All right. Thank you for the introduction. My name is Jen. I'm one of the critical care pharmacists at UC Davis. And today I'm here to talk about benzodiazepines for severe alcohol withdrawal. This is the title I was provided. The title I've given this presentation myself is that benzos still relevant. So I have no financial disclosures here. Our objectives here are to describe the optimal use of benzodiazepines to mitigate the risk of complications and adverse effects. And I want this to be a little bit of a how-to session on how to incorporate evidence-based medicine and provide some practical tips in developing your own institution's alcohol withdrawal algorithm. Just a disclosure here, not a ton of evidence, as in the prior talks. It may not surprise you, but there's not a lot of groundbreaking new evidence in benzodiazepines for alcohol withdrawal. So I'll focus on the pragmatic side. Before we begin, I wanted to briefly remind us of the pathophysiology we've been talking about here today. We've probably all seen this before, hopefully more sophisticated than my attempt in paint. But this is most of us, hopefully, at homeostasis. We've got our inhibitory neurotransmitter GABA, excitatory neurotransmitter glutamate existing in harmony. In acute intoxication, we have the alcohol weighing down on the GABA side, potentiating the inhibitory effects. And with chronic use, what happens is upregulation of glutamate, downregulation of GABA receptors, which results in acute withdrawal, overexcitation, excess of glutamate. And so it's important to remember that when managing alcohol withdrawal, the backbone of this must, backbone of therapy needs to address this particular imbalance. Predictably, symptoms are what we'd expect from overexcitation. You see anxiety, tremors, agitation, seizures. And the worst possible outcome here is delirium tremens. Luckily, we have two to three days before the onset of delirium tremens. And so our goal in alcohol withdrawal therapy is to treat the patient effectively before we progress to delirium tremens. Based on the current body of evidence, the American Society of Addiction Medicine released these guidelines in 2020 that Dr. Duby referred to earlier. And here they reinforce the fact that benzodiazepines are first-line treatments. However, I know we all teach our learners that benzos are bad, benzos are associated with delirium. It's almost a bad word in some of our ICUs. So what I want to go into next is shift into if we need to use benzodiazepines, how do we choose a lesser of evils? We look at our available benzos in front of us, and we want an agent that is available in IV formulation. We want an agent that has a rapid time to peak, and we want an agent that has a longer half-life so that we don't then induce benzo withdrawal later on in the course. Given these, diazepam stands out for its rapid peak. It also has a context-sensitive half-time, which means that the clinical duration is dependent on the amount that's already in the system. So this quick peak is really important to ensure that you realize the full effect of the dose before you give the next dose and prevent dose stacking. A common concern I hear is, what about in our cirrhotic patients or patients who have liver damage? The traditional teaching is to avoid hepatically metabolized benzodiazepines in liver failure. And yes, while diazepam half-life has certainly increased in liver failure, we can avoid the risk of accumulation by adjusting dose on eventual advised patient response. The way I think of this in our pharmacy brain or my pharmacy brain is, it's like dosing vancomycin and CKD. It doesn't mean you can't use it. You just have to watch carefully and decrease the frequency if you need to. So now that we have our benzodiazepine of choice, let's move on to our game strategy. How do I maximize efficacy while minimizing the damage? From the current body of evidence, symptom-triggered therapy has emerged as a preferred treatment strategy. It's associated with shorter duration of therapy, less overall medications required, reduced length of stay, all when compared to a fixed dosing strategy. Furthermore, an early focus benzodiazepine load has been associated with decreased length of stay. And this recommendation was also reflected in those earlier ASAM guidelines. So to use symptom-triggered therapy, we need to find a way to detect these symptoms. Historically, the CWA abbreviated scale has been utilized in the literature and is frequently quoted. However, this has never been designed for an ICU population. It was designed for outpatient clinics to detect potential severity of future withdrawal and to triage patients to go from ambulatory versus inpatient management. It also includes questions like, does light appear to be too bright or does your head feel full? It's a little cumbersome to perform. And especially if we're dosing medications every 15 to 30 minutes, it's not very feasible. So in the past decade or so, people have caught on to this current lack of assessment scale. And there's been a veritable alphabet soup that's emerged. And so everything from the scales we all know, CAM-ICU, RAS, but there's also been things like MINDS, PAWS, SAWS, SHOD, lots of different acronyms here. So when looking at your own institution's alcohol withdrawal protocol, it's important to review these alcohol withdrawal scales to see, these are the questions I would take into consideration. So how long does the assessment take to perform? Is it feasible for a bedside nurse to assess this on a frequent basis? What was the scale designed for, outpatient clinics versus an ICU setting? And does the scale cover all expected symptoms of alcohol withdrawal? So RAS is something, or Richmond Agitation Sedation Scale, is something that's all familiar to us. It doesn't require much training for the nurses to utilize, but it doesn't capture those non-agitation symptoms of withdrawal, the sweating, hallucination, orientation, and tremors. So there's a deficit there. And some institutions have chosen to do multiple scales, RAS for agitation and SHOD for non-agitation as a combination. So we have our choice of benzo. We've decided to pursue symptom-triggered dosing. We have figured out what scale we wanted to utilize. And so now we search for the minimum effective dose. Our goal here is to escalate diazepam dose until symptoms resolve for the clinical duration of the medication, which for diazepam is about 15 to 30 minutes. So we start with a lower dose, 10 milligrams, and assess the duration of effect. Keynote here is that if the patient becomes over-sedated, it's very unlikely due, their reason for agitation is unlikely to be due to a GABA imbalance or a GABA deficit. And so you can almost rule out alcohol withdrawal as an etiology or the reason for agitation in that scenario. If that initial dose is inadequate to provide symptom relief for the full 15 to 30 minutes, you can escalate at the next dosing interval. So let's say going from 10 to 20 milligrams. Once you reach that minimum effective dose that works for that 15, 30 minute period, you can repeat that same dose the next time the symptoms recur. And eventually, you'll find that the doses will kind of self-de-escalate after the patient is sufficiently loaded. So visually, this is how I picture the dose escalation therapy. Another disclosure here, I am not an artist, and this is also done on pain. So you can see the first couple doses here, the 10, the 20, maybe 30 milligrams you give. It's a quick onset, but doesn't seem to help the patient for the full 15, 30 minute interval. And right around maybe 40, 50 milligrams, you can see that this medication works for that clinical duration. And the frequency of dosing will self-taper. Especially in trauma, we see a lot of positive blood alcohol levels. But it's important to note that acute intoxication does not necessarily predict the likelihood of withdrawal. So here in a lot of cases, the time of last drink is more important than the specific alcohol level on admission. And we want to avoid anchoring on the fact that just because somebody has a positive alcohol level on admission, that predicts their withdrawal in any way. Truly the risk of withdrawal is highest in those who have a history documented of alcohol withdrawal. And we want to ensure in an agitated patient that all other etiologies of agitation are ruled out. With the last few minutes here, I wanted to highlight some of the differences between the medical and the trauma population. And so depending on where you work, alcohol withdrawal can look a little bit differently. So this is an example of a patient who we included in our study several years ago. And this was a medical ICU patient. Their ethanol level was almost negative on admission. But you can see that they triggered a lot of symptom therapy management, received quite a load of diazepam on day one. But their symptoms quickly resolved. And with an appropriate load, they were able to get downgraded from the ICU around day three. In contrast, the trauma patient, we had for this patient that was included, ethanol levels on presentation were in the 300, so very, very high intoxicated. And we saw their symptoms emerge more on day two or day three, where they required a load a little later on in the hospitalization. But with the appropriate load, they were able to get downgraded about five or six days after admission. These significant doses are definitely not typical or standard. But it does speak to the degree of gap unbalance and how every patient will have a different degree of gap unbalance that you'll need to figure out and manage effectively. So in summary, we want to treat the underlying pathophysiology. We want an agent that has GABAergic effects or anti-NMDA effects. We want to ensure that we individualize therapy to each patient's gap unbalance and time it relates to the timeline of their withdrawal. We want to utilize symptom-triggered therapy paired with a validated assessment scale. We want to find that minimally effective dose for that patient and utilize it for the minimally effective needed duration, sorry, minimum needed duration. So at our institution, we utilize a five to seven day stop time for all of our benzodiazepine orders to reduce the risk of benzodiazepine-induced delirium. And with that, I thank you all for your time. And I'm happy to answer questions.

benzodiazepines

alcohol withdrawal

diazepam

symptom-triggered therapy

GABA-glutamate imbalance