Good afternoon, everyone, and welcome to today's Journal Club Spotlight on Pharmacy webcast, which is supported by the Society of Critical Care Medicine CPP section. I'm Lauren Lozano. I will be the moderator for today's Journal Club. I'm a clinical specialist in the cardiothoracic and transplant ICU at University Health in San Antonio, Texas. A recording of this webcast will be available to registered attendees. Log into mysccm.org and navigate to the My Learning tab to access the recording. Thank you for joining us. A few housekeeping items before we get started. There will be a Q&A after each of today's speakers. If you would like to submit a question, please do so throughout the presentation into the question box that's 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, and then please follow us along and participate in our live discussion on Twitter, following hashtag SCCMCPPJC and hashtag PharmICU. Please note the disclaimer stating that the content to follow is for educational purposes only. All right, let's get started today. So I'd like to introduce our speakers for today. Each will give about a 15-minute presentation, followed by a Q&A session. Our first presenter today is Kayla Kahn. She is a PGY-2 critical care pharmacy resident at Memorial Hermann in the Texas Medical Center in Houston, Texas. She will present on antibiotic treatment for seven versus 14 days in patients with bloodstream infections. Our second presenter is Natalia Smith. She is a PGY-2 critical care pharmacy resident at the University of Maryland Medical Center in Baltimore, Maryland. Today she will present on a randomized trial of intravenous amino acids for kidney protection. And our last presenter today is Angela Castro, a PGY-2 critical care pharmacy resident at UC San Diego Health in San Diego, California. The presentation today will be on propranolol as an anxiolytic to reduce the use of sedatives for critically ill adults receiving mechanical ventilation or the PROACTIV trial. We'll start our first presentation and turn things over to Kayla Kahn. Hello, everyone. Can everyone hear me? Yes, we can hear you, Kayla. Thanks, Lauren, for the introduction. Like she said, my name is Kayla. I'm a PGY-2 critical care pharmacy resident at Memorial Hermann in the Texas Medical Center. And today we'll be talking about antibiotic treatment for 7 versus 14 days in patients with bloodstream infections, also referred to as the BALANCE trial. So to start with some background, we know that patients who are hospitalized with bloodstream infections have significant complications related to their course of therapy. And really the goal of this study was to answer the question in patients who are hospitalized with these bloodstream infections is 7 days of treatment with antibiotics non-inferior to treatment with 14 days, specifically regarding 90-day mortality. So bloodstream infections are very severe infections, and they account for 2.9 million deaths per year worldwide. This is a significant cause of morbidity and mortality in the United States as well, and it's something that we commonly see in our ICUs. In other types of infections, we know that shorter durations of therapy have been shown to be non-inferior to longer durations of therapy. These have been shown in infections like pneumonia, intra-abdominal infections, cellulitis, and pyelonephritis. However, there's currently a lack of data in patients who have bacteremia. And so the goal of this study is to kind of fill that gap in literature and identify if shorter duration is just enough for patients with bloodstream infections. With shorter duration for bacteremia, the goal would be to reduce antibiotic exposure. However, it's currently unknown what duration is sufficient in order to avoid clinical failure. So the purpose of this study really is to find that non-inferiority area, what is sufficient, but not too much. So the authors of this study predicted that 7 days of treatment would be non-inferior to 14 days of treatment with respect to mortality at 90 days. And they also predicted that 7 days of treatment would decrease antimicrobial exposure, complications, and resistance. So this was a multi-center, open-label, randomized, controlled, non-inferiority trial. And they included adult patients who are admitted to the hospital with a positive blood culture with a pathogenic bacteria. What they mean by this is bacteria that were suspected to be truly an infection rather than something that could be a contaminant, such as one out of four half-epidermidists in a patient who has a sufficient immune system. They excluded patients who were immunocompromised, those with prosthetic heart valves or endovascular grafts, other indications where they might require prolonged treatment, those being endocarditis, osteomyelitis, empyema, et cetera. And they also excluded patients with Staphylococcus aureus or Staphylogenesis bacteremia, since those would also require a prolonged duration of therapy relative to some of our other bacteremias. The intervention for these patients was 7 days, and the control group was 14 days. And the primary outcome, as we mentioned, was death at day 90. The other outcomes that they explored were in-hospital and ICU mortality as well as length of stay. If patients developed a relapsed bacteremia, adverse events and allergies, C. diff, and secondary infections, mechanical ventilation duration, and ventilator-free days, antibiotic-free days, and then duration of vasopressors and vasopressor-free days. They anticipated needing a sample size of 3,626 patients with a 22% anticipated 90-day mortality rate, and they selected a non-inferiority margin of 4% to achieve 80% power. So, to start with some of our baseline characteristics, originally the study was driven to only include ICU patients. However, a couple of months into the enrollment period, they decided to extend it into the floors. So, we can see here that primarily the patients were ICU-level of care, however, by the end of the data collection period, a little less than half were on the floor or in an intermediate care status. Most patients had bacteremia from a source being the urinary tract, second and third most common sources being intra-abdominal and lung. There were, of course, other sources, however, those were much less frequent. The most common pathogen that was identified was E. coli, around 45% of patients. The next most common species were Klebsiella and Enterococcus. There were a ton of bacteria that were isolated, but these were the most common. And most patients had gram-negative bacteremia with a monomicrobial type of infection. There were very few patients that had polymicrobial infections and only a couple that had gram-positive infections. So, looking at our primary outcome, which was all-cause mortality at day 90, they split this up into three different groups, first being intention to treat, and they had a little over 1,800 patients in the seven-day group and almost 1,800 in the 14-day group. And what they found was that there was no difference in all-cause mortality at day 90 between these groups, with 14.5% of patients in the seven-day group and 16% in the 14-day group experiencing 90-day mortality. The percent difference was 1.6%, and that confidence interval is negative 4 to 0.8. We can also see that they identified similar results in the per-protocol and the modified intention to treat studies or groups, where, again, there was no statistically significant difference between the two groups. So, here, what we're seeing is the forest plot for the different outcomes that were selected. So, again, at the top, we're having our intention to treat, and here, just to orient you to the values that we're looking at here, with 0 being, of course, the risk difference, and then 4 being our non-inferiority margin. So, we can see that the seven-day group was non-inferior to the 14-day group with respect to all of the populations. The other outcomes that were explored were listed here below the mortality outcome, so hospital mortality, ICU mortality, duration of vasopressor use, relapsed bacteremia, antibiotic-free days, C. diff infection, and secondary infection. And what we see here is that there was no major difference between, really, any of these outcomes. We do see that there were more antibiotic-free days in the seven-day group, and this makes sense just based on, you know, how long we expect those patients to be on antibiotics. However, if we look at those interquartile ranges, they do kind of come close to being similar. C. diff infection, there's also no difference in this outcome, and then similarly with secondary infection. So, the authors ultimately concluded that among hospitalized patients with bloodstream infections, antibiotic treatment for seven days was non-inferior to treatment for 14 days. For a couple of critiques, there was minimal attrition. Again, this was appreciated, and we can see that, you know, this certainly made for a strong study. I thought that the inclusion and exclusion criteria were appropriate. It's certainly important that we exclude those patients who automatically will require more prolonged durations of therapy, such as our staph aureus patients or those with empyemas or endocarditis, those other sources that can cause bacteremia. Those would be important and critical to exclude. I thought that doing a non-inferiority study was appropriate for the question. They were looking to see if shorter duration is appropriate, and this is reflective of the other studies that have been done. I appreciated the clinical outcome being objective. Mortality is something that cannot be argued with, so not something that is left up to opinion. And then I thought the non-inferiority margin of 4% was appropriate. For some weaknesses, we saw that several of the patients were not ICU patients, and so relatively low severity of illness is seen among the patients that were included, and so we have to be cautious when applying this to our extremely sick patients who are in the ICU. We do know that investigators were not blinded until after 7 days. Sorry, they were blinded up to 7 days after that. They could have been unblinded, and so there is some potential for performance bias as physicians, nurses, et cetera, could have been treating patients differently once they knew what group they were in. The study was not powered to assess various subgroups, and while it is interesting that they reported information on that, we can't necessarily take it as a fact. Something else to consider is that 90-day mortality is, while an objective outcome, could be related to other conditions, non-infectious causes of death. Certainly, when we're looking at 7 versus 14 days of therapy, using a 98-day outcome might have been too far out, as those patients could have passed away for other reasons. However, it is important to note that we are relatively confident in that outcome based on the confidence interval that was seen. Other questions that I have, really, after the results of this study is, what factors independently predicted mortality? It would have been helpful to have some type of progression analysis or more data on how those patients performed after they left the hospital, and maybe what were those causes of death in those patients who did pass away? Was it infection-related or related to something else? I also question if results would be similar if the study was powered only to assess ICU patients with high severity of illness. We have to be cautious whenever taking information that applies to a certain population. While our ICU patients were included, and initially the primary group that was studied, they did not make up the entire population. Then the last question, really, is, are there cost benefits to patients and the health systems? We know that shorter durations of antibiotic therapy, of course, requires less antibiotic use. However, we also have to balance that with the fact that if these patients ultimately end up requiring antibiotics later on, does that balance out? That's just something that could be answered in something in a different style of study. My conclusion and my takeaways, I believe that seven days of treatment is likely sufficient for most patients with bacteremia who, again, don't have a prior indication for extended therapy. But it's really important that we critically assess improvement of our patients. This is certainly something that we're doing on the multidisciplinary team. It's also important that we identify the source and find that the source is controlled. This is not something that they provided a ton of information on with this study, so that is something that's really important whenever we're rounding on our patients and assessing them. Next, because the study was not powered to directly assess results in sicker patients, we have to be cautious when applying results of the study to patients with very high severity of illness, such as those with a high APACHE-2 score or SOFA score. It's important that we evaluate that as our patients are improving or their clinical status is changing. If they are not rapidly improving, I would be hesitant to stop antibiotics earlier. And based on the results of this study, I think the ideal patient would be someone who is immunocompetent, has a well-defined source of infection with adequate source control, and clear resolution of septic shock. Again, I would hesitate to apply the results of this study to someone who is still on vasopressors, not adequately and quickly improving, defervescing quickly. And then other areas of research that are really left behind is specific to the ICU and septic shock-focused population. I would also like to see other mediation and other regression analyses that would be able to show us exactly why those patients passed away or what are the correlations between certain characteristics and the outcomes that we're seeing. So, for our first polling question, for most critically ill patients with bacteremia without an indication for prolonged treatment, how long do you normally treat with antibiotics for your patients? Second question, for patients with bacteremia without an indication for prolonged therapy, does your institution currently have a protocol for duration of antibiotic therapy? All right. Thanks, you guys, for listening. I'm happy to take any questions. Great. Thank you, Kayla. Thank you, Kayla, for this great presentation on this really interesting topic. And as the questions, we do have about 10 minutes. So, if you do have a question, please feel free to provide in the question section in the control panel. I will go ahead and get started with the first question. I really appreciated that you really carved out who you would not extend this to on the seven-day therapy and really identifying that maybe we don't have enough information on the more critically ill patients. So, I really appreciate that. That was definitely one of my questions. To elaborate on that, is there any source that you might reconsider for extending this seven-day versus 14-day therapy? That's a good question. I think really what it comes down to is, are we able to obtain source control? So, whenever I think about something like an intra-abdominal infection, we have data that says that we can do shorter durations of therapy based on something like the STOP-IT trial. However, another limitation of that study really is the population that was included was not all of them were critically ill, and sometimes we're not able to really get source control for those patients. So, for something that we need to go in and surgically drain the source, and we're not able to do that due to their severity of illness, that would be someone I would hesitate to not apply that information to. I think for a patient who had a skin and soft tissue infection that can't be debrided or is not clearly improving, that might be someone that I would be hesitating to extend this to. So, I think it really just depends on how they're clinically improving, and if we have other evidence that their infection is clearing via imaging, so I think it really is patient-dependent. Yeah, I completely agree. And I did just note in the subgroup, the patients that did have a source from the lungs, and although this is really just hypothesis generating, but those patients also weren't able to see that non-imperiority. So, maybe, again, considering their clinical status, as you mentioned. Sure. Great. I do have an additional question. I wanted to know, did this trial change your outlook on seven versus 14 days of therapy given the recent evidence on this topic? And then, what do you feel that this trial added to the current data that we have? Yeah. You know, I think that something that is really our role as a pharmacist, one of the biggest things that we're responsible for is antimicrobial stewardship, and so I think, for me, it provides a little bit more comfort in my really clear septic shock patients who improve extremely rapidly with just one or two doses of antibiotics or quickly off of pressers. It helps me feel a little bit more comfortable coming off of antibiotics sooner, but I think, you know, as with, you know, our complicated, critically ill patients that are not rapidly improving and we have to start thinking about other sources of infection or identifying, you know, where else this could be coming from, you know, I do think that's an area that is still missing from practice, but I think, really, what it comes down to is, like, promoting that discussion on the team and providing a little bit more comfort with peeling back on antibiotics whenever the patient is clinically ready, so I think that's kind of where I feel a little bit more comfortable and it provides some evidence for, but there are always still remaining questions, especially for our extra-sick population, you know, as is probably consistent with most disease states in the ICU population, those patients who are really, really sick, we have to be extra-cautious about, you know, applying these studies that include a broader population, too. Great. Thank you, Kayla, for your time and for presenting on this topic today. Thank you. Before we move on to our next presenter, we would like to ask a brief polling question regarding today's attendance to gain a better understanding of our overall attendance to ensure continued support of this Spotlight on Pharmacy webcast. If you have a moment, please take time to fill out this quick poll. How many attendees are you viewing this webinar with? Thank you. Now, I'd like to introduce our second presenter, Natalia Smith. Thank you for the introduction, Lauren. So my name is Natalia Smith. I am a current PGY-2 in critical care at the University of Maryland Medical Center, and today we'll be discussing a trial that was published in the New England Journal of Medicine back in August of 2024, titled A Randomized Trial of Intravenous Amino Acids for Kidney Protection, also known as the PROTECTION trial. For background, for the purpose of this trial, the incidence of acute kidney injury in our post-cardiac surgery patients is very high. It can vary based on what type of definition of AKI we're using as well as the type of surgery, but the incidence has been shown to be up to 70% in certain populations. So we care about this because AKI is a huge risk factor for the development of chronic kidney disease. It utilizes a lot of medical resources and increases our risk of mortality. One of the risk factors for AKI post-cardiac surgery is time on cardiopulmonary bypass, which can decrease renal blood clot flow by over 50%, leading to decrease in renal hypoperfusion. Currently, there's no consensus on how to best prevent AKI post-cardiac surgery. However, a common strategy is to maintain renal perfusion through the use of fluids. So amino acids have been theorized as a potential preventative strategy. Due to animal studies that demonstrate they can increase renal perfusion, renal oxygenation, as well as increase glomerular filtration rate. Some previous studies have demonstrated potential for a renal recovery after receiving amino acid infusions. And in particular, there was one single center pilot study of 69 patients that showed that continuous amino acid infusions actually reduced the rates of AKI in our adult cardiac surgery patients requiring cardiopulmonary bypass. Based on this previous literature, the protection trial set out to evaluate whether intravenous amino acid therapy would reduce the rate of acute kidney injury in patients after cardiopulmonary bypass during cardiac surgery. This was a double-blinded randomized controlled trial conducted at 22 centers across three different countries. Patients were included if they were 18 years of age or older, if they were undergoing an elective cardiac surgery requiring cardiopulmonary bypass, and if they're expected to stay more one or more nights in the ICU. And then patients were excluded if they were on renal replacement therapy beforehand or expected to be on it after, and those who had chronic kidney disease of stage four or greater. So patients who are enrolled in this trial were randomized to either the placebo group or the treatment group. The placebo group received continuous infusion of lactated ringers, while those in the treatment arm received amino acids continuous infusion. This was dosed at two grams per kilogram of ideal body weight per day, up to 100 grams a day max. And of note, the patients in the placebo group received the equivalent rate as those in the amino acid group. And also they did take into consideration patients who were receiving enteral and parenteral nutrition and adjusted the continuous infusion to make sure they weren't going over this two gram max. The patients who were included in this trial, they started the continuous infusions right after cardiac surgery, and they were continued on it until one of the following criteria was met. 72 hours went by, they were discharged from the ICU, they were initiated on renal replacement therapy, or they passed away. The primary endpoint for this study was occurrence of acute kidney injury within the first week after surgery. Of note, the way they defined acute kidney injury followed the KDGO criteria for staging. However, they only used the serum creatinine components. They didn't include AKIs based on urine output. For the secondary endpoints, they also looked at severity of AKI, use and duration of renal replacement therapy, duration of ICU and hospital length of stay, duration of mechanical ventilation, and death. For statistical analysis, it was determined that a sample size of 3,500 patients was needed to provide 90% power to detect a 20% lower risk of AKI in the amino acid group, assuming a baseline rate of AKI being 25%. Statistical analysis was set at the two-tailed 0.05 alpha level for hypothesis testing. And dichotomous data was compared using the two-tailed chi-square test or Fisher's exact. In total, the study recruited over 3,500 patients with roughly 1,700 patients in each of the two arms. The median age that we saw was in the mid-60s. The majority of patients were male, about 70%, as well as white, around 98%. The median preoperative serum creatinine was just under one, and the median left ventricular ejection fraction was around 60. These patients spent roughly 90 minutes or one and a half hours on cardiopulmonary bypass, and the vast majority of our patients, over 90%, received either a CAVG, mitral valve, aortic valve surgery. In terms of the amount of fluid they received of either amino acids or lactated ringers, they received 1,200 mLs or 1.2 liters. The primary result of this study in hospital AKI within one week after surgery occurred in 26.9% of our amino acid group patients versus 31.7% of those in the placebo group. This was a statistically significant difference. When evaluating the AKI by the stages, there was a statistically significant difference when evaluating stage one and stage three AKI. However, this was not seen in stage two AKI. And across our secondary outcomes, there was no difference in rates of renal replacement therapy, mechanical ventilation, ICU or hospital length of stay, or mortality. And there was no notable difference in safety outcomes. All in all, the authors of the protection trial concluded that continuous amino acid infusion resulted in a lower rate of AKI compared to when crystalloid solutions were used and without any effects on adverse events. So looking at some of the pros and cons of this study, on the pro side, this was a large randomized control trial, including over 3,000 patients. For a cardiac surgery study, it did have relatively broad inclusion and exclusion criteria. And there was no significant difference between baseline characteristics. Provided that your institution has access to amino acids, it is fairly feasible to apply what they did in practice as they basically put patients on a set rate that didn't require titration and didn't require much monitoring as well. When we look at the limitations of this study, there are several to consider. First was their definition of AKI. So while they did use the KDGO criteria for AKI, they only used the serum creatinine component and didn't take into account urine output decreases. So this may have underestimated the total number of AKIs seen in the study. Additionally, there was no standardized protocol for how all these different centers should prevent or manage an AKI or when they should be initiating renal replacement therapy. So the practices could vary from center to center by provider, and this potentially could have influenced outcomes. Also, the study has limited generalizability, especially when thinking about a US population. Most of the centers were based in Italy and the population was largely white and overall relatively healthy at baseline. In addition, they had a higher proportion of valve surgeries to cabbages, which is maybe a slightly different mix than we may see in the US as well. Since over 90% of the patients underwent an elective cabbage or valve surgery, it's unclear how this may be applied to other types of surgeries. And another factor that I think is important to consider is that the primary outcome was essentially a serum marker and didn't really take into or wasn't a patient-centered outcome. While AKI does have these downstream negative outcomes that we know about, the study didn't show any difference in these renal replacement therapies, length of stay or mortality. Additionally, the study didn't factor in cost and potentially the cost savings of using amino acids versus lactated ringers. For my interpretation of this study, the primary outcome of acute kidney injury reduction was statistically significant with a number needed to treat of only 21 patients. However, when we looked at the breakdown of AKI, this was largely driven by stage one and the true clinical impact of stage one AKI is unclear. The rates of stage two and stage three AKI were very low. And while stage three AKI was statistically significant, a lower rate in the amino acid group, the number needed to treat to see a difference in that was 72 patients. And overall, this didn't lead to any difference in our renal replacement therapy. Additionally, there was no difference in any of our secondary outcomes, which were all more clinically relevant or more patient-centered outcomes. So before we go into overall takeaways from the study, we have some of our polling questions, mostly to see how patients are managing their post-cardiac surgery patients and preventing AKI. So for our first poll question, does your institution give continuous infusions or have a protocol for giving continuous infusions post-cardiac surgery? All right, we've got quite a little bit of a mix here. And then for our next polling question, I would be interested to see if anyone actually tried, has ever tried using IV amino acids for renal protection at their institution. Interesting, I'm impressed that a site has done that. I will say we fall into the last category where at Maryland, we don't actually stock amino acids in our institution. So that would be a bit of a change to make for us. All right, so my final takeaways regarding the protection trial. So overall, I did think this was well-conducted and a robust randomized control trial with a large patient population. However, I think the clinical applicability is rather limited as there was a lack of patient-centered outcomes that we saw. And it was primarily focused in elective CABG-involved patients and overall encompass a more stable population. So it's harder to say how it would affect all of our cardiac surgery patients, non-elective as well as surgeries that were not CABGs-involved. Do this, it would not impact practice at my institution. Also taking into consideration, we don't have stock amino acids. So it would have to be a quite a robust outcome for us to change that practice. However, it does provide some questions for future research, such as looking at optimal rate and duration of fluids. One potential thought was that these patients only received 1.2 liters and sometimes we found at our institution maybe resuscitating them a little bit more, maybe more beneficial, or possibly trial bolusing versus continuous infusions. Additionally, looking at applications in other surgical populations or critically ill populations who are also risk at AKI could expand its use. These are my references. And I would be more than happy to take any questions. Thank you for your time. Thank you, Natalia, for this presentation on the protection trial. If you do have a question, please feel free to add it into the question box in the control panel. That is where we will be actively checking for questions. Natalia, thank you for pointing out one of the biggest probably concerns that I myself also had with the outcome and that it was not patient-centered. I wanted to ask, did trial provide any data on long-term changes in serum creatinine? So beyond this seven-day mark, did they look at outcomes at 30, 90 days? And did the difference maintain? Yeah, that's a great question. So the question is, did these outcomes, were they prolonged or did they study look into that? From what I saw, they didn't comment on long-term outcomes. I can definitely always double check and make sure I didn't miss that. But I wouldn't personally expect it to change. We're already kind of doing this prolonged seven days, so a whole week after the cardiac surgery where we're looking for rates of AKI. And so I imagine that within that time period, so many other things could have possibly happened. And the majority of our patients were only in the ICU for a very short time. So it is a good question to think about whether there is more long-term benefits, but not that I saw in this study. And did they comment on maybe some medications that would cause, that could increase a patient's risk for AKI that are commonly used or that can be used in cardiac surgery? Every institution may be a little bit different. Do you mean in terms of like what they received after the surgery? Yes, like antibiotics, pain control medication. No, they listed the pre-op medications that patients were on and some of those that could have led to AKI. But I think that's a great point of considering like what patients were receiving while they were inpatient. As there's multiple things that can lead to AKI and not just like the cardiac surgery, cardiopulmonary bypass. Yes, thank you. And thank you again for pointing out the key takeaways and the strengths and the areas of further research for this trial. They're very good job. Thank you. Now we will move on to our final presenter for today. Ms. Angela Castro. Hello everyone. My name is Angela Castro, PGY2 Critical Care Pharmacy resident at UC San Diego Health. I have no disclosures to announce and my presentation is a proactive approach to blocking stress in the ICU. So a little bit of background is that up to 40% of patients in the ICU are mechanically ventilated and we use sedation to help patients feel more comfortable while they're on the ventilator. However, our traditional sedatives do have limitations which brings up the question, is there an agent that can be used to reduce the need or reliance on these traditional sedatives? So patients who are critically ill have increased agitation and delirium that is driven by hyperactivity and the sympathetic nervous system. The locus surrealis, which is that blue dot located in the brainstem is responsible for releasing norepinephrine to the amygdala, hippocampus, hypothalamus and prefrontal cortex. And these areas of the brain are responsible for wakefulness, attention, behavioral flexibility and cognitive control, which can ultimately lead to agitation and delirium when it's hyperactive. And so then that leads us to potentially a beta blocker as a potential agent as it can help block that sympathetic activation. Dexmedetomidine works similarly to block some of that norepinephrine release, but propranolol on the other hand blocks norepinephrine from working in the forebrain and also decreases that sympathetic nervous system activation. So there's growing evidence for the use of propranolol in patients with traumatic brain injuries and within the burn population. And so the PROACTIVE trial is attempting to expand that patient population that propranolol therapy could be applicable to. So the PROACTIVE trial is the propranolol as an anxiolytic to reduce the use of sedatives for critically ill adults receiving mechanical ventilation. And it was published through SCCM in February, so just last month. The primary objective was to investigate whether enteral propranolol reduces the need for IV sedatives in mechanically ventilated ICU patients by better addressing that agitation and delirium component. So about the study, the study was an open label randomized controlled trial. It was multi-site across three academic medical centers within their medical and surgical ICUs. They enrolled 72 patients between January of 2021 and October of 2022, and it was really born out of the COVID pandemic. For primary outcomes, they looked at a change in sedative dose from baseline to study day three. And for secondary outcomes, they looked at the proportion of the patients who are within target RAS range to keep them better comfortable as well as incidents of delirium, ICU length of stay, and of course, if there are any adverse events. Patients were included in the study if they were adults that were anticipated to require mechanical ventilation and also anticipated to have a stable RAS target for greater than 48 hours. Patients also had to have a minimum sedative infusion dose for more than 24 hours of either propofol at greater than 1.5 milligrams per kilo per hour, which if you're used to seeing that as micrograms per kilo per minute, it comes out to 25 micrograms per kilo per minute, or a midazolam infusion greater than one milligram per hour. Patients were excluded if they required a neuromuscular blocking agent at the time of enrollment. So if the patient was on a cesatricurium infusion, for example, if they had any contraindications to beta blockers, this could be first, second or third degree heart block or bradycardia at baseline or hypotension requiring three or more vasopressors or any one vasopressor at greater than the amounts listed below. Patients were also excluded from the study if they didn't have any enteral access as they were looking at enteral propranolol administration. So the starting dose of propranolol that they used was 20 milligrams every six hours, and they were reassessed for titration every 24 hours. At the same time, the care teams were prompted to assess whether or not the sedation target could be achieved with lower doses of IV sedatives every time they were asked to assess whether the patient could be titrated up on the propranolol. Patients were also not increased on their propranolol dose if they were not able to have a stable heart rate of greater than 70 beats per minute. For the control arm, it was just a standard sedation protocol with either propofol or midazolam and titrated to a RAS target specified by the team. On average, the patients were pretty similar between the two groups. Their average age was 54 years old, 69% male. Do wanna point out though, more patients with a positive CAM ICU score in the control group, which could potentially mean that patients had a bit more higher agitation and delirium at baseline in the control group than the intervention group. Only about 30% of the patients had a COVID diagnosis. As you remember, this was completed during the COVID pandemic. Otherwise, patients had a very broad range of indications. Patients also had a relatively low SOFA score of four to five which meant that patients were overall low acuity, but however, this also increases its generalizability because it had a very broad patient cohort. Some more things about the patients is that there was more patients in the control group who were on beta blockers at baseline. Also more patients in the propranolol group were on low dose face suppressors at enrollment and also had higher norepinephrine requirements at baseline. So for the outcomes. So the study authors compared with baseline, there was a 53.9% decrease in the sedative dose on day three in the propranolol group compared with the control group, which saw a 33.9% reduction. They used a Mann-Whitney U test to calculate this difference and it was statistically significant. And you can see it there on the graph as well, that at day three, there was a reduction in the sedative amounts. For secondary outcomes, there was more patients with a RAS assessment within the target range. And there was no significant difference in delirium-free days, ICU or hospital mortality, as well as ventilator-free days. The mean duration of mechanical ventilation was 13 days versus a mean duration of propranolol use was 10 days. And so although the addition of propranolol didn't have a large impact on ventilator days or hospital length of stay, it may still have had an indirect benefit for patients in the sense that they may be more comfortable without receiving larger amounts of sedatives. So taking a look at the adverse events, they were pretty similar between the two groups, but a couple of things I wanted to point out was that there was a higher incidence of bradycardia in the control group, which is not what you would normally expect when adding a beta blocker to a patient's therapy. And then there was a 70% of patients in both groups required the addition of another vasopressor due to hypotension. So both of the groups had similar amounts of hypotension. For the strengths and limitations of the study, main strength is that it was the first randomized control trial that evaluated propranolol for sedation reduction. It was a multi-center trial, which in general is a very good study design. For limitations, the study was fast-tracked due to being done within the COVID pandemic, which led to the study being an open-label design. This could have led to bias in the form of the Hawthorne effect, and the results may not be completely generalizable to all ICU patients. For example, they didn't include patients in cardiovascular or neuro ICUs. So the study authors concluded that propranolol was a reliable sedative-sparing strategy in ventilated ICU patients. And taking that a step further, I think with a blinded randomized control trial with a larger cohort, it'd be better suited to see if propranolol has an effect on more clinical-type outcomes like ventilator-free days, ICU length of stay, or hospital length of stay. Now we can add this new trial to our growing body of evidence for the use of propranolol as an anxiolytic within a very broader patient population. Overall, thinking about the patients included in the study, I think propranolol could be considered for patients who have a lower SOFA score admitted to a medical or surgical ICU, and those who could tolerate propranolol and also a quicker titration of sedatives with the potential benefit of decreasing sedative requirements and reducing the sympathetic activation that ultimately leads to delirium and agitation for our patients. Then we have our first polling question. So does your ICU use propranolol or other beta blockers as part of sedation or agitation management? Lack of data seems to be the most popular choice. And yeah, I agree. This is really the first trial of its kind to attempt to look at the use of propranolol as a potential sedative sparing agent. So more evidence is definitely needed in order to really put this into clinical practice. And thank you, and happy to take any questions. Great, thank you, Angela. Yes, we will open it up now to the Q&A session. And thank you for pointing out and really doing a great job to outline maybe the patient population that this wouldn't be extended to because it wasn't heavily looked at. I do definitely have PAWS in a cardiovascular unit using this as well. Did have a question. You commented the result was statistically significant, but with the reduction of sedative requirements and what they found, do you feel like this has a clinical significance? Yeah, that's a great question. So yeah, I think because of the way that they did the study in the sense that they only looked if there was a reduction in the sedative requirements at day three, it didn't quite capture, but perhaps maybe what happened further along in the clinical course. So it's kind of hard to apply it to kind of every patient. And I think definitely larger study might be better suited in order to help point out some of those larger, more clinical impact type of outcomes such as the ventilator-free days or total ICU length of stay or hospital length of stay. Yes, and even looking at patients that were able, what was the number of patients that were able to come off sedation completely? It really just showed the percent reduction in the sedative requirements. So it definitely, while statistically significant, not sure how this relates to clinical significance in that reduction. And then again, the clinical outcomes, as you mentioned, were not different. And then one, go ahead if you have further comments. Oh, no, go ahead. And the last question here would just be, if you were creating a protocol for sedation weaning, would you include propranolol and at what point would you include it in the protocol? Yeah, great question. I think it's really hard to tell exactly at which point would be like the optimal point because they didn't quite look at timing of how soon propranolol was added to these patients regimens. It was just if they kind of met the requirements of whether they had like low dose vasopressor requirements and they were just on the sedative infusion for 24 hours. Otherwise, besides that, it was very broad in terms of like at what point did they add it. So I definitely feel like more studies need to be looked at in terms of timing specifically. Otherwise, I think you could kind of follow that just if the patient is stable enough that they could potentially handle adding on a beta blocker in general. But be very patient specific in that sense. Great, thank you. That concludes our presenters for today. I wanna give a big thank you to our three presenters and all of the audience for attending. As a reminder, this Journal Club is available every third Friday of the month. So please join us from two to 3 p.m. Eastern for the next Journal Club Spotlight on Pharmacy. And that concludes our presentation. Thank you very much.

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Pharmacology

Renal

Neuroscience

2025

Antibiotics

Analgesia and Sedation

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critical care pharmacy

antibiotic treatment

bloodstream infections

acute kidney injury

amino acid therapy

mechanically ventilated ICU

propranolol

therapeutic strategies