidelines using adjunctive ketamine improves outcomes in patients with DT. This was also a retrospective observational cohort study in non-intubated ICU patients with DT. Now, in comparison to the Wong paper, this had slightly higher number of patients where it was 63. Now, in terms of intervention, this was a pre- and post-implementation study. So the pre-guidelines for this institution was they managed symptom-triggered... They managed the patients with alcohol withdrawal with symptom-triggered benzodiazepine along with other adjuncts such as phenobarb, dexamethamidine, propofol, et cetera. Now, post-guideline, they included the baseline or the pre-guideline cocktail along with the addition of ketamine. Also note the infusion dose here was a little different. So it was 0.15 to 0.3 milligram per kilogram per hour. Their outcomes was to look at the ICU length of stay, benzo requirements, as well as the rate of intubation. Now, in contrast to the Wong paper, the authors found a significant reduction in the mean ICU length of stay. And this mean of the length of stay was actually reduced by close to three days, which I thought was pretty exciting to look at. Additionally, the mean dose of benzodiazepines were also reduced, and this was statistically significant. And lastly, the intubation rates were also deemed to be lower in the ketamine group. In terms of adverse drug reactions, they basically saw over-sedation in a few patients. Now, with all this popularity that was ongoing with ketamine and so much interest, there was another study published in 2018 by Shaw and colleagues with a similar objective. This was also a retrospective study, and the number of patients that were included were also fairly small. There were only 30 patients. The intervention here was slightly different, so the ketamine here was much higher dose. In fact, it was tenfold higher than the previous papers that I just mentioned. So the dose here was 0.75 milligram per kilogram per hour, and they also had the other adjuncts, which was basically a lorazepam infusion. The outcomes that they looked at was the time to symptom control, as well as lorazepam infusion reduction at 24 and 48 hours, as well as ICU length of stay. The bottom line for the study was they did indeed see a reduction in symptom within one hour, and they did see a benzo requirement reduction as well, and this was also statistically significant. The downside was six patients that were not intubated required intubation, and the thought was it was probably because of the fact that the dose was much higher, and maybe that's why they required intubation, because they were over-sedated. Additionally, two patients experienced hypertension as well, and the mean ICU length of stay was 8.2 days. So what did we learn from these three studies? And I'll give you my takeaway. So I think, based on these studies, the success of ketamine in patients with severe alcohol withdrawal is plausible, as well as, overall, I think it's safe. Having said that, despite these three small studies that we just looked at, I think the biggest concern was the potential confounder of the other agents that were used. So there were several other adjuncts that were used in the study, so it's really hard to tease out what was really the true efficacy of ketamine. I will say that the PIZON study really had meaningful patient-oriented outcomes, but I think at this time, we just don't know what is the optimal timing as well as the dosing strategy, so I think that remains to be unknown. And I think in the future, when we do design studies, I think it may be worthwhile looking at whether initiating ketamine a little bit earlier in the course of the treatment, if that's going to have an impact, especially before we give all these megadoses of benzos or other adjuncts that we're using. And I say this because ketamine was initiated fairly late. So in the Wong study, it was initiated at about 33 hours, and in the PIZON study, it was about 41 hours. I think while we know that well-designed studies are indeed needed, I think at this point in time, I think it may be considered as an adjunct for adjunct to GABA agonist for managing this disorder. All right, so next up is dexamethamidine. Very popular agent. We all love it. We use it for sedation purposes as well as other indications. So given that I only have 10 minutes, I'm not going to belabor all the different things that are listed here. I think despite the popularity of dexamethamidine, what's important to note is that it does not target the underlying pathophysiology of withdrawal. So it lacks GABA activity, and hence, it should not be used as a monotherapy agent. The other thing to consider is that prolonged use of dexamethamidine has also been reported to lead to withdrawal. So we need to be mindful of that. As well as it can indeed mask withdrawal symptoms as well. I think over the years, several case theories as well as retrospective and a few randomized control trials, although they were small in nature, were published. So I think what we really learned from these studies is that dex may be a viable agent to use as an adjunct. Dex was definitely associated with improved symptoms, as well as it did reduce the need for benzo requirements, but it was short term. So it was only the first 24 hours that it reduced the requirements, and it does reduce the mechanical ventilation. We love dexamethamidine, obviously, because of the fact that it doesn't depress the respiratory drive. So I think that's probably one of the reasons why it's so popular. Having said that, I think we need to be mindful of avoiding it in perhaps hemodynamically unstable patients. All right. Next up is gabapentin. Oh, I already got a three-minute warning. Okay, quickly. What about gabapentin? So I don't think the exact mechanism of how it works has been elucidated, but I think it's likely by increasing the GABA concentration through the direct GABA synthesis and the interaction with alpha 2 delta subunit of the calcium channels. And what that does is basically reduces the release of all the excitatory neurotransmitters. I think gabapentin appears to be a potentially attractive adjunct because it has sedative, anxiolytic, anticonvulsant properties, and it has been shown to improve alcohol withdrawal associated insomnia. The downside is that use thus far, as far as I'm aware of, has been reported in a variety of outpatient and inpatient detox center, as well as psych centers. And there's really not a whole lot of studies in the ICU setting. I just want to quickly review this one study that was published in 2019 by Levine and colleagues. And really, their objective was to evaluate high-impact dose of, I'm sorry, to evaluate the impact of high-dose gabapentin on benzo, requirements, alcohol withdrawal symptoms, as well as hospital length of stay. This was, again, a retrospective study. And the patients were included in this study if they were in the ED presenting with severe alcohol withdrawal, and they scored on the CEWA with a greater than or equal to 15. High-dose gabapentin was defined as greater than or equal to 1,800 milligrams per day, and it was added as an adjunct in the first 48 hours versus the other group was just standard of care. Primary endpoint was to really just look at the lorazepam-equivalent amounts of benzo and secondary outcomes listed there for you. I'm sure I have, what, one more minute, right? Okay. All right. So in terms of endpoints, it was indeed shown to be efficacious. So the high-dose gabapentin patients did have a lower amount of benzos. The hospital length of stay was also statistically significant. Time from admission until transfer to a lower level of care was also statistically significant. And in terms of side effects, both groups were pretty equivalent. So there was not much of a difference. I think at this point, given the evidence that we have available, I don't think we can support the widespread use of gabapentin to manage alcohol withdrawal. And from what we know about all the data that we have, it appears to be the most effective when initiated within 24 to 48 hours at high doses. If we do consider using it, we should be mindful of the age, renal function, and that should help us guide the dosing. And again, we have to be, we always need to make sure that, you know, the patient is in two sedated where they can't take it orally because it's only available as an oral agent. So we all know currently we have no guidelines in terms of management as well as assessment for alcohol withdrawal syndrome in the ICU setting. But the good news is in 2021, the ATS published their research statement. And I think that is exciting. And I think it's encouraging that hopefully in the near future, we'll have more guidance in terms of how to manage these patients. So in conclusion, I think the current evidence supports the use of adjunct. We need to be careful. Having said that, I think a lot of research still needs to be done. We have a lot of unanswered questions such as, you know, which patient is it going to benefit the most? What is the exact dosing? When should we initiate this? And many other unknowns. With that, I thank you for your attention. Thank you.

ketamine

dexmedetomidine

gabapentin

alcohol withdrawal

adjunctive therapies