Hello, and welcome to today's Journal Club Critical Care Medicine webcast. This webcast, hosted and supported by the Society of Critical Care Medicine, is part of the Journal Club Critical Care Medicine series. In today's webcast, we feature two articles from the August issue of Critical Care Medicine. This webcast will only be available to registrants on demand within five days, five business days. Log on to MyFCCM.org and navigate to the My Learning tab. I'll now turn it over to our moderator, Tony Gerlach. Hi, everyone. My name is Tony Gerlach, and I'm a clinical pharmacist at Ohio State University Medical Center in Columbus, and I will be moderating today's webcast. Thank you all for joining us. Just a few housekeeping items before we get started. First, there will be a question and answer session at the conclusion of the presentation. Please submit your questions to the presentation and just type them into the question box located on your control panel. Second, if you have any comments to share during the presentation, you may also use the question box, too. Third, everyone joining us today for the webcast will receive a follow-up email that will include an evaluation. Please take five minutes to complete the evaluation as your feedback is greatly appreciated. The disclaimer for today is this presentation is intended for educational purposes only. The material presented is intended to represent an approach, view, statement, or opinion of the presenter, which may be helpful to others. The views and opinions expressed herein are those of the presenters and do not necessarily reflect the opinion or views of SCCM. SCCM does not recommend or endorse any specific test, position, product, procedure, opinion, or other information that may be mentioned. And now I would like to introduce today's speakers. Dr. Patrick Lawler works in the Cardio-Intensive Care Unit at Toronto General Hospital and is an Assistant Professor of Medicine in the Divisions of Cardiology and Critical Care Medicine at the University of Toronto. He is also the Co-Director of the Clinical Trials and Translation Unit at the Peter Monk Cardiac Centre at University Health Network. His primary research interest lies at the intersection of cardiovascular disease and critical illness, focusing on the prevention and complication of critical illness, as well as individualizing critical care through biomarkers, clinical staging, and sub-phenotyping approaches. His work is funded by the CIHR, NIH, NHLBI, the Government of Ontario, and others. His work has been published in the New England Journal of Medicine, JAMA, Intensive Care Medicine, the European Heart Journal, Circulation, and elsewhere. Our second presenter today is Dr. Mip Sapkhan, who is an Intensivist in Clinical Science in Vancouver General Hospital ICU, which is affiliated with the University of British Columbia. He completed his medical degree, as well as his doctorate, at the University of British Columbia and completed a sub-specialty training at the University of Cambridge under Professor David Minnan. His research interests include delineating the pathophysiology of hypoxic ischemia brain injury after cardiac arrest using a translational approach encompassing multimodal neuromonitoring and cellular-based analytics. Thank you both for being here today. Now I will turn over things to our first presenter, Patrick Lawler. Well, thanks very much, Tony, and to SCCM for the privilege to present some of our science on behalf of the Critical Care Cardiology Trials Network. In the first slide, I think it's loading. There we are. Well, my disclosures, I'll leave that up for just a moment. None are relevant to this talk. Okay, so background is that mortality is frequently approximated at about 40% in patients with cardiogenic shock and in clinical practice when we're meeting with families and making care decisions, this number frequently enters in our minds as we conceptualize courses and outcomes for the patients. But there has been an increasing recognition overall in critical care, as well as in particular in cardiogenic shock, that clinical stages may exist within the disease state reflective of an illness severity spectrum, whereby it may be possible to individualize patients' prognosis and perhaps eventually to individualize therapeutic decision making on the basis of their clinical stage. An analogy would be the TMN staging system in oncology, whereby depending on the extent of metastases and involvement of the tumor outside of a primary location, it may or may not be appropriate to do surgery, get chemotherapy, do other kinds of treatments, so it's a concept of clinical staging that's increasingly thought of in critical illness, including cardiogenic shock. In 2019, the Society for Cardiovascular Angiography and Interventions proposed a framework for categorizing cardiogenic shock into five clinical stages, and we sought to determine whether or not that was applicable in a registry setting using clinical data from a multi-center observational study. So that was in the Critical Care Cardiology Trials Network, which is an investigator-initiated multi-center network of time 24, but an increasing number now of advanced cardiac intensive care units in Canada and the United States. In all of those centers, patients for two-month snapshots were collected over two years, from 2017 to 2019, and so in total it was about four months of data from each of those centers that was used in this analysis. Shock was defined as hypertension from more than 30 minutes, or the need for vasopressors to sustain the blood pressure, as well as evidence of malperfusion. All right, so patients were categorized on the basis of the SKY stages, and so importantly we approximated the SKY stages because they were developed to be facile for clinicians at the bedside who were making decisions about a patient in front of them, but they had some challenges in terms of their movement in a registry setting. So we made some adaptations that overall looked at the performance of this pragmatic application of those criteria. Our definitions are listed here. Essentially, there's stage A, which is at risk. These are people that have high risk underlying etiologies for shock that are commonly seen and may progress. We know that about at least a third or maybe more of cardiogenic shock developed after hospitalization for one of these diagnoses. B is for beginning. That's the earlier phases of cardiogenic shock. We start to see signs of hypotension, but before we have elevated markers of malperfusion. C is cardiogenic shock. It's where patients are on an inotrope or a vasopressor and have one or so abnormality in their lab work consistent with malperfusion. D is for deterioration, whereby they are multiple vasopressors, inotropes, new escalating mechanical circulatory support or rising biomarkers of malperfusion, and then finally extremis are those patients that are really very sick with significant metabolic acidosis and evidence of malperfusion on the basis of their lactate. These are the comparisons. This is in the paper in detail. It's of interest between our pragmatic application as well as the SCI application, SCI definitions specifically. But overall, we had relatively good alignment of what we were able to ascertain based on how they initially described the framework. We had a total of 8,240 CIC-rate admissions that were reviewed, of which 24% were found to be either at risk of cardiogenic shock or have cardiogenic shock. The distribution across the five stages I just mentioned is listed here, 33%, 7, 16, 23, and 21. The demographics for patients based on their SCI stage are shown here, and I think there are a couple of interesting elements. One is that overall, within the comorbidities, that second kind of lighter gray tab, there was a bit of an increase in the prevalence of comorbid conditions across the stages, but it really wasn't very striking, and it certainly wasn't the basis, I think, for some of the results that we'll see later. Certainly there were relatively more patients with diabetes, hypertension, but you can see the numbers, for example, for those two ranged from 28% to 38%, 57% to 59%. Really, these aren't very significant changes. This isn't sort of like a marked gradient in underlying comorbid disease that sort of contributes to the stages. In contrast, of course, as expected, we do see for the clinical features of illness severity, increased SOFA scores, increased shock IABP2 scores, and then an increased proportion of patients that had a cardiac arrest prior to their inclusion in this cohort. ICU resource utilization also, as expected, is markedly increased across the stages, so small proportion receiving mechanical ventilation early on, up to more than three out of four by the time we reach stage E. Renal replacement therapy reaches one out of four, and basic hemodynamic monitoring also reaches more than four out of five participants. Overall, as you can see, kind of gradients across all the stages, which we would expect consistent with increasing illness severity, and therefore increasing ICU resource utilization. In terms of the management of shock, there's also a few other elements here. The number of vasopressors, of course, is by definition increasing over the stages. Mechanical circulatory support also, and included intrauric balloon pump, as well as other forms of MCS in the last row there. All right, so the mortality, the dark blue is CICU mortality, and then the hashed lines are in-hospital mortality. Again, I've included the modified stages here at the top, just as a reminder. Overall, mortality, as you can see in the cohort, actually was 39% for all participants with cardiogenic shock. So that starts here and then goes forward. In contrast, you can see a marker gradient of mortality, whereby those with classic cardiogenic shock have only an in-hospital mortality of a little over 15%, whereas those with that sort of extremist cardiogenic shock, it's almost two out of three don't make it out of the hospital. So when we're sort of putting that 39% at the bedside, we really have to sort of acknowledge that there is this wide gradient that exists across the stages, and that may have relevance for clinical decision-making. Oops, sorry about that. For the stratification on the basis of whether this was acute myocardial infarction-related cardiogenic shock or not, we overall saw the same patterns, only different numbers, but the overall same pattern of increasing gradient of mortality across the spectrum of the stages there. And for cardiac arrest, same thing. Overall, if they hadn't been in-hospital cardiac arrest, or excuse me, out-of-hospital cardiac arrest, they generally had a higher mortality, but for the most part, that gradient was preserved across all of these stages. All right, the results were overall similar when we looked at patients with either kind of quote-unquote pure cardiogenic shock or otherwise a mixed shock and distributed shock. The association between SKY stages and mortality was also significant after we adjusted for SOFA score or the IABP SHOCK2 score, suggesting that there may be an incremental predictive ability of these stages to inform prognostication for mortality risk. And then we report the discrimination based on the C-statistic for the in-hospital mortality and CCCTM participants based on the SKY stage was 0.85, which of course is high with a likelihood of sort of being 0.5, whereas it was 0.829 for the SOFA score and 0.76 for the IABP SHOCK2 score. So, again, the modified SKY stages overall did improve the predictive accuracy of SOFA as shown here based on the likelihood ratio test, as well as the IABP SHOCK2 score. So in conclusion, although mortality and predictive shock remains high in our cohort, as in many contemporary cohorts and clinical trial populations, about 39%, it varies considerably on the basis of patient's clinical severity stage. So the CCCTM scheme that we've developed, this pragmatic implementation of the SKY shock stages, was effective at classifying patients into a mortality gradient that does seem to have clinical significance. The classification may be useful for understanding and comparing risk also in distinct shock populations, comparing the results of clinical trials on the basis of what kinds of patients they enroll, and also for clinical prognostication, including at the bedside. And we certainly have talked about this on a number of occasions on rounds. One day it may also be applicable to therapeutic decision-making, and that's the thought that I wanted to finish with, thinking broadly on. Overall in critical care, for example, in sepsis, there's been hundreds of trials that have been negative or neutral, I guess, in the context of lots of promising treatments. And one of the ideas is that there may have been sort of an inadequate accounting for the between-patient heterogeneity that may exist in critical illness. And that between-patient heterogeneity could be captured a couple of different ways. One way could be this concept of subphenotyping, whereby we say, you know, there's a proportion of patients with acute respiratory distress syndrome that have a hyper-inflammatory physiology, and then there's a proportion that don't. And the proportion with hyper-inflammatory physiology may respond to some of the treatments that we give that target the inflammatory activation in that disease. The proportion that don't have it, of course, may not, and may in fact be harmed. Most of the leukocyte transcriptomics studies also suggest that maybe about 60% of patients with the sort of classic features of immune activation, and then a predominant proportion then, a proportion nevertheless, that are having more sort of immunosuppressed features that sort of HLA downregulation and evidence of endotoxin tolerance and T cell exhaustion. So it may be kind of necessary to think about the subphenotype when we decide which patients should be kind of targeted for what therapies. Clinical staging, though, may also add another dimension to that sort of on the basis, as I say, of the TMN model, where we say what disease sort of process or stage, I guess, in the disease process are patients at, and is it sort of at a point where certain interventions are helpful or not. We recently applied that thinking in a trial of therapeutic anticoagulation patients with COVID-19, whereby we stratified patients on the basis of their illness severity up front, and used a group sequential stopping adaptive design to try to figure out if there was a difference in the treatment effect within those groups. We also further stratified patients on the basis of biomarkers, which may be another way to try to look at that, and overall did, in fact, see that there were differences in the treatment based on illness severity. We've seen this in other things, in cardiogenic shock as well, we know that complete revascularization not beneficial in patients that have overt cardiogenic shock, but based on the complete trial may be beneficial in patients at risk for cardiogenic shock. So again, it's a concept of trying to figure out where the patient is on the disease trajectory, deciding if they need surgery or chemotherapy for their cancer, or what kind of revascularization or drugs or other mechanica support they need for the cardiogenic shock. So overall, I think these might be tools that could be more effective in clinical trials and perhaps the next frontier in cardiogenic shock. I certainly importantly have to acknowledge the contribution of the Critical Care Cardiology Trials Network investigators, Dr. David Morrow, who leads that group, and a number of my friends and collaborators shown here, as well as other, including new members of the network. Thank you. Thanks very much for the invite. My name is Nipsey Khan, I'm from the University of British Columbia, I'm very privileged and excited to present to you our article entitled, Goal-Directed Care Using Invasive Neuromonitoring Versus Standard of Care, a Matched Cohort Study. The funding disclosures I have aren't pertinent to this presentation at all, but are from national funding organizations that do help support some of our work. Hypoxic ischemic brain injury is a primary determinant of clinical outcome after cardiac arrest, and in fact, upwards of 80% of the clinical outcome determined in hospital is directly attributable to HIBI. The survivors who subsequently go home and are independent also suffer from significant neuropsychiatric sequelae, making HIBI one of the most elusive disease entities that exists in critical care medicine today. The pathophysiology of HIBI is complex, and here depicted at the level of the neurovascular unit, which is the primary anatomical and functional homeostatic unit that exists within the brain, a complex interplay between cells such as astrocytes, as well as which encase the vascular endothelium or the cerebrovasculature, and how they interplay with the surrounding neurons and other glial cells maintains homeostasis, and it's at this site where the deleterious effects of ischemia reperfusion injury can occur. Now, in the healthy setting, you see an astrocyte encasing the cerebrovascular at the top part of the figure, and its intersections with the surrounding neuron and cell body, surrounded by lots of glucose and oxygen molecules. After ischemia reperfusion injury, all sorts of pathophysiological mechanisms are occurring, some of which include microvascular thrombosis, breakdown of the blood-brain barrier, neuroglycopenia, cerebral hypoxia, and then subsequent depletion of intracellular ATP and thereafter cell death. And it's that secondary injury after successful return of spontaneous circulation, which we are trying to prevent. Traditionally, the secondary injury of which there are a number of mechanisms that occur, one of the postulated mechanisms that underpins this injurious state is that of secondary brain hypoxia, or lack of oxygen after resuscitation. And so, clinically, simplistically, we try to balance with supportive measures, optimizing oxygen delivery and improving oxygen utilization to mitigate this secondary ischemia injury. Now, if cerebral oxygen delivery is so important, well, what's it equivalent to? We all know from medical school and undergrad physiology courses that oxygen delivery is equivalent to the arterial oxygen content plus overall blood flow. Now, and for all the rest of the vital organs, that equates to cardiac output. But in the setting of the brain, it's slightly different because the brain has intricate regulation of its own blood flow. And two of the clinical factors that do regulate cerebral blood flow include the arterial carbon dioxide tension. And in the setting of a normal left ventricle, the mean arterial pressure is the predominant determinant of cerebral blood flow, especially in low intracranial pressure states. Now, there's been a number of observational studies which have looked at blood pressure, so the importance of mean arterial pressure and outcome following cardiac arrest and outcome of HIBI patients, each of which has demonstrated observationally that, of course, there is an association between arterial hypotension or higher blood pressures and improved neurological outcomes. But each of these studies, although important, has tremendous confounding, specifically, it's unknown whether the augmentation of mean arterial pressure or the optimization of oxygen delivery is associated with better outcome or perhaps it's part of what Dr. Lawler was alluding to in his presentation, the degree of myocardial dysfunction and subsequent hypotension drives that finding. We had a chance to do a systematic review a number of years ago, and a medical student of ours concluded that, in fact, looking at all the available data to date, that improved neurological outcomes were associated with higher blood pressures of cardiac arrest. But perhaps the most important part of this conclusion statement is that there's need for further research. And so starting in 2019, two small but really nicely done randomized control trials of hemodynamic augmentation or optimization using randomizing patients into a low normal MAP group, so MAP of 65 to 75 versus a high MAP group, so mean arterial pressure of 85 to 100 were conducted. The neuroprotect trial was published in the European Heart Journal, and the coma care study was published in Intensive Care Medicine. Now, each study had about 100 patients or so, and the primary outcomes were not clinical in nature, although they did look at cerebral performance score, but were predominantly quantifying the ischemic burden on MRI in the setting of the neuroprotect trial, and then biochemical evidence of cerebral injury quantified by biomarkers, principally neuronal specific enolase in the coma care trial. Regrettably, in both studies, the primary outcomes were not different, nor were the secondary clinical outcomes. So this presents a discrepancy between the perceived importance of optimizing oxygen delivery and then the lack of biological or clinical efficacy. So the question that we've had as a research group are, are there missing links in the pathophysiology, and do we know clinically what these important physiological factors are that determine and characterize the cerebrovascular physiology of patients after return of spontaneous circulation? And that set the stage for one of our initial studies, whereby we investigated the burden of brain hypoxia and tried to identify the optimal mean arterial pressure in patients after arrest using invasive neuromonitoring. Published in 2019 in CCM, ultimately what we showed here was that despite best attempts using an invasive intraparenchymal oxygen catheter that measures in real time the oxygen tension within tissue, patients continued to have episodes of brain hypoxia for the approximately 40% of the monitoring period, despite best attempts to normalize it. Additionally, there was tremendous heterogeneity in individual patients. So what I've shown here on the right side of the screen are two patients' individual curves of plotting against the brain tissue oxygenation. Overall, there's a significant relationship amongst the cohort, but each individual line represents an individual patient. And suffice it to say, there's tremendous heterogeneity in what that relationship looks like in individual patients, suggesting that the cerebral vascular physiology is distinct and that it is individualized. Now, as part of this study, we decided to do an additional analysis of goal-directed care. So by placing invasive neuromonitoring into post-arrest patients, what were we able to glean and learn from that versus patients who are managed with standard of care as per international AOCOR guidelines. Patients in this study were adults, so greater than 18 years of age, returned to spontaneous circulation greater than 10 minutes, had an unconfounded post-resuscitation GCS of 8 or less, who were enrolled within 72 hours of ROSC, and who had no other concurrent central nervous system injury. In the standard of care group, all these patients underwent TTM at 36 degrees. Mean arterial pressure, as per our standard of care in our unit, is maintained greater than 65. We maintained strict normal capnea and normal oxemia, and then rewarming up to 37.5 was conducted at the end of the TTM duration. Now, in terms of the goal-directed group, these patients underwent invasive neuromonitoring using a dual lumen catheter. I've shown a quadruple lumen catheter here, which is what we do now, but a dual lumen catheter using a LICOX catheter, which measures PBTO2, so the brain tissue oxygenation, and an intracranial pressure catheter. We also placed for near-infrared spectroscopy in terms of a non-invasive measure and used continuous SgO2 as well. All of this data goes into a computer software program at 300 hertz, of which we're able to derive secondary variables and included temperature and entitle monitoring. Now, in overall, during the study period, 21 patients were included within the goal-directed group. A total of 44 were included in the standard of care group and in the matched cohort, approximately, so another 21 patients were included. Now, although we've shown improvement in favorable neurological outcome in this cohort, that's really not the point of this manuscript. The point of this manuscript is to demonstrate feasibility, but also to highlight the individual variation of what we see in this cohort. When we look at the differences in care, so how did the individualized monitoring or the invasive neuron monitoring change care? Well, we ended up seeing patients in the goal-directed group have a higher mean arterial pressure, more sedation, not really differences in the norepinephrine, but lower temperature, as well as hemoglobin levels were the same and arterial carbon dioxide levels were the same. So, this doesn't really allude to why we saw the improved outcomes. Principally, the current data that we have to date in common care and neuroprotect suggest that mean arterial pressure by itself may not be the driver of better outcomes. Further, the TTM2 trial demonstrating differences in temperature also probably is not accounting for that. And so, the improvement in outcomes in our study were probably related to the fact that we had a longer duration of care in these patients and then differences likely within the prognostication. Interestingly, though, there's things to be learned from the invasive neuron monitoring. So, despite, again, our best attempts at trying to normalize brain tissue oxygenation, patients did continue to experience some episodes of brain hypoxia. There was a relatively low burden of intracranial hypertension and cerebral perfusion pressure. So, what our colleagues were using to drive blood pressure or to optimize cerebral perfusion was quite a bit higher than even we would typically use in traumatic brain injury states. And finally, the jugular venous oxygen saturation, a little bit on the higher side, demonstrating that there may be a dysfunction in the ability of oxygen to offload into the brain despite optimization of cerebral perfusion. Most interestingly, in our supplement, we've included every single patient's individual depiction of what their neuron monitoring looked like. And this is where probably the most rich part of our data is included. And I've only included patient one and patient two here, but you can see that there are tremendous differences in what these patients' curves did, in fact, look like. So, here in patient one, the mean arterial pressure is upwards of 100 at some cases, whereby it's only once we get to about 100 does the PbO2 even come above 20. That, if we're to extrapolate from TBI, the cutoff for brain hypoxia. Conversely, in patient two, tolerated a much lower mean arterial pressure with relatively stable PbO2 levels. And looking through the rest of the 21 patients, again, there was tremendous variation in the relationship between mean arterial pressure and PbO2, highlighting, again, the individual nature of the pathophysiology of this disease. And so, our conclusions as part of this are really, you know, this very, very preliminary study. Goal-directed care was associated with the six-month favourable neurological outcome, but that's really, again, not the point. There's significant work required to confirm this finding in a prospectively designed study. But the biggest thing to glean, I think, from our manuscript is the individual nature of this disease with respect to the pathophysiology and the relationships between clinical variables associated with optimisation of cerebral oxygen delivery. And clearly, the next steps are to use more non-invasive monitoring techniques to increase the generalisability of these findings so that we can treat people as individuals instead of a one-size-fits-all approach. I'd like to acknowledge the following individuals for not only their work in this manuscript, but in our research programme in general. They're fully indebted to all of them. And I'll turn it back over to Dr. Gerlich. Well, thank you to both Dr. Lawler and Dr. Sekhon for their amazing presentations, and I personally learned a lot. And for the audience, please feel free to ask any questions in the questions tab, and I will get to them. And I think both of these can help with some of our complex patients, especially right now since I'm dealing on my clinical service NIBI patient currently. And I think just to kind of the leading question, the hard thing is what can we do to get people on looking at this, which you kind of alluded to, because not everyone has the capability of using micro-dilutions and Lycox and ICP monitoring as you did. So what steps do we think we can be done so more centres can actually individualise some of this care to actually improve outcomes in these patients? Yeah, such a great question. And you hit the nail on the head, and although invasive nerve monitoring I think provides important insights, it's not generalisable across centres, but it's also not generalisable across different demographics of patients who undergo cardiac arrest. For example, the patients who've had antecedent STEMIs because of thrombolysis or antiplatelet use, it's really not safe to place invasive nerve monitoring. So what can we do to try to increase the generalisability of these findings? So one of our existing research programs now is to link a series of novel brain biomarkers, beyond neuron-specific ELAs, but brain biomarkers with point-of-care testing, things like neurofilament light, as well as tau or gliofibrillary acidic protein, and link the invasive physiology or the knowledge that we're getting from the invasive nerve monitoring with respect to the recognition or detection of brain hypoxia to systemically circulating brain-specific biomarkers. Much like we have a liver panel for the liver or troponin for myocardial injury, are there ways that we can develop and provide context to these brain biomarkers with the invasive nerve monitoring so that then you can use this at other sites as well. So that's one of the areas that we're very interested in and actively pursuing. In terms of non-invasive monitoring, regrettably, we had a lot of hope for near-inferred spectroscopy with respect to use in cardiac arrest patients. It seems to be an effective tool to detect the moment of return of spontaneous circulation, but we've shown not only healthy people, but also as part of our 2019 paper in CCM, that there really wasn't, no matter which way you look at it, an association between systemic variables implicated in cerebral blood flow and then the RSO2. And it probably has to do with something related to the abnormal oxygen diffusion that occurs. So that, unfortunately, has not really panned out for us as a viable technique to use non-invasively. So yeah, we're very interested in looking at the brain biomarker aspect of this thing. Well, thank you very much for that. Now this is for Dr. Lawler. Specifically looking at your data out there, the two sub-phenotypes are comorbid conditions that seem similar, but a little bit low. And your patient population, are those with sepsis contributing to their cardiogenic shock and what significance liver disease plays into it? Is there any way that we can really assess the next steps about how the Society of Angiography and Intervention Clinical Shock Stages can actually assess cardiogenic shock in those two patient populations? Thanks, Tony. A spectacular question. And Preston, because we've actually done that study in another cohort, more with the idea, as you say, of we increasingly see mixed shock, we increasingly see executive shock in the cardiac ICU. And rather than sort of develop a new score, obviously for sepsis, the idea was more just does this score work kind of in broad populations of cardiac critically ill patients? And let's say the shock isn't quite differentiated yet, does it sort of still perform? And there's a question of distributive or mixed shock. We specifically looked at mixed and distributive shock included in the overall kind of denominator of shock in the data that I showed in the sensitivity analysis. The results were very similar in the C3TN data. In the separate study, we've just signaled out patients with septic shock in a cardiac intensive period setting and more to come on that. But it does seem like their overall is persistence of that risk gradient across the spectrum in patients with septic shock. Very good. I'm glad I was leading you to some next good research. But seriously, I think you kind of hit the nail on the head. We're starting to see, especially at least in my center, more and more people are living longer. So they're having, you know, a lot more abnormal heart per se heart function, or we're seeing a lot more with liver disease. And really, sometimes those are really tricky diagnoses to make. Is this shock due to cardiogenic or sepsis, or is it just the underlying disease state? So I think it'll be very interesting to look at all those patients. And kind of in a follow-up question with that, is, you know, it did seem at least in the study that those with stage D and E compared to others really had higher comorbidities. Did you look, or I'm sure you probably have or are looking in to something like a Charleston comorbidity score or equivalent? And what did that, what did those play out with your results? Yeah, that's a spectacular question. Also, we didn't look specifically at the Charleston comorbidity index. What was interesting, what we did see, you know, when we looked at sort of prevalent comorbid diseases, we didn't really see a major gradient. We did see a small gradient, but nothing really big. What we did see, though, was an increasing prevalence of prior cardiovascular diseases in the more critically out of last stage D, E patients. So what, you know, I was so struck by, as someone who does biomarker work, also was, you know, we usually see these biomarkers just track these gradients of chronic disease and illness severity. But in this case, it really was, at least from my perspective, looked a lot more like it was a related, like the scale kind of captured more kind of chronic prevalent cardiovascular disease and acute conditions, but not so much sort of comorbid disease. But, you know, there is a small gradient there, although at least it was modest. Well, thank you very much. And this is for you, Matt. Ideally, how would you proceed to determine, is it something specific with the school-directed therapy? So are the sum of the parts greater than the parts themselves, or is it something specifically you did to help really tease out what we should be doing in the future in our patients that do have cardiac arrest or might depend on different types of reasons for cardiac arrest? Yeah. So, you know, with respect to the optimization of oxygen delivery, you know, and what is it with that, what variable specifically, you know, should we target? You know, I think that the question is much more complex, or the topic is much more complex. We make the assumption that if we get oxygen convectively, convective oxygen delivery to the microvasculature, we make the assumption that normal diffusion occurs and then normal utilization occurs. And so solely focusing on the macro physiological variables like CPP, like transfusion, like carbon dioxide tension, things that affect convective oxygen delivery, I think only gives us a real small piece of the puzzle. The next steps, I think, are how best to integrate and to optimize diffusion of oxygen across, but probably more so how to optimize utilization. What are the areas in ischemia, reperfusion, pathophysiology at the cellular level that are accounting for mitochondrial dysfunction, that are accounting for dysfunction in the proteins implicated in glycolysis, in the Krebs cycle? Because I think, you know, getting oxygen to the brain is great, but the fact that it's also got to be utilized normally. And so that's, I think, the next step of ischemic brain injury research is pairing the macro physiology to what's happening at the microvasculature and at the cellular level to attack the ischemia, reperfusion, biology at all levels. You know, we're probably short of identifying specific efficacious agents at this precise time, but I think that also speaks to why the outcomes have been so bad in this disease for so long, because we've not had insights. And I think these series of studies provides a basis and a foundation to build upon to identify those therapeutic targets. Now, I mean, that really makes sense to me. And just as you were explaining it, my first thought is, is if you think it's utilization of oxygen, are we actually giving the wrong drugs to these people, especially, you know, when we want to do therapeutic temperature management, is propofol potentially the wrong drug if it can cause mitochondrial damage? And is it really impairing the utilization and the cells that really need the oxygenation the most? So there's much more on that, I'm sure, but I think it gives us some insights in the future of where we might need to do a lot more research. Yeah, no, I completely agree with you. And, you know, the fact that the outcomes are so bad in this disease, I think, points to the fact that, you know, one, we need to make it a priority, but two, we need to be humble about, instead of what we know about it, what we don't know about it. Yeah, no, I definitely can agree more with you. And the next question is for you, Dr. Lawler, especially when you look at your data with the class A, B, and C shock, but especially the B and C shock, it seems like, you know, obviously they had a lot less mortality. Are there any interventions that you would support, especially in those to help prevent the progression to the more severe forms of shock? Yeah, spectacular question again. You know, we kind of briefly touched on it, but I think the clinical staging, it's one of the great examples in cardiogenic shock care. If you look at the idea, you know, for a very long time in cardiogenic shock, we thought the most important thing was to get the myocardium as much blood flow as possible, so we would open up as many kind of blockages as we thought feasible in the acute setting. After the culprit shock trial came out a few years ago, showing the fact that there actually was a worsened risk of composite myocardial infarction, renal, or excuse me, death and renal failure in the setting of myocardial infarction, we then steered away from that, and we were only going to focus on what we think is the culprit vessel, and then special circumstances only considering more. That's quite different than in patients, so that would be sort of stage C, D, E populations. Patients with stage A, or maybe even some with stage B, that were included in the complete trial, there did seem to be a benefit to multi-vessel revascularization. Admittedly, not all at the kind of same sitting potentially, but that concept that, you know, early on in the hospital course of a patient who's admitted with STEMI has a single vessel culprit that probably is beneficial to fix the rest of the vessel to reduce risk of reinfarction and other events kind of longitudinally thereafter. So, I think that's a great example of where, you know, sort of like surgery or systemic chemotherapy, it's helpful in some people in some stages of the disease, but it's not helpful in other people in other stages of the disease. So, I think that's one example, I think, of where the staging can kind of help us conceptualize it. And, you know, we naturally, I think, when the trials were designed, people weren't sort of thinking about this as kind of the same disease on a different spectrum, but I think when we set up the framework with the stage A at risk and B beginning, it does make it clear that there is a role for prevention and some of these treatments are, in fact, probably preventing deterioration to other higher severity stages. Great question. Well, it seems to me too, I mean, this is kind of some of the similar process for what Mip just said is what we don't need to know is we can do a good job of getting oxygen to where we need to go, either the myocardium or the brain, but what can we do to get those cells to utilize it optimally? And I think that's where we need to go with research next. And if we can answer maybe some of that questions, we might be able to help with both of these disease processes. Yeah, that's a spectacular question. We really don't have, you know, myocardial energetics in the acute setting and in chronic heart failure, of course, are quite altered. And the substrate shift between fatty acids and glucose utilization has really marked it. And I think that's one of the areas, absolutely, as you say, where, you know, because from a practical perspective, we take care of a number of patients that have an ejection fraction of 10%. And those patients can, we may call them in clinic, they're playing tennis, they have functional life, they're compensated both hemodynamically, but also metabolically. In contrast, someone who has a large anterior STEMI may have an ejection fraction of 30% if they could be in cardiogenic shock. I think that speaks both, as you say, to the sort of hemodynamic maladaptation, but also as you and Dr. Scott spoke to about the concept of metabolic adaptation and the acute sort of stress or something versus the chronicity that allows more of a subtle shift over time. Well, very good. And I have learned a lot today. And with that, I think that's the end of our presentation. So I would like to thank you both for being here today. And I would like to thank our audience for listening today. And yet again, for all those who joined us today, you will receive a follow-up email that will include an evaluation. Please take five minutes to complete the evaluation. Your feedback is greatly appreciated. And on a final note, please join us for our next Journal Club on Thursday, the 23rd. This concludes today's presentation.

cardiogenic shock

clinical staging

mortality gradient

clinical decision-making

hypoxic ischemic brain injury

invasive neuromonitoring

neurological outcomes

individualizing care