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July Journal Club Webcast: Spotlight on Pharmacy ( ...
July Journal Club Webcast: Spotlight on Pharmacy (2021)
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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 Brianne Mefford, Medical Intensive Care Unit Pharmacist at University of Kentucky in Lexington, Kentucky. 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. Thanks 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 a question throughout the presentation, type into the question box located on your control panel. You will 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 the live discussion on Twitter, following hashtag SCCM, CPPJC, and hashtag PharmICU. SCCM provides the following disclaimer. This presentation is for educational purposes only. The material presented is intended to represent an approach, view, statement, or opinion of the presenter, which may be helpful to others. The views and opinions expressed herein are those of the presenter and do not necessarily reflect the opinions or views of SCCM. SCCM does not recommend or endorse any specific test, physician, product, procedure, opinion, or other information that may be mentioned. And now I'd like to introduce your speakers for today. Each will give a 15-minute presentation followed by a Q&A session. Our first presenter today is Amanda Roberts, a PGY-1 pharmacy resident at Beaumont Hospital Royal Oak in Royal Oak, Michigan. Our second presenter is Tricia Nguyen, a PGY-1 pharmacy resident at UC Davis Health in Sacramento, California. And our third presenter is Adelaha Yahia, a PGY-2 critical care resident at Detroit Receiving Hospital in Detroit, Michigan. And now I'll turn things over to our first presenter. Hi, everyone. My name is Amanda Roberts, and I'm the PGY-2 critical care pharmacy resident at Beaumont Hospital in Royal Oak, Michigan. For this journal club, I'll be reviewing the BEAST study, which evaluated the association between premorbid beta blocker exposure and sepsis outcomes. Before we get started, I wanted to state that I have no conflicts of interest in relation to this presentation. The objectives for this presentation are to discuss the positive and negative consequences of catecholamines and sepsis, to analyze the clinical trial data of beta blocker use in sepsis, and to interpret the BEAST study. Before we start talking about the BEAST trial, I wanted to provide some background information. Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host's response to infection. Typically, when a patient is septic, their body tries to restore homeostasis through the production of endogenous catecholamines. In addition, as I'm sure we're all aware, if fluid resuscitation is inadequate, exogenous catecholamines such as norepinephrine are administered. These result in a hyperadrenergic response, which can cause negative effects such as cardiomyopathy, ischemia, and hyperglycemia. The concept of decatecholaminization aims to reduce this adrenergic stress resulting from sepsis, and the use of beta blockers is one proposed strategy. However, the use of beta blockers in sepsis is controversial. Beta blockers are able to effectively control heart rate and diminish some of the detrimental effects of beta adrenergic stimulation mentioned on the previous slide. However, their known inotropic and hypotensive effects are concerning in patients who are already hypotensive and not adequately perfusing. There are two main classes of beta blockers, the cardioselective, which mainly target beta 1 receptors in the heart, and noncardioselective, which act on both beta 1 and beta 2. In addition to their cardioprotective effects, there's some evidence that beta blockers can also affect glycemic control, decrease lactate, and play a role in modulating the immune system, which can help to decrease some of the negative consequences of sepsis. There are only a handful of studies that have been conducted in humans which have evaluated the effects of beta blockers in sepsis. The first study by Gutierrez and colleagues is a retrospective study in adult MICU patients that did not find a significant association between beta blocker use and mortality in sepsis. The next two retrospective studies by Smittinger and Maccia found improved outcomes in sepsis with beta blocker exposure. The study by Maccia and colleagues found a significantly lower 28-day mortality in the beta blocker group. And although the Smittinger and colleagues did not evaluate mortality, they did find a significant decrease in norepinephrine, vasopressin, and milrinone dosages. The last study by Morelli and colleagues was a single-center randomized control trial evaluating the use of Esmolol. Although mortality was a secondary outcome in the study, the authors found the Esmolol group had a lower 28-day mortality. Now let's take a look at the most recent study evaluating the use of beta blockers in sepsis, the DEIS trial. The purpose of this study was to determine if there is an association between premorbid beta blocker exposure and sepsis outcomes. In addition to examining the effects on mortality, the authors wanted to also examine beta blockers' effects on organ dysfunction, glycemia, and lactateemia, which was a new focus compared to the previous studies. They also decided to compare cardioselective and non-cardioselective beta blockers. The BEAST study was a multicenter retrospective cohort study conducted between January 2014 and December 2018 and included adult patients admitted to the ICU for sepsis. Patients in the NEPPN and Pilsen cohort, which represented patients from the Czech Republic and Australia, respectively, were selected according to the sepsis III consensus definition, whereas the EICU cohort, which represented patients from the United States, was selected according to ICD-9 diagnosis codes. As subsequent episodes of sepsis are associated with increased mortality, only the first episode of sepsis was included. The only exclusion criteria was concurrent prescriptions of two or more beta blockers. Patients were then divided into two groups based on whether or not they had been prescribed a beta blocker prior to the episode of sepsis, and those with a beta blocker were further divided into the cardioselective or non-cardioselective beta blocker group. The primary outcome of this study was mortality, which was measured at two time points, ICU and hospital mortality. There were several secondary outcomes, which included the frequency of hypo- and hyperglycemia, lactate levels, organ dysfunction, mechanical ventilation, renal replacement therapy, and ICU and hospital length of stay. For the statistical analysis, the authors converted the APACHE scores to Z-scores so that they could directly compare them and account for variations between the study cohorts. Multivariate logistic regression was performed to analyze the association between premorbid beta blocker exposure and mortality. Propensity score matching was used to conduct further sensitivity analysis, and Koch's hazard regression model and Kaplan-Meier analysis was performed for the survival analysis. After applying the inclusion and exclusion criteria, there were 1,556 patients included in the premorbid beta blocker exposure group and 2,530 patients in the group without premorbid beta blocker exposure. Those in the premorbid beta blocker exposure group were significantly older, had a lower incidence of septic shock, and a higher APACHE scores. When looking at the primary outcome mortality, the unadjusted analysis, which is not shown on the slide, did not show a significant association between premorbid beta blocker exposure and mortality. However, after adjusting for several covariates, the multivariable logistic regression analysis suggested that premorbid beta blocker exposure was associated with decreased ICU and hospital mortality. When looking specifically at the cardioselective and noncardioselective beta blockers, only the noncardioselective beta blockers were associated with a significant decrease in ICU and hospital mortality. The results of the propensity score matching were similar to the whole cohort. Taking a closer look or further look at mortality, in the Kaplan-Meier curve, there is not a significant difference found in the unmatched cohort. However, after propensity score matching, beta blocker exposure was found to be associated with a significant decrease in ICU discharge mortality. In the Cox hazard regression analysis, beta blocker exposure was found to be associated with a significantly decrease in ICU discharge mortality in both the unmatched and matched cohort. One of the main secondary outcomes was organ function. This slide compares some of the most relevant organ function variables that were evaluated on days 1 and 3 of ICU admission. Premorbid beta blocker exposure was associated with a significantly higher day 1 and 3 GCS score, significantly higher serum creatinine on day 1, significantly higher mean arterial pressures on days 1 and 3 of ICU admission, and significantly lower day 3 total norepinephrine equivalence. However, there were no significant differences in overall SOFA scores, and there were also no significant differences in the progression of organ dysfunction between day 1 and 3 in all of the study parameters. For the other secondary clinical variables that were evaluated, only the significant difference was the rate of mechanical ventilation. There weren't any significant differences in lactate levels, glycemic control, or renal replacement therapy. The authors also conducted subgroup analyses for each of the patient cohorts and for each sepsis definition, but no significant differences in mortalities were found in any of the subgroup analyses. Overall, the authors concluded that premorbid exposure to beta blockers, particularly the non-cardioselective beta blockers, may be associated with decreased sepsis mortality. They also found that beta blockers, in addition to their cardioprotective effects, may have modulation of other organ functions, however, did not find an association between premorbid beta blocker exposure and initial glycemic control or lactate levels. The BEAST trial has several strengths and limitations. The strengths of the study were that it was a multicenter and international with a large patient population. The authors did try to account for confounding variables by conducting propensity score matching and subgroup analyses. However, there were also several limitations. Some of the main limitations include the significantly higher rate of septic shock in the group without beta blocker exposure, the interoperative variability in the GCS and SOFA score calculations. We weren't provided any information on the doses or duration of beta blocker therapy prior to the sepsis episode or if beta blocker therapy was continued during the hospital admission and the limited information regarding additional sepsis treatment. Overall, I thought the research question, in addition to the primary and secondary outcomes, were clinically relevant. Although there have been advances in sepsis management, which have reduced morbidity and mortality, further improvement is still needed. In addition, there are limited therapies preventing organ dysfunction. In addition, I thought the study design and methods appropriately addressed the research question. However, there were some flaws. Given that the study was retrospective, we can only determine an association between beta blocker exposure and any of the study variables. There were also some confounding variables that were not accounted for, including the higher rate of septic shock in the group without beta blocker exposure. And as we know, septic shock has higher rates of mortality. We also do not have any information to compare the treatments patients received for sepsis besides the reported total norepinephrine equivalents. The study does have some information bias as there's provider variability in GCS and SOFA score calculations. GCS calculations can also be affected by intubation and level of sedation. And the group without beta blocker exposure had a higher mechanical ventilation rate. In terms of generalizability, the study does have good external validity given the few inclusion and exclusion criteria. However, the authors provided very limited patient information. For example, we were not told if these were medical, surgical patients, or both. After further analyzing the results, I believe the decrease in ICU and hospital mortality associated with the premorbid beta blocker exposure was both statistically and clinically significant, with a decrease of 20% and 16% respectively. However, when looking at the organ function, despite the statistically lower incidence of neurologic, cardiac, and respiratory failure in patients with premorbid beta blocker exposure, only the lower incidence of neurologic failure was clinically significant. There was only about a two-point difference in the mean arterial pressure and a 5% difference in the mechanical ventilation rates between the two groups. But the median GCS score was 14 in the premorbid beta blocker exposure group and only 9 in the group without beta blocker exposure. The effects on neurologic function may be due to inflammation or immune response modulation. However, we do not know the patient's baseline GCS scores prior to the study. However, we do not know the patient's baseline GCS scores prior to the sepsis episode, so more research is needed to evaluate this. Overall, the BEAST trial demonstrated that premorbid beta blocker exposure may lead to positive outcomes in patients with sepsis. However, given the significantly different baseline characteristics, especially relating to the severity of illness and the several study limitations previously mentioned, further evidence is required before change in practice is justified. Prospective and randomized trials would be helpful to provide answers to four main questions. What is the optimal duration of beta blocker exposure prior to sepsis? Is it beneficial to continue or initiate beta blockers while the patient is septic? If beta blocker use during sepsis is beneficial, what is the appropriate timeframe to resume or initiate a beta blocker, and which beta blockers are most beneficial? Now that we've analyzed and interpreted the BEAST trial, I'm curious to know what your thoughts are and what you typically do in practice, which brings us to our first polling question. In clinical practice, when a patient is admitted with sepsis, do you initially hold their home beta blocker, yes or no? Looks like the majority with 86% said yes, which is what I've seen in my practice and what I expected from this poll. And now on to our second polling question. When do you feel comfortable restarting a home beta blocker in a patient with sepsis? When they are admitted, after discontinuation of vasopressors, once they're transferred out of the ICU, or when they are discharged from the hospital. Looks like the majority, again, was 86% said after discontinuation of vasopressors, which is also typically what I've seen once the patient is more hemodynamically stable and not needing those vasopressors, especially if they're tachycardic, restarting the home beta blocker. So, we're going to go ahead and get started with that, and we're going to start off with Here are my references. Thank you for letting me talk to you guys today about the BEAST trial, and at this time, I will open it up for any questions. Thank you so much, Dr. Robert. It looks like one of our first questions of the day is, do you know if authors were able to determine compliance on prior-to-admission data blockade? That's a great question. No. They did not mention any information on dosages. They were not able to confirm if the patient was still taking it. The only thing they knew was if the patient had a prescription for a beta blocker prior to the sepsis episode. They also didn't specify the timeframe prior to the sepsis episode that they included for a recent prescription of a beta blocker. Thank you so much, Amanda, for participation in our journal club today. Now I would like to take an attendance poll. How many attendees are you viewing this webinar with? Thank you so much, and now I would like to introduce our second presenter, Dr. Trisha Nguyen. Hi, everyone. My name is Trisha Nguyen, and I am a current PGY2 Critical Care Pharmacy resident at UC Davis Health. And today, I will be talking about the discordance between respiratory drive and sedation death in critically ill patients receiving mechanical ventilation. I have no interests or relationships to disclose. Our objectives today is to describe current guidelines, recommendations regarding sedation practices, describe the potential use of airway occlusion pressure as a marker for respiratory drive, summarize the primary and secondary outcomes, and discuss the clinical applications of the findings. So, acute respiratory failure is the most common reason that critically ill patients require intensive care unit admission. Medications are used to facilitate lung protective strategies and prevent ventilator-induced lung injury. However, the healthcare team must also mitigate the side effects of the medications. Current practice is to titrate to surrogate goals to achieve respirolysis, and some of the surrogate markers include the Richmond Agitation Sedation Scale, also known as RAS, the Critical Care Pain Observation Tool Score, which is also known as CPOT, and also to ensure that respiratory rate is set to ventilator rate. Respiratory drive is the intensity of the respiratory center's output that determines the effort that is exerted in each breath, and it is derived from the autonomic and behavioral input. Chemosensory input aims at minimizing changes of material carbon dioxide and pH, while the descending input is responsible for adaptive changes of breathing patterns during complex activities such as exercising. In patients with acute respiratory distress that are mechanically ventilated, pain, agitation, and delirium could all influence drive, and current guidelines recommend targeting these using well-validated instruments to achieve therapeutic targets with medications. Patient ventilator asynchrony can also affect respiratory drive, and in many cases, sedation is used to regulate respiratory drive to facilitate mechanical ventilation. Airway occlusion pressure is a bedside tool that can be used to assess respiratory drive and can be measured using a full-feature ICU ventilator. Essentially, it is a mini-inspiratory hold and the patient's attempt to initiate their own breath. These graphs help explain how the ventilators measure the occlusion pressure during the maneuver. So first, the ventilator inspiratory valve remains closed during the first 0.1 second of the next patient-triggered inspiratory cycle. And while the valve remained closed, no airflow is delivered, as depicted on the first blue graph at the top and at the very end where it says zero flow. And so occlusion pressure is then measured as the patient attempts to inhale against the occluded airway, which is depicted in the red graph, and it generates a negative pressure. After a 0.1 second occlusion, the inspiratory valve opens and then the flow is delivered. The 0.1 second occlusion is thought to be too small to be detected by anyone that is conscious or unconscious. In a study that was referenced, the airway occlusion pressure was explored as a bedside tool to assess respiratory drive, and it was found that it would be a reliable tool to detect inspiratory efforts. Respiratory drive is not commonly monitored, however, and sedation targets are often utilized as a surrogate marker for respiratory drive. Sedation is thought to help decrease or inhibit spontaneous respiratory efforts, which is also known as respirolysis, and many expert opinions recommend adjusting sedation depth as a surrogate marker for respiratory drive. In the 2018 PATIS guidelines, it was recommended that light sedation in mechanically ventilated adults be utilized whenever possible, and this is the only guidance regarding sedation that is stated. Currently, there is also a lack of literature specific to sedation depth and respiratory drive, and the first two studies that are listed here discuss more regarding various strategies to focus on ventilation of synchrony. The ACQUIRISIS trial emphasized the importance of synchrony to lung protective ventilation strategies for acute respiratory distress, in which they utilized neuromuscular blockade agents and found that there was improved survival and increased time off ventilator without muscle weakness. The ROSE trial further looked at continuous infusions to sashicarium with deep sedation versus routine neuromuscular blockade with light sedation, and it was found that when utilized with light sedation, it did not reduce mortality and increase adverse effects. The third trial listed here is the most similar, and it studied light and deep sedation and frequency of ventilator dyssynchrony, in which ventilator dyssynchrony was reduced by deep sedation. However, it was found that harmful tidal volumes were still delivered despite being on deep sedation. Again, these studies do not address respiratory drive and sedation death. So what we do know is respiratory drive is not routinely monitored in clinical practice, and sedation targets are used as a surrogate marker for respiratory drive. Current practice assumes sedation suppresses respiratory drive while light sedation preserves it, and deep sedation is commonly prescribed in mechanically ventilated patients as it might help facilitate respirolysis to facilitate lung protective ventilation and mitigate patient ventilator asynchrony. What we don't know is the relationship between sedation and respirolysis, which leads us to our study, Discordance Between Respiratory Drive and Sedation Death in Critically Ill Patients Receiving Mechanical Ventilation, and the study was conducted to evaluate the association of respiratory drive with sedation death in patients with acute respiratory failure requiring invasive mechanical ventilation. And so this study design was a prospective observational study, and it took place in two month-long periods in 2016 and 2017, and it was done in five ICU units at an academic medical center. Population were mechanically ventilated critically ill patients. For observations, airway occlusion pressure was measured every 12 hours for three days. They also took sedation death, so RASCOR's CPOT, the confusion assessment method for ICU, along with vitals, ventilator settings, and most recent blood bath. Of note, analgesic and sedative exposures were taken also. For propofol, it was micrograms per kilo per minute for sedation, and for midazolam, it was midazolam equivalents in milligrams and fentanyl equivalents in micrograms for analgesics. For primary outcome, the association of airway occlusion pressure with RAS was studied, and for secondary outcomes, it was ventilator-free days through day 28, duration of mechanical ventilation, and ICU or hospital length of stay. For the inclusion criteria, critically ill patients were included along with invasive mechanical ventilation initiated within the previous 36 hours. For exclusion criteria, neuromuscular disease compromising respiratory function, obstructive airway disease causing expiratory flow limitation, chest tube with active air leak, tracheostomy, and ventilator lacking the capabilities to measure airway occlusion pressure. For the statistical analysis that were done, for the primary outcome, it was the Pearson and Spearman correlations with the alpha of less than 0.05, and for secondary outcomes, it was the Poisson regressions and logistic regression models, also alpha of less than 0.05. Next are the results, and first we will talk about the patients. So there were 61 patients that met criteria. Of those 61, 5 were excluded because 4 lacked ventilator capabilities, and 1 had neuromuscular disease, and at the end, there was 56 patients that were analyzed. From the 56 patients that were included, there were a total of 197 eligible bedside measurements taken from these patients that were included in the final analysis. The typical patient in the study was a 63-year-old male who was intubated for hypoxemia. The median time from intubation to enrollment for these patients was 19 hours, and the medium Apache 2 score was 32, which has a predicted mortality of approximately 70%. For these patients, the majority of them were enrolled with a propofol drip, and most of these patients had a median VASc score of negative 4. For the observation, in about half of the evaluations, patients were found to be deeply sedated with a RASc score of negative 4 to negative 5, 75% of these patients had at least one study assessment indicating deep sedation, during approximately 6% of these evaluations, patients had behavioral indications suggestive of pain, and during a fifth of the evaluations, patients screened positive for delirium. This figure presents airway occlusion pressure values according to RASc scores for all observations. On the x-axis, we have RASc scores, and on the y-axis, we also have airway occlusion pressure. Underneath the x-axis, you can see the number of observations that were recorded. There were a total of 197 evaluations, and the range was 0 to 13.3 cm water. The highlighted block was added to show the general range of normal airway occlusion pressure values in healthy individuals, which is defined as 0.5 to 1.5 cm water. Only 19% of airway occlusion pressure measurements were in normal range. As seen on this graph in the red box, many of the highest airway occlusion pressure values were observed in patients with RASc scores negative 3 to negative 5. In about 25% of all measurements, the airway occlusion pressure exceeded the upper limit of normal, which is 1.5, and in about 40% of patients, had at least one evaluation with that exceeding of the upper limit of normal. Conversely, 50% had about an airway occlusion pressure of 0, which indicated no respiratory drive. Shown here in this figure is a plot of the airway occlusion measurements and its associated RASc scores that were collected, shown on the x-axis, and on the y-axis is the measurement time. You can see all values crosses 0, which indicates that the cross-sectional analysis found that respiratory drive is poorly correlated with sedation death. For the secondary outcomes, patients with moderate respiratory drive on average had more ventilator-free days than those who had no drive or high drive, and airway occlusion pressure was not found to be significantly associated with mortality. So for the discussion portion, the author's conclusion stated that sedation death is a poor circuit for respiratory drive in critically ill patients with acute respiratory failure. Deep sedation often did not surprise respiratory drive, while light sedation did not necessarily mean that respiratory efforts were preserved. Those with moderate respiratory drive had more ventilator-free days, and monitoring respiratory drive could be useful to evaluate whether the intended clinical effect is achieved and to recognize an undesirable side effect when it is prescribed for other indications. For my study evaluation, this study was a prospective study, however, there were no comparator groups. The study had an appropriate and applicable population, however, I felt it had low patient enrollment for the time period that it was designated for, and patients were enrolled for five ITUs at an academic medical center. I also found that the population's general eligibility could be limited. For example, it was surprising that no patient's meeting criteria for enrollment were excluded for obstructive airway disease, which meant that nursing a bedside titrated sedation to order graph scores. However, this may be different at other institutions and is limited to staff availability. The rationale for sedative or targeted death scores was also not recorded during this study. I thought this was a novel study because, although a lot of studies have looked at airway occlusion pressure as a bedside assessment for respiratory drive, this was the first to correlate it with sedation death, the current surrogate marker. However, airway occlusion pressure has its limitations, especially in patients who have neuromuscular weakness, which the study did exclude for. However, measurements could also differ between ventilators due to different measurement techniques. And lastly, the study results prove further research to be conducted regarding the topic, as it shows that sedation death may not be a reliable marker, and that is the current practice that is utilized. My takeaway points, airway occlusion pressure is an accessible marker for respiratory drive. Airway occlusion pressure was variable throughout the range of sedation death. Sedation death may not be a reliable surrogate marker of respiratory drive, and further studies need to be conducted to explore sedation death and respiratory drive effects on clinical outcomes. For example, if you do monitor and target airway occlusion pressure, how would we go about modifying this? And this leads me to my two polling questions. For my first polling question, does your institution have a method for measuring respirolysis other than RAS? Yes, no, or unknown. If there's 73% no, so that is usually what we have also. Usually we don't have any way to measure for spirulitis such as occlusion airway pressure and we usually just use RAS scores. And then for the next question, would you consider obtaining airway occlusion pressure along with sedation depth such as RAS scores based on the study to supplement your clinical practice? Yes or no? So, the poll results are 70% no, and that, I am surprised, but we can also talk about it a little bit more. Okay. And at this time, I would like to thank everybody for listening in, and I would like to open up the floor for questions. Thank you so much for your presentation, Dr. Nguyen. That was very interesting. It looks like we have one question so far. How do you feel that this study aligns with previous studies evaluating ventilator synchrony via the asynchrony index and sedation depth? I think that's a great question. I'm not sure if they are specifically related to a specific study, but just from my literature research, I felt like this was different in the sense that it was looking at sedation depth as well as respiratory drive using airway occlusion pressure, which I found to be limited when I was doing my literature search. In terms of the previous literature that I had listed, I think it is different because those previous literature, such as the ROSE trial or the ACQUIRASIS trial, looked at neuromuscular blockade, and these patients were excluded if they had neuromuscular blockade. However, if they had a more specific trial that they are referring to, I would like to apologize because I'm not sure if I know the one that they are talking about or asking about. Okay. Thank you. It looks like we have one other question. How do you plan to utilize airway occlusion pressure in your clinical practice? You stated that you currently do not utilize it where you practice now. Is this something that you think should be utilized in combination with sedation practices? Thank you for that question. I thought about this a little bit. I think, first off, I would need to check in with my respiratory therapist. I personally do not know if our ventilators do have the capability to do so. In the best-case scenario, that would be great, but I also think that it would require a lot of training as well as just very specialized or specific protocols. I think it is something that could be utilized in the future, however, right now, I would not utilize it in my practice until more either protocol-wise is used, along with the rest. But for me, I don't necessarily think that I would use it with my practice, no. Okay. Thank you so much. That's going to conclude our Q&A session. Thank you, Dr. Tricia Nguyen. Thank you. Now, I'd like to introduce you to our final presenter, Dr. Adelaha Yahia. Hi, everyone. My name is Adelaha Yahia, and I'm the PGY-2 Critical Care Resident at Detroit Receiving Hospital. The journal article I will be presenting is Turley Placidum Plus Albumin for the Treatment of Type 1 Hepatorenal Syndrome, also known as the CONFIRM trial. I do want to state that I have no conflict of interest in this presentation. Starting with our background, Type 1 Hepatorenal Syndrome, or HRS-1, is a form of rapidly progressing kidney failure that occurs in patients who have advanced cirrhosis. It's defined as doubling of the patient's baseline serum creatinine level to greater than 2.5, or a 50% reduction in their creatinine clearance to less than 20, in a time of less than 14 days. Hepatorenal syndrome has a very high mortality rate, and when left untreated, the two-week mortality is about 80%, with a three-month survival of only 10%. Vasopressors are commonly used in the treatment of HRS-1 in combination with albumin. This is used to counteract the hemodynamic abnormalities associated with advanced cirrhosis in HRS-1. The agent we are going to be discussing is Turley Placidum, and this is a synthetic vasopressin analog with V1 receptor selectivity in the splenic vasculature. We have several trials that have studied Turley Placidum with albumin in HRS-1. Here I want to highlight three randomized controlled trials that are more recent and what they found. The first trial, published in 2015, compared Turley Placidum to mitodrine and octreotide combination, which is commonly used here in the U.S. They had 49 patients included with both HRS-1 and 2. The primary outcome found a significant difference in recovery of renal function, with 70% versus 29%. So Turley Placidum in this trial was shown to be substantially more effective. The second trial, published in 2016, compared Turley Placidum to placebo. They had 196 patients with HRS-1, but didn't find a significant difference in reversal. The last trial here compared Turley Placidum to norepinephrine. There are other studies, and most studies have generally found norepinephrine to be equally as effective as Turley Placidum. This trial here, though, with 120 patients with HRS-1, found a significant difference in reversal of HRS-1 with Turley Placidum, 40% versus 17%. They also found renal replacement therapy was significantly less at 57% versus 80%, and then even found a difference, a significant difference in 28-day survival of 48% versus 20%. Looking at what our current guidelines recommend, the International Club of Ossetics 2015 and the European Association for the Study of the Liver 2018 guidelines recommend Turley Placidum plus albumin as first-line therapy, and then norepinephrine as an alternative when Turley Placidum is not available. The American Association for the Study of Liver Diseases, their 2021 guidelines also recommend a vasoconstrictor plus albumin as first-line. However, Turley Placidum right now is not currently FDA-approved in the U.S. It has been denied twice for approval in the past for reasons that more safety outcomes needed to be shown. This brings us to the trial that I'll be discussing. The confirmed trial was published in the New England Journal of Medicine in March 2021. The hypothesis for this trial was that Turley Placidum plus albumin, as compared with placebo plus albumin, is effective and safe in adults with cirrhosis and hepatorenal syndrome type 1. As the author stated, they wanted to confirm that Turley Placidum was safe and effective. This was a randomized, double-blind, placebo-controlled phase 3 trial, and they enrolled patients from 60 sites across the U.S. and Canada between July 2016 and July 2019. The trial was funded by the drug sponsor Mallin-Crottet Pharmaceuticals, who also designed the trial. Here are patient criteria. So they included patients, adult patients with cirrhosis and ascites, who had an increased serum creatinine of at least 2.25 and a predicted doubling or predicted doubling of their serum creatinine within two weeks. Patients had to have no sustained improvement in their kidney function at least 48 hours after both diuretic withdrawal and plasma volume expansion with albumin. On the right side here, we have the exclusion criteria. Their intervention was Turley Placidum one milligram or placebo IV every two minutes, every six hours, together with albumin. The study investigators did strongly recommend albumin to be used in a dose of one gram per kilogram of body weight to a maximum of 100 grams a day on day one, and then 20 to 40 grams daily thereafter. Treatment with Turley Placidum or placebo was continued until 24 hours after serum creatinine level or value was less than or equal to 1.5 with two consecutive measurements or up to the maximum of 14 days. And then if the patient's serum creatinine decreased by 30% by day four, the dose of the study drug was increased to eight milligrams daily. For their endpoints, the primary endpoint was a verified reversal of HRS-1, which was defined as two consecutive measurements of serum creatinine less than or equal to 1.5 at least two hours apart up to day 14. And then patients had to survive without renal replacement therapy for an additional 10 days after. They had four secondary outcomes here they listed. So the first one, incidence of subjects with HRS-1 reversal, and this was just defined as one measurement of serum creatinine less than 1.5. Next was the durability of HRS-1 reversal, which was defined as reversal without renal replacement therapy up to day 30. And then the incidence of HRS-1 reversal in patients who met SIRS criteria. And last was HRS-1 reversal without recurrence by day 30. Here's an outline of the study design. So after randomization, trial period was up to 14 days. Secondary efficacy endpoints were collected at day 30. Data on adverse events was collected for up to seven days after the first dose. And then serious adverse events were collected up to 30 days after treatment period. Transplants pre-survival, they collected up to 90 days, and overall survival at 90 days was assessed. For statistical analysis, an efficacy analysis was performed in the intention to treat population. They required a sample size of 300 patients to provide 90% power to detect a significant difference between the groups for our primary outcome. Multiple amputations were used to account for missing endpoint data. And then they used the Hodgeberg procedure, which is a method to get rid of type 1 errors to assess the four secondary endpoints. Moving on to our results now. So for randomization, they screened about 2,300 patients, 309 were eligible for trial, and then 300 were randomized, 199 assigned to terlaplacin, and 101 assigned to placebo. For baseline characteristics, there were no major differences between the groups. As you can see here, serum creatinine average was about 3.5 in each group. The tolubilirubin was about 13 and 15 in each group. The CHOP-2 scores averaged around 10, and the MELD score was about 33 for both groups. So this does show us these are very sick patients. And then I did want to highlight that the majority of patients did receive albumin, with 83% in the terlaplacin group receiving a mean of about 200 grams over five days. And then the placebo group, 91% of them receiving about 240 grams mean over five and a half days. Here we have our primary outcome. So on the y-axis, the percentage of patients, and on the x-axis, terlaplacin versus placebo. And we see that we had verified HRS-1 reversal in 32% of the patients in the terlaplacin group versus 17% in the placebo group, and this was statistically significant. For our secondary outcomes, again, here on the y-axis, the percentage of patients, and we have our outcomes on the x-axis. The first outcome, hepatorenal syndrome reversal, 36% versus 16%, this was significant. For our second outcome, looking at norenal replacement therapy after reversal for up to 30 days, 32% versus 16%, and this was also significant. The third outcome, hepatorenal syndrome reversal in patients who met SIRS criteria, 33% versus 6%, and this was also significant. And then the last outcome, patients having verified reversal with no recurrence up to day 30, 24% versus 16%, so this was not significant. I did want to highlight some other secondary endpoints. Looking here at transplant-free survival up to 90 days, so on the y-axis, we have survival distribution and then days on the x-axis, and we see here that there's no significant difference between terlaplacin or placebo group with regards to transplantation. Looking at overall survival up to 90 days, we see that there's no difference initially between the patients. At 90 days, there was a death that occurred in 51% in the terlaplacin group versus 45% in the placebo group. A subgroup analysis was done for the primary outcome based on their baseline characteristics. I did want to highlight the difference in HRS reversal according to their baseline serum creatinine. So, we see here that the terlaplacin did not make a major difference in patients who had a baseline serum creatinine of less than 3 or those that had a serum creatinine greater than 5. Where we have the most clinically significant difference for HRS reversal was in the patients whose serum creatinine was between 3 and 5. Moving on to the safety outcomes, one patient did receive one dose of terlaplacin, so they were included in that arm for safety analysis. Adverse events of any grade were similar between the two groups, and the most common adverse events were abdominal pain, nausea, and diarrhea. However, for more serious adverse effects, we see here that the placebo group had more hepatobiliary disorders, but the terlaplacin group had more infections and respiratory disorders. I did also want to note that the terlaplacin arm, they had about 12% of patients that had an adverse event that led to discontinuation of the study arm versus 5% of the placebo arm. And then we're looking at the cause of 90-day death from adverse effects. Death due to respiratory disorders occurred 11% in the terlaplacin group versus only 2% in those receiving placebo. So the author's conclusion was that the use of terlaplacin plus albumin was more efficacious than placebo plus albumin in producing verified reversal of HRS1 in patients with decompensated cirrhosis and HRS1, and also that terlaplacin was associated with serious adverse events, including respiratory failure. Now moving on to my study critique, I think overall this was a very clinically relevant trial to be conducted. This is the largest randomized control trial we have investigating a treatment outcome for HRS1, which is a disease state with very high morbidity and mortality, and we currently have no FDA-approved treatment for HRS1 in the U.S. Terlaplacin has been shown to be superior to current therapies used here, including norepinephrine and metadrine plus octreotide combination. And then the drug is also used as first line in many other countries. For the study design and methods, strengths I found were that this trial is very well designed. It's multicenter, randomized, double-blinded, and placebo-controlled. I think they had appropriate and clinically significant outcomes to measure both the efficacy and the safety of terlaplacin. For statistical analysis, efficacy analysis used an intention to treat population, which I think adds strength for better external validity. For some limitations, one possible weakness is that they didn't allow for terlaplacin continuous infusions. There are trials out there comparing continuous infusion versus bolus regimen of terlaplacin, which found that continuous infusion was safer with less adverse events. And then for the last point, there was a recently published trial, a TIR trial, which showed that daily infusions of albumin can increase risk of pulmonary edema and volume overload in patients with cirrhosis. And as you've seen in the study, the patients did receive a large volume of albumin daily. For measure outcomes, a strength is that they did have a more stringent definition of hepatorenal syndrome reversal from previous trials, as they required two consecutive measurements. The sample size also was met that we needed to provide power for the primary outcome. One possible weakness is that we did see a difference in mortality of 51 versus 45%, but the trial was not a power-detected difference in survival. And we would have needed a much larger patient population to check that difference. The patient population, I think, had appropriate inclusion and exclusion criteria. The child's PUE and MELD scores are both standardized tools that are used to assess cirrhosis, mortality, risk, and severity. They also stratify patients by creatinine level and pre-enrollment large volume paracentesis, which I think adds to the strength that the patient population was normalized appropriately. Overall, I think the patient population provides strong external validity, as there were 60 sites and patients had a range of causes for their cirrhosis. One limitation is a potential for bias, as Mel and Jorda, the drug sponsor, designed the trial, and an employee from the company completed the statistics. My clinical interpretation for this trial is that TRLI+, plus albumin, can significantly increase the chance of hepato-renal syndrome 1 reversal and avoiding renal replacement after initial treatment completion in patients with moderately advanced HRS1. So, we do see that it does decrease that Q morbidity in HRS1, and there may be more benefit for patients for the use of TRLI+, when their serum creatinine is between 3 and 5 initially. However, TRLI+, was shown to have more serious adverse events, and did not improve rates of transplantation despite HRS1 reversal early on, and then there also might be an increased risk for mortality. The takeaway points for this presentation are one that, overall, this was, I think, a very well-designed trial that confirms benefit of TRLI+, for acute treatment of HRS1 with decreased renal replacement therapy, but it does not show a benefit for bridge to transplantation or mortality. TRLI+, should be used with caution in patients with respiratory conditions, though I do think it would be interesting to study TRLI+, with a lower amount of albumin volume, and see if adverse events or respiratory events differ. I would make no recommendation to change current practice in my institution, as this drug is not available in the U.S., and then I think future research is needed to study TRLI+, safety in more moderate HRS1, which is the patient population where we see the most efficacy for the drug. Last, I do also want to note that, based on the results of this trial, the FDA rejected approval of TRLI+, for the third time, and thus, it does remain unavailable in the U.S. And that brings us to our audience polling questions. Question 1, what therapy is currently used most often to treat HRS1 at your institution? A, albumin, B, octreotide, plus midodrine, C, norepinephrine, or D, vasopressin. Albumin, so then we have most answers with 48% of Octreotide plus Midodrine, which is also from the practice here at the Detroit Medical Center from speaking with specialists what they use most often. And then albumin was second with 39%, which I expected these results. Our second question, when choosing an agent to treat HRS-1, would you be more likely to use Tertitustin if it was available as a result of the confirmed trial? Yes, no, or unsure. No, oh 59% was no and 30% with yes. I would lean a little bit more towards yes but not surprised with the results. That concludes my presentation. Thank you, everyone, for listening. And with that, I'll take any questions. Thank you so much for a great presentation. We have a few questions about, since terlopressin is unavailable in the United States, is there a product available that you think would produce a similar outcome? So it's an analog to vasopressin, but it's the only product that we have that's selective, that B1 selectivity for splentic vasculature. From trials that have been done, norepinephrine has been shown to be most similar to it. So a lot of the trials have shown similar efficacy as norepinephrine. So I think that would be the closest agent over vasopressin, though it is a vasopressin analog. Great. Thank you. Another question. What benefit do you think albumin has other than volume replacement in this patient population? What benefit does albumin have? So my understanding is that albumin will remove some of the fluid from the abdominal space and return it more to the vasculature. So I think patients will not be in a state of shock more or reducing fluids to their kidneys. So that would be the benefit that I see of albumin. It keeps them, I guess, more hemodynamically stable. Unless you have another pathophysiological explanation. It looks like we have another question. What about the use of phenoldepam? What drug was that? Phenoldepam. I'm not familiar with that drug. Apologize. Is it phenoldepam? Is that a calcium? Correct. I did not come across any readings with a treatment of hepatorenal syndrome in that drug. I will look into that. Great. Thank you. And it looks like that concludes our Q&A session for the day. Thank you so much for your presentation. Thank you, guys. Thank you to our presenters today and the audience for attending. Please join us on the third Friday of every month from 2 to 3 PM Eastern Standard Time for the Next Journal Club, Spotlight on Pharmacy. That concludes our presentation today.
Video Summary
In this Journal Club Spotlight on Pharmacy webcast, three presenters reviewed different journal articles related to critical care pharmacy. The first presenter discussed the BEAST study, which evaluated the association between premorbid beta blocker exposure and sepsis outcomes. The study found that premorbid beta blocker exposure, particularly with non-cardioselective beta blockers, may be associated with decreased sepsis mortality. However, further research is needed before changes in practice are justified. The second presenter discussed a study on the discordance between respiratory drive and sedation depth in critically ill patients receiving mechanical ventilation. The study found that sedation depth is not a reliable surrogate marker for respiratory drive, and further studies need to be conducted to explore the effects of sedation depth and respiratory drive on clinical outcomes. The third presenter discussed the CONFIRM trial, which evaluated the use of terlipressin plus albumin for the treatment of type 1 hepatorenal syndrome. The trial found that terlipressin plus albumin was more effective than placebo plus albumin in producing reversal of hepatorenal syndrome, but it did not improve rates of transplantation or overall survival. The presenters provided their interpretation of the studies and their implications for clinical practice. Overall, the webcast provided valuable insights into the current research in critical care pharmacy.
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Pharmacology, Cardiovascular, Research, 2021
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"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.
Follow the conversation at #SCCMCPPJC."
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