Hello, and welcome to today's Journal Club Spotlight on Pharmacy webcast, which is supported by the Society of Critical Care Medicine's CPP section. My name is Grace Beebe, and I'm a clinical pharmacy generalist in critical care and emergency medicine at Henry Ford Hospital in Detroit, Michigan. I'll be moderating today's webcast. A recording of the webcast will be available to registered attendees. Log on to MySCCM.org and navigate to the My Learning tab to access the recording. A few housekeeping items before we get started. There will be a Q&A after each of today's speakers. To submit questions throughout the presentation, type into the questions box located in your control panel. You'll also have the opportunity to participate in several 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 CPP JC and hashtag PharmICU. Please note the disclaimer stating that the content to follow is for educational purposes only. And now I'd like to introduce you to your speakers for today. Each will give a 15-minute presentation followed by a Q&A. Our first presenter today is Madeline Pausch, a PGY-2 critical care pharmacy resident at University of Arkansas for Medical Sciences Medical Center in Little Rock, Arkansas. She will present on long-term outcomes after treatment of delirium during critical illness with antipsychotics, MIND-USA, a randomized placebo-controlled phase 3 trial. Our second presenter is Shelby Brookshire, a PGY-2 critical care pharmacy resident at Atrium Health Wake Forest Baptist Medical Center in Winston-Salem, North Carolina. She will present on dexmedetomidine for reducing mortality in patients with septic shock, a randomized controlled trial known as DCAT sepsis. And our third presenter is Nathan Stadnik, a PGY-2 critical care pharmacy resident at Corwell Health West, Butterworth and Blodgett Hospitals in Grand Rapids, Michigan. She will present on antibiotics with or without rifaximin for acute hepatic encephalopathy in critical, excuse me, critically ill patients with cirrhosis, the AIR-E trial. And now I'll turn things over to our first presenter, Madeline Pausch. Hello, everyone. My name is Madeline Pausch and I am the PGY-2 critical care pharmacy resident at the University of Arkansas for Medical Sciences Medical Center in Little Rock, Arkansas. Today we'll be discussing, here we go, an article that recently came out this past August titled Long-Term Outcomes After Treatment of Delirium During Critical Illness with Antipsychotics, MIND-USA, a Randomized Placebo-Controlled Phase 3 Trial. So to understand the outcomes of this trial, however, we must first understand the timeline of the original MIND-USA trial or modifying the impact of ICU-associated neurological dysfunction, which was published back in 2018. The goal of this trial was to evaluate the effect of heliperidol or zeprazidone on the duration of delirium, mechanical ventilation, ICU length of stay, as well as the incidence of readmission and mortality when treating delirium during critical illness. When the acute outcomes of MIND-USA were reported, the long-term outcomes were still being assessed. Therefore, earlier this year, the authors reported those results regarding the effects of heliperidol and zeprazidone on the long-term cognitive, functional, psychological, and quality of life outcomes after the treatment of delirium during critical illness, which is the trial that we'll be discussing today. We'll begin with an overview of delirium, explore some existing treatment options, and highlight the gaps in literature that prompted this study. So delirium is defined as a neuropsychiatric syndrome that's characterized by acute and fluctuating disturbances in attention, awareness, and cognition. Delirium can manifest as either hyperactive delirium, where patients are more active, restless, agitated, or combative, or hypoactive delirium, which is when patients are more somnolent, tired, or depressed. This is a fairly common occurrence in the ICU that affects roughly 50 to 75% of patients who are mechanically ventilated. Additionally, the development of delirium is associated with numerous adverse outcomes. Acutely delirium can interfere with patient care, which can ultimately delay the recovery from their critical illness. Not only that, delirium can present in ways that are distressing for both the patient and their loved ones. Clinically, however, delirium is linked to higher mortality, prolonged mechanical ventilation, extended hospital stays, and ultimately an increase in hospital costs. Even after resolution, its effects may persist, with longer durations of delirium increasing the risk for long-term cognitive, psychological, and functional impairment, lasting anywhere from months to years. So for these reasons, an effective treatment of delirium in the ICU could alleviate those symptoms acutely, but they could also potentially improve those long-term cognitive, psychological, and functional outcomes. Antipsychotics are frequently used to treat delirium, including first-generation or typical antipsychotics, including haloperidol, and second-generation or atypical antipsychotics like zeprazidone, olanzapine, and cotiapine. The most recent PADIS guidelines recommend against the routine use of haloperidol or atypical antipsychotics, as studies have shown no difference in the duration of delirium, mechanical ventilation, ICU length of stay, or the incidence of mortality. The key word is routine, though, as patients experiencing severe distress or those who are agitated and might pose a risk to themselves or to others might benefit from that short-term use of haloperidol or atypical antipsychotics until those symptoms resolve. Similarly, the original MIND-USA trial found that there was no difference between haloperidol and zeprazidone and placebo on the duration of delirium and those other secondary outcomes. However, the long-term effects of using antipsychotics to treat delirium remain unclear. Only two trials have investigated the effects of haloperidol on long-term quality of life after delirium during critical illness. That includes the AID-ICU trial and the Uridice trial, and both found no difference when compared to placebo. Only the latter, the Uridice trial, which had a small sample size and was terminated early, evaluated any long-term cognitive outcomes. So these trials highlight a gap in the literature, which is where this study comes into play. Their objective for this study was to assess the long-term effects of haloperidol and zeprazidone on delirium during critical illness regarding those cognitive, functional, psychological, and health-related quality of life outcomes. Next we'll review the original trial's methods, including its design, population, and interventions, as well as the follow-up and statistical analysis for the long-term outcomes of the MIND-USA trial. This trial was a randomized, double-blind, placebo-controlled Phase III trial conducted at 16 medical centers across the United States. Patients were eligible for inclusion in the long-term follow-up study if they were adults admitted to the MICU or SICU with respiratory failure, septic shock, or cardiogenic shock that developed delirium during their ICU stay. Pertinent exclusion criteria include receiving ongoing treatment with an antipsychotic medication, a history of allergy to the study medications, neuroleptic malignant syndrome, or TRASAD2.0, QT prolongation, which they defined as a QTC greater than 550 milliseconds, had a life expectancy less than 24 hours or rapidly resolving organ failure, as well as severe cognitive impairment at baseline, which they determined by both a medical record review and a baseline score of 4.5 or greater on the informant questionnaire on cognitive decline in the elderly, the IQ code. And this questionnaire ranged from 1 to 5, with higher scores indicating a more severe cognitive impairment. If delirium was not present at the time that informed consent was obtained from the patient, trained research personnel evaluated patients twice daily until delirium was present or until death, discharge from the ICU, development of any exclusion criteria, or a max of five days. The incidence of delirium was assessed using the confusion assessment method for the ICU, which is a validated tool that identifies delirium on the basis of an acute change or fluctuating course of mental status, plus inattention, and either disorganized thinking or altered level of consciousness. When delirium was present and the inclusion and exclusion criteria were adequately met, patients were randomly assigned in a one-to-one-to-one ratio to either haloperidol, ziprasidone, or placebo via permutated blocks with stratification according to trial site and age greater than or less than 70 years. All medications were administered every 12 hours. They were colorless and also administered intravenously for blinding. The doses were 2.5 milligrams for haloperidol, 5 milligrams for ziprasidone, and an equivalent volume for placebo. If patients were greater than 70 years, they received half of that dose or volume. And you can see here on the slide the maximum dose per day for haloperidol was 20 milligrams, and the maximum dose of ziprasidone per day was 40 milligrams. So monitoring for those receiving treatment included a CAM ICU assessment twice daily and also safety assessments daily and up to four days after discontinuation. If the patient remained delirious and were not at the max dose, their dose was doubled. If the patient had two negative CAM ICUs, their dose was halved. And four negative CAM ICUs, their dose was held. If there were any serious adverse events, they were at the end of the 14-day trial, or if patients were discharged from the ICU, the medication was then permanently discontinued. As for our study outcomes, at three months and 12 months after randomization, patients' cognitive, functional, psychological, and quality of life outcomes were assessed using validated tests and questionnaires, which were administered via telephone by trained study personnel who were masked to the treatment assignment. The long-term primary outcome was pre-specified at the beginning of the MIND-USA trial as the patient's T-scores on the Telephone Interview for Cognitive Status, or TIC, score, which is a validated test of global cognition. Age-adjusted TICs T-scores of 35 or lower represented a cognitive impairment. Secondary outcomes also included disability and activities of daily living, PTSD, quality of life, hospital readmissions, and finally, employment status. As far as statistical analysis, data was assessed via an intention-to-treat analysis. However, the analysis of the three- and the 12-month outcomes included only surviving participants that had completed at least one partial follow-up assessment. They utilized the same sample size for the analyses of all the outcomes, imputing data with a model-based multiple imputation. However, the post-hoc sensitivity analyses utilized only complete data. Other statistical models included proportional odds logistic regression, multiple variable logistic regression, Kappa-Meier curves, and log-rank tests. Significance for all analyses were set at 5%. Now let's discuss the results of the trial. So initially, 566 patients were randomized into the intention-to-treat group of the MIND-USA trial. So that's 184 patients in the placebo group, 192 in the haloperidol group, and 190 in the zeprazidone group. Survivors that were eligible for the three- and 12-month follow-up included 108 in the placebo group, 106 in the haloperidol group, and 115 in the zeprazidone group. Baseline characteristics were balanced across the groups. A majority of patients were white males with a median age of around 57 to 59. The most common admitting diagnoses were ARDS, sepsis, and airway protection. Most patients were receiving invasive ventilation in the medical ICU. The median IQ code scores, characterizing that baseline cognition, were similar between groups, as were the Charles and Co. Morbidity Index scores, APACHE-2 scores, and SOFA scores. First, I just wanted to point out some of the more interesting statistics. So at least one-third of the patients reported cognitive impairment at both 3 and 12 months. Additionally, more than 50% reported that they were unable to work due to cognitive or physical limitations. And while those numbers are concerning, the primary outcome of the TICS-T score was not statistically significant in the haloperidol or zeprazidone groups when compared to placebo at both 3 and 12 months. Similarly, you can see here that there were also no differences in the secondary outcomes that were regarding disability and activities of daily living, quality of life, PTSD, employment, or hospital admissions. And lastly, they found no differences in 3- and 12-month mortality between the two groups compared to placebo. So finally, we'll now summarize the information and ascertain how we can apply the results of this trial to our current clinical practice. So we know from the original MIND-USA trial in 2018 that the use of haloperidol or zeprazidone did not impact the duration of delirium in patients with acute respiratory failure or shock. And similarly, we see now that in the long-term outcomes of MIND-USA, the use of haloperidol or zeprazidone did not improve long-term cognitive, psychological, or functional outcomes. So some of the strengths and limitations to note include this was a large multicenter trial with broad inclusion criteria for generalizability. It was a double-blind placebo-controlled design. They utilized validated patient-centered outcome measures by trained staff, and this does address a gap in literature as far as long-term outcomes of critically ill patients go. Limitations include the administration of cognitive assessments via telephone. So while this probably helped with their retention, it might not be an adequate score of their cognitive ability. Additionally, they could not adjust results for multiple comparisons, and this does increase our risk of type 1 error or false positives. And additionally, based on my experience, I thought that their choice of antipsychotics studied might be a limitation with haloperidol and zeprazidone. The results of this trial, I feel, support the recommendations that are currently outlined by the PADIS guidelines. So haloperidol or atypical antipsychotics have shown no difference in the duration of delirium, mechanical ventilation, or ICU length of stay, as well as incidence of mortality. And now the results show that there's no difference in the long-term cognitive, psychological, and functional outcomes. Therefore, we can utilize the recommended dexmedetomidine as well as nonpharmacologic measures to treat delirium in the critically ill. So for our first polling question, how often do you see antipsychotics prescribed for delirium in your ICU practice? Never, rarely, occasionally, frequently, or always. Okay, yeah, these results are roughly what I expected. So in my ICU experience, antipsychotics are prescribed occasionally to frequently, typically within the context of the PADIS guidelines recommendations for patients with hyperactive delirium that may interfere with their care or impact their recovery. That's my experience, at least. All right, and as for our second polling question, let's see if this will progress. There we go. Which antipsychotic do you most commonly see used for delirium management in the ICU? Haloperidol, olanzapine, quetiapine, or zeprazidone, or another agent? All right, these results are pretty similar to what I experienced in ICU as well. So with quetiapine and olanzapine kind of being the most common in my experience, I thought it was really interesting. I had my first order for Ziprasidone the other day, and I thought that's kind of funny given my journal club today. All right. Thank you guys. All right, and that concludes my journal club today. What questions can I answer for you? Okay, Madeline, the first question I have, I found it interesting that somewhere between like 30 to 50 percent of each group required inpatient care during the follow-up period, but I didn't see that it was incredibly well-defined in the journal article. Were you able to find anything to elaborate, like what was considered inpatient care? Was it just one hospital admission, or did that include like long-term care, anything of that nature? That is a great question. As far as what I've seen in their articles and supplementary appendices, I did not see an explicit definition. I would imagine that it would just be hospital admissions, but that is merely speculation. Okay, and then one more question for you. So, given that this study found no long-term benefit, previous studies found no short-term benefit, what's the primary role that you think antipsychotics have in ICU delirium? When would you recommend it for your patient? Absolutely. So, in my experience, and having read these trials and guidelines, I think the place for antipsychotics are kind of right where the PADIS guidelines say that they should be. So, in patients that are experiencing hyperactive delirium, that's kind of interfering with their care or with the safety of themselves or others. So, I don't feel as though it might be the right choice for ICU delirium. However, that does seem to be kind of the common intervention that many healthcare professionals make. Okay, and then we have one more question. Did they report if any patients transitioned from decreased cognition at three months to then no issues with cognition at the later date? That's a good question. So, it looks as though the incidence at 12 months did decrease. So, at three-month cognitive impairment, it was about 37 percent or 30s and 33s, and then the 12-month cognitive impairment kind of decreased in the placebo group, but it kind of didn't really change in the haloperidol or zeprazidone group. But, explicitly, they didn't say which, you know, if they did experience it, did they resolve or vice versa. Okay, that concludes our Q&A session. Thank you so much, Madeline. Thank you. So, now I'd like to introduce our second presenter, Shelby Brookshire. Thank you for the introduction. Like Grace said, my name is Shelby Brookshire, and I'm a PGY-2 Critical Care Pharmacy resident at Atrium Health Wake Forest Baptist Medical Center in Winston-Salem, North Carolina, and I'm going to be presenting on dexmedetomidine for reducing mortality in patients with septic shock, a randomized controlled trial, also referred to as DCAT sepsis. The article was published in July of this past year in CHESS. I have no disclosures to make regarding this presentation. For a little bit of background, the initial protective adrenergic stress response to sepsis and the release of catecholamines is crucial to maintain tissue perfusion and counteract autonomic dysfunction. However, prolonged catecholamine production can result in myocardial injury, thromboembolic events, immunosuppression, and insulin resistance. Sympathetic overstimulation may also cause downregulation and desensitization of alpha-adrenergic receptors. Catecholamine hyposensitivity may also contribute to further hemodynamic instability and poor outcomes, and there have been some animal models that have demonstrated high doses of alpha-2 agonists can actually increase vasopressor responsiveness in septic patients. Ruediger and colleagues coined the term decatecholaminization, which refers to strategies used to blunt endogenous catecholamine release, reduce exogenous catecholamine administration, and blunt the inflammatory response. Dexmetatomidine is a selective alpha-2 adrenergic agonist, which, as proposed before, is thought to increase vasopressor responsiveness and reduce catecholamine administration. It is administered as an IV infusion that can be titrated using different parameters. It undergoes hepatic metabolism and has a half-life of about 1.5 hours. And some notable adverse effects include hypotension and bradycardia. Morellian and colleagues published in JAMA in 2013 looking at septic shock patients, and they compared the use of Esmolol to conventional management. And unsurprisingly, you can see a significant decrease in heart rate, when using Esmolol. But for some secondary outcomes that looked promising, they saw a reduced 28-day mortality, as well as reduced norepinephrine requirements. And then there was a secondary analysis of the SPICE-3 trial, comparing dexmetatomidine versus usual care. And you can see that in patients that were greater than 65 years of age, across all categories of illness severity, they did see a reduced mortality of about 97.7%. However, that mortality did not hold true for patients less than 65 years. And then the DESIRE trial done in 2017 did not see a difference when comparing dexmetatomidine to sedation without dexmetatomidine in 28-day mortality, as well as ventilator-free days. So the study question was, does decolonization with dexmetatomidine lower the in-hospital mortality in patients with septic shock? And this brings us to our first polling question. At your institution, what do you typically use as a titration parameter for dexmetatomidine? Heart rate, blood pressure, rascal, or none of the above? Yes. So unsurprisingly, our institution, we also titrate to rascal. And we will see shortly that the trial used a different parameter. So this is a very interesting kind of new approach to using dexmetatomidine. So this was a single-center, prospective, randomized, open-label trial conducted in post-surgical ICUs of Mansoura University Hospital in Egypt from April 2022 to February 2022. And this was a single-center, prospective, randomized, open-label trial conducted in post-surgical ICUs of Mansoura University Hospital in Egypt from April 2022 to February 2022. And it was unfunded. The authors included adults with septic shock with a heart rate greater than 90 beats per minute and stabilized at a MAP greater than 65 for at least six hours. And they defined septic shock as the start of norepinephrine infusion to maintain a MAP greater than 65 in the presence of sepsis. They excluded patients with severe cardiac dysfunction, history of heart block, presence of a pacemaker, or severe valvular heart disease. They also excluded chronic liver disease, traumatic brain injury patients, patients with a hemoglobin less than seven, inability to give consent or declining, and then those that had already reached hemodynamic stabilization prior to inclusion as well as pregnancy. Patients were randomized to dexmetatomidine or usual care. For the dexmetatomidine group, they started the infusion at 0.2 micrograms per kilogram per hour without a loading dose. And they titrated by 0.1 microgram per kilogram per hour. And that was to maintain a heart rate of 60 to 90 beats per minute. Their maximum rate of infusion was 0.7 micrograms per kilogram per hour. And they conducted the infusion over 48 hours and then tapered for one hour. For both groups, they received fluid, vasopressors, mechanical ventilation, and sedation per the 2021 Surviving Sepsis Campaign Guidelines. For primary outcome, they looked at all cause in hospital mortality. And then their two secondary outcomes were the mean norepinephrine equivalent dose calculated over the first three days after enrollment or death, as well as the need for an additional vasopressor, which they defined as the addition of epinephrine. They looked at many exploratory outcomes, including new and persistent AFib, mean heart rate, MAP, and temperature over the first three days, incidence of AKI. They looked at SOFA, SAPS-2, and APACHE-2 scores over the course of the trial, as well as ICU and hospital length of stay and shock-free days. For the sample size calculation, they concluded that they would need 86 patients to estimate a 25% risk difference in the primary endpoint with 80% power and a significance level of 0.05. And they expected the in-hospital mortality for the non-dexamethamidine group to be 0.65 compared to 0.9, which was based on previous trials done by Rudiger and colleagues. The primary and secondary outcomes were performed as a per-protocol analysis, and the primary outcome was compared using the chi-square test of independence. Additionally, the authors did a multivariable logistic regression, and they adjusted for age, birth, sex, SOFA score, and being mechanically ventilated. As far as baseline demographics, the groups were pretty well matched. You can see that the mean age was around 60, with slightly more males, around 53% in both groups. Patients were obese with BMIs of 27 and 29, and the majority of patients did have diabetes and hypertension. Additionally, important to note that the chronic liver disease, considering they excluded Class C, these were patients with liver disease classified as Class A and Class B, but a decent proportion in both groups. And then the primary cause of sepsis among both groups was abdominal or biliary. You can see over 80% in both groups had that as the source of infection. Baseline demographics that were concluded additionally is the norepinephrine at inclusion was kind of high among both groups. It was 0.78 compared to 0.82, but pretty similar. And then additionally, their Apache scores were pretty similar as well, at around 28, so estimating about 55% mortality. And almost half of patients were ventilated at inclusion among both groups. And then the mean heart rate when they started the dexmedetomidine infusion was 140 compared to 136. As far as the primary outcome, they did not find a statistical difference between the in-hospital mortality between the two groups. However, you can see that there were 17 deaths in the dexmedetomidine group and 25 deaths in the control group. And although not statistically significant, that does seem to be clinically significant since that is the difference of eight deaths. And then additionally, after adjusting for the variables previously mentioned, they still did not find statistical significance for in-hospital mortality when comparing dexmedetomidine to the control group. There was also no statistical differences between ICU or 28-day mortality. As far as vasopressor outcomes, you can see that there was no difference in the mean norepinephrine equivalent dosage at three days. It was 0.55 compared to 0.61, and that was not statistically significant. However, the authors did find a statistically significant difference in the epinephrine requirement, where six patients in the dexmedetomidine group required the addition of epinephrine, whereas 15 in the control group required. And additionally, when adjusting for the variables previously mentioned, they did find a statistically significant difference in the three-day norepinephrine equivalent dosage with an adjusted odds ratio of negative 0.14. For some of the secondary exploratory outcomes, they did not find differences regarding mechanical ventilation, duration of mechanical ventilation, SOFA scores, AKI incidents, ICU or hospital length of stay, as well as shot three days. Unsurprisingly, they did find a significant difference in heart rate. So the dexmedetomidine group went from about 140 at baseline to 103 after three days compared to the control of 114. Additionally, you can see that there was a statistically significant difference in the rate of persistent AFib, with seven in the dexmedetomidine group and 15 in the control group, with a relative risk of 0.47. So the authors concluded that dexmedetomidine in patients with septic shock did not reduce in-hospital mortality, the unadjusted norepinephrine equivalent dose, or the SOFA score. Some strengths of this trial. So the trial design, with it being a randomized controlled trial, benefits the outcomes that we're looking at. Additionally, like I mentioned before, the dexmedetomidine group and the control group were pretty well balanced in the patient population. However, it is important to note that the majority of the patients were from Egypt and the source of infection, like I said, was abdominal. This was a clinically relevant primary outcome when looking at in-hospital mortality. So thinking about patient characteristics and importance of intervention. Additionally, the authors did do the multivariable logistic regression, and that helped account for many of the confounders that we think of in critical care. For limitations, with this being a single center study, it can be hard to generalize to other practices as clinical institutions do things differently. However, they did use the surviving sepsis campaign guidelines, which is what we also follow here in the United States. This was also an unblinded trial, leading to potential bias there. And then the multiple exploratory secondary outcomes, the trial was unable to really assess these in a very powerful way. It's interesting to look at these outcomes, but not necessarily something that we can apply straight to practice. And then lastly, this was a pretty small sample size of only 90 patients, and it was specifically done in a post-surgical ICU, so may not be able to apply to some of our other ICU settings. One of the key takeaway points from the trial is that there was, I would say, a clinically significant difference in death between the two groups, although it was not considered a significant reduction. Patients that received dexmedetomidine did achieve significant reductions in heart rate, and they were able to maintain their MAP values, but that is also in the presence of vasopressors. Lastly, dexmedetomidine reduced the need for the addition of another vasopressor and the risk of persistent atrial fibrillation. Okay, this brings us to polling question number two. If using dexmedetomidine for heart rate, what is your discontinuation strategy? Discontinue without weaning, wean 5.1 micrograms per kilogram per hour until off, wean by greater than 0.1 micrograms per kilogram per hour until predetermined level, and then vary from patient to patient. Okay, so it looks like the majority of patients were weaning 5.1 microgram per kilogram per hour until off, which in my clinical practice, that is what we have typically done. However, I have also seen it done discontinued without weaning and taking into consideration the way the patient is presenting, so all reasonable answers. All right, that concludes the journal club presentation. I'm happy to take any questions. Okay, Shelby, the first question I have for you, based on your clinical practice, what do you think of the authors selecting epinephrine as the refu infusion or additional vasopressor as their outcome of interest in the setting of septic shock here? Yes, great question. So in my clinical practice, primarily treating septic shock patients, the majority of these patients I'm treating are in the medical ICU, so a slightly different patient population. However, our second-line pressor is typically vasopressin. There are certain patient populations in which we do reach for epinephrine as our second-line pressor, but I do think that is another great limitation to point out as the rescue vasopressor being different than some other clinical practices or guidelines as well. Definitely agree with that. And then I found it very interesting that there was very little information regarding infection or antibiotic treatment as these could impact some of the outcomes of interest. So if you were one of the study investigators, like what else would you want to look at, or select, or evaluate kind of related to infection to kind of help control for those things? Yes, I definitely agree. I think when reading this trial initially, it stood out to me that I didn't include this in baseline demographics, but most of these patients had a significant leukocytosis, unsurprisingly. I think both were greater than 20. Again, with this being an abdominal source, we know that control of the source is the most important treatment, and that was not really commented on in this trial, as well as culture results and antimicrobials. So I think if redesigning this trial, I would definitely report out culture results that we have, if source control was obtained, and then what antibiotics and duration of therapy were used, because that is a big clinical indicator for things like mortality, which have been proven by previous trials and guidelines. Awesome. Thanks so much, Shelby. Thank you. All right. That concludes our Q&A session. Thank you again, Shelby. Now, I'd like to introduce our final presenter, Nathan Stadnyk. Hi. I'm Nathan Stadnyk, yes, and I will be going over the ARRAE trial today. Our objectives today is to evaluate the methods and results of the ARRAE trial, and also critique the author's conclusions and determine applicability to current practice sites. Rifaximin is a common medication utilized for hepatic encephalopathy, or HE, and it has current FDA approval for recurrent HE. It does have coverage against gram-positive and negative bacteria, such as use as E. coli coverage and traveler's diarrhea, and it's also non-absorbable, so it really remains within that GI lumen itself. It can also help reduce the amount of endotoxins and also the pro-inflammatory cytokine levels within the GI system. And as I mentioned before, it is approved for recurrent hepatic encephalopathy, but not for acute, really due to the lack of studies associated with it. So it has been proven to lower mortality when used in combination with lactulose and L-ornithine L-aspartate, or Lola, according to recent meta-analysis. However, this is found to have a very low to actually moderate certainty of evidence with this as well. So often, critically ill hepatic encephalopathy patients are placed on broad-spectrum antibiotics, really due to complications from the underlying disease. And so the use of rifaximin has an unclear role in preventing endotoxin rise locally within the gut. And it was theorized that there could be a synergistic effect and also reduction in local endotoxin levels when rifaximin is added. And the ARRI trial is going to be the first study to assess the addition of rifaximin in this specific population. So this leads us to our first polling question that we have. At your hospital system, do you commonly utilize rifaximin for acute hepatic encephalopathy? And if so, how often do you use it? I see here that a majority of you guys actually do use it for acute hepatic encephalopathy, so it'll be interesting to see if this presentation will change your mind with that. So their hypothesis was, does the addition of Rifaximin to broad-spectrum antibiotics for critically ill cirrhotic patients affect acute overt hepatic encephalopathy? So this is a prospective single-center, double-blind, randomized control trial published in the American Journal of Gastroenterology with an intention to treat design and pre-protocol analysis. The intervention was adding Rifaximin 500 milligrams by mouth, either placed down a feeding tube as well, twice daily for 14 days in addition to regularly prescribed antibiotics based on the provider's discretion, and broad-spectrum antibiotics was defined as any regimen with cephalosporins, a penicillin with a beta-lactamase inhibitor, carbapenems, fluoroquinolones, macrolides, and also glycopeptides. So the primary endpoint was a two-grade reduction and or complete resolution of HE, along with various secondary endpoints that are listed there, and there was also further a subgroup analysis comparing decompensated cirrhosis and also acute onchronic liver failure patients. So the researchers noted that previous reports had demonstrated that resolution of hepatic encephalopathy occurs in up to 93% of patients receiving Rifaximin, Lola, and also Lactulose, and so they had a margin of around 15% in hepatic encephalopathy resolution, and that ended up being 88 patients in each arms, adding in a 5% attrition rate, leading to 92 patients in each arm, or a total of 184 patients. So for descriptive, parametric, and non-parametric for data was used. The student t-test was used for any continuous data. The x-squared or Fisher exact test was used for any categorical data. The Kaplan-Meier survival analysis really was used to assess the resolution of hepatic encephalopathy and in-hospital mortality, and a stepwise univariate and multivariate Cox regression analysis was used to determine the predictors of hepatic encephalopathy resolution, and a receiver operative characteristic curve analysis was used to identify the ideal cutoff for predictors that were significant in a multivariable analysis. So the inclusion criteria were adults admitted to the ICU with overt hepatic encephalopathy and a history of cirrhosis, with cirrhosis being defined as a clinical history of decompensation, that being ascites, previous hepatic encephalopathy, or variceal bleeding, with supportive imaging or biopsy findings, and the selected exclusion criteria are listed with acute liver failure defined as less than four weeks from jaundice to encephalopathy, and chronic liver failure, chronic renal failure defined as a EGFR of less than 60 for greater than three months, and again these were selected exclusion criteria, so there were other criteria as well. So there were 260 patients that were assessed and 76 of them were excluded, mainly for grade 1 hepatic encephalopathy or acute liver failure, leading to 84 patients being included total, with each being, with each arm including 92 patients, and for the per-protocol analysis in the antibiotics only, it included 90 patients, and two of those ended up having rifaximin added to their regimen, and in the antibiotics plus rifaximin group, their per-protocol analysis included 89 patients, as three patients eventually were discontinued on rifaximin itself. Looking at the decompensated cirrhosis patients, there were 46 in the antibiotic only group, and 42 in the antibiotic plus rifaximin group, and then acute on chronic liver failure, it was 46 versus 50 patients as well. So these are the selected results from this trial as well, so the primary outcome had similar rates of hepatic encephalopathy reduction or resolution, with the secondary having similar rates of in-hospital mortality, length of stay, nosocomial infection rates, along with endotoxin level changes, and the results and statistics are provided for you there. Looking at the subgroup, the decompensated cirrhosis had significant reduction in in-hospital mortality and nosocomial infection rates, really compared to the control regimen, however there are no statistically significant differences in the other subgroup, that being acute on chronic liver failure, or in those other subsections of the decompensated cirrhosis. So the author's conclusions was that rifaximin added to broad-spectrum antibiotics does not affect the resolution of hepatic encephalopathy in critically ill cirrhotic patients, and it does not decrease the incidence of infection or also endotoxin levels as well. So looking at the strengths of the study itself, the clinical question is relevant and really appropriate for this study. Rifaximin already has an established effectiveness in hepatic encephalopathy, and really has properties that could make it useful for an additional therapy consideration. The study design outcomes were all appropriate, and the population included in the trial was appropriate for the ICU level of care. So they had a SOFA score of 8.9 versus 8.8 in the intervention group, and also rates of mechanical ventilation being 32% versus 28%. Lactulose was also started on all patients, again having that prior established benefit, and the underlying disease states were also similar to the general population, with that etiology primarily being from alcohol being 64 to 68% in each group, followed by NASH being 14 versus 17, and also viral being 10 versus 7. And also the criteria for inclusion and exclusion were rational and also appropriate for this desired patient population, and no signs of biases were discovered in this review. So some weaknesses with the journal itself, or with the article itself, is that it was a single center, so it really does limit its generalizability, as other hospitals or even countries could have different resistance rates or even availability of antibiotics. The L- ornithinine and L-aspartate that Lola has prior research showing benefit in this population, so is used in 41% of those in the treatment group versus 50% in the antibiotics only group, along with it only being utilized in patients without an acute kidney injury, and this really does limit the results that were found of this trial. Hepatic encephalopathy was also only assessed once per day, between 9 a.m. and 10 a.m., and this really could have underestimated the differences between the protocols by only assessing once per day. And also the acute on chronic liver failure subgroup had higher SOFA and West Haven scores, indicating a more severe disease, and this could be the reason why rifaximin had no effect in this population and could have affected the overall results as well. So of the results that were statistically significant, specifically those with decompensated cirrhosis, the trial really wasn't powered to determine this, so the results cannot be truly accepted. So all of the primary or secondary endpoints in the primary analysis had no statistical or clinical significant results, along with the subgroup of acute on chronic liver failure. However, there was potentially significant statistical and clinical significance within the subgroup of decompensated cirrhosis in mortality and nosocomial infections, and looking at kind of that risk versus benefit, a number needed to treat that was calculated ended up being 47 patients. So some takeaway points, furthermore, is that the study design was appropriate. However, there could have been a potential benefit in conducting a non-inferior analysis as well between the two groups, and also the exclusion of the trial was appropriate, but does have areas that really could have been improved upon. So it was appropriate to ensure proper lactulose use for each of these patients. However, there could have been improvement in the use of Lola or exclusion, along with assessing hepatic encephalopathy more than just once a day, as they could have actually utilized the entire healthcare team to really alert them to possible resolution of the symptoms. Furthermore, the validity of the trial is really limited to internal, as this is a single-center randomized control trial, and the resistance rates of typical organisms and rates of fraud spectrum antibiotics could really vary hospital to hospital and region to region, further limiting that external validity. And clinically, these results have limited applicability, and as it really does not change any guideline recommendations or clinical practice, and rifaximin is still appropriate to use as an adjective agent for unresolved recurrent hepatic encephalopathy. So with reviewing this trial, I personally would not change any pharmaceutical-based recommendations for acute hepatic encephalopathy patients. I'll continue to recommend lactulose and add rifaximin as needed for these patients. However, this study does come upon some interesting areas of further investigation, so the results for improving mortality outcomes and reducing nosocomial infection rates and decompensated cirrhosis really warrant further trials, and the outcomes in hepatic encephalopathy for specific broad-spectrum antibiotics would also be appreciated, and similar trials including a larger, broader patient population would be beneficial for generalizability. So this leads us to polling question number two. So with these results, are you more, less, or unchanged in your likelihood to use rifaximin for acute hepatic encephalopathy? And it's interesting to see that all of you said unchanged in your regimen. I kind of agree with that as well, as I mentioned earlier, so that is good to see. And with that, I will open it up to any questions that people have. Great job, Nathan. The first question I have for you, you mentioned that the use of Lola in both groups was definitely a limitation, could have, you know, caused some confounding in the results. Were patients who were taking rifaximin before this admission able to be included in both groups, or would they have to be in the rifaximin-only group, or were they excluded altogether, and kind of how do you think that might have played a role? Yeah, so if I'm looking at this correctly, the rifaximin, those who were taking it prior to, they were excluded for this patient population because they were already previously on this medication. It could have limited the outcomes from this, just that patients with already an established benefit for rifaximin would have already been excluded from the forefront, so that could have limited the outcomes as well. But this, I think this is mainly looking at the addition of rifaximin for those acute hepatic encephalopathy patients, rather than the kind of the FDA approval for recurrent, which is probably why most of the patients outpatient would be on it. Okay, thank you. And then rifaximin in general, it's thought to be pretty safe and well tolerated from like an adverse events perspective. So given that it's still, at the end of the day, an antibiotic, did you find anything in your research, or would you be concerned about potential induction of antibiotic resistance with routine use? Not that I saw kind of like showing any rifaximin resistance. I personally didn't dig that deep into kind of looking at resistance itself. Usually it is reserved kind of just for those like as-needed indications, so those who can't really tolerate lactulose, you know, those who can't have or no resolution kind of with with the established therapy at, you know, target doses. But I specifically didn't see anything regarding, you know, its use or its increase in the risk of resistance rates for anything. Okay, there's been some literature that's come out recently that has suggested rifaximin might play a role in increasing daptomycin resistant enterococcus, which was just, I found this out recently. It's very timely for your journal club. I figured I would ask if you knew. Okay, well that includes, yeah, of course, that includes, concludes our Q&A session. Thank you so much, Nathan. Great job. And thank you to all of our presenters today and to the audience for attending. Please join us next journal club. It will be on the third Friday of the month from 2 to 3 p.m. Eastern Standard Time for the next journal club spotlight on pharmacy. And that'll conclude our presentation for today. Thanks again, everyone.

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