Hello, everyone, and welcome to today's Journal Club Spotlight on Pharmacy webcast, which is supported by the Society of Critical Care Medicine CPP section. My name is Tia Collier, and I'm the Medical Surgical ICU Clinical Pharmacist and PGY2 Critical Care Pharmacy Residency Program Director at UNC Health Rex in Raleigh, North Carolina. I will be moderating today's webcast. A recording of this webcast will be available to the registered attendees. Log into mysecm.org and navigate to the My Learning tab to access the recording. A few housekeeping items before we get started. There will be a Q&A after each of today's speakers. To submit questions throughout the presentation, type into the question box located on your control panel. You will also have the opportunity to participate in several interactive polls. When you see a poll, simply click the bubble next to your choice. You may also follow and participate in live discussion on Twitter following hashtag SCCM CPP JC and hashtag PharmICU. Please note the disclaimer stating that the content to follow is for educational purposes only. And now I'd like to introduce your speakers for today. Each will give a 15-minute presentation followed by a Q&A. Our first presenter today is Kennedy Powers, a PGY2 Critical Care Pharmacy resident at Virginia Commonwealth University Health in Richmond, Virginia. She will present on effects of tall man lettering on visual behavior of critical care nurses while identifying syringe drug labels, a randomized in-situ simulation. Our second presenter is Alexis Morabi, PGY2 Critical Care Pharmacy resident at VA San Diego Healthcare System in San Diego, California. She will present on phenobarbital-based protocol for alcohol withdrawal syndrome in medical ICU, pre-post implementation study. And our third presenter is Alyssa Shaler, PGY2 Critical Care Pharmacy resident at Froedtert and Medical College of Wisconsin, Froedtert Hospital in Milwaukee, Wisconsin. She will present high-dose nitroglycerin infusion description of safety and efficacy in sympathetic crashing acute pulmonary edema, the high-dose SCAPE study. And now I'll turn things over to our first presenter. Hello, everyone. As was mentioned, my name is Kennedy Powers. I'm a PGY2 Critical Care Pharmacy resident at VCU Health. I'm very excited to present this journal club to you today that is going to look at the effects of tall-man lettering on nursing behavior. Our objectives for the day, we're going to define the role of tall-man lettering in medication safety. We'll summarize some key concepts related to eye-tracking technology, which was a really large part of this study. We'll interpret the results from this article related to tall-man lettering and medication errors. And lastly, we won't do much of this together, but I hope that this will stimulate you to discuss strategies to implement tall-man lettering in hospital pharmacy practice if you don't have that as a regular practice already. So, before we begin, as I'm sure many of us have experienced and are aware, medication errors occur in about 5% of inpatient medication orders, and that depends on which reference you look at. However, I know that many of us have probably been a part of or seen medication errors occur in the inpatient setting. And one of the things that we can do to combat inpatient medication errors is to utilize tall-man lettering. And tall-man lettering originates from the FDA Name Differentiation Project that was started in 2001, and essentially what they wanted to do was just highlight the differences in similar drug names by capitalizing dissimilar letters. And there is a process by which names are determined, so you can see some of those here. We won't go into that today, but there is a process by which drugs go through to determine what those names will be, but this is largely driven by an organization that I'm sure we're all pretty familiar with, so the Institute for Safe Medication Practices, or ISMP. And the ISMP maintains a list of uppercase and bolded medications. And you can see at the bottom of the slide here just an example of some of these medication pairs that they maintain a list of. In addition to them maintaining a list, they also conduct surveys with potential drug name pairs as new drugs enter the market, or comparing them to old drugs to assess practitioner recognition, to assess confusion or acceptance of these proposed tall-man lettering strategies. And I think it's also really important to note that the Institute for Safe Medication Practice does have an international branch, and that will become kind of important when we talk about where the study was done. But before we move on, I wanted to look at our first polling question of the day, just in your own opinion, do you believe that tall-man lettering reduces medication errors? Yes, no, or maybe I'm unsure. All right, so it looks like about 75% of us say yes, and the other 20% maybe were unsure. So we are actually going to discuss next some literature surrounding this area. All right, so there is some literature actually surrounding the use of tall man letters, but most of this data actually exists in the laboratory setting and not in real-life scenarios. I wanted to highlight this study for you that was published in 2004 by Salekin colleagues where they assessed 20 non-healthcare trained professionals with very similar technology, eye tracking movement technology, like we're going to talk about today, with a mixture of tall man and non-tall man lettered drugs. Once again, this was in a laboratory setting. These were non-healthcare trained professionals, but you can see here that there was a difference in the error rates where non-tall man lettered medications did have more errors than tall man lettered. And so that's kind of going to bring us to the study that we're looking at today. So this was published in BMJ in 2023. They were looking at the effects of tall man lettering on the visual behavior of critical care nurses while identifying drug labels. This was a simulated prospective eye tracking study that was done at University Hospital Zurich in Zurich, Switzerland. It was an in-situ study where they were randomized in an in-situ simulation, but it did provide a realistic drug selection scenario. And this was done at around like a five to six month period in August to December of 2020. They included certified ICU nurses that were at least 18 years or older that were employed at the participating institution, and they excluded those nurses that had any visual disturbances. And you can see a little bit of a breakdown of things that they included in those exclusions. Let's move on and look at the methods for the study. So they did have 200 syringes that were split into 100 syringes that were tall man letter coded and then 100 that were non-tall man letter coded. And within these, they had 10 syringes per set. And this is just an example here on the right side of the screen of the look-alike, sound-alike pairs and trios that they utilized. And you can see here that some of these medications, while this was done in Switzerland, these are medications that we may regularly see in our ICUs here in the States. So I thought that was just really important for us to note as that will become important when we look at our external validity of the study. So what they did is the participant was asked to identify and select a specific medication while they were wearing these eye-tracking technology glasses. And once they selected the syringe that they thought was the correct one, they would place it on a predefined surface, and that would end the experiment. And after the end of the experiment, they asked them to fill out a post-experiment questionnaire, which included information about baseline demographics of the participants. They asked them questions about their experience with tall man lettering. Any personal assessment of limitations of the study, if they were familiar with tall man lettering or perceived it to be helpful, et cetera. And we will get to see some of that data here in just a minute. But let's not forget, this was an eye-tracking study, so what does eye-tracking really look like? So there were four main terms, four main aspects that they looked at in this study, which they largely used as surrogate markers for spending more time in an area may mean that you are less likely to make an error. So the dwell time is just the cumulative time that's spent on the area of interest on the syringe. The fixation count is the cumulative number of fixations on that specific area of interest. And then fixation duration, as you can imagine, is the cumulative time that was spent on that area of interest. And then lastly, the number of revisits. This was the number of times that the nurse's gaze returned to that area of interest that it had already looked at before. And we'll get to see how this comes into play whenever we see the results of the study. The primary outcome was error rate, and then they did also look at these eye-tracking measurements between groups. And then secondarily, they looked at, of these syringes that were labeled with tall man letters, did the positioning of that tall man letter section within the label make a difference? And this is just an example here of this look-alike, sound-alike pair. So this was ephedrine or epinephrine. And you can see here on the left side, this was where the tall man letters were in the middle to end versus if they were at the beginning. And we'll look at that data in just a second. They did utilize linear mixed-effect models, which was appropriate for this study. And they utilized a two-sided p-value of less than 0.05 to be considered statistically significant. So what did they find in this study? I think there are a few things that are very important for us to note about the nurses that were involved in this study. First of all, these nurses had a very long duration of professional experience. So these are more of our seasoned nurses. You can see the average total professional experience in years was around 18 years, with the range being 6 to 23 years. And many of these nurses actually had professional experience in the ICU of around 6 years. It was kind of surprising to me to see that about 60% of these nurses were not familiar with tall man lettering. And they did perceive tall man lettering to not be helpful. But I do think it's important, when we talked about before how a lot of this data is in the laboratory setting, that they did note that this experiment was realistic. So on a score of 1 to 10, 10 being that they totally agree, they did think that this was more realistic. And that the drugs that were utilized were realistic. So for the primary outcome of error rate, you can see here that there was a statistically significant difference between the two groups, where tall man letters, tall man lettered syringes had a significantly less error rate than non-tall man letter syringes. And when you look at the dwell time and the number of revisits, which once again, they kind of use this as a surrogate marker, you can see that there was significantly more dwell time and more times that they revisited those areas of interest, which may indicate that these nurses were thinking a little bit more critically or looking at these a little bit longer, which may reduce our error rate. For the tall man letter positioning in the drug name, you can see that between all of our eye tracking endpoints that we looked at before, whenever the tall man letter positioning was in the middle to end, as opposed to the start, you can see that their dwell time, number of revisits, duration of fixation, all of these were significantly longer in that middle to end, middle to end group, which really, like I said before, this is kind of a surrogate marker, but definitely something to take note of that when those tall man letters are in the middle to end of the word, instead of at the beginning, our nurses may be spending a little bit more time looking at those areas of interest, which could potentially reduce medication errors. Now, for the limitations, of course, eye tracking is not something we do on a regular basis and gaze patterns do not represent a full picture of cognition. I've mentioned this a few times, but utilizing that dwell time as a surrogate marker for error rate is definitely something that I think they relied on in this study, but certainly there are more things that go into cognition than just eye tracking or gaze patterns. As far as this being a simulated study, I do think that the generalizability is much better than the previous literature that surrounds this area, especially because this was done in a more realistic setting with healthcare trained professionals who are routinely utilizing these drugs and routinely in practice. And then once again, that I think does add to the external validity of this study. And there was a question that the authors had of bias in terms of selection bias with regard to the medications that they chose. However, just looking at the medications that they did choose, like I mentioned before, these are medications that we would also routinely see here in the United States. And arguably, that's more important for us to pay attention to those medications that we handle on a daily basis where we may be operating more on an autopilot situation. So, I think they did have a question of selection bias. However, I do feel like that was very well made up for in this study. The authors concluded that the use of Tallman letters reduced error rate and that Tallman letters did change visual attention compared to non-Tallman letter coded labels. And then it also differed between the location of the Tallman letters within those syringe labels. And largely, I would absolutely agree with what they found. So, the use of Tallman letters did reduce error rates in the simulated study. Like I mentioned before, it was performed in a more real-life scenario than prior studies, which I think is really helpful. And I do think that Tallman letters should be regularly utilized for labeling our medications in the electronic medical record and on our physical medication labels in the inpatient setting to help try and reduce medication errors. So, we're going to move on and look at our last two polling questions of the day. This is more a question about your practice at your institution. Does your institution utilize Tallman letters, yes, in the EMR only, yes, for physical labels on medications only, yes, for both, or no, we don't regularly utilize Tallman letters, or maybe we're unsure? Yeah. So, most of our participants, they do utilize Tallman letters in the EMR and for physical labels, which is certainly similar at my institution. It's actually not a requirement, but certainly, it is best practice. So, not surprising to see this, but I am glad to see it. And then our polling question three, if your institution does not regularly utilize Tallman letters, will you revisit implementing its use? Yes, no, or no, my institution already utilizes Tallman letters. Perfect. Well, very great to see that. For our 4% of participants who don't regularly utilize it, definitely something to keep in mind and potentially to implement at your institution to reduce medication errors, but awesome for all of us that do already utilize Tallman letters at our institution. And with that, I thank you all for your participation, and I am happy to take any questions that you have. For anyone who has any questions, please feel free to put those in the question box. And Kennedy, I can go ahead and get us started, kick us off with a question here. Do you feel in this study that the medications that were viewed and the medication pairings in the study were pertinent to accurately depict most common errors that might be seen with different medications in the ICU that don't utilize Tallman lettering? Yeah, that's a really excellent question, and I think it's something that I was actually really glad to see the medications that they utilize, because I think that even when you look at, for example, diazepam, diltiazem, lorazepam, these are all very different medications, but they kind of utilize them together to, I think, give us more of a picture of maybe what that might look like in real life if you're grabbing from a place perhaps that doesn't have a Pyxis or an automated dispensing cabinet or anything like that. But I do think that the medications that they picked were certainly things that, and that they paired together, were things that I think could be easily confused. Definitely, there are a lot more medications that could be easily confused with each other, but I think depending on what their practice is at their institution, and they didn't comment a lot on why they picked these medications, but I certainly think that it is, I didn't feel like it limited the study in any way. If anything, I felt like it was probably a good choice for them, if not for their institution, also kind of to give us a little bit more of that external validity. Awesome, thank you so much. And then the other question that we have in the box is, what other strategies do you use in your ICU to reduce errors such as look-alike, sound-alike medications? Yeah, that's a great question also. I think one of the things that is really beneficial for us, and I think for most institutions, is that we utilize automated dispensing cabinets, which can definitely reduce those errors because sometimes you have to scan the drug, or you have to type in more than just two or three letters of the drug to pull it up, to pull for the patient. So I think that that's a really, really influential part. Additionally, all of the medications that are in our PICSUS machines are labeled with Tallman letters on the physical package, which I think is really helpful. Even the ones that we package in-house, those are labeled with Tallman letters, which I think will definitely help in reducing those medication errors. Wonderful. And as I see no other questions in the box, I will go ahead and conclude our Q&A session. Thank you so much, Kennedy, for that wonderful presentation. Now, I'd like to introduce our second presenter, Alexis Marabi. Good afternoon. Thank you very much for that introduction and the opportunity to present today. My name is Alexis Marabi, and I am the critical care pharmacy resident at the Veterans Affairs Healthcare System in San Diego. Today, I will be discussing a pre-post-implementation study that was published April of this year in the Critical Care Explorations Journal. I have no personal or financial conflicts of interest to disclose. Here on this first slide, I have included a table of abbreviations that are used throughout this presentation. So, for a brief background of management for alcohol withdrawal syndromes, or AWS, although there are no universally accepted guidelines for AWS, the American Society of Addiction Medicine recommends benzodiazepines as first-line, and they do allude to various dosing strategies, such as symptom-triggered, fixed-dose, or front-loading. They briefly mention phenobarbital as a less desirable alternative or potential adjunct therapy. More recent 2023 guidance from the American Academy of Emergency Medicine specified preference of parenteral benzodiazepines and utilization of symptom-triggered as opposed to scheduled dosing regimens. They do acknowledge phenobarbital as an emerging treatment, especially as a monotherapy due to its self-tapering effects, which may lessen intensity of downstream care, such as reduction in ICU admissions and need for mechanical ventilation. Chronic alcohol use leads to downregulation of inhibitory and upregulation of excitatory receptors. The etiology of alcohol withdrawal is due to this dysregulation of GABA and glutamate. As mentioned previously, the mainstay of therapy for alcohol withdrawal syndrome is benzodiazepines, which modulate GABA-A receptors. Phenobarbital is an older medication from the 1920s that has a potential added benefit of dual mechanism, so it has both GABA agonism and glutaminergic suppression. Traditionally, it has been used for AWS that is refractory to benzodiazepines, but emerging evidence has led to increased use as a monotherapy. Additional benefits of this medication include a longer duration of action and predictable PKPD. Before I move on to more of the literature, I wanted to ask the audience what your institution most often uses as treatment for severe AWS in the ICU. The options are IV benzodiazepines, IV phenobarbital, a combination, or provider preference. It looks like the majority of the audience chose IV benzodiazepines, which is what I had sort of anticipated. That's what our standard of care is here at VA San Diego. It looks like there has been a decent amount in the audience that does use IV phenobarbital as first line, and then also a combination of benzodiazepines and phenobarbital, although we don't have a specific protocol for phenobarbital that is often used for refractory or patients that are not responsive to IV benzos. So, now on to some of the evidence. So, most of the evidence for phenobarbital use in AWS comes from studies that were conducted in the emergency department. This slide shows some of the ICU specific publications that have led up to the study. Gold et al. in 2007 was one of the first studies that evaluated benzodiazepines as a monotherapy treatment. This is a study that Gold et al. in 2007 was one of the first studies that evaluated benzodiazepines and phenobarbital for alcohol withdrawal in MICU patients specifically. This study showed significantly lower intubation rates in the post-guidance group, and it was notable that there was a statistically significant increase in benzodiazepine and phenobarbital doses. The majority of these studies shown here, with exception of Nguyen and Goudberlais et al., showed an association between phenobarbital use and decreased length of stay. However, for these specific studies, this may have been due to confounding factors such as having non-protocolized management and severity of admission of the actual illness rather than alcohol withdrawal. I believe the Goudberlais study included patients that had varying APACHE scores. I do also want to point out that throughout these studies there was a wide variability of dosing strategies such as combination of both oral and IV phenobarbital in the Tidwell et al. study from 2018 and varying dose escalation using various tools such as CWA or RAS in the Dubietz et al. study. More recent studies such as Shaw from 2022 did compare a front-loading as opposed to symptom-triggered phenobarbital, and I wanted to include that study just to demonstrate there's a wide variety of phenobarbital use in the ICU. The purpose of this study was to evaluate the efficacy and safety of a phenobarbital versus benzodiazepine-driven protocol rather than use of phenobarbital as an adjunct. The primary outcomes for efficacy include the ICU length of stay in days. Secondary outcomes include intubation, need for ICU readmission, need for interventional other than medications such as restraints, sitters, and additional medications, and then lastly medication adverse effects. All of the patients that were admitted to the MICU with a primary diagnosis of alcohol withdrawal syndrome per ICD-10 codes were reviewed. They were excluded if they were intubated prior to admission, pregnant, had left AMA, or had contraindications to phenobarbital such as severe hepatic renal impairment or significant interruptions. The benzodiazepine-based protocol that was used at the site included escalating doses depending on CWAS scores. If there were inadequate responses to benzodiazepines, per intensivist discretion, alternative medications or further benzodiazepine doses could be utilized. The protocol that it was compared to or the revised standard of care was a phenobarbital-based protocol that had an initial 260 milligrams IV push with subsequent symptom-triggered 130 milligram push doses. This protocol was not allowed to be used if patients had received a benzodiazepine within one hour and any further dose of benzodiazepines were prohibited if patients were started on this protocol. Further restrictions are shown in the red box on the left and then just wanted to point out that both of these protocols were driven by CWAS scores. This leads to my next question for the audience. Which monitoring tool does your institution utilize for treating or escalating therapy for alcohol withdrawal in the ICU? It looks like the majority of the audience chose CWAS, which is also what we use. But it does look like the second most common is RAF scores. This was similar to what I expected. There was a survey from 2018 and I believe a little over 60 percent of hospitals in the northeast region of the U.S. had used CWAS and then the next most common was RAF scores. Thank you. So for the study, of the 353 patients that were identified, there was a total of 102 that qualified for the study. There were 51 patients in each arm. The most common reason for exclusion from the study was an alternative reason for ICU admission other than alcohol withdrawal. This helps the authors eliminate confounding factors that contribute to length of stay in ICU and potential need for intubation. The baseline characteristics in each group were similar, so inferential statistics were appropriately used. They demonstrated no difference in age, gender, ethnicity, and comorbidities. This patient population was predominantly white, male, and mid-50s with the most common comorbidity of hypertension. Additional characteristics that were evaluated, the last time to drink, previous AWS history, initial labs, CUS score, and severity of AWS were similar across both groups. The authors had also done additional linear regression analyses to show that this population had more severe alcohol withdrawal than not. The main difference between the groups, obviously as you can see on the bottom, were the cumulative dosing. So there was significant difference between lorazepam equivalents and phenobarbital doses. For the results, the bolded values indicate statistically significant differences between the groups. The phenobarbital group had a shorter ICU and hospital length of stay, lower mechanical ventilation, lower need for adjunct medications, and lower need for restraints. There was a difference between the two groups with maximum CUL scores and scores at the MICU discharge. However, there were no differences in ICU readmission rates and there were no differences in medication-related side effects. Based on these results, the author concluded that rapid escalating doses of phenobarbital is safe and effective alternative to benzodiazepines. The biggest limitation of this study was the relatively low median benzodiazepine doses used. So if you recall, it showed that only approximately 21 milligrams of lorazepam equivalents were used and that's pretty low for severe alcohol withdrawal requiring ICU level of care. This may lead... explains the need for adjunct medications used. It was appropriately powered, which they had included those calculations throughout the study. They did mention some potential selection bias. So this phenobarbital protocol was implemented in 2020 during the pandemic. Patients may have been redirected to other facilities in their healthcare system depending on availability of beds. Another potential limitation was the use of CWAL, although this has been debated in literature and most hospitals do use this for dosing. This tool does require patient cooperation. So I think collecting more objective data, such as RAS values, may have strengthened the study just to kind of have that additional information. And then lastly, this protocol did allow for dosing discretion, which may have affected efficacy results. However, the linear regression analysis helped mitigate some of these limitations that were discussed. Overall, the study had contributed to literature that supports monotherapy in patients with severe AWS in the ICU. I think that these results are most appropriately applied to patients that are admitted exclusively for alcohol withdrawal syndrome, and this should be strongly considered when applying these results. Although not mentioned in this specific protocol, I would also be cautious or try to avoid phenobarbital in patients with severe cardiac disease, as phenobarbital is a cardiac depressant. However, they did show there are no differences in hypotensive events. And then before this becomes a new standard of care, I do want to see larger multicenter randomized trials, and especially with higher cumulative benzodiazepine doses, I think that the potential underdosing definitely would affect differences in efficacy from the study. One ongoing randomized trial to look out for in the future is the PARI study, which is going to compare fixed dose lorazepam in combination with PRN dosing to phenobarbital in patients admitted to the ICU. I think that scheduling benzodiazepines will help minimize potential underdosing and this as a confounding factor onto the results. Here's a slide with my references, and I just wanted to open up the floor to any questions that you may have. Thank you. Thank you so much, Alexis. I did have a quick question for you. In the study, do you think that the timing of withdrawal from the phenobarb initiation or utilization actually plays an impact in the efficacy of the phenobarb itself? You're asking about the timing of withdrawal? Yeah, so do you think that, you know, when patients first come in, do you think that waiting to give the phenobarbital versus immediately starting a patient on phenobarbital would make a difference in the efficacy scene? Yeah, so I think they didn't mention explicitly the timing or look at administration times, but I do think that with phenobarbital, it is important to treat early on. So I think patients with a history of severe alcohol withdrawal, it's relatively safe, as mentioned before, it has pretty predictable PKPD. So I think having that initial dose early on would be beneficial, although they did not mention exactly when it was given. That higher dose of the 260 milligrams is potentially beneficial. The Shaw et al. study that I had mentioned previously did show benefit in having a higher front-loading as opposed to symptom triggered. So I think having an earlier administration would improve the outcomes and reduce incidences of intubation and more severe withdrawal. Great. The next question is, did the protocol account for any potential drug interactions with phenobarbital? Yeah, so I can go back to that slide. They were in their actual protocol for phenobarbital. It was restricted to patients in the ICU, but any patients that had significant medication interactions were not able to use this medication. So that's another large kind of downside of using phenobarbital for patients. So it is a SIP inducer. So if patients, as you may have seen, the patients who had received phenobarbital did not get phenytoin, that is definitely a significant medication interaction. Patients who may be on antivirals or other medications that you do not want to affect levels, I think would not be candidates for this medication. But that was incorporated in their post-institution standard of care. Awesome. I would just stay on this slide because the next question is, would you recommend the use of phenobarbital for patients with liver disease? So I think that patients with very severe hepatic dysfunction may not be the best candidate for this. I know that for our site, even for diazepam, we try to avoid it due to metabolites and it can have kind of variable pharmacokinetics. But additionally, patients with very severe hepatic dysfunction may be at risk for hepatic encephalopathy. So we do want something that has a shorter duration of action, especially when you're doing neurochecks. I did like that their protocol here actually kind of forces them to take a step back and reevaluate other etiologies of agitation or somnolence in these patients. So that was an additional safety measure that this protocol had that was not mentioned in their benzodiazepine group. Although, you know, Package Insert does not recommend explicitly any renal or hepatic dose adjustments, I would avoid it in that patient population. Awesome. The next question asks, with patient outcomes, if they required intubation in the ICU after enrollment? So that, could you repeat that one more time? Yeah, it said, was patient outcomes collected if they required intubation in the ICU after enrollment? Yes, so intubation was one of the endpoints that they had looked at. As long as they did not arrive to the ICU intubated and were admitted directly from the emergency department, then they were included in the study. Wonderful. Next question was, at your institution, do you use higher doses in your center, such as loading doses of 5 mix per kicks or even 10 mix per kick? So we have two protocols that we use at our institution. So we do use kind of like an escalating dose, so it is dependent on the actual CWAS score itself. But we do use larger doses, and then we do have limitations on total daily dosing that requires physicians to re-evaluate therapy. Awesome, and I promise final question said, did the study mention phenobarbital failures that needed to then add benzos on? Have you noticed this in your practice in treating alcohol withdrawal in the medical ICU? So they did not mention a need to transition to benzodiazepines. They only included information for alternative agents that were used in the protocol, such as Presidex, oral clonidine, certain antipsychotics. But that is something that I think would have been important to know. But no, that was not included in the study. And then the second part of that question was about what we have seen in our MICU. That's correct. So I've only seen phenobarbital a handful of times. A lot of our intensivists actually prefer not to use it because it is an older medication. They kind of see benzodiazepines as a cleaner version for phenobarbital. I think phenobarbital has some adverse effects that are undesirable but in a short term are likely safe. The one patient that I have seen that was started on phenobarbital actually required readmission. And then that patient required much higher benzodiazepine doses and we actually needed to start them on infusion. So anecdotally, I haven't really seen it or the one time that I have it wasn't efficacious at controlling their alcohol withdrawal. Wonderful. Thank you so much. So that's going to conclude our Q&A session. Thank you so much Alexis. And now I'd like to introduce our final presenter, Alyssa Shaler. Thank you for the introduction and for the opportunity to speak today and to talk to everyone about the high-dose SCAPE study. So for some background information, sympathetic crashing acute pulmonary edema or SCAPE is also known as flash pulmonary edema as well as crashing pulmonary edema. And it is caused by an acute severe increase in blood pressure which ultimately leads to increased cardiac filling pressures that transmit back through pulmonary vasculature and cause intervascular fluid to weaken to the pulmonary interstitium and alveoli. So it is associated with acute heart failure and can occur over minutes to hours. The American College of Emergency Physicians does recommend use of non-invasive positive pressure ventilation as well as nitrate therapy and adjunctive therapies such as loop diuretics in order to manage these patients. However, the optimal dosing strategy for nitrates is unknown. Levy and colleagues performed a non-randomized open-label single-arm study at two tertiary care facilities in Michigan from February of 2003 to August of 2004 and included adults presenting to the emergency department with decompensated heart failure as well as a systolic blood pressure greater than or equal to 160. And then these patients also had to have failed traditional therapies which the authors used or defined based on the AHA 2000 guidelines for the evaluation and management of heart failure. And that included 100% high flow O2 with a non-rebreather mask as well as sublingual nitroglycerin and furosemide. Patients received a nitroglycerin infusion that was titrated to a maximum dose of 400 micrograms per minute. And overall 29 patients were included in the study. And overall in terms of intubation, non-invasive positive pressure ventilation, and ICU admission, rates were decreased for all of those with use of nitroglycerin compared to patients who did not receive nitroglycerin. And so the authors concluded that high dose nitroglycerin is less frequently associated with intubation, use of non-invasive positive pressure ventilation, and ICU admission. Another study by Wilson and colleagues was a retrospective observational cohort, again out of another teaching hospital in Michigan, from January 2007 to July of 2011. And it also included adult patients who presented to the ED with acute heart failure who required IV nitroglycerin. This study was a little bit different in that it sought to compare resource utilization, comparing bolus nitroglycerin, bolus plus infusion nitroglycerin, or a combination of the two. This study had quite a few more patients at 395 patients. And overall after logistic regression was performed, there was a statistically significant difference between bolus and infusion for both ICU admission and hospital length of stay. But there was no difference between infusion versus combination therapy for those two outcomes. In addition, I did want to note that incidence of intubation was 16.9% with combined nitroglycerin plus bolus, or nitroglycerin bolus plus infusion, 8% with bolus alone, and then 8.8% with just infusion. So the takeaway from this study was that bolus nitroglycerin is associated with lower ICU admission rates and hospital length of stay compared to nitroglycerin infusion. I did want to note that there have been other case reports and case theories that have looked at high-dose nitroglycerin infusion, some of them starting at an initial rate of 400 micrograms per minute. But again, the optimal dosing strategy is unknown. So here's our first audience poll. Does your institution use high-dose nitroglycerin boluses, infusions, or a combination to manage states? OK, so it looks like most institutions use infusions or kind of a combination of both, which seems to be similar to what our institution does as well. OK, and then the next poll is, what adjunctive therapies does your institution use to manage SCAPE? Great. So, overwhelmingly, it seems like most institutions add diuretics and then potentially add that ACE or ARB therapy as well. Moving on to methods for this study, the hypothesis of this study was that high-dose nitroglycerin infusion is a safe and reasonable alternative to intermittent high-dose nitroglycerin boluses. This study did not have designated primary and secondary outcomes, but rather just had multiple outcomes in order to assess safety and efficacy, so all of the outcomes are listed here. They included initial and lowest systolic blood pressure, incidence of intubation, hypotension, and AKI, as well as admission level of care and length of stay. In addition, the authors wanted to assess the impact of variables related to adjunctive therapies received in the ED, so they included a composite outcome of intubation, hypotension, or AKI within 48 hours, and then looked at the specific therapies of IV nitroglycerin greater than or equal to 200 mics per minute within the first hour, use of sublingual or IV bolus nitroglycerin prior to infusion, use of loop diuretics, and then use of ACE inhibitors or ARBs. This study was a retrospective chart review at an emergency department at a tertiary care center. It was performed from January 1st of 2018 to December 31st of 2018. Patients were included if they were adults who presented to the ED with an initial systolic blood pressure greater than or equal to 160. They also had to receive high-dose nitroglycerin, which the authors defined as a dose of greater than or equal to 100 micrograms per minute within the first hour, and then they also had to show signs of respiratory distress, which included pulmonary edema on chest X-ray imaging, oxygen saturation less than 90%, use of noninvasive positive pressure ventilation, and a respiratory rate greater than or equal to 30 breaths per minute. There were no exclusion criteria for this trial, and then although there was no set protocol for the use of nitroglycerin in SCAPE, patients could receive a 200-microgram bolus with the start of their infusion and then up to a maximum rate of 300 micrograms per minute that was titrated based on discretion of the bedside physician. For statistical analysis, categorical variables such as frequencies and percentages were used along with chi-square and Fisher's exact. Those variables included means with standard deviation as well as medians and interquartile ranges along with the Mann-Whitney U-test, and then statistical significance was defined as a p-value less than 0.05. Moving on to results, you can see the baseline characteristics of the patient population here. Overall, 67 patients were included in this trial, and then I did just want to highlight that over half of patients were male along with majority of patients being of African-American race. The initial systolic blood pressure prior to nitroglycerin initiation was 211 millimeters of mercury, and then the initial oxygen saturation was about 98%. In addition, over half of patients had heart failure, and then over half of those patients with heart failure did have an EF less than or equal to 40%. I did want to note that the additional markers of illness for patients such as Apache 2 score or SOFA score were not included in the baseline characteristics, so we really kind of just have that oxygen saturation to go off of in terms of patient acuity. Overall, 48% of patients received a nitroglycerin bolus prior to infusion start. Those boluses were primarily 100 to 200 micrograms, however, 2 patients did receive a bolus dose of 1,000 micrograms prior to infusion. The median peak nitroglycerin infusion dose was 200 micrograms per minute, and overall, the median duration was about 5 hours, so when you look at the admission level of care, majority of patients did go to the ICU, which depending on this institution's protocols, being on that continuous infusion could have put them in that category of needing to have ICU admission. In addition, 73% of patients received noninvasive positive pressure ventilation. Over half received loop diuretics, which was a median dose of 120 milligrams of furosemide equivalent, and then about 34% of patients received ACE inhibitor or ARB therapy. In addition, 24% of patients received nitroglycerin infusion only, and then 42% received nitroglycerin plus a loop diuretic, followed by 18% receiving nitroglycerin plus an ACE or an ARB, and then 16% receiving both ACE, ARB, and loop diuretic, along with the nitroglycerin infusion. I also wanted to point out the percent decrease from initial systolic blood pressure to the lowest systolic blood pressure in these patients, so you can see that based on all of these therapies, blood pressure was decreased over 30% from the initial systolic blood pressure, but the authors did not include the timeframe over which this decrease occurred, so that is unknown. In terms of the composite unfavorable outcome, 21 patients experienced that composite unfavorable outcome, 14 required intubation, 9 required AKI, and you can see the distribution of the timeframe over which that AKI occurred, and then only 3 patients experienced hypotension. The authors also sought to identify baseline characteristics that might impact the incidence of an unfavorable outcome. However, after logistic regression, none of these baseline characteristics were significant. Looking at those initial variables related to adjunct therapies received in the ED, only a dose of greater than or equal to 200 micrograms per minute of IV nitroglycerin within the first hour was significantly associated with the composite unfavorable outcome, and that was even after logistic regression. Moving on to some discussion points of this study, there was no comparator to assess outcomes in clinical relevance, so you couldn't really assess whether or not bolus had different impact on intubation rates or ICU admission in the specific patient cohort compared to IV infusion. Also, there was a composite unfavorable outcome, which included intubation and hypotension and AKI, and because 21% of patients required intubation, that's likely the driver, but the significance of that is, again, unclear given that there's no comparator. In addition, there were higher intubation rates in this study compared to some of the prior studies that I talked about, and the question of whether AKI and hypotension are clinically relevant unfavorable outcomes compared to intubation or ICU admission is also unclear. As I mentioned prior, additional markers of patient acuity, such as APACHE-2 scores or SOFA scores, weren't included. We only have that baseline oxygen saturation to go off of, which was a median of 98% and seems to be relatively high, so maybe a lower patient acuity in this population. We also don't know the timeframe of the blood pressure reduction, although there were low episodes of hypotension reported, and then, lastly, the authors did not compare the composite unfavorable outcome among the combination groups, so we weren't able to see the effect of nitroglycerin plus a loop diuretic or plus an ACE or an ARB and see how that affected that composite unfavorable outcome. Some strengths of the study was that it was a larger sample than prior studies. They didn't have any exclusion criteria, so they could include a wide range of patients with a wide range of acuities presented to their ED. They also assessed some of the co-interventions that occurred in the ED to see how those impacted the outcome. And then some limitations of the study was that it was retrospective, so there could be some selection bias or possibility for incomplete or inaccurate chart review. And then they didn't have a defined nitroglycerin protocol, so that could have been another limitation for the study. So overall, in conclusion, high-dose nitroglycerin for the management of SCAPE may be a safe alternative to bolus dosing. However, initial infusion rates greater than 200 micrograms per minute within that first hour did seem to increase that risk of the composite unfavorable outcome. So again, the optimal initial dosing rate and titration strategy is unknown. Majority of patients were admitted to the ICU, so it doesn't seem to impact this position, but that could depend on the hospital infusion protocol. And then ultimately, larger trials are needed to validate some of these findings. What questions do you have for me? Alyssa, thank you so much for that great presentation. Just curious, with the initiation of this high-dose nitroglycerin, do you think that timing makes a difference in these patients' presentation as far as efficacy to prevent that intubation? Yeah, that's a good point. The average, or I think the median time to initiation of the nitroglycerin infusion was 17 minutes. So I think that definitely addressing or identifying this disease state early does impact need for intubation, and kind of catching it in the early stages can be helpful. So it could be that maybe this study, there was a little prolonged duration before they started the infusion, so that could have impacted intubation rates as well. But I think early initiation and early identification of SCAPE is important for outcomes. Wonderful. And with these composite outcomes, do you think that these helped the study or maybe hindered the overall impact of the study itself? I think that kind of just goes back to comparing incidence of AKI versus ICU admission or intubation are potentially maybe more impactful or more clinically relevant. So I did like that they had that composite outcome and tried to look at the use of some of these adjunctive therapies and whether or not those impacted that composite outcome. But I think potentially intubation rates and ICU admission might have been a better composite outcome compared to maybe incidence of hypotension and AKI. Wonderful. I definitely think I would agree with you on that one. Well, thank you so much. That concludes our Q&A session. So thank you so much, Alyssa, and thank you so much to our presenters today and our audience for attending. Please join us on the third Friday of the month from 2 to 3 p.m. Eastern Standard Time for the next Journal Club Spotlight on Pharmacy. That concludes our presentations for today. Thank you, everyone. Thank you.

Journal Club Spotlight

Pharmacy webcast

tall-man lettering

medication errors

visual attention

phenobarbital-based protocol

alcohol withdrawal syndrome

ICU length of stay

intubation

high-dose nitroglycerin infusion

Webcast

Quality and Patient Safety

Behavioral Health and Well Being

Cardiovascular

Quality and Patient Safety

Alcohol and Substance Abuse

Pulmonary Edema

Professional

Select

2023

Behavioral Health and Burnout