Good afternoon and welcome to today's Journal Club Spotlight on Pharmacy webcast, which is supported by the Society of Critical Care Medicine CPP section. I especially want to thank everyone coming out after a long and difficult week of planning for COVID-19. I'm April Quidley. I am a Supervisor for Critical Care and Emergency Medicine and a Residency Program Director at Vidant Medical Center in Greenville, North Carolina, and I'll be moderating today's webcast. A recording of this webcast will be available to the registered attendees, so you can log on to the SCCM website and find it under the My Learning tab. Just a few housekeeping things before we get started. There will be a Q&A session after each of the speakers today. To submit questions throughout the presentation, type in the question box located on the control panel. There will also be an opportunity to participate in several interactive polls. When you see a poll, simply click on the bubble next to your choice. SCCM provides the following disclaimer. This presentation is for educational purposes only. The material presented is intended to represent an approach, view, statement, or opinion of the presenter, which may be helpful to others. The views and opinions expressed herein are those of the presenters and do not necessarily reflect the opinions or views of SCCM. SCCM does not recommend or endorse any specific test, physician, product, procedure, opinion, or other information that may be mentioned. And now I'd like to introduce your speakers for today. Each will give a 15-minute presentation followed by questions. Our first presenter is Kelsey Beatrice. She is a PGY-2 critical care resident at the University of Mississippi Medical Center in Jackson, Mississippi. She's unfortunately unable to be with us today, and so Tessa Wiley, a surgical ICU pharmacist at the University of Mississippi, will deliver her presentation. Our second presenter is Adam Mohamed. He is a PGY-2 critical care resident at St. Luke's Hospital of Kansas City in Kansas City, Missouri. And our third presenter is Chloe Schmidt. She is a PGY-2 critical care resident at University of Wisconsin in Madison, Wisconsin. And now I'll turn things over to our first presenter. Okay. Hi, everyone. Thank you, April, for that introduction. As she said, I will be presenting for Kelsey today. All of the slides that I'll be presenting is all of her work. So today, we'll be discussing the effect of stress ulcer prophylaxis with proton pump inhibitors versus histamine 2 receptor blockers on in-hospital mortality among ICU patients receiving invasive mechanical ventilation, also known as a peptic trial. I want to note that myself nor Kelsey has any disclosures. Critically ill patients are at risk of developing stress ulcers that may result in clinically important gastrointestinal bleeding after suppression agents such as proton pump inhibitors and histamine 2 receptor blockers are used for prophylaxis of stress ulcers. The American Society of Health System Pharmacists last released their guidelines on stress ulcer prophylaxis in 1999. Two independent risk factors for stress-related ulcers in critically ill patients were identified, which include mechanical ventilation for greater than or equal to 48 hours and coagulopathy defined as platelet count less than 50,000 and INR greater than 1.5 or a partial thromboplastin time of greater than 2 times the control. The use of proton pump inhibitors versus histamine 2 receptor blockers for stress ulcer prophylaxis varies across practice sites and likely varies in your own institution. While acid suppression may be helpful in reducing the risk of GI bleeding, it may also be harmful. Proton pump inhibitors are stronger acid suppression agents compared to histamine receptor blockers and have been linked to the development of mesocomial pneumonia, C. diff infection, multidrug-resistant organism colonization, and immunosuppression. PPIs are more likely to reduce overt GI bleeding compared to histamine 2 receptor blockers, but the difference in mortality between the two drug classes is currently unknown. The sub-ICU study compared IV pantoprazole to placebo in at-risk ICU patients. Included ICU patients had to have at least one risk factor for clinically important GI bleeding, which was shock, use of anticoagulant agents, renal replacement therapy, mechanical ventilation, liver disease, and coagulopathy, among others. For the primary outcome of 90-day mortality, there were no differences seen. GI bleeding was statistically more likely to occur in patients receiving placebo. So we'll get started with our first polling question. The question is, what is your preferred stress ulcer prophylaxis agent for mechanically ventilated patients? Is it PPIs, H2R blockers, internal nutrition with no stress ulcer prophylaxis agents, or internal nutrition with stress ulcer prophylaxis? Okay. It appears the majority selected H2 receptor blocking agents. I would say at our institution, PPIs as well as internal nutrition with no stress ulcer prophylaxis agents seem to be preferred. I've got a second one for you guys. So when are stress ulcer prophylaxis agents initiated in your mechanically ventilated patients? Okay, so it appears the majority selected at the time of ICU admission, or about 56%. I would say that's kind of on par with here, too. It seems to be easier for our medical residents to remember that and then for us to make recommendations on rounds. Thank you, guys, for that. We'll move on to the actual study. So, the authors of the PEPTIC trial set out to answer the question, the mechanically ventilated intensive care unit patients, does administration of proton pump inhibitors or histamine-2 receptor blockers for stress ulcer prophylaxis reduce 90-day mortality? This was an open-label cluster crossover randomized trial completed in ICUs in Australia, New Zealand, Canada, England, and Ireland. Adult patients requiring invasive mechanical ventilation within 24 hours of ICU admission were eligible for the study. Patients with an ICU admission diagnosis of GI bleeding were excluded. When the trial was first registered, the primary end point was to be a composite of, I'm sorry, back up, guys. Participating ICUs were randomized one-to-one to administer PPIs or HTR blockers to eligible patients for six months. At the end of the six months, the ICUs crossed over to administer the other stress ulcer prophylaxis agent to eligible patients for another six months. Because this trial was open-label, the treating clinician decided the stress ulcer agent dose and route of administration as it pertained to the randomization of the unit at that time. Either prophylactic agent could be administered regardless of the ICU treatment randomization if the clinician considered this to be preferable. If upper GI bleeding did occur, a PPI was administered at the clinician discretion regardless of the ICU's treatment randomization. Now, when the trial was first registered, the primary end point was to be a composite of clinically important upper GI bleeding, C. diff infection, and episodes of mechanical ventilations lasting longer than 10 days. The primary outcome was then changed in 2017 to include all-cause mortality in hospital during the index hospitalization at up to 90 days from the date of the index ICU admission. This change was made prior to any site-completing recruitment or any data review. Secondary outcomes included upper GI bleeding defined as overt GI bleeding and one or more of the following features within 24 hours of the GI bleed, spontaneous decrease in systolic blood pressure, mean arterial pressure, or diastolic blood pressure of 20 millimeters of mercury or more, initiation of treatment with vasopressors or 20% increase in vasopressor dose, a decrease in hemoglobin of two, or a transfusion of two or more units of packed red blood cells. The incidence of C. diff infection, hospital, and ICU length of stay were also secondary outcomes. Tertiary outcomes included duration of mechanical ventilation and ventilator-associated outcomes. The calculated power was 80% at a significance level of 0.05. Two-sided t-tests were performed to detect an absolute reduction of 2.4% in the primary outcome. A total of 26,828 patients were included in the final analysis. These patients were on average 58 years old, mostly male, and more than half were admitted to the ICU after elective or emergency surgery. Median time in the ICU represents the time available for exposure to stress ulcer prophylaxis and was under three days for both groups. Of the patients admitted to units randomized to receive PPIs, 82.5% received PPI alone represented in blue, 11.5% of PPI patients received no stress ulcer prophylaxis at all. Of the patients randomized to receive H2R blockers, only 63.6% received H2R blocker alone depicted in red, 20.1% of H2R blocker patients received a PPI instead, and 11.2% of patients received no stress ulcer prophylaxis. PPIs and H2R blockers will continue to be represented in the colors blue and red, respectively, throughout the remainder of the presentation. All-cause mortality within 90 days of index hospitalization occurred in 18.3% of PPI patients versus 17.5% of H2R blocker patients. The reported relative risk was 1.05 and P-value 0.054. Clinically important upper GI bleeding occurred in 1.3% of PPI patients versus 1.8% of H2R blocker patients. The reported relative risk was 0.73 and a statistically significant P-value of 0.009. Days until discharge alive from the ICU was 3.6 and 3.3 days for both groups. Ventilator-associated conditions did not occur in more patients who received PPIs. However, this was not statistically significant. I will note that this data was only available for participants from the eight Canadian ICUs. There was no difference in hospital length of stay, duration of mechanical ventilation, or rate of C. diff infection. Median duration of mechanical ventilation was 48 hours. When evaluating the primary outcome mortality in subgroups, cardiac surgery patients showed an increased risk of mortality with use of PPIs. After stratifying patients by their APACHE-2 scores, patients whose score fell between 18 and 23 also demonstrated an increased risk of mortality with use of PPIs, but no differences were seen between patients whose score was 24 or greater. The authors concluded that in-hospital mortality was higher with PPIs compared to H2R blockers, although this was not statistically significant. Now, let's move on to the discussion of the article. This is the largest enrollment of critical care patients ever, with roughly 27,000 patients included. Included ICU patients had to have a requirement for mechanical ventilation, which we know is a well-established risk factor for the development of stress ulcers. The trial was completed in various countries and 50 ICUs, and true to real-world practice, patients were able to pick the drug, dose, and route of agents. The Supplemental Appendix breaks this down further, and you can see that commonly used accessible agents for both drug classes were utilized. The outcomes were patient-centered and previously studied controversial endpoints that were chosen to better understand treatment effects. Limitations of this trial include potential inclusion of patients without risk factors for GI bleed or who are already bleeding at admission. A quarter of the H2R blocker patients received a PPI, which may have contributed to the lack of a statistically significant finding. The median time in the ICU was less than three days, which means most patients received only three days' worth of stress ulcer prophylaxis. It is difficult to interpret if three days of PPIs lead to increased mortality or if patients would even go on to develop C. diff infections or ventilator-associated conditions in such a short amount of time. With a non-mechanical ventilation time of 48 hours, ventilator-associated conditions only collected from the eight Canadian ICUs and no incidence of pneumonia outcome limits interpretation of how PPIs may affect the development of pneumonia. Enteral nutrition was not discussed in this trial. Enteral nutrition serves patients by providing more than calories. It maintains gut integrity, perfusion, and preserves the gut microbiome. In a 2018 meta-analysis, stress ulcer prophylaxis with enteral nutrition showed no added benefit to enteral nutrition alone in ICU patients. Early enteral nutrition, defined as enteral feeding in the first 48 hours of mechanical ventilation, is associated with improved outcomes, such as shorter duration of mechanical ventilation. It is still unknown the extent of protection enteral nutrition provides from stress ulcers, but it does have a role to play and may have changed outcomes in this trial had it been collected and addressed. Stress ulcer agents are dynamic medications that should change if our patient's dynamics also change. We should evaluate the need for prophylaxis as patients transition into and out of the ICU on daily patient care rounds and discontinue when these agents are no longer needed. The only inclusion criteria for this trial was the requirement of mechanical ventilation. We know the other independent risk factor for stress ulcer development is coagulopathy, but this was not included or evaluated in the study. In addition, there are other high-risk patient populations that may have been more likely to be affected by treatment randomization. Further subgroup analyses should be done to evaluate the need for stress ulcer prophylaxis in at-risk groups. Finally, only the drug and route were identified in the supplemental appendix. While this contributes to the external validity of this study, there may have been a particular drug, dose, and route that was associated with better or worse outcomes. This information was not further explored in the trial, but could enlighten providers to the optimal regimen for our patients. Clinically, histamine 2 receptor blockers may be better for cardiac surgery patients and patients with high illness severity determined by APACHE-2 scores. Histamine 2 receptor blockers are likely a safe choice for prophylaxis for many mechanically ventilated ICU patients, but PPIs may be better for known GI bleeds or patients with an increased risk for a GI bleed. Statistically, there were no differences in 90-day hospital mortality, length of stay, incidence of C. dysinfection, or mechanical ventilation. The number needed to treat was 125 for 90-day mortality with histamine receptor blockers, and the number needed to treat for upper GI bleed with PPIs was 200. Based on the PEPTIC trial and prior evidence, an approach to stress ulcer prophylaxis should always be patient-specific. For patients requiring mechanical ventilation for greater than or equal to 48 hours without coagulopathy, cardiac surgery, chronic liver disease, and patients with high illness severity, it seems reasonable to use histamine 2 receptor blockers. For patients with known GI bleeding or coagulopathy without chronic liver disease, a PPI may be preferred. No stress ulcer prophylaxis is needed in patients who are intubated for less than 40 hours, no coagulopathy, or are tolerating enteral feeds. Here is a summary of a few practice points based on everything we just discussed, noting that the revised trial may provide further answers on this topic. IV pantoprazole will be compared to placebo with the primary efficacy outcome of clinically important upper GI bleeding and the primary safety outcome of mortality. Okay, thank you, guys. This concludes Kelsey's presentation, and I'll take any questions at this time and answer based on my own thoughts and interpretations. Thank you, Tessa. I think that provided a good overview of the trial. If you have questions, feel free to use the chat window there to send those on. We'll start off with one, which is, what was your take on the way and why the authors changed their primary endpoint and then selected mortality as an outcome? Yeah, I think for me, that's just kind of the size of the study that they were shooting for, and in their mind, they thought this was more clinically relevant. I wish they would have stuck with their original primary outcome, because I think that's also very clinically relevant. And as we know, mortality is really hard to find physically significant in any study, for the most part. But I think it just had to do based on a more clinically relevant outcome. Yes. And then another question from the audience is whether or not, in practice, we should DC PPIs if patients are C. diff positive. Yeah, I think that's a great question, something that's actually come up on rounds quite a bit. You know, I think if they still have risk factors, if they're still mechanically ventilated or, you know, hopefully they don't have a GI bleed and C. diff at the same time, I think it's reasonable to continue or at least continue some sort of stress ulcer prophylaxis. What I've done in practice is either switch to a histamine 2 receptor blocker agent or just, you know, discontinue stress ulcer prophylaxis if it wasn't needed. All right. Let's see if anybody has any more questions. And you alluded to this a little bit, but what also was your take on the length of stay for the patients in this trial and the impact that may have had on the outcome? Yeah, I think it had a huge impact. I mean, the length of stay was quite short. I don't know if this just had to do with the ICUs that they selected to be a part of the study, but it's not applicable, at least to my practice and probably to the majority of our practices because 72 hours in the ICU is not super common for the majority of patients. So I think it's one of the probably biggest weaknesses and something that I definitely look at when interpreting the results of this study. I agree completely. That's all for questions for this. I'd like to now introduce our second presenter, which is Adam Mohamed. All right. Good afternoon, everyone. Thank you for the introduction, and thank you all for joining us today for the SCCM Journal Club. Today, I'll be discussing the dexamethasone treatment for the acute respiratory distress syndrome or the DEXA ARDS trial. I do not have any disclosure regarding this presentation. As you may know, acute respiratory distress syndrome or ARDS is a life-threatening respiratory condition that occurs in almost 10 percent of all the ICU admissions and 23.4 percent of the mechanically ventilated patients. The incidence of the ARDS in the U.S. is almost 193 cases per 100,000 admitted patients, which is higher than other countries in Europe. ARDS also carries an estimated mortality from 27 to 45 percent. ARDS is a largely under-recognized disease, and usually we start seeing the ARDS occur seven days after the initial incidence. As you may know, ARDS is associated with severe hypoxemia, diffused infiltrates, and reduced lung compliance and ventilator dyssynchrony as well due to lung stiffness. It is characterized by three progressive phases. Phase one is the sequential excitative phase, which happens usually within 24 hours and is characterized by the loss of the alveolar epithelium interstitium endothelial complex and results in accumulation of inflammatory markers. Then it moves to phase two, which is the proliferative phase. It happens between seven to 10 days, and the body is trying to regenerate the alveolar endothelium cells and proliferation of types of two cells. And then we come to phase three, which is the fibrotic phase. It doesn't happen in all of the ARDS patients, but it can happen, and it causes worsening of alveolar function, and it causes increase in mechanical ventilation and ICU length of stay as well. The current treatment strategies for ARDS include a variety of non-pharmacological and pharmacological therapies. Non-pharmacological include lung protective ventilation per the ARDS network protocol, proning position, which should decrease the mortality in the PROSAVE-A trial, as well as ECMO. Pharmacological therapies include conservative fluid management, which should more ventilator-free days and ICU-free days in patients with conservative fluid management. Corticosteroids, ensuring appropriate and adequate sedation and analgesia to ensure ventilator compliance, and neuromuscular blockers, as well as a variety of other investigational therapies. The current evidence for steroids in ARDS is based on three main studies. All of them are multicenter double-blind RCTs. The study by Midori and colleagues in 1998 and the ARDS network study in 2006 looked for steroid treatment in ARDS patients, in patients who have ARDS for at least seven days. And the Midori trial in 2007 looked for the steroid treatment in patients with early ARDS. As you can see here, they used, all the studies used different methylbutadienylone regimens compared to placebo, and the primary outcome is listed here. Moving to the results of those trials, so the Midori and colleague trial in 1998 did not find a statistically significant difference in mortality at 10 days. It was numerically different, but there was an improvement in the lung injury scale by at least one at day 10, and it was statistically significant. The ARDS network study in 2006 couldn't find an improvement in 60-day mortality. However, the number of ventilator-free days as well as the ICU-free days were statistically better with using the methylbutadienylone. Finally, the Midori and colleagues in 2007 looked with primary end point of extubated with one or more point reduction in the lung injury scale found a statistically significant improvement with the methylbutadienylone. So currently, I believe there is a lot of unanswered questions regarding the use of steroids in ARDS patients. What is the optimal dose? What is the optimal duration? What is the role of early steroids in ARDS patients? As you saw, most of the available literature are composed of small studies. The hypothesis of this trial is that early administration of dexamethasone in addition to conventional treatment in patients with established moderate to severe ARDS will decrease the duration of mechanical ventilation and decrease the mortality rate. That takes us to our following question number one. At your institution, do you routinely use early corticosteroids in patients with moderate to severe ARDS? So the majority, 83%, said no. So we'll see if the DEXA-ARDS trial will change your opinion today. Moving to methods. So this study was an investigator-initiated multicenter randomized controlled trial. The investigators enrolled patients in 17 intensive care units in teaching hospitals across Spain. Patients were at least 18 years old, intubated, and mechanically ventilated, and had acute onset of ARDS as defined by either the American-European Consensus Conference criteria for ARDS, or the Berlin criteria for moderate to severe ARDS were included. And the included variety of patients, pregnancy, brain death, terminal stage cancer, DNR orders, treatment with corticosteroids or immunosuppressive drugs, enrollment in another trial, if they have severe COPD or congestive heart failure. Patients were randomly assigned either to dexamethasone or dexamethasone plus conventional care or just conventional care. If the patients were assigned to the dexamethasone group, then they will receive the first dose immediately after being randomly assigned, no later than 30 hours after ARDS onset. Dexamethasone dose was 20 milligrams IV daily from day one to five, and then 10 milligram daily from day six to 10. Treatment duration was 10 days or until extubation. The supportive management of patients enrolled in this trial was not strictly controlled. Physicians were asked to follow recommendation for usual critical care management. Neuromuscular blocking agents, sedation, prone positioning, and lung recruitment strategies were allowed at the discretion of the attending physician. The ARDS network protocol was used for the assessment for readiness using spontaneous breathing. The outcomes for this trial, the primary outcome was the number of ventilator-free days at 28 days after randomization. Secondary endpoints included 60-day all-cause mortality, duration of mechanical ventilation, ICU and hospital mortality, hyperglycemia, barotrauma, and new infections during the ICU stay. The statistical analysis, the investigator estimated that they need 294 patients to 315 patients to achieve 80% power to detect, an increase in the number of ventilator-free days by two days in the dexamethasone group, or a 15% absolute reduction in the 60-day mortality. And the rest of the statistical analysis tests listed here for your reference. Moving forward to the results. So, almost 1,000 patients were evaluated. Only 27% of those patients were enrolled. 62% were excluded. The most common causes for exclusion was receiving steroids or immunosuppressants, 39.6%, followed by patients having severe chronic respiratory disorder, or having ARDS for more than 24 hours. Then, the investigators randomly assigned 277 patients, 139 patients assigned to the dexamethasone group, and 138 assigned to the control. The enrollment happened between March 28, 2013 to December 31, 2018. And the Data Safety Monitoring Board decided to stop the trial due to the enrollment rate after enrollment 88% of the patients. Here is the baseline characteristics of the patients. As you can see, the average, the mean age is 56 years old, and the majority of patients were males. I'd like to highlight here that time from intubation to randomization was 2.1 days, and time from ARDS diagnosis to randomization was one day. And the most common causes of ARDS were pneumonia, sepsis, and aspiration, with pneumonia more than 50% of the patients had pneumonia. The characteristics of the ARDS at randomization, as you can see here, I'd like to highlight that most of the patients had moderate ARDS, with PO2-FIU2 ratio of 142, and the tidal volume of almost 6.9 enrollment with a peak end expiratory pressure of 12.6. For the efficacy outcomes, for the primary outcome of ventilator-free days at 28 days, as you can see here, the ventilator-free days, as you can see, the primary endpoint of ventilator-free days, it was higher by five days in the dexamethasone group. Also, the dexamethasone group had a statistically significant and clinically significant better outcomes across all the secondary endpoints. That include all-cause mortality at 60 days with a difference 15% number needed to treat of seven, which was mainly driven by increased rate of multi-organ dysfunction in the control group. The dexamethasone group had lower ICU mortality and hospital mortality by almost 12%, as well as the actual duration of mechanical ventilation was shorter in the dexamethasone group compared to the control. For the safety outcome, there was no difference between the two groups. However, there was a trend towards more hyperglycemia, but it did not reach statistical significance. As you can see here, this is the Kaplan-Meier survival estimates during the first 60 days. And as you can see, the break in the mortality happens between day 10 and 20. The authors concluded that findings suggest that early administration of dexamethasone could reduce the duration of mechanical ventilation and overall mortality in patients with established moderate to severe ERDS. Moving to our critique and discussion of this trial. So the strength of this trial, this trial is addressing the controversy of using corticosteroids for the treatment of ERDS, question that sometimes we encounter during trials. Overall, this was a well-designed study. It has a pragmatic design. It mirrored the practice. The sample size as well. The author did use probability model to examine different situational states. And that's why they had a range of sample size range. The primary and secondary endpoints were chosen appropriately. The author used intention to treat analysis and the time to randomization actually met the study objective. As you remember, the time from ERDS to randomization was one day. The ICU management were similar between the two groups as shown in table S4 in the supplementary appendix, except for pruning. Moving to the limitations. The open-label design of the study, however, most of the endpoints were objective. But still, the open-label may affect the clinician decision in different treatments. There wasn't 1% difference between expected and observed mortality. The etiology of pneumonia was not discussed. Viral versus bacteria. The authors did not mention that. The source of sepsis was not discussed as well as source control. Fluid management and fluid status was not discussed. As you know, conservative fluid management can affect some of the endpoints. The percent of patients with shock was not mentioned as well. 86% of the enrolled patient had moderate ARDS. There was a higher use of prone positioning in the control group. It can be due to either patients not improving or sicker patients in the control group. The incidence of myopathy was not discussed, which was in the ARDS network trial in 2006, there was a higher incidence of myopathy in the methylbrinazolone group. Sedative agents used as well as sedation goals was not discussed. Especially if we are looking at a ventilator-free days, these two, the sedation and the sedation goal can have a great impact on ventilator-free days. One of the limitations as well is that not all the centers had ECMO capability, which may raise the question about the ability of centers to manage patients with severe ARDS. However, the authors did an analysis to exclude those kind of patients and still the mortality was lower with the dexamethasone in the dexamethasone group. The takeaway points is early use of dexamethasone improved the outcomes in patients with moderate to severe ARDS. The results mainly apply to patients with ARDS secondary to pneumonia and or sepsis. Dexamethasone offers several advantages over other steroids. Once daily dosing, non-weight-based dosing and less mineralocorticoid effects. The change in my practice, I reutilized the dexARDS protocol for my patients with moderate to severe ARDS secondary to pneumonia and or sepsis. There is still some unanswered question. What is the role of delayed steroids in ARDS after 14 days? Role of steroids in persistent ARDS and managing patient with septic shock and ARDS? Which steroid to use in duration as well as dose? That takes us to our second polling question. Based on the dexARDS finding, would you recommend early dexamethasone in patient with severe to moderate ARDS? Well, still the majority will not use it. However, there is an increase in the number of yes. Thank you very much for joining us today and I'll take any questions. Thank you, Adam. I've already gotten quite a few good questions for you. One of the first ones is, did the study look at all at the incidence of critical illness polyneuropathy, specifically also if they were used in combination with neuromuscular blockers? And is that something that you would worry about? Yes, this is one of the things, as well as the myopathy, they did not look at the critical illness polyneuropathy. And they mentioned that 58% in the dexamethasone group and 59% in the control group actually received neuromuscular blocking agent. But however, they did not mention the incidence of the critical illness polyneuropathy. Also, another question is, do you think that the differences in practice and management during the enrollment period between 2013 and 2018 had an impact on the study? It may. I believe the authors in the supplementary appendix looked at different enrollment years. They couldn't find a difference between the enrollment years. But it may very well have an impact on the outcomes. And then just a couple more questions. Did the authors look at the study did the authors look and report about the patients that received other ARDS treatments in terms of the details about paralytics or other agents? Yes, so there was no, they mentioned a neuromuscular blocking agent, which was 58% in the dexamethasone group, 59% in the control group. They looked at recruitment maneuvers, which was 64% in the dexamethasone group and 66% in the control group. They looked at prone positioning as I mentioned. And they looked at ECMO use as well, which was 3.6% in the dexamethasone group versus 6.5% in the control group. And the authors looked at that, considered all the ECMO patients as mortality. And they still found the mortality benefit with the dexamethasone. And they did another analysis where they removed all the ECMO patients from that analysis. And still, the benefit, they could see a benefit of dexamethasone in the mortality. Great. And then just the last question for you. Why do you think they chose to use two different types of inclusion criteria, the AECC and the Berlin criteria for entry into the study? And do you think that had an impact on the results? That's a very good question. I think part of it because they had a lot of different hospitals and they left it up to the special clinician to management. However, on the enrollment, they did a standardization at 24 hours of ARDS incidents just to make sure that the patient met the definition of ARDS by both criteria. So at 24 hours of ARDS incidents, they had a standardized mechanical ventilation strategy and they looked at the patient, looked at if the patient met the criteria or not. So that can mitigate a little bit the differences in practice. I agree. They did a good job of trying to control for that. And that's all the time we have for questions for Adam. So I'd like to introduce now the final presenter today, Chloe Schmidt. All right, thank you. So I'm gonna be talking about the 65 trial, which looked at the effect of decreased exposure to vasopressors on 90 day mortality in our elderly patients greater than 65 years of age. And I have no disclosures or conflicts of interest that pertain to this topic. All right, so first we'll go into a little bit of background on why we target current map values that we do in our septic patients. So what retrospective studies from the early 2000s showed that we have a persistent map below 60 and below 65. There is an increase in mortality. So that's what this graphic shows. The more hours you spend with a map below 60, the greater the 28 day mortality. And the surviving sepsis campaign guidelines do recommend an initial mean arterial pressure of 65 millimeters of mercury in patients with septic shock requiring vasopressors. And the 2012 version of the guidelines actually suggested targeting a higher initial map in older patients than for those with chronic hypertension and coronary artery disease. However, the 2016 update acknowledged that there is really no evidence for targeting a map value greater than 65 in any patient group, and so that was removed. Okay, so in 2014, the sepsis and mean arterial pressure, or sepsis spam trial, randomized 776 patients with septic shock to a goal map of 65 to 70, or 80 to 85 for up to five days. And what they found is that there was no difference between the two groups in all-cause mortality at 28 or 90 days. So that's what the Kaplan-Meier curve is showing on the left there. And then they also did some subgroup analyses, and they found that the higher map goal was well-tolerated overall, except for an increase in AFib. And then for those with a history of chronic hypertension, those patients actually had less need for renal replacement therapy with a higher map goal. So this is kind of where people first started getting interested and do other patient populations require a different map goal. The Ovation trial was completed in 2016, and this trial randomly assigned critically ill patients who were presumed to suffer from vasodilatory shock to a lower 60 to 65 versus higher 75 to 80 map target. And the primary objective of this trial was to actually measure the separation in mean map between the groups. So it was kind of a feasibility trial. And they did find that there was no difference between the two groups in all-cause mortality. So it was kind of a feasibility trial. And they did find that they were able to achieve a difference in map between the two groups of nine millimeters of mercury. And then the study also examined adverse events and mortality for pre-specified groups. What they found is that there was no statistically significant differences in adverse events between the two groups. Although I think looking at some of the arrhythmia risk, one could argue that there is a clinically significant higher arrhythmia risk in the higher map target group. And then subgroup analysis revealed a trend towards lower mortality in patients greater than 75 years of age. And treatment effect did not differ between patients with chronic hypertension, heart failure, or duration of vasopressor therapy prior to enrollment. All right, so then this is a pooled analysis of both the CEPCPAM and Ovation trials. And what they did is they combined the patients in the two trials and then controlling for trial and site, they looked at the odds ratio for 28 day mortality for the higher versus lower map targets. And they did not find a statistically significant difference. And then they did find that the treatment effect varied by duration of vasopressors before randomization, but not by chronic hypertension or congestive heart failure. All right, and then this is a graphic from that same pooled analysis, which shows the odds ratio of adjusted mortality by age. And it's kind of a confusing diagram, but the best way I can explain it is that when the dark black line crosses one, the lower map target is favored. And so kind of looking at the trend on this graph, they did pull patients greater than or equal to 65 years of age. And they found a absolute risk reduction in mortality of 8.6% in the lower versus higher map target group. However, the test for age by map target effect modification was not statistically significant according to this model. The gray area on this graph is the 95% confidence interval and it crosses one. All right, so now we'll go into the details of the 65 trial, which primary objective was to determine whether reduced exposure to vasopressors through permissive hypotension reduces 90 day mortality in ICU patients greater than 65 years of age with vasodilatory hypotension. So this was a pragmatic open multicenter parallel group trial that randomized patients to permissive hypotension for a map goal of 60 to 65 versus usual care at the discretion of the treating physician. Again, the primary outcome was 90 day mortality here. And they were trying to find a 6% absolute risk reduction in mortality, taking two thirds of the absolute risk reduction found in that pooled analysis. All right, so what they found is that there's no statistically significant difference in 90 day mortality in the intervention versus usual care group. They also did not find a statistically significant difference in ICU or hospital mortality. Looking at the straight percentages in the primary outcome, the results do favor the permissive hypotension approach with a 41% versus 43.8% 90 day mortality in the permissive hypotension versus usual care group respectively. Unfortunately, though, we can't really even assume non-inferiority here since this trial was designed specifically to detect superiority, which the intervention group did not meet criteria for. I also wanted to draw your attention to the vasopressors that were utilized in this trial. So most patients, about 78% in each group were on norepinephrine. This trial was completed 65 ICUs in the UK, sticking with their favorite number of 65. And so there were some agents that we don't really see utilized too much here, domaterraminol and turlopressin. Not too surprisingly, the permissive hypotension group required less vasopressor for a lesser period of time. And they actually converted the mean rate to norepinephrine equivalent on micrograms per kilo per minute. And the permissive hypotension group was 0.12 and the usual care group was 0.15. And then they did not find any difference in serious adverse events or need for renal support between the two groups. They also looked at a couple of different patient oriented outcomes. So they looked at a scoring tool for cognitive decline. And basically the result is on a scale from one to five and a score of three means that the subject is rated on average or no change in cognitive function. So both groups did pretty well from a cognitive standpoint. And then they also looked at health related quality of life at 90 days, which this tool requires patients to describe their health on five different dimensions. And then they anchor that score on a scale from zero, meaning death, or one to perfect health. And they didn't find any big difference between the two groups in that area either. And then they did subgroup analysis of patients with chronic hypertension and actually found a trend towards lower 90 day mortality in patients in the permissive hypotension group. And then they also looked at need for renal replacement therapy and days alive and free of renal support. And when they did look at that, they found a lower need for renal replacement therapy in the usual care group. However, the permissive hypotension group had more days alive and free of renal support. And these results are a little bit confusing and conflicting in my mind. And I do think that further investigation is needed before we can definitively recommend a different map target for different subsets of patients, such as our patients with chronic hypertension. So overall, I think this was a very well designed and realistic trial that had good internal and external validity. For example, they enrolled patients 24 seven, and I did like that they used usual care instead of standard of care as the control group. This was also a fairly large trial size and a multi-centered design. And I appreciated that they included some patient oriented secondary outcomes. Some of the issues I have with this trial are that the amount of separation in blood pressure between the groups was fairly small, only about six millimeters of mercury with considerable overlap. And I think it's difficult to believe that that small, the degree of map separation can cause a change in all cause mortality. And then although patients in the permissive hypotension group targeted a map of 60 to 65, the actual median map in that group was not within that range, it was actually 66.7. Thus it's debatable in my mind, whether this was truly a permissive hypotension group or merely a good achievement of a conventional target at the lower end of that range. And then the mortality in this trial was actually higher than they anticipated in their statistical design. So that could have compromised their analyses. The other point I wanted to draw your attention to was that in this trial, treatment began some hours into the patient's ICU stays. It was about three hours on average. Therefore, it remains unclear whether a map target of greater than 60 is adequate during the initial phase of resuscitation, which often occurs in the emergency department or initially upon arrival to our ICU. All right, so take home points for this trial. I think the study does show that targeting a map of greater than 60 millimeters mercury is safe. You know, I think we all kind of have a philosophy of less is more. And, you know, we might be able to get patients off of vasocrossers quicker and use lower doses by targeting this map value. You know, I can't really say definitively whether or not the mortality trend found in this trial is real. However, it does appear safe. And then I think it would be kind of interesting to investigate the necessity of an upper limit on a map target, because trials have kind of found again and again that oftentimes we overshoot. And I think just having a map target greater than 60 or greater than 65, sometimes we miss the mark and overshoot, and that could lead to more adverse effects. And then I think further studies are really needed to assess alternative map targets in specific subsets of patients, like chronic hypertensive patients. All right, and with that, we'll go into the polling questions. So the first one being, prior to this trial, did your institution aim for different map targets in vasodilatory shocks based on patient attributes? All right. So I'm seeing occasionally as the most common answer. And I would say that's the same over at UW Health here. On patients, obviously, with spinal cord injuries, we're targeting a higher MAP. And then occasionally, we do have a large population of chronic liver disease patients here in Wisconsin. And sometimes, we do have difficulty weaning them off of pressers. And so occasionally, we'll target a different lower MAP value to assist with weaning. All right. Then we'll go to polling question two, which is, based on the 65 trial, would you recommend a lower MAP goal for elderly patients with vasodilatory shock in your ICU? All right, so I think the most common answer in some scenarios, and I kind of agree with that. I think, you know, some are going to change their practice based on the results of this trial, and some of us are going to wait for further evidence, and I don't think either answer is completely wrong. Personally, I feel comfortable implementing a lower MAP target in my elderly patients, but honestly, I still have some hesitancy to do so initially within the first few hours. And I do think that, you know, potentially targeting a MAP of 60 to 65, we could end up with a lower average MAP than what was found in this trial, and we don't really know if that would be harmful. Interestingly, I was just glancing through SCCM's COVID recommendations, and they do actually recommend a MAP of 60 to 65 within those recommendations, so I'll have to read a little bit more about that, but I'm interested to see if they'll change future guidelines. I'm sure they'll at least mention this trial. All right, and with that, I'll take any questions. Thank you so much, Chloe, for outlining the trial for us. Please enter any questions you guys have in the chat window there, and I'll start off by asking, I know you mentioned that there was no apparent difference in adverse events between groups, but what is your take on the possibility of there being a difference in renal failure, specifically for patients who were randomized in the permissive hypotension group? Yeah, that's a great question, and I think it's difficult to say because what was found in the 65 trial conflicted with what was found in the CEPCPAM trial, and I don't think I can draw a conclusion based on those conflicting results. And then another question, as you brought up the question that still remains about what to do with those elderly patients that have hypertension, and specifically, what is your practice in managing hypotension in the patients that have that history of high blood pressure? So, my practice is not to change my MAP target based on history of chronic hypertension. I just don't think the evidence is there, and it's not something I see our providers asking about or pushing for here. All right, it looks like we're running out of time. I want to thank each of the presenters today for finding time and for you all in attending today especially during this busy and stressful time right now. Next month, please join us again on the third Friday, 2 to 3 p.m. Eastern Standard Time for the next Journal Club. And that's all that we have for today.

PEPTIC trial

proton pump inhibitors

H2R blockers

stress ulcer prophylaxis

DEXA ARDS trial

dexamethasone treatment

acute respiratory distress syndrome

65 trial

vasopressors