SCCM Resource Library-March Journal Club Webcast: Spotlight on Pharmacy (2022)

Video Transcription

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 Adam Mohamed, Critical Care Clinical Pharmacist at St. Luke's Hospital of Kansas City in Kansas City, Missouri. I'll be moderating today's webcast.  A recording of this webcast will be available to registered attendees. Log into mysccm.org and navigate to the My Learning tab to access the recording. Thank you for joining us.  A few housekeeping items before we get started. There will be a Q&A after each of today's speakers.  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 on the button next to your choice.  You may also follow and participate in live discussion on Twitter, following hashtag SCCMCPPJC and hashtag PharmICU.  Please note that 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 Dr. Anna White, PGY-2 Critical Care Resident at Denver Health  Medical Center in Denver, Colorado. Our second speaker is Dr. Kathy Toh, PGY-2 Critical Care Resident at Memorial Hermann Hospital TMC in Houston, Texas.  And our third speaker is Dr. Matthew Jornstad, PGY-2 Critical Care Resident at Eskenazi Health in Indianapolis, Indiana. And now I'll turn things over to our first presenter.  Hi, everyone. Thank you for the introduction and thank you all for being here today. I'm going to be reviewing the PLOS trial, which was published in the New England Journal  of Medicine in January of this year, and compared the use of a balanced multi-electrolyte solution versus saline in critically ill adult patients.  Let's start out with some background information. So we know that the administration of IV fluids impacts our patient's volume status as well as their electrolyte balance.  Historically, 0.9% sodium chloride, or NS, has been the most commonly administered IV fluid within the intensive care unit.  Over the last several years, we've had the publication of some randomized controlled trials, which we'll discuss on the coming slides.  And there's been growing concern about the association between the use of normal saline and an increased risk of acute kidney injury as well as an increased mortality rate.  For this reason, over the last several years, we've seen an increasing popularity of the  use of our balanced multi-electrolyte solutions, including plasmolyte-148 and lactated ringers.  Before we get into the literature, I wanted to take a step back and just point out some of the different components of these fluids that we commonly use for resuscitation in  our patients, directing your attention specifically to the sodium and chloride content. The sodium content of our plasma is around 140 milliequivalents per liter, and chloride  is around 100 milliequivalents per liter. As you can see, with both plasmolyte-148 and lactated ringers, these values more closely mirror our plasma concentrations.  But with the use of normal saline, you can see that it's exponentially higher in sodium content and especially chloride content.  So what is the proposed mechanism of injury regarding the use of normal saline? As previously mentioned, the chloride content of normal saline is about 50% higher than  our physiologic levels. The theory is that by administering large volumes of normal saline, it can lead to a  higher relative increase in our plasma chloride than plasma sodium and drive a metabolic acidosis  because as we have a relative chloride increase, this precipitates a reduction in bicarbonate.  The metabolic acidosis can affect our myocardial function as well as renal and intestinal perfusion and our cells' ability to buffer potassium.  And this is a mechanism by which normal saline has been associated with an increased mortality rate.  Now I want to spend just a couple of minutes going over some of the recently published randomized controlled trials.  Starting with the SPLIT trial, which was published back in 2015, this study included around 2,000  patients who were randomized to either plasmolyte or normal saline, and there was a median volume of 2 liters received per group.  There was no significant difference between groups regarding the rate of AKI within 90 days, the need for new renal replacement therapy, or mortality rate.  The SPLIT trial was followed by the SMART trial, which was published three years later and included nearly 16,000 adult patients admitted to the ICU.  Patients in this study were randomized to either a balanced solution, which could be lactated ringers or plasmolyte, versus normal saline, and there was a median of 1 liter  received per group. The primary outcome of the SMART trial was a composite of major adverse kidney events  within 30 days, which they found to be significantly higher among the patients who were randomized to receive normal saline.  There was no significant difference in the mortality rate at 30 days, however, in a subgroup analysis of patients who met criteria for sepsis at baseline, mortality was about 5%  higher among the patients who received MS. Most recently, we had the publication of the BASICS trial, which was published in 2021 and included nearly 11,000 patients.  Again, patients were randomized to either plasmolyte or normal saline, and they achieved higher fluid volumes in this study with a median of 2.9 liters per group.  There was no significant difference between groups regarding 90-day mortality, but again, in a subgroup of patients who had traumatic brain injury, mortality was about 10% higher  among patients who were randomized to the balanced solution, and there was no difference in the need for new renal replacement therapy.  The hypothesis of the PLUS trial was that 90-day mortality would be significantly lower with the use of plasmolyte-148 as compared to normal saline in critically ill adult patients  requiring fluid resuscitation. The PLUS trial was a randomized controlled trial conducted across 53 different ICUs with double-blinded design and two parallel groups.  Patients were randomized through permuted blocks of varying sizes as well as being stratified by site.  Patients received their assigned trial fluid for all fluid resuscitation for up to 90 days after randomization, so long as they remained in the ICU.  Other fluid, preferably D5W, was used to dilute drugs for which either trial fluid was deemed incompatible or if compatibility data was lacking.  All other treatments were administered at the discretion of the prescriber, and the type of fluid was not dictated by the study protocol once the patient left the ICU.  Patients were eligible for inclusion in the PLUS trial if they were age 18 and older and required fluid resuscitation and the use of a balanced solution or normal saline were  considered to be equally appropriate. Patients also had to be expected to be in the ICU for at least three consecutive days.  Patients were excluded from the trial if they had specific fluid requirements or had received  a disqualifying fluid resuscitation, which investigators defined as at least 500 cc prescribed and administered in the ICU.  Additionally, patients were excluded if they were considered to be at imminent risk of death or had a life expectancy less than 90 days or if they had a traumatic brain injury  or were at risk of cerebral edema. The primary outcome of the PLUS trial was death from any cause within 90 days of randomization.  Investigators also had several pre-specified secondary endpoints. I have them listed for you here on the slide.  To name a few, they looked at peak serum creatinine within seven days of randomization, maximum  increase in creatinine in the ICU stay, as well as the receipt of new renal replacement therapy.  Using the statistical analysis of the study, investigators calculated that they would need to recruit 5,000 patients to provide 90% power to detect an absolute difference of 3.8% in  90-day all-cause mortality. This power calculation was based off an estimated baseline mortality of 23% and it's being changed  during recruitment due to recruitment issues with COVID-19. For the primary outcome, investigators used repeated risk differences with 95% confidence  intervals and they also ran several secondary analyses with imputations for missing data. For secondary outcomes, investigators used repeated measures, linear mixed models, and  cumulative incidence functions to analyze time to life discharge with accounting for death as a competing risk.  Moving on to our results, a total of 5,037 patients underwent randomization and we ended  up with 2,515 in the balanced multi-electrolyte solution group and 2,522 in the normal saline group. The baseline characteristics between groups were well-balanced.  To point out a few important characteristics, you can see that our average age between groups was around 62 years old.  Around a third of the patients were admitted to the ICU from the emergency department. The median APACHE-2 score between groups was 19 and about two-thirds of the patients were  mechanically ventilated at baseline. 40% of the patients met the criteria at baseline and regarding the baseline creatinine and  chloride measures, they were comparable between the two groups. The median duration of treatment was six days in both groups and the median volume was 3.9  liters in the balanced group. I'm sorry, this is actually a typo. It was 3.7 liters in the normal saline group.  Prior to randomization, around 60% of the balanced group and 20% of the normal saline group received at least 500 cc of the opposite fluid and after randomization, around 60%  of the balanced group and around 5% of the normal saline group received 500 cc of the opposite fluid.  Volumes of other IV fluids, blood products, total Is and Os, and urine output were comparable between groups and the arterial blood pH was significantly higher and serum chloride  was significantly lower in the balanced group, so the difference between groups was minimal  with a mean difference in pH of 0.01 and chloride was about 2 milliequivalents per liter at any time point.  Regarding the primary risk of 90-day mortality, there was no significant difference between groups.  The balanced group had a 90-day mortality rate of 21.8% versus 22% in the normal saline  group. This interaction provided an odds ratio of 0.99 with a confidence interval that crossed  one and an absolute risk reduction of negative 0.15 with a confidence interval that crossed zero.  As previously mentioned, investigators did several secondary analyses of the primary outcomes including multiple imputation for missing data, adjustment for baseline risk  factors and exclusion of patients who received a substantial amount of a fluid they were  not assigned to, as well as looking at predefined subgroups and across all of these secondary  analyses, the results for the primary outcomes were the same, there was no significant difference between groups.  I did briefly want to bring up the subgroup analysis of deaths from any cause that they performed, specifically directing your attention to the subgroup of patients who met criteria  for sepsis at baseline, and they also split patients up by an APACHE-2 score of less than  25 and greater than or equal to 25, and within these two subgroups, there was still no significant difference regarding 90-day mortality.  For our secondary outcomes, there are several. I will save you the time from looking at all of these absolute risk reductions, none of them are statistically significant.  To point out a few of the peak serum creatinine was about 1.76 milligrams per deciliter in each group, maximum increase in creatinine was about 0.4 milligrams per deciliter and  nearly 13% of patients in both groups had a new requirement for renal replacement therapy.  The author concluded that normal saline resulted in a significantly higher chloride level and a lower pH, although it had no significant effect on kidney function.  They concluded that this study provided no evidence that the use of a balanced solution in preference to normal saline resulted in lower all-cause mortality or risk of AKI,  but that the confidence intervals around the results encompass either a modest increase or decrease in either of the outcomes with the use of a balanced multielectrolyte solution.  Moving on to my critique of the study, starting off with internal validity, I think the internal validity of the study is strengthened by its design.  It was a double-blind, randomized controlled trial. They used blocking and stratification to ensure their groups were balanced.  They used an intention-to-treat analysis, which makes it more pragmatic. They also looked at a patient-centered primary outcome of 90-day mortality.  I believe they performed a robust statistical analysis that accounted for several confounding  factors, and they also looked at several pre-specified subgroups in which there had been a mortality  difference demonstrated in previous trials, particularly the SMART trial with the subgroup of stepset.  The internal validity is weakened because a significant proportion of the balanced group received open-label normal saline at around 60% before and after randomization.  Additionally, the fluids administered outside of the ICUs were not protocolized, and the power calculation and target sample size was changed during recruitment.  They were initially trying to recruit about 8,800 patients to detect a mortality difference of 2.9%, and that ended up being changed during COVID-19.  The external validity of this study is strengthened by it being a multicenter study with a large patient population.  They had minimal loss to follow-up, and their baseline characteristics were well-balanced between groups.  They also included patients with a new renal replacement therapy requirement at baseline, which had been an exclusion criteria of previous studies.  I also think we were able to capture a more medically ill patient population than has been previously studied.  So, a third of the patients were admitted from the emergency department, meeting an APACHE score of 19 in both groups, and around 40% of patients met criteria for a sepsis  diagnosis. And then, lastly, we did achieve higher fluid volumes with the PLOS trial than we've seen in previous trials, with that median of 3.7 to 3.9 liters per group.  The external validity is weakened. One thing for us just to consider is the relative availability or use of plasmoly in relation to the use of lactated ringers.  Additionally, we're missing a lot of compatibility information for lactated ringers, and investigators  cited this as one of the main reasons why so many patients in the balanced group received open-label NS.  And then, lastly, only about 8% of patients were hospitalized for trauma in each group,  which makes it difficult for us to extrapolate the results of this study to the trauma population.  For my final thoughts and application to practice, I think the PLOS trial is a large, well-designed study with a robust statistical analysis plan.  One of the major things we can glean from this trial is that although patients who received  NS had a higher serum chloride and lower pH, it did not have an impact on any of the kidney injury endpoints or the mortality rate.  I think that all of the randomized trials we have to date are limited by either less than ideal volumes or the receipt of a non-randomized fluid.  With that being said, in the context of all available literature, I believe that if a mortality difference exists, it's likely small.  And I believe that the PLOS trial demonstrates that for volumes of 3.5 to 4 liters, the use  of either plasmonite or normal saline is likely appropriate for fluid resuscitation for most patients.  However, specific patient populations may be better suited for a specific fluid. For example, our patients with traumatic brain injury are likely better suited to normal  saline, and perhaps patients with diabetic ketoacidosis can resolve their acidosis faster with the use of a balanced crystalloid. And that brings us to our first polling question.  Does your institution use plasmonite-148 or lactated ringers as a balanced crystalloid for fluid resuscitation?  So it looks like about 75% of responders said lactated ringers. This is similar to what I was expecting to see, at least in my own experience.  The use of lactated ringers has been a lot more popular as opposed to plasmonite-148, and I believe that plasmonite is still quite a bit more expensive per liter than LR.  And that brings us to our second question. Maybe. There we go. In your practice, do you favor the use of a balanced crystalloid or normal saline for  fluid resuscitation of patients with sepsis?  And it looks like we have about 82% of responders taking balanced crystalloid. Again, I think this reflects what I was expecting to see. I think that the PLUS trial does,  I certainly favor balanced crystalloid as well, just because physiologically it makes more sense to me. But I think the PLUS trial does at least provide us  with some evidence that for small to moderate volumes of fluid or up to three and a half to four liters, likely the use of normal saline or balanced crystalloid  is safe for the majority of patients.  And that is everything that I have for you today.  I would be happy to take any questions that you have for me at this time.  All right, so I have a first question here. How do you feel about the number of the group of patients who receive more saline after randomization, 63 versus 3.5%?  What are your thoughts on this? Yeah, I think that's a great question. And it's a great, just a great point. The overall design of these studies,  this isn't the first study that we've seen this in where patients are receiving substantial volumes of open label fluids or the fluid that they weren't randomized to.  And this study is really no different. So around 60% of patients in the balanced group received open label NS prior to and after randomization.  I do think that it hurts the internal validity of the study a little bit. But with that being said, they did do a secondary analysis of the primary end point  where they account for all of those patients and removed them. And when they removed all the patients in the groups who received the opposite fluid  from which they had been randomized, there was still no significant difference between groups regarding 90 day mortality. So I do think it is a potential limitation  to the internal validity of the study, but I think they at least accounted for it in their statistical analysis.  I have a second question here. In critically ill patients, is a primary outcome of 90 day mortality a stretch? Do you think it is feasible to assess this  within a clinical trial due to the many confounders that can affect mortality?  I think that is also an excellent question and something that I had considered myself, especially when you're looking at the median duration  of intervention was around six days in each group. And we're looking at a primary outcome of 90 day mortality. I do agree with you, there are a lot of potential confounders,  especially once they leave the ICU. I think the idea is that if any substantial organ dysfunction was present prior to them leaving the ICU,  they would be able to detect it at that 90 day end point. With that being said, I think maybe the addition of,  what am I trying to say? Not a patient, oh, like a quality of life assessment in addition to the 90 day mortality out points they were looking at,  maybe that could provide us a little bit more evidence as to how the patient was doing down the road at the 90 day line.  Another question here, did they quantify how much fluid the patients received outside of just resuscitation maintenance fluids?  Yes, I believe they did. Um, I know they did, and I know it's somewhere in one of the graphs in the paper. I do not remember, unfortunately, off the top of my head. I'm sorry.  All right, and we have a last question here.  Excellent presentation, Anna. What do you think is the biggest reason or reasons for the difference in outcomes between studies like PLOS versus BASICS versus SMART?  Yeah, I think one of the major differences between the SMART trial and this one is that if we simply look at the study design,  they used a primary composite end point in the SMART trial. And if you look at those composite end points individually, there was no significant difference between groups.  Also, another thing that I've noticed, they only achieved one liter per group, which is substantially lower than we would be hoping for in a study that's designed like this.  I think that the BASICS trial and the PLOS trial are able to provide a little bit more evidence and insight into this patient population,  and perhaps maybe have a bit more of a pragmatic design where we're seeing those higher fluid volumes administered. But I think that the SMART trial,  one of the other major drawbacks is that it was also a single-center study, and we have now two studies, the BASICS and the PLOS trial,  demonstrating with these larger multi-center studies that had single primary outcomes instead of a composite outcome. They kind of support the idea that there's likely no difference  in these volumes of two to three to four liters between groups when we're looking at the use of normal saline versus a balanced crystalline.  All right, that concludes our Q&A session. Thank you, Dr. Anna White.  Thanks, everyone.  Before moving on to our next presenter,  we would like to ask a brief polling question regarding today's attendance to gain a better understanding of our overall attendance to ensure continued support  of this Spotlight on Pharmacy webcast.  How many attendees are you viewing this webinar with?  All right, now I would like to introduce our next presenter, Dr. Kathy Toh. Hi, everyone, my name is Kathy Toh, and I am a PGY2 critical care pharmacy resident  at Memorial Hermann Texas Medical Center. Today I will be presenting comparison of 5% human albumin and normal saline for fluid  resuscitation in sepsis-induced hypotension among patients with cirrhosis, also known as the FIRST study, which was published in 2021.  I do not have any potential conflicts of interest to disclose. The annual incidence of sepsis is approximately 300 per 100,000 population.  Mortality ranges 30 to 80% in these patients, and the use of early fluid resuscitation have shown to improve survival in patients with sepsis.  However, the mortality in cirrhotic patients with sepsis and the presence of organ failure is high.  Mortality is 55% with two organ involvement and 100% with three or more organ involvement.  The 2021 surviving sepsis guidelines recommend the use of IV crystalloids as first-line therapy for fluid resuscitation for patients with hypoperfusion, and only recommends the use  of albumin in patients who have already received large volumes of crystalloids. Cirrhotic patients with sepsis may have hemodynamic alterations different to those without.  At baseline, they have neonatural pressure, which may be lower, and this could potentially be due to beta blocker used for prophylaxis. Their cardiac output is higher.  Their baseline lactate levels are higher, but their lactate clearance is also delayed. Their volume status is unique, since the patients often present intravascularly depleted due  to third spacing, so there should be caution with volume overloading these patients as well. Recent literature has compared the use of albumin to crystalloids.  The SAFE trial focused on fluid resuscitation in critically ill adult patients, while the alveolus investigators evaluated whether or not 20% albumin and crystalloids would improve  outcomes compared to crystalloids alone in critically ill subject patients. There were no differences in mortality or any of the other endpoints.  However, there has not been a randomized controlled trial comparing the two in septic patients with cirrhosis.  So our first polling question is, what patient population do you often see albumin used for fluid resuscitation?  It looks like 72% of the audience that see cirrhosis patients, which is something that I did expect to see, however, I do, about 16% of the audience does see all of the above,  and I also agree, I have seen it used in each of these indications as well, but majority  see cirrhosis patients. The study aimed to assess the choice of fluid and its fluid responsiveness in patients with sepsis-induced hypotension with cirrhosis.  This was an open-label, prospective, randomized control trial completed between February 2014  to January 2015. Patients were included if they were adults 18 years or older with cirrhosis,  if they were admitted to the emergency department, intensive care unit, or high-dependency unit,  and if they presented with hypotension, which was defined as a mean arterial pressure less than 65 millimeters of mercury, and they had to have a suspected or documented infection.  Patients were excluded if they received 500 milliliters colloid or 2 liters of crystalloid  within 12 hours of presentation, if they were already on a vasopressor or inotrope, if they  had a history of acute variceal bleed or structural heart disease, if they were requiring hemodialysis,  if they had non-sepsis causes of hypotension, severe cardiopulmonary diseases, and as well as advanced hepatocellular carcinoma. Patients were randomized to receive 5% albumin  or normal saline. Albumin was administered as a 250 milliliter bolus at a maintenance  infusion of 50 milliliters per hour for 3 hours. Normal saline was administered as 30 milliliters per kilogram with a maintenance infusion of 100 milliliters per hour for 3 hours.  The primary objective was to compare the efficacy in reversal of hypotension with an absolute increase of mean arterial pressure to 65 or greater, sorry, there should  be a greater than equal sign there, at the end of 3 hours. The secondary objectives evaluated  of mean arterial pressure was 65 or greater at the 1 hour and 2 hour mark, as well as evaluated heart rate, urine output, arterial lactate, and mortality at the end of 1 week.  The study assumed an improvement in hypotension among patients treated with normal saline to be  60%, an improvement with albumin to be 85%, they used an alpha of 5% to get a power of 90%.  The investigators aimed to enroll 140 patients in each group to meet power with a superiority margin of 10%, but then they assumed 10% attrition and enrolled 154 patients  in each group. CHI-squared or Fisher's exact test was used for categorical data analysis.  Student's T-test or Mann-Whitney U-test was used for continuous data.  The ANOVA two-way test was used to assess change over a period of time.  And since mortality was a secondary endpoint, the Kaplan-Meier survival curve was used as well.  Of the 2,462 patients admitted to the ICU in high-dependency units, 397 patients were screened for inclusion. 61 patients were excluded, and the main reasons for exclusion  were acute variceal bleed, advanced hepatocellular carcinoma, or if they received IV fluids.  336 patients then underwent randomization, and out of those patients, 308 patients were included. Each group consisted of 154 patients.  The pertinent baseline characteristics are shown here. There was not any statistically  significant differences in the patient baseline characteristics. The mean age was 49 years old.  The majority of patients were male. Serum creatinine was elevated in both groups at 2.3 and 2.2. Patients' albumin were 2.3 and 2.2 at baseline. Mean male score was 31.9 and 30.1.  The mean SOFA scores were approximately 10, and mean MAP at baseline was 52 and 53.  Alcohol use was the most common ideology for cirrhosis, and pneumonia was the most common ideology for sepsis.  Overall, only 23 patients out of both groups in the entire study achieved reversal hypotension at the end of the first three hours. Improvement in mean arterial  pressure of 65 or greater was higher at one hour with the albumin group and at three hours with the albumin group as well. Heart rate was significantly lower in the albumin group  than normal saline group across all three hours. Arterial lactate was evaluated at the end of two  and three hours. Lactate was significantly lower in the albumin group at the end of three hours.  The proportion of patients surviving at the end of day one, five, and seven were higher in the  albumin group. The most common cause of death was related to multiple organ failure and end-stage  cardiopulmonary events in both groups. The investigators also evaluated urine output as a secondary outcome. However, the difference was not significant. As for adverse events,  there was no significant difference in pH and no new onset of metabolic acidosis or pulmonary edema.  Upon multivariate analysis, the investigators found that female gender and SOFA score were found to be predictors of non-responsive fluid resuscitation.  Again, survival is depicted here on the Kaplan-Meier curve. You can see albumin was shown in the blue line. The survival remains  higher than the normal saline group during this duration.  The strengths of this study was that it was a randomized controlled trial. The patient's baseline characteristics were representative of high acuity patients  based on their lactate levels, MAP, and MELD score, which was associated with 52.6 mortality risk.  The study was also specific to cirrhotic patients. The endpoints that were assessed were clinically relevant to the intervention since the endpoint evaluated hypotension reverso  as well as lactate, which is associated with morbidity and mortality in patients with sepsis.  There was also good adherence to protocol with 91.6% adherence. The weaknesses of this study was that this was a single-center open-label study, which limits generalizability.  Overall, there was only 23 patients in the entire study that achieved reverso of hypotension, which is a pretty small number of patients. Patients were assessed every hour,  but it's unclear if patients were able to receive additional interventions if needed during that  hour, specifically those who remained hypotensive. In the normal saline group, some patients had  spontaneous bacterial keratinitis documented, and patients also had elevated serum creatinine,  but it's unclear if diagnosis such as hepatic renal syndrome was diagnosed, which would be an  indication for LWIN use. However, patients in the normal saline group would not be able to receive  LWIN for that indication. The patients' outcomes were also assessed over three hours and survival  over one week. We would not be able to assess the long-term benefits of LWIN within the study.  Although the results for sustained reverso of hypotension were statistically significant,  the endpoint did not meet the predicted outcomes that LWIN would have a response rate of 85%.  The overall response rate for LWIN was 11.7%. This makes me question the sample size calculation.  And although survival was found to be significantly higher in the LWIN group, clinical significance is unclear since survival was only assessed over one week.  Clinical significance is unclear since survival was only assessed over one week, and although the investigators used the seven days based on average days in the ICU,  this is a short period of time in value mortality compared to previous studies. Additionally, their baseline MELD scores were associated with a greater than 50% mortality risk,  as I mentioned, so it's unclear what survival would actually look like for these patients after one  week. Overall, flu resuscitation with 5% LWIN did result in more sustained reverso of hypotension  compared to normal saline in patients with cirrhosis and sepsis-induced hypotension.  However, the overall number of patients that sustained reverso was small,  and although the results showed a significant difference, the endpoint did not meet predicted outcomes like I mentioned. The clinical applicability of this study is limited  since the long-lasting benefits of LWIN are unclear. Again, patients were evaluated for three  hours since LWIN will remain in the intravascular space during the first three hours, but then it  will move to the extravascular compartment afterwards. Based on the results of this study,  I would not change my current practice due to how I understand LWIN to work due to the limited time  that LWIN remains in the intravascular space, and also septic patients have leaky capillaries  which could result in pulling more volume out. There's also just overall limited evidence on  its long-term effects. Future studies should focus on the effects of larger volumes of LWIN  or longer infusion time to evaluate long-term effects. Additionally, since newer studies have evaluated the use of balanced crystalloids compared to normal saline, future studies  should consider comparing the use of LWIN with balanced crystalloids.  For our last polling question, based off the results of this study, would you recommend use of LWIN as initial fluid resuscitation in this patient population?  It looks like 62% of the audience answered B, and 32% answered C, depends on circumstances. This is kind of what I expected to see with the majority of the data.  Still not really supporting outwomen use, but there are some circumstances where we may have to initiate outwomen.  And that concludes my presentation. Thank you for listening. I will take any questions now.  Thank you. My first question is, they presented the baseline serum curiatinib. Did the authors include how many of those patients presented with the AKI?  Yeah, so they actually did report that 70% of those patients presented with an AKI at baseline. And then only around 2% to 5% of those patients  were reported to have CKD at baseline. So that's where I thought, maybe if these patients are presenting with an AKI, we should have also like worked out with hepatorenal syndrome,  which could be an indication for L women use, which the normal signaling group would not have been able to receive.  Second question here is, did the author account for sustaining the map with vasopressors, the need for vasopressors to sustain the map in addition to the fluids? Yes, they did.  So patients who did not maintain their blood pressures during each hour would actually be started on a vasopressor. However, those patients were not included  after the following. Like, so if they received vasopressors during the first hour, they were not included in the second hour or third hour and so on.  All right. Well, thank you. Thank you very much, Dr. Cassito. That concludes our Q&A session.  Now I would like to introduce our final presenter,  Dr. Matthew Jornstad.  Thank you. So today's journal club, I'm gonna present the evaluation of continuous inhaled epiprostanol in the treatment of acute respiratory distress syndrome,  including patients with SARS-CoV-2 infections.  And these are the abbreviations that I'll be using throughout my presentation today.  And so just diving straight into some background around ARDS. And so largely the treatment for ARDS is supportive care with the goal of treating the cause, improving oxygenation,  and limiting pulmonary edema in our patients. And some of those adjunct treatments that we use are corticosteroids, fluid restriction, neuromuscular blockers, prone positioning,  pulmonary vasodilators, and finally ECMO. But specifically looking at pulmonary vasodilators, and in this instance, inhaled epiprostanol,  it's used more as an adjunct therapy in our severe ARDS population. And currently at my institution, it's kind of more utilized as a salvage therapy  when other treatments are already maximized. But it is a prostacyclin, and it has that selective pulmonary vasodilation, and it's been shown to improve oxygenation  in the P to F ratio in our patients.  The evidence of inhaled epiprostanol in ARDS is very limited. A lot of them are limited to small retrospective studies, and the same is seen with our COVID-19 ARDS studies  that there's just very limited in small population sizes in these studies that currently evaluate its use.  Some of that literature, we had Santi Etal, released in TELUS in 2021, looked at the use of inhaled EPO in COVID-19 ARDS, and they found that there was a positive response rate  in about 50% of the time when it was utilized. In this study, they defined a positive response rate at about as a 10% change from the patient's baseline.  But they also found that there was some variables that were associated with this positive response was patients who had a lower P to F ratio responded better,  as well as patients with a prone position.  Lee Etal, published in 2020, also looked at the use of inhaled EPO in COVID-19 ARDS, and they found that there was a positive response rate of about 62.8%.  They defined this positive response rate as an increase in a 20% change, which is a little bit different from the previous study I mentioned,  but they really only found that it benefited patients. Inhaled epiprostanol really only benefited patients when it was combined with the use of prone positioning.  DeGrado Etal, published in 2019, also looked at its use in COVID-19 ARDS, and found that there was a positive response rate only about 42.1% of the time,  and found no variables associated with that positive response. This study defined a positive response as a change in P to F ratio by 10%.  And then lastly, we have the Callot et al study that was published in 2017, so pre-COVID, and they found that there was a positive response rate  about 60% of the time in these patients, and they defined a positive response rate a little bit differently than the previous couple of studies.  Instead of bringing it down to as a percent change, they looked at a point change. So theirs was defined as a positive response  would be a 10-point increase on the patient's P to F ratio.  They also found variables associated with that positive response rate, and found that, kind of differing from our other studies, that a higher P to F ratio benefited better,  and also compliance of their respiratory system, so their ventilation.  The purpose of this study today is very similar. So they wanted to identify the positive response rate to inhaled EPO in adults with ARDS, which that includes COVID-19 patients,  and then also was trying to see if there was any variables associated with this response.  And this leads me to my first polling question. Does your institution commonly utilize inhaled epoprostanol for COVID-19 ARDS,  non-COVID-19 ARDS, both, or do you not currently use it?  Yeah, it's kind of what I was kind of thinking, that there is utilizing more for both, potentially maybe more use in the COVID-19 ARDS, and as well with this do not use.  I know currently at my institution, prior to COVID-19, we didn't regularly use inhaled epoprostanol for ARDS patients, but then once COVID-19 and our epidemic hit,  we started to utilize it more, and then now we're continuing to utilize it for both non-COVID and COVID-19 ARDS.  So this study was a retrospective observational study that looked back at patients from January 2016 to February of 2021, and it was a multi-center, single health system,  done at a single health system in Missouri, and they included patients who were at least 18 years old, had an ARDS diagnosis found with ICD codes,  and then patients had to receive inhaled epoprostanol and then patients had to receive inhaled epoprostanol. These patients were excluded if they received ECMO  prior to the initiation of inhaled epoprostanol, or if ECMO was initiated within that six-hour time window they were looking at when inhaled epoprostanol was initiated.  If patients were excluded if they utilized inhaled epoprostanol for any other indication besides ARDS, and if the duration of the inhaled epoprostanol was less than six hours.  For their statistical analysis, they utilized descriptive analyses for their baseline data and then used a multivariable logistics regression analysis for their primary outcome,  and then utilized a Wilcoxon-signed rank test and student T-test for their secondary outcomes, and I deemed their analysis and their use of these as appropriate for this study.  And so the primary outcome that they looked at was the variables associated with a positive response to inhaled epoprostanol. Again, they defined that as an increase  in the patient's P-to-F by 10% within that six hours of that inhaled EPO initiation. Some of the secondary outcomes they looked at was that positive response rate,  and then a change in the P-to-F and the SpO2 to FiO2 within six hours.  And so they started with screening 687 patients and ended up including a total of 331 patients in their study.  The patient population was predominantly more male and predominantly more white patients with an average baseline P-to-F ratio in the patient population to be 71,  as well as a baseline average SOFA score to be 11. The etiology of the patients' ARDS was about 33% pneumonia and then 33% COVID-19,  and then 17.5% sepsis,  a limited influenza, and the rest were all just labeled as other,  and then their severity being primarily severe around a majority of their patient population with the next majority of their patient population having moderate ARDS severity.  Again, those were defined by the Berlin score. Therapies that were used in these patients prior to inhaled epoprostanol were steroids, about 50% of the time, neuromuscular blockers,  about 50% of the time, diuretics, a little bit less, around 40%, bronchodilators, 15%, and then prone position utilized about 30% of the time  prior to the initiation of inhaled epoprostanol.  And this leads me to polling question two. So select all that apply. What other adjunct treatments does your institution commonly utilize in ARDS?  As I expected, a little bit of differentiating things. So corticosteroids, about 28%. Neuromuscular blockers looks like about 13%. Diuretics, about 5%.  And then prone positioning, about 54%. With the new study of dex-ARDS that came out in late 2020, I can see where steroids are maybe not fully  come on board because there's differentiating data out there with our steroids.  And so looking at our outcomes, our results were our primary outcomes. So there was two variables that were associated with that positive response to inhaled epiprostanol.  And so first of all, what they found was it was statistically significant with the baseline P to F ratio, as well as if patients had the SARS-CoV-2 related ARDS.  And then for the results for our secondary outcome, so I liked how they listed it as the total population and then separated them out by the COVID-19 ARDS  and then the non-COVID-19 related ARDS. And so overall, you can see that about 68.3% had a response rate to inhaled epiprostanol. And then further breaking it down, about 60%  have the COVID-19 related, 60% response rate with the COVID-19 related ARDS. And then a lot more, the 72.7% in our COVID-19, non-COVID-19 related ARDS.  And so all those were statistically significant. And that linear regression model that they did showed that the higher the P to F ratio of the patient  at baseline, and if the patient had COVID-19 ARDS, there was a significant inverse association to the change in the P to F ratio at six hours.  And so the authors concluded that inhaled epiprostanol was associated with a positive effect in most moderate to severe ARDS patients, which  included those patients with COVID-19 ARDS. The lower baseline P to F ratio and non-COVID-19 ARDS were significantly associated with a positive response to inhaled epiprostanol.  And so, continuing the study, so I think this study does have some really good strengths. So to date, what I could find was it's the largest study to assess variables  with positive response rate to inhaled epiprostanol, and also included both COVID-19 ARDS and non-COVID-19 ARDS patients, which if you look back at those previous studies  that I reviewed, they were either one or the other COVID-19 or non-COVID-19. I think their outcomes match their hypothesis, and then the majority of the population  that we would think that we would go to to utilize inhaled epiprostanol are those patients with the severe ARDS, which that was the majority of our population.  Some of the limitations, so it's a retrospective single system design. It did kind of lack that comparator group, and most patients were white and male,  so it might be a little bit less generalizable to the public. One of the other limitations is the other adjunct therapies, like our corticosteroids, our diuretics, prone positioning  were not protocolized, so it could have happened when that six-hour window was started with that initiation of the epiprostanol. Some of those other agents potentially could  have been started at that time. I would state that a number of their patients did require a P to F ratio to be calculated from the SpO2, and they did this from taking the SpO2  and calculating the PaO2. Upon my research on this method, calculating the PaO2 from SpO2 can give us a pretty good estimate of a patient's PaO2,  but it's not going to be as accurate as an ABG would be. I think it's always important to think of if the outcome is a clinically relevant endpoint, and so kind of think of,  is this P to F ratio really clinically relevant? And then along with that, the study didn't collect any maybe clinically relevant data in the sense of time on the ventilator  or really comparing mortality to see if there was a statistically significant difference in mortality. And then lastly, I would state that no adverse events  was collected on the use of inhaled epiprostanol.  And so results of this study were actually similar to those past studies. In COVID-19 and non-COVID-19 ARDS, both saw an increase in the P to F ratio  from utilizing inhaled epiprostanol therapy. And the inhaled epiprostanol changes in the P to F are seen more in patients with that lower P to F ratio.  And then I brought in a little bit of the table from the previous slide. And although we do see a statistical difference, there may not be a clinical benefit.  As you can see, even though they all had that positive response rate, the change in their P to F ratio still would classify them as severe.  So they were severe ARDS prior to the initiation of epiprostanol. And at that six-hour post inhalation of the epiprostanol, they're still technically classified as severe ARDS.  And so the takeaway, so my conclusions is this was, I think, for a retrospective study, it was very comprehensive and did have a relevant study objective.  If it shows the benefit of inhaled epiprostanol in low P to F patients in both COVID-19 ARDS and non-COVID-19 ARDS, in regards to increasing the P to F ratio, both some caveats  of a large number of the patients did have missing ABGs. So we utilized that calculated P to F utilizing SPO2. And then other adjunct therapies were not  protocolized, which could have potentially affected some of the results. For clinical applicability, I think this supports a common current clinical practice  that we do see, especially with our epidemic. And I think it helps provide some better guidance on when best to utilize inhaled epiprostanol. The use of inhaled epiprostanol in ARDS  may be controversial if it does provide clinical benefits. But in sites that do utilize it, like mine, it is commonly tolerated well by patients and can be fairly inexpensive.  But at the same point, it's going to cost more to utilize this if we didn't utilize it. And then lastly, I would just note that it does bring some administration challenges.  So being a continuous nebulization, it can interrupt if patients are receiving bronchodilators. And also, just being able to make sure that that drug is on the floor and being  able to be administered at that continuous nebulization. And really, the next steps for this kind of literature is we really want this prospective multicenter comparative study.  Potentially, ones that have primary outcomes to maybe look at days on the ventilator, mortality, to really assess the clinical benefit of inhaled epiprostanol.  And all this may be hard, although this may be a little bit hard due to a limited number of patients who have severe ARDS.  And with that, what questions do you guys have?  All right. There's the first question here. What adverse effects you would have expected from inhaled EPO, or you would want to see collected  if this study were repeated, or to be repeated? Yeah, that's a good question. So if this study were to be repeated, so some of the adverse drug effects  we can get with using inhaled epiprostanol is we can't get that thrombocytopenia  and some of the other common ones. So you can get that hypotension since it is a vasodilator, as well as you can get flushing and nausea, vomiting.  So the main one that I would want to see is hypotension, which might be a little bit hard due to a bunch of other factors, but really that thrombocytopenia.  Second question here, you mentioned that the PFT ratio, although statistically significant, it may not have a clinical benefit. So again, what clinical benefit you would like to see  if this study to be repeated or in future studies? And how much PFT ratio, change in PFT ratio you would like to see, just call it significant?  So I think it comes down to, I think first of all, if we think P to F ratio is a good outcome that we can  measure, but I think what we're currently not having,  and it's gonna be kind of hard in this patient population just because they do have severe ARDS and don't have the best outcomes just in general.  But one of the things I think I would like to see in studies is their effect on, if utilizing inhaled epiprostanol, do we see patients who are getting off the vent faster?  Do we see patients have better mortality than patients who don't? I think that's some of the data that's really missing currently out of literature.  Third question, there has been some studies  in some of the pathologics reports that's showing a microthrombi with the COVID-19 severe ARDS.  Do you think the antiplatelet effect of that enhanced EPO would benefit patients?  Yeah, I think that's one of the things that this article did touch on was, there is this concern that there is a difference in pathophysiology with our COVID-19 ARDS  than compared to ARDS to other etiologies. And so what they think is patients who have COVID-19 ARDS have a more diffuse alveolar damage, and then they also have that damage  to the pulmonary vascular system that can activate that coagulation cascade leading to thrombosis. And so, and with it, that happening within the pulmonary vascular system,  that's where our inhaled epiprostanol works. And so I think this study shows that, even if there is that different pathophysiology, that there is still some benefit  in utilizing inhaled epiprostanol in these patients.  All right. That concludes our Q&A session. Thank you, Dr. Matthew, your staff. Thank you.  Thank you to our presenters today and the audience for attending. Please join us on third Friday of the month from 2 to 3 p.m. Eastern time  for the next Journal Club Spotlight on Pharmacy. That concludes our presentation today.

Video Summary

This Journal Club Spotlight on Pharmacy webcast discussed the use of a balanced multi-electrolyte solution versus saline in critically ill adult patients. The presenters reviewed several randomized controlled trials that compared the two fluids and found no significant difference in mortality rates. They also discussed the potential mechanisms of injury associated with the use of normal saline, such as metabolic acidosis and impaired organ function. The presenters concluded that for volumes of 3.5 to 4 liters, both balanced solutions and normal saline are likely appropriate for fluid resuscitation in most patients. However, they noted that specific patient populations, such as those with traumatic brain injury or diabetic ketoacidosis, may benefit from a specific fluid. The second presenter discussed the use of 5% human albumin versus normal saline for fluid resuscitation in sepsis-induced hypotension among patients with cirrhosis. The presenter highlighted a study that found a positive response rate to albumin and identified lower baseline P-to-F ratio and non-COVID-19 ARDS as variables associated with a positive response. The third presenter discussed the use of inhaled epiprostanol in the treatment of acute respiratory distress syndrome, including patients with SARS-CoV-2 infections. The presenter reviewed several studies that found a positive response rate to inhaled epiprostanol in both COVID-19 ARDS and non-COVID-19 ARDS patients, particularly in those with lower baseline P-to-F ratio. The presenter concluded that while the use of inhaled epiprostanol may have some benefits in improving oxygenation, more research is needed to assess its clinical benefits, such as days on the ventilator and mortality rates. Overall, the webcast provided an overview of the current evidence regarding the use of these fluids and inhaled epiprostanol in critically ill patients and highlighted the need for further research in these areas.

Asset Subtitle

Pharmacology, Pulmonary, Sepsis, 2022

Asset Caption

"The Journal Club: Spotlight on Pharmacy webcast series focuses on pharmacy topics. This event is held on the third Friday of each month and features lively discussion and in-depth presentations on the latest research.

Anna White, PharmD, MBA
Finfer S, Micallef S, Hammond N, et al. Balanced multielectrolyte solution versus saline in critically ill adults. N Engl J Med. 2022 Mar 3;386(9):825-826. doi: 10.1056/NEJMoa2114464

Cathy To, PharmD
Philips CA, Maiwall R, Sharma MK, et al. Comparison of 5% human albumin and normal saline for fluid resuscitation in sepsis induced hypotension among patients with cirrhosis (FRISC study): a randomized controlled trial. Hepatol Int. 2021 Aug; 15(4): 983-994.

Matthew Bjornstad, PharmD
Niss HL, Mohamed A, Berry TP, Saettele TM, Haines MM, Thomas EL. Evaluation of continuous inhaled epoprostenol in the treatment of acute respiratory distress syndrome, including patients with SARS-CoV-2 infection. Ann Pharmacother. 2022 Jan 13;10600280211069182. doi: 10.1177/10600280211069182

Follow the conversation at #SCCMCPPJC."

Meta Tag

Content Type Webcast

Knowledge Area Pharmacology

Knowledge Area Pulmonary

Knowledge Area Sepsis

Knowledge Level Intermediate

Knowledge Level Advanced

Membership Level Select

Membership Level Professional

Tag Fluids Resuscitation Management

Tag Acute Respiratory Distress Syndrome ARDS

Tag Sepsis

Year 2022

Keywords

balanced multi-electrolyte solution

saline

critically ill patients

fluid resuscitation

traumatic brain injury

diabetic ketoacidosis

5% human albumin

sepsis-induced hypotension

inhaled epiprostanol

acute respiratory distress syndrome

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