Hello, my name is Dipali Dixit. I'm a clinical associate professor at the Ernest Marriott School of Pharmacy as well as a clinical specialist at Rebel Wood Johnson University Hospital in New Brunswick, New Jersey. I will be discussing updates in the management of alcohol withdrawal. Listed here are the learning objectives. We're going to start out by talking a little bit about the pathophysiology as well as the associated clinical complications with alcohol use disorder. We'll also be discussing and comparing objective scoring tools that are used to stratify patients with this disorder and certainly we'll be discussing pharmacotherapy for the management of this disorder as well. Let's start out with a little bit of background and its impact. So we know that in the United States the prevalence of alcohol use disorder in 2019 was estimated to be around 15 million. We are all aware of the fact that alcohol use disorder certainly is common in the acute care setting where up to 42% of the patients admitted to the hospital with this disorder and up to 30% of the patients can be admitted to the ICU as a result of this disorder. We certainly know that alcohol withdrawal associated complications are common as well. In fact 25% of hospitalized patients end up developing alcohol withdrawal syndrome and as a result a certain population can end up requiring intensive care level of care certainly for the management of severe withdrawal or worst-case scenario where they develop delirium tremens. The other complications associated with this disorder include increased risk of nosocomial infections such as pneumonia, UTI, etc. Certainly if these patients end up on a ventilator they may end up being on a ventilator longer and all of this is going to lead to an increase in hospital as well as ICU length of stay and certainly these patients are at risk for increased mortality and all of this also leads to higher cost. So let's talk a little bit about the pathophysiology. So we certainly know that there's an augmentation of the nervous system due to the ethanol exposure. So our current understanding is that when there is acute alcohol exposure alcohol acts by stimulating the inhibitory GABA receptor and inhibiting the excitatory NMDA receptor. The overall synergistic effect of these mechanism produces sedation, decreased cognition, and autonomic attenuation. Now during chronic alcohol exposure what we see is the alcohol leads to down regulation of the GABA and up regulation of the NMDA receptor that results in continued need for alcohol to maintain this new chemical equilibrium and avoid the withdrawal. Now if someone ends up deciding that they are going to give up alcohol in their sudden abstinence or abrupt cessation from alcohol this will result in an imbalance in the inhibitory GABA and an excitatory NMDA tone. So what we see here is a increase in the glutamate and a decrease in the GABA which is what results in the brain hyper excitability as well as the autonomic over activity. So now moving on to the clinical manifestation as well as the timeline associated with alcohol withdrawal. Before we get into the four different categories of manifestation I just want to make two points. One is that the manifestation can certainly vary in severity and secondly that not every patient that drinks experiences withdrawal. So with the sympathetic or the autonomic hyperactivity in terms of occurrence this can be universally present in patients and this is usually a result of increase in norepinephrine. This can actually be seen as early as six hours after the last injection of their drink and can be you know seen as long as two to five days. Symptoms can be mild or moderate where these patients can have anxiety, hypertension, tremor, tachycardia as well as insomnia and the moderate symptoms include things like diaphoresis, nausea, vomiting and psychomotor agitation. Let's talk about the alcohol hallucinosis that these patients experience. About 30% of the patients experience this and in terms of when this course can be initiated it can be as early as eight hours and up to 48 hours after cessation of their last alcohol drink. This can last up to six days and in terms of signs and symptoms predominantly it's auditory hallucination but certainly we can they can have visual as well as tactile hallucination. These patients actually have a clear sensorium and this is really the key distinction between this and the delirium tremens. So these patients are able to distinguish as to what they are hearing or seeing is not really real. So unlike the mild symptoms that we just talked about, withdrawal seizures certainly require IC level of care as well as management. This occurs in about 10% of the patients and the onset can be within 12 to 48 hours although keep in mind it can occur earlier within six to eight hours of cessation of alcohol and duration can be up to six days and the type of seizures that are commonly seen is the generalized tonic-clonic seizures. The most feared complication is progression to delirium tremens. The other thing I want to point out is that development of DT is certainly been associated with a 3.5 fold increase in the odds of death and for this reason too that these patients certainly require ICU level of care as well as management. Approximately 5% of patients will develop DTs which typically occurs around three to ten days after the last drink. Although you know generally speaking it will peak at five days and can occur in in about seven days. Although I do want to point out that there are some papers that have reported that DTs may be developed or delayed rather up to 12 days as well. In terms of signs and symptoms the hallmark withdrawal is delirium combined with autonomic hyperactivity and keep in mind this is severe in nature as well as alcohol hallucinosis. Physiologically this manifests as tachycardia, hypertension and fevers, hypothermia, tachypnea as well as various respiratory and cardiovascular related complications. This slide basically summarizes the various stages of alcohol that we just discussed previously. I just want to point out that in clinical practice these stages may certainly be less distinct and may have an overlap and again just keep in mind that the manifestations can certainly vary in severity as well. So the diagnosis of alcohol withdrawal is generally made based on assessment of patient's history as well as clinical symptoms. Having said that given the diversity of the withdrawal symptoms and the signs the differential diagnosis for alcohol withdrawal is extremely broad. So early in the process the differential can include things like myocardial infarction, pulmonary embolism, hyperthyroidism, various infections, intoxications etc as well as other things that are listed here for you. But the important thing here is that if there is a suspicion of that you know there should be a consideration of ruling these things out and you can do that by getting an ABG, doing various imaging, getting ammonia levels, getting a tox screen, looking at patient sources of pain etc. So the point here is that we should not just be anchoring on that this is alcohol withdrawal but certainly making sure that we ruled out other things as well. So we should be using alcohol withdrawal assessment tools to determine withdrawal severity as well as to guide symptom trigger therapy. So that's what we're going to be talking about in the next few slides. So the first tool I'm going to talk about is essentially a triage tool. It's referred to as the prediction of alcohol withdrawal severity scale. This is a validated tool to identify those at risk for severe alcohol withdrawal syndrome. It does have three different parts. So part A is where we are looking for the threshold criteria and we'll be asking these specific questions to the patient and each question if it's positive then it will score the patient with one point. Part B is based on the patient interview and part C is based on the clinical evidence. So essentially if a patient ends up having a score of four or more this is going to suggest that the patient is at high risk for moderate to severe complicated alcohol withdrawal. I also want to point out that this particular scale is both highly sensitive and specific especially when a score threshold of four is used. This slide basically goes over the various risk factors for severe alcohol withdrawal syndrome. Essentially anybody with a SIVA of greater than equal to 20, patients with various comorbid conditions, prior alcohol withdrawal syndrome as well as alcohol dependence, prior alcohol related seizures as well as prior DTs. So another scale that can assess severity of alcohol withdrawal is the revised SIVA. Indeed it is very popular and is used frequently by many institutions to guide treatment. This scoring tool actually integrates an assessment of 10 discrete components upon patient interview to reach a maximum composite score of 67. I do want to quickly point out that patients that score between 8 to 15 are considered to be in mild withdrawal whereas 15 to 20 is considered moderate withdrawal and anything greater than 20 for a SIVA score is considered severe withdrawal. Although it's a popular tool there are certainly inherent limitations associated with this tool. So first and foremost is that it requires patient to be able to communicate and be cooperative so if the patient has a change in mental status and they're not able to communicate then really we can't use this particular assessment tool. The assessments and the parameters are subjective. There is no inclusion of vital signs. It can be labor-intensive for our nursing colleagues. It can take about 5 to 10 minutes to administer and this does require serial assessments. So as a result of these limitations the clinical validity of this tool may be unreliable despite its widespread application across institutions. So the next screening tool I'm going to talk about is the Minnesota detoxification scale also known as the MIND scale. So with the MIND assessment it includes actually fewer screening domains than the SIVA and is indeed less subjective. The other advantage of this tool over SIVA is in especially in the ICU setting is because it does not require patient participation. So this tool is becoming increasingly popular within the ICUs. So another withdrawal severity scoring tool is the SHOT scale. So it's kind of a simplified version of the SIVA. So it's simplified where it only includes four items and these are easy to remember. So it's things like sweating, hallucination, orientation, and tremor. It has been validated against SIVA and like I said it is definitely gaining popularity. The next scale I'm going to talk about is our sedation agitation scales that we use to titrate our sedatives. And again we use this very often in our ICU. So we've specifically used RAS. I'm sure others use SAS or the sedation agitation scale. And the advantage of this is that we don't need to be communicating with the patient directly. So if your patient is unresponsive on a ventilator so this is ideal scale to use. The other advantages we assess the symptoms of withdrawal and the impact of the therapy with this assessment tool as well. So in summary we can use either CAGE. I know we didn't talk too much about it but essentially we can use this to determine if someone has an alcohol use disorder. And then we can use the PAWS to determine the severity of alcohol withdrawal that the patient is going to experience i.e. like which direction they will go into in terms of severity. And then we have all these various assessment tools. So we can use SIVA and then we have SHOT and MINDS and all the other things that are listed here. And the ease of use with a SHOT which only includes four parameters versus SIVA which has ten parameters. I think the other assessment tools are certainly gaining a lot more popularity. In terms of the overall goals of care for these patients are really to keep these patients safe as they experience their symptoms of withdrawal. You want to certainly use the pharmacotherapy to alleviate the symptoms that we'll talk about in a few minutes. We want to prevent progression of symptoms and to treat their underlying comorbidities. The other thing is if they are overly sedated then we want to ensure there's adequate airway protection. Certainly have adequate fluid resuscitation as these as these patients come in. Volume depleted very often. We also want to make sure that the nutrition support is also implemented as these patients are severely malnourished. We want to address the electrolyte imbalances that they may present with as well as the therapy for preventing Wernicke encephalopathy with high-dose thiamine. Talking a little bit about the pharmacology, we previously talked about the dysregulation of GABA and the NMDA receptors. We have a couple of different pathways to target these receptors so we can do that together or even independently depending on the agent that we're using. On the GABA side we have benzodiazepine. By far they are the primary treatment of choice and certainly there's a growing role for barbiturates as well. On the NMDA side we have ketamine and barbiturates and there's been a lot of research done on these two agents as well and we know that both of them affect the GABA as well as the glutamate. All right so let's go ahead and start talking a little bit about the benzodiazepines. So as mentioned in the previous slide we all know that they are the cornerstone of therapy for managing these patients. Unfortunately there's been really no prospective comparison of benzodosing strategies particularly in our critically ill population. And then we are well aware of the dose dependent associations with side-effectings like somnolence, respiratory depression, delirium, etc. The other thing is that we are recognizing increasingly that there is a cohort of patients they are the benzo-resistant so severe alcohol withdrawals syndrome and this suggests that we may need to start considering alternative first-line agents or perhaps adding adjunctive therapies to our patients. I do want to mention that in practice we generally do not have one specific benzo agent that has been deemed to be superior but we do use longer-acting benzodiazepines such as chlorodized epoxide or diazepam and the rationale behind that is that it may offer a smoother withdrawal. There have been different dosing strategies that have been employed including things like symptom-triggered fixed dose versus front-loading and among these strategies symptom-triggered treatment is often most favored and essentially what we do is that instead of giving them a around-the-clock benzodiazepine what we do is that these patients they're on some sort of a withdrawal or a sedation scale and with scores above thresholds they receive as needed benzodiazepine therapy. Next I want to quickly talk about the landmark study that was published in 2007. This was conducted by Gold and colleagues and the objective of the study was to determine whether escalating doses of benzodiazepine when combined with phenobarb improves outcomes and this was a pre and a post study. So they actually used the rapid escalation of diazepam and the criteria for ICU admission was where patients received 200 milligram of diazepam in four hours or a single dose of diazepam which was 40 milligram. The primary endpoint was intubation as a result of alcohol withdrawal. I do want to point out that there was a similar study that was published in 2014 by Duby and colleagues and this was a very similar study the only key difference was that they had looked at a broader population that where anybody that entered the ICU with alcohol withdrawal. So here's the protocol from this study so essentially the protocol emphasized escalating doses of diazepam in combination with phenobarb so when patients remained agitated within the hour of getting diazepam the doses was escalating to a point where the patient was able to receive 150 milligram per dose of diazepam. Now if the agitation continued then escalating doses of IV phenobarbital was given to a maximum dose of 260 and the continued and the continued administering diazepam at maximal doses as well. In terms of their primary outcome, surprisingly the use of higher doses of diazepam in combo with phenobarb was actually associated with the two-fold reduction in the utilization of mechanical ventilation. In addition there was a trend towards decreased length of stay and nosocomial pneumonia and this is when you compare it with the pre-guideline group. Benzodiazepines are frequently used with the symptom triggered scales and really have become the mainstay. Keep in mind that they are not validated in the ICU meaning the symptom triggered scale such as CY is not validated in the ICU and the other point I want to make about benzodiazepine is to ensure that we have pharmacokinetic optimization and we'll talk about that in the next slide. So I want to quickly talk about the concept of context-sensitive halftime where we want to make sure that the pharmacokinetic of benzodiazepines are optimized. So the phenomena may be seen with actually either benzodiazepine or phenobarbital. So we all know that these are highly lipophilic agents with long half-lives. So what does that translate into? So essentially what we see is that there is a short duration of action when the drug is first given, meaning the first dose. And the short duration of action is essentially because it distributes out of the CNS into the plasma and then into the tissues. But over time, the duration of action actually increases with each dose as it slowly accumulates to steady state. So what are the implications of this? Well, we generally have to give a loading dose and then, you know, this is why when we're using these long-acting agents such as phenobarb or valium, we don't need to taper them. We can just turn it off or just stop the agent because of their long half-life. So this slide goes over the PKPD of the various agents that are used for alcohol withdrawal. So this table is broken down into onset of action, the amount of time it takes to peak, as well as the half-life and the metabolism. So again, as you can see here, diazepam has a really long half-life of about 20 to 70 hours. And then phenobarb, as mentioned previously, has a really long half-life as well. And again, we can use these agents to our advantage where we don't need to come up with the protocol to taper them off. We can just, you know, leave it as be and then they actually auto-taper over time. Now I just want to talk about the symptom-triggered approach. So the key about this particular approach is that it does indeed individualize treatment based on the patient's severity. It is recommended by the American Society of Addiction Medicine to use this approach for managing patients. Symptoms are assessed regularly by providers using a standardized scale, which often is the CWO. Some of the benefits, and again, this is when they've done various studies, some of the benefits of symptom-triggered approach is that indeed we use less medication and then there's a shorter duration of treatment. However, on the flip side, the way it's conducted may be dependent on staff training as well as availability. So there is a subset of patients that experience severe withdrawal, and these are the patients that don't respond despite escalating benzodiazepines. So the refractory withdrawal symptoms is defined as the requirement of greater than or equal to 40 milligrams of diazepam or equivalent benzodiazepine, and it's been given within an hour from managing the patient. These are the patients that are higher risk for ending up on a ventilator as well as nosocomial infections such as pneumonia, and this certainly translates into higher ICU length of stay. The mechanism behind this refractory withdrawal is that there's a profound downregulation of the number and function of GABA receptors, and there's an upregulation of the excitatory receptor, essentially the NMDA. So now that we've talked about the cornerstone of therapy of alcohol withdrawal using benzodiazepine as well as acknowledging that certainly there are limitations with using just benzodiazepine, especially in patients that are refractory, so what are the alternative agents that we can consider? And that's what we're going to be talking about in the upcoming slides. So the first agent I'm going to talk about is phenobarbital, and it is a super exciting time for phenobarbital, especially given that there's been several recent publications with positive outcomes when phenobarbital was used for managing alcohol withdrawal syndrome. So let's just step back and renew some of our memories about phenobarbital since we know it's an older drug. So we know that it is a longer-acting barbiturates with anti-epileptic sedative and hypnotic properties. In terms of mechanism of action, it basically augments benzodiazepine efficacy at the GABA receptor and inhibits the glutamate receptor. In terms of its pharmacokinetic, they're very favorable, so it works fairly quickly, and it has a long half-life, which is what we want for a smoother withdrawal. In terms of route of administration, phenobarb can be actually given orally, IV, or IM, so that's good. And the issue that we don't have a quite clear answer on is really what is the ideal route of administration? My thought is that the ideal route would really depend on the severity of the withdrawals. If someone is in severe withdrawal, IV route is really the way to go. But for whatever reason, if we can't get an access of an IV, then we have the alternative for using the IM route of administration. In terms of its side effect, the acute side effects are actually dose-related and how quickly it is administered. So CNS is the first thing that we always think about, which certainly can lead to over-sedation. Then there's always a concern about respiratory depression and in patients that receive the nystagmus or ataxia. Again, these are signs, early signs of toxicity, so we need to keep a close eye on that. And then hypertension can also be seen, but certainly can be limited if the infusion of the phenobarbital is limited to 50 to 60 milligrams per minute. In terms of safety concerns, we know that phenobarbital has a narrow therapeutic index. We're all well aware of the drug-drug interactions that we can see as this is a CYP3A4 inducer. And the question that I always think about is, can these side effects and not side effects, drug-drug interactions really happen with a single dose? I'm not quite sure of that, but again, we as pharmacists need to be very vigilant about monitoring for the drug-drug interactions. In terms of monitoring, the safe therapeutic index for phenobarbital, especially for the seizures, has been 15 to 30 and certainly potential toxicity can be seen if the level is greater than 40 milligrams per liter. Now, we certainly know that we don't use the levels for monitoring for efficacy purposes, but I do often obtain levels just to make sure that where we are with the number and how much more room do we have to give phenobarbital. So anytime we're approaching 40, then I would start backing off of phenobarbital. There have been several proposed dosing strategies for a phenobarbital when it's used for alcohol withdrawal syndrome. So the front loading, which it's like 10 milligrams per kilogram using the ideal body weight. Then there is a study showing using fixed dosing where you're giving the 60 milligram, 130, 260 milligram, and these can be administered every 20 to 30 minutes. I would caution you against using beyond a 25 milligrams per kilo of the ideal body weight in a 24-hour because then we run into the risk of toxicity. And then if someone has received so much phenobarbital, then maybe we don't have the right diagnosis and we need to start considering other things and maybe it's just something else other than withdrawal. The question that still remains is, do we just use this as monotherapy or adjunctive therapy for patients that have a severe withdrawal? And I think people are doing all different types of therapy or the way they're using it, it's quite different. I don't think we have a clear answer. At my institution, we have used it as monotherapy successfully. We have also used it adjunctively with benzodiazepine, but again, you want to be very cautious because then you run into the problem of maybe potential respiratory depression. So I think he is monitoring these patients closely, but certainly we know that we're having positive outcomes with using phenobarbital. And next we'll talk a little bit about some of the studies evaluating phenobarbital's role. So this was one of the first studies that evaluated the role of phenobarbital for alcohol withdrawal syndrome. So Rosenson and colleagues published a prospective randomized double-blind placebo-controlled study that included a total of 102 patients where there were 51 in each group. And really their objective was to evaluate whether a single IV phenobarbital dose, which was 10 mix per kilo, combined with a standardized lorazepam-based protocol decreases ICU admission. The authors concluded that the patients that received phenobarbital had fewer ICU admissions, and this was pretty significant. In addition, they saw that there was a decreased use of lorazepam as well, and really there were no side effects that were noted in this study. Since the study that I just discussed was published, several studies have been published which were pre-imposed in natures, and ultimately they showed there was a benefit in using phenobarbital for the most part. This is a study that was published literally last year in 2023, and they had a similar objective where they wanted to assess the efficacy and safety. The different thing that they did here was they actually used a fixed dose of phenobarbital where it was 260 followed by 130, and this was given every 15 to 30 minutes as needed. Ultimately, the protocol that used the rapidly escalating doses of phenobarbital actually showed that it was definitely an effective and safe alternative to benzodiazepine. So I would just say that there's definitely been a shift in the literature looking for an alternative to benzodiazepine, and I truly believe that phenobarbital in the right patient is definitely a reasonable alternative. Okay, so let's talk a little bit about dexamethamidine when we're all very familiar with dexamethamidine as it is frequently used in the ICU for sedation purposes. Dex as well as its counterpart, nalclonidine, are often commonly used for withdrawal symptoms. We're well aware of the side effects associated with it, which is bradycardia and hypotension. The key thing to remember is that dexamethamidine should not be used as monotherapy only because it has no GABA activity, and the key thing that we want to prevent in these patients is seizures. So we should be very mindful of that. The other thing is if a patient has been on dexamethamidine for several days, we should always keep in the back of our mind that there may be a dex withdrawal going on as well, so that's another thing to keep in mind. Over the years, several case series retrospective studies as well as small randomized clinical trials have been published using dexamethamidine and have shown some benefits. What we learned from What we learned from all these different studies is that dexamethamidine may be a useful adjunct to benzos and it has been associated with improved symptom management, also reduces the need for benzos in a short term, i.e. 24 hours, and has reduced mechanical ventilation. The great thing about this agent is that it does not suppress your respiratory drive, and the other thing to note is certainly we should be avoiding in our patients that are hemodynamically unstable. I'll quickly discuss the next agent, which is propofol, another commonly used sedative in the ICU setting. We're all familiar with how it works. It does have ideal mechanism of action along with reliable pharmacokinetics. The downside is that we just have very little data that has evaluated its role for refractory alcohol withdrawal. So I think the bottom line is that maybe it is a viable option as an adjunct to benzo in patients that are on a ventilator, but I think it lacks clear safety efficacy advantages over other treatment options that we have available. Ketamine is an NMDA receptor antagonist with favorable pharmacokinetic properties such as a very quick onset of action as well as a short duration. Ketamine was approved in 1970s as an anesthetic and since then there has been continued interest and has been explored for its role in various conditions such as the pain syndrome, depression, status epilepticus, as well as substance use disorder. Ketamine may serve as an adjunct to benzo due to its effect on the NMDA receptor and targeting the underlying pathophysiology of withdrawal where we see a up-regulation of the NMDA. Benefits of using ketamine in DTs was actually recognized as early as 1970s and the investigators in these studies used a higher doses and despite the higher doses it was deemed to be an agent with a safe profile. One of the first study in the ICU setting to evaluate the adjunct of ketamine was conducted by Wong and colleagues. The objective of this study was to determine safety and efficacy of ketamine in the management of alcohol withdrawal. This was a retrospective cohort study of adult patients that were initiated on ketamine for the management of active DTs. The total number of patients included in the study were 23. The primary outcome was changes in benzodiazepine requirements at 12 and 24 hour post ketamine initiation. The results basically showed that there was no statistically significant difference in benzo requirements before and after initiation of ketamine at 12 and 24 hours. The mean time to ketamine initiation was 33 and the authors simply concluded that ketamine appears to be effective where it can reduce benzo requirements and it was well tolerated. In 2018, Paizan and colleagues also published a study evaluating the role of adjunct ketamine. The objective of their study was to determine if treatment guideline using an adjunct of ketamine improves outcomes in patients with DTs. This was a retrospective observational cohort study in non-intubated ICU patients with DT and the total number of patients in this study was slightly higher where it was 63. In the intervention, this was a pre and a post ketamine guideline implementation study. So the pre-guideline management at this institution was a symptom triggered benzo plus or minus a phenobarb as well as other adjunctive agents. Post guideline, it was the inclusion of a pre-guideline plus a ketamine infusion and a dose of 0.15 to 0.3 milligram per kilogram per hour until DTs had resolved. The outcomes in this study that they looked at were ICU length of stay, benzo requirements as well as rate of intubation. So in contrast to the Wong 2015 paper, the outcomes in this study were pretty exciting. So the authors actually found that there was a reduction in mean ICU length of stay and a regression analysis showed that this reduction was translated to about 2.8 days. So I thought that was super exciting. Additionally, they found a mean reduction in benzodiazepine dose and again this was also statistically significant. And lastly, the intubation rates were less likely in the ketamine group. With so much interest in ketamine, there was another paper that was published in 2018 by Shah and colleagues with a similar objective. This was also a retrospective study that included severe alcohol withdrawal patients and there were a total of 30 patients that were included. The interventions, the ketamine dose here was actually higher than the previous papers. So here the dose was 0.75 milligram per kilogram per hour. The bottom line was the results showed that ketamine infusion was able to reduce all alcohol withdrawal symptoms within one hour. And they also showed a reduction in benzo requirements and this was statistically significant. There were six patients though that required mechanical ventilation after ketamine initiation and the thought was that maybe this was related to a higher dose of ketamine that was used. Additionally, two patients experienced hypertension as well. The mean time to ketamine infusion initiation was 41 hours. So after reviewing these three studies, what is the potential application to a clinical practice? I think the success of ketamine in this population is definitely plausible and it has been shown to be fairly safe. Having said that, despite the encouraging results, I think the biggest potential confounder in my mind was the fact that there were several other adjunct agents that were used. So it was really hard to tease out what was really the true efficacy of ketamine. I will say that there were meaningful patient-oriented outcomes in the Python study, but the optimal timing dosing strategy really remains unknown at this time. Perhaps in the future studies, we may want to explore if the efficacy of ketamine may be better if it's used earlier as an adjunct to benzo before these patients get a ton of benzodiazepine or even other adjuncts. And I say this because ketamine in the studies that we just evaluated was initiated actually fairly late. So in the Wong study, it was 33 hours. In the Shaw study, it was initiated at 41 hours. I think while we know that well-designed trials are definitely needed, I think ketamine can be considered as an adjunct and it's been shown to be pretty well tolerated as well. Next up is gabapentin. The exact mechanism of this agent has yet to be elucidated. We think that it mitigates alcohol withdrawal syndrome by increasing GABA concentration through direct GABA synthesis. I think gabapentin is a potentially attractive adjunct agent as it has sedative, anxiolytic, and anti-convulsive properties. It has been shown to improve alcohol-associated insomnia and I think generally speaking, it has been reported to be well tolerated. Now the use of gabapentin has been reported in a variety of inpatient settings such as detox as well as site-centered and outpatient, but we really have no data of its utility in the ICU settings. This study may be worthwhile just quickly reviewing. So this was published by Levine and colleagues in 2019 and the objective of this study was to evaluate the impact of high dose gabapentin on benzo requirements, alcohol withdrawal symptoms, as well as hospital medical stay. So this was a retrospective cohort study at a large academic center. They included a total of 100 patients and 50 in each group. The patients that were included in the study were ones that showed up in the ED with a diagnosis of severe withdrawal, and this was deemed to be measured by using a SIVA where it was greater than or equal to 15. There were two groups, so one group got high dose gabapentin, which was defined as greater than or equal to 1,800 milligrams per day in the first 48 hours versus those who did not receive gabapentin. I already mentioned what the primary outcome was, but again, they wanted to look at the mean lorazepam equivalent amounts of benzos that were administered during the hospitalization in the two groups. So the endpoints of the results basically showed that the high dose gabapentin group required significantly lower overall amounts of benzodiazepine, and this was statistically significant where the value was 0.03, and these patients had a shorter length of stay, which was also statistically significant where the p-value was 0.03. So the literature investigating the utility of gabapentin to manage alcohol withdrawal syndrome is actually currently somewhat limited, and I think at this point there's not enough evidence to support the widespread use of this agent for managing these patients. But if there is a point or the right patient to use this particular agent in, you want to make sure that they're getting the right dose, and this should be especially within the first 24 to 48 hours that they should get the high dose of gabapentin, and then you always want to consider the patient's renal function as well since the gabapentin is clear to the kidneys. So I think at this time there's just not enough evidence to support the widespread use of this agent to manage alcohol withdrawal in the ICU setting. Gabapentin appears to be most effective when used in high doses and initiated within the first 24 to 48 hours. The other considerations is that we need to take into account a patient's age as well as renal functions, and that should help us guide dosing recommendations. And certainly if your patient is way too sedated and they're not able to take this drug orally, then that's another barrier in using gabapentin. More recently there's been some interest in using baclofen for alcohol withdrawal syndrome. So if you think about the mechanism of action, it definitely has the GABA-B receptor agonist properties that could be beneficial for our alcohol withdrawal syndrome patients. So recently our French colleagues published a paper in 2021 that actually looked at whether baclofen can benefit our patients that are at risk for alcohol withdrawal syndrome. The investigator's objective was to really assess whether high-dose baclofen reduces agitation-related events compared with placebo in patients that are on a mechanical ventilator. The study design, this was a phase III double-blind placebo-controlled randomized trial that was done in 18 ICUs in France, and the total number of patients that were included in this study was 314 patients. The baclofen dose was in the range of 50 to 150 milligrams per day. The primary endpoint was the percent of patients with at least one agitation-related event over the treatment period. So the bottom line in the study was that the patients that did receive baclofen were significantly less likely to have an agitation event during the treatment period where it was 20% versus 30%. And this was statistically significant as well. The downside was that the baclofen group had a significantly longer duration of mechanical ventilation as well as a longer ICU length of stay. And I think we can probably say this was as a result of excessive sedation from the baclofen. I personally have not used baclofen for this particular indication in my ICU, but I guess there will be a lot more information and more studies done similar to this one to really determine the place in therapy for baclofen for the management of alcohol withdrawal. So I think it's been well recognized by various organizations that currently there are no guidelines to help us with the assessment and the management of alcohol withdrawal in the critically ill population. In response to this, in 2021, the American Thoracic Society published their research statement indicating that there is a much need for research in this particular area. So I think this is a very exciting time. And I think in the near future, we will have a lot more direction when we manage these patients. So I think in conclusion, early recognition and prevention is the key for managing these patients. I think generally speaking, benzos are still regarded as a gold standard, although current evidence has demonstrated that adjunctive agents can reduce the dose requirements of benzos with limited side effects. So I think there's definitely a role for adjunctive therapy, and it may be considered when managing severe alcohol withdrawal syndrome. I think the bottom line is additional research is needed, and we need to figure out which patient population is going to benefit the most. We need to also figure out the exact dosing and the time of initiation. So I think there's a lot more work to be done, and thank you for your attention.

alcohol withdrawal

management

pathophysiology

clinical complications

scoring tools

pharmacotherapy

GABA

NMDA receptor