Good afternoon, everyone. I think we'll go ahead and get started. This session is the year in review for the CPP section, slotted for one hour. My name is Seth Bauer, and I will be moderating this session. We have three excellent speakers that will be telling us about a variety of topics today. In order to ensure each of the speakers has time to present their information, we'll be holding questions until the end. I'll invite all of our speakers up to the panel, and then invite you all in the audience to use the microphones to ask any questions you may have. And we'll just jump right into our first presentation. Our first presenter is Dr. Natasha Lopez. She's a critical care pharmacist in the medical ICU at Massachusetts General Hospital in Boston, Massachusetts. Dr. Lopez, thank you. Thank you for the introduction, and I wanted to thank the CPP committee for having me here today to discuss this topic. And my objective today will be to recommend opioid sparing adjunct, as well as alternative therapy for management of pain in critically ill patients. So in 2017, as you guys are most aware of, the U.S. Department of Health and Human Services declared the opioid epidemic a public health emergency. And it's estimated that the economic burden from prescription opioid misuse alone totals up to $78.5 billion a year. And as you can see in the graph depicted onto the right, this is just showing the overdose rates involving opioid use. And 40% of these deaths involve a prescription opioid agent. So this epidemic has really led us to look at, you know, our prescribing practices at all stages of the patient care, from ICU to hospital discharge. And pain management is something we deal with on a daily basis. You know, pain is reported as one of the most stressful events that patients and family members experience during their ICU stay, as well as after their ICU stay. And if we undertreat pain, this can increase the risk of developing chronic pain. In addition to that, there has been a movement for more analogous sedation. So using opioids more for its respiratory depressant properties, and using it more as a sedative. So it's understandable that we would be concerned that, are we in a force inducing this opioid epidemic? And additionally, how can we appropriately manage these patients' pain, but opioids spare and prevent tolerance, withdrawal, and hyperalgesia? And one of the methods discussed is going to be multimodal agent therapy. And just recently, there was a meta-analysis and systematic review that looked at utilizing non-opioid analgesics, either as an adjunct or as an alternative to opioid agents. Now, they looked at data up to July of 2018, and there were five randomized control trials that actually fit into the criteria. And they found overall that non-opioid therapy, there was an opioid sparing effect that was statistically significant. When they subcategorized into the specific agents, that being Tylenol, ketamine, and neuropathic medications, including gabapentin and carbamizepine, it did show that each of those agents had a significant decrease in opioid consumption. Another analysis that looked at multimodal agents was looking at level one trauma patients, and this was a single retrospective cohort study that was looking at pre- and post-implementation of a multimodal pain management order set. Primarily included scheduled Tylenol, as well as your neuropathic medications, lidocaine patches, and NSAIDs. The primary outcome that they were looking at is depicted in the graph here to the right. And they were looking at the cumulative oral morphine equivalents over days two through five. And as you can see here, this being the pre-cohort and the post-cohort, there was a significant decrease in the amount of opioid requirements. In addition to looking at their opioid requirements during their ICU stay, they looked at the patients up to discharge. And one thing that was interesting that they found was 60% of the patients were prescribed a higher daily dose at discharge than they required the 24 hours prior to discharge. In addition, they also found that 41% of patients who required no opioid agents were discharged with an opioid prescription. So this is something that we might want to think of as pharmacists, you know, coordinating with our, you know, step-down colleagues to see what exactly is happening up to discharge. So what do we have as options for multimodal therapy? I really wanted to focus on agents that we might not feel as comfortable using in practice as well as maybe have more literature to kind of support their use. So I'll be talking more about lidocaine and ketamine. So lidocaine's early clinical evidence for analgesic effects really came from chronic neuropathic pain. And lidocaine infusions have been looked at administering preoperatively and its impact on postoperative pain and with mixed results. Currently, the PADIS guidelines suggest not routinely using IV lidocaine as an adjunct for opioid sparing properties for our ICU patients. And primarily because of the limited literature that we have. And this is kind of depicted here. This study is actually from 2017. But this is really the one study that we have in a general ICU patient population. And they were looking at continuous infusion as an adjunct analgesic in our ICU patients. And it was a multi-center retrospective chart review in which they reviewed 21 patients with a mean age of 66. Roughly around 95% of these patients had a surgical intervention prior to receiving lidocaine. They didn't mention what ICU they were actually admitted to. In addition, the mean dose of lidocaine administered was about .93 milligrams per minute. And the mean duration was around 48 hours. Their primary outcome was looking at the mean time to a 20% decrease in pain scores after lidocaine implementation. Which they found 3.3 hours, which was statistically significant. In addition to that, this graph below is just showing the pain scores in this lighter gray line. As well as the morphine dosing equivalents in six-hour time blocks pre and post. And I've color-coordinated it so you can look at which time buckets coordinate. And as you can see, really clinically significant is the six-hour to 12-hour, as well as 18 to 24-hour. It's a large decrease in your opioid requirements. But me as the pharmacist, you know, you think this is an antiarrhythmic agent, neurotherapeutic index drug. What about safety? So they found that three of the 21 patients did have to discontinue lidocaine because of adverse effects. And I just want to point out the key demographics, being heart failure and acute renal failure. So potentially decreased elimination in those patients. And then the primary reason for discontinuing was altered mental status. So that's important to consider because altered mental status is usually the first sign of toxicity that you're going to see even before the cardiac toxicity. Another additional patient population that this is being looked at is in our emergency department. In 2018, there was a systematic review looking at the safety and efficacy of lidocaine in the ED. And they found four of the six randomized control trials found either a comparable or superior reduction in pain scores. Now the patient population really was composed of renal colic patients, as well as limb ischemia patients where they saw a benefit. And efficacy in other areas really wasn't further adequately tested. There were limited reporting of the actual adverse effects in these studies. So overall, the authors concluded that, you know, before IV lidocaine is routinely used in our ED, further research is needed. So in 2019, there were two randomized control trials that were evaluating lidocaine versus a comparable opioid agent. And each of these studies looked at patients that were presenting in acute pain, as well as severe pain with an NRS score greater than seven. Patient populations included abdominal pain in one study, and then undifferentiated pain in the other. The lidocaine dosing schemes varied. One study using a flat dose of 120 milligrams, and the other doing a weight-based dosing, and then in its comparison, opioid. The outcomes that they were looking at was improvement in pain scale at 90 and at 60 minutes. They hypothesized that lidocaine would be superior than their opioid counterpart, which they did not prove. In addition to that, they found that the lidocaine group in the study with Chinon and colleagues actually required 25% more rescue dosing than the hydromorphone group. So some considerations for lidocaine in practice. One big thing, you know, remembering it's hepatically metabolized, has active metabolites. As far as therapeutic drug monitoring, it's useful for assessing toxicity, but its correlation with efficacy is limited. It's still beneficial in maybe those patient by patient selections, so opioid tolerant, maybe neuropathic pain if there's a contraindication to an epidural. So I think before we implement lidocaine for every patient or put it in our pain and sedation algorithm, it really needs further evidence looking at the optimal dosing duration, as well as clinical outcomes. So that brings me to ketamine. This is definitely a hot topic. I think there were 13 abstracts on ketamine this year. So currently, there are three societies, including anesthesia and pain medicine, consensus guidelines that recommend the use of ketamine for acute and chronic pain. And currently, the PADIS guidelines suggest using low dose ketamine as an adjunct to opioid therapy when seeking to reduce opioid consumption. The evidence to support this is really limited to one randomized control trial in surgical ICU patients. So the current evidence I wanted to bring to light is the study that was done by Garber and colleagues that was looking at continuous infusion ketamine for adjunct analogous sedation in mechanically ventilated patients, in which they looked at 104 patients in this multicenter retrospective chart review. These patients were mean age, 40 years old. Forty percent of these patients were in the surgical ICU, and about 75% of these patients were opioid naive. The concomitant analgesia and sedation was primarily at 46% fentanyl, and then 35% of these patients were also fentanyl and propofol. Their median starting dose was 5 micrograms per kilogram per minute of ketamine for a median duration of 91 hours. And for their primary outcome, they were looking at the percent change in analgesia and sedation dosing at 24 hours after ketamine, in which they found a significant difference of 20% decrease. And in these two graphs, here in A, being the fentanyl dose requirements, and in B, being the propofol dose requirements, you can see at each 12-hour time marker, there's a statistical difference in decreasing these dosing requirements. Of note, they did also look at dexmedetomidine and midazolam, which had no dose decrease requirements. They also did find that 60% of these patients did experience tachycardia, and 70% of these patients actually had a decrease in vasopressor requirements. So this moves me on to my next study that was a retrospective single study that was done at Massachusetts General Hospital, and they were looking at the impact of low-dose ketamine on continuous opioid infusions in our mechanically ventilated SICU patients. And they included 40 patients, and they were looking at 24 hours prior to and 24 hours after ketamine, with the primary outcome of change in morphine equivalence at the 12-hour marker. Key demographics, these were mainly trauma in vascular surgical ICU patients. 65% of these patients were opioid naive. We had a starting dose of 5 micrograms per kilogram per minute, and a duration of about 1.9 days. For their primary outcome, they found a significant difference in that 12-hour post-ketamine, and as well as the 24-hour post-marker. For some of the secondary outcomes, similar to Garber and colleagues, they found a significant decrease in the propofol requirements in these patients, as well as a decrease in their vasopressor requirements. And the last study that I wanted to really talk about was ketamine infusion for pain in adults with multiple rib fractures. And this was a single-study, prospective, randomized double-blind trial that was looking at patients from the age of 18 to 65 that had at least three rib fractures. And they randomized 91 patients to either ketamine, 2.5 micrograms per kilogram per minute, versus a placebo, which was standard of care. And their primary outcome was looking at the reduction in the numeric pain score at 24 hours. As far as key demographics, number of rib fractures was a median or mean of six. They had an injury severity score of around 13 to 17. About 45 to 55 of these patients were actually in an ICU, and about 83% of these patients did receive ketamine for greater than 36 hours. And for their outcome, they actually did not find a significant decrease in that numeric pain score at that 12 to 24 hour, nor did they find it for the 24 to 48 hour time marker as well. In addition, for their secondary outcome, they did look at oral morphine equivalents, and they did not find a decrease in between the two groups. Of note, they did do a subset analysis, which examined patients with an injury severity score greater than 15, which they did find a decrease in their opioid requirements. And so, the authors concluded that potentially it's maybe the more severe patients that maybe might be beneficial with ketamine. So, thanks to considering clinical practice. So, again, this is another agent that is hepatically metabolized, considering cardiovascular monitoring, as well as the psychomimetic effects. I think for our patient population, we've kind of added on that opioid as well as maybe non-opioid tolerant patients might benefit from ketamine, as well as there might be a potential as an adjunct, not only analgesia, but sedation for these patients. Further evidence that I think that we might need with ketamine is more pharmacokinetic data in our critically ill patients, primarily cirrhotic patients, patients with heart failure or poor perfusion. Comparison of different dosing strategies, as well as clinical outcomes. I think we've kind of established somewhat that, you know, ketamine does have opioid sparing properties, but how is it as far as, you know, does it make the patient mobile? Yeah. And the length of mechanical ventilation would be interesting to look at. Optimal duration of therapy, as well as there's little, limited in literature on the impact of delirium with ketamine. And then it would be interesting to look at comparative trials to other adjunctive therapy. So with that, I would just want to thank the CPP Committee, as well as my mentor, Russell Roberts and Steven Lemieux. Thank you. Thank you, Dr. Lopez. And again, we'll be holding questions until the end, and we'll have a panel discussion. Our next presentation is by Dr. Jessica Elifritz, who is a clinical pharmacist who practices in the hematology oncology medical ICU at The Ohio State University. Notice I got the the in there. I live in Ohio, therefore I know that is a required part of The Ohio State University. And her topic will be one that is near and dear to her heart, I'm sure. It is managing a new frontier in medicine, caring for the hematology oncology critically ill patient. Dr. Elifritz. So I'd also like to thank the Programming Committee with CPP for inviting me to speak on this topic. So my learning objective is going to be to describe management strategies and associated complications of emerging and novel therapies for the critically ill hematology oncology patient population. But I'd like to start by talking a little bit about hematology oncology critical care in general. Over the past decade, we've definitely seen an expansion in these services, with estimates of 15% of cancer patients occupying ICU beds at this point. So several factors have contributed to this. One is the rapid development of novel treatments, as well as improved survival of hematology and oncology patients. But with these novel treatment options, including targeted therapies and immunotherapies, we're also seeing increased complications that are going to require life-sustaining treatment in the ICU setting. So when hematology oncology patients are admitted to the ICU, the critical care pharmacist is faced with balancing the patient's acute illness, along with any chemotherapy, chronic immunosuppression, as well as the underlying cancer diagnosis. So to do this, there's some important things that you should be aware of. The first is making sure you're obtaining a thorough oncologic history, and this should include any chemotherapy or immunotherapy that the patient has received. Next is going to be recognizing toxicities, as well as complications, so that you can make appropriate recommendations. And the third thing, and I can't stress this enough, is going to be collaborating with hematology and oncology practitioners as you're providing care. So as critical care pharmacists, we've all definitely cared for cancer patients. And I think a lot of us are more familiar with some of these multitudes of complications. So the infectious complications, metabolic, or other complications, such as thromboembolism, diffuse alveolar hemorrhage. What people might be less comfortable with are going to be some of the treatment toxicities. And what I'm going to focus the remainder of this talk on are going to be the toxicities due to targeted agents and immunotherapies. Specifically, chimeric antigen receptor T-cells, as well as immune checkpoint inhibitors. And I will be taking a slightly different approach to probably what you've seen for traditional pharmacy urine review. As I really want to focus on identifying these toxicities, as well as providing the audience with resources to use when you encounter these patients in clinical practice. So I'll start with chimeric antigen receptor T-cells, or CAR T-cells. So briefly, CAR T-cell therapy involves obtaining T-cells from a patient, genetically modifying them to express chimeric antigen receptors that then targets various markers on end cells. In this case, tumor cells. So there are currently two FDA approved agents. These both target CD19 and are used for select hematologic malignancies. We do see complications frequently, though, in patients that receive CAR T-cell therapy. So most commonly, cytokine release syndrome, or CRS. And then neurotoxicity, which is now termed immune cell associated neurotoxicity syndrome, or ICANS. So with these toxicities, we're seeing activation of the T-cells that then interact with macrophages, either via T-cell derived cytokines or co-stimulatory receptors. These macrophages are then producing a variety of cytokines and chemokines, including interleukin-1 and interleukin-6, which are causing these end organ, or these toxicities, specifically CRS and neurotoxicity, or ICANS. So patients that are treated with CAR T-cells do experience with a good deal of frequency these toxicities. However, we're starting to get some real world data outside of the clinical trials. So what's presented here is actually a real world in 274 patients at various centers who received CAR T-cell treatment. And it's from a group out of MD Anderson that published the authors Nostrophil and colleagues. So they reported that cytokine release syndrome occurred in 92% of patients, with 7% experiencing the more severe toxicities of greater than or equal to grade 3. And then ICANS occurred in 69% of patients with 33% experiencing more severe grades of greater than grade 3. Of note from this real world abstract, 32% of the patients required admission to the intensive care unit. So this diagram outlines the timeline of when you expect to see toxicities. So prior to T-cell infusion, patients are going to receive a lymphodepleting conditioning regimen. And then on day zero, we'll receive that T-cell infusion. Cytokine release syndrome most often occurs within 10 days following infusion. But the median time to onset is three days. While ICANS can be biphasic and can occur early and concomitantly with cytokine release syndrome, medium time to onset of six days. But it also can have late onset. So cytokine release syndrome is defined as superphysiologic response following any immune therapy that results in activation of endogenous or infused T-cells or other immune effector cells. It's going to be driven by the release of cytokines. And some key hallmark features are fever, hypotension, as well as capillary leak. And if it's not appropriately recognized and treatment initiated promptly, you're going to see progression to multisystem organ failure and potentially death. So it is a medical emergency that again warrants appropriate identification and prompt treatment. So you probably on that last slide were noticing some similarities between the clinical presentation of septic shock. And that's going to be one of the more difficult things to distinguish in clinical practice. So this is a 34-year-old patient with refractory diffuse large B-cell lymphoma who received CAR T-cell infusion. And this is going to outline her clinical course following that infusion. So you can see on day two she began to develop fevers. So at that time with her being neutropenic, workup and management of febrile neutropenia is important. So obtaining appropriate cultures and infectious workup as well as beginning broad spectrum antibiotics. But however, she's also in the timeframe where there's clinical concern for cytokine release syndrome which would also present similarly. So you really have to concomitantly manage her cytokine release syndrome with sepsis or potential neutropenic fevers. So this patient on day three continued to be febrile as well as had some new hypotension. So before returning the case, I want to go through some of the national guidelines that are available. So this was published in 2019 from the American Society of Transplant and Cellular Therapy. This is consensus guideline for both. They have cytokine release syndrome as well as for ICANs which grades from one to four with the grade four being the more severe symptoms as well as life-threatening side effects. With this guideline, these guidelines are mostly being what's adopted by a lot of centers across the United States and kind of being used as the gold standard. You will notice that any grade fever is going to be a hallmark symptom. But then the severity is also going to be based off of hypotension, need for vasopressors as well as hypoxia. So the mainstay of therapy for cytokine release syndrome will be tocilizumab which is an anti-IL-6. It's dosed at 8 mg per kg every six to eight hours and you can give up to four doses. Another key component is going to be corticosteroids. And so I think this is one thing that critical care pharmacists and practitioners have kind of had drilled into their mind is that we should avoid steroids at all costs in cytokine release syndrome because we don't want to blunt the T cell response of the CAR T cell treatment. However, this viewpoint's been challenged recently. We might still hold off on being as quick to pull the trigger on stress dose steroids in the setting of septic shock. However, if patients really are exhibiting cytokine release syndrome or ICANs and they really need to be promptly started on corticosteroids because that's going to be a key part of actually treating and preventing progression of those symptoms to the higher grades. And there's a few different studies that are now looking at is there actually a blunted T cell response and it appears that there's probably not as big of a concern as initially had been thought. So this is the treatment algorithm for cytokine release syndrome. And we don't have an updated algorithm yet from the American Society of Transplant and Cellular Therapy. We're expecting those to come out within this year. So this is based off of the CAR TOCS group out of MD Anderson. And most centers will have a similar algorithm with some specifics for their center. But you can see that tocilizumab is going to be the mainstay of treatment and should be used in grade one if fever persists for greater than three days and any grade two. When you have ongoing toxicity in either grade three or grade four, that's when corticosteroids should be administered. So dexamethasone, 10 milligrams every six hours. And then for grade four using methylprednisolone, one gram IV daily. That's given for three days with then rapid taper. There's going to be a lot of supportive care measures and this is going to be a key component for any critical care pharmacist to play. So administering fluids like you would for other distributive shock states and assessing fluid responsiveness and then managing vasopressors. We also see the development of multi, or you can see the development of multisystem organ failure or just other isolated organ toxicities. So supportive care for those organs is also going to be very important. As I mentioned previously with cytokine release syndrome, you're definitely concurrently also managing sepsis. And with this being a very immunocompromised patient population, you need to make sure you're assisting with thorough workup for any, not just bacterial infections, but also antifungal or viral illnesses that could occur. So to continue through this patient case, who remained febrile on day three and had new hypotension, fluid administration was started as well as norepinephrine and two doses of tocilizumab were given. However, the patient continued to have her symptoms progress. And on day four, you can see ongoing fevers as well as new hypoxia. So ultimately, her norepinephrine doses escalated. She also had increased, or decreased urine output and required intubation and transfer to the ICU. So she definitely meets grade four and should be started on high-dose methylprednisolone one gram daily. So ICANS is going to be the other hallmark toxicity associated with CAR T syndrome. So global aphasia is going to be the main thing that you see with the neurologic symptoms. But you can also see tremor, myoclonus, impaired attention, muscle weakness. Seizure and cerebral edema with increased intracranial pressures are going to be the more serious side effects that can develop. And in order to screen for ICANS, the immune effector cell associated encephalopathy score or ICE score is used. So this is performed daily and documented in the patient chart. This dysgraphia, which is shown at the bottom, shows how rapidly these symptoms can progress. So this is just a handwriting sample one day apart. And you can see the rapid decline there. So similar to cytokine release syndrome, ICANS does have grading. You can see the ICE score as well as a depressed level of consciousness decreasing as you go from grade one to grade four. And then any seizure or elevation in intracranial pressure would classify the patient as either grade three or grade four based on the severity. I do want to note when you see seizure in these patients, it's usually nonconvulsive. So obtaining EEG is going to be important to monitor for development of complications. There also is a treatment algorithm. Some key things to note is that there's really not a role for anti-IL-6 therapy with tocilizumab unless there's concurrent cytokine release syndrome occurring. So corticosteroids really are going to be the mainstay with patients that have either grade two or grade three ICANS receiving dexamethasone 10q6 or methylprednisone 1 gram mg per kg Q12 hours. And then with the higher toxicity of grade four receiving methylprednisone 1 gram IV daily. Supportive care measures are going to include seizure prophylaxis for all patients. Usually levotriocetam is used just due to lack of side effects and ease of monitoring. And then definitely monitoring for development of severe complications with EEG, LP if not contraindicated, as well as head imaging. If any seizure or elevations in intracranial pressure occur, you really would use the same treatment that you would for other patient populations. So there's not one anti-epileptic drug that's been proven to be superior. You would, for ICP management, you would use hyperosmolar therapies. So nothing differently that you need to do for this patient population should those occur. I do also want to mention with both CRS and ICANS and these high doses of corticosteroids, there's been some recent literature regarding invasive fungal infections, and specifically infections due to molds, estimates between 2 to 7% in patients post CAR T cell infusion. So this is an area you should definitely be aware of and be monitoring your patients closely for. And most centers are beginning to make recommendations for adjustments to kind of their prophylactic strategies. So prophylaxis against infection during treatment of these patients is something you kind of can't forget to also be working towards. So I do want to point out some additional resources and guidelines that you can utilize if you do see these patients. So I already talked a little bit about the CARTOX and their treatment algorithm. And then there's the American Society of Transplant and Cellular Therapy, which I think is kind of becoming the gold standard of guidelines that people are using. But we don't have an updated treatment algorithm from this group yet. We're expecting one soon. And there's also guidelines from the National Conference of Cancer Network. There are some phone applications as well. So this could be something if you don't encounter these patients often that you might want to consider downloading to use. So even though CAR T cell therapy has gotten a lot of publicity, I want to also talk about another class of medications, the immune checkpoint inhibitors. So these are medications that have become very widely used in cancer treatment regimens over the past decade. They are another type of immunotherapy. And there's a few agents that have been used, but there's many more that are actively in clinical trials. So I would expect to see even more of these within the next few years and decades. So this type of immunotherapy is going to activate cytotoxic T cells. The way that it does it is by inhibiting signaling, specifically CTLA-4, PD-1, or PD-L1. And so by disrupting basically these checkpoints that in the human body are used to kind of downregulate the immunosystem, the immune system, cancer cells are actually taking advantage of these and evading destruction. So these agents act by blocking that signaling to activate the immune system and T cells and ultimately lead to destruction of the cancer cells. And like I said, they have shown an increase in survival, so we're seeing them utilized in a lot of treatment regimens. The first two that were developed were ipilimumab and nivolumab, and there's even more that are under development with an expanding use of indication for these medications. The reason that we care about them definitely in the ICU is going to be related to their adverse event profile. So the activity of the T cells is what causes them to be effective, but it also can cause immune-related adverse events. And so I'm going to highlight a few. They can impact any organ system, but there's definitely ones that you commonly would see in the intensive care unit. So in my practice in a medical ICU, I see a lot of pneumonitis as well as gastrointestinal complications like colitis. There's definitely endocrine toxicities. So you might see a patient be admitted with DKA due to new onset type 1 diabetes. You can also see hypotension due to adrenal insufficiency or either hypo or hyperthyroidism. And then there's an increasing reporting within the literature of cardiovascular toxicities like acute myocarditis as well as neurologic toxicities like Guillain-Barre syndrome or myosinia gravis. So this is why I want to highlight getting that good patient history is very important because I think many of us are probably encountering these in practice, whether we are identifying them or not as being the causative agent. And it can be challenging to differentiate these toxicities from other syndromes that patients might present with. To illustrate that, this is a 54-year-old patient who came to the ICU with fever, hypoxia, and hypotension and did have ARDS with a P to F ratio of 80. Important past medical history was melanoma with meds to the brain and lung, COPD, and depression. And they had received the immune checkpoint inhibitors nivolumab and ipilimumab cycle 2 three weeks ago. In terms of differential, definitely this patient could have pneumonia or a COPD exacerbation. Or it could even be that they have progression of their lung meds as all possibilities for the respiratory failure. But something that we shouldn't overlook is going to be the possibility of pneumonitis secondary to nivolumab and ipilimumab. So, in practice, it can be difficult to differentiate these. But something that you really need to look at is going to be the timing of onset. The incidence of these immune adverse events are going to vary based on the specific agent and specific organ that's involved. However, meta-analysis of various clinical trial data puts this at 15 to 90% with severe immune-related adverse events occurring in 0.5 to 13% of patients. There is a much higher incidence when combination therapies are used. So, in this patient case, for example, they got ipilimumab and nivolumab combination. This chart on the right shows that the timing is usually going to be within weeks to months of initiation of the agent. You can see gastrointestinal, hepatic, and pulmonary toxicity were about a median of 7 to 8 weeks, while some of the endocrinologic toxicities have a longer time to onset of 10 weeks. And then, basically, there's not a whole lot of data, but there are ongoing efforts to categorize some of the more rare cardiovascular and neurologic toxicities. So, the time was 65 days for cardio with a range of 2 to 454 days with neurologic toxicities being reported within 2 months in regards to case series that are available. So, with management of immune-related adverse events, they're definitely going to be graded with grade dictating the treatment. Mostly in the intensive care unit, you're going to be seeing grade 3 or grade 4, where patients will receive prednisone at a dose of 1 to 2 mg per kg per day or equivalent. Now, patients that receive steroids are generally going to be treated with longer courses, over 4 to 6 weeks with taper based on response. But, there are patients that are steroid refractory, and this is where things become less defined in terms of what agents should be used. Generally, if patients don't respond within 48 to 72 hours of steroids, a second agent should be added. Some that have been evaluated are mycophenolate and calcineurin inhibitors. In terms of colitis and fliximab, as a single dose, either 5 or 10 mg per kg has been used. And then, with either neurologic toxicities or the acute myocarditis using IVIG or plasmapheresis, and with acute myocarditis, there's also some data with rituximab as well. So, again, there's many guidelines that are available. These are just a few that I want to point out. And really, if you are seeing a patient with this toxicity, you should go to the guidelines to see if there's any other organ specific management that should be used. And so, I'll conclude by just saying that hematology, oncology, critical care is going to be a growing field. There's a lot of novel therapies that are going to have complications. So, as an ICU pharmacist, you need to be able to recognize these. And with it being an evolving field, expect many updates to guideline recommendations as well as evolving data out there about really when these toxicities occur and what the most effective treatments are. Thanks. Thank you. Thank you, Dr. Ella Fritz. Our last presenter of this session will be Dr. Cassie Barton, who specializes in trauma surgery and emergency medicine at Oregon Health and Sciences University, and she will be giving an update on emergency medicine. Dr. Barton. Thank you, guys, for coming, and thank you to the section for having me. I'll hop right in. I was given the objective to just cover what happened in emergency medicine within the last year. No financial disclosures, but I'm pretty sure I'm talking in exclusively off-label indications for all of these medications. So bear with me. This is my only reference to my title, but today I'm going to discuss two trauma-related articles, ESET, which deals with status epilepticus, and then a glucagon review, because it's a pet peeve, honestly. But it was a busy year in emergency medicine, and we have a lot of topics and different articles that could have been easily presented in this format as well, and so there's lots of reading to be done. So I'm going to start out with trauma, and we're going to talk about tranexamic acid. The idea is actually using it in a fairly novel way, which would be in traumatic intracranial hemorrhage, TBI or ICH. The idea just being that you're going to stop bleeding, you're going to stop progression of bleeding, and then stop sequelae that you get from those problems. It has an excellent safety profile over many years, and we have used tranexamic acid in bleeding trauma patients for a while now. The idea of using TXA in TBI has been around for a bit, and while these studies are small and they have different inclusion criteria in different sizes, they all seem to have a lot of the same signal, which is decreased intracranial hemorrhage volume expansion. So if we can make these bleeds smaller or not allow these bleeds to get bigger, can we improve outcomes? So CRASH-3 decided to look at just that. Can tranexamic acid prevent or reduce intracranial hemorrhage expansion and improve outcomes? It was an international multicenter RCT, and they used the classic trauma dosing, one gram bolus followed by one gram over eight hours versus a matched placebo. They included all patients with a traumatic brain injury, and that was either a GCS less than or equal to 12 or an intracranial hemorrhage on imaging. They had to be there within three hours from injury. There's an asterisk there because they started out at eight hours, but then when the CRASH-2 data came out showing there's likely a more benefit within a shorter amount of time, they readjusted this, and they readjusted their power calculation. We're very upfront about it. And then they excluded patients, really very few patients, to be honest, but they did do a pre-specified analysis and said upfront that they're going to analyze the data when you take out patients with a GCS of three on admission or unreactive pupils, so those less likely to do well. Well what'd they find? First off, they had a 10,000 patient recruitment goal, and they did not meet this. The population looks like a trauma population. It skews young and male. They had low incidence of hypotension, but they did have a severe TBI population, so that GCS score of three to eight was a large percentage of their population, about 40% in both groups. So what did we find? Does it work? Well, no, there's no difference between groups. So there is, when you use the entire population, there is not a difference in head injury-related death within 28 days of patients who receive this therapy. And then if you do that pre-specified analysis where you take out the people that they don't think are going to do well, the same is true. You can see that the null value is included in both of those confidence intervals, therefore we say that this would be a negative study. No, don't worry, we didn't stop there. So if you look, actually, at a different subpopulation, the GCS in the mild to moderate groups, GCS of nine to 15, it actually shows that there's a signal here. Maybe it's beneficial in this population. Dive down further, and maybe the earlier we give TXA, the better their outcomes are. It's a temporally related difference here. No difference in the severe GCS, those with GCS of three to eight, no difference when you gave it. Maybe the dye was already cast before you were able to get to them with TXA. Well, it's an interesting article, though, right? It's a large randomized control trial, the biggest one on the topic to date, well-blinded. They were very fair in their analysis, I do believe. But I think that it's going to be hard to apply this data. Not all TBI patients benefit. They didn't meet their goal. While the population was quite large for a study of this kind, the confidence intervals are still pretty wide. And then if I get to keep being picky, I feel like I'm getting a little nitpicky this far down the list. But there was no measurement of hematoma expansion, which you can do in most types of head injuries. You also didn't know if they had a VTE screening protocol, so potentially if there was safety outcome differences, you're not really sure what that happened. And then if you believe the data coming out of Denver about hyperfibrinolysis or fibrinolytic shutdown, they didn't measure these parameters. So there's potential in here that there are subpopulations that could either very much more benefit or even have a detriment to tranexamic acid therapy. So what do we do now? Well, we wait for the ROC data to come out. So there's a resuscitation outcomes consortium that I was really hoping was going to have this paper published by now. But they actually are looking at pre-hospital tranexamic acid in this population. Different dosing regimen. They looked at a 2-gram bolus or the classic 1-gram, and then 1-gram over 8 hours versus placebo. And they're going to have some interesting data as soon as that's published. So hold tight. The answer is coming. Sticking on the pressors or the trauma track, can we use vasoactive agents for hemorrhage? No gasps. I was expecting a couple, but the classic teaching is you do not give pressors to bleeding trauma patients. You're going to make them bleed faster. That's a classic teaching that I've given to my students and that I've received myself. But if we look a little bit deeper, there's actually human and animal studies that show that patients who are in hemorrhagic shock actually have very low vasopressin levels. And this could probably be for a lot of reasons. They're used up. They're endogenous stores. It left them when the blood left their body. And then they're replaced with component therapy or whole blood that has a low vasopressin content. There's a couple reasons that could be. And so the idea being that if we replace the vasopressin content in these patients, you can restore appropriate vasomotor tone. You're going to be able to direct blood flow where it needs to go and even, you know, help with platelet function and fix it. So a group out of Pennsylvania, I do believe, the AVERT shock trial asks, will vasopressin decrease blood product need in hemorrhage? Straightforward. It was a randomized double-blind placebo-controlled trial. They gave vasopressin as a bolus of four units, followed by a titratable but capped at .04 unit per minute infusion versus a matched placebo. And they included all adult but not elderly trauma patients who were actively bleeding. So six units of product within 12 hours of injury. They excluded patients that were likely not going to really benefit here or had other resuscitation limitations on board. They looked at how much crystalloid they received and other blood loss outcomes. So when you look at the results, you find that it's a relatively small trial, about 50 patients in each arm. Again, it skews towards the classic trauma population, young and male. But of note, it has a very high rate of penetrating mechanism of injury. And so 80% of these patients were shot or stabbed. That may limit external validity depending on what your trauma population sees. The source of the hemorrhage was the chest or abdomen in everyone. And they looked like bleeding trauma patients. They were tachycardic and hypotensive. But they found out. I think this is the most shocking trial I'm going to give to you right now. Well, that and ESET. But they were able to cut the amount of blood product that they gave these patients in half from three liters to 1.7. It's a small trial, but that's a big difference. That's true if you broke it down into each of the components of therapy. The crystalloid remained the same. Interesting, the estimated blood loss remained the same. And of course, because they were getting one vasopressor, the group that got vasopressin needed less norepi than the other group. So the big, they weren't powered to find out if there was adverse events between the two groups. Like, let's just be honest. They are not going to be detecting big differences in adverse effects. But there was no increase that they found in complications. And they decreased the amount of blood product they gave these people. I don't think that the story is done with vasopressin in bleeding trauma patients by any means. But this is an interesting study. Okay, totally changing gears. Anti-epileptic drugs in patients who have already failed. Okay, so we know we need to fix status epilepticus when it shows up on our door, right? You need to avoid an ICU admission, adverse outcomes up to mortality in children. There's no question. Benzos are first line of therapy in status epilepticus. I don't think that's up for question. And it probably won't be. The real question is, okay, that didn't work. What's next? What is my second line therapy? And the 2016 guidelines came out. You have three options. You can use levotiracetam, valproate, or fosfinitoin. Now, the data supporting each of these suggestions of second line therapy is shockingly bad. Levotiracetam and fosfinitoin are listed as second line agents in status epilepticus with a level of evidence of U. I reviewed that. I was shocked. I didn't remember that before ESET. And there's really no agent. So the ESET trial is looking to find out which anti-epileptic is best in patients who have failed benzos. So this was a prospective multicenter randomized blinded adaptive trial. Remember, adaptive is the cool way you can do a trial where you can adapt it as it goes on. And maybe the arm that's showing the most benefit, you can move more patients into that arm, suggesting that they'll get more beneficial treatment. You can do the study with fewer patients over a shorter amount of time. It's a cool idea. The intervention. Levotiracetam, 60 mg per kg. So this was the update in the 2016 guidelines. And a lot of people really adopted this. So you only have to be 75 kilos to get 4.5 grams of Keppra when you walk in the door. That's a lot of Keppra, right? But it's been around for a while. If you look at the data that that's supported on in those guidelines, it actually is minimal. And everything that they reference and that you can find is 20 per kilo. But they talk about ESET coming out. And they'll be able to prove it based on this trial. Interesting approach. Fosminatone, dosed at 20 mg per kg. Classic dose. I think the cap might be a little bit low at 1,500 milligrams. You'd ask a lot of people. And 2 grams is what you're going to hear more often. And then you have Valproate at 40 mg per kg, maxed at 3 grams. They included children and adults aged 2 years of age and older who have seized for 5 minutes. They got a dose of a Benzo. And then they continued to seize for at least 5, but not greater than a half an hour. So that's who we're looking at here. That's the time course as to where you're getting to them. So they could be quite a ways into their seizure that day by the time you saw them in this study. The primary outcome was absence of seizures and improving responsiveness at one hour without need for any more anti-epileptic drug or intubation. And then they, of course, looked at safety and other outcomes. What'd they find? Okay. So they found the group seemed fairly balanced. They have a young age, average of 33, split between male and female. Majority had a history of epilepsy. They do have the lorazepam dosing listed here. So on average, they got about 5 mg of lorazepam. So you could argue that this might not be optimized. You could definitely give more Benzo up front. But I think it's fairly real world what we would see. And they had been seizing. Remember the whole timeline. They could be in there. They'd already been seizing or in status epilepticus, I should say, for about an hour each before they were randomized. So what'd they find? Ugh. All of our agents work less than half the time? Yikes. So 45 to 47% of the time, your second line AED is going to work. No differences in ICU admission between the three groups. No differences in length of stay were found. This is just a visual to show you how overlapping these three arms are. They are almost identical. When you look at adverse, you know, your safety outcomes, there's no differences either. There's maybe a little bit more hypotension and phosphonatone. It's probably a room full of pharmacists. Everybody goes, that was expected. But then if you say that, you kind of always have to look and be like, well, death was increased in the Keppra group. But nobody ever mentions that little guy. But really, these are all non-statistically significantly different. So really, there's no differences in any of these safety outcomes. So what do we say? Well, I mean, the statistical conclusions are pick whatever one you want. And but I think the more nuanced answer is all second agents fail. All second line agents fail more than half the time. So really, start thinking ahead. So when you're giving that second agent, when you have a patient who's failed benzos and you're, you know, asking the pharmacist to get you phosphonatone or you're going for the levotiracetam, really, you should probably be thinking about what your next step is because chances are that's not going to stop this. Also, there's been a lot of talk about like this proves that if you're going to dose levotiracetam or Keppra, it's easier to say. If you're going to dose Keppra, you need to go big or go home. Like that's what a lot of people have said. I don't think that that shows that. I think that it shows that you can go big with your levotiracetam dosing and there's not any difference. But if there's two other trials that came out this year that I don't have time to cover here which are CONCEPT and Eclipse, and yes, they're pediatric, but they compare phosphonatone to Keppra as well at a dose of 40 mg per kg and they also show no difference. And so really, I feel like this shows that you can go big with your levotiracetam dosing. But really, is it superior? I don't know that that has been set yet. Oh, and last but not least, glucagon. I feel like glucagon for esophageal impaction comes back every couple of years, cycles back through. All right, so medical management of esophageal impaction is preferred, less costly, less risk. And in the guidelines, glucagon is listed as a potential treatment option. But the studies showing its efficacy have been mixed and there's a significant cost and side effect profile associated. There was an analysis that came out in pharmacotherapy this year looking to try to put this question to rest, really does glucagon work in this clinical scenario? Their inclusion criteria were just all trials in humans that had a comparator arm, not a high bar to meet. And they looked at treatment success and then rates of adverse effects and time to resolution. They found five studies to be included, vastly different sizes and locations. Most of these were in the emergency department, but some were not. And the dosing was 1 mg of glucagon and the dose could be repeated. A lot of these trials also allowed other agents, including benzodiazepines or nitroglycerin. And they defined success as clinical signs and symptoms, except for the pediatric study that looked at coin impaction, and they used radiographic evidence to make sure that that coin went down. So what did they find? That there's no difference, that glucagon is as good as placebo and it is associated with more adverse effects. Don't do that anymore, please. Thank you for your time. Thank you, Dr. Barton. I'll ask our other two presenters to come up in case there are any audience questions. I think we have time for one or two, depending on how long the question is. If you have a question, please approach the microphone. I have a question regarding two things. One is the mention that, like, you know, the pediatric population, that the 40 mg per kg compared to phosphonatant, there was no difference. So my concern is why we are concerned with 60 mg per kg load when there's a max dose of, like, you know, 4.5 grams, actually, in the trial. That's the first question. The second question is, how do we, they use the phosphonatant dose of max 1500 mg in the trial. I come from the state of Wisconsin where, like, you know, it's 100 kg and 120 kg patients over there. So how do I dose them with phosphonatant? That's a great question. I think for safety, oh, I'm going to answer your, I'm going to ask you to repeat your first, what was the first question, was it, it was about the Keppra dose, I apologize. I think what the statement was that, like, you know, that 60 mg per kg of Keppra is probably a higher dose and maybe not be superior to 40 mg per kg of Keppra which was used in the pediatric population. So my question is, why is there is a concern, like, you know, even if we are doing 60 mg per kg when there's a max dose of 4.5 gram because in terms of the side effect profile, even if you do 40 mg per kg versus 60 mg per kg, how is that going to make a difference because the goal over here is stopping the seizures, right? And maybe if I do 60 mg per kg, I may stop the seizure. They may wake up, like, you know, mean, but I stop the seizure. Yeah, I think that, I think that that is a classic thought, right? So the question is, well, you guys all heard, but that's not shown. It's shown that even if you go big in that study, you still failed. More likely than not, it didn't work. And I feel like that's all of our classic thought is more must be better. And I think that this study shows that even if you maximize your Keppra dosing at 60 mg per kg that it fails the majority of the time. And I don't mean to say that I think in adults or even in a mixed population that 40 mg per kg of Keppra is equivalent to 60. I'm saying that that hasn't been proven, that I think most of the data out there is at 20 mg per kg, especially the data that the guidelines are based on. And really, there hasn't been a comparator at the higher end of the recommended dosing because there's such little literature on this topic. And so I think that when you look at a lot of the blogs that are out there and a lot of the teaching and the slides that are being presented, at least locally for me, they say, you know, go big or go home on your Keppra dosing. We have to give everybody 60. And I just don't think that that's honestly proven in the literature. And then phosphonatone dosing, how do you dose it in a large, large person? I think you bolus and you cap, some people would argue that you could increase that dosing cap to 3 g of phosphonatone in larger populations, but you run into safety and side effect problems. And I think that you have a lot of options there and you could either, seizing obese person is a problem. And I don't know that I have a succinct answer for that. I apologize. So in terms of like, you know, the 50% which you mentioned about like stopping the seizure, which is not a surprise, because if you see the VA cooperative study, it showed that it's not that like, you know, it's going to be higher rate of like, you know, stopping seizures. So I think it's not the idea of the study was not to see what rate it was. It was comparing three agents, right? And seeing like, you know, whether one is superior than the other, which clearly there's no winner over here. It's just we have to use the right dose to stop the seizure. And that was probably like, you know, the main thing, because I see a lot of ER uses like, you know, one gram of Keppra for every seizure patient coming to the ER, which is not the right thing either, right? So I'll just jump in and ask this dialogue to continue after the end of the session and have one more question. Yeah. I hope it's not about anti-epileptics. Oh, you know it is, Seth. I mean, come on. Yeah, sorry. But I will have another one if I can squeeze it in. But just one comment on the study, on the ESET. Couple things that, from the clinical standpoint, please don't forget. Number one, the dose was an underdose for all the benzodiazepines. Like 80% of patients were underdosed. They did not receive the 0.1 milligram per kilo and the 4 milligram max that we recommend in the guidelines. And they got a cumulative dose that made it to that point. It's our first dose that counts. So you've got to dose it right. Give 4 milligrams of lorazepam when you're going to treat status. In regards to the other AEDs that they looked at, they also didn't put them on until an hour later. We want to stop status within an hour. So we're already behind the eight ball. So we've already got possible GABA, internalization of receptors, different things. So in all reality, I think the biggest thing it showed is we do this all wrong. We need to give the right dose of benzodiazepines up front, give a good dose to get good levels on the phenytoin or phosphenytoin and the valproate. And then, again, I agree with you, 3 grams versus 4,500. Nobody said one's better than the other for this. And just be aware they do have the behavioral side effects with the levotrastamine, especially in our neurocritical care patients. We presented that data at NCS, and it's got a very high behavioral ADR in these patient populations. Just critically evaluate that article for yourself, because there's a lot of things that we aren't doing right that we need to do better. And then I had a question on the opioids. Have we missed the boat in that we don't do enough pre-op dosing of medications to really help us then post-op so we don't get that hyper pain syndrome post? Yeah. There is literature looking at just plain surgical patients, not in the ICU. So I didn't address that. But yes, I think we do miss the boat, and that's something that at Mass General we try to practice our surgical intensivists is, you know, dosing them with an agent prior and then hopefully seeing that decrease after. Typically using even methadone prior to can decrease their opioid, overall opioid requirements post-operatively. Thank you. Unfortunately, we've run out of time. I'll ask our presenters to join me afterwards in case anybody else has any additional questions. Thank you all for your attendance, and hope you have a great rest of your day.

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