Thank you very much for having me today. I'm honored to talk about this. Now, it's a pretty large topic to cover in 15 minutes. Here are my disclosures related mainly to pulmonary hypertension. So today, I'll be reviewing toxicities of immune checkpoint inhibitors and other targeted therapies for cancer, specifically looking at immune effector cell therapy, specifically cytokine release syndrome and ICANS, which is the neurotexicity associated with immune effector cells, toxicities related to monoclonal antibodies, and immune checkpoint inhibitors. So really, when I think about the toxicities that occur with these remarkable therapies that have come out on the market in the last 20 years that have changed the way that we look at cancer therapy, I try to understand, what is it trying to do? We've talked a lot at this conference, I feel like, over the last few days about immune dysregulation, particularly in relation to sepsis and immune paralysis. Well, in immunotherapy, we're doing exactly the opposite. What typically happens with your cells is that your T cells should recognize the non-self cells, i.e. cancer cells, and kill them. Well, the cancer cells then develop immune editing, and they evade our natural immune responses. So immune therapy is just revving up your immune system to then kill the cancer cells. And so when we look at that, it's the immune effector cell therapy, specifically CAR T, which has revolutionized our hematologic malignancies and improved outcomes, but is associated with some pretty severe and potentially fatal toxicities. Monoclonal antibodies, which also have a number of toxicities, and immune checkpoint inhibitors, which, again, has revolutionized some of our solid organ malignancies, specifically in lung cancer, sarcomas, melanoma, breast cancer. The toxicities are mainly related to this immune response, so the hyperinflammatory response that leads to end organ damage. We can also have antigen-mediated that is an on-target, off-tumor effect. And that recognition of the tumor antigen causes some unwanted side effects that ultimately lead to organ failure. And this is when they present into our intensive care units. As I mentioned, it's exploded over the last 10 to 20 years. And we're going to continue to see an explosion of immunotherapy. There is over 200 CAR T trials out there right now, looking at not just in hematologic malignancy, but solid organ tumors, and even autoimmune disease. So at some point, you will always see a patient in your ICU that has a toxicity related to this or is undergoing treatment with it for an oncologic diagnosis. This is just really a few of the different therapies, and just to show that it continues to increase over time. Specifically, looking at CAR T cells. As I mentioned, it's been a revolutionary therapy. It's very exciting, because it has a durable and lasting response. And patients who were relapsed or refractory are now living longer. And so that's incredible. But what can happen is they can develop CRS and ICANs. So when you think about CAR T therapy, it can be autologous, which is the majority of the patients receive, or allogeneic. So with the autologous, the cells are extracted from the patient. They then undergo some viral, they use a viral vector to inject the antigen into the cell. The cells undergo expansion. The patient receives conditioning therapy, and then the cells are re-infused into the patient. It's considered a living drug, because it has a durable and lasting response, which is important to note, because some of the effects of CRS depend upon when that expansion occurs. So in some forms of CAR T, it can happen within the first one to two days, where you have more rapid expansion of the cells, leading to an increased inflammatory response and cell death. Or it can be a slower expansion, and that may happen in the next four to six days after infusion of the cells. So there are six different CAR T products out on the market for relapse or refractory lymphomas, and more recently, multiple myeloma. As I mentioned, there is a number of toxicities. Specifically, we hear about CRS, which during COVID became a hot topic as well, but was familiar to many of us taking care of these CAR T patients prior. And then immune effector cell associated neurotoxicity are easier to say ICANs. HLH, or macrophage activation syndrome, tumor lysis syndrome. Delayed effects can be hypogammaglobulinemia or B-cell eplasia. And then infection. Infection is always key in these patients, and even bacterial and invasive fungal infections can occur. Today, we won't touch on that that much, but any of us that are intensivists will always have antibiotics on board in these patients. CRS is a clinical syndrome that's really a super physiologic response that is in reaction to the CAR T cells. The prevalence varies, and it depends on the CAR T construct, but majority of patients will have a form of CRS. Severity of CRS can occur in about 30% of patients, so will land in the ICU. And about 20% of patients require high dose vasopressors. It usually appears within the first seven days, but again, it can vary depending on the CAR T construct or the underlying malignancy, and can even occur at about 10 weeks time. This is looking at what happens at the cellular level, and it's mainly driven by a cytokine release. So the cytokines that we focus on are typically IL-6 that corresponds to the peak of your CRS, IL-1, TNF-alpha, interferon gamma, and that determines the severity. We know that higher levels of interferon gamma and IL-6 correlate with SOFA scores and overall morbidity and mortality. Here's a schematic looking at the time frame from when you would see peak CRS and ICANNs. CRS and ICANNs can overlap, which is important to note, because it's treated differently than if you have ICANNs alone. When we have CRS concomitant with ICANNs, we treat with tocilizumab targeting IL-6 and corticosteroids. When you have ICANNs alone, you're typically treating with corticosteroids, and in many centers now, anakinra targeting IL-1, but not utilizing the IL-6 pathway that may actually increase the severity of the neurotoxicity. Here's the grading system. Patients will present into the intensive care unit at grade 3 and definitely at grade 4 as they start on vasopressors and have increased oxygen requirements. The CRS grading system is based upon fever, hypoxia, and hypotension. You cannot have CRS without fever, but it also depends on whether or not they received an antipyretic or if they had received a dose of tocilizumab that could blunt that febrile response. So taking the patient as a whole is always important. The management is really, there's not a great set of guidelines right now to guide you, but each institution has their own set of guidelines, and it's based upon corticosteroids and IL-6, as I mentioned. Anakinra is also being utilized, particularly in refractory cases. ICANS is also very common, occurring in majority of patients, and severity can be in 30% to 40% of patients. It can be fatal, particularly if it presents with cerebral edema and status epilepticus. The duration, it can be 10 to 15 days, which is hard when you're watching a patient who's incredibly encephalopathic, but most of these are reversible, particularly if it happens in the acute phase and occurs with concurrent CRS. The symptoms can range from minor things, such as dysgraphia, tremors, inattention, all the way to status epilepticus and seizures, or excuse me, and cerebral edema. Here is the grading system. Again, grade 3 to 4 should land a patient in the ICU, so we should be familiar with how we will treat them. Management, as we would for anyone with a seizure disorder or increased intracranial pressure, is nothing different besides our standard of care. Monoclonal antibodies have also a number of side effects. The hypersensitivity reactions, or infusion reactions, typically occur acutely. When you think about it, it can be an IgE-mediated or non-IgE-mediated anaphylactic or anaphylactoid reaction. Most of them will occur at the second infusion, except for cetuximab, which can occur with the first infusion. CRS can also occur with monoclonal antibodies and can be difficult to differentiate between an anaphylaxis reaction. So typically, if it's hours after the infusion, you think it's more CRS than it is an infusion-related reaction. But again, it's hard to always differentiate. Cardiac toxicity can occur. Pulmonary toxicity with pneumonitis, thromboembolic events. Neurotoxicity with press, ischemic stroke, intracranial hemorrhage, aseptic meningitis, encephalopathy. And then renal toxicity with interstitial nephritis, thrombotic microangiopathy, tumor lysis syndrome. Here are some specific monoclonal antibodies that have higher incidence of different types of toxicities. And so being aware of which drug the patient was on and what toxicity can occur is also important. Immune checkpoint inhibitors, typically seen in our solid organ malignancies, PD-1 and PD-L1 and CTLA-4, they're really taking the brakes off of the immune system and trying to rub it back up to, again, kill those cancer cells. So when we see toxicities, it's the immune-related adverse events. Pneumonitis can occur and is treated with steroids. Determining the grade is really important for any of these toxicities, because as the oncologists look to re-dose the patient, it depends on the grading system. The NCCCN guidelines have specific grading systems and recommendations for treatment. Cardiac toxicities with myocarditis, pericarditis, and dysrhythmias. The myocarditis is incredibly rare, but is very fatal. And so being aware of the fact that myocarditis can occur is important. Myocarditis also can occur with myasthenia gravis and myositis. And so looking at different features of that just to keep on your radar. Neurotoxicity, as I mentioned, myasthenia gravis is one. Myasthenia gravis does not present like our typical bulbar or ocular manifestations initially. It's more of a respiratory event. So that's where we'll see these patients coming into the ICU. And you're treating with steroids, which is different than we would for any other form of myasthenia. Guillain-Barre, cerebral edema, aseptic meningitis, and press, and seizures. Nephrotoxicity, again, tumor lysis syndrome, interstitial nephritis. Hepatic toxicity can occur, and infusion reactions can occur, but are rare. The pathophysiology on why we're having a response is predicted based upon loss of self-tolerance. Do they have underlying subclinical inflammation? Do they have an underlying autoimmune disease? And there can be molecular mimicry as well. We're learning more and more about the microbiome. I think there's another session going on talking about microbiome right now. But we've found that, particularly in the gastroenteritis and immune-related adverse events related to GI, it can reflect the underlying microbiome and determine the severity of their toxicity. So I think it's incredibly fascinating, and a lot more to learn. There are 70 different toxicities that can be associated with immune checkpoint inhibitors. So it affects every organ system. And so anything that a patient comes in with, it should be on our radar. So we will see all of it. The severity can be severe in grades 3 to 5, and about 20% to 60% of patients, depending on the underlying malignancy and the drug, can happen in the ICU. It's not as predictable as the time course that we'd see with chemotherapy or radiation therapy. And it varies between agents. I really like this schematic here that looks at the amount of toxicity, but then the severity of it. So with PD-1 and PD-L1, it's very common to have a colitis, but typically does not result in severe disease where they have perforation or land in the ICU due to their enteritis. However, you can see that with myocarditis, very rare, but it's all red because of the high mortality. Pneumonitis also has significant morbidity and mortality associated with it. Here is some form of a time course, but again, it can vary. Most do occur within the first three months, but can actually even happen after discontinuation of the drug. Risk factors are patient-specific, so if they have underlying autoimmune disease, ILD, tumor-specific, a high disease burden, specific types like melanoma, have more associated with colitis, agent-specific. The recognition is key to management. We think that about 16% of ICU admissions were drug-related, and that's really an underestimate of what we're seeing, and again, it's going to continue to grow. So really working with your oncologist in a multidisciplinary fashion is incredibly important for us how to manage these patients, because it also has long-term effects. We don't wanna limit someone's therapy that could be potentially life-saving if we're able to get them through that event. The prognosis depends upon the underlying toxicity, and again, myocarditis and pneumonitis have a higher prognosis, or worse prognosis. Here is a very busy slide, but it's just kind of a nice approach to how to manage immunotherapy-related toxicities. You think about when did they have their product. Was it CAR-T, a monoclonal antibody, an immune checkpoint inhibitor? Which one was it, how many days from onset, what type of organ toxicity, and then breaking it down from there. When I think about patients that come into the ICU with cancer, I think, do they have a disease that's just unrelated to cancer, or is it related to their antineoplastic therapy, is it tumor progression, or is it a malignancy-related complication? And so these are the ways that I try to approach patients that come into the unit. Thank you very much, appreciate your time. Thank you. Next up, we have Dr. Marina Rabinovich talking about potential causes of euglycemic ketoacidosis. She's a clinical pharmacy specialist in the medical ICU, and also the director for the PGY-1 Pharmacy Residency Program at Grady Memorial Hospital in Atlanta, Georgia. She practices in critical care, and is very involved with the training of residents and students. She's actively, actively involved with SCCM and her local chapter at the Southeast Chapter, so we're really glad to have her today. Thank you for the introduction, and thank you for being here today. I have nothing to disclose, and by the end of this talk, hopefully you'll be able to recognize causes and risk factors associated with the development of euglycemic ketoacidosis, and understand and design and management of euglycemic ketoacidosis. So diabetic ketoacidosis, or DKA, is a pretty well-established complication of a well-known complication of type 1 and type 2 diabetes, defined by a clinical triad of hyperglycemia, metabolic acidosis, and ketosis. Hyperglycemia typically is the hallmark presentation of DKA, but in some patient population, the serum glucose levels are actually gonna be normal, despite the associated metabolic acidosis and ketosis, and that condition is deemed euglycemic ketoacidosis. Current American Association of Diabetes, sorry, American Diabetes Association guidelines define euglycemic ketoacidosis as blood glucose of less than 250 in presence of metabolic acidosis and ketosis. Euglycemic ketoacidosis was first described in 1973, when monitoring colleagues reported 37 cases of young adults with insulin-dependent diabetes presenting with DKA, but a blood glucose of less than 300, and 16 cases of blood glucose less than 200. All of those patients reported having vomiting and reduced carbohydrate intake in the preceding days. To this date, the true incidence of euglycemic ketoacidosis is unknown, largely due to varying definitions of the blood glucose cutoffs in the reported literature, as well as increasing use of medications that contribute to euglycemia and a high rate of misdiagnosis. The pathogenesis of diabetic ketoacidosis is pretty well established, and is a result of absolute or relative insulin deficiency associated with increase in cardioregulatory hormones, such as glucagon, cortisol, catecholamines, leading to increase in hepatic gluconeogenesis, accelerated glycogenolysis, and impaired use of glucose by the peripheral tissues, leading to lipolysis and increased mobilization of 340 acids from the adipose tissue, resulting in ketone body formation, such as beta-hydroxybutyrate and acetoacetate, all leading to the well-known condition, which is the DKA. There are several predisposing factors that contribute to DKA that are listed on this slide, but ultimately, any condition that increases cardioregulatory hormones, paired with insulin deficiency, will result in DKA. The underlying pathophysiology of euglycemic ketoacidosis has to do with reduced serum glucose availability, and that could be either due to reduced hepatic production, decreased caloric intake, or enhanced renal excretion of glucose, leading to, again, insulin deficiency, which then sets off the ketogenesis, increasing counterregulatory hormones, such as glucagon, which then further enhances renal excretion of glucose, leading to euglycemic ketoacidosis. There are many different conditions that have been described in the literature that trigger euglycemic ketoacidosis. Some of them are listed here, but the two that we'll focus on today are the use of sodium glucose transporter 2 inhibitors and CRRT, or continuous renal replacement therapy. Starting with the SGLT2 inhibitors, there are five SGLT2 inhibitors currently available on the market that are FDA-approved for management of type 2 diabetes, and also protective effects in patients with heart failure and carotid and kidney disease, with or without diabetes. It's also used as an adjunct for type 1 diabetic patients, although that is an off-label use. And more recently, in May of 2023, a first SGLT1 inhibitor has been approved for management of type 2 diabetes as well. SGLT2 co-transporter basically inhibits or is responsible for reabsorption of nearly 90% of filtered glucose in the proximal convoluted tubule. So inhibiting this transporter will greatly enhance the renal excretion of glucose, and that's how the mechanism behind correcting glucose, blood glucose with these agents. For the SGLT1 and 2 inhibitors, in addition to renal excretion of glucose, they also inhibit SGLT1 in the gut, and therefore decreasing absorption of glucose in the small intestine. There are several benefits of SGLT2 inhibitors that have been well-documented in the literature and the studies. In addition to decreasing A1c and blood glucose in general, they contribute to healthy weight loss, lowering blood pressure, lower requirements for insulin, lower risk of hypoglycemia, and favorable protective cardiovascular effects. There have also been a number of safety concerns associated with these agents that are listed here, and the one that we'll discuss is the DKA or mucocemic ketoacidosis. So SGLT2 inhibitors will contribute to the reduced serum glucose availability basically due to enhanced renal excretion of glucose, and because of that, many patients will end up reducing their insulin use as well. So leading to the same pathogenesis we already described or discussed for the ketoacidosis. SGLT2 inhibitors also increase glucagon production, which can enhance further urinary glucose loss. About two years after the first drug was approved, the first SGLT2 inhibitor was approved, FDA published a warning saying that SGLT2 inhibitors can cause DKA and UDKA in patients with type one and type two diabetes, and that was based on a case report, a few case reports that were published. The analysis of the FDA adverse event reporting system reported 51 cases with potentially seven-fold increase in risk of DKA, and 71% of those cases were deemed euglycemic, with a mean time to onset of about 43 days. With the popularity of these agents currently, the number of these case reports are increasing and will continue to increase since we, again, these drugs are being used quite widely. But overall incidence so far is still unknown, and reported to be pretty low, about 0.1 to 0.8%, which might be higher with type one diabetics compared to type two. The data from these case reports is also supported by the data from the large randomized controlled landmark trials that these agents were studied in, and looking at the type two diabetic data showed almost over two-fold increase in incidence of DKA compared to placebo, and with type one diabetics, nearly three-and-a-half-fold increase in incidence of DKA. But again, the overall event rate seems to be pretty low, less than one event per 1,000 patient years. And now that these agents are being used in patients who are not diabetic, and just as a cardio and renal protective agent, there have been already two case reports published recently of patients without diabetes experiencing euglycemic DKA, and having challenges with management due to fluid load and such. So something to keep in mind, that these patients do not have to have diabetes to experience euglycemic DKA. One of the most common presenting symptoms of euglycemic DKA has been reported to be nausea and vomiting associated with abdominal pain. Polyuria, polydipsia, and severe mental status changes are not as common with euglycemic DKA as it is with DKA. So anytime patients present with GI symptoms and they are taking SGLT2 inhibitors, there should be a very high suspicion for DKA, euglycemic DKA, especially if the glucose is low. Some of the risk factors that have been reported as well for patients who are taking SGLT2 inhibitors listed here, among the high risk factors, again, is going to be decrease in insulin intake, decrease in carbohydrate intake. Any surgical or medical procedures that the patients are scheduled for, those patients are gonna be very high risk for developing euglycemic DKA if they're continuing to take SGLT2 inhibitors. Vomiting, dehydration, and overall caloric, decrease in caloric intake is gonna be the highest contributors. Moving on to CRT as a potential cause of euglycemic ketoacidosis. CRT's become a pretty popular modality in the ICU for solute and toxin clearance and volume removal. There are several different modalities for CRT with the most common one utilized, at least at our institution, being continuous venous hemodiafiltration, which utilizes both diffusion and convection as well as ultrafiltration using a semipermeable membrane that effectively removes low and moderate size solutes and molecular size solutes, including glucose and various amino acids. There are several commercially valuable replacement fluids that are utilized during CRT to replace electrolytes and volume, but commonly what's utilized is a phosphate containing CRT solution to mitigate the need to continue to replete phosphorous in these patients. However, that fluid does not contain any glucose and can significantly impact the net glucose loss in these patients who are also potentially probably being underfed or not fed due to hemodynamic instability. So it has been reported that patients who are receiving CRT with a glucose-free solution can lose up to 160 grams of glucose per day, which translates into over 600 calories per day. And as far as protein losses, on top of the CRT removing amino acids, critically ill patients, as you know, are in a protein calorie deficit and malnutrition due to critical illness and also underfeeding. So it's been reported that patients in the ICU can lose up to 17 grams of protein per day and have total losses up to 25 grams, nitrogen losses up to 25 grams. So all that will contribute to overall serum glucose levels being reduced, and then, again, coupling with hypoinsulinemia and insulin resistance, increasing counterregulatory hormones leading to euglycemic ketoacidosis. There are very little published literature on CRT as a trigger for euglycemic ketoacidosis. In this prospective analysis of about 120 patients receiving CRT with glucose-free containing solution demonstrated that 15% of their patients developed euglycemic ketoacidosis during CRT therapy. Only half of those patients had diabetes or were diabetic. None of their patients were receiving enteral nutrition. And the average time to ketoacidosis identification was about 43 hours. And in this slide, it shows that administration of glucose or enteral nutrition and insulin successfully resolved ketosis in these patients. And that brings us to the next section is management of euglycemic ketoacidosis. The diagnosis of euglycemic ketoacidosis is probably one of the most important factors just because most of the times it's delayed since there's not a marked increase in hyperglycemia or in glucose. And there are so many different causes for why patients may be having metabolic acidosis, especially if they're critically ill. So obtaining a detailed history, especially medication use, off-label medication use, illicit medication use, as well as metabolic panel specifically looking for beta-hydroxybutyrate would be very important in order to differentiate the diagnosis of euglycemic DKA. As far as management, once the diagnosis is established, the management is quite simple and straightforward. Similar to DKA, first step is to restore fluid and with balanced crystalloids. And it's imperative to go ahead and initiate IV insulin and concurrent IV dextrose administration in these patients as soon as possible despite the normal glycemia or potentially even low blood glucose levels. So dextrose is used to increase the serum glucose levels in order to be able to administer insulin. But even though listed here as the last step, probably should be considered as a initial intervention is management of underlying etiology is trying to figure out why this patient is experiencing euglycemic ketosis. And dealing with that either whether it's nutrition or holding HGLT2 therapy. As far as holding the HGLT2 inhibitors, any patient, again, who's taking these agents and experiencing nausea and vomiting or any GI illness should be instructed to hold the medication. Any time patient are hospitalized due to acute illness and ordered NPO status, these agents should be held. If patients are not able to drink or eat consistently, these agents should be held. Patients who are scheduled for surgical or medical procedures, these agents should be, FDA actually recommends holding these agents at least three to five days prior to the procedure. So it is extremely important to have these agents listed on medication list that are to be held prior to, very operatively, or prior to surgical procedures. And then any time patients are having, making medications that are insulin pump or insulin doses or any malfunction of an insulin pump warrants holding HGLT2 inhibitors. Patients should also be instructed to follow the STITCH protocol that's listed here any time they're experiencing symptoms of ketosis or having acute illness, GI illness. And that involves stopping the agent, testing for ketones, injecting insulin, eating at least 30 grams of carbohydrates, hydrating, and seeking medical advice. So in summary, take-home points is that while it is an uncommon complication, it is a life-threatening emergency and early diagnosis and aggressive management can decrease morbidity and mortality from this condition. Any patient receiving CRT therapy, especially with a glucose-free solution, should be considered at risk for euglossemic ketosis, especially if they're a diabetic or not receiving adequate nutrition and not receiving any insulin therapy. Clinicians should be aware of possible triggers for euglossemic ketoacidosis, especially in patients taking HDLT2 inhibitors and holding these agents or instructing patients to hold these agents if they do exhibit any of the risk factors. And early diagnosis and aggressive management should reverse euglossemic ketosis relatively quickly. Thank you for your time. Thank you. Thank you, Marina. For our final presentation today, we will be welcoming Dr. Ellen Burnham to talk about recreational drug toxicities. She is a professor of medicine in the Division of Pulmonary Sciences and Critical Care Medicine and the Department of Medicine at the University of Colorado. A lot of her research focuses on alcohol and substance misuse, so we're excited to hear her talk about this topic. Thank you. Good afternoon, everybody, and thanks for attending this talk and thank you for the invitation to speak today about what's a pretty broad topic. I'll hit on the salient points of a number of drugs, but would recommend that you visit some of the references on the slides at your convenience. Here's my disclosures. I have no conflicts. So I just wanted to acknowledge up front that it's really possible to inhale most all of the substances that I'll talk about today, and the reason that people use many of these illicit and some commercially available substances is really that quick onset of action to the CNS to get that mind-altering effect that is the main reason that people use recreational drugs. It also provides a more intense effect than some of the other routes that people can use these substances, such as ingestion, and it's maybe nicer to use in that there's no needles involved. Substances can be inhaled via a couple of major routes, the first being burning the product or combusting the product, followed by inhaling the smoke, and you think about that in the setting of the use of cannabinoids and other drugs. You can also vape substances where you heat but don't burn the substance, followed by inhaling the resultant vapor, and there's a variety of ways to consume vaped products, including commercially available tabletop vaporizers, e-cigarettes or vape pens, illustrated there on the right at the bottom, and then dabbing, using a very concentrated amount of product that's superheated with a blowtorch and then inhaled through a glass device, and so there's, just to know, there's a lot of different ways to vape. Vaping is increasingly popular, not just for nicotine-containing products, but for others as well, and here's just a couple of studies to give you examples of that. In Canada, about a quarter of cannabis users endorsed using cannabis via vaporization, and another study from the UK looking at people who used recreational drugs, 2,500 or so individuals, about a third of them endorsed using a number of different kinds of drugs through electronic vaping devices, and about 9% of them endorsed active use of some sort of vape device for a number of different kinds of drugs, not just cannabis, but you'll see on the bottom there, cocaine, heroin, tryptamines, and ketamine as well. So just to briefly touch on cannabis, and I really just want to emphasize that it's a very complex product, and so it's been difficult for studies to move forward for that reason and others, but it contains a large percentage of what are non-cannabinoids that are compounds such as terpenes and flavonoids, fatty acids, et cetera, so it's the majority of what you find in cannabis, and then only about 20% of what's in cannabis, this is plant cannabis, are cannabinoids, the ones you've heard of, delta-9, delta-HTHC, and cannabidiol. Cannabis and other cannabinoids, including the body's endogenous cannabinoids or endocannabinoids, as well as synthetic cannabinoids, interact with a number of different receptors. The best described are G-protein-coupled receptors that include CB1 and CB2 receptors. However, it's important to note that cannabinoids can act through a number of other channels as well, including TRIP channels and other incompletely described mechanisms that lead to the number of physiological effects that have been ascribed to cannabis, including mood-altering effects as well as effects on immunity and other end organ properties as well. Cannabis intersects with critical care in a number of ways. Probably the best described way that's come to light so far was shortly before the COVID-19 pandemic, when the EVALI pandemic or epidemic was noted, primarily among younger male users of vaporized cannabis. And this involves a presentation of acute hypoxic respiratory failure, bilateral pulmonary infiltrates without a clear infectious cause. Not really clear what this is mediated through, although there have been some associations with vitamin E acetate, which acts as a diluent to help to solubilize the cannabinoid to allow it to be used via vaporization. Some of you may have taken care of patients with cannabis hyperemesis syndrome, which is cyclic, almost sometimes intractable vomiting relieved with hot showering, less effectively with antiemetics. And we can have taken care of patients in our ICU who come in with profound volume depletion and acute kidney injury. It's also important to think about cannabis use and cannabis hyperemesis in the setting of DKA. Patients may present in clear DKA, but perhaps not as acidotic as you might expect them to be because of a concomitant metabolic alkalosis. Cannabis can also lead to the need for ICU care because of its relationship with severe psychosis, particularly among individuals using edible forms of cannabis who aren't used to the delayed effects of this type of ingestion route. And of course, cannabis can be seen in association with trauma. To touch on synthetic cannabinoids, which I think are becoming more problematic in those states that haven't legalized plant-based cannabis types. Over the years, these synthetic cannabinoids have evolved in their structure and become more potent as evidenced by the lower EC50 compared to agents that were developed earlier in the 20-teens. Pharmaceutical companies actually started to develop these substances much earlier than the 21st century. The substances, the SCs that are available now for purchase come in a variety of colorful packaging and go by a bunch of funny names such as Spicer, K2, et cetera. Most of these cannabinoids are related somewhat chemically in structure to THC. And as I mentioned, they act through some of the same receptors that Delta-9-THC acts through. All have a similar functional group structure. And the reason that companies have tried to continue to develop these compounds is basically to evade detection and therefore regulation, but also to enhance the efficacy for end users at lower doses. So SCs can be consumed in a variety of different ways. One common way is illustrated in the picture on top is to take some inert plant-based material and spray it with an active synthetic cannabinoid and then the end user can smoke this substance in joints or pipes. There's also forms that can be vaped and these products can also be ingested in a tea-like formulation. Important to remember that these aren't pure compounds and their metabolites are also active as well. So think about SCs in patients who are coming into your ICU with very excited delirium. Some studies note self-talk or inappropriate laughter as symptoms. These do not come up on your talk screen as THC positive to know. And oftentimes case reports have reported on the mixing of SCs with other substances that can have really harmful effects. One was a rat poison, a long-acting warfarin, where end users came in not only psychotic but also with hemorrhage issues. No reversal agent in supportive care is really the order of the day. So I'll touch briefly on fentanyl. I think we're all pretty familiar with the pharmacology of fentanyl in this room, but I just wanted people to be aware that fentanyl, compared to many other opioids, has a better transmucosal bioavailability and actually was studied late in the 1990s and early 2000s via an inhaled route for efficacy in acute pain management, which I thought was kind of interesting. Since fentanyl is commonly used with other medications, it's really difficult to get a handle on the scope of the fentanyl problem in particular. For recreational use, fentanyl can be inhaled, as I mentioned, anything can be inhaled, but also can be ingested. So we had a patient come in fairly recently who had reported smoking fentanyl patches, and I'm like, how in the world do you smoke a patch? Well, there's gel on the patch that you can remove and you can inject it, smoke it, snort it. You can boil a patch and drink the liquid as a tea, or you can chew the patch. And here's just a picture in the top right-hand corner of how to smoke a fentanyl patch. You take part or all of a patch, put it on a piece of foil, heat the foil with a lighter, and then inhale the resultant vapor or smoke with a little glass pipe. So pretty straightforward, unfortunately. Anyway, I'm trying to keep this a little lighter in the afternoon. Fentanyl tablets, people are very, I mean, at the bottom line is people are very creative with how they can figure out how to inhale substances. That's really a take-home point from this talk. Fentanyl tablets, similarly, you can think of creative ways to use fentanyl tablets as well, or one can. Very commonly, we're seeing fentanyl combined with other substances nowadays, particularly xylosine, more on that in a minute. People come in with acute symptoms referable to fentanyl consumption, complaining of, not surprisingly, shortness of breath or lung pain in higher amounts. I'm sure most all of you in this room have cared for or been involved with the care of a patient with fentanyl overdoses, where patients come in with respiratory or even cardiac arrest. Fortunately, for fentanyl, unlike any of the other substances I'll talk about, there is a reversal agent, naloxone, and there are fentanyl test strips that are becoming increasingly available across the country. On the bottom right is a picture of one that I found that you could buy on Amazon. Xylosine, also known as the zombie drug or Trank, has been implicated in a series of overdose deaths in the Philadelphia area and in some other parts of the country as well. This was initially developed as an antihypertensive back in the 60s, but was found to be too potent for human use since it was relegated to the veterinary world. And I like to think of xylosine as sort of a supercharged clonidine or dexmedetomidine that has activity via the alpha-2 receptor, and it has a real high affinity for presynaptic receptors to mediate its sympatholytic effects. It's been found increasingly as an adulterant in a number of recreational drug mixtures, including with fentanyl. These mixtures are known sometimes as Trank dope, and it's an inexpensive way to make the high from fentanyl last longer, but therefore, it also increases the likelihood of overdoses. In the bottom right-hand corner was just a series of decedents who came in through the Miami-Dade Medical Examiner's Office and the number of those individuals where xylosine was detected has really spiked in recent years. The DEA noted in some 2022 data that about a quarter of the fentanyl powder being seized was actually adulterated with xylosine, so a very high percentage of drugs that are contaminated. And in murine and other studies, there are synergistic effects on lethality when fentanyl and xylosine are used together, so a very potent and very deadly combination. Xylosine can be injected often with fentanyl, and this is what can lead to the chronic toxicity related to xylosine, that is, some of the skin wounds that have been reported, although interestingly, these wounds can be found at areas of the body that are distal to, or not related to injection sites with this drug. Xylosine also can be inhaled as other drugs I've talked about. Generally, effects are pretty quick and last around eight hours or so. So think about xylosine being present in your individual who comes into your ICU very altered, of course, but also in those individuals in particular who have shock or who have bradycardia because of those alpha-2 effects from the drug. Test strips are in development. This drug is not reversed with naloxone. That being said, you should have a low threshold to use naloxone because of the concomitant use with fentanyl that patients have, and this drug is not removed by dialysis. Ketamine has been more in the press and on social media recently due to the death of Matthew Perry. This, again, is another old drug that was developed initially as a PCP alternative, and we all know of it now as an injectable anesthetic. That at low or moderate doses has analgesic and anesthetic properties and some hypnotic properties as well, but at higher doses, and users can be associated with sort of out-of-body experiences that some describe as going down the K-hole. Ketamine acts through a number of different receptors to give it this kind of multiple types of effects, including NMDA and opioid receptors, and fortunately, therapeutically, there are a number of applications where it's very useful in the clinical setting that are increasing and will likely continue to expand over time. We know that ketamine has a rapid onset of action when given IV, so it's useful for things such as RSI, but this drug is also just, to be aware, it's also used in the community by an IV route for control of acute behavioral issues. It actually was implicated in the death of Elijah McClain in the city of Denver a couple of years ago. Because of some benefits in the use of esketamine for issues with psychiatric disorders and different neurologic disorders, there's been an emerging interest for ketamine's use in these areas as well, and although ketamine is not approved for any psychiatric disorder, as far as I'm aware, there have been the emergence of a number of ketamine infusion centers across the country, and I counted about 15 to 20 in Denver alone. These are unregulated centers. They're not affiliated with any sort of hospital system, and I believe that over time we may see additional toxicities related to people attending these clinics and receiving therapy for different mental illnesses and neurologic illnesses with ketamine, and this is one report from the medical examiner with Matthew Perry who was found to have ketamine in his bloodstream in the range used for general anesthesia, so really not explainable without someone going back multiple times to get infusions in these centers. So ketamine can be administered intravenously in more controlled settings, but it can commonly be snorted or smoked as well. Effects via this route take a little bit longer than by the IV route, around 10 minutes or so, and the symptoms with ketamine can persist for many hours. There is some tolerance that's associated with consistent use, such as in the setting of Matthew Perry, and the diagnosis, again, have to have a high index of suspicion for this being present, of course, but patients can present with psychosis, depersonalization, impaired consciousness, et cetera. Generally, airway tone and respiration are preserved unless someone is exposed to very high doses of this medication, but think about the sialeria that can sometimes be seen in the setting of ketamine use, even in controlled clinical settings, and that might be a tip that this is a ketamine toxicity picture. Generally, cardiovascular and GI features aren't very prominent with ketamine intoxication, and ketamine's usually not the sole cause of death if someone expires from a toxicity presentation. Ketamine not detected on your intox screen, so very difficult to identify at the point of care, and treatment, again, is largely supportive, low-stimulus environment, judicious use of benzodiazepines, et cetera. So I'll just round out the afternoon with psilocybin, which is the least nefarious of the drugs that I've mentioned today. This is the substance found in magic mushrooms, and it's now being touted as a panacea for better mental health. This is a tryptamine alkaloid that's found in a certain species of mushrooms, along with other compounds, including muscarine, things that I can't pronounce, the active metabolite is psilocin. I can pronounce psilocin, I got that one. This psilocin, the active metabolite, interacts with five-hydroxy tryptophan receptors and contributes to effects that are akin to the use of LSD. This drug has been tested in clinical trials for major depressive disorder. However, it's not a mushroom-derived or natural product. It's a synthetic form of psilocin being used in these clinical studies. The drug works through the autonomic nervous system or alters the autonomic nervous system, so that engenders most of the symptoms that we see from psilocin exposure. There's a theoretical risk to serotonin syndrome in patients as well, but the side effects are more psychological. And I just mentioned this drug because I think we're likely to see an increase in the use of this medication with changes in legislation across the country. In the top right-hand here, you can see that in Colorado and Oregon, we've fully decriminalized psilocybin use for home purposes, and some other states. The cities within those states have decriminalized psilocybin use as well, illustrated in blue. And based on my little bit of research, it's apparently very easy to grow mushrooms at home, and since people tend to get their medical information from online sources, friends or family, I think that mushroom poisoning might increase in the next short period of time, and this can be seen in individuals anywhere from a quarter of an hour to a couple hours after they eat, who present with a compatible history and prominent muscarinic effects, such as those uplisted here. Treatment, again, largely supportive. And you can see that among individuals who presented for an ingestion or toxicity and reported to the National Poison Database System, the amount of psilocybin exposures has really increased since 2012, when these drugs started to be explored for different psychiatric benefits. So a few take-home points. I hope I've convinced you that it's possible to inhale or smoke pretty much anything with a little know-how and a little thought, which is unfortunate, but causes a great deal of toxicity to many people. So the mainstay of therapy for most of these drugs is really just supportive care, but please remember that co-ingestion of these substances is really the norm and not an exception. It's important to take a good history in physical, obtain collateral to figure out what's causing symptoms, low threshold for clinical toxicology testing, low threshold for using naloxone, which is really our only reversal agent at this point in time. This is just one other study that I found. It was recently published, looking at patients presenting to 20 or so EDs in Europe with drug toxicity and among individuals who needed immediate ICU attention. This was primarily, the risk was primarily found to be most elevated among individuals who were 35 years of age or older who had used drugs together, so polysubstance use, or had used recreational drugs in combination with ethanol. So perhaps not surprising, but keep those folks in mind because they generally are sicker. And thank you very much for your attention. Thank you.

critical care

immune checkpoint inhibitors

cytokine release syndrome

CAR T-cell therapy

euglycemic ketoacidosis

SGLT2 inhibitors

recreational drug toxicities

synthetic cannabinoids

naloxone