Hello, everyone, and welcome to today's Journal Club, the Spotlight on Pharmacy webcast, which is supported by the Society of Critical Care Medicine's CPP section. My name is Russ Roberts. I'm currently a clinical pharmacy manager at Massachusetts General Hospital, and I'll be today's moderator for the webcast. A recording of this webcast will be available to registered attendees. You can log into mysccm.org and navigate to the My Learning tab to access the recording. Thanks for joining us. There's a few housekeeping items before we get started. So there will be a Q&A session after each of today's speakers, and I'll moderate that. To submit questions, which I highly encourage, throughout the presentation, type it into the question box located on your control panel. I hope this will be very interactive. You will also have the opportunity to participate in several interactive polls from the speakers. When you see a poll, simply click the bubble next to your choice. In terms of the disclaimer, SCCM does provide the following disclaimer that I will read to you. This presentation is for educational purposes only. The material presented is intended to represent an approach, view, statement, or opinion of the presenter, which may be helpful to others. The views and opinions expressed herein are those of the presenters and do not necessarily reflect the opinions and views of SCCM. SCCM does not recommend or endorse any specific test, position, product, procedure, opinion, or other information that may be mentioned. And now, I'd like to introduce your speakers for today. Each one will give a 15-minute presentation, again, followed by, hopefully, an interactive Q&A session. Our first presenter today is Olivia Esqueros, who is the current PGY-2 critical care resident at NYU Langone Health in New York. Our second presenter is Nick Vollmer, who is the current PGY-2 critical care resident at Mayo Clinic Hospital in Rochester, Minnesota. And our third presenter is Liliana Gonzalez, who is the current PGY-2 critical care resident at UC Health Memorial Hospital in Colorado Springs, Colorado. And now, it's my pleasure to turn things over to our first presenter. Hi, everyone. My name is Olivia. For this journal club, we'll be discussing the MENDS-2 trial. And my presentation is titled, Mending Sedation Perceptions. I have no disclosures or conflicts. Over the course of this presentation, we'll review the current sedation guideline recommendations, describe the pharmacology of dexmedetomidine, evaluate and critique the MENDS-2 trial, and identify potential practice changes and areas for future research. Currently, best practices for sedation, according to the 2018 PADIS guidelines, favor light sedation and utilization of a non-benzodiazepine sedative with either propofol or dexmedetomidine. But when choosing between these agents, there is limited high-quality evidence to make one agent preferred over the other. So, let's take a look at some of the prior literature comparing the two agents. So, this first RCT by Herr and colleagues compared dexmedetomidine to propofol in 295 patients undergoing CABG. There was no difference found in their primary outcome of time to extubation. And opioid requirements were significantly lower in the dexmedetomidine group, with only 28% requiring use of morphine, compared to 69% in the propofol group. The next study we'll discuss is the PRODEX trial. It looked at ICU patients requiring light to moderate sedation while on mechanical ventilation for greater than 24 hours. The median propofol dose was 28 mics per kilo per minute, and the median dexmedetomidine dose was 0.9 mics per kilo per hour. One of the secondary outcomes that they investigated was the patient's ability to communicate pain, which was significantly better in the dexmedetomidine group. However, although these patients were better able to communicate their pain, there was no difference in their fentanyl requirements overall. The PRODEX trial also showed that there was no difference in duration of ICU stay, a median of 7 v. 8 days, or duration of mechanical ventilation, a median of 4 v. 5 days. This last RCT compared dexmedetomidine, propofol, and midazolam when used as short-term sedation in post-operative mechanically ventilated neurosurgical patients. This trial was a little bit smaller, with 30 patients in each group. And overall, there was no difference in duration of mechanical ventilation. The trial had the fastest time to extubation, and dexmedetomidine use resulted in significantly lower post-operative fentanyl use. One important principle of sedation is analgo-sedation. However, evidence is lacking on the role of opioid infusion. There is a general consensus on the appropriate use of opioids in the ICU, in that infusions should be used for baseline pain, frequent boluses should be used for intermittent pain, and infusions should not be up-pitrated for agitation or for delirium. However, how often are we adhering to these principles, and are opioid infusions even necessary? So, Enzuida and colleagues looked at 75 ICU patients weaning from mechanical ventilation with P-O methadone, after being on at least five consecutive days of fentanyl. The methadone group had more successful weans by day five, and also had a significantly shorter wean time. Overall, methadone led to faster weaning time from mechanical ventilation, and this potentially implied that fentanyl infusions can delay weaning from mechanical ventilation. Straum and colleagues looked at 40 ICU patients requiring mechanical ventilation and compared a no-sedation versus sedation strategy. The group with sedation had a shorter duration of, sorry, without sedation, had a shorter duration of mechanical ventilation, ICU, and hospital length of stay. They concluded that it's possible to manage mechanically ventilated patients with low doses of opioids without sedation. So, this brings us to our first polling question. Are opioid infusions required for all critically ill mechanically ventilated patients with sepsis? Okay, so looks like no one answered the poll. 93% said no, and then I guess the other 7% were yes. Okay, so just quickly to review before going into our trial, we should talk about the effects of dexmedetomidine that they may have in sepsis. So based on some animal studies and sepsis models, there's some evidence that dexmedetomidine may inhibit inflammation, enhance the activity of the immune system, and also reduce its systemic reaction by lowering cytokine concentrations. It also plays a neuroprotective role by inhibiting apoptotic pathways and promoting biomimetic sleep. All of these effects could theoretically improve clinical outcomes, particularly in patients with sepsis. So based on this discussion of the prior literature and the most recent PADIS guidelines, the current gaps in the literature regarding choice of sedatives are listed here for your reference. So with that, it brings us to our Journal Club article. The objectives of the MENS 2 trial was to answer the question, does dexmedetomidine lead to better short-term and long-term outcomes than propofol and mechanically ventilated adulthood sepsis? This was a double-blind, randomized controlled trial across 13 centers in the U.S. They enrolled patients between May 2013 and December 2018. Follow-up was at 14 days for their primary outcome and up to six months for their secondary outcome. They included all adult patients who were sequentially admitted to medical or surgical ICUs who had a suspected or known infection and were treated with continuous sedation for invasive mechanical ventilation. They had 10 exclusion criteria overall, but of note, they excluded patients with baseline cognitive impairment, if they had anticipated immediate discontinuation of their mechanical ventilation, the neuromuscular blockade for greater than 48 hours, or if they were mechanically ventilated for more than 96 hours before inclusion. Overall, 4,800 patients were screened, 4,400 were excluded, and 432 patients got randomized in a one-to-one ratio to dexmedetomidine or propofol, and patients were stratified based on their enrollment site and age. In terms of the sedation protocol, the concentrations of the trial drugs were prepared so that the same infusion rate resulted in similar sedative effects. The bedside nurses titrated the study drug infusion rate every 10 minutes to the goal sedation level based on the patient's weight. The rescue sedation protocol indicated that if patients were under-sedated while on the maximum study drug dose, then intermittent opioids should be used or fentanyl infusion should be increased. The primary outcome was the number of days alive without delirium or coma during the 14-day intervention period. Secondary outcomes included ventilator-free days at 28 days, death at 90 days, and global cognition at six months. They had a slightly slower-than-anticipated enrollment, so they adjusted to have a power of 85 percent for their primary outcome, and they had 80 percent power for their secondary outcome. For their outcome analysis, they used a modified intention-to-treat analysis, and for outcomes, they used a proportional odds logistic regression and cost-proportional hazard regression. So, overall, 432 patients were randomized, with 214 in the dexmedetomidine group and 208 in the propofol group. At six months follow-up, there was 106 in the dexmedetomidine group and 101 in the propofol group. Regarding their baseline characteristics, the median age of patients in the study was 60 years old. They were predominantly white, and the source of infection was mainly blood and lungs. In terms of severity of illness, median APACHE-2 scores were 27, and about 50 percent of the patients were in shock or requiring vasopressors. They were on mechanical ventilation for about a day prior to their enrollment, and there was a high baseline level of delirium of about 40 percent. Prior to enrollment, most patients were between a light and coma level of sedation, and the choice of sedatives comprised predominantly of propofol at 60 percent, compared with only around 15 percent of patients using dexmedetomidine. Seventy percent of the patients had opioid use prior to their enrollment. The trial drug was initiated a median of 22 hours after patients met inclusion criteria. They received fairly low median doses of the trial drugs for a short duration, 0.27 mikes per kilo per hour of dexmedetomidine for a median of three days, compared with 10.2 mikes per kilo per minute of propofol for a median of four days. In terms of supplementation of the sedation regimens, they had low off-label use of each trial drug in the two groups. They did, however, have a high daily fentanyl dose of 68 mikes per hour in the dexmedetomidine group and 56 mikes per hour in the propofol group. In both groups, they only received about 4 milligrams of midazolam per day. They had good protocol adherence overall. Patients were at their target sedation level 60 percent of the time that they were on the trial drug. In terms of their primary outcome, there was no difference of days alive without delirium or coma at 14 days, and it was about 11 days for both groups. There was also no difference found in their secondary outcome of ventilator-free days at 28 days, which was about 24 days in each group. There was no difference found in mortality at 90 days, which was 40 percent, and of no at 15 days, they did have a mortality rate of 30 percent. There was no difference in their global cognition at six months between the two groups. And regarding the safety, there was no difference between the groups in organ dysfunction, hypotension, severe lactic acidosis, or symptomatic bradycardia. The propofol group had less self-extubation and higher triglycerides that led to eight discontinuations. The dexmedetomidine group had less ARDS and signs of trial drug withdrawal. So, overall, for the authors' conclusions, they concluded that among critically ill adults with sepsis, dexmedetomidine did not lead to better outcomes than propofol with respect to their predefined outcome. In terms of my critique related to the design, I thought it was good that it was a multicenter study and that, except for the bedside nurse, it was blinded. However, there was slower than anticipated enrollment and strict exclusion criteria, which could have potentially impacted their generalizability. In terms of the methods, it was great that they allowed clinicians to set sedation targets. They achieved good separation between the groups regarding sedative exposure. They targeted a light level of sedation. The protocol tried to limit concomitant sedation and analgesia. Their rescue protocol incorporated low-dose antipsychotics, and they also used a validated scoring test for their six-month cognitive evaluation. I believe the primary outcome was chosen appropriately, given that it's in line with the first men's trial, and it would also help answering their study question. However, I think with the duration of time on the study drug being so short, the 14-day period for the primary outcome may not have been ideal for interpreting these results. As an alternative primary outcome, it could have been time to extubation or duration of mechanical ventilation. A few limitations of the methods were that they used fentanyl as the first line for rescue sedation. They had cross-contamination of sedative use, although it was lower than in previous trials, and they performed every 10-minute titration for the trial drugs, which may not have been ideal for a drug like dexmedetomidine. Regarding their results, they had a high rate of follow-up for those who were eligible, which was a strength. However, there are several limitations to note with some of the results, the first being that the trial drug was started about a day after patients met inclusion criteria. They also had very low doses and short durations of the study drug, in addition to high doses of fentanyl, although a percentage of the population of fentanyl was not given. These limitations make it difficult to attribute the results of the trial to these study drugs. Additionally, they had low prior use of dexmedetomidine and high rates of delirium at baseline. Lastly, there was a high mortality rate at 15 days, which may impact the assessment of some of the secondary outcomes. So, this brings us to our second polling question. Will the results of the study change your practice regarding sedation? Okay, so 98% said no, so it's higher than expected. And lastly, I think we have one more polling question. So, are the doses of sedation used in your clinical practice lower, the same, or higher than this study? Okay, so I think it looks like lower was 15%, same had 28% and higher 58%. So it looks like about 60% of the viewers have used higher doses than in this study. All right, so the results of this trial have definitely enhanced our understanding of propofol versus dexmedetomidine. At NYU specifically, we already have a multimodal approach to sedation and monitor RAF and CAM-ICU throughout the day. The doses and duration of mechanical ventilation that we see specifically in our patient population varies greatly from those reported in this study. So overall, I don't think our practices will change as a result of this study. In conclusion, prior literature supports the use of either propofol or dexmedetomidine. And this present study showed us that among a heterogeneous critically ill patient population with suspected sepsis, as an adjunct to fentanyl infusion, low dose propofol and dexmedetomidine have similar safety and efficacy profiles. Future studies are needed to be done to investigate sedation regimens with higher doses and longer duration of the study drug. I'm also looking forward to and I'm excited to see the examination of the pro and anti-inflammatory cytokine differences between the two sedative agents. And this trial will report them out separately. So with that, I'll conclude my presentation. Thank you for your time. I'll now open it up for any questions or discussion. Thank you. So our first question comes from the audience. How will this study apply to patients who require deeper levels of sedation? I think especially given that about, at least on initial presentation, 36% of patients in both groups had a RAS, negative four, negative five, or coma, although we don't know why they need to achieve that. Yeah, so that's a good question. So I'm not sure if because we had such low doses of the sedative agents within this trial, it's unclear if these results can be extrapolated to patients that require deeper levels of sedation, say if they're neuromuscularly blockaded. And so I think that's why some future studies would be necessary to try and see if there's any difference between the two agents if they had longer durations on the trial drug or if they used higher doses to kind of get that deeper level of sedation. Our next question is, do any of the differences in adverse effects observed between the agents leading to select Propofol versus Dexmed in a specific patient population? So based on the side effects that they reported, there was no really difference in hypotension or bradycardia, but we do see those kind of effects with some of the drugs. So I think still based on the clinical factors and patient-specific factors, there is some benefit to choosing one drug over the other. The Dexmedetomidine group did have less ARDS present, so maybe more in our COVID population that we're seeing now, it would be favorable to have Presidex on board. However, they usually require deeper levels of sedation as well. So it's unclear maybe the placement therapy for that, but they didn't find a lot of differences between the side effects profile in general. And as our last question, I'll piggyback off that. And you talked about the effects of Dexmedetomidine earlier during sepsis, but I didn't notice there was anything about temperature dysregulation. So I'm wondering what your stance is now with some of the emerging temp dysregulation data out there of propofol versus Dex, and does that change your decision? So for temperature regulation, I'm not sure about the current data about temperature regulation regarding Dexmedetomidine and propofol, but I do know that Dexmedetomidine is thought to decrease some heat injury capabilities and have kind of more effects in the cardiovascular system that way. And so I'm not sure if something like that would be a benefit in patients with sepsis if they're having fevers or overall more cytokine response that was kind of making them more hypermetabolic. It could have some benefit in that. I'm interested to see the data that they release later on about the cytokine levels and concentrations between these two agents. From the data that I looked at previously between propofol and Dexmedetomidine, I didn't see a lot of differences other than animal studies between these two agents and some of their effects on systems during sepsis. Well, thank you. So this concludes our Q&A session for this first presentation. So thank you again, Olivia Ascaris, for giving this awesome presentation. Now I'd like to introduce our second presenter, Nick Vollmer. Good afternoon, everyone. Thank you so much for having me. Over the last year, COVID-19 has swept across both the country and the nation with over 122 million cases worldwide and 2.69 million deaths. With this, clinicians, healthcare personnel, and researchers have tried to find ways to find interventions that may impact the outcomes of these critically ill patients with COVID-19. One such category of medications includes the interleukin-6 receptor antagonists. With numerous studies coming out showing potentially benefit, no change in outcomes, or even possibly harm. Recently though, in the New England Journal of Medicine, the interleukin-6 receptor antagonists in critically ill patients with COVID-19, also known as REMAP-CAP, was published that might help answer some of these questions. As Russ mentioned, my name is Nick Vollmer. I am the PGY-2 in Critical Care at Rochester, Minnesota at the Mayo Clinic. And today we're gonna be talking a little bit about the REMAP-CAP trial. But before we jump into the trial, I wanted to first start and see from the audience, which IL-6 receptor antagonist or antagonists does your institution utilize? Whether it be tocilizumab, serolumab, both, or none. So pretty much what I had expected here, and it's pretty similar to what I see in my clinical practice, with the majority being tocilizumab, not very much serolumab or both, and a little bit being none right now. And I think that this landscape is actively changing for use in IL-6 receptor antagonists in COVID-19. So I think most of us are familiar with this graph of the course of COVID-19, with the Y-axis representing severity of illness compared to the X-axis being time, and the red line through the middle representing a patient's clinical course. COVID-19 is typically represented by an acute profound viral response, which slowly kind of weans off over time and is replaced by a host inflammatory phase. And it's around this time as the host inflammatory phase is ramping up that the severity of illness of patients typically also starts to ramp up. Previous trials looking at things like remdesivir, corticosteroids have shown benefit, and I've actually shown a higher benefit or effect when used at certain time points in this clinical course of COVID-19, specifically as that host inflammatory phase is ramping up. So where does interleukin-6 fit into this picture? As we know, interleukin-6 is a cytokine released as an acute phase reactant, and it actually stimulates inflammation. So the concept being, if we can use an interleukin-6 receptor antagonist to kind of stop the inflammation and thus blunt the host inflammatory phase, can we reduce the overall negative sequelae from COVID-19 in these patients? That being said, previous literature up to this point has been mixed, and overall relatively negative, I would say. I listed out three major trials here looking at interleukin-6 receptor antagonists in COVID-19. However, there are plenty more out there as well. The first trial being the IMPACTA trial in which the population had no mechanically ventilated patients, and their outcomes found in the composite outcome of mechanical ventilation and mortality at day 28 that it was statistically significantly lower in favor of the interleukin-6 receptor antagonists. However, when they looked at the individual outcomes like overall mortality on its own, that significance was lost. The second trial being the COVACTA trial which 38% of patients were mechanically ventilated only found a statistically significant outcome of shorter time to hospital discharge with no other impacts on clinically relevant outcomes like mortality at day 28. And the last trial also recently published was the RECOVERY trial in which 14% of patients were mechanically ventilated but specifically looked at patients with hypoxia and elevated CRPs and found that the interleukin-6 receptor antagonists overall had lower mortality and a higher proportion of patients discharged alive at 28 days. So you can already see from these three trials alone that there's a lot of mixed signals or responses and outcomes coming from the interleukin-6 receptor antagonists, I think leaving a lot of clinicians wondering where does it fit in my care or my arsenal of regiments for patients with COVID-19 and how do I best use it? Thus leading to the question of the REMAP-CAP study which was do the interleukin-6 receptor antagonists specifically tocilizumab and sirulumab impact survival and organ support in critically ill patients with COVID-19? Now this study was pretty innovative and unique in its design as it was an international open-label adaptive platform trial. Whether being international is 113 sites in six different countries all around the world. It was this adaptive platform trial similar to the recovery trial if you're familiar with that design. From April 19th which is what the first date that a patient received tocilizumab through November 19th of 2020 which is when it closed because they met their predefined efficacy endpoint. Now patients in this study were randomly assigned to one intervention in each domain. So with its adaptive platform trial style or methodology basically patients would get randomized to interventions within each of these unique domains. And so this domain being reported as the immune modulation therapy domain whereas other domains could include antiviral therapy, corticosteroid therapy to name a few. To be included in this study patients had to be adults with clinically suspected or confirmed COVID-19 admitted to the ICU receiving either respiratory or cardiovascular organ support defined as invasive or non-invasive mechanical ventilation underneath non-invasive mechanical ventilation included high flow nasal cannula at a rate of 30 liters per minute with an FiO2 greater than 0.4. Cardiovascular organ support was defined as the necessity of an intravenous infusion of vasopressors or inotropes. Additionally patients had to be enrolled within 24 hours of admission to the intensive care unit. Exclusion criteria included imminent death as described by the treating clinician, hospitalized for greater than or equal to 14 days with COVID-19 symptoms or an ALT-AST greater than five times the upper limit of normal or platelet count less than 50. Of note this is not an all exhaustive list of the exclusion criteria for this trial and additional exclusion criteria can be found in the supplementary appendix. In this study or the immune modulation therapy domain of the REMAP-CAP study patients could be randomized to one of five different interventions. Tocilizumab, Sirulumab, Control and Akinra or Interferon Beta-1a. Now you'll note that the top three are in red as we only have results or data back on these three specifically as Anakinra and Interferon Beta-1a have not met their primary efficacy endpoint and thus the data is not yet available for them. And so we only can talk to Tocilizumab, Sirulumab compared to Control. The primary outcome was a composite of number of respiratory and cardiovascular organ support free days up to day 21 or patients could have any ordinal number from negative one up to 21 with negative one indicating mortality or death and a clinically significant difference was a minimum of 1.5 days difference. Secondary outcomes included hospital mortality, 90 day survival, respiratory or cardiovascular support free days and then time to hospital or ICU discharge. The statistical analysis of this trial is rather complex but I think appropriate for the design of the study. They utilized the Bayesian cumulative logistic model adjusted for location, age, sex and time period. And furthermore, they had predefined statistical criteria which was determined to define the trial conclusion. So how this basically worked in practice was they had numerous different statistical outcomes that they were checking every month at interim analysis analyses and if they met that, they would stop the trial and then report the results. And so that's why we have the Tocilizumab and Sirulumab specifically but not the Anakinra or Interferon one. For patient enrollment, the overall remap cap enrollment was 2,046 patients. From there, 43.7% went into the immune modulation therapy domain and from there, 40.8% received Tocilizumab, 5.4% received Sirulumab, 7.7% received the other intervention so the Anakinra or Interferon and then 46% were in the control arm. When looking at patient characteristics, there was no major differences in baseline characteristics between the different arms. Here, I've reported the overall patient group characteristics which is pretty representative, I would say, of a critically ill COVID patient you might see in your intensive care unit. A mean age of 61.4, a median BMI of 30.5. Of note, 93.3% of patients in this study did receive a glucocorticoid. Also of note, the recovery dexamethasone study was published in about June and so after that, that was considered standard of care for patients to receive. One third of patients within this study did receive Remdesivir and then the median P to F ratio was 116.5 and all patients had an elevated CRP or D-dimer. In terms of drugs received, the Tocilizumab, 92% of patients received one dose. This was dosed at eight mix per kg of actual body weight with a max dose of 800 milligrams. Furthermore, 29% of patients actually did receive a second dose. The clinicians had the option to administer a second dose if they felt that the first dose did not yield a clinically sufficient result and they could administer that second dose within 12 to 24 hours at the same dose. The Sorrelumab, 90% of patients had one dose and that was a one-time dose of 400 milligrams with no option for redosing. In terms of organ support at baseline, looking at respiratory organ support, 29% of patients were on high-flow nasal cannula or invasive ventilation and then 42% were on non-invasive ventilation. Furthermore, looking at cardiovascular organ support, 19% were on an intravenous infusion of vasopressors and no patients were on inotropes. And as we recall for inclusion, patients could be on either respiratory or cardiovascular organ support. That's why it doesn't equal 100%. When looking at the primary outcome, both the Tocilizumab and Sorrelumab did meet the statistically significant and clinically significant increase in median organ support-free days with 10 and 11 respectively compared to the control. Furthermore, what was interesting was with this model, they were able to identify that the estimates for treatment effect were actually higher in conjunction with glucocorticoids compared to either arm independently, suggesting an additive benefit of using both an IL-6 receptor antagonist and the glucocorticoid. So it's not a question of using one or the other, but using them in conjunction. Furthermore, there were hints in the model that there may be a synergistic effect, but they stated that there was not enough patients and data yet to truly state that yet. And looking at secondary outcomes, in-hospital mortality was both clinically and statistically significantly lower with both Tocilizumab and Sorrelumab with a number needed to treat of 13 and 8 respectively. This benefit was still realized at 90 days as it was also both clinically and statistically significant. So we know that it was efficacious in this trial. However, was it safe for patients to receive? When looking at serious adverse events, 2.5% of patients receiving Tocilizumab did report a serious adverse event compared to zero in the Sorrelumab group compared to 2.7% in the control group. When we break down the actual adverse events that occurred, the majority in the Tocilizumab were bleeding events, but I've note there was one secondary bacterial infection in that group. Furthermore, looking at the control, there were seven thromboses and four bleeding events. So what is my critique of this study? Some of the strengths identified was first, obviously it was a multicenter randomized controlled trial conducted in 113 sites in six different countries all around the world. I think this definitely improves its external validity and generalizability to other practice sites. Second, while the Bayesian analysis was a little bit complex and hard to wrap your mind around, I think it was appropriate given COVID-19, we have new trials coming out every day, thus changing our interventions every day. So it allowed them to adapt to the specific stuff that's already coming out and see if there was really a benefit of the IL-6 receptor antagonists. And lastly, I thought that they did a nice job of requiring randomization within 24 hours of ICU admission on cardiovascular respiratory organ support, really trying to homogenize their patient population for those critically ill patients where the in-host inflammatory response may be the highest. Some limitations. First, it was an open-label design, so it could potentially bias it to the treatment arm. Second, not all patients received the allocated medication. As you recall, 92% of patients in the tosalizumab arm received a first dose, and 90% in the cerulomab arm actually received a first dose. And this was due to patients being excluded for not having available outcomes or withdrawing consent. And lastly, the low cerulomab usage. Only 5.4% of patients, or 48 patients in number, actually received cerulomab, which is overall low, although it did still meet its efficacy endpoint, which is why we have the data for it. With this model, they're actually able to compare cerulomab versus tosalizumab versus control. And so I'll be interested as they're continually still recruiting patients and evaluating these questions to see if cerulomab versus tosalizumab, if there's any difference there to be noted. So why is a difference noted in this study from previous studies? Well, first, there's a higher acuity of illness based on their inclusion and exclusion criteria, I think potentially pointing to where IL-6 receptor antagonists would yield the highest benefit. Second, the concomitant steroid use of 93% in this study compared to a study like Covacta, for example, which only had 19%. As we noted in that primary outcome, there is a potential hints at additive benefit between the IL-6 receptor antagonists and steroids. And this is also represented in the recoveries trial where 84%, I believe, had a concomitant steroid use in addition to the interleukin-6 receptor antagonists, which also saw positive outcomes related to the IL-6 receptor antagonists. And lastly, as every day we learn more about COVID-19, we're constantly improving our management of COVID-19 patients, and thus overall improving our outcomes with this patient population. So, key takeaway points from this study. The IL-6 receptor antagonists are associated with significant benefit, especially in severely ill COVID-19 patients in conjunction with glucocorticoids. Second, I think clinicians should consider utilization of either tocilizumab or sirolimab in critically ill COVID-19 patients if they're admitted to the ICU within 24 hours on cardiovascular or respiratory support. And lastly, I thought it was really interesting that their model was able to find this additive benefit, almost hinting at synergistic benefit between the IL-6 receptor antagonists and corticosteroid therapy. And it makes me wonder or curious if there are other therapies in COVID-19 that we're utilizing that may have this additive or synergistic effect that the studies are just not prepared to look for or identify. And so I'd be curious what other research out there will come out looking at this question specifically. With that, that'll lead me into my second polling question here. Would you recommend an IL-6 receptor antagonist in the management of COVID-19 and which one? A, yes, tocilizumab. B, yes, sirolimab. C, yes, either tocilizumab or sirolimab. Or D, no. So we have interesting results here, 68% saying yes, tocilizumab, 12% saying yes, either tocilizumab or sirlimab, and 21% saying no. I'd say this is pretty reflective of the clinical practice I'd see, with the majority do getting tocilizumab, some getting either, a small proportion getting none. I will say tocilizumab, in my experience, has been used at a higher degree compared to sirlimab, mostly due to cost and availability. With that, thank you all so much for listening, I hope you enjoyed the presentation and found it interesting. I would love to open it for any questions, comments, or discussion that the audience may have. Thanks, Nick. So, now we'll open it up to questions. I'll go ahead and start it off. So, I was wondering if you can comment on who might it be appropriate to use this therapy in, you know, in terms of, when you look at the data, I wonder, is there a difference between those who are not mechanically ventilated and those who needed invasive mechanical ventilation, in terms of severity illness? And then along with that, you did mention a higher acuity of illness in this study, there were severe COVID, but as I looked at the data, that's not really a high acuity of illness for my ICU patient, meaning an Apache of 12 and pressers of 19%, to me is not that highly acute. I'm wondering if you can comment on, again, may, who is it best to use this therapy in? Is it, you know, just somebody with minor respiratory and cardiology, or cardiology, cardiac symptoms to try not progress? Or would you have this in somebody with, you know, respiratory, renal function that's impaired right at the beginning, you know, they're septic, et cetera. So I wonder if you can comment on that. Yeah, that's a great question, Russ. And I'll start by kind of answering with the higher acuity of illness. My intention with that was that these patients were just transferring to the ICU and requiring that CV or respiratory organ support. So they were in that, I would say, escalating course of COVID-19, where the host inflammatory phase is ramping up. And so they're trying to really pinpoint where it may be of most benefit. And so I think that that is definitely a patient population that you should potentially consider it in. In addition to that, when you compare it to the recovery trial, for example, the recovery trial had less severity, acuity of illness, I would say, compared to this trial. And it still yielded good benefits or outcomes. And so I still think the jury is somewhat out there in terms of who's the best patient to utilize it in. But I would say based off the recovery and this trial specifically, we are recognizing that IL-6 receptor antagonists are a benefit in more patients than we may have initially thought based off the previous initial literature showing mixed results. And so I would feel comfortable utilizing it. And obviously any patient that's just admitted to the ICU with severe COVID-19 in conjunction with a glucocorticoid up front. I think one of the challenges that's still out there that we're not really sure about is there's been in the previous literature outside of COVID-19, the question of interleukin-6 receptor antagonists potentially immunosuppressing patients and increasing the risk of secondary bacterial infections, which I've been glad to see a lot of these trials have not reported a high incidence of secondary bacterial infections. But I still think we also need more data research to ensure that we're not worsening their overall immune system with these therapies too. Does that answer your question, Russ? Yeah, thank you. So I'm going to end it with a twofer from the audience. One is, would you use a CRP cutoff to determine who should receive TOSI? And then along with that, another hot topic on here is basically a ton of questions asking, who would you consider giving a second dose in and what criteria? Yeah, both excellent questions. So in this study, if you look in the supplementary appendix, they actually did do three tercell groups of CRP cutoffs and found significant benefit in all three cutoffs. So essentially you could use TOSILIZUMAB at any CRP cutoff, I would say, comfortably. And the second question was, who would I consider giving a second dose to? This is a challenging question, because I was kind of alarmed with the 29% receiving a second dose based off their methods. And I actually watched a video from one of the authors who mentioned that they tried to evaluate those patients that did receive the second dose, but they were just more severely ill and they were unable to really quantify which patient population should be best to receive that. And so similar to the trial, I'd honestly potentially give it to patients that are not getting a good clinical response to the first dose. But I honestly don't think we have a lot of research or data to guide who's the best to get the second dose and who will yield a good clinical response from that second dose. Perfect. Well, this includes our Q&A session. Again, thank you so much, Nick, for giving this presentation. And now I'd like to introduce our final presenter, Liliana Gonzales. Okay. Hello, everyone. Like mentioned, my name is Liliana Gonzales, and I am the current PGY-2 Critical Care resident here at UC Health Memorial Hospital in Colorado Springs, Colorado. The article that I'm going to discuss today was published earlier this year and is entitled Does Switching Norepinephrine to Phenylephrine in Septic Shock Patients Complicated by Atrial Fibrillation with Rapid Ventricular Response Improve Time-to-Rate Control? I chose this article because it poses a unique clinical question that could have the ability to change our vasopressor recommendations in patients with atrial fibrillation who are also in septic shock. During septic shock, increased systemic inflammation and sympathetic tone increases myocardial oxygen demand and increases the risk of developing tachycardia and arrhythmias. In a 2014 study, it was demonstrated that patients with septic shock who developed new onset atrial fibrillation during hospitalization read an increased risk for developing AFib after hospital discharge. Additionally, patients with new onset atrial fibrillation during their initial hospitalization read an increased risk of long-term complications from atrial fibrillation, including hospitalization for heart failure, ischemic stroke, and increased mortality at five years when compared to patients who did not develop atrial fibrillation. Additionally, the use of norepinephrine can also increase the risk of developing AFib when higher MAP goals are targeted. One study demonstrated that when a MAP goal of 85 was targeted, 6.7% of patients developed AFib compared to 2.8% of patients with a MAP goal of 65. Use of other catecholamine vasopressors, specifically with beta-1 affinity, have also been associated with an increased risk of developing tachyarrhythmias when compared to norepinephrine in patients who are in shock. Phenylephrine is the only adrenergic agent that lacks beta activity. Therefore, it may provide a decreased risk in the development of tachyarrhythmia when compared to phenylephrine, or when compared to norepinephrine. However, this was looked at not very much in other studies, so we're going to talk about two. In a 2019 retrospective analysis of patients with septic shock by Ballack and others, norepinephrine was associated with an increased risk of tachyarrhythmia when compared to phenylephrine. However, this was not statistically significant. Of note in this analysis, there was no difference in mean heart rate before or after the initiation of phenylephrine. In a prospective controlled trial of patients with septic shock, phenylephrine was found to produce a significant decrease in heart rate when compared to patients who received norepinephrine. The study that we'll discuss today primarily sought to fill gaps in literature regarding the rate control effects of phenylephrine for patients with septic shock and concurrent atrial fibrillation. The hypothesis examined in the study was that in patients with septic shock who experience atrial fibrillation or flutter with rapid ventricular response, switching from norepinephrine to phenylephrine will provide sustained heart rate control when compared to patients who remain on norepinephrine for vasopressor support. This study was a single-center retrospective cohort study of patients from January 2016 to April 2019 with an order for norepinephrine and phenylephrine. Patients in the study were included if they were at least 18 years of age upon admission. They were patients in either the medical or surgical intensive care units. They had a diagnosis of septic shock as defined by sepsis 2, which included having two or more of the following criteria, so they had a temperature greater than 38 degrees Celsius or less than 36 degrees Celsius, a heart rate greater than 90 beats per minute, a respiration rate greater than 20 breaths per minute, a white blood cell count of greater than 12,000 cells per microliter or less than 4,000, and these patients also had to have evidence of infection. Patients enrolled in the study also had to have a MAP of less than 65 prior to vasopressor initiation, and finally, these patients had to have developed atrial fibrillation or flutter with ventricular response while on norepinephrine. Patients were excluded if they had cardiogenic shock or mixed cardiogenic and septic shock, or if they were patients post-cardiac surgery, and they also excluded patients who had concomitant vasopressors or inotropes aside from vasopressin. In the study, categorical data were evaluated using chi-squared and Wilcoxon rank sum tests, and continuous data were assessed through time-varying Cox proportional hazard model. The primary endpoint was sustained heart rate control after time zero, which was defined as the first documented time that the patient developed atrial fibrillation or flutter with rapid ventricular response based on electrocardiogram reading from the patient chart. Sustained heart rate control was defined as heart rate less than or equal to 110 beats per minute over two consecutive hours. Secondary endpoints included the proportion of time with a heart rate less than or equal to 110 beats per minute over the first 48 hours, the total duration of vasopressor requirement, whether or not the patient achieved rate control at either hour 24 or at hour 48, both hospital and ICU length of stay, and patient mortality at 30 days. Depicted in the table are relevant baseline characteristics of the patients in the study. Of the 39 patients in the norepinephrine group and 28 patients in the phenylephrine group, baseline characteristics were similar between the two groups with respect to age, baseline MAP and heart rate, baseline presence of atrial fibrillation, use of either home or acute rate and rhythm agents, and initial norepinephrine dose. Of note, significantly more patients in the phenylephrine group had a cardiac arrest at baseline. Moreover, while the APACHE-2 scores were similar between the norepinephrine and phenylephrine groups, it's important to note that patients in the phenylephrine group had a higher APACHE-2 score correlating with an increased risk in predicted mortality at baseline. Patients in the norepinephrine group had a median of 55% predicted risk of mortality compared to patients in the phenylephrine group where there was a 75% median predicted risk of mortality. For the primary outcome defined as sustained heart rate less than or equal to 110 beats per minute over two consecutive hours, unadjusted analysis of patients showed that patients who received phenylephrine had a statistically significant likelihood of attaining rate control. However, further analysis of the primary outcome adjusting for acute or home use of rate or rhythm agents and prior history of atrial fibrillation showed that use of phenylephrine did not significantly increase the likelihood of sustained rate control. Analysis of secondary outcomes showed that there were no differences in the proportion of time within rate control, hospital or ICU length of stay, duration of vasopressor use, and 30-day mortality between patients who had received norepinephrine or who was switched to phenylephrine. Similarly, 30-day mortality was similar to what we'd expect when we consider our baseline APACHE-2 scores in both the phenylephrine and the norepinephrine group. The authors of the study suggested that there is a potential clinical effect on achieving rate control when switching from norepinephrine to phenylephrine when this cannot be excluded in patients with septic shock and concomitant atrial fibrillation with rapid ventricular response. The study attempted to answer several relevant or a relevant question with regard to the use of phenylephrine over norepinephrine in patients who are in atrial fibrillation with rapid ventricular response and concomitant septic shock, which might have the potential to change the way we make medication recommendations in these particular patients. The inclusion criteria of the study were appropriate to the question with respect to the definition of septic shock in presentation of atrial fibrillation. Moreover, exclusion criteria were appropriate, limiting patients with cardiogenic shock and the potential for adverse outcomes with the use of phenylephrine. While patients with atrial fibrillation prior to study enrollment and use of home and rate and rhythm controlling medications were not excluded, the authors did control for these factors in their statistical analysis. Of note, the authors in the study did not adjust their statistical analysis for severity of patient illness. So while the APACHE-2 scores were similar between the two groups, it would have been nice to see if the results of the study would be different based on patient severity, possibly indicating a specific patient where phenylephrine could be preferred. Ultimately, due to the retrospective nature and small sample size, generalizability of the study results are limited. Aside from its retrospective nature, one major study fault was the lack of standardization guiding switch from norepinephrine to phenylephrine. Patients switching to phenylephrine, and when exactly within their time course of care these patients were switched, was left to provider discretion, further limiting how we apply this to our patients. Furthermore, in the adjusted analysis, patients were excluded if they had received a rate or rhythm control agent during the study time. However, no data was provided regarding the timing or dosing of these agents. From the study discussion, we know that some patients were started on amiodarone drips at the same time as phenylephrine or shortly after the start of norepinephrine, but we don't know any further dosing or patient characteristics from the start of these medications. Based on its mechanism of action and receptor profile, we would anticipate that phenylephrine would be our agent of choice in septic shock patients who develop atrial fibrillation and require vasopressor support. However, the results of the study do not support the hypothesis of sustained rate control, which was defined as a heart rate less than or equal to 110 beats per minute over two hours with phenylephrine in the specific patient population. Adjusted analysis showed that phenylephrine and norepinephrine provide similar rate control in septic shock patients who develop atrial fibrillation or flutter with rapid ventricular response. Moreover, several limitations with respect to study design and intervention protocol significantly limit wide application of these results to a variety of patient populations. While I would not change my current practices as a result of the study, I could see a place for phenylephrine in patients with septic shock with atrial fibrillation who are either approaching maximal rates of norepinephrine or who could not tolerate norepinephrine for a reason. This is primarily due to the similarities in heart rate control, duration of vasopressor needs, and no change in overall mortality as depicted by the secondary outcomes. In order to determine the true effect of phenylephrine on rate control in patients with septic shock and concomitant atrial fibrillation, larger, prospective, and controlled trials are needed. So now for some questions. Do you plan to switch on phenylephrine in septic shock patients who develop atrial fibrillation or flutter with rapid ventricular response? A, not currently, but we're looking into it. The second choice is yes, it's our current practice to switch. Or no, we have no plans to consider this therapeutic option. Or lastly, norepinephrine is our drug of choice, but if needed, we will add on phenylephrine. Okay, so it looks like the majority of patients will add on phenylephrine if needed, which is kind of the same conclusion that I came to. And it also looks like some proportion of listeners do switch automatically from norepinephrine to phenylephrine, which is interesting. And the next question is, when would you consider switching to phenylephrine in septic shock patients who develop atrial fibrillation or flutter with rapid ventricular response, either upon presentation, after a norepinephrine trial without effective rate control, or the decision to initiate phenylephrine varies on a case-by-case basis? Okay, yeah, so like I thought, most people, it just kind of depends on how the patient is progressing, which I feel like based on the results of this study makes the most sense. And with that, I will take any questions that anyone has. Okay, thank you. So we have time for two questions. I think you've answered most of my questions with your polling questions, so I appreciate those. The first question is, do you know the rate of the other medications that the patients were receiving, such as like amiodarone? And I would piggyback off that and also say, do you know if albuterol dosing was collected and how aggressive they were with that? Because I know we have a problem at my institution sometimes with that, with AFib and RBR. No, they did not talk about the rate in which amiodarone was started or how long amiodarone drips were continued, nor to your second question either. And another question is, I'm wondering if you had any thoughts on how this fit in with the recent analysis on pushed-dose penilephrine in sepsis prior to norepinephrine in the ED by the CHEST article that came out in 2020 by Hahn and colleagues. I don't know how these two would fit in together. Yeah, I don't know. That's something that I would have to think about and look at a little bit more to give you a clearer answer. Well, certainly this still remains controversial. I think your poll showed that a lot of us either switch it out or cut the norepinephrine down with penilephrine. So I still think we've got a lot of research to do to see if this actually is a plausible process. So with that, I will say this concludes our Q&A session. And again, thank you, Liliana. I want to thank – yeah, I want to thank you and all of our presenters today and the audience for attending. We really appreciate it and the interactive session. 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. And that will conclude our presentation for today. So everyone have a nice afternoon. Thank you.

Journal Club

critical care pharmacy

sedation

propofol

dexmedetomidine

interleukin-6 receptor antagonists

COVID-19

tocilizumab

serolamab

phenylephrine