Hello, 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 Wanting Huang. I am the Critical Care Pharmacy Specialist and PGY2 Critical Care Pharmacy Residency Program Director at UC San Diego Health in San Diego, California. I will be moderating today's webcast. A recording of this webcast will be available to register attendees. Log into mySTCM.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 X or formerly known Twitter, following hashtag STCM CPP JC and hashtag Pharmacy. I see you. Please know the disclaimer stating that the content to follow is for educational purpose only. And now I would like to introduce your speakers for today. Each will give a 15 minute presentation followed by a Q&A. Our first presenter today is Dr. Nandini Patel, PGY-2 Critical Care Pharmacy resident at Brecken and Women's Hospital in Boston, Massachusetts. She will present on effectiveness of sublingual buprenorphine for pain control in the ICU. Our second presenter is Dr. Andrea Laycox, PGY-2 Critical Care Pharmacy resident at St. Anthony Hospital in Lakewood, Colorado. She will present on ceftriaxone to prevent early ventilator-associated pneumonia in patients with acute brain injury. And our third presenter is Dr. Kyle Humphreys, PGY-2 Critical Care Pharmacy resident at UAB Hospital in Birmingham, Alabama. He will present lentinel and organ failure in patients with septic shock, the STRESS-L randomized control trial. And now, I will turn things over to our first presenter. Hi everyone, my name is Nandini Patel and I'm currently a PGY-2 Critical Care Pharmacy resident at Brecken and Women's Hospital. Today I'll be presenting on an article titled Effectiveness of Sublingual Buprenorphine for Pain Control in the ICU. As we know, the PADIS guidelines emphasize the principles of analogous sedation and analgesia-based sedation. Implementation of guideline recommendations are outlined in the ICU Liberation Bundle, A to F, which is listed on the slide. We'll be focusing on A, which stands for assess, prevent and manage pain, and C, choice of analgesia and sedation. We know that acute pain is typically treated with intravenous opioid pushes, and if the pain persists or recurs, an opioid infusion is typically added. When patients are ready to be transitioned out of the ICU to the floor, clinicians schedule enteral medications in addition to intermittent IV opioids. I do wanna mention that the American Pain Society and American Society of Anesthesiologists recommend the use of oral over IV opioids in patients who can tolerate them. This brings us to the mechanism of action of buprenorphine. We know that buprenorphine is a partial agonist at the mu-opioid receptor, but it also is an antagonist at the delta and kappa receptors, which is purported to play a role in this limited GI motility effects that we see and reduced respiratory depression. It's also an agonist at the ORL1 receptor. In terms of its analgesic effects, buprenorphine does provide full analgesic effects. As a partial agonist, it has a ceiling effect for respiratory depression, which is typically cited to occur at sublingual doses of about 60 milligrams. Compared to our full mu-receptor opioid agonist, buprenorphine does have reduced effect on BRS in recruitment, which is another mechanism why we see reduced overall side effects of buprenorphine compared to our full opioid agonist. In terms of our picture on the bottom right, I also wanna draw your attention to the fact that buprenorphine has a preference for binding to receptors in the spinal cord versus the higher CNS or the brain. Again, this is another factor that's reported to have an effect with the reduced euphoria and respiratory depression that we see with buprenorphine. In terms of PK property, sublingual buprenorphine and buco-buprenorphine are pretty comparable, and they have a prolonged duration of action and a long half-life compared to our typical enteral opiates that we see in the ICU such as oxycodone and hydromorphone. The formulations that we have may be useful in patients that have concerns regarding gut absorption as this is available in a sublingual tablet and bucle film. Overall data with the use of sublingual buprenorphine in critically ill patients is limited, but highlighted here are two retrospective studies. The first study was conducted in adults admitted to the ICU who had a pain regimen that had transdermal buprenorphine. The authors found no significant difference in the median probability of significant pain as well as no significant difference in the median oral morphine milligram equivalents per ICU day. However, total opioid consumption was significantly greater in the transdermal patch group. However, this was attributed to a significantly longer length of stay in this cohort. The second retrospective study highlighted here was done in adult patients with opioid use disorder on sublingual buprenorphine or buco-buprenorphine as outpatients. The authors found that about 44% received buprenorphine with an average dose of eight milligrams per day and full agonist opioid use was more frequent on days when buprenorphine was not administered. This brings us to our first polling question. Do you or your colleagues currently use sublingual and or buco-buprenorphine for acute pain management in the ICU? A, all the time. B, sometimes in surgical patients only. C, never thought about it. Or D, sometimes given concerns regarding absorption. As expected, 0% across the board and we'll find out more as we delve into this study. The objective of the study was to compare pain control and opioid consumption in critically ill patients who were treated with sublingual buprenorphine or enteroxycodone during the ICU admission. It was a retrospective cohort study conducted in all patients with opioid use disorder and the outcomes were as follows. The first cohort was a group of patients with a retrospective cohort study conducted in Australia and adults 18 years and older admitted to the medical and surgical ICUs who received sublingual buprenorphine or enteroxycodone were included. Exclusion criteria included admission to neurologic or cardiovascular ICUs, having less than 10 pain scores recorded. Those who received both buprenorphine and oxycodone and epidural transdermal form of buprenorphine and if the intervention was initiated greater than 72 hours from ICU admission. Again, the intervention was sublingual buprenorphine versus enteroxycodone for acute pain management and selection of analgesics was largely based on clinician discretion. However, the authors did mention that sublingual buprenorphine use was often guided by whether or not patients could tolerate opioids via the gastrointestinal tract. The primary outcome was a probability of significant pain during ICU admission, which was defined as a score of four or greater on the numerical rating scale and six or greater on the behavioral pain scale. Secondary outcomes included opioid consumption during ICU stay measured in morphine milligram equivalents, duration of mechanical ventilation and ICU length of stay. Exploratory outcomes included proportion of patients who had RAS scores that deviated from goal ranges. Specifically at this institution, the RAS goal was negative two to one for most patients and ICU mortality. In terms of statistical analysis, the target sample size of 143 patients based on a difference of about 10%, which they extrapolated from their previous study in the transdermal patch group. The propensity score matching was used to balance the groups and Wilcoxon-Ransom test was used for the primary and secondary outcomes. They did perform two sensitivity analyses, both were multivariable regression analyses and the first one adjusted for propensity match variables and the second one used a modified definition of the primary outcome in which the behavioral pain scale was normalized to a scale of zero to 10. They also performed subgroup analyses across two groups of those who had a surgical diagnosis versus those who didn't, those who had an opioid use history prior to hospitalization versus those who didn't and those who required mechanical ventilation versus those who did not. In terms of baseline characteristics, we can see that in the propensity match cohort, there were no significant differences and this is evidenced by the standardized mean difference being less than 0.2 and specifically in this study, they looked at a standardized mean difference score of less than 0.1. Again, no differences with baseline characteristics. In terms of use of other agents, about 38% of patients in the total group required propofol and about 45% were on fentanyl. We can see that there was multimodal analgesia implemented as evidenced by greater than 70% use of Tylenol in both groups. In terms of the intervention, time to median time to first dose in the buprenorphine group was 33 hours versus 22 hours in the oxycodone group and the median first dose received in the buprenorphine cohort was 0.2 milligrams versus five milligrams for oxycodone. The median cumulative number of doses was three in the buprenorphine group versus four in the oxycodone group and the median cumulative dose of buprenorphine in the study was 0.8 milligrams versus 20 milligrams of oxycodone. The primary outcome, you can see there was no significant difference between the probability of significant pain and this was true on all days of ICU admission as evidenced by the graph. The results of the sensitivity analysis were consistent with the primary analysis findings. In terms of secondary outcomes, there was no significant difference with regard to opiate consumption between the two groups. There were days of mechanical ventilation as well as ICU length of stay and specifically there was a median of three days spent in the ICU. In terms of exploratory outcomes, there was no significant difference regarding deviations from the goal RAF scores and there was no significant difference in ICU mortality. In terms of their subgroup analysis with regard to the primary outcomes or probability of significant pain, the authors found no significant difference with regard to those requiring mechanical ventilation, versus those without an opiate history as well as surgical status and there were also no significant differences among the subgroups with regards to opiate consumption. The authors concluded that sublingual buprenorphine is as effective as enteral oxycodone with regard to pain control and opiate consumption in the ICU. And this brings us to our second polling question. What formulations of buprenorphine are available at your institution? A, sublingual and bucle, B, sublingual, bucle, transdermal, intravenous, C, sublingual, bucle, transdermal, or D, sublingual and transdermal? It's pretty interesting. So we have an interesting split. Most of our institutions do seem to have the bucle form available and this is something I'll bring up as we go through the various strengths and limitations of this study and how we would potentially implement this. So this brings us to our discussion. Overall, there was appropriate inclusion and exclusion criteria used in the study and a strength was definitely the use of propensity score matching. However, by nature of this method, there may have been residual confounding due to other variables that may have remained unbalanced. For example, chronic pain requirements and type of surgical procedure. In general, this patient population primarily had a low severity of illness evidenced by the relatively low apache and the low risk of heart disease. In addition to the relatively low apache, three scores, the low opiate consumption in patients and less than 40% required mechanical ventilation. About 62% of the population had a surgical diagnosis, limiting the generalizability of the results. There was similar use of other sedatives and analgesics between the groups, which is great because that reduces confounding that we may have seen due to the other agents. In terms of the intervention, sublingual buprenorphine was compared to an appropriate standard of care. As we know, enterooxycodone is often used in our critically ill patients and the sublingual formulation is a novel idea that might provide some benefits. The choice of intervention, however, was based on clinician discretion, which may have led to some selection bias. And the dosage strength that was used in this specific study was a 0.4 milligram sublingual tablet, which is available in Australia, but not available in the United States. Overall, the dosing strategy was unclear. Based on the median cumulative dose and the ICU length of stay, it seems that an as-needed dosing strategy was used, but this was not specifically stated by the authors. Some of the things I do want to mention with the intervention is regarding challenges with administration, especially in our mechanically ventilated patients and provider comfort using buprenorphine. In terms of endpoints, they did use the numerical rating scale and behavioral pain scale in this study, but other institutions might use different pain scales or different combination of pain scales and have different protocols, which may not make these results broadly applicable. The authors reported opiate consumption in terms of oromorphine milligram equivalents versus fentanyl equivalents, and other endpoints of potential interest were not evaluated, such as adverse effects, one notable being respiratory depression. There was uncertainty regarding the clinically important effect size of the 10% difference used, but overall appropriate statistical tests were used to evaluate outcomes, and it was nice to see the use of sensitivity in subgroup analyses. In general, insufficient evidence exists to recommend the routine use of sublingual buprenorphine for acute pain control in critically ill patients, but it may be considered in select patients and various factors limit the generalizability of this study. Theoretically, buprenorphine is an attractive option to bypass the first pass metabolism. It has a ceiling effect for respiratory depression and low risk of withdrawal at low doses used for pain management. And some disadvantages, although, include that there are challenges with administration, especially in our mechanically ventilated patients, provider comfort using buprenorphine for acute pain may not be there, and there are concerns regarding dose stacking, especially in patients with dynamic pain requirements. Arguably, this patient population may not have been the ideal population to test this intervention is, as patients in this study were not in the ICU for a long time, used overall low doses of opioids and less than 40% required mechanical ventilation. Further data is needed to guide the use of sublingual buprenorphine in critically ill patients. And thank you, I'm happy to take any questions. Thank you. Thank you, Nadine, excellent presentation. I have a question for you. You mentioned in your conclusion slide that the further investigation will be needed. Do you feel at this point, based on your research for this presentation, that they're having enough evidence to support sublingual buprenorphine using critically ill patients that we can start thinking about a randomized control trial? And if you think this retrospective study provide enough evidence, how would you design your study groups? Yeah, that's a great question. I think some of the things to take away from this study are that there might be only a select patient population where we might be comfortable. For example, a patient who has a stable pain requirement, we may not be as worried about like dose stacking and overshooting in terms of going back to enteral or other full agonist opioids, in which case we might have those opioids acting as well as the longer acting buprenorphine in the background as well. So I think where we might see a role and based on the results of the study, how they use it is a patient who have a stable pain requirement. These patients had an overall low requirement for pain. I think that's not ideal because obviously want to use in patients who actually require it and see what the role there might be. There is data to support using buprenorphine in chronic patients with chronic pain. So I think stable pain requirements, patients who may be a surgical patient population might be ideal, but I would like to see both medical and surgical patients and have a more even split to kind of see what the differences might be and then do potentially a subgroup analysis. I think in general, if we were to do a randomized control trial, we would want to use a comparable opioids, in this case, enteroxycodone was used. I think that's still a reasonable intervention to compare to, but I think we need a patient population that is more representative of what we see in our typical ICU. So more patients might be mechanical ventilated, they have higher opioid requirements, greater ICU length of stay. And then we randomize them to get enteroxycodone or sublingual buprenorphine and have a clear dosing strategy. But I think something like Q8 hour buprenorphine might be useful and we can start PRN versus oxyPRN and then go from there and see how the intervention functions. But I think this is a difficult question to answer and I don't think all the answers are there because of the different challenges and dynamic pain requirements with critically ill patients. And again, I think another thing specifically, depending on where the study is done, for example, if it's conducted in the United States, we would have to use like the buccal buprenorphine, which sublingual and buprenorphine formulations have comparable bioavailability characteristics. So we could use about the 150 mikes buccal film in this study, the median dose of buprenorphine received was about 200 mikes. So that would be the closest we'd be able to get in terms of a study based out in the United States. Wonderful, thank you. What, there was some clarification questions was any, did the author evaluate Cal score to determine if the patient were put into active withdrawal? Was there any reported in the study? Yeah, there was actually no opioid withdrawal reported in the study. The authors didn't specify how they evaluated that and it's really just a small sentence that they have in their discussion. And I would definitely want to know more information about that, but I would based on the PK properties and the sort of data that we already have available at low doses, less than two milligrams, typically the likelihood of withdrawal is really low. And in this study, patients seem to have gotten really low doses. So just from that standpoint, you know, we wouldn't have, I don't think I would have expected to see much withdrawal anyway. And last question, is there a timeline you will recommend for initiation? It seems maybe it should be used sooner before the tolerance to opioids is built. So I think that's a great question. And I think that's going to depend on a variety of factors. For example, when we have, I think one of the key things is that it's challenging to use this in someone with dynamic pain requirements. So when we have a patient who's sort of stabilized and then we're comfortable transitioning them to an enteral regimen, we can initiate, we can initiate buprenorphine and then go from there. I do think with the use of other opioids, it's at the low doses, it's just sort of, I think, challenging to hash out. You know, if we, I guess the question would be like, if you're starting it earlier, would you run the risk of displacing other opioids and having patients not adequately recovered with pain or having withdrawal? But again, at the low doses that we use for pain, again, I don't think this would be likely. And then we could start with a low dose and sort of up titrate when patients have a stable pain requirement and then go from there. That concludes our Q&A session. Thank you, Nadine. Before moving 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. How many attendees are you viewing this webinar with? Is it just me to five people, five to 10 people, or greater than 10 people? Now, I would like to introduce our second presenter, Dr. Andrea Leica. So, thank you again for that introduction. My name is Andrea Leal-Cox. I'm a PGY-2 critical care pharmacy resident at St. Anthony Hospital in Lakewood, Colorado, and I'm excited to be chatting with you all today about this article, Cetriaxone to Prevent Early Ventilator-Associated Pneumonia in Patients with Acute Brain Injury. It came out almost two months ago now and has caused quite a bit of buzz in the time since, and so I'm excited to review this data and discuss how this may impact practice at the end. So, moving into some background, this article addresses the fact that certain patients, such as those with acute brain injury or post-cardiac arrest, may be at increased risk of early ventilator-associated pneumonia, or VAP, due to aspiration prior to infection. Two articles of note that have investigated this include the ANTHARTIC trial, which looked at 48 hours of IV amoxicillin and clavuanate and saw significantly reduced rates of early VAP, specifically in patients who were post-cardiac arrest and undergoing targeted temperature management. However, they did not find a significant difference in their impact on patient-centered outcomes. Further, the SUN ICU trial looked at selective digestive tract decontamination, which involved oral care, gastric antimicrobial suspension, and four days of IV antibiotics, and found that that bundle of interventions did not impact mortality in critically ill patients requiring mechanical ventilation. However, a post-hoc analysis of this study, specifically looking at brain-injured patients, did show a mortality benefit. Thus, these investigators in this article sought to assess if a single dose of cetreaxone given to patients with acute brain injury may prevent early VAP and impact-related outcomes. Moving into their methods, they conducted a multi-center, randomized, double-blind, placebo-controlled superiority trial. This occurred in eight university hospitals in France and examined adult patients intubated with an expected ventilation duration of at least 48 hours following acute brain injury. A further look at their inclusion and exclusion criteria shows that they were specifically looking at patients with coma due to head trauma, stroke, or subarachnoid hemorrhage, and excluded those with coma due to tumor, infectious disease, or cardiac arrest. They also excluded patients with previous hospitalization within the last month and those expected to receive antibiotic prophylaxis within 24 hours of randomization. The intervention they administered was cetreaxone 2 grams IV over 30 minutes, once versus placebo. It was necessitated that this be given within 12 hours of endotracheal intubation and within 48 hours of hospital admission. They also stratified their randomization by GCS less than 8 or greater than or equal to 8. Their primary outcome was the development of early VAP occurring on day 2 to 7 of mechanical ventilation, per their definition. This was adjudicated by two senior intensivists masked to the study group who reviewed all cases of VAP. Their definition for VAP was listed below using the American Society of Thoracic Surgeons definition, which includes at least two clinical criteria listed there, new or worsening consolidation on chest x-ray, and positive respiratory culture with the yield cutoffs listed here for sites of attainment. This largely matches the anthartic definition, though they looked at a few more criteria in the anthartic trial, such as an increase in sputum or purulent sputum, increased ventilator settings, and the anthartic VAP window is day 0 to 7. So, this feels a little bit more narrow to hone in on a more appropriate VAP definition. Their secondary outcomes they examined were examined at two time points. So, the top half there was examined at ICU discharge or day 28, and they also further examined some at day 60. So, the ICU discharge or day 28 outcomes included the instance of late VAP and ventilator-free days, as well as antibiotic-free days. They also looked at functional status and mortality and using modified Rankin scale for functional status assessment. Modified Rankin scale and mortality were also examined at day 60, as were ICU-free days and hospital-free days. Some other clinical practice and definitions of note include their standard ICU care for the prevention of ventilator-associated pneumonia. These included head of bed elevation to 30 degrees, standard hand hygiene for staff, and mouth care every eight hours. There were some differences in this standard of practice. Some centers used chlorhexidine, being in three centers, or sterile water in six centers. This is another point of controversy in the prevention of ventilator-associated pneumonia, as more recent meta-analyses have suggested that there may be no difference between these two practices. However, historically, chlorhexidine has been used to prevent VAP. In addition to calling out these clinical practices in this study, there was no auditing or reporting of adherence to these practices, however. For their sample size calculation, they based this on a predicted incidence of early VAP of 30% in the control group and 15% in the intervention group, for which they calculated they would need 354 patients for a 90% power and a two-sided alpha of 0.05. For their outcomes analyses, they used appropriate statistical tests, including Chi-square or Fisher's exact tests for categorical data, and T-tests or Mann-Whitney U-tests for continuous data. They also adjusted their incidence of VAP for covariates, including death being considered as a competing risk, where a patient experiencing mortality early would have less risk of developing VAP early, and then the ventilator weaning was considered a censoring event, as if a patient was liberated from the vent, they would not meet the VAP definition. For their results, they examined and assessed more than 2,000 patients and excluded quite a few for being expected to receive antibiotics outside of the study intervention. This would largely exclude polytrauma patients who may receive open fracture for prophylaxis or facial fractures or EBD placement. The others did not specify that breakdown, but that would be my assumption. And then they excluded 366 patients for being ventilated greater than 12 hours before being able to receive study assignments or more abundant status. That left them with 345 patients randomized and ultimately 162 patients in the septor axon group reanalyzed and 157 patients in the placebo group. Some notable baseline characteristics to call out include that the most common etiologies of severe brain injury were subarachnoid hemorrhage and brain trauma. The most commonly occurring GCS score range was in the 4 to 8 range at 60 and 65 percent of each group. And they were able to relatively quickly achieve their intervention early. And it needed to be given within 12 hours. And the median time was seven hours. 24 patients did also receive antibiotic prophylaxis for a surgery, as noted in that lower right hand corner. So they tried to predict those that would need antibiotics and exclude them. But a small number did end up receiving antibiotic prophylaxis, but relatively low compared to their 300 plus person enrollment. And they also noted which patients received chlorhexidine mouth care versus sterile water. And this was fairly balanced between the two groups. And again, reflective of that controversy in practice and difference among centers. Their primary outcome was significant. They found that the incidence of early VAP was lower in the ceftriaxone group compared to the placebo group at 14 percent versus 32 percent. The most commonly isolated bacteria in those events of early VAP included methicillin sensitive Staph aureus, Streptococcus species, Haemophilus species, and E. coli. Of note, they had relatively low rates of drug resistance. There was one methicillin resistant Staph aureus cultured and one ESBL enterobacteriaceae. Again, in those incidences of early VAP. The ceftriaxone group also had a greater median ventilator free days at nine versus five days. And also a greater number of antibiotic free days at 21 versus 15 days. Again, those two outcomes were assessed at 28 days. Modified Rankin score or functional status was similar among the two groups at both time points of 28 days and 60 days. However, 28 day mortality was lower in the ceftriaxone group at 15 percent versus 25 percent. This did not remain statistically significant at 60 days, although it continued a numerical trend favoring the ceftriaxone group. At day 60, the ceftriaxone group also had more ICU free days and hospital free days. So from this, the authors concluded that a single dose of ceftriaxone decreased risk of early VAP in patients mechanically ventilated for acute brain injury. They recommended including this in all bundles for the prevention of VAP in this patient population, which is a fairly strong conclusion. Authors will often conclude that more evidence is needed being the first in this area to study this. And so they offer this fairly strong conclusion and an easy way to implement it with implementing this into bundles or order sets. Which brings me to my personal conclusions and discussion, thinking about the applicability of this. I think they appropriately identified a high risk population, looking at that subgroup of patients with brain injury, that also saw some benefit in the SUD-ICU trial. They also used an appropriate VAP definition, trying to narrow in on some clinical criteria, and those were adjudicated. The adjudication appeared to be fairly strict, as around half of the VAP cases that were clinically reported were not adjudicated by the intensivists who were blinded to study assignment. They also looked at relevant patient-centered outcomes, and I think that's one of the main strengths and takeaways from this presentation, is the translation to more antibiotic free days. Though the mortality could be up for debate on what is most contributing to that, I would have been surprised if ceftriaxone was the only contributor, though there were no significantly different baseline characteristics to point to for that mortality difference. Some limitations include that there is no monitoring for standard of care adherence, as previously mentioned. And VAP definitions, in general, can be notoriously inaccurate. I think they did the best that they could. But specifically including microbiological yields may have led to a falsely low rate in the ceftriaxone group. They also used a longer VAP definition than some prior studies, although similar to the anthartic trial, which begs the question of is ceftriaxone always adequate to prevent more late occurring incidences of VAP, in which you may see more antibiotic resistance. There's also a low prevalence of antimicrobial resistance seen in this study. There are only two multidrug resistant organisms reported. And so this may not be appropriate for all settings to implement this. This may not be applicable to patients with a history of drug resistance or in units that have higher rates of drug resistance. And this also brings up a question of what is the long term impact of this on antibiograms to give all patients the ceftriaxone dose up front. But again, I think that overall, greater antibiotic free days is compelling. So my personal conclusions and application include that an early single dose of ceftriaxone to prevent early VAP in intubated patients with acute brain injury was associated with a decreased risk of early VAP. And the patient-centered secondary outcomes I think are also compelling in this, including the decreased antibiotic and ventilation exposure, as well as 28-day mortality, ICU and hospital length of stay. However, I think some further information is needed on safety. There would not have been power to detect differences in some safety events, such as incidence of C. diff infection, as well as more information is needed on antibiotic resistance, as this may not be applicable to all centers with higher rates of drug resistance. And with that, that brings us to our first polling question. Do you use selective oral decontamination or selective digestive tract decontamination at your institution? So I see the majority are dressed over a majority and fairly split, but leaning towards not using this. And so it seems to be fairly split as it was in these investigators centers where three centers use florexine and six use sterile water. And then my second polling question is, is your institution considering changing VAP prophylaxis to match this study protocol? So yes, we've implemented a formal practice change, or have you seen some informal practice changes? Then there's that third option in the middle. Maybe you're in the process of discussing. Fourth, this study does not provide sufficient evidence, or you're unsure and have not yet discussed this data. I see 51% there saying this study does not provide sufficient evidence for a change. I would say my institution currently are in that 9% category. Maybe we're in the process of discussing more among our team. Alright, so with that, I'd love to hear some more discussion with a bit of a split there on the opinions of impact in practice for this intervention. There is a clarification question. Did the authors examine if a difference in the rate of C. diff infection occurred between two groups? No, they did not. And this would have been something that would have been something that I would like to know. And if this is implemented at institutions, definitely something to examine with some retrospective data after implementation. Looking at the baseline characteristics in the supplemental, there were significantly more patients in the placebo group requiring surgery than the septal axon group. I think you mentioned that the use of surgical prophylaxis were the same between two groups. How would you interpret the results that placebo group might need more surgery, despite getting the same amount of surgical prophylaxis, and how that would impact your interpretation of the result? Yes. And so the authors noted that the rates again were similar of antibiotic prophylaxis, although it was not further delineated. And so seeing that more hard reported number of the rates of surgery being required, I wonder if some of those patients required surgery early and they counted the septal axon dose as adequate. Really, the impact potentially of that, though, would be that if there were increased rates of surgery in the placebo group, that could be protective as well of BAP. And so if anything, I think that would kind of decrease our difference in BAP screening among groups. With the increasing resistance and concern for MC producers, should we consider the possibility of using cefepine instead of septal axon if considering the use is actually for prophylaxis in this population? I think that's an excellent question. And so that leads me to thinking about local antibiograms and thinking about implementing this. And so at my institution, thankfully, we have some relatively lower rates of MC inducible, MC producing bacteria in our instances of BAP. But if your institution had higher rates, I think that using cefepime could be an alternative again. But as we start moving towards using broader and broader antimicrobials, you may get a little bit more pushback from our infectious disease colleagues and antimicrobial stewards when thinking about trying to limit our use of even broader agents. But I think cefepime could be reasonable in a patient with a history of inducible MC or in an institution with a less friendly antibiogram than my own. Why do you think at 60 days, the difference in mortality was no longer significantly different? Another excellent question. So at 60 days, they likely lost some of their power to detect that. It did seem to follow a fairly similar numerical trend. So still 20 percent in the septary axon group versus 30 percent in the placebo group. And so to me, it was reassuring of holding true in a numerical trend sense. I think they just lost some statistical power at that end point. What are your thoughts on the specific antibiotic choice within the study with ceftriaxone? And if the patient, of course, they excluded the patient with allergy to cephasporin or penicillin, I think, what would be your alternative to using those patients should also receive a prophylaxis dose? So the question was, I'm not sure if there are two parts to it, but I'm mostly going to address that second part of thinking about allergies. And so if a patient had a penicillin allergy, of course, I would do some more investigating as we often encounter someone who has an unlabeled penicillin allergy where it's not much specified the type of response they had. I first try to do some digging as many patients can still be appropriate for ceftriaxone even if they have a penicillin allergy listed, but if it was a true concern for allergy and not wanting to give ceftriaxone. Personally with the limited evidence in this study, I would avoid using some alternatives that would unfortunately have some broader coverage and may not see benefit, so I'm still on the fence personally about the applicability of this intervention, and so with that, without having strong evidence to back the administration of antibiotics, I would question whether that patient needs antibiotics, but I'd love to hear from the submitter of that question if they feel differently. That concludes our Q&A session. Thank you, Andrea. Now I would like to introduce our final presenter, Kyle Humphrey. Hey, everybody. I'm Kyle, and today I'm going to be talking about the Landilol and organ failure in patients with septic shock or the STRESS-L randomized clinical trial, and so just to start off here, just to take it way back to the basics here, when we're talking about sepsis, we're really talking about according to the surviving sepsis campaign guidelines as a life-threatening organ dysfunction that is caused by a dysregulated host response to infection, and so we define that as two or more of the SERS criteria plus a source of infection, and so this graphic here has a lot of information on it, but really all it is trying to convey is that ordinarily there is a balance between the pro-inflammatory response that is caused by pathogen factors such as viral load or the virulence of the pathogen and RNA anti-inflammatory response, and so when we're talking about sepsis, the surviving sepsis campaign recommends prompt resuscitation and antibiotics in order to reverse the cause of sepsis, and then also supportive care with things like vasopressors in order to maintain a MAP greater than 65 millimeters of mercury. And so the reason the beta blocker topic came up is because there's been some research historically about this, and so research from as early as the mid-1960s has suggested that excessive beta-adrenergic stimulation can exacerbate shock states, and so in 1969 there was a group led by Burke et al. who injected a group of healthy dogs with strains of E. coli and then gave some of them IV propranolol to see what would happen, and what they found is that the dogs that had received IV propranolol fared much better than the dogs who did not and actually had an increased survival rate, and so this kind of sparked some of the interest in this topic. So we have had some trials looking at this before, and so we start here with a trial that was a non-randomized case series of tachycardic septic shock patients who were either given IV esmol or who were given IV esmol infusion to reduce their heart rate by 20%, and so as you can see from the graphic here, this study showed that IV esmol infusion could be used to reduce patients' heart rate without compromising their mean arterial pressure, their stroke volume, increasing their norepinephrine requirement, or changing a lot of other hemodynamic variables, and so really from this graphic, all I want you to know is that on the right side here, there were no statistically significant differences in anything, any of these hemodynamic variables except for the heart rate, which is to be expected with a beta blocker. So moving on to a pilot study here of 25 septic patients requiring norepinephrine to maintain a MAP of 65 and who also had a heart rate of greater than 95, in this study patients were given esmolol to achieve a heart rate of 80 to 94 beats per minute, and so this study showed that IV esmolol could be given safely to reduce heart rate without compromising stroke volume, as with the last study, but this time there was actually a reduction in norepinephrine requirements from baseline, which you can see at the bottom of the graphic here, so at 24 hours, the norepinephrine requirements were lower than they were when they started. So obviously in this study there were changes in heart rate as to be expected like with the last study, and as a result, these patients' cardiac index went down as well, but the stroke volume and the mean arterial pressure remained unchanged in this time period. And so finally, a more recent study, this was the same author as the one before that I just showed you, but this time they performed a randomized control trial, looked at esmolol and its effect on heart rate control and hemodynamic and clinical outcomes for patients with septic shock. So again, this wasn't RCT, so they looked at septic patients who required norepinephrine to maintain 65 and who also had a heart rate of 95 or greater, so similar to the trials they performed prior, and they were randomized to either receive esmolol infusion or a control. So their objective was to see if esmolol could reduce the heart rate, which of course it did do, but more interest was sparked here from the reductions in norepinephrine requirements, which you can see on the left in the esmolol group, and then also the massive reductions in 28-day mortality that they found with the esmolol group demonstrated on the right, and so this was statistically significant, and so it sparked some interest in this topic even more. So moving into our study here, the hypothesis of our study really is that beta blockade would result in reductions in the sequential organ failure assessment, or SOFA score, for tachycardic patients with septic shock who are receiving norepinephrine. Their primary endpoint was the mean SOFA score while the patients were in the ICU after randomization with the idea that their study was going to be powered to find a one-point reduction in SOFA scores for their intervention group. Secondary endpoints here were 28, 90, and hospital survival, both the dose and duration of vasopressors administered, and then the ICU and hospital lengths of stay. They also looked at safety outcomes such as bradycardia, hypotension, and then also rates of heart block and arrhythmia. So the inclusion criteria for this study were adult patients who were treated in the ICU who had septic shock as defined by the Sepsis-3 criteria, so just to remind everybody on that, that is confirmed or suspected infection, new organ dysfunction defined by a change in their SOFA score by greater than two, also a blood lactate greater than two millimoles per liter at any point, and a vasopressor requirement, so patients who do have shock. And so also these patients had to have a heart rate of greater than 95, and they had to have vasopressor use at greater than or equal to 0.1 mics per kilo per minute of norepinephrine for greater than or equal to 24 hours. They excluded, honestly, a variety of patients, and so they had a very extensive list of exclusion criteria which I chose not to include because it is burdensome to look at. But notably, they did exclude patients who were tachycardic for pain or discomfort and patients who had vasodilatory shock from things other than sepsis, and so did a pretty good job of honing in on patients who are tachycardic because of their septic shock state. And so as far as the intervention, so patients were randomized into either their intervention group where they received landiolol infusion, and in the control group, patients did not. And so this was an open-label trial because one group was receiving a beta blocker and one group was not. And so if you are like me, you're seeing this landiolol drug and you have no idea what it is, but really this is just a drug that's not available in the U.S. It is a highly selective beta-1 adrenoreceptor antagonist, so just very cardio-selective beta blocker, which is metabolized by ester hydrolysis, giving it a rapid onset and rapid offset. So I kind of think of it like Esmolol. And so the usual dosage range per the manufacturer for this drug is 10 to 40 mics per kilo per minute. And so in this trial, patients were randomized to either get the drug or not. And so if they were receiving the drug, it was started at a mic per kilo per minute and titrated by one mic per kilo per minute every 15 minutes until they achieved a heart rate of 80 to 94 beats per minute. So the trial drug was stopped when vasopressors were off for 12 hours and the patient was within their heart rate goal. And then as far as the statistical analysis they performed, they performed a statistical analysis using the intention to treat population. They included all participants in their analysis, and then they also looked at the adherence to their study protocol and reported that as well. And so based on characteristics here, there were, you know, I didn't label it on accident, but the left column is the Landiolol group and the column on the right is the control group. And so there were 63 patients in each group that were analyzed. So overall, the patients were pretty similar in both groups. Median age around 56 and 59% of the patients were male. But some of the things that I think were interesting that they brought attention to in the trial was the focus of infection that was primarily in the lungs and abdomen. So we see about 75% of patients in both groups have some sort of pneumonia or abdominal infection. We also see a similar rate, about 70, 75% of the patients who had community acquired infections, so not that many nosocomial infections. And then as far as beta blocker administration, one of the interesting things is that a pretty large group of patients in the control group did receive beta blockers during their ICU admission prior to randomization, and it was much lower in the Landiolol group. And then the lactates, they reported in milligrams per deciliter, but for both groups, their mean lactate was about four and a half millimoles per liter, which is not a low number. And then also the norepinephrine requirements and SOFA scores are reported here as well, similar in both groups. And so as far as results, you can see here from this graph, the mean SOFA score over 14 days was not different in the Landiolol group and in the standard care group. In fact, the SOFA score in the Landiolol group was higher than the SOFA score in the control group. So it was not a statistically significant difference. As you can see from the graphic here, at about day eight, the SOFA scores for the patients who are receiving Landiolol seem to be a bit higher than those who are in the standard of care group. So this right here is a busy slide, and so I'm not going to talk about all of this, of course, but you can see from the p-values listed on the right that none of the other exploratory outcomes that they looked at were statistically significant and that Landiolol did not improve any of these variables. Something that's interesting is that, in fact, there were actually non-significant increases in mortality for Landiolol infusion at both 28 and 90 days. We can also see closer to the bottom of the graphic that there was a longer mean duration of norepinephrine associated with Landiolol use, and there was a higher cumulative and median norepinephrine dose in the Landiolol group as well. So here I've provided you with another very busy slide, but you can see that the lactate for both groups was not statistically significant, although numerically it was higher in the Landiolol group, and the only statistically significant difference that we found from this study was that there was lower MAPs in the Landiolol group and significantly lower heart rates in the Landiolol group. So the authors from this study concluded that in patients with septic shock and tachycardia treated with norepinephrine for more than 24 hours, an infusion of Landiolol did not improve their organ dysfunction, organ function, as measured by the SOFA score at 14 days from randomization. And, in fact, found or they showed that there was a signal of possible harm in the intervention group. And so, interestingly, this study originally was supposed to include about 340 patients, but it was actually stopped early by the Independent Safety Review Committee for signaling possible harm. And I've already told you that the 28-day and 90-day mortalities were not significantly higher in the treatment group, but they were numerically higher, and so they stopped short after only enrolling about 120 patients, and so there were 53 patients in each of the groups here. So strengths and limitations, you know, for strengths, I do think this is a well-designed randomized controlled trial with an appropriate outcome SOFA score that is related to sepsis and sepsis outcomes. I do think they chose their exclusion criteria appropriately to eliminate some populations who we expect to fare worse with beta-blocker therapy. Again, I didn't tell you all of them, but they excluded patients like with heart block because they knew that those patients were just going to do worse with beta-blocker therapy, but they also excluded patients who had heart failure because we might expect those patients to do better with administration of beta-blockers. And I also think their intention to treat analysis increases the external validity if we were going to try to apply this to our practice. As far as limitations, I think there were quite a few. They did use an unfamiliar study drug, and so I think it's a little hard to draw conclusions from this, specifically to practice in the United States because we don't use Lendi a lot. And then what was interesting to me is that they didn't report the fluid status, the microbiology results, or the antibiotic use for the patients in either of these groups. And so they did specify in their trial protocol that providers were supposed to follow sepsis guidelines and use fluids and use antibiotics, but we don't know exactly how much or what antibiotics they did use, and we don't know what they were using to monitor the patient's fluid status during this time. And one other thing is that there was a lower mortality in the standard of care group than we expected. And so based on their SOFA scores of 10, we expect there to be about a 50% in-hospital mortality rate, and we only saw a 30% mortality rate in their control group. And so I think this could have confounded some of their results as well. The applications to practice Lendi a lot therapy does not improve organ function in patients with septic shock and tachycardia. In fact, Lendi a lot could possibly be harmful in this patient population, and surrogate endpoints for sepsis management, such as SOFA score and lactate, were worse with Lendi a lot administration, though not statistically significantly so. All right, so for my first assessment question here, do you generally recommend stopping beta blockers for patients who require beta suppressors at your institution? Yes, no, or it depends. And if you've got a really interesting scenario and you'd like to tell us about it, maybe put it in the chat. Yeah, the overwhelming majority says yes. I don't think that is not really unexpected. That pretty much aligns with what we do at our institution as well. So assessment number two, which aspects of sepsis management do you find yourself most involved with? Is it antimicrobial selection, beta suppressor management, fluid management, or other? Again, probably not something totally unexpected. I guess maybe beta suppressors I would expect to be a little bit higher, but antimicrobial selection, I don't think that surprises anybody. I feel like we're all very involved with that. So those are my assessment questions. And so now I'm happy to answer any questions you might have. Excellent presentation. I think we have just a little time for questions. Do you think the findings of this studies are due to the time of the inclusion being more than 24 hours on beta suppressors, since patients may be in the cold phase of septic shock and beta blocker may not be helpful at that point? Do you think early beta blocker might be helpful? Yeah, I mean, I definitely think it's possible. Ultimately, I think that the results of this study, and even though they weren't powered to detect the mortality difference here, and that wasn't their primary outcome, I think that this trial kind of shows that there might be some harm to giving beta blockers to these patients, generally speaking, and it just might not be a great idea to be initiating beta blockers. So I don't know if I believe it's necessarily related to the time. As I do, I just think it might be related to the overall, is this a good idea, period. So do you think this finding of this trial can be extrapolated to ethmologs, since you said this is the closest analog to not do all in US? I think that's an interesting question as well. It does have pretty similar pharmacokinetics, and it actually has, I think, an eight times stronger affinity for the beta-1 receptor than even ethmolol does, and so I do think it would be a pretty fair comparison to extrapolate these results to ethmolol here. You know, it's interesting because we do have the trial from one of the groups that looked at ethmolol for this indication, but there were some problems with that ethmolol trial, and so one of the biggest things from that is that their control group had greater than 80% mortality in their control group, which is way, way higher than was expected based on the SAPS-2 scores for their patient population, and so I personally do think we could extrapolate this to ethmolol, even though we have another study saying that there was a reduction in mortality. I just think there were other problems with that study that kind of limited it. The previous study you mentioned is the Merle Bradley study with ethmolol. Actually, based on the study design, they use a lot more hemodynamic monitors, such as the A-lines, the cardiac output monitoring. Do you think that possibly, other than the, you mentioned about high mortality rate in the placebo group, do you think that potentially was helpful in that study to select out the populations that might be not suitable for beta-Balker? That's why their results are so different than the ethmolol study. I do. I definitely do think that helps. I think it's unfortunate because our institutional practice, at least where I am, we don't routinely have the types of cardiac monitoring that you might want for a patient. This criteria is certainly not in the medical ICU, really anywhere outside of the ICU, but I definitely think that the fact that there was more invasive and more cardiac monitoring was helpful there. And again, it just goes back to the fact that I think it's interesting that the authors of this study didn't include, they didn't even include information about the open-label vasopressors and inotropic agents that the patients in their study got. And so that's one of the things about the STRESS-L study is that, you know, these patients could have received open-label vasopressors and inotropes, but they didn't tell us what the rates of that were. And so I just think there's overall a lot of information about these patients, such as hemodynamic status, that we just don't know which limits the study in comparison to a small study. Thank you. That concludes our Q&A session. Excellent job, Kyle. And thank you for our presenters today and the audience for attending. Please join us on the third Friday of the month from 2 to 3 p.m. Eastern time for the next Journal Club Spotlight on Pharmacy. That concludes our presentation today. Thanks, y'all.

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