Hello, and welcome to today's Journal Club Spotlight on pharmacy webcast, which is supported by the Society of Critical Care Medicine's CPP section. My name is Brian Kopp, clinical pharmacy specialist, surgical trauma ICU at Banner University Medical Center Tucson in Tucson, Arizona. I will be moderating today's webcast. A recording of this webcast will be available to registered attendees. Log into mysccm.org and navigate to the My Learning tab to access the recording. Thanks for joining us. A few housekeeping items before we get started. There will be a Q&A after each of today's speakers. To submit 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 discussion on Twitter, following hashtag sccmcppjc and hashtag pharmicu. Disclaimer, please note the disclaimer stating that 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 Austin Dawkins, PGY-2 critical care pharmacy resident at Nebraska Medicine in Omaha, Nebraska. He will present on prolonged sedation with sevoflurane in comparison to intravenous sedation in critically ill patients, a randomized controlled trial. Our second presenter is Amy Kearns, PGY-2 critical care pharmacy resident at Mercy Health St. Vincent Medical Center in Toledo, Ohio. She will present on dual antiplatelet therapy versus alteplase for patients with minor non-disabling acute ischemic stroke. And our third presenter is Susan Schrader, PGY-2 critical care pharmacy resident at Cleveland Clinic Heelcrest Hospital in Mayfield Heights, Ohio. She will present delirium in ventilated patients receiving fentanyl and morphine for analogous sedation, findings from the analgesic trial. And now I'll turn things over to our first presenter. Thank you, Brian. I'm excited to be able to speak with you all today on the trial titled Prolonged Sedation with Sevoflurane in Comparison to Intravenous Sedation in Critically Ill Patients, a Randomized Controlled Trial. As I get started here, I have no disclosures to mention with regards to this presentation. So background on this trial here. So sedation, as you all are very aware, is often required during the use of mechanical ventilation for our patients. Conditions such as propofol and midazolam might cause a hemodynamics instability or prolonged sedation following discontinuation. Volatile anesthetics are an option that have been potentially utilized in the operating room and other procedures for patients that are undergoing sedation during these procedures. And new technology has allowed these to be capable of utilizing while on the floors for our patients. These volatile anesthetics typically have a rapid onset and offset and have minimal impact on hemodynamics. Previous studies have been done with regards to use of volatile anesthetics in critically ill mechanically ventilated patients, and these have shown short term that sevoflurane may improve our time to awakening as well as mortality compared to our IV sedation options or standard of care. So as we're looking at our study design here, this was a randomized controlled prospective single center phase 2B trial in which patients were randomized using an envelope method in which patients, whenever they were undergoing their treatment, were given an envelope to determine how they would then be transitioned to following their procedure or intubation. Our patients were included if they're greater than 17 years of age, were going to be admitted to the ICU, and then requiring mechanical ventilation via an ET tube with an anticipated duration of greater than 48 hours. Exclusion criteria were if they had an absence of indication of sedation for greater than 48 hours as well as any prior sedation for greater than 48 hours. Our pregnant patients were excluded as well as patients with a poor prognosis or an acute liver or severe lung failure. In total, there was 40 patients that were initially recruited for the propofol group as well as then there were 36 patients evaluated for the sevoflurane group. Our patients across both groups were primarily male patients that were in their mid-60s with a BMI of about 26 or 27. Our primary indications for ventilation were either a postoperative continuation of ventilation or our second most common option was for a neurologic or neurosurgery procedures. When looking at our treatment, so propofol, if it were utilized for our patients, it was continued immediately following intubation or postop and titrated to appropriate RAS goals for our patients. The trial investigators felt that with prolonged use of propofol that there was an increased risk of developing infusion reactions such as propofol-related infusion syndrome. In that case, the propofol was switched to midazolam at day four of treatment. For our sevoflurane group, the new technology anaconda system was utilized for infusing our sevoflurane from patients. An initial dose of 8 mLs per hour was utilized with titrations made at 0.5 or 1 mL per hour to achieve an appropriate RAS goal for our patients. Primary outcome that was studied in this trial was time to awakening following sedation discontinuation and then time at target sedation. Additional outcomes that they investigated were hemodynamics, opioid requirements while on sedation, ICU length of stay, hospital length of stay, and then adverse events. Statistical analysis that was performed here, our alpha was set at 0.05 and a power of 80% was estimated using the previous studies that were utilizing volatile anesthetics for continued sedation. Unfortunately, our trial investigators did not know how many patients were needed to be included for that power to be reached. Our primary endpoint was evaluated with an intent to treat population and secondary outcomes evaluated with a per-protocol analysis. Our data was analyzed using ANOVA for our parametric data and then non-parametric data was evaluated using a Mann-Whitney U-test. Again, our trial investigators did not know which data was parametric versus non-parametric when evaluating the outcomes. As we look at our primary outcome here with our median time to extubation or spontaneous breathing following discontinuation of the sedation, we do see that there was a statistical difference in which our semofluorine group did have a decreased median time to extubation in which that patient population had a time to extubation of 26 minutes compared to 375 minutes in our propofol group. As we then begin to investigate our secondary outcomes in this trial, first we can look at our hemodynamics of our patients. Shown for you here are the maps that were noted for our patients across the timeframe listed below. The trial investigators did note that there were significant differences which are noted with either the asterisk or the plus sign on the graph shown. While these statistical differences might be seen at various time points, the authors concluded that there was no overall clinical difference between the patients when evaluating our map across the various time points. As we look at our opioid utilization, we see that there was a statistical difference in which our patients that were utilizing the semoflurane did utilize a higher amount of opioids throughout their sedation. The trial investigators used either remifentanil or sufentanil for their opioids during their sedation in which both were utilized more often in our semoflurane group. When evaluating length of stay for our patients, both the ICU length of stay and hospital length of stay was not statistically different for our patients. Of note, as we look at our ICU length of stay, the ICU length of stay for our patients in both groups was greater than 20 days. This shows that our propofol group was utilizing a higher amount of midazolam compared to propofol as initially noted by the trial and since they were switched at the fourth day during their treatment. Adverse events, so adverse events that were noted by the trials are listed here for you. There were no significant differences noted by the trial investigators on the amounts of adverse events per patient in each group and all adverse events were not able to be directly related to the sedation choice. Strengths of this trial, so the strengths of this trial, we do have clinically relevant secondary endpoints compared to our primary endpoint which might not be typically clinically relevant. Our prolonged duration of ventilation for patients is a strength for this trial as our previous trials did have a more acute duration of ventilation. So this does show the potential efficacy of our medication at a prolonged period of time. And this is also our largest trial to date for 7-fluorine limitations. So when we are looking at their time to discontinuation of this, time to awakening following discontinuation, the use of propofol was switched to midazolam which as you know pharmacokinetically potentially could take longer to wean off for our patients. Our primary endpoint as previously mentioned is typically not as clinically relevant for our patients though for certain populations we might want to have a quicker onset and offset which could be related to our neurological patients which do have a higher amount seen compared to maybe other sedation trials. While I listed this as a limitation strictly because of our external validity to other patient populations, when looking at our neurologic patients we can potentially see this as a benefit to allow them to have a greater chance of awakening or quicker awakening to allow for neurologic assessment. And then finally, our authors did have some ambiguous statistical analysis. As mentioned previer, they did not give us the number of patients needed to meet power in this trial as well as then not allowing us to understand which data points were evaluated using parametric or non-parametric study analysis. The author's conclusions during this trial, so with this trial we did see that there was a decreased time to extubation when we had our severoflurane utilized in patient sedation. The authors concluded that this does represent a promising alternative to conventional ICU IV sedation. They do comment though that the further study is warranted to verify the data shown here as well to further evaluate for any potential safety issues or long-term outcomes not seen in this trial. Then looking at the clinical relevance and my point of view from this trial, so the six hour reduction to time to extubation does not seem to impact our clinical outcomes. So we do have the decrease in time to extubation which can be important for patients, but when we're not changing our overall ICU length of stay or hospital length of stay, this benefit might be only specifically needed for certain patient populations. Our most likely patients to benefit from this could potentially be our neurologic patients in which we're looking to do a neurologic exam quicker for our patients, but unfortunately at this time we do have need for the specialized anaconda equipment which is not heavily utilized or purchased for most hospitals. So then some of the polling questions I want to ask you all today. So how often does your institution utilize seboflurane or other volatile anesthetics outside of the operating room? Okay, I think that's what I would have expected seeing here. My institution also does not utilize volatile anesthetics outside the operating room. At this point in time I feel that it's not very commonly utilized outside, but I do think it's interesting to see that we have a handful of locations that are potentially using a volatile anesthetic outside of the operating room. And then my second question for you today was based on the information provided here, would you consider using seboflurane for sedation outside of the OR and how frequently would you consider using it? Okay, I think that is also supported by what this trial has shown here, that you would not consider using seboflurane or other volatile anesthetics at this time. I do think that this data does have potential for allowing us to use in select patients, particularly those that have a shorter need for ventilation or potentially are neurologic patients. But at this point in time I do not believe this trial has shown enough clinical relevance for us to be using seboflurane in a more consistent basis. And with that I will open up for any questions. Thanks, Austin, great presentation. Austin, since you looked into the article, I'm interested in your thoughts on the selection of midazolam as the transition agent and how you think that might have impacted the results of the study, either in terms of a negative or a positive impact. Yeah, so the authors commented based on the fact that they wanted to switch to avoid any of the infusion-related outcomes with propofol. I feel switching to midazolam might have been an inappropriate option compared to what their primary outcome was going to be. Extubation does have a much higher ability to disperse into tissue and make it more difficult to wean off of patients, and a longer time to extubation is something that we consider a very typical piece of midazolam usage. So then using that to compare against something in which propofol potentially wouldn't have had that same difficulty with sedation makes it hard for us to interpret sometimes how we would see that for our patients. So I do feel that it probably hurt this trial overall to be switching to midazolam compared to either continuing propofol sedation or looking at other options such as ketamine or a lighter sedation with something like dexmedetomidine. If your institution were to utilize cevoflurane for sedation in the ICU, what barriers would have to be overcome with regard to equipment, staffing, and education? Yes. So based on my research with the anaconda system, as best I could, it seems like it is an adapter to the patient's ventilation system, which would mean that we would need RT, or our respiratory therapist, to have a level of education based on the utilization of that adapter, but it does seem like it's a relatively easy connection piece associated with that. So adaption would probably be a relatively simple education. Medication, utilization, and side effects would also probably be a consideration for us to look at for these patients. So as it is a volatile anesthetic and is potentially in the air for our respiratory therapists or other staff members, we'll probably have to have education on safety and side effects that they could experience as well, so we're not putting them at risk. And then Medicaid, or the actual receiving of the equipment, it does appear that each adapter is a 24-hour period for use in the patients, so it's probably that there would have to be a high amount of supply available if we were to have a longer duration of use for patients. It looks like just one other question here for you. Does sevoflurane have any analgesic properties, and can you please elaborate on the mechanism of action in pharmacology? So for sevoflurane, I am not aware of any analgesic effects for it. It's working centrally in our brainstem to inhibit our neurotransmitting system by blocking the GABA receptors that are centrally acting. Okay, not seeing any more questions. We'll go ahead and move on. Now I'd like to introduce our second presenter, Amy Kearns. Hello, all. Thank you for joining us here today. My name is Amy Kearns. I am a PGY-2 critical care pharmacy resident at Mercy Health St. Vincent Medical Center in Toledo, Ohio. Today I will be presenting the ARAMIS trial, which is stool antiplatelet therapy versus alteplase for patients with minor non-disabling acute ischemic stroke. I have a poll question right off the bat. I was curious to see which fibrinolytic agent is used at your institution for acute ischemic stroke. Is it alteplase, tenecteplase, or do you use another agent? At my institution, we have switched to tenecteplase as our agent of choice for acute ischemic stroke, and it looks like that was the most frequent answer as well. And so just taking that into consideration that this trial is using alteplase, but at the end, I will mention a new trial that will be using tenecteplase in this patient population. So first, I would like to touch on the current guidelines for acute ischemic stroke that are published through the American Heart Association and American Stroke Association. These were last updated in 2019, and there is a subsection for patients who present with a minor non-disabling acute ischemic stroke, which is an NIH stroke scale of 0 to 5. The current recommendation for alteplase is that it is not recommended for those specific patients with an NIH of 0 to 5. However, there is a recommendation for daft therapy within 24 hours as well as continued for up to 90 days after patients who presented with a non-cardioembolic ischemic stroke with an NIH of less than or equal to three. I wanted to highlight two landmark trials that led to the current recommendations in our guidelines and impacted the trial that I will be discussing today. The first study is the CHANCE trial which was published in 2015 that evaluated daft therapy versus aspirin monotherapy for patients with a minor ischemic stroke or TIA. Most of the patients in the study did have a minor stroke and the overall treatment groups were daft therapy versus aspirin for 90 days. The conclusion was that daft therapy was associated with a statistically significant reduction in the rate of reoccurring strokes. That was their primary outcome. The conclusion was that the combination therapy of clopidogrel and aspirin was superior to aspirin monotherapy in preventing a reoccurring stroke within 90 days. The next study is the PRISMS trial which was published in 2018 that compares ultraplaced versus aspirin monotherapy for patients with a minor non-disabling acute ischemic stroke. The overall primary outcome for this was functional outcomes with a modified Rankin scale of 0 or 1 at 90 days. The study was terminated early due to low patient recruitment as well as financial issues. Although no definitive conclusions can be drawn from this study, it did appear that both treatment options had similar effects on functional outcomes for patients with a minor stroke. This is what leads to our current trial today. It's slightly different from the PRISMS trial in that this is comparing dual antiplatelet therapy versus ultraplaced. The objective of the ARAMIS trial is to investigate whether dual antiplatelet therapy is non-inferior to IV thrombolytics among patients with a minor non-disabling acute ischemic stroke. The percentage of minor non-disabling acute ischemic strokes is increasing. It accounts for approximately 40 to 50 percent of all strokes that are seen in the emergency department. This is definitely a very applicable topic, especially since those are seen very frequently. This study is a multi-center, open-label, blinded endpoint, non-inferiority randomized clinical trial. This occurred in 38 hospitals in China over a three-and-a-half-year time period. Patients were included in this study if they were 18 years of age or above, had an acute ischemic stroke with an NIH stroke scale of less than or equal to 5. The patients were required to have a score of 1 or less in single-item scores as well as a 0 in the consciousness component. Patients were required to have a CT or MRI on admission to identify that there was an ischemic stroke present, and patients must be able to receive treatment within 4.5 hours of their symptom onset. Patients were excluded if they had a pre-stroke disability, which was characterized by a modified Rankin score of greater than or equal to 2, a history of an intracranial hemorrhage, as well as a definitive indication for anticoagulation. The patients were randomized in a one-to-one ratio to either receive DAPT or alteplase. The DAPT therapy was 300 milligrams of clopidogrel with 100 milligrams of aspirin on day one, followed by 75 milligrams of clopidogrel with 100 milligrams of aspirin for 12, plus or minus 2 days, and then guideline-directed antiplatelet therapy, which was either DAPT or monotherapy aspirin based on guideline recommendation for a total of 90 days. The alteplase group, the dose was 9 milligrams per kilogram, administered in our usual fashion of 10 percent over the first minute and remainder over the hour, and a max dose of 90 milligrams. Patients were then eligible for antiplatelet therapy after 24 hours of receiving alteplase, and then it was guideline-based antiplatelet therapy for 90 days as well in that group. The primary outcome of this study was excellent functional outcomes with a modified Rankin score of 0 or 1 at 90 days. There were several secondary outcomes, but the two that I would like to highlight today are favorable functional outcomes, which was a modified Rankin score of 0 to 2 at 90 days, and early neurological deterioration at 24 hours. There were two safety outcomes as well that included symptomatic intracranial hemorrhage within 90 days as well as any bleeding events. I listed the baseline characteristics for the patients included in this study here. The average age for patients included was around 65 years old. More than two-thirds of the patients were male, and I wanted to specifically highlight some of those baseline characteristics that stuck out at me. So, 75 percent of all patients included had no symptoms at randomization, had a modified Rankin scale score of 0 at that time, and overall, the stroke cause was pretty much undetermined in most of the patients as well. There were 760 patients randomized in this study. Their prediction was 666 patients to meet a power of 80 percent, and so they did supersede that value. Patients had a medium time from onset of symptoms to treatment. It was approximately 181 minutes. The median NIH stroke score at randomization was 2, and for those that had a responsible vessel, it was primarily in the anterior circulation. Now to dive right into our primary outcome results. So, this was excellent functional outcomes, which was a modified Rankin score of 0 or 1 at 90 days. This occurred in 93.8 percent of patients in the DAPT therapy group and then 91.4 percent in the ALT place group. As this was a non-inferiority study, to meet non-inferiority, it was designated that the lower limit of the confidence interval needed to be greater than negative 4.5 percent to meet non-inferiority, and they did meet that with negative 1.5 percent, and so overall, the final conclusion was non-inferiority between DAPT and ALT place for excellent functional outcomes at 90 days. I also wanted to show this depiction from the article showing the distribution of the modified Rankin scale scores at 90 days. So, majority of the patients did have a score of 0 or 1, and then you could see beyond that what those patients experienced. Now looking at secondary results in the safety outcomes that were evaluated. The first one is a modified Rankin score of 0 to 2 at 90 days, which was classified as favorable functional outcomes. There was no difference between the two groups. The second secondary outcome I am highlighting is early neurological deterioration at 24 hours, so this is an increase in their NIH stroke scale score as well as long as it was not due to an intracranial hemorrhage, and overall, those were statistically significant, showing that ALT place was associated with a higher rate of early neurological deterioration of that time frame. From a safety outcome standpoint, the rate of symptomatic intracranial hemorrhage at 90 days was 0.9 percent in the ALT place group and 0.3 percent in the DAPT group, which is not a statistically significant difference. And then finally, there was a significant difference between any bleeding events with ALT place being associated with more. Overall, the conclusion of this study was that among patients with minor non-disabling acute ischemic stroke, DAPT therapy was non-inferior to IV ALT place with regard to that primary outcome of excellent functional outcome at 90 days. Some of the strengths of this article were that it was a large sample size. It did meet power with a randomized design, and patients had similar baseline characteristics. The outcome analysis was blinded, and there were various sensitivity analyses on the primary outcome as well as the subgroup analysis, which can be found in the article, which just gives us more information when we have individual patients in front of us to see where they would fall in terms of their primary outcome. And finally, limitations include that the treatment randomization was actually open-label, and so providers that were reading the imaging results could also determine treatment, so there could be potential bias in there, as well as there was a high crossover rate between groups, so patients that were originally included in the DAPT therapy group were transitioned to receive ALT place and vice versa, so overall could affect the integrity of the recruitment process and consent process. So overall, DAPT therapy is non-inferior to ALT place for patients presenting with an acute ischemic stroke. I know in my practice, I am seeing a higher rate of IV ALT place or connective place being used for those minor non-disabling strokes, and so this trial ultimately supports and provides evidence to possibly doing that in patients with a lower NIH Stroke Scale score, and so that would not technically change in my practice here, but I'm interested to see how it affects the next update of our guidelines for acute ischemic strokes. And finally, there is a trial underway called the TEMPO2 trial that's specifically evaluating connective place for minor non-disabling acute ischemic strokes with a large vessel inclusion, and so it'll be interesting to see those results as well. In summary of everything that we discussed today, as I mentioned, DAPT treatment is non-inferior to ALT place for treatment of minor non-disabling acute ischemic strokes, and DAPT is actually associated with a lower risk of bleeding events. There were some differences in the aspirin dosing and overall length of therapy for DAPT that is commonly used in the United States, so repeating with our standard protocols, I think, would be very beneficial, and I just wanted to highlight that it is important to weigh the risks and benefits when determining what treatment plan is being made for patients presenting with the minor acute ischemic stroke. My final question for you today as we look at different treatment options for patients with a minor non-disabling acute ischemic stroke is for patients with an NIH stroke scale less than or equal to 5, what is commonly used at your institution? Is it monotherapy antiplatelet agent, dual antiplatelet therapy regimen, fibrinolytics, or other? Okay, dual antiplatelet therapy is first, and there are a handful of sites using fibrinolytics primarily, which I see in my practice it can go between DAPT and fibrinolytics, and so in summary, that concludes my study that I wanted to review with you today. I will gladly answer any questions at this time. Okay, thank you, Amy, for that great presentation. We're going to move into some questions and answers here. Okay, here's our first question. This study, as well as the background investigations you reported, look at clopidogrel use with aspirin. Do you think there is a role for other P2Y12 inhibitors in minor stroke? All right, thank you for that question. From my practice thus far, I primarily see clopidogrel and aspirin being used. However, there may be some specific contraindications to using clopidogrel where other P2Y12 inhibitors would be the next option, and so for most of the literature that I've reviewed thus far, it's primarily in DAPT therapy with clopidogrel and aspirin. I think that's something that I would be interested to see is more data supporting the use of other P2Y12 inhibitors, specifically for minor acute ischemic stroke. Can you comment on the 12-day dosing that is mentioned in the trial? Why specifically this duration of time was picked? Sure, yes. So, specifically with the CHANCE trial that I mentioned prior that looked at DAPT therapy for prevention of reoccurring strokes, most of their benefit in preventing a subsequent stroke was seen within the first two weeks, and so I know that this trial referenced the CHANCE trial on multiple occasions, and that's what led to their decision to have a DAPT, a designated DAPT length of therapy for 12 plus or minus two days. That was my understanding, and I think that is a difference in what our guidelines recommend with 21 days, and so kind of comes back to my thought of repeating that here with our standard dosing and length of DAPT would be more beneficial to our patient populations and the management that we, I see more commonly here. Finally, Amy, how is this going to impact your practice, or how will the results of the study impact your practice? Sure. So, even prior to this study being published, I was already seeing fibrinolytics being used for minor non-disabling acute ischemic strokes, so the NIH score of less than or equal to five, and although current guideline recommendations are to not use alteplase, I was seeing it in practice, and so I think this overall supports the use of either agent, especially when it comes to preventing further disability in patients after an acute ischemic stroke, and so this ultimately I will use to help support the decision in using alteplase versus DAPT therapy in patients who present with these specific criteria, and one thing I think is important to consider is the subgroup analyses in this article where, you know, most of the, it was actually preferred to use alteplase in patients with a NIH score of greater than or equal to three, or greater than three, so four to five, and so using the subgroup analyses to kind of figure out what may be the most beneficial cause for the patient in front of me is how I plan to use this study. It looks like we probably have one more question. I think we have some time to get to it. I think it's a pertinent question, or a question I like, given the patient population this was studied in. Did they perform any lab testing to assess patient response to complicit growth? Pat, I did not see any mention throughout the article on specific follow-up for lab monitoring. I know that there was specific follow-up to, you know, determining what their modified Rankin scale was at different time frames within the 90-day study period, but I did not see anything about lab testing, which I think is an excellent question and something to evaluate more if the study was repeated. All right, that concludes our question and answer session. Thank you very much for that presentation, Amy. Great job. And now I'd like to introduce our final presenter, Susan Schrader. Thank you, Brian. Today I'm going to be talking about delirium in ventilated patients receiving fentanyl and morphine for anal sedation. As a provider who works in the ICU, we all know delirium is very common. The BRAIN ICU trial found that patients with a longer duration of delirium had a profound cognitive decline at 12 months after an ICU stay. The study also found that delirium is an independent predictor of mortality in ventilated patients. I really like this picture because it really shows the complex nature of delirium and how there are multiple factors that increase the risk of delirium, like pain, agitation, sleep deprivation, age, and more uncommon factors like inability to communicate, hunger, and thirst. The PATIS guidelines are recommendations on pain, agitation, delirium, immobility, and sleep-desperate disruption in patients in the ICU. The guidelines recommend a protocol-based anal sedation assessment and management to reduce the sedative requirements and ICU length of stay. The usual therapy is pain should be treated before a sedative agent is considered. The guidelines believe that certain medications can provide both sedation and analgesic properties. When it comes to preventing delirium in the ICU, the PATIS guidelines recommend non-pharmacological interventions. The guidelines recommend against using atypical antipsychotics for delirium, and if a medication is needed, the guidelines recommend dexmedetoxin. Recommendations for the anal sedation comes from Stroman colleagues from their prospective randomized trial in patients undergoing mechanical ventilation. Patients are divided into two groups, patients with analgesic and no sedative medications versus the control of only sedative medications. The primary outcome was days without ventilation, which was four days longer in the no sedation group with a p-value of 0.01. Recommendations for dexmedetoxin or Presidex comes from the only randomized control trial from Reed and colleagues that evaluates Presidex for delirium. The study was a double-blind placebo-controlled trial in mechanically ventilated patients with delirium. The intervention was dexmedetoxin or placebo. The primary outcome was ventilator-free hours, which was 24 hours greater in the Presidex group compared to placebo with a p-value of 0.01. Now comes to our first polling question, which is, how often does your health system utilize atypical antipsychotics in the ICU to treat delirium? And that's what I see at my last hospital and the hospital I'm currently at is a lot of our providers first reach for, try to reach maybe for like Seroquel or Olanzapine to help with these patients in the ICU with their delirium. The analgesic trial in 2021 was an open-label, two-center clustered remuneration cluster crossover registry trial comparing fentanyl and morphine for anal sedation in mechanically ventilated patients. The primary outcome was number of ventilator-free days at day 28. There were a total of 681 patients randomized, 344 patients received fentanyl, and 337 received morphine. When it came to the primary outcome, the fentanyl group had an increase in ventilator-free days at 26.1 days compared to 25.3 days in the morphine group with a P-value of 0.001. Fentanyl also had a shorter length of stay in the ICU compared to the morphine group. The results of this study could possibly be related to the pharmacokinetics of fentanyl and morphine. Morphine is renally cleared, so it will accumulate in renal failure, and acute kidney injuries are very common in the ICU. Also morphine metabolites are active compared to fentanyl, where the metabolites are inactive. With the active metabolite and the accumulation in renal failure, this causes morphine to have a longer effect compared to fentanyl, which could explain the results of the analgesic trial. Now we'll be going into a secondary analysis of the analgesic trial. We'll first start with the methods. So the design of this study was a secondary analysis of the analgesic trial, which again was a prospective, open-label, clustered randomization, clustered crossover trial. Two hospital ICUs were randomized to one of the drugs for a six-month period, then they crossed over to the other drug for six months. The objective of this secondary analysis was to determine the impact of fentanyl versus morphine on the incidence of delirium. Adult patients who were mechanically ventilated were included into the study. The study did exclude patients who had cardiac surgery during the study. Their clinicians deemed anelocidation was not required. And lastly, patients on end-of-life care. The providers decided when anelocidation infusion was required. Nurses used the Richmond agitation scoring system to assess sedation. Their goal RAS was negative two to one. The ICU had routine delirium prevention strategies in place. They had daily sedation spontaneous breathing trials as well as mobilizing patients as soon as possible. If a patient did become delirious, quetiapine, haloperinol, or olanzapine were utilized. The primary outcome was the incidence of delirium in patients receiving fentanyl compared to morphine. The secondary outcomes were type and dose of antipsychotic and anelocidation medications used, the dose relationship of fentanyl and morphine to the use of antipsychotic medications, and lastly, the relationship between the use of antipsychotic medications and outcomes. These outcomes were ventilator-free days, duration of ventilation, ICU-free days, ICU length of stay, hospital-free days, as well as ICU and hospital mortality. The continuous variables were analyzed using Wilcoxon rank sum test and categorical variables were analyzed using either Chi-square or Fisher's exact test. Multivariable analysis were performed on defined covariance, which were age, sex, apathy two score type of emission, and diagnosis at emission. Time-to-event outcomes were shown in the Kaplan-Meier curves and compared using long-rank test. Power was not defined in the study, but it was defined in the analgesic trial as 0.8 and alpha was set at 0.01. I will go into the results. Out of the 681 patients in the analgesic study, a total of 291 patients were determined to have delirium, with 116 patients in the fentanyl group and 132 patients in the morphine group. The average patient was a 60-year-old male with an apathy score of 18. The only significant difference between the two groups was looking at coexisting disorders. The morphine group had a higher incidence of liver dysfunction with 49% compared to 35% in the fentanyl group. When it comes to the primary outcome, the incidence of delirium occurred in 46.5% of patients on fentanyl compared to 39.1% receiving morphine. The fentanyl group were 19% more likely to have delirium compared to the morphine group with a p-value of 0.05. Now we're going to look at the secondary outcomes. The use of analacidation medications were not different according to opioid treatment except for the dosing of propofol, which was the most common analacidation use. The difference was around 2 micrograms of propofol, which is not clinically significant but it was statistically. The fentanyl group had a higher mean dose of propofol compared to the morphine group, which I said is still not clinically significant. 25% of patients received midazolam and 25% received diazepam. This is a high percentage of patients receiving benzodiazepines, which could introduce a confounder for delirium. The use of antipsychotic medications were not different between fentanyl and morphine. The most common antipsychotic use was catepine. This graph shows the linear relationship between the dose of fentanyl or morphine received to the probability of an antipsychotic medication used. At 1000 milligrams of morphine or equivalents, there was a 45% chance of receiving an antipsychotic medication. Of the 292 patients with diagnosed delirium, 157 of these patients received an antipsychotic medication and 41% of patients did not receive any medications for their delirium. Through the outcomes were significant. Duration of ventilation was shorter in patients with delirium without an antipsychotic medication. ICU free days were longer in the delirium and no antipsychotic medications. And lastly, hospital mortality was significantly decreased in patients who received an antipsychotic medication. But when it was adjusted for those confounders that I recently stated, it was not significant with a p-value of 0.08. This will come to our last poll question, do these results make you consider altering your current practice? Yeah, especially since this is a secondary analysis and I will talk more about some of the limitations, I would agree with the majority of you saying no. I will go into the discussion. So the authors conclude that delirium was 20% more likely in the fentanyl group compared to the morphine group, but these need to be interpreted with caution because the original study was not powered to detect a difference. They needed 1,400 patients, but only 681 patients were in the study. Lastly, the adjusted hospital mortality was not significant in patients with delirium who received antipsychotic medications compared to the ones who did not. Now I'll talk about some strengths and limitations. Some of the strengths of this study was the patient population was diverse. Patients came to the ICU from the emergency room, the medical surgical floors, the operating room, with many different diagnoses like cardiac, neurology, trauma, and surgery. Another strength is that the study was a novel concept that has not been researched before. There were several limitations of this study as well, though. This was a secondary analysis leading to an increased bias and lack of control over the data collection process. There was a high percentage of benzodiazepine use, which could introduce a confounder that was not in the multivariable analysis. Patients in the delirium group had a significant longer ICU hospital stay, which is also another confounding variable that was not in the multivariable analysis. Propofol has no analgesic properties, but it is highly sedative. This medication can highly affect delirium. The study published the results in milligrams per hour. They did not use the weight-based calculation, so it is hard to determine how these patients were dosed based on their weight. Patients could have been underdosed or overdosed, which could lead to more or less delirium. Lastly, 12 patients in the morphine group, which is around 4%, also received fentanyl. Even though the duration was short, this could introduce bias into the study. Overall, it is important to remember that analgesic and sedative medications have a risk of delirium, including fentanyl, which is historically used to help really decrease delirium. The study did not mention how compliant the units were at using non-pharmacological interventions to prevent and treat delirium, but from my view, all ICUs can improve in this. It is important to orient the patient on the time and date every day, as well as to increase early mobility, turn on lights during the day, improve hearing and vision with hearing aids or glasses. These interventions are the key to preventing delirium from setting in. The reason non-pharmacological intervention is so important is because there is limited data from clinical studies for treating delirium. Currently, there is only one RCT that supports using Prestidex. This study supports not using any antipsychotic medications for delirium, but it would be interesting to see a follow-up study comparing delirium with patients who receive Prestidex. And with that, I will open up for any questions. Great, thank you very much for that presentation, Susan. We'll go ahead and open it up to some questions here. Could you talk a little bit about how delirium was assessed and maybe some of the limitations in terms of the method that they determined to have delirium? Yeah, so this was determined based on multiple different things, more like if they had a diagnosis like an ICD-10 code, if they had a CAM-ICU positive result in their chart, as well as just any type of note in their medical record that showed that they were delirious during their hospitalization stay. The nurses were always trying to do a rascal of negative two to one, which was very similar between the two groups, but they did not do, at least did not publish what their CAM-ICU, if they were CAM-ICU positive or negative each day. So I think that would have been very interesting to see because that would have given more information on maybe when they started to see that delirium settle in, if it was more in the beginning or longer in their ICU stay. But in terms of the original study, the analgesic study showing benefit of using fentanyl over morphine in ICU-free days, and then results from this suggesting essentially the opposite in with respect to delirium. So how do you resolve those discrepancies and, or why do you think we did see some of those discrepancies? I think a lot of these discrepancies did come from confounding variables that were not determined in the multivariable analysis. And also just because it is a secondary analysis of another trial. I think it's very important in any patient in the ICU to start with non-pharmacological interventions before going into like an antipsychotic or a Prestidex. So I think it's very important to focus on that before trying to use a medication to help with delirium. I really see that all medications that we can use in the ICU to help with analgesic and sedative medications can have a risk of delirium. So sadly, it's hard to try to prevent this, especially just in the setting of the ICU in general. So it's very important to try to prevent and help delirium from setting in because there is a really tough decision either to do fentanyl or morphine, especially fentanyls are more preferred just because of the pharmacokinetics. So it would be hard to use morphine in some of these patients who are in the ICU, which at least from the secondary analysis does show that it has a lower risk of delirium. How often do you use morphine in your ICU practice? How does that impact the applicability of these results? Yeah, that's a good question. I have only seen morphine used in patients with end-of-life care, which I think that is really based again on the pharmacokinetics. We are really not worried about renal accumulation. We are more worried about keeping that patient comfortable, making sure they're breathing appropriate. So I think it would be hard to apply this to patients who are not on end-of-life care because we regularly do not use morphine. We either use fentanyl or Dilaudid, something like that instead. So I think it would be hard to generalize this to the general ICU population. Looks like just maybe one more question we can take from the audience. What non-pharmacologic strategies were utilized for delirium prevention? So they did not state certain ones that they used. They just did the common. We made sure to have a spontaneous sedation and breathing trial each day, as well as looking. The providers were required to assess the patients twice a day to see if they were even needed for the ventilation anymore. Those are the only ones that they mentioned in the study. It would have been, I think it'd be very important to see what other pharmacological preventions they did use and see how accurate they were at using those daily. All right. We'll go ahead and make that the last question. We'll conclude the session. Thank you again, Susan, for that great presentation. Thank you to all of our presenters today and the audience for attending. Please join us on the third Friday of the month from 2 to 3 PM Eastern Standard Time for the next Journal Club Spotlight on Pharmacy. That concludes our presentation today.

Journal Club Spotlight on Pharmacy

critical care medicine

prolonged sedation

sevoflurane

intravenous sedation

critically ill patients

dual antiplatelet therapy

alteplase

delirium