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 Kaitlyn DeHoff, a clinical pharmacist specialist in emergency medicine at Trinity Health Oakland and Pontiac, Michigan. I will be moderating today's webcast. A recording of this webcast will be available to registered attendees. Log into mysccm.org and navigate the My Learning tab to access the recording. A few housekeeping items before we get started. There will be a Q&A after each of today's speakers. To submit questions throughout the presentation, type into the question box located on your control panel. You will also have the opportunity to participate in several interactive polls. When you see a poll, simply click the bubble next to your choice. You may also follow and participate in live discussions on Twitter, following hashtag SCCMCPPJC and hashtag PharmICU. Please note the disclaimer stating that the content to follow is for educational purposes only. And now I'd like to introduce your speakers for today. Each will give a 15-minute presentation followed by a Q&A. Our first presenter today is Ben Arends, a PGY-2 critical care pharmacy resident at Sanford Medical Center Fargo in Fargo, North Dakota. He will present on prothrombin complex concentrate versus frozen plasma for coagulopathic bleeding and cardiac surgery. Our second presenter is Danielle Wojcik, a PGY-2 critical care pharmacy resident at Swedish Medical Center. She will present on inhaled sedation and acute respiratory distress syndrome, the CESAR, randomized clinical trial. Our third presenter is Deanna Farrella, a PGY-2 critical care pharmacy resident at Yale New Haven Health in New Haven, Connecticut. She will present on comparing the hemodynamic effects of ketamine versus fentanyl bolus in patients with septic shock, a randomized controlled trial. And now I'll turn things over to our first presenter, Ben Arends. Thank you for the introduction, Kaitlin. My name is Ben Arends. I'm from Sanford Medical Center, and I will be presenting today on the prothrombin complex concentrate versus frozen plasma for coagulopathic bleeding and cardiac surgery, the FAERS-2 clinical trial. So a little bit of background on this topic. The first trial going over here was looking at 100 cardiac surgery patients with cardiopulmonary bypass, and they were looking at prothrombin complex concentrate, PCC, versus frozen plasma. They looked at 15 units per kilogram for their PCC and then 10 to 15 mLs per kg for their plasma dosage, and they found no difference in their chest tube output. And then they also looked at secondary outcomes of transfusion requirements. So things like red blood cells, platelets, cryoprecipitate, plasma transfusions without any statistical difference. And based on their information, they concluded that PCC and plasma have similar safety and efficacy profiles. A different study, the FAERS trial, the pilot study for this study, looked at 101 patients. It was a feasibility study looking at PCC, 1,500 to 2,000 units based on weight versus frozen plasma, three to four units based on weight as well. And I'll get into how they decided. It's a similar protocol to this trial. They were not empowered to detect any sort of clinical outcomes for safety and efficacy, but they did look at them, and they did see statistical differences in their chest tube drainage and transfusion requirements, found this to be a feasible practice, and then went forward with this study. And they did see no differences in any sort of adverse events. So getting into our two treatment options. So prothrombin complex concentrate. We know the big things we think about are our four factors, right? So factor 2, 7, 9, and 10. Volume is about 40 mLs per every 1,000 units. Costs about $1 to $2 per unit. And for this study, we'll say the average cost per patient would be about $2,000 a dose. Our onset's very quick, minutes. It's fairly easy to compound, get to your patients, and administered fairly quickly. So our frozen plasma, we have our different components, coagulation factors, albumin, protein CNS, as well as antithrombin. And PCC has some of those, but not to the same degree. And then each unit is about 250 mLs, so much more volume than compared to our PCC, which is important to keep in mind. Cost is generally about less than $100 a unit. So for patients in this study, the maximum cost, we would say, would be right around $400 per dose. Our onset's minute to hours. Obviously, we have to thaw this medication, administer it a little bit more slowly because of that larger volume, which can delay some of that. So that's potentially the risks and benefits of each. And then also adverse events we think about with frozen plasma, as well as any sort of product like this, things like transfusion reactions. And then with that larger volume, fluid overload is a big component as well. So moving into our study, we're looking at comparing the efficacy and safety of PCC with frozen plasma in patients undergoing cardiac surgery with coagulopathic bleeding. Our study design, it was a multicenter, unblinded, randomized controlled trial. It was across 12 sites in the US and Canada. The population they chose was adults undergoing cardiac surgery with cardiopulmonary bypass. They had to have active or anticipated bleeding after termination of that cardiopulmonary bypass or a known or suspected coagulation factor deficiency. And that could be defined as something like an INR greater than or equal to 1.5, or if their site had viscoelastic testing, if there was any sort of abnormal things on like a tag or a rotam, something like that. And then their intervention was looking at four factor PCC, 1,500 to 2,000 units versus frozen plasma, three to four units. And the dosing for that was based on whether you were 60 kilograms or less, or greater than 60 kilograms. So if you were 60 kilograms or less, it was 1,500 units of four factor PCC or three units of frozen plasma. And then if you were greater than that, 2,000 units versus four units. And then also for this patient population, which we'll see more in a later when I get into the slides a little further. But the weight-based dose of this study was around 23 units per kilogram for that four factor PCC group. The primary outcomes they looked at were hemostatic response, defined as the need for hemostatic intervention. And this would be any sort of like administration of a hemostatic product, so any sort of transfusions, as well as any need for intervention, like a surgical reopening. Secondary outcomes they looked at was kind of that global hemostatic response. So they're like post-intervention, was there a drop in hemoglobin, bleeding via chest tube drainage, any incidence of severe or massive bleeding, incidences of adverse events, as well as total and individual components transfused. Moving into results and baseline characteristics, we see the age of our patients right around mid-60s, so 67 versus 64 in our two arms. There are about 400 patients total, 200 each arm about. And then a big thing here in the weight, looking at our weight-based categorizing for these patients, the vast majority of these patients were greater than 60 kilos. So more than 90% of these patients either received that 2,000 units of PCC or the four units of frozen plasma. So important to keep that in mind when applying this study. A lot of these patients had an elective procedure, so about 80%. So 17% were non-elective in the PCC versus 21 in the frozen plasma. Pre-operative labs, nothing too crazy there. And then a lot of these were considered complex surgeries. So about 70% was defined by the authors as there were two or more procedures going on. And I'll get into the procedures on the next slide, but there had to be two or more for it to be considered a complex surgery. And so the procedures that they were looking at and that were most commonly seen were things like aortic valve, CABG were the two most common, and then ascending aortic, mitral valve, aortic arch, and tricuspid valve, that kind of were their six most common. There were more that were less common, but those were the most common ones. And then for IMP, that's investigation medicinal product. So that was their product in this situation. About 20% of patients in the study received a second dose of their product with PCC or frozen plasma. And then as you can see the weight-based dosing here, about 23 or 24 for the first dose for PCC units per kg. And then that frozen plasma was about 12 mLs per kg. And so if we think about the two background studies, this PCC dosing was higher than that one study that showed no difference, but the frozen plasma would be about the same. And then obviously this study does mirror the FAERS trial, that pilot study. And then our cardiopulmonary bypass duration, about 171 minutes in the PCC versus 176 in the frozen plasma. And then when we start looking at our primary outcome, so we can see our effective hemostatic response, there was a significant difference favoring the PCC group. So about 78% versus about 60%. And then when we break down the components of what was driving that difference, we can see that from surgical reopening of bleeding, there was no numeric difference, but that was it. And then when we look at need for second dose of our investigational product, there was a difference there favoring the PCC, as well as difference in platelet transfusion need, again, favoring PCC patients requiring less. There was also a difference seen in our non-investigational product PCC, where more of that was done in the frozen plasma group, which makes sense. And then also in the use of activated recombinant factor 7, again, favoring the PCC where less of that was used. So those were kind of the four big factors that drove this difference in hemostatic response. Then when we look at our secondary outcomes, so things like severe massive bleeding, six versus five events or patients, no difference there. As far as total blood product transfusions at 24 hours when we remove our investigational medicinal product, it was 6.6 versus 9.3 units. So again, favoring that PCC group requiring less blood product transfusion. Adverse tube drainage, favoring the PCC group, again, 691 mLs versus 923 mLs. And this was statistically significant both at 12 and 24 hours. Further secondary outcomes, so things like mortality, seven versus eight, again, no difference. Thrombocytotic events, eight versus 15, no difference. AKI did favor the PCC group, so about 10.8% versus 18.8%, 22 versus 39 patients, again, statistically significant there. And then serious adverse events, again, favoring the PCC group, 77 versus 98, with a p-value of 0.02. When we move into the office conclusion, based on the results of these studies, they came to the conclusion that PCC had a superior hemostatic efficacy and may have safety advantages compared to frozen plasma in patients who require coagulation factor replacement for bleeding during cardiac surgery. They also came to the conclusion that PCC may provide benefit for reducing the number of blood products required and thus reducing the exposure to blood products for our patients and the risks that potentially come with those. Moving into strengths and limitations of this study, so it was a randomized multicenter trial based in the U.S. and Canada, which, at least for my practice, I think fits well with the type of patients that I would see. They did evaluate important clinical and blood supply outcomes, so clinical outcomes, things like surgical reopening, adverse events to our patients, and blood supply outcomes, need for transfusion requirements, certainly a good thing to keep in mind, trying to limit the stress on the blood supply and the amount that's needed, those are in dire need. And then also a wide variety of cardiac surgery types, I think it's important to have that so you have a generalized ability across the cardiothoracic surgery realm. And then long cardiopulmonary bypass time, so in our potentially most sick patients, they did show this benefit here, which is great to see. However, they did have some limitations. First limitation I want to get into is this was an unblinded treatment, providers, just with the type of product you're administering, you would be aware of it, which certainly can influence whether you jump to another product sooner or later, knowing kind of what each component carries with it. They did exclude those with recent thromboecolic events. And like I did touch on earlier, this dosing was higher than previous studies. So, you know, a 23, 24 unit per kg, so slightly higher dose with the option to give a second dose. Again, that long cardiopulmonary bypass time, both being a strength and limitation, just from the fact of, you know, would this apply to patients who are not requiring cardiopulmonary bypass or require shorter time on cardiopulmonary bypass? And then I think a composite outcome also potentially limits this study because in their mind for that primary outcome, considering that surgical reopening was evaluated the same compared to any sort of transfusion, whether it was one unit of platelets transfused. So keeping that in mind as well. Overall, my takeaway from this study, I think PCCA may offer a better way to manage cardiac surgery patients by reducing the need for hemostatic interventions, as well as the burden on blood supply. It may be especially helpful in patients who cannot tolerate large volume infusions. Further investigation is needed into the cost analysis of this product and how it can be applied to more wide. And then at this time, I would not strongly be pushing for this to be used, except for in specific patients, knowing that the biggest driver of this was really our transfusion requirements and the cost analysis really hasn't been done to evaluate that. We'll move into our first polling question. So at your institution, what percentage of cardiac surgery patients receive PCC intraoperatively or within the first 24 hours of surgery? And so the majority of people voted that less than 25%, which I think fits. And I think that mostly goes along with what I see at my institution. There are some of you that were in that 25 to 50, and then a few in the more than 50 as well. And then our next slide is our second polling question here. Would you consider advocating for the use of PCC in cardiac surgery based on the current literature and in particular, based on this study's results? And the vast majority said, yes, this information opens the door for some use, but further needed for expanded use. And I think that goes along with kind of where I sit based on this information. And with that, we'll move into some questions. Thank you for your presentation, Ben. I have a question for you. So based on all of the outcomes that you saw that PCC influenced over fresh frozen plasma, do you think that there would be a cost benefit to using PCC in these patients? Knowing the cost of the blood products, I'm not sure there would be a cost, but I think it would be closer than we might think. I think it would be very close knowing that potentially having those blood products might influence where patients have to stay in the hospital, which can also rack up a cost as well. But I do still think it might favor, might be more expensive in the PCC group. All right. Thank you, Ben. That concludes our Q&A session. Before moving on to our next presenter, we would like to ask a brief polling question regarding today's attendance to gain a better understanding of our overall attendance to ensure continued support of this Spotlight on Pharmacy webcast. How many attendees are you viewing this webinar with? Is it A, is it the first one, just me? Is it two to five people, five to 10 people, or greater than 10 people? Looks like we have a lot of solo watchers today. Thank you for taking the poll. Now I'd like to introduce our second presenter, Danielle Wozniak. Hello, everyone. Thank you for joining. My name is Danielle, or Dani. I'm a PGY-2 resident, Swedish Medical Center in Seattle, Washington, and I will be discussing the CSAR randomized clinical trial, looking at inhaled sedation and acute respiratory distress syndrome. So we probably are very familiar with acute respiratory distress syndrome, or ARDS, that I will be referring to as the remainder of this presentation. We do know this is associated with high mortality rates in our patients, especially with prolonged stays in the ICU and progression of this disease state. One of our key therapies here is mechanical ventilation for facilitation of oxygenation and ventilation, and ventilator synchrony is key. Sedation is often required to maintain this synchrony, and this can progress into need for deep sedation with need of neuromuscular blockade. Looking at some of our inhaled volatile anesthetics, such as seboflurine, these have been shown to work for ICU sedation, and patients often may actually experience shorter time to awakening and a shorter length of ICU stay in mechanical ventilation. However, looking specifically at the utility in ARDS, there is a small study that did show some improved oxygenation and lower epithelial injury with seboflurine compared to midazolam. However, based on its small study size, it's often somewhat discredited if this can really be applied generally to our patients. I was looking further into its utility. Briefly, before I get into this presentation, at your institution, how frequently are volatile anesthetics used in the ICU for sedation? Routinely, occasionally, rarely, or never? It looks like people here joining us, 80% had chosen never. That also aligns with my institution here. I've never seen them be used for ICU sedation, but a couple people in the audience maybe occasionally or rarely have seen them, so that's interesting. This study was looking to determine the efficacy and safety of inhaled seboflurine compared with intravenous propofol for sedation in our patients with ARDS. This was a multi-center, phase three, open-label, assessor-blinded, randomized clinical trial, which took place from May of 2020 through October of 2023 in 37 intensive care units in France. It included a total number of 687 patients who were assigned one-to-one for sedation with seboflurine or propofol. These patients were moderate to severe ARDS, so they were in deep sedation with neuromuscular blockade for up to 48 hours, or until they had a PaO2 to FiO2 ratio of at least 115 millimeters of mercury for eight hours or more, with an FiO2 of 0.6 or lower. Patients who were in light sedation had daily awakening and spontaneous breathing trials as a standard in our ICU patients, and patients who were included were waiting for 12 hours until the onset of ARDS, including prone positioning in their treatment as well. Patients included were adults at least 18 years of age, had to be undergoing mechanical ventilation, meeting the Berlin Definition criteria for ARDS for less than 24 hours, with moderate to severe ARDS, with a PaO2 to FiO2 ratio of under 115 millimeters of mercury, and had to have a PEEP of greater than or equal to eight centimeters of water. Patients were excluded if they were pregnant, had suspected or proven intracranial hypertension, long QT syndrome, history or predisposition of malignant hyperthermia or liver disease from volatile anesthetics, hypersensitivity to seboflurine, propofol, or cystatricurium. Patients with a persistent bronchopleural fistula, or those who had mechanical ventilation needs for more than 120 hours before being enrolled in this study. So looking at inhaled seboflurine versus intravenous propofol for a sedation is our procedure here. Before we go further into this study, how comfortable would you feel with managing sedation with inhaled anesthetics like seboflurine in your intensive care unit? Would you feel comfortable? Yes? No? Possibly with some additional training? Or would you only feel comfortable with inhaled anesthetics in the ICU if it was under the management of an anesthesiologist? So it looks like 54% of people would feel comfortable with managing these in an agent like seboflurine in the ICU if they had some additional training. People here would be comfortable only if it was under the management of an anesthesiologist, and 8% of us would not feel comfortable with managing this. I think that's a fairly reasonable distribution up there. I'm not quite sure where I would fall yet. I definitely think if it was going to be implemented, I would want some additional training as well. So outcomes here in this study are primary endpoint being days alive and off of invasive mechanical ventilation from randomization through day 28, and some secondary efficacy endpoints being 90-day survival, additionally looking at mortality at 7, 14, and 28 days, and hospital mortality at 28 days after randomization. Additionally had some safety endpoints looking at changes in hemodynamic measures, acute kidney injury through day 7, new onset of supraventricular tachycardia or atrial fibrillation, severe hypercapnic acidosis with an arterial pH of less than 7.15, the development of malignant hyperthermia, propofol-related infusion syndrome, pneumothorax, or bronchoplural fistula. For statistical analysis off of the re-evaluation of systemic early neuromuscular blockade trial or the ROSE trial, they had a hypothesis of 30-35% 28-day mortality in these patients, and had a number needed, 680, to provide 80% power to detect a mean difference of two ventilator-free days at 28 days with a standard deviation of around 8. The primary analysis looked at the unadjusted modified intention to treat patients and results with the median differences in standardized hazard ratios with a 95% confidence interval. They did have two different protocol analyses that did go and further exclude patients who had some protocol violations. However, I will not be diving into this too much, just wanted to state that they included these two protocol analyses as well. Diving into our results. So sample size, they evaluated 2016 patients for inclusion and 1,316 were excluded, leaving 700 to be randomized, which got divided into 346 into the cevophorene modified intention to treat patient population and 341 into the intravenous propofol modified intention to treat patients. Pulling out some of the key demographics here in the patients, we can see a mean age of around 64, 65 years across groups, majority being male gender, BMI around 28. Most patients having one day time from ICU and admission to being randomized into the study. And then our two main causes of lung injury being pneumonia or COVID-19. And wanting to just state there was some overlap between these patients and what the study also called COVID-19 pneumonia. So a bit of overlay between those two causes of lung injury. Additionally, a large percentage around 74% of patients needed some sort of vasopressor ionotropic support before being randomized in here. Around 80% were on antibiotic therapy. Around 65% of patients on corticosteroid therapy. Majority of patients needing high flow oxygenation before intubation. Looking at the PAO2 to FIO2 ratio before randomization being 111 in the inhaled cevophorene group compared to 107 in the intravenous propofol group. Both patient populations being tachypneic with a respiratory rate of around 26. And some patients were in prone positioning prior to randomization, however, was not common in the majority of patients. Now looking at our primary outcome here, again, days alive and off of mechanical ventilation from randomization through day 28. So you can see in the inhaled cevophorene group, our median being zero days, ranging from zero to 11.9 days. And our intravenous propofol group being a median of zero days, ranging from zero to 18.7 days. So a little bit difficult to see what that really looks like in this chart form. We can see here, when we are looking at this bar graph, that zero day line being incredibly high in both groups, in our cevophorene and our propofol group, because this outcome looks at days alive and off of mechanical ventilation. So if patients deceased during this trial, they were counted as zero days. And if patients were mechanically ventilated for longer than 28 days, they were also counted as zero days. Looking at our secondary endpoints here, so the key secondary endpoint looking at death at 90 days, fairly consistent, our cevophorene group around 52.9% compared to the propofol group being 44.3%. You can see this trend similarly in the mortality at 28, 14, and 7 days as well, just slightly higher in the inhaled cevophorene group percentage. And then looking at ICU-free days through day 28, we can see median zero days in both groups. However, we do see a larger range of ICU-free days in the propofol group, ranging from zero to 15, compared to cevofluorine being ranging from zero to six days. Looking at safety endpoints, the only thing really significant to point out, a lower rate of AKI in our propofol group at day seven. But pulling in specifically to this graphic from this study, focusing first on this bottom red box. So acute kidney injury, we can see no acute kidney injury is more common in our intravenous propofol group with 42% compared to only 31.8% in the inhaled cevofluorine being without acute kidney injury. And then we additionally can see the dose of norepinephrine or epinephrine in the cevofluorine group being higher than our patients on the propofol group, which I think is quite interesting since you usually think of propofol being a sedative agent that affects our blood pressure. So I would expect almost to see higher needs of vasopressor support in propofol compared to cevofluorine. So interesting to see that here as well. Now from this study, some of its strengths, this had a large sample size. They met their need of 680 patients for power detection. They were evenly matched with that one-to-one matching with not very many patient characteristics really deviating from either group. And they did maintain their sedation targets throughout the duration of this study. However, dosing of the corticosteroids was not included that I think it would be interesting to know if that varied between patients as well as the additional dose and frequency of additional analgose sedation was not collected for these patients. The prominent cause of ARDS in these patients was COVID-19 and that COVID-19 pneumonia overlay, which may be difficult to obviously be really applicable to other patient populations outside of that. This makes sense for the time being during the COVID-19 pandemic. And then I do think that including patients who are deceased as a zero ventilator free day may have skewed some of that data. And I am quite interested of what that might have looked like if patients who deceased during the study were excluded and how that might change the outcomes from this study. However, it was not reported in that manner. So then looking here at the use of sedatives within the first week after randomization, I really think this helps visually see that yes, even though both groups were able to maintain their sedation targets, we can see in the seboflurine group on the left, especially at days six and seven, they have a much higher number of patients with additional agents being used. And that most common agent is propofol with those vertical striped lines. Comparing this to the propofol group on the right, that yes, there was additional need for other agents, but it is less frequently seen in the number of patients. From the study, our patient populations were evenly matched and did have a sample size to meet the predetermined power. However, inhaled seboflurine resulted in fewer ventilator free days at 28 days and a lower survival at 90 days compared to the intravenous propofol group. There was an increased rate of AKI as well as the seboflurine treatment group. And I do think that this primary endpoint may be skewed by including these deceased patients in the zero ventilator free days group, but ultimately there's no way of knowing what this looks like if these patients are removed. As to how we can apply this to our current practice, I do think that there may be room for inhaled anesthetics for utility in ICU sedation. However, when we're looking specifically at our ARDS patients, I would not recommend for the use of inhaled seboflurine over our agents that were more commonly used, such as intravenous propofol from the outcomes of this study. Some of my references included here. And thank you for joining and listening to me. What questions may you all have? Great job, Danielle. Thank you. If you were to redesign this study, what would you do differently? Yeah, a great question. So I do think that the inclusion data for these patients, inclusion and exclusion, I would keep fairly consistent. However, I do think one of the biggest limitations in this study that I get a little bit held up on is that they had patients included as zero ventilator free days with the phrasing of their primary outcome being days alive and off of mechanical ventilation. I do think it would be more interesting to see maybe those results separately. They did account for mortality in multiple different endpoints. But if we're looking at this agent being used, I would be intrigued to see what it actually looks like in patients who survived that duration. So I think my biggest change would be to sort of remove the, not inconsistency, but that result there that I think really does sort of blur our outcomes with the high mortality rate of these patients and see what that looks like when the number of patients who deceased within the 28-day study period are removed and how that might affect the numbers in this case. Awesome. Thank you so much. That'll conclude our Q&A session. Thank you, Danielle. I'd now like to introduce our final presenter, Deanna Ferrella. All right. Hi, everyone. Thank you for that introduction, Caitlin. So again, my name is Deanna Ferrella. I am PGY-2 Critical Care Pharmacy resident at Yale New Haven Hospital. And today, I will be presenting on comparing the hemodynamic effects of ketamine versus fentanyl bolus in patients with septic shock. For some brief background here, we all know that patients with septic shock present with decreased systemic vascular resistance. So in these patients, it's really imperative that we maintain the role of cardiac output for oxygen delivery. So in these patients with a decreased systemic vascular resistance, we really need to increase our cardiac output in order to maintain an adequate blood pressure. Looking very briefly at ketamine, ketamine is a noncompetitive NMDA receptor antagonist that blocks glutamate, which causes sedation. And importantly, ketamine is characterized by cardiovascular stimulatory effect due to release of endogenous catecholamines. So potentially, mechanistically, ketamine can increase cardiac output. When looking at some of our previous data here, a lot of data on ketamine is looking at boluses in response to RSI. So our first study here was a prospective observational study looking at systolic blood pressure in response to ketamine bolus. And what they found was that in patients with a low shock index, they had an increased systolic blood pressure in response to ketamine bolus. And for those with a high shock index, they had an unchanged systolic blood pressure and potentially were more hypotensive than not getting ketamine. Our next study here is a retrospective cohort study that wanted to compare the incidence of hypotension between ketamine and etomidate after endotracheal intubation. And what they found here was that hypotension was less prevalent in the ketamine group. The next study, again, is another retrospective study that wanted to evaluate the association between our sedative dose adjustment and post-intubation hypotension. And they looked at multiple different doses of ketamine here. But really, what they found was that at both high and low dose ketamine, it was not related to post-intubation hypotension. And finally, our last study here was an observational cohort study that wanted to compare the adverse effects between etomidate and ketamine and sepsis. And what they found was a higher post-intubation hypotension in the ketamine group. So really, all of this previous data is to say that there's variable effect of ketamine on hemodynamics, really highlighting the need for a randomized controlled clinical trial to look at the effect of ketamine on hemodynamics and determine if it can actually increase the solid blood pressure and potentially cardiac output, which then brings me to our study today, which is published in the Journal of Anesthesia titled Comparing Hemodynamic Effects of Ketamine versus Fentanyl Bolus in Patients with Septic Shock. The primary objective of this study was, again, to evaluate the effect of ketamine versus fentanyl on cardiac output in patients presenting with septic shock. This was a randomized controlled trial, randomized double-blinded controlled trial at a single center. Patients were included if they were over the age of 18 presenting with septic shock requiring vasopressors to maintain a mean artillery pressure of over 65 despite adequate fluid therapy and a lactate of over 2. All patients were mechanically ventilated and required a bolus of sedative to resume sedation after a period of sedation vacation. And notably here, our patients were enrolled after the resuscitative phase of septic shock management, so patients after they were recognized to have shock, after they had achieved euphelemia, and after they had achieved a stable dose of vasopressors. And they note here that patients were evaluated for fluid responsiveness and hypovolemia according to the surviving sepsis guidelines via our dynamic measures of fluid responsiveness. Patients were excluded if they were hemodynamically unstable, so if they had a map of less than 65 despite appropriate volume replacement and pressors. If they required low-dose pressors to a norepinephrine rate of less than 0.05, if they had a poor cardiac window on ultrasound, which would, of course, confound our primary endpoint of cardiac output, if they had an allergy to a drug, increased ICP, or if they were pregnant. Patients were randomized in a one-to-one fashion to receive either a ketamine bolus of 1 milligram per kilo or fentanyl bolus of 1 microgram per kilo. And notably, as I said prior, all patients have received a sedation vacation. So the study defined this as an interruption of ongoing sedation where patients were then assessed for wakefulness. So patients had a RAS of greater than minus 1 with the ability to obey simple commands. They noted that when it was time to resume sedation per provider discretion, patients received a bolus of the study drug with a target RAS of minus 2 to 0. I think it's interesting that this study looked at time to resume sedation per provider discretion. I know typically, at my institution, we would look at the RAS score to determine if a sedative is needed. And this was just determined the bedside based on provider discretion. When looking at our endpoints, our primary endpoint was the delta cardiac output six minutes after drug administration. And they also looked at your left ventricular outflow diameter, velocity time integral, and other hemodynamic markers, such as cardiac output at 3, 6, 10, and 15 minutes, stroke volume, heart rate, mean artillery pressure, and then incidence of post-induction hypotension, so hypotension in response to these sedative boluses. They noted here that this hypotension was further defined as a mean artillery pressure of less than 65, and patients then had to be managed by increasing the norepinephrine rate by 50%. In terms of our statistical analysis, categorical data was analyzed via frequency and percent, and a chi-squared test. Continuous data was presented as a mean standard deviation or median quartiles, and then analyzed via a student's t-test or a Mad-Whitney test. They utilized a p-value of less than 0.05 for statistical significance. And in their sample size calculation, they noted that they needed a number of 72 for a study power of 80% to detect a difference in 10% delta cardiac output. So moving in here to our patients, you'll notice that 95 patients were assessed for eligibility, of which 86 were randomized in a one-to-one fashion to ketamine or fentanyl. So we ended up with 43 patients in each group. And all patients in either group had both received the intervention, none had discontinued the intervention, and all were included in the final analysis. When looking into our baseline characteristics here, you'll see that largely the two groups are very similar in our baseline characteristics. Our median age was around 60 years old, and patients were appropriately split between male and female gender. When looking at our comorbidities here, you'll see that there's quite few comorbidities listed for these patients. Most commonly, about a third patients in each group had hypertension, and about 50% of patients in each group had diabetes. But interestingly, prior to sepsis, a lot of these patients didn't have many baseline comorbidities. So potentially, this population might be a little less sick than the typical patient I might see in my hospital presenting with septic shock. When looking here again at our baseline characteristics, most patients were sedated with fentanyl prior to randomization in this study, at a median rate of 50 micrograms per hour, which is similar between the groups. All patients here were noted to be on a norepinephrine rate of 0.3. And I think this is interesting. We know in septic shock, norepinephrine is our first-line vasopressor, so it's great that this was included. But they didn't comment on which, if any other, vasopressors patients were on. So potentially, at a rate of norepinephrine, patients come vasopressin. And additionally, the study didn't comment on if patients were treated with streptosteroids as well. So unclear, really, if patients were ultimately being treated for septic shock, but we do know that their baseline norepinephrine rate was 0.3. Our baseline SOFA score here was four in each group, which again, is quite a low SOFA score, potentially a little lower than the septic shock patient I might see at my institution. So a lot of these patients probably didn't yet have multi-organ failure when included in this study. Our baseline mean arterial pressure in the group was 88 and 87 in either group, which again, is quite high above our goal of 65. So it might lead me to believe that maybe patients could have tolerated lower pressor doses than a norepinephrine rate of 0.3. And interestingly, while not significantly different in terms of heart rate, stroke volume, and cardiac output, you'll notice that the stroke volume and cardiac output is numerically lower in the ketamine group versus the fentanyl group to begin with. And our cardiac output was not low in either group to begin with either. It was about 6.3 and 7 in either group. Further moving on to our primary outcome, which is the delta cardiac output at six minutes, you'll see that ketamine had a positive delta cardiac output and fentanyl had a negative cardiac output at every time point that was analyzed in this study. However, when we look at our post-induction hypotension, while fentanyl resulted in a negative delta cardiac output, this didn't translate into a significantly increased amount of hypotension in the group. Looking here at some of our figures from the trial, again, you'll see that at every time point that was analyzed at 3, 6, 10, and 15 minutes, ketamine had a significantly higher cardiac output and fentanyl resulted in a decreased cardiac output. But again, cardiac output here never really dipped below 4 in either group. So patients never became compromised. When looking at our stroke volume, again, very similar to our cardiac output, stroke volume was increased in the ketamine group at all time points and decreased in the fentanyl time group at all time points. And interestingly here, we have the RAS or sedation scores for both of our groups here. So you'll notice that our patients here, when they were bolus with ketamine or fentanyl, they had a RAS score of around plus one. And throughout each time point in this study, the RAS score was similar between the groups. So while potentially ketamine may have had a more favorable hemodynamic effect, both of these agents did provide similar and adequate sedation throughout the observation period. So looking into some of our strengths and limitations of this study, I think some of our major strengths is the randomized design of this study. And additionally, excluding those with low norepinephrine requirements. I think this is interesting because for patients who might be transiently on vasopressors, the hemodynamic effect is probably not as important as preserving in those requiring high-dose vasopressors. So I like that they had excluded those with norepinephrine of less than 0.05. Other strengths of this study include that they met power with their sample size calculation. And I do agree with all their inclusion criteria. It seems that they really had lined up with our surviving sepsis guidelines in terms of success for fluid responsiveness and vasopressors to maintain a MAP of over 65. In terms of limitations, I do think there are some significant ones to this study. First of which being that this is a single center study limiting our generalizability. Additionally, our primary outcome here was not a clinical outcome. The study here looked at cardiac output. We can't really tell if this will translate into better clinical outcomes, like decreased PRESSA requirements, decreased days on the vent, decreased ICU length of stay, or even mortality. Another limitation here is that the need for a bolus sedative was at the provider's discretion. So it leads me to wonder if patients even needed a bolus of sedative at all. Some patients can kind of hang out around a RAS of 0 to plus 1 without sedatives. Additionally, the study analyzed bolus-dosed sedatives but not continuous infusion. So we know that ketamine increased cardiac output over a 15-minute time frame. But it's unclear through just this study alone if this would be sustained through multiple hours on a continuous infusion. And again, thinking back to the applicability of our patient population, I think with the mean SOFA score of 4, not too many comorbidities in the group, I think it might not be as applicable to the typical patient I might see with septic shock at my institution. And then moving in here to our conclusion and takeaways, the authors concluded that in patients with septic shock, ketamine produced a higher cardiac output and stroke volume compared to fentanyl bolus with no difference in our actual RAS score. In terms of my takeaways, I think both groups provided similar sedation and ketamine did have significantly more favorable hemodynamic profile. I think the study does have limited generalizability and a lack of clinical efficacy endpoints, which I really would be looking for to further use in our studies. I think future directions from this include more large-scale randomized controlled trials looking at ketamine for both septic shock and other disease states. I do think that potentially ketamine can be utilized in these patients. So my first polling question here is, how is ketamine currently utilized at your institution? Is ketamine used as a first-line sedative, ketamine is used as a second- or third-line sedative, or ketamine is not used as a sedative at your institution? So it seems that most participants here note that ketamine is used as a second- or third-line sedative or not used at all as a sedative. And no one responded that ketamine was used as a first-line sedative, which, again, I think is in line with how ketamine is utilized at my institution as well. And for my second polling question, how will the findings of this study influence your recommendation for the use of ketamine as a sedative for septic shock? Would you increase the use of ketamine, decrease the use of ketamine, or no change in your use of ketamine? So it looks like some participants noted increase in the use of their ketamine, a majority of participants noted no change in their use of ketamine. And that's a conclusion that I would agree with based on the data presented here. And I do think it's interesting that ketamine did result in an increased cardiac output, but I don't think from this trial we can definitively make a conclusion that it's better than other sedatives or that we should be using it more often than we currently are. And with that, I will take any questions from the audience at this time. Great job, Deanna. Do you think that ketamine should be favored in this settings, or do you think that there are patients whom fentanyl might still be better for? Yeah, I think that in the majority of patients, fentanyl might still be better, potentially in patients that I'm more concerned about a decreased cardiac output in. But again, I don't find this data to be as compelling to be recommending ketamine as a first-line sedative. I probably would still reach for fentanyl in a majority of my patients as a first-line sedative as opposed to ketamine. Thank you very much. That concludes our Q&A session. Thank you, Deanna. 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 for the next Journal Club Spotlight on Pharmacy. That's going to conclude our presentation for today.

Webcast

Pharmacology

Pulmonary

Sepsis

Analgesia and Sedation

Anticoagulation

Shock

2025

Professional

Select

critical care pharmacy

prothrombin complex concentrate

cardiac surgery

inhaled sedation

acute respiratory distress syndrome

ketamine

septic shock

clinical trials