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 Kelly Keats, and I'm a critical care clinical pharmacist in the medical ICU at Wellstar NCG Health in Augusta, Georgia. I will be moderating today's webcast. A recording of this webcast will be available to registered attendees. Log in to mysacm.org and navigate to the My Learning tab to access the recording. A few housekeeping items before we get started. There will be a Q&A after each of today's speakers. To submit questions throughout the presentation, type into the question box located on your control panel. You will also have the opportunity to participate in several interactive polls. When you see a poll, simply click the bubble next to your choice. You may also follow and participate in live discussion on Twitter, following hashtag SCCNCPPJC and hashtag PharmICU. Please note the disclaimer stating that the content to follow is for educational purposes only. And now I'd like to introduce your speakers for today. Each will give a 15-minute presentation followed by a Q&A. Our first presenter today is Sterling Feininger, a PGY-2 critical care resident at the Ohio State University Wexner Medical Center in Columbus, Ohio. She will present on safety and efficacy of reduced dose versus full dose alteplase for acute pulmonary embolism, a multi-center observational comparative effectiveness study. Our second presenter is Adriana Gooden, a PGY-2 critical care resident at WellSpan York Hospital in York, Pennsylvania. She will present on tight blood glucose control without early parenteral nutrition in the ICU. And our third presenter is Yumi Oh, a PGY-2 critical care resident at Boston Medical Center in Boston, Massachusetts. She will present effects of early administration of vasopressors on new onset arrhythmia development in patients with septic shock, a retrospective observational cohort study. And now I'll turn things over to our first presenter. Thank you so much for that introduction. Like you mentioned, I'm going to be presenting today a journal club on safety and efficacy of reduced dose versus full dose alteplase for acute pulmonary embolisms. Objectives for this presentation will be to review pulmonary embolism and current treatment recommendations, provide brief reviews of previous trials focusing on the safety outcomes, even though the studies were evaluating efficacy, and lastly, analyzing the recent study on reduced dose versus full dose alteplase, highlighting the safety outcomes and discussing its potential role in therapy. For patients with PE with echocardiography and or biomarkers compatible with right ventricular dysfunction, but without hemodynamic compromise, or in other words, a submassive PE, the ASH guideline panel suggests anticoagulation alone over the routine use of thrombolysis in addition to anticoagulation. This is a conditional recommendation based on low certainty in the evidence of effects. For patients with PE and hemodynamic compromise, also known as a massive PE, the ASH guideline panel recommends utilizing thrombolytic therapy followed by anticoagulation over anticoagulation alone. And this is a strong recommendation despite low certainty in the evidence of effects. Potential risk factors or risks after treatment include risk of hemorrhage, angioedema, pulmonary edema, pulmonary re-embolization, pleural effusion, thromboembolism, and hypotension. The approved dose for PE is 100 milligrams, but this was more of an arbitrary dose determined by earlier studies, leading to the question, can we potentially reduce the dose and obtain the same effective outcomes? There are many previous studies and I only have time to highlight a few. The first compared alteplase full dose, 100 milligrams to placebo, in addition to unfractionated heparin drips in submassive PE patients. The study showed higher rates of in-hospital death or clinical deterioration meeting escalation of care, i.e. CPR, embolectomy, rescue thrombolysis, and the placebo group. To highlight the safety outcomes, the study found no statistical significance in death or major bleeding, which was 0.8% versus 3.6%. The second study by Wang et al compared recombinant tissue plasminogen activator, alteplase, 100 milligrams versus 50 milligrams, focusing on our massive PE patients. Death rates were similar in both groups with a trend towards lower bleeding complications in the reduced dose. And they also did a subgroup analysis for patients less than 65 kilos that did show a statistical significant difference with the reduced bleeding episodes for reduced alteplase dose. And the final study compared Hafter's alteplase compared to full dose alteplase. And in a matched cohort, there was a statistical significant increase in risk of requiring treatment escalation in the reduced dose. However, the rates of bleeding were similar. So given the contradictory information available from previous studies, patients, or more information is needed to guide clinical decision-making, hence the need for this study. The purpose of this study was to compare efficacy and safety of full dose versus reduced dose alteplase for pulmonary embolisms. And the design was a multi-center retrospective observational study from January 1st of 2012 to December 31st of 2020. Like the previous trials, the study included adults greater than 18 years of age that received IV alteplase for the treatment of PE, but the exclusion criteria seemed to be less extensive than the previous studies. But like most of the studies, they excluded patients utilizing alteplase for cardiac arrest. For primary outcomes, I'm gonna be focusing on the safety portions of the outcome. So the primary outcomes I'm gonna focus on is seven-day mortality and PE-related mortality or hemorrhage within seven days. PE-related mortality, meaning deaths with PE as the primary cause. And then secondary outcomes, I'm gonna focus on 30-day and one-year all-cause mortality. Patients were classified as receiving full dose with 100 milligrams of alteplase over two hours or reduced dose where they received 50 milligrams over two hours, or another group had 10 milligram bolus over one minute followed by 40 milligrams over two hours. Patients were also initiated on unfractionated heparin drips at guideline-directed doses at the diagnosis of PE and titrated using anti-TIN-A levels or APTT ranges. For statistical analysis, they used propensity score, weighting to adjust for imbalances, categorical variables were compared using chi-squared tests, continuous variables were compared using T-tests or Wilcoxon rank sums, and the alpha was set at 0.05 for statistical significance. Patients were around the age of 60 with 54% of the patient population being men, 36% experienced a massive PE, SOFA score was around 1.7 and about 4% of these patients needed CPR. Overall, there really was no notable differences between the groups aside from a higher lactate level in the full-dose alteplase group. The study did report both unweighted and weighted results, but the weighted results helped compensate for the full-dose patient population being sicker at baseline. So for a primary outcome, looking at the weighted outcomes, there was no statistical significant difference between PE-related mortality, all-cause seven-day mortality and any hemorrhage. The results of hemorrhage was broken down into minor hemorrhage, major extracranial hemorrhage and intracranial hemorrhage, all of which were not statistically significant. And at the time of the bleed, there was about 35 to 46% of patients that were actually super therapeutic on their anticoagulation regimen. For secondary results, both the all-cause 30-day mortality and one-year mortality rates, again, were not statistically significant. And the authors also did a logistics regression to account for age, alteplase dose, weight and the use of antiplatelets and found that invasive procedures performed within 30 days of thrombolysis was independently associated with hemorrhagic complications. So based on these results, the authors concluded that reduced-dose alteplase had similar outcomes to full-dose regimen with lower bleeding risk. Some strengths of the study include that additional information to inform optimal dosing for PE without cardiac arrest, knowing lower doses are likely just as effective as the original 100 milligram dose. The study also confirmed what previous studies had shown and it reflected real-life practice. Limitations include that the retrospective, or it was a retrospective observational study design. There was potential bias introduced with alteplase dosing because it was provider-driven and the amount of data available given the fact that it was retrospective in nature. So my personal conclusions, it's hard to fully utilize this data without definitive practice changing since about 92% of them were on full systemic anticoagulation and about 35 to 46% were super therapeutic on their anticoagulation at the time of hemorrhage. Additionally, patients with massive PE were more likely to receive full-dose alteplase, but I do think this is extremely thought-provoking to potentially make adjustments for certain patient populations or at least open that door for conversation prior to determining a patient's dose. So I plan to give a stronger consideration for reduced dose specifically in those at higher risk for bleeding. So patients that are less than 65 kilos that have had recent invasive surgery or plan to have surgery in the next 30 days are just a few patients that I would consider reducing the dose for. Some remaining questions that I have though is since some institutions are transitioning to tenecteplase as their only fibrinolytic on formulary and given the fact that historical trials have shown efficacy of tenecteplase but increased risk of hemorrhagic stroke and extracranial bleeding, I'm wondering is there potentially a reduced dose of tenecteplase that may still be as effective but also safer for these patients for the treatment of PE? And then another question, is there a potential or is there safety and efficacy of reduced dose alteplase doses less than 50 milligrams for PE? So to finish off this presentation, I do have two polling questions. The first one is, do you have an alteplase order set or policy that stratifies patient's bleeding risk to determine an alteplase dose for PE treatment? Okay, actually 91% said that they don't have a order of policy, which I was just curious to see if any other institution had them, but I was not surprised by that answer. And my second question is how do you dose alteplase for pulmonary embolisms without cardiac arrest at your institution? Do you get the full dose of 100 milligrams? Do you do 50 milligrams, potentially even 25 milligrams, all of the above? And about 86% said they give the full dose of 100 milligrams, which is the FDA dose or the FDA indication for the dosing, but about 7% of y'all also said all of the above, so it would be interesting to see what other institutions or how other institutions practice. I know at my institution we give a 10 milligram bolus over or as a push and then it's 90 milligrams over the next two hours. And here are my references and I can answer any questions. You mentioned some of the earlier trials that looked at alteplase for pulmonary embolism and many of those trials reported rates of bleeding that were a lot lower than what this trial reported. Do you want to speak on, you know, which of those, which bleeding rates you think are probably most realistic for these patients? Yeah, that's a really good question. I think the bleeding rates for this particular study, since it's also more in line with what real-life practice is like and the fact that standard of care has also progressed throughout the time, because I think the first study I mentioned was back in 2002 and this one was most recently published at the beginning of this year. I think some of the bleeding rates that they talked about, at least with the like intracranial hemorrhage and extracranial hemorrhage, because the study wasn't necessarily powered to reach or assess that for the results. I think the rates that we got from this study would also potentially be different if we did have more patients included or if they were able to include more patients. So I think, I feel like I'm going back and forth between them, so I apologize, but I would be more in line with what the study, the most recent study said for bleeding rates to expect for alteplase. Thank you very much. The other question I wanted to ask you is, some of the other studies picked primary in, primary endpoints that were more looking at need for progression, the need to do thrombectomy or need to give more, more alteplase or tenecteplase if they had done reduced dosing. I don't think you had a lot of time to get into that for this specific study, but can you expand on if they looked at any of those outcomes? Yeah, so this particular study was looking at efficacy, but it wasn't necessarily looking at if they needed additional therapy, whereas I feel like previous studies in the past looked specifically at did we need to escalate therapy, which I think is a really interesting consideration for these studies to see did we give enough, did we not give enough. Again, I feel like I don't necessarily see this as much in practice because we do have so many alternative options for these patients, whether or not we take them straight to thrombectomy. But I know the study did look and they didn't see a statistical difference between efficacy of lower dose versus high dose in this particular study in comparison to the earlier studies that did. Specifically, a couple showed that they did need increased risk of treatment escalation when they use lower doses. Well, thank you very much. That will conclude our Q&A session, so thank you Sterling. All right, I'd like to introduce our second presenter. It's Adriana Gooden. Hi, good afternoon. Thank you so much. My name is Adriana Gooden. I'm the PGY-2 critical care pharmacy resident at WellSpan York Hospital, located in south central Pennsylvania. Today, I'm discussing tight blood glucose control without early parenteral nutrition in the ICU, and this was published in the New England Journal of Medicine in September 2023. Historically, the first study examining tight blood glucose management in critically ill patients took place in 2001 in surgical patients, demonstrating reduced morbidity and mortality associated with tight blood glucose control between 80 and 110 milligrams per deciliter. The same authors repeated this study in medical patients several years later in 2006, which did not maintain that same benefit, actually showing no difference in mortality. These studies notably included patients receiving parenteral nutrition, which of course introduces intravenous dextrose directly into the bloodstream. The landmark study following in 2009 marks the standard of care as we know it, favoring some degree of blood glucose control between 140 and 180 milligrams per deciliter for most ICU patients, which demonstrated an increased mortality in those with tighter control. This has often been attributed to a higher incidence of severe hypoglycemia in the tighter group of the NICE sugar trial, which had a severe hypoglycemia incidence of about 7%, and controversy does exist surrounding necessity of even this degree of blood glucose control. Therefore, the study that we are discussing today by Gunst and colleagues set out to determine the impact of tight blood glucose control compared to a more liberal approach, this time excluding those who received early parenteral nutrition, defined as the first seven days of the ICU stay. We now know that early parenteral nutrition in critically ill patients is associated with increased hyperglycemia and infection, and this population was not excluded from previous guideline-making studies. Adult patients in the first seven days of the ICU stay without parenteral nutrition were assigned to either tight blood glucose control, 80 to 110 milligrams per deciliter, versus liberal blood glucose control, 180 to 215 milligrams per deciliter, to determine any reduction in length of time that ICU care was needed, measured as ICU length of stay in days and discharge alive from the ICU. This was a randomized controlled parallel group study, which randomized patients one-to-one and stratified according to diagnostic category. The study timeframe took place between September 2018 and August 2022 across 11 ICUs from two university hospitals in Belgium. The primary endpoint was duration of ICU dependency analyzed by student t-test and discharge alive from the ICU analyzed with a Kaplan-Meier plot. Notable secondary endpoints include 90-day mortality and severe hyperglycemia, which were analyzed with the chi-squared test. The sample size was calculated to detect a reduction in ICU dependency by one day with 80% power and 95% certainty. All adult patients at least 18 years of age or older at a participating ICU were eligible. Patients were excluded for reasons that precluded them from being defined as critically ill, such as receipt of oral nutrition or lack of invasive monitoring or central venous lines. Additional exclusions were plans for early parenteral nutrition, patients suffering from diabetic ketoacidosis or hyperosmolar coma, or those with an insulinoma. Just over 24,000 patients were screened for eligibility, with about 15,000 being excluded, mostly because they were not considered critically ill, leaving the appropriate number of patients randomized to meet the pre-specified power. Looking here at the basic demographics, including age, sex, weight, history of diabetes, and APACHE-2 score, these were balanced between the groups. Of note, I wanted to point out that 28% of patients in both groups were diagnosed with sepsis according to the Sepsis-3 criteria. In terms of diagnostic category, almost half of the patients in both groups were post-cardiac surgery patients. The remaining population had mixed diagnoses, which was the intent of the investigators in order to have a broader population. Blood glucose values maintained good separation between the groups. However, as you can see in the liberal group, the median daily and the median morning blood glucose levels for each patient were in the 140s, with a range that fell below the intended blood glucose target of the group. Severe hypoglycemia incidence was quite low in both groups. The incidence of hypoglycemia from previous landmark trials that were associated with the worst outcomes in the tight control groups were 5-7%, so as you can see, the incidence in this study in both groups, 0.7-1%, is significantly lower than the incidence in those trials. In terms of the primary outcome, the length of time that ICU care was needed was not significantly different between the two groups. Each group had a median of 3 days in the ICU, and the hazard ratio for discharge alive was 1, and was not statistically significant with a p-value of 0.94. Deaths at all endpoints, including ICU, in-hospital, and at 90 days were no different between the groups. Several important secondary outcomes included acute kidney injury, defined as development of acute kidney injury stage 3, according to Kodago, or the new use of re-replacement therapy. These both did reach statistical significance, favoring tight blood glucose control. Several laboratory tests were examined to determine the presence of liver dysfunction. Only p-gamma glutamyl transferase and alkaline phosphatase met statistical significance, again favoring tighter blood glucose control. New infection was also assessed, which was not significant between the groups. Overall, the only statistically significant differences were both markers of acute kidney injury favoring tighter control, and the two previously mentioned liver function tests, both favoring tighter control. Despite the statistical significance, by looking at the percentages in each group, the clinical significance is unclear. Overall, the author concludes that hyperglycemia is less pronounced without early parenteral nutrition, and the logic algorithm avoided iatrogenic hypoglycemia. There were no differences in the length of ICU dependency or mortality between groups, with reduced AKI and liver dysfunction potentially favoring tighter control. Limitations included inability to blind, ICU bed shortages, and treatment heterogeneity. Overall, the research question is relevant to determine if tight blood glucose control affects ICU length of stay and mortality, which is similar to the aim of previous trials, but now appropriately excludes parenteral nutrition, since we now know that early use is associated with infectious complications and slower recovery. The design with a more liberal glucose group than previous trials is that the patient is more likely to have The design with a more liberal glucose group than previous trials decreases the number of patients receiving insulin in the first place, which reduces the risk of hypoglycemia. With that, it's more data to suggest avoidance of early parenteral nutrition in the ICU. Previous trials were shown to have increased incidence of hypoglycemia, which may have contributed to the increases in morbidity and mortality, and with improved technology such as the logic insulin algorithm, the risk of hypoglycemia can be more easily avoided, therefore teasing out the effects of varying blood glucose goals. However, there are a few key limitations to the study. Because the study took place in a single country, there may be some differences in the patient characteristics compared to average Americans, therefore decreasing external validity. The logic insulin software is a complex algorithm that's not widely available everywhere, therefore the incidence of hypoglycemia could actually end up being higher in real-world practice attempting to reach the blood glucose values in these groups, which was shown in previous studies without the use of these tools. And it's unknown if these results would apply if other explicit clinical decision support tools were used. The overall glucose values in the liberal group were lower than the intended goal, making it difficult to draw conclusions about the stated range of 180 to 215 milligrams per deciliter. Given the mixed population, it's difficult also to draw conclusions about any particular group over another, although the discussion did mention some associations, such as potentially better outcomes in neuropatients. The study also included many post-operative cardiac patients, and the results suggest that liberal blood glucose may not be harmful in terms of infection and ICU dependency. However, this does contraindicate the Joint American Heart Association American College of Cardiology 2021 guidelines that suggest patients undergoing coronary artery bypass graft surgery should be targeting a blood glucose of 140 to 180 to reduce complications such as sternal infection. And lastly, there is no mention of corticosteroid use in either population, and 28 percent of patients in each group had sepsis. So to me, this begs the question if other glucose or insulin-altering medications were used in an unbalanced manner between the groups. In conclusion, tighter control of blood glucose without iatrogenic hypoglycemia does not affect ICU dependency or mortality. Specific populations may potentially benefit from different blood glucose thresholds. These results add evidence to omit early parenteral nutrition in the ICU to reduce the need for blood glucose control. Next steps in advancing patient care include continuing to avoid parenteral nutrition when applicable in the early stages of ICU stay, and to explore availability of explicit clinical decision support tools. My references are listed here. And my first polling question, does your institution currently utilize logic insulin titration algorithm or a similar software? Yes or no? 78 percent saying no. I sort of expected the majority to say no, but I am interested that 22 percent of those in attendance right now said yes. So that's exciting. And next, at your institution, who drives the titration protocol for continuous insulin infusions? Nurse, provider, or pharmacist? 88 percent nursing, 10 percent provider, and two percent pharmacist. I wasn't sure about the pharmacist, but that's great that two percent responded pharmacist. Same with our institution with nursing driving our protocol. So it kind of falls in line with my institution. All right. Thank you, everybody, so much for your attention and participation. I'd love to answer any questions. So you mentioned that this trial used a lot of cardiac surgery patients and a lot of neurology patients. Are there any other things within the demographics of the study that you think may have changed the outcome or we may have seen a different outcome if we'd had different demographics? Well, obviously, the study population is critically ill. So, you know, a lot of these comorbidities, I'll call them such as sepsis and whatnot, definitely are going to change the outcome if that weren't there, because with that brings a whole other host of additional medications potentially that could alter the outcome. So that would be one of them. But, of course, it's always going to be present in critically ill patients. I think that sort of goes, I just think it's hard to say because it was such a mixed bag of patients that if you've really focused on one group or even just instead of diagnostic category, just going by ICU group in general, it might have been a little bit more helpful to at least target a certain population than how it was designed here. Although I do understand their intent to try to make it generalizable. Yes, I completely agree with that. I think there's a lot of questions that still need to be answered, specifically along the realms of sepsis, but also just the number of patients who had pre-existing diabetes and the fact that the blood sugars were truly not that different between both groups. I wanted to ask another question about insulin software and if you have experience with insulin software, or if this study has made you reconsider if that's something that your institution would want to invest in. So I have no experience myself with insulin software and this was sort of the first time that I've really read a lot about it. It's interesting to me because of course the group that utilized the software had such a low incidence of hypoglycemia, which is one of the benefits that is mentioned why it's so great. But if you look at the liberal group, you know, there are no differences, but they didn't utilize the software. So it's kind of curious to me about what their algorithm truly looked like or how applicable that algorithm, whatever they used on their side, would be because, you know, they didn't utilize the software and there was no difference and there was still such a low risk of hypoglycemia. So it's kind of, it is interesting because I know the recommendations are starting to come out in guidelines to recommend these types of softwares, but it's kind of interesting that the other group didn't use it and they had such a low incidence of hypoglycemia. So I wonder, you know, could we do that instead? Or if you don't have access to obtaining the software, is this an alternative compared to whatever we're doing now? Right. Did the authors by chance publish their protocol that was not with the software? I just wonder if they used a more mild insulin dosing and that maybe helped them avoid some of the hypoglycemia. Right. You know, I know they published some more specifics in their protocol, but from off the top of my head, I can't remember them exactly posting the entire algorithm. Well, thank you very much for answering our questions. We'll go ahead and conclude our Q&A session. So thank you, Adriana. I'd like to introduce our final speaker today, Yumi Oh. Hi, everyone. Thank you for that introduction. And so today I will be presenting on the Journal Club of the Effect of Early Administration of Vasopressin on New-Onset Arrhythmia Development in Patients with Septic Shock. So starting off with the background, so the 2021 Surviving Sepsis Campaign, as we know, recommend norepinephrine as a first-line vasoactive agent. Studies have shown up to 12.4% of dysrhythmia rates in patients due to the beta-adrenergic agonism. And studies have also shown that new-onset AFib as well as arrhythmias are associated with poorer outcomes, including renal failure, mortality, as well as increased ICU length of stay. And so the addition of vasopressin is recommended by the campaign as the next-line agent in order to decrease the total catecholamine requirement. I wanted to highlight this study here in 2014 by Reardon and colleagues. So this is a single-center retrospective study of adult patients admitted to the MICU with septic shock requiring catecholamines and vasopressin therapy. So there was a total of 71 patients that were included, and patients were either split into the early group, which was defined as initiation of vasopressin within 6 hours, or late group, which was when they were initiated within 6 to 48 hours of the catecholamine initiation. And here in this study, the catecholamine therapy included norepinephrine, epinephrine, phenylephrine, as well as dopamine for at least 6 hours or more. And their definition of new-onset arrhythmia was any non-sinus rhythm in a patient with no known history of arrhythmias, including atrial fibrillation or ventricular tachycardia. And so looking at the baseline characteristics, there was no difference in the APACHE-2 score map, as well as lactic acid, but patients in the early group tended to be younger and did have less norepinephrine as the catecholamine at baseline. And then on average, vasopressin was initiated at 2 hours in the early group compared to the 21 hours in the late arm, which was expected. And then looking at notable results in the study that I wanted to point out today, they did have higher incidences of new-onset arrhythmias in those that were initiated on vasopressin later on during the catecholamine infusion. But there was no difference regarding mortality, hospital length of stay, or ICU length of stay here. The next study I wanted to point out is the 2021 study, which was a single-center retrospective study of around 250 patients. And so for this study, patients were on norepinephrine as the first vasopressor for at least 6 hours. And they were split up into 2 groups, into those who developed dysrhythmias and then those who did not. And of note, this study did exclude those patients who received dopamine. And so looking at the baseline characteristics here, there was no difference in age, SOFA score, or history of dysrhythmias to begin with. But of note, there were, in the no dysrhythmia arm, patients that have a higher number of home antiarrhythmics. And the initial lactate was statistically significantly higher in those that did develop dysrhythmias. And they also required a higher maximum norepinephrine dose. And so in total, there was around 65% of the patients that did not develop arrhythmias compared to 34% of patients who did develop arrhythmias. And so those who did not develop dysrhythmias did have longer ICU as well as vent-free days in addition to lower mortality rates that were seen. And the study also did a multivariable logistic regression and found that the duration of norepinephrine and the maximum norepinephrine dose were independent predictors of increased rates of arrhythmias. And so now I wanted to dive into our study that I wanted to talk about today. So the study objective was to determine whether the early administration of vasopressin was associated with a lower incidence of new onset arrhythmias in septic shock patients. This was a retrospective single-center cohort study. And again, here as well, the patients were split up into early or late vasopressin group, which was defined as early less than six hours, and then late vasopressin group if they were initiated within six hours or greater. The study did a good job at the beginning laying out a couple of definitions that I did want to highlight. So for septic shock, this was defined as by using ICD-9 or 10 codes of severe sepsis with septic shock or septic shock. And they also had to have suspected or proven infection that meant presence of cultures or if they received antibiotics within the first 24 hours of septic shock onset. And they also defined onset of septic shock as the date and time of norepinephrine initiation. Then the resolution of septic shock was when both norepinephrine and vasopressin was offered at least 24 consecutive hours. And then culture positive meant that patients had positive bacterial culture results obtained within 72 hours of the onset of the septic shock. The next two definitions, so the first one is new onset arrhythmias, and patients had to have both of these criterias, which were if they received an antiarrhythmics or rate-controlling agent during or after septic shock onset or resolution. And they had to have clinically relevant new onset arrhythmias required confirmation by board certified cardiologists. And they looked at EKG, telemetry, as well as just clinical data surrounding why they received the medications. Then we have the new onset arrhythmia classification split into supraventricular tachycardias, including SVT, atrial fibrillation, and atrial flutter. And then ventricular tachycardias, including ventricular fibrillation and sustained or non-sustained ventricular tachycardia. So for inclusion criteria, they included everyone adult, 18 years and older, diagnosed with septic shock if they received vasopressin and norepinephrine and admitted to the MICU or the CT or surgical ICU. On the other hand, they excluded patients that received any other vasoactive or inotropic agents, as I have listed here. If they had a history of cardiac arrhythmias, and that meant one out of the two criteria that I will mention, the first one being if they had an ICD-9 or 10 code consistent with cardiac arrhythmias in the 12 months prior to the admission, or if they were administered an antiarrhythmic or rate-controlling agent before the onset of the septic shock. And then lastly, if they were admitted from an outside hospital. For the outcomes that the study looked at, for primary, they looked at incidence of new onset arrhythmias. And then for secondary, they looked at the different types of arrhythmias, total number of arrhythmias, time to onset of the arrhythmia, septic shock duration, length of ICU and hospital stay, the need for renal placement therapy, the total exposure, and maximum doses of norepinephrine as well as vasopressin. And then lastly, they looked at in-hospital mortality. Diving into the data analysis, so the study did a continuous data using the Mann-Whitney-Hughes test as well as the Hodges-Lehman method to estimate median differences between groups and associated conference intervals. And then for categorical data, they analyzed using the Chi-square or the Fisher's exact test. And they did the odds ratio and the confidence interval by doing the multivariate logistic regression model. And then lastly, they did a time-to-event analysis using the Kaplan-Meier method. And so now I want to go over the results of this study. And so there were around 2,000 patients that were eligible for inclusion. And around 1,500 patients were excluded. And I wanted to point out that most of the patients here were excluded because they received different vasopressors or inotropes. And then that led to around 200 patients in each arm for the early and the late vasopressin group. Now for baseline characteristics, overall, it was pretty well balanced between the two arms. But I wanted to point out a couple of characteristics. And so on average, patients were around 60 years old, Caucasians, with no differences regarding the APACHE-2 scores as well as the Charleston Comorbidity Index. And then for preexisting conditions, most patients had COPD, diabetes, hepatic, as well as renal disease. This is a continuation of the baseline characteristics. So most of the patients were mechanically ventilated upon the onset of the septic shock. Common source of infections were pulmonary and urinary in both groups with around 60% of the patients with a bacteremia. And I really wanted to highlight the septic shock treatment because this was pretty similar between the two arms. So there was no difference seen regarding the net fluid balance on the day of shock, appropriate empiric antibiotic therapy. And around 40% of the patients did receive stress dose steroids, which was defined as at least 200 milligrams of hydrocortisone or its equivalent. And then lastly, as expected, the time to initiation of vasopressin was statistically significant with the initiation of average of two hours in the early group compared to 17 hours in the late group. Now for the results, looking at the primary outcomes, so there was no statistically significant difference regarding the incidence of new onset arrhythmias here. Then looking at the secondary outcomes, there were no difference in the different types of arrhythmias as well as the time from new onset arrhythmia from shock onset or from vasopressin initiation. However, those that did receive vasopressin early did have less exposure to norepinephrine. And they also had a shorter duration of shock as well as ICU length of stay in addition to in-hospital mortality and fewer patients did receive new renal replacement therapy. And then the last thing I wanted to point out from the study was that they did do a multivariable logistic regression analysis to assess for any covariates as potential risk factors for new onset arrhythmias. And so they looked at different factors as they have listed here, just to point out a few, time to vasopressin initiation, the APACHE score, and the max dose of norepinephrine. However, none of these covariates were significantly associated with the development of new onset atrial fibrillation. And so in conclusion, the authors concluded that among septic shock patients treated with vasopressin and norepinephrine, initiation of vasopressin within six hours of septic shock was not associated with a decreased incidence of new onset arrhythmias. And so now I wanted to go over some strengths and limitations that I thought of. And so for strengths, the study did include only patients who received norepinephrine and vasopressin, which, as previously mentioned, previous studies did include other vasopressors and inotropes. So this kind of helps minimize potential confounding factors. Next, the study did exclude patients with history of prior cardiac arrhythmias, but they did only look for the last 12 months, which could be potentially a limitation as well. I thought they did a good job outlining the definitions up front regarding the septic shock, as well as the arrhythmia component. All of the EKGs had to be confirmed by a board-certified cardiologist in this study. And then lastly, all antiarrhythmics, as well as rate-controlling agents that were given, had to be reviewed for the indication before deeming that this was used for new onset arrhythmias. As we know, medications such as beta-blockers can be used for a multitude of reasons. And then, on the other hand, regarding limitations, as we know, this was a retrospective single-center study, and so there are many limitations that do come along with that. Additionally, the study did not mention at what point the patients were initiated on steroids, and in this study, there was around 40 percent of the patients that were started on steroids. I think it just would have been interesting to have known. And then the next two that I wanted to mention, which is kind of comparing this study to the previous study that I mentioned, was that there was a lower incidence of new onset arrhythmia here of less than 10 percent, where previous events were up to 30 to 60 percent in the prior studies. And so with the lower event rates, this could be a little bit harder to draw conclusions. And then, additionally, the average time to vasopressin addition in the late arm was 17 hours in this study, which was earlier than our previous study that I mentioned, which was at 21 hours. And then there was no comment on the median norepidose at the time of vasopressin initiation, which I thought would have been interesting to see. And then, lastly, there was no comment on the norepinephrine salt formulation used in this study. One of the sessions that I attended at SECM this year did talk about the new position paper regarding the reporting of norepinephrine salt formulations, and so how that may impact studies. So I think this is something that the study should have included as well. And so I just wanted to kind of go and do a quick comparison of our previous study in 2014 to today's study. And so regarding vasopressor use, the one in 2014 did allow for epinephrine, norepinephrine, as well as dopamine, compared to this one only allowed norepinephrine as the vasopressor of choice. And then regarding the definition of new onset arrhythmias was slightly different, but not too different in general. And then for the study today, the EKGs did have to be confirmed by cardiologists, where the previous study did not. And then the next comment that I wanted to make was the initiation of vasopressin regarding the time, which I mentioned that in the study today, the late ARM was initiated at 17 hours compared to 21 hours in the RAVEN study. And then the last point was that the new onset arrhythmia incidence was much lower in this study today. And so in conclusion, there was no difference regarding the incidence of new onset arrhythmias, but there was shorter shock duration, ICU length of stay, in-hospital mortality, and less patients did receive new renal replacement therapy. And so although this is really not as practice changing, I think that this is something that we can consider, something that I will definitely consider moving forward and trying to start vasopressin earlier rather than later to hopefully reduce the total catecholamine requirements. And so this is my resource. These are the resources. And so I do have two poll questions. So my first one today is, at your institution, is there a protocol for the addition of vasopressin? A, yes, based off of the norepidose. B, based off of the duration of the shock. C, based off of both the norepidose and the duration of the shock. And then D, we do not have a protocol. Okay, I think this is also the answer that I had expected, that we do not have a protocol. And then the next question. And so in your practice, do you prefer to add vasopressin earlier or later? So early as in less than two hours, B, two to five hours, C, six to 12 hours, D, greater than 12 hours, or E, you don't have a preference. Perfect. It looks like the majority, 52% of the audience said early, two to five hours, and I think that is also kind of where I land between the earlier two to five hours as well. Thank you for participating. And then now I will take any questions. Let's go ahead and add any questions to the question box, but I'll get us started. I really like that you pointed out that they didn't discuss the median norepinephrine dose before starting the vasopressin. I also thought it was very interesting that only 40% of the patients were receiving steroids. Do you think that impacts how we can apply this to practice? Can you speak a little bit to your own practice for both addition of vasopressin and steroids? Yeah, so I think it is interesting that only 40%, I thought that was kind of a lower percentage regarding the vasopressin, or sorry, the steroid initiation. And then normally, I would start the steroids when the norepinephrine as well as the vasopressin are already on. So that kind of makes sense regarding the timing, but I would also have to look at when it was really initiated regarding the norepinephrine to figure out why only a lower amount of patients got the steroids. But normally, I think there are some studies out there that did a systematic review of vasopressin, and they normally would add on the vasopressin when it's around 0.2 to 0.5 mics per tick per minute of the norepinephrine, which is kind of similar to when you would also maybe consider adding on stress dose steroids. Thank you. I have one other question for you. I think one of the biggest limitations of this study is obviously that it was a single center retrospective study. So if you had all the money in the world and you were able to design a more robust study to look at this question, how would you want your study set up? I think I would want my study set up to where I did really, there were lots of strengths with the study, especially having a cardiologist on board looking at EKGs, and I think that was really the big thing with this study. So continuing that and then continuing, I would really want to monitor more closely regarding timing of the blood pressure monitoring, as well as have an arterial line for everyone. I think something else would be, I'm trying to think what else I would want to do. I think really the only thing I would really add was the median dose of norepinephrine. It's the big part that I really want to study, but nothing too different from what they had done in the study. I agree with you. I think it would have been really nice to have a more protocolized approach for addition of vasopressin, especially if you were to do an RCT. It would be nice to have your group definitely following a specific protocol. With it being retrospective, it's a little bit hard to tell what was provider preference versus what is truly similar across groups. Well, thank you. Thank you very much to Yumi for the great presentation. That will conclude our Q&A session. So thank you to our presenters and the audience for attending today. Please join us on the third Friday of the month from 2 to 3 p.m. Eastern Standard Time for the next Journal Club Spotlight on Pharmacy. And that will conclude our presentation today. Thanks, everyone. Thank you so much.

Journal Club Spotlight on Pharmacy

critical care pharmacotherapy

reduced dose alteplase

acute pulmonary embolism

tight blood glucose control

parenteral nutrition

vasopressors

septic shock

clinical implications

Webcast

Pharmacology

Pulmonary

GI and Nutrition

Sepsis

Pulmonary Embolism

Nutrition

Shock

2024

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