The title, thank you, the title's not meant as a threat. I'm starting the timer for 12 minutes. When it goes off, it'll start playing sprinkles, and I will sit down. My co-speakers negotiated me down to 47 slides. It's 12 minutes, so buckle up. I don't have anything to disclose. I would just say that in terms of my perspective, I've worked for the last 20 years in critical care, primarily at academic medical centers, and I should say that phenobarbital and the benzodiazepines are used off-label for alcohol withdrawal. I think we all know that. These are my affiliations. I work, as Linda said, at the University Medical Center, UC Davis. I teach for Turo University and for UCSF. I'm gonna start off with a little bit of story time, but it's gonna be quick, down to 11 minutes. First of all, we know that chronic alcohol exposure leads to downregulation of GABA receptors and upregulation of, or increased expression of NMDA, and that focus-protocolized system-triggered therapy is associated with improved outcomes for patients, especially with severe alcohol withdrawal. Phenobarbital, as you know, is not a new medication. The receptor targets and tools were identified some 70-plus years ago, but we're still exploring and discovering effective uses for both the benzodiazepines, barbiturates, and other adjunctive therapies. Phenobarbital is still considered a relatively dangerous or dirty medication by many bedside clinicians. So let's take a moment just to get to know barb. I would highlight that it actually targets both the GABA and NMDA receptor pathways. That's an advantage. Maybe a disadvantage is that its onset is delayed, compared especially to something like diazepam or lorazepam, and that it has a really long or sustained duration of action, which you could attribute to its half-life. Make sure you check the GABA receptor on your bingo card. And I just would acknowledge that this is a, this is not a classic key-lock relationship between these medications or chemicals and this neurotransmitter. It's actually a complex tetramer that undergoes conformational change in response to GABA or medications. Phenobarbital uniquely increases the frequency and duration of chloride channel opening. And in contrast to the benzodiazepines, no endogenous GABA is necessary for its activity. And GABA depletion is pretty common in alcohol use disorder. Terms of advantages, there are a number for phenobarbital, including the efficacy for refractory alcohol withdrawal syndrome, and a relatively wide therapeutic index, although I think that's controversial. Terms of disadvantages, there's no reversal agent, and overdose can lead to prolonged over-sedation. Let's take a quick glance at the evidence, down to eight and a half minutes. There's a lot of emerging evidence, as you can see. This is a more and more popular therapy, and I think it's popular both at the bedside and in research. At last count, there are about 150 papers available on PubMed and Embase. But as you might expect, that number rapidly melts in the harsh or cold light of a systematic review. So here are some of the reasonable questions that I sort of abstracted from, or would want to answer in treatment of alcohol withdrawal with phenobarbital, the basics being just who, should we focus this therapy, what agent, what dosing strategy, and how should we monitor patients to ensure safety? Perhaps it's worthwhile to start with the guidelines. That's always a good place to start, I think. These snuck out in May of 2022, when we were all distracted by a different kind of problem. I actually miss them, despite my obsession with this topic. Just highlighted some of the takeaway points or recommendations. Phenobarbital is reserved for alternative use by experienced providers for prophylaxis. Also is considered a preferred alternative for severe, complicated, and refractory alcohol withdrawal syndrome. What about the dosing strategies? So how should we use it? First question, I think, is about the loading dose. There are a number of studies exploring this question or the strategy. The most common dose used, which would be the big takeaway from this slide, perhaps is the 10 milligram per kilo. I'll take a minute to unpack the study by Rosenson and colleagues. I think these guys launched the conversation of phenobarbital with their paper in 2013. This RCT focused on the effect of a loading dose on initial level of care. So whether patients were admitted to a floor, ICU, or discharged home. As you can see, the strategy substantially reduced the need for ICU admission and escalation of care. Shaw and colleagues sought to validate these findings with an observational study in 2022. There are some key differences in the loading strategy, as you can see. They started with a 10 milligram per kilo front load, and then added sort of a sequential or incremental dose to that for patients that continue to require intervention. This phenobarbital front load was associated with a substantial decrease in the rate of continuous sedation, respiratory failure, and mechanical ventilation. So what do we know about the load so far? It appears to decrease the need for ICU admission, use of continuous infusion, and mechanical ventilation, and is associated with a relatively low rate of adverse drug events. How to load, I mentioned the 10 milligram per kilo, up to maybe a gram as an opening bid. Focus on that first 24 hours of alcohol withdrawal symptoms with close monitoring, as you can see. What about adjunctive therapy? I can't click fast enough. Four minutes. Okay, so we have, for adjunctive therapy, there are a range of methods and dosing strategies reported, so it's little wonder that there's mixed findings in this category. However, this approach appears to be effective when therapy is focused on early intervention in combination with escalating doses. Excuse me, of benzodiazepines. Phenobarbital appears to be a reasonable adjunctive therapy for refractory alcohol withdrawal syndrome, and protocolized symptom-triggered therapy in combination with benzodiazepines appears to decrease ICU length of stay and increase ventilator-free days. Happily, my conclusions align with the guideline recommendations. That's always a good thing. What about phenobarbital versus the benzodiazepines? So this is sort of the head-to-head comparison that we all love and want to see. The study by Malone and colleagues is the only comparative study that I could find, so let's take a moment to unpack it. This was an observational study comparing a phenobarbital load and taper to symptom-triggered therapy with benzodiazepines alone. The primary outcome was focused, or primary outcomes focused on respiratory complications. As you can see, the phenobarbital load and taper compared favorably to benzodiazepines, symptom-triggered therapy for those respiratory complications of pneumonia, increased oxygen requirements, and mechanical ventilation. In summary, phenobarbital monotherapy as it compares to phenobarbital, and again, this is one retrospective observational study, was associated with decreased respiratory complications, decreased ICU and hospital length of stay. Okay, I would be remiss if I didn't also mention some of that experienced bedside use, or experience from bedside use. Foremost, I think it's essential that you confirm a diagnosis of alcohol withdrawal, or at least triage patients based on their risk of experiencing alcohol withdrawal, and I listed some of the tools for doing that. If in doubt, you can always start with a test dose, and that's where the 65 to 130 milligrams, or one to two milligrams per kilogram can be very effective. And then triage mild versus severe alcohol withdrawal, or risk for severe alcohol withdrawal with tools like PAWS. And then built into any protocolized approach, you should have a strategy for monitoring and follow-up as well. It's also critical that the therapy focus on, or only be used to treat symptoms of alcohol withdrawal, and not other indications for sedation. I would suggest using phenobarbital early. Most of the studies that I found demonstrated that, or the demonstrated benefit with phenobarbital employed it very early in the course. That's also true of the benzodiazepines, I think, as you'll see from Dr. Lee's talk. And then this is the last point, increased benzodiazepine exposure, or phenobarbital tends to leverage the benzodiazepines the patient's already received. So if you have a patient that you're using phenobarbital sort of as a bailout for refractory alcohol withdrawal, you have to be really careful that you don't jump to that five to 10 milligram per kilo load, and I would suggest instead using a relatively small loading dose of one to two milligrams per kilo. And that's it, 58 seconds to spare. Thank you.

phenobarbital

alcohol withdrawal

benzodiazepines

ICU reduction

respiratory complications