Thanks so much for the opportunity to talk this afternoon. Thank you for also reading the title that I'm also going to avoid. These are my disclosures. An additional disclosure is that currently ECMO is not regulated, not regulatory cleared for cardiogenic shock, which is the main use in this population. Adding to what the previous speakers have already mentioned, the mechanisms of drug-induced cardiotoxicity are wide, but specific to this presentation, we're really going to be speaking about the cardiac medications leading to cardiotoxicity. So that's going to be the ion channel inhibition, cardiovascularly targeted agents, and maybe cardiac glycosides. But as was already mentioned, cardiac glycoside overdose is much less a clinical issue for us at the moment. So cardiac medication overdose, as we're going to discuss it in this pointy end of the presentation this afternoon, is mainly calcium channel and beta blockers. And although it seems like the medications are generally used benignly in clinical care, they are the sixth and seventh leading cause of death associated with toxins in North America. And they're particularly problematic because patients are often optimized enough with dose that they don't need a lot of additional agent in order to get up into that beyond the therapeutic range. The cardiotoxicants can then depress cardiac contractility, as previously mentioned, due to the blockage of membrane channels and or receptors, and the conducting of myocardial tissue is all affected. This results in cardiac dysfunction from depressed conduction, contractility leading to bradycardia, hypertension, and peripheral organ dysfunction when inadequate oxygen delivery results. Cardiac arrest is obviously the ultimate path that we try very hard to avoid. So just to be completely clear that here at SCCM today, we're not advocating the use of ECMO and very invasive therapies for all patients who present with cardiotoxic overdose. As previously mentioned, the initial stabilization for these patients would still be considering GI decontamination, depending on conscious state and time from the ingestion. Some judicious intravenous fluid resuscitation, remembering that the patients are presenting with an overdose of presumably their cardiovascular medications. Intravenous calcium in the case of calcium channel blocker. Atropine, as previously mentioned, given to everybody, not often of clinical effect in this population, and glucagon for the beta blockers. And for patients who don't respond to that initial therapy, you kind of move into the second phase. And that's, as discussed earlier, often includes high dose insulin, vasopressors, and inotropy. If indeed the pulse rate's inadequate, the bedside echo or clinical exam suggests that contractility of the heart is affected, or the patient has vasoplegic shock. So if those things aren't corrected with initial resuscitation and then escalation to these vasoactive infusions, at that point, it's worth identifying what the mechanism of the patient instability is, so the clinical presentation. So if the heart rate's inadequate, we're dealing with bradycardia. Considering chronotropy, particularly with the use of beta adrenergic agents, is unlikely to be effective if the patient's been beta blocked, but you can certainly consider the addition of inotropes and pacemaker placement if your system is set up for that. If the patient's actually got impaired myocardial function, and they're presenting with more cardiogenic shock, then the appropriate therapy should be titrated. And that includes, again, the use of high dose insulin therapy, inotropes as required. And then if the patient is not responding, consideration of escalation to mechanical circulatory support. Distributory shock is also complicated in this population, because after consideration of additional therapies, such as methylene blue and IV lipids, mechanical circulatory support's complicated by the sorts of flows that patients need, and so they often need multiple venous drainage cannulas to be able to achieve adequate support. And just to be entirely clear, as we're moving through this entire algorithm of therapy for patients, in a North American study of U.S. toxicological registry patients, only 0.004% of patients end up requiring mechanical circulatory support. So if you leave this talk thinking that we're advocating ECMO for all patients for these overdoses, that's entirely not the case. It's a tiny little proportion of the population that are exposed. But it is what I'm going to spend the rest of the time talking about. And so here we go. For those of you unfamiliar, ECMO is obviously the incorporation of a blood pump with an oxygenator in order to not treat the cardiogenic shock, but rather deliver adequate oxygen to tissues such that other organs aren't affected while the patient is recovering from their cardiac overdose. The use of the massive cannulas and the circuit for ECMO also facilitates both awaiting usual metabolism to clear the agents from the patient or encouraging that with the use of renal replacement therapy or hemodialysis. So the mechanism of support can be useful for both oxygen delivery as well as clearing the agent. So if we think then about that tiny little population of patients who end up receiving ECMO or ECLS support for a cardiotoxic medication overdose, what are their outcomes? There's lots of single center studies, very small patient numbers. But in the recent years, there's been a number of multi-center registry-based studies. And they're the ones that I'm going to focus on for the rest of the presentation. So in this study of the ELSO registry, the investigators looked at 15 years' worth of data for drug-induced cardiogenic shock supported by ECMO. There are 104 patients. And 49 of those were supported on ECMO purely for ingestion of cardiovascular agents, so no IV agent use. And those patients ended up with a proportional survival of 59% unadjusted. You can also see by the graphic that there's been increasing deployment of VA ECMO for cardiogenic shock in the context of toxicology for adult patients over the course of the 15-year period. Just thinking back to the algorithm that we looked at before we moved on to just talk about ECMO, these patients appeared to follow the type of escalation in care that the algorithm would have advocated in that the majority of them were already being managed with vasopressors, 90%. Many of them receiving multiple vasopressors. And renal replacement therapy was already in place in 50% of the patients when they went on ECMO. Transvenous pacing was also in use in a proportion of the patients. And there was concomitant use of intra-aortic balloon pump as well. The author's conclusion was that as the largest study evaluating the clinical utility in VA ECMO in acute poisoning, their findings are actually pretty good. They showed a reasonable survival to hospital discharge. And they noted that the patients tended to have less comorbidities than other indications for ECMO support for cardiogenic shock. This is a review that we did looking at toxicological poisonings that resulted in ECMO use in children. Overall, the numbers were actually very small in kids, even though ECMO at this stage was used more frequently in children. We looked at a decade of patient population as well. The increasing utilization demonstrated for adult populations wasn't there for pediatric patients. But of 28 children who were supported with ECMO for toxin exposure, only nine of those were supported purely for ingestion. And of those, the majority survived to hospital discharge. So that's seven out of nine. That's a much higher survival rate than we would expect for pediatric ECMO support normally. This is a different registry study. And this one's going to take a little bit longer just to explain, because the graphic's a bit more complicated. But in this study of 18 years of data from the US poison centers, you can see that ECMO utilization is increasing over the duration of the study in the adult population. So the adult graphic is represented by the shades of red bar graphs. That's patients supported per year. And survival in the light red mortality represented by the darker red bar graph. You can also see that the same increase in use is not present in this database either in pediatric population. Those patients have stayed at a fairly low rate of use of ECMO for poisoning. Importantly, although the use of this therapy has increased over time, there's been no change in the mortality rate in patients that are supported with ECMO for this indication over the course of the duration in either the pediatric or adult population. When we look only at patients in this data set that were supported for cardiovascular agent toxicity, which is what the talk is actually about, that only represented 44 out of the 210 total patient population. And that population from a different registry, probably with some overlapping patients to the ELSO registry, similarly had a very reassuring survival to hospital discharge rate of 75%. So even though these patients that we're talking about supporting with mechanical circulatory support represent the very pointy end of patients who failed resuscitation through other support strategies, once they're cannulated to ECMO, there's a very reassuring recovery rate of the cardiovascular function and survival to hospital discharge. So much so that as expert consensus statements for poisonings, particularly with calcium channel blockers, have been formed, it's actually a similar algorithm to the one that's represented in the emergency medicine paper previously. And the recommendations include, for those patients with ongoing myocardial dysfunction not responding to all of the other avenues of resuscitation, stabilization, and support, that patients should be considered for VA ECMO or ECLS if that's available. Of note, they'd recommend that in the context of bradycardia, or high degree to AV block leading to the cardiovascular instability, that moving towards a pacemaker as first line therapy would be strategically appropriate. Although if cardiac arrest persists or the patient becomes more unstable, you can still see that there's a path there to VA ECMO according to the guidelines. So what does this actually look like in clinical practice? Most centers now do have ECMO programs. And so a number of guidelines have come out, including the calcium channel blocker guidelines specifically, but many written by experts in the field. And overall, although they each have different categories and slightly different specifications, looking at all of them together, I think that we're probably in agreement that a relatively short run of ECMO, which is often hours to days in this population, for a turn of normal cardiovascular function is a potential benefit of VA ECMO support in this group. That ECMO can be managed with additional extracorporeal therapies, such as hemodialysis or continuous renal replacement therapy, and that can expedite clearance of the agent and again return the patient back to normal function, ideally with fewer consequences of the VA ECMO support because it's just a short run. Importantly, ECMO can be used as a bridge to both diagnosis and then antidote therapy if it's available, or to an alternate support strategy if longer term dysfunction persists. And of note, the opinion pieces recommend that outcomes of VA ECMO in this population of toxic agent therapy-induced cardiogenic shock have better outcomes than other indications for ECMO support for cardiogenic shock. So we shouldn't really back away from using them if the patients have ended up in a position where they're not well supported with other therapies. And so across the list of opinion pieces recommending therapy, the indications for VA ECMO in this group of patients are basically, in the absence of a contraindication, ECMO should be considered for patients with acute poisoning, with refractory cardiogenic shock, and some of the publications have actually defined that with a little bit more granular detail as listed. So a low systolic blood pressure, suspected or documented myocardial dysfunction, evidence of end-organ dysfunction, which we're hoping to reverse with better oxygen delivery to tissues, and all of this despite moving through that algorithm of escalating therapy, adequate fluid resuscitation, vasoactive support, titrated, indicated therapies including antidotes, high-dose insulin therapy, glucagon, and potentially considering intralipid emulsions as well. Importantly, many of the opinion pieces address what they're recommending for patients who have a witnessed cardiac arrest in the setting of acute poisoning. And this would be that institution of eCBR, extracorporeal cardiopulmonary resuscitation, should be considered if there's no return of circulation within 10 minutes. And that would obviously be in settings that have systems in place to participate in that sort of cannulation. They recommend timely referral and cannulation are ideal, but note that good outcomes have been achieved even after up to 180 minutes of well-performed CPR. That's all I've got for you, and I think the panel's going to come up so that we can answer some questions. Thank you.

ECMO

cardiotoxic medication overdose

drug-induced cardiotoxicity

calcium channel blockers

beta blockers