and I'm an Intensive Care Unit Clinical Pharmacist at Northwestern Memorial Hospital in Chicago, Illinois. I will be moderating today's webcast. A recording of this webcast will be available to registered attendees. Log in 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 question box located on your control panel. You may also follow and participate in live discussion on Twitter following hashtag SCCM, CPP, JC and hashtag PharmICU. Please note 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 that may be helpful to others. The views and opinions expressed herein are those of the presenters and do not necessarily reflect the opinions or views of SCCM. SCCM does not recommend or endorse any specific test, physician, product, procedure, opinion or other information that may be mentioned. And now I'd like to introduce our speakers for today. Each will give a 15 minute presentation followed by a Q&A. Our first presenter today is Nicholas Quincetelis, PGY2 Critical Care Pharmacy resident at New York Presbyterian Hospital in New York, New York. He will present on thiamine for renal protection in septic shock, also known as the TRIPS trial. Our second presenter is Casey Olson, PGY2 Critical Care Pharmacy resident at Memorial Health University Medical Center in Savannah, Georgia. She will present on cefepime versus piperacillin-tazobactam in adults hospitalized with acute infection. And lastly, our third presenter is Caitlin Butler, PGY2 Critical Care Pharmacy resident at Morton Plant Hospital in Clearwater, Florida. She will present on dexmedetomidine versus propofol, an effective combination with ketamine for adult procedural sedation, a randomized controlled trial. And now I'll turn things over to our first presenter. Hello everyone, my name is Casey Olson. I am the PGY2 Critical Care Pharmacy resident at Memorial Health in Savannah, Georgia. And today I'll be presenting my journal club on cefepime versus piperacillin-tazobactam in adults hospitalized with acute infection or the ACORN trial. For some background, patients with suspected infections frequently receive empiric antibiotics, as we know. And the surviving sepsis guidelines do recommend that an anti-pseudomonal antibiotic be a part of this regimen. Cefepime and piperacillin-tazobactam are often the anti-pseudomonal antibiotics that are chosen from. And as we know, they have similar efficacy against gram-negative bacteria. There have been a few observational studies looking at cefepime that have reported neurotoxicity that can range anywhere from agitation to coma in patients receiving cefepime. And in piperacillin-tazobactam, there have been randomized trials comparing treatments for MRSA that found that the addition of an anti-pseudomonal beta-lactam to vancomycin does increase the risk of AKI. And based on these, there have been no randomized clinical trials that compare cefepime versus piperacillin-tazobactam. Therefore, it is unknown whether these risks differ between the two drugs. The objective of this study was to determine if the choice between cefepime and piperacillin-tazobactam affects the risks of acute kidney injury or neurological dysfunction. This was a pragmatic open-label parallel group randomized comparative safety trial that included adult patients in the emergency department or medical ICU that received cefepime or piperacillin-tazobactam within 12 hours of hospital admission. Patients were excluded if they had an allergy to cephalosporins or penicillin, if they received more than one dose of an anti-pseudomonal cephalosporin or penicillin within the previous seven days, if they were incarcerated, or if the clinician determined that one of the two drugs was a better treatment option for the patient. For our treatment groups, they used cefepime two grams IV push every eight hours. That was administered over five minutes. And piperacillin-tazobactam 3.375 gram bolus over 30 minutes followed by 3.375 grams every eight hours. And this was the extended infusion, so it was done over four hours. And the treating clinician determined the duration of the antibiotic therapy and whether to administer additional antibiotics or not. For the outcomes of the ACORN trial, the primary outcome was the highest stage of AKI or death arising between randomization and day 14. And this trial used the KDGO criteria for creatinine level to define the stage of AKI. And so surviving patients without new or worsening AKI received a score of zero. A stage one AKI was a serum creatinine of 1.5 to 1.9 times the baseline, or an increase by greater than or equal to 0.3 milligrams per deciliter. A stage two AKI was a serum creatinine 2 to 2.9 times the baseline. Stage three was a serum creatinine greater than or equal to three times the baseline. An AKI with a serum creatinine of greater than or equal to four, or receipt of new renal replacement therapy. And patients who died received a score of four. For secondary outcomes, the first one was major adverse kidney event at day 14. And this was a composite of death, receipt of new renal replacement therapy, or persistent kidney dysfunction, which was defined as a final inpatient serum creatinine that was greater than or equal to two times the baseline level. And the second outcome was days alive and free of delirium or coma within 14 days. And this was the number of calendar days on which a patient was alive and without a positive assessment on the CAMICU score, or a RAS of negative four or negative five. For statistical analysis, the original design of the trial was to enroll 2,050 patients to provide an 80% statistical power to detect an odds ratio of 0.65 in the primary analysis. The trial was revised based on recommendations from the monitoring board and increased the sample size to 2,500 patients to provide 92% statistical power to detect an odds ratio of 0.75 in the primary analysis. And this was the design that was used for the trial. A total of 3,806 patients met inclusion criteria with 1,172 patients being excluded. And that left 1,214 patients in the Cefepime group and 1,297 patients in the Pipericillin-Tazobactam group. Baseline characteristics were pretty similar within the group. As you can see, the median age was over 55 with majority of patients being male and presenting with sepsis. About 26% of patients did have a suspected intra-abdominal sores. And over 75% of patients in each group did have vancomycin on enrollment as well. And as you can see here, majority of patients, over 50% in each group, had no AKI at baseline. Looking at our primary outcome, which again is acute kidney injury or death by day 14, you can see that this was not statistically significant between groups with an odds ratio of 0.95. And majority of patients did survive with only about 7% in each group expiring at the day 14. For secondary outcomes, the major adverse kidney events at day 14, again, was not statistically significant with only 10% in the Cefepime group versus 8.8% in the Pipericillin-Tazobactam group. However, the delirium and coma-free days within 14 days, more patients in the Cefepime group did experience delirium and coma. Delirium and coma. And so this was statistically significant with less patients, or excuse me, with patients in the Pipericillin-Tazobactam group having more delirium and coma-free days within 14 days. For our author's conclusions, the highest stage of AKI or death did not differ between patients receiving Cefepime or Pipericillin-Tazobactam. However, patients that received Cefepime did experience more neurological dysfunction. For my critique, I think there were several strengths of this study. It being randomized clinical trial is very huge with a large sample size and comparing the safety of two commonly used antibiotics that we see almost every day in practice. And it did include patients with baseline kidney dysfunction and those receiving vancomycin, which I think is really important, looking at what our patients do get when they come in and receive sepsis protocol. However, there were multiple limitations as well. So this was a single center study and it was completely unblinded. It had a very short median days of treatment and this could limit generalizability to patients that receive longer durations of treatment. The authors also failed to collect other types of neurological dysfunction, so things like seizures, agitation, myoclonus, would have been interesting to see these things. And then the method of administering and the dosing of the antibiotics, I believe was a limitation. I think it can limit generalizability to institutions that use different methods of antibiotic dosing and administration. In conclusion, there was no difference found between groups regarding the highest stage of AKI or death. This was a well-designed study, however, it was not without some limitations. And I'd be curious to see if the same results were found in a multi-center randomized study or in patients receiving longer duration of treatments. And now I'll open it up for questions from the audience. Thank you, Casey. Our first question from the audience is, can you briefly discuss your thoughts on the author's dose, route, and frequency of both drugs utilized within this trial? So I think with the dosing, I know at my institution, we use the 4.5 grams of piperacil and tazobactam in our more acute patients. And I think this limitation was really with the 3.375 grams with CLSI guidelines recommending that we use the higher dose of the piperacil and tazobactam in these acutely ill patients. And this trial did not use that. So I think it would be interesting to see if results were different with that higher dose of the piperacil and tazobactam. Our next question from the audience is, did the study discuss any EEG findings to support the reported increased neurologic adverse effects from safepine? And the study did not discuss any EEG findings to support the reported increase in neurological adverse effects. Again, I think it was really a limitation that they only, they didn't look at all types of neurological dysfunction. They left a lot of things out, and I think it really would have been interesting to see if they would have done EEGs or if other kinds of neurological dysfunction were present in these patients. Again, thank you so much for attending today, and thank you for listening to my presentation. And that concludes our Q&A session. Thank you, Casey. Now I'd like to introduce our next presenter, Kaitlyn Butler. Hello, my name is Kaitlyn Butler, and today I'll be presenting my journal club looking at a study on the effects of safepine on the brain and the brain's function. Today I'll be presenting my journal club looking at combining dexmedetomidine versus propofol with ketamine for adult procedural sedation and analgesia. I have nothing to disclose regarding anything that may be referenced in this presentation. Throughout this presentation, we will review the available guidelines for procedural sedation and analgesia in adults, and we'll also discuss ideal drug characteristics as well as combining certain drugs in order to target those ideal drug characteristics. To give a little background, the ASA guidelines define procedural sedation and analgesia as providing a moderate sedation and analgesia level during painful procedures. And this is often done in the emergency department setting as a way to prevent the patient from having to go into an operating room. Currently, there is no guideline preferred agent. However, some ideal drug characteristics do include a rapid onset, a short duration of action and recovery time, the maintenance of hemodynamic stability, and of course, minimal side effects. There are several agents that are used in procedural sedations. However, there's no one single agent that's currently available to hit all of these ideal characteristics. Because of this, a combination of sedatives is often utilized in order to help maximize those ideal properties. Two common combinations that we typically see include ketamine and propofol, termed Ketafol, and ketamine and dexmedetomidine, termed Ketadex. Alone, propofol and dexmedetomidine can both cause bradycardia and hypotension, whereas ketamine can cause tachycardia and hypertension, as well as emergency reactions. It is theorized that utilizing a combination of these sedatives will help balance out those hemodynamic effects, as well as prevent the ketamine-induced emergency reactions. And by doing this, you thus get the ideal drug properties for procedural sedation that we covered in the previous slide. There have been a few studies to evaluate the sedative combinations. However, most of those studies are pediatric-based. There are, though, three adult studies that we will now review. The first study, which was conducted by Mahaj and colleagues in 2017, compared Ketadex versus Ketafol boluses, followed by a continuous infusion in patient post-CABG procedure. All the patients additionally received fentanyl for post-op analgesia. And the results of the study actually found that Ketadex reduced the additional fentanyl requirements when compared to Ketafol. And there were also no differences in hemodynamic effects noted. The next study, which was conducted by Azekani and colleagues in 2021, compared Ketadex versus Ketafol versus ketamine monotherapy in patients undergoing procedural sedation in the emergency department. They primarily looked at recovery agitation, and they found that Ketadex and Ketafol both reduced the incidence of recovery agitation when compared to ketamine monotherapy. They also saw no difference in hemodynamic effects, which included hypotension, bradycardia, and oxygen desaturation. The final study here was conducted by Singh and colleagues in 2022. And this study looked at Ketadex versus Ketafol for procedural sedation in patients undergoing an ERCP procedure. They found no difference between the two agents in terms of the need for rescue boluses for further sedation. However, they did find that Ketafol was associated with lower mean SpO2, whereas Ketadex was associated with lower mean arterial pressure. Despite these three studies, the data for identifying the optimal procedural sedation agent regimen to use in the emergency department for adults is still lacking. Which brings us to the study for today's journal club, which is titled Dexmedetomidine versus Propofol, an effective combination with ketamine for adult procedural sedation. The objective of the study was to evaluate Ketadex, Ketafol, and ketamine in adults undergoing procedural sedation in an emergency department, while also comparing efficacy and safety profiles. This was a prospective double-blind randomized controlled trial conducted between September 2022 and February 2023 at two hospitals in Iran. 135 patients underwent block randomization and 45 patients were assigned to one of three groups. The first group was Ketadex, which was a combination of ketamine and dexmedetomidine. The second was Ketafol, which was a combination of ketamine and propofol. And the third was ketamine monotherapy. And I have the doses listed here at the bottom of the screen. Adult patients were included if they required procedural sedation for a procedure in the emergency department, had an ASA physical status of one to three, and I have the definitions listed there on the right. And they also had to have a visual analog scale pain score of at least four. Patients were excluded if they had received a sedative or analgesic in the prior 24 hours of the procedure. They had severe organ dysfunction or systemic illness, persistent hemodynamic instability, history of psychosis, pregnancy, or verbal visual disabilities. The procedure was relatively standardized for all study patients. There were six different types of procedures that were included, which I have listed on the left-hand side of the screen. The targeted sedation level was based on a RAS score of negative four to negative five. And an additional lower dose of ketamine was given if RAS exceeded negative four at any point. The two agents were combined and diluted in a single syringe by an independent nurse who was not involved in the study or the patient care. And then the dose was administered slowly over four minutes. For endpoints, the primary endpoint was sedation parameters, which included induction and recovery time. And secondary endpoints included hemodynamics, additional ketamine requirements, recovery agitation in which Midazolam was given, and then adverse effects. For statistical analysis, using a least significant difference of 0.2 for efficacy outcomes and 13% for safety outcomes, as well as a power of 80% and an alpha of 0.05, a sample size of 42 patients per group was determined. For data analyses, the tests that I have listed here were used depending upon the type of data that was being analyzed. Now onto our results, starting with baseline characteristics. Your average patient was 39 years old, male, and the most common procedure was fracture reduction. Pain scores, ASA physical classification, procedure type, and most of the vital signs were very well balanced. However, although it wasn't statistically significant, I think it's important to note that the systolic blood pressure was lower at baseline in the ketamine monotherapy group. And this brings us to our final results, looking at our primary outcome first, which included sedation parameters. And sedation parameters was broken up into induction and recovery time. Starting with induction time, Ketodex did have the longest induction time at about 4.7 minutes, and ketamine had the shortest time at around three minutes. The difference between the two agents was significant. However, there was no statistical significant difference when comparing Ketodex to Ketofol. The second half of the primary outcome was recovery time, where Ketofol did have the shortest recovery time at about 26 minutes. And the difference between Ketafol and Ketodex as well as Ketafol and Ketamine was statistically significant. For secondary outcomes related to sedation, there was no significant difference between Ketodex and Ketafol regarding additional Ketamine requirements or severe recovery agitation. However, the Ketamine monotherapy group did require significantly more additional sedation both during the procedure and during that recovery period. Onto our hemodynamic outcomes, starting with heart rate. There was a greater increase in heart rate at the five minute mark in the Ketamine group. And the difference in mean heart rate increase at five minutes was significant when it was compared to both the Ketodex and Ketafol. So ultimately we saw more increase in heart rate with Ketamine monotherapy. For blood pressure, they did observe a greater change in mean arterial pressure from baseline with the Ketamine and the Ketafol groups. And the mean difference in this change was significant when compared to Ketodex. It is important to remember though, when thinking back to our baseline characteristics, Ketamine did have that lower systolic blood pressure at baseline, and this may have impacted the comparison that I have listed here. Finally, for our hemodynamics, Ketodex did have the least reduction in SpO2 from baseline to five minutes at 1.9%, whereas Ketafol had the greatest reduction at 6.5%. And this was a statistically significant difference when comparing the Ketodex and the Ketafol groups, but not when compared to Ketamine alone. Finally, with our outcomes for safety events, starting with respiratory health, starting with respiratory events, I know this is a lot to look at on the screen, so I'm gonna break it down the best I can here. Starting with the respiratory outcomes, a total of 72 patients, which is almost half of our study population, required supplemental oxygen, which is represented by that oxygen desaturation line. However, there were no significant differences noted between any of the groups. Next, for cardiovascular adverse events, the Ketamine group was associated with significantly more tachycardia and hypertension when compared to the other groups. And this was expected based on Ketamine's typical hemodynamic profile. The Ketamine group was also associated with more recovery agitation, with few differences when comparing Ketodex and Ketafol. And finally, the only major side effect differences between Ketodex and Ketafol included dry mouth, which was largely led by the Ketodex group. In critique of the study, starting with strengths, this was a randomized and blinded trial, which is gonna increase the internal validity of the study. Patients who received other sedatives or analgesics within 24 hours prior to randomization were also excluded, which reduced a potential confounding variable. They also covered both the primary and secondary outcomes, which again increased the internal validity. And finally, this is the largest study to date comparing Ketodex and Ketafol in the adult population. For limitations, at the end of the day, only 135 patients were included, so therefore our sample size was still pretty small, which is gonna limit the generalizability of the study. This was also conducted outside of the United States, which may also limit the generalizability. They also targeted a very deep sedation level based on a RAS of negative four to negative five, although the ASA guidelines do recommend targeting more of a moderate sedation level. And I think this may have led to that high rate of respiratory side effects that we saw when looking at the safety outcomes. They didn't report the full statistics on the hemodynamic outcomes, they actually only provided the line graphs and the significant values that I shared with you guys, so I think that is a limitation in itself. And finally, this was not powered for superiority or non-inferiority, therefore we're unable to conclude which sedative strategy was truly the best. In conclusion, Ketodex and Ketofol improved sedation parameters compared to ketamine alone, and that we saw minimal differences in the induction time and improved recovery time specifically with Ketofol. Ketodex also had the best preservation of SpO2 and mean arterial pressure, and both Ketodex and Ketofol had better preservation of heart rate when compared to ketamine alone. Ketamine was also associated with more agitation and cardiovascular effects. However, ultimately, I think there's still a lot of questions regarding which agent is truly superior, and because of this, more studies are necessary to determine the optimal strategy for procedural sedation in adults. And here are my references. Great presentation, Kaitlin. One of the first questions that we have from the audience is what are your thoughts on the use of IV push dexmedetomidine? This isn't commonly used in practice due to the hemodynamic issues that are associated with it, specifically hypotension and bradycardia. So I do think it's interesting that they still used dexmedetomidine pushes. However, I do think the addition of the ketamine, we did see a better preservation and hemodynamic effects. I think it presents an interesting question on how we should go about doing this in a procedural sedation setting. Our next question from the audience is, are there any other modalities that could have been used at bedside to monitor for safety of these agents other than heart rate, systolic blood pressure, and oxygen saturation? So this study specifically looked at SpO2 monitoring. They did not use Entitle, which is different than most practices here in the United States. I know my institution, we have respiratory therapy at bedside who is constantly monitoring Entitle CO2. So I think that presents more of a accurate representation of oxygen saturation. However, I don't think there's anything wrong necessarily with using SpO2. You're still getting a pretty accurate interpretation of their oxygen status. And that might be what was only available at that particular institution. So I don't think there's necessarily anything wrong with using SpO2. And that concludes our Q&A session. Thank you, Caitlin. Now I'd like to introduce our final presenter, Nicholas. Hi, everyone. My name is Nicholas Cucinturlis, and I am one of the PGY-2 Critical Care Pharmacy residents at New York Presbyterian Hospital located in New York City. And today I'll be discussing a trial called Thiamine for Renal Protection and Septic Shock, aka the TRIPS trial, which was published in the American Journal of Respiratory and Critical Care Medicine this past September. Of note, I have nothing to disclose for today's presentation. Kidney injury is a common and detrimental outcome of sepsis and septic shock. Previous research has mainly focused on restoring kidney blood flow to mitigate this injury. However, more recent studies have shown that septic kidney injury can occur even without prolonged low blood flow. And it primarily involves cell apoptosis rather than just tissue necrosis. Mitochondrial dysfunction leading to cellular apoptosis is a less explored pathway for organ injury in sepsis. Thiamine, which is a vital cofactor for aerobic respiration has been linked to organ function, especially in the kidney. And given the high concentration of mitochondria in the kidney and its reliance on thiamine, previous studies have investigated thiamine as a potential adjunctive therapy to protect the kidney and septic shock with overall mixed results, but no safety concerns. There have been several studies looking into the clinical benefits of thiamine in patients with septic shock, however, many of which included additional therapies such as the VITAMINS trial, which evaluated the impact of vitamin C, thiamine, and hydrocortisone on time alive and off vasopressor support. The two prior studies I wanted to highlight was a study conducted by Danino and others in 2016, as well as another study in 2014 by Woolham and others. Both studies included patients with septic shock, however, the Danino study included two centers and was prospective. Patients were randomized to receive either 200 milligrams of ibithiamine or matching placebo twice daily for seven days or until hospital discharge and concluded that administration of thiamine did not significantly improve lactate levels or other outcomes in the overall group of patients with septic shock and elevated lactate. A unique finding of the study was that in the subgroup analysis of patients with baseline thiamine deficiency, patients in the thiamine group had significantly lower lactate levels at 24 hours and a possible decrease in mortality over time, suggesting that there may be a benefit in thiamine deficient patients. Moving over to the Woolham study, which was a retrospective single center study that compared patients who received thiamine within 24 hours of admission to those who did not receive it. Unlike the Danino study, the Woolham study did conclude that thiamine administration within 24 hours of admission in patients presenting with septic shock was associated with an improved lactate clearance and a reduction in 28-day mortality compared with match controls. There were, however, several limitations to the study, including that there was a large percentage of patients with cirrhosis who are not representative of the typical patient population observed in traditional trials of septic shock and perhaps accordingly, their mortality rates were also higher than recent studies in septic shock. And additionally, while the study did not include or exclude patients based on the dose of thiamine they received, two-thirds of the thiamine group received 500 milligrams every eight hours for 72 hours when compared to the Danino study, which was dosed at 200 milligrams twice daily. Also in the Woolham study, females responded more favorably, which introduces the question if there's an increased likelihood of thiamine deficiency among female patients with septic shock. As we can see, the literature is a little controversial and some interesting questions have been introduced, which brings us to the TRIPS trial, which aimed to evaluate whether thiamine supplementation can mitigate kidney injury in patients with septic shock. This was a blinded placebo control trial conducted at three different medical centers in the United States. It received funding from the National Institute of Health and General Medical Sciences. The study's objective was to assess whether thiamine supplementation attenuates kidney injury in patients with septic shock. Moving into the inclusion and exclusion criteria, we can see there were a few inclusion criteria. Essentially, the study included adult ICU patients with septic shock, in which septic shock was defined by a suspected or confirmed infection, the receipt of vasopressors, and a serum lactate level of greater than two millimoles per liter. The other inclusion criteria were patients with a serum creatinine of greater than one. And the purpose of this was to enrich for a population already at risk for acute kidney injury. Exclusion criteria include patients with a clinical indication for thiamine administration, such as patients with alcohol use disorder or a known or highly suspected deficiency. Other exclusion criteria include kidney replacement therapy within the past 30 days, patients who are on comfort measures only or anticipated to have withdrawal of support within the next 24 hours, protected populations such as pregnant women and prisoners, and lastly, patients with a known thiamine allergy. From my perspective, these exclusion criteria are appropriate as including some of these may impact study outcomes. The study period was conducted between September, 2018 and April, 2022. As we can see, a large number of patients met exclusion criteria. And while 95 patients were randomized, ultimately 88 patients were analyzed as some of those original 95 patients did not end up receiving the study drug. Of the 88 patients analyzed, 42 of which were randomized to the thiamine group and 46 to the placebo group. When looking at the baseline characteristics, I included in this table the most common variables between both groups. There were more males without a significant past medical history in the placebo group. When comparing the past medical history of both groups, patients with coronary artery disease, congestive heart failure, COPD, and chronic kidney disease were higher in the thiamine group. I wanted to highlight that the groups do not appear very homogenous. As you can tell with COPD, liver disease, and some of the other factors, as you can tell with COPD, liver disease, and some of the other variables. 17 to 19% of patients who trained both groups also had CKD at baseline, with most patients having an unknown CKD stage. Moving to the table on the right, we can see the various suspected septic shock sources, which was mostly intra-abdominal and urinary. However, a large amount of patients, particularly in the thiamine group, were classified as having an other source, which was not defined in the study. The median SOFA score in both groups was approximately four, which is associated with a 20.2% mortality. And lactate concentrations were mild to moderately elevated with a median of 2.9 and 3.1 in the thiamine and placebo group, respectively. As I alluded to earlier, patients were randomized in a one-to-one fashion to receive either IV thiamine, 200 milligrams every 12 hours for three days, or a matching placebo of normal saline. Serum creatinine concentrations were measured at baseline and every 24 hours for three days after enrollment. The trial was quadruple-blinded, meaning that participants, investigators, clinical teams, and outcome surveyors were blinded to the allocation. And essentially only the research pharmacy at each site providing the study drug was aware of the allocation. The primary outcome of this study looked at change in serum creatinine 72 hours after enrollment. It is important to address that it has been shown that serum creatinine may lag and is not always accurately reflective of real-time renal function. Secondary outcomes included the receipt of renal replacement therapy, ICU-free days through day 28, in-hospital mortality, acute kidney failure as defined by stage three on the CADIGO AKI scale, change in serum lactate concentration over 72 hours, the incidence of delirium on day three after enrollment, change in the SOFA score over the 72 hours after enrollment, and lastly, change in other markers of kidney injury, notably cystatin C, neutrophil galatinase-associated lipokilin, AKA NGAL, and kidney injury marker one, AKA KIM1. These were assessed between enrollment and 24 hours after enrollment. In my perspective, measuring these other markers of kidney injury may be beneficial. However, as we can see, the secondary outcome is looking at 24 hours after enrollment compared to the primary outcome, which looked at 72 hours after enrollment. And this may be too soon to see an improvement and may not provide as useful information as if they had both been assessed at the same time. Lastly, a subgroup analysis was also conducted in thiamine-deficient patients, which was defined as a thiamine plasma level of less than eight nanomoles per liter. From a statistical analysis perspective, the primary and secondary outcomes were appropriately performed in the modified intention-to-treat population. Baseline characteristics were reported via descriptive statistics. And then for the primary endpoint, a compound symmetry covariance structure was utilized. For patients who died or started on renal replacement therapy, the last known streum creatinine with a 20% increase was used for analysis, which could have potentially impacted the primary outcome. Secondary outcomes were compared appropriately using a logistic regression analysis. Wrapping back around to the primary endpoint, the mean streum creatinine in 72 hours after enrollment was 2.24 versus 2.79 in the thiamine and placebo group respectively, which was found to be not statistically significant with the p-value of 0.07. As I mentioned earlier that streum creatinine may lag and not accurately reflect present time kidney function, you can see in the graph on the right that thiamine saw a mild drop or no change in streum creatinine compared to placebo, which appears to have a more steady uptrend in streum creatinine. This information is further depicted in this table here. So it is possible that with a longer study period, there may have been a more significant change in streum creatinine. Secondary outcomes are listed in the table, which were mostly not statistically significant, with the exception being ICU-free days after 28 days, in which patients who received thiamine had significantly more ICU-free days. Additionally, of the other kidney function markers, only NGAL was statistically significant. However, it is a little difficult to interpret its clinical significance, given that the other markers were not statistically significant, and it was checked 24 hours after enrollment compared to 72 hours like the primary outcome. In the subgroup analysis, which looked at patients with thiamine deficiency, there was no difference in streum creatinine between the intervention and placebo groups. Thiamine deficient patients who received thiamine had less cadago stage three kidney failure of 57.1% versus 87.5% and lower in-hospital mortality of 28.6% versus 68.8% than those who did not receive thiamine. However, these were not found to be statistically significant with p-values of 0.14 and 0.22, respectively. The authors concluded that in patients with septic shock, there was no statistical difference in streum creatinine over 72 hours in patients who received thiamine compared to those who received placebo. Some limitations of this study include its overall small sample size, which may have led to potentially underpowering to detect a difference in streum creatinine. Also, when comparing both the placebo and thiamine groups, there appears to be an imbalance in baseline characteristics. Additionally, optimal dosing of thiamine in septic shock is not well-defined either in the literature or in this study, therefore making it a little bit difficult to interpret how thiamine dosing in this study compares to other studies and its overall primary outcome. Some other limitations include that plasmas and serum thiamine levels may not accurately reflect total body stores. The time period of the primary outcome may have also been too short to detect a difference, and variability in sepsis management may have impacted study outcomes. My overall assessment of the TRIPS trial is that thiamine supplementation may not have a significant impact on kidney injury over the 72-hour period studied. The higher number of ICU-free days observed in the thiamine group suggests a potential benefit in terms of reduced ICU stay, but is more of an exploratory analysis. The lack of significant differences in outcomes between thiamine-deficient patients receiving thiamine and those receiving a placebo may indicate that thiamine deficiency itself may not be the primary factor influencing kidney injury in septic shock. The potential benefits observed in terms of ICU-free days in the subgroup analysis for thiamine-deficient patients may warrant further investigation or consideration in future study, as well as looking at different dosages, durations, or patient populations. And I'll open it up for questions from the audience. Great job, Nicholas. Our first question from the audience is, are there any other medications and or factors that the authors could have factored into complete a sensitivity analysis on the primary outcome? I believe the authors could have included various other factors and medications that may have impacted the primary outcome. Some of these would include measuring urine output throughout the study period, checking a 24-hour urine collection, checking kidney function markers at the same time as the primary endpoint compared to 24 hours after enrollment, et cetera. Additionally, while the study reported suspected sources of sepsis, the authors did not report on the use of antimicrobials, including potentially nephrotoxic agents, such as vancomycin, aminoglycosides, antivirals, et cetera. Regarding management of sepsis, while the study reported the median amount of IV fluids received, it's unclear if this was sufficient based on each patient's body weight. And there was also minimal reporting of vasopressor selection, dose, and duration, therefore making it difficult to determine adequate renal perfusion throughout the study. Our next question from the audience is, do you think selection bias is of concern with the amount of patients they excluded from the study? Of the 1,092 patients assessed for eligibility, 997 were excluded. And while this may appear to be concerning, trial design, including the inclusion exclusion criteria, were specified prior to enrollment of patients. The primary reason for exclusion was that 305 patients had a clinical indication for thiamine, which is an appropriate exclusion criteria from my perspective. Additionally, given the regular trial monitoring in accordance with an IRB approved monitoring plan and quadruple study blinding, I do believe that the risk of selection bias was minimal in the TRIPS trial. Great job, Nicholas. That concludes our question and answer session. Thank you. Thank you to our presenters today and the audience for attending. Please join us on the third Friday of the month from 2 to 3 p.m. Eastern Standard Time for the Next Journal Club Spotlight on Pharmacy. Our Next Journal Club will be February 16th from 2 to 3 p.m. Eastern Standard Time. And that concludes our presentation today. Thank you.

critical care pharmacy

ACORN trial

cefepime

piperacillin-tazobactam

acute kidney injury

dexmedetomidine

propofol

ketamine