Thank you, everyone. It's my honor to be here today. My name is Brittany Bissell Turpin. I am an advanced clinical pharmacist coming out of Kentucky. It is my honor to represent our task force, looking specifically at norepinephrine challenges as it pertains to the critical care community. So for myself, I have no disclosures as it pertains to this presentation, and I personally just have one sole objective today, and that is to talk through current challenges with norepinephrine concentration variability. Specifically, this is discussing how we report norepinephrine concentrations and how we take these considerations into our practice, especially looking at a multicenter and a multinational level. So this task force was developed in the latter half of 2023 based on some recognition and awareness of a group of different individuals. Some appear with me today and some not up on the stage, but really just a number of clinicians that started to develop or become aware of potentially inconsistent reports of norepinephrine and how we report norepinephrine concentrations in our literature. And so you'll see here a couple of those key papers that have been published in the last year or so, and I want to call direct attention to Dr. Leon's publication and then that of Dr. Viroshefsky that really looked deeper into what we're seeing from a clinical standpoint in the reporting of norepinephrine doses. So let's talk a little bit more about what I'm really leaning into here. So this was our position paper that was published earlier this week. Please take some time to look at it. I have to call attention to this group of authors. It has been a huge honor to be able to work with definitely the most efficient group of authors that I've ever been a part of and just an amazing team and super effective. And Dr. Khanna was able to grab everyone's headshot to show, I'll just bring a little bit of attention to the group here. I'm not sure if everyone wants this to be up there, but nonetheless, just an amazing group of authors with so much insight from so many different practice backgrounds, an amazing group of educators, clinicians, researchers. It's really been my honor. So let's get into it. From a pharmacology standpoint, norepinephrine, as well as many other drugs, is available via a salt formulation. We refer to the drugs that we most commonly think of as APIs or active pharmaceutical ingredients. So when we talk about norepinephrine or epinephrine or vancomycin, we're really referring to the drug. And that's what we're thinking about as clinicians when we're applying these medicines to our patients at bedside. Unfortunately or fortunately, we must require salt formulations for about 50% of all medicinal agents, 70% of intravenous agents in order to actually administer these medications safely to our patients. This is dependent on a number of different factors, whether it be the chemistry of the actual agent or pharmacokinetic or pharmacodynamic expectations or other factors. And so norepinephrine is one of those agents. So norepinephrine's salt formulation or the conjugated salt form allows us to administer this medication intravenously. And this is because of the underlying low water solubility of the medication. So what does this mean? Not a lot in direct practice. Not a lot of attention is probably paid attention or called to or called for when we talk about the salt formulations and whether we're using one versus the other. But this may have some implications in reporting. And so there's three key salt formulations that we have with norepinephrine. We have norepinephrine bitartrate, we have norepinephrine tartrate, and norepinephrine hydrochloride, also known as noradrenaline to our European and other colleagues. In the United States, we heavily focus on the use of norepinephrine bitartrate, whereas in European countries, we see the tartrate formulation. And in some countries, such as Germany and Austria, we see the utilization of the hydrochloride salt. Now, the weight is obviously much different with a salt formulation, as those agents are then heavier than maybe just the active pharmaceutical ingredient. We see a two to one ratio, essentially, with our bitartrate and tartrate formulations, and we'll focus on that for the majority of the presentation. So again, from a pharmacology standpoint, not a huge impact in which salt formulation we use with the slightly different isomer and that water molecule that we see there. So not a huge consideration in our active everyday practice of what salt formulation we're applying to patients at bedside. Where we do need to start considering the implications of salt formulation comes in our labeling and reporting. So the salt formulation or base concentration and what is reported in labeling is really dependent both on the manufacturer as well as the country. We know that about half of intensivists reported in a survey that they're unaware of the salt formulation that is given in their intensive care unit or their critical care unit. And I think that's pretty true for most of us. We're not looking for what salt we're actively administering every day. Which again, may not have a lot of direct implications to our patient care at bedside, but it is important when we talk about how we report these doses across different institutions and across different countries. In the United States, we typically discuss norepinephrine exposure on the basis of the API or the base concentration. So that one milligram of norepinephrine. However, some of our colleagues in Europe and elsewhere may report either the base or the salt formulation. So you may see a two or a one milligram per ml concentration depending on where you're at. And Dr. Viresky actually looked at a review of 32 different countries and really helped us start this task force with his work looking into the different prescribing informations that were available worldwide. And in his review of 32 different countries, he found that prescribing information consistently as expected does include your salt formulation and also includes the base concentration. Where things start to differ is when it comes to the active drug label. With four countries actually listing the salt formulation as the concentration on the label. So a difference than you would see from the base concentration. Interestingly enough, two manufacturers specifically would label their drugs on the basis of the country that they were supplying to. So not even necessarily consistency within the direct manufacturing process or their labeling process and techniques. So what does this look like at bedside? We have here an example. So you have prescribing information as listed here with a highlight on the bottom that is going to report exactly what is expected and what you see in that medication. So you have a base concentration on the left of one milligram per ml which is what is represented on the label. However, if you were to have an agent that reports specifically the salt concentration on the label as there to the right, you're going to see the same drug concentration but it actually represents what is 0.5 milligrams per ml of base. So half really of the dose if you compare these two agents just at base value. So if we're administering these to our patients and we have what appears to be a very similar patient population in the smart pump that we have on the left compared to the smart pump on the right, we may be administering what appears to be the exact same dose in two different patients. But when you dig further, you actually recognize that you may be administering either 50 percent or double the expected dose. And what implications does this have on the critical care community? Well, a group could think of quite a bit. I'll try to keep them short and simple here. Probably the most obvious and most prevalent are the implications for research. When we talk about enrollment, particularly in multinational multi-center studies, if you're utilizing or you have different centers that are utilizing different standards for dose reporting, you can have a lot of heterogeneity in the patient population for enrollment. If you're using enrichment procedures or you're trying to look at dose equivalency or you're trying to look at exposure ratios and overall outcomes, you may be really comparing for lack of a better term apples to oranges just within that cohort itself and not intentionally. There may be inconsistency of findings, and when we're looking at, you know, polled estimates or meta-analyses and things of that nature, we may be combining very heterogeneic populations unintentionally. And so this, of course, then translates to our clinical guidelines. We have surviving sepsis guidelines and others that specifically call for initiation or weaning of different agents based on certain vasopressor thresholds. And so, again, if we're not reporting a consistent value or utilizing a similar concentration across all cohorts, we may have some confusion in how we're implementing these agents. For prognostication, of course, whether we're using salt formulation versus base concentration as a reporting is going to make a difference. And in clinical practice, of course, the most important area, bringing all of these things into fruition for active patient care, we may have heterogeneity in our own practices, but we also may be deviating from the evidence base that we know it. So in image form, if we take, for example, enrollment procedures in a clinical trial, you'll see here on the top left we have two different cohorts. One center, for say, that is dosing their norepinephrine based on the salt formulation, and one that's utilizing the base concentration. If we have a predefined enrollment threshold based on our underlying norepinephrine base concentration, if a center is unknowingly utilizing tartrate salt, titrate or bitartrate salt concentrations as their dosing parameter, they may end up enrolling patients much quicker than they would technically be eligible for enrollment into this clinical study. And in image B and image C, you'll see similar scenarios where, depending on how fast or slow the titration is going, you can see very different inclusion timing or parameters for these patients, depending on what center or country, et cetera, where the patient is enrolling. Worst case scenario, potentially, is our image D here, where you may potentially enroll a patient because you're reporting double the dose concentration that otherwise would have never actually met that enrollment threshold in other circumstances. So several implications in study enrollment procedures. And this is not uncommon to us, right, in the critical care arena. We know there are several trials out there that many in this room have participated in and learned from and utilized in their everyday practice that have predefined enrollment thresholds for norepinephrine exposure or norepinephrine equivalents. Some of these trials specified SOFA scores or organ failure assessment, which, again, does have influence by the norepinephrine dosing at enrollment. So if we look at prognosis and how we prognosticate our patients on the basis of catecholamine exposure, you'll see here to the right, if you're looking at a difference of the dose reported by the salt formulation versus the base concentration, you have the potential for very different predictions in mortality, considering what number or what concentration you're putting into our calculation. This amplifies even further when you have patients with other types of organ failure. Again, you have the potential for stark differences in your expected mortality in these patient populations, which is important in our clinical trials, but important at bedside and in practice as well. And, of course, some of the authors that I had mentioned earlier have tried to make efforts to look at how we prognosticate patients on the basis of catecholamine requirements, but these data become limited if we don't think through, again, our underlying concentration and what doses we're actually reporting and using to find these different predictive values. You'll see here on the bottom left the graph by Dr. Leone and colleagues that show very different dose ranges at the same expected mortality rate. So I've talked about some of these already, but, again, relevance to clinical practice is really, really present in a number of different ways. We have our organ failure assessment scores. We have the surviving sepsis guidelines that we're taking to bedside with us every single day. We also have our ECMO and extracorporeal life support guidelines that also include catecholamine requirements as a potential marker for adjunctive therapies. We also have our vasopressor equivalent calculations, which some of our authors on this panel as well have made a lot of effort into trying to develop calculators and scores and able to use vasopressor equivalency in order to compare our agents, utilize these agents in a similar value or range in order to enroll patients in studies. There's a lot of effort that's been dedicated to evaluating these criteria, and what we're reporting, again, matters quite a bit when comparing these different agents. If we think through our clinical approaches at bedside and how this may actively impact what we're doing for patient care, the top image here is how we may consider weaning agents on the basis of dose reporting. So if we are a facility that is reporting our salt formulation, you're going to see here that the dose is going to remain higher as reported for a longer period of time than you would see from a base concentration. So if you're waiting to wean certain adjunctive agents, et cetera, until you hit a certain dose threshold, you're going to hit that much later if you're utilizing your salt concentration as your marker for wean of that therapy. And the opposite is then true for the initiation of adjuncts, right? So if we're waiting until we have a certain dose met before we initiate other adjunctive therapies, we're going to do so much quicker with using the salt concentration as our dosing mechanism versus what we would with base. And so potentially over-utilization of our adjunctive agents or longer duration of these adjunct agents that maybe wouldn't be seen with a more uniform dosing standard. So in conclusion, there are a few different options when it comes to our salt forms of norepinephrine. And the utilization and dose reporting can manufacture not only by the country but also by the drug manufacturer. And the impact, obviously, as I've already stated, can be seen across a number of different domains, whether that's drug operations or clinical bedside practice or research in itself. I'd be remiss if I didn't make a couple of acknowledgments. Again, it's been an honor to work with this panel. We appreciate all of the ESICM and SCCM staff and leadership that has been able to form this group and allow us to produce this work. So thank you. Well, thank you, Brittany. That's really been a great overview. And I'm going to ask, Ashish, can you introduce yourself as a senior author and then make a couple of comments? Sure. So hi, everyone. Ashish Khanna. I had the pleasure and honor of leading the SCCM side of this task force as a co-chair. And by way of introduction, I'm a critical care anesthesiologist, and I'm working currently at the Wake Forest University School of Medicine. I think, as Brittany rightly pointed out, this was a great group. It came together quickly and efficiently once we identified the problem and we understood the implications of the problem, and the group put together a set of broad-based recommendations. But essentially, as Brittany has highlighted, the problem is clinical care, patient safety, prognostication, and interpretation of research findings, including work that has already been published. Mark Leone, if you look at his publication, has clearly highlighted how maximum norepinephrine dosages used for prognostication will be really, really different if the authors specify base versus chart rate. That difference is essentially a half in terms of the overall prognostication implications. So the number one thing that we as a joint task force, and I'll let Jan chip in here, want to emphasize is that we would recommend the global adoption of a uniform standard as far as norepinephrine reporting and formulations are concerned. And our recommendation is norepinephrine-based for the sake of simplicity to moving forward that this would be adopted as a global standard. The downstream implications are, yes, for hospital pharmacies to be aware of the differences in norepinephrine-based versus chart rate, and also for the ICU general workflow where we do feel that when you put an order in the EMR, you should be specifying norepinephrine-based versus chart rate, because tomorrow you're going to use the same data for your large retrospective data sets. You're going to use the same data as thresholds when you enroll patients on randomized trials where you're enrolling on the basis of a certain norepinephrine-equivalent threshold. So there's downstream implications, and we need to move quickly so we can, you know, obviously we cannot change what we've done in the past, we're at least moving forward. We can, as far as patient care, patient safety, and implications for clinical trials are concerned, we know exactly what we're doing with norepinephrine dosing. And I will turn it over quickly to Jan to provide his perspective. Thank you very much, Shish, and hello, everybody. My name is Jan de Waal, I am an intensivist at Ghent University Hospital, and I co-chaired this task force from the ESICM side. As already nicely explained, you know, the different implications, of course, don't stop at clinical care. Research was mentioned a few times, and I think at every stage in a research activity when writing up the protocol to reporting, actually, the results, I think it's important to continue to use this norepinephrine base as the standard, and it should be explicitly mentioned, as well as any conversion, of course, if necessary or relevant. But also a recommendation is to the manufacturers to adequately label these drug formulations on the package, on the vials, just to make sure that everybody is using the correct perspective. Not that this is something urgent, but, of course, there should be no delay. We know where the problem is, the solutions have been put forward, and therefore our recommendation is not to delay the implementation thereof in clinical practice, in research, and also for manufacturers. I think that pretty much sums up what we recommended based on the data presented by Brittany, and I think this is up for discussion, of course. Sandy, I'll ask you to introduce yourself also, but you're PharmD, you're the past president of the society as well, and this is about norepinephrine. This release is specifically about norepinephrine, but there are other drugs like phenytoin, for instance, et cetera. As we think about the next steps, what are your comments about the impact of this and this type of approach for many other drugs, or maybe you might mention some? Actually, that would have been my exact comment, which is about awareness, actually. I think that's one of the most important points that this is bringing up, is not just for norepinephrine, but it's about awareness overall. I think that about 50% of the clinicians knew what kind of norepinephrine product that they had in their units, but if I asked everybody a similar question about maybe morphine, which is also available as a sulfate, as hydrochloride, as well as a tartrate. And we'd assume most often you use morphine sulfate. And so that probably would be the answer. But during times of drug shortages, we've switched over to hydrochloride. And people may or may not be familiar with that, right? Did it matter? Well, guess what? The base is similar between them. It didn't matter in those scenarios. But in this one, we have a different situation, right? The salts aren't comparable to the base, and that's why this is being highlighted as an issue. So I actually see some of your recommendations as best practices for all drug studies going forward that we make sure we clearly identify the product that we're using so that we can take that into consideration as well, because it could come up in another situation. So that's what I really see. The takeaway message here is best practices for studies going forward. So we see if these issues arise. Craig's got a comment, then I'm gonna turn it over to Ellie. But I'm just gonna ask you to raise your hand if you know which formulation of norepinephrine you use in your unit. Raise it high. Okay, put those down. And now those that actually don't know which formulation of epinephrine you use in your unit, raise it high. So I think it's an awareness. It's like a 50-50 thing. I can see it from up here. You might not be able to see it from back there. Only other one comment I wanted to make too is when you're using different salts, it's also a compatibility issue, right? And that, I don't know if it's been highlighted enough as well. So you're using a different salt of a different product, guess what, you're gonna have to look into what the compatibility is for that product. So knowing what salt you're using is important in those situations as well. Thank you very much. Craig, you had a question? I was actually gonna sort of do it. Vee and I just didn't ask for the show of hands. But if I had, I was actually literally gonna do that, proving we don't prepare in advance. But if I had a guess, I would have guessed that even though it was 50-50, even though it wasn't, there were more people who said they didn't, my guess is that would differ very significantly by specialty. So as I'm looking on the stage, I'm looking at about half MDs and about half pharmacists. And I would imagine that just about every pharmacist in the entire room would know that. And I think if we asked MDs and APPs, not as clear about nurses, the number would be quite smaller. So I don't think it's a 50-50 actually. Thank you. I would like first to congratulate the group and for this very wonderful joint effort, very well published. So it's a really great thing for all science and all our specialty. I have just a comment. I understand the importance of giving norms and using operational definitions for disease because it helps really getting to cure and getting to having a clear criteria for improvement. You said, and I understand that for the sake of simplicity, you are using the Bayes as the reference. But then you would maybe overstate patient severity and maybe induce a kind of undermining patient severity and maybe considering rescue strategies at a different time point. How do you think is going to actually impact on the way we are getting to a second life strategies as they are increasing the use in our ICUs? That's a great question. I will say that, again, based on what we know, and I will be the first to admit that we did not look at our surveys or our data came mostly from the EU and from the Americas. We haven't looked at the rest of the global population. In general, the Bayes formulation is the one that is being more commonly reported and that's how the drug is dispensed. So the group did conclude that we know that there is one type of formulation that's very commonly used. We're already familiar, pharmacies are familiar, so there's less change involved in that. Logically speaking, it would be easier to go with what is commonly being used. I do agree with you that yes, there are countries that use Tartrate and yes, there would need to be, if we go to Bayes all over, then those countries would really need to make heavier adjustments in how they have, not just what their pharmacies do, but how they have thought about doses of norepinephrine. Thank you very much, Ashish, and I think we are just on time to get to the next presentation. I can see here Professor Sheila Miatra. As you know, Sheila is the president of the Indian Society of Critical Care Medicine and she's going to report on the research priorities. We have a very, very important joint effort from the two societies from which we can be not only proud for the scientific reason, but also because we are all convinced that it saves lives on a daily basis in rich countries and less rich countries and all over the world. Professor Miatra. Good morning, everyone. Thank you for that very kind introduction. I'm going to be speaking about the Surviving Sepsis Campaign Contemporary Research Priorities and I'm really grateful to the European Society of Intensive Care Medicine and the Society of Critical Care for Medicine for giving me this opportunity. Before I start, I'd like to state my disclosures. I have no financial disclosures, a conflict of interest, but I am a member of the Surviving Sepsis Campaign Research Committee and also a member of the Surviving Sepsis Campaign 2025 Guidelines Committee and a steering committee member of the Asia-Pacific Sepsis Alliance. I'd also like to thank Dr. Craig Cooper Smith for sharing some of his slides for this presentation. So, I'm sure all of you have seen this paper which was published just two days ago on Friday, Surviving Sepsis Campaign Research Priorities 2023. I hope all of you have read it. So, I'm just going to give you a broad overview because I want to have more time for discussion. I want you to go back and read this paper. So, I'm just going to give you like a little teaser on what we have for this paper. So, a little about the Surviving Sepsis Research Committee. Now, this is a multi-professional group which has representation from the European Society of Intensive Care Medicine and the Society of Critical Care Medicine. And there are 16 members, and I was very proud to be one of the members on this committee, and I looked after the domain on resuscitation. So, these 16 members, multi-professional group, and of course, we had two very dynamic past presidents who were co-chairs of this paper, from ESICM, Daniel DeBacker, and from SCCM, Craig Cooper Smith, both past presidents who were co-chairs and led this entire research committee. So, just going a bit about the surviving sepsis priorities, the entire process. So, this 16 committee members represented SCCM and ESICM, and they were chosen by the presidents of both the organizations, and they decided to include authors with expertise in a wide variety of topics related to sepsis. And some of the authors were from the SSC, previous iterations of the SSC guidelines, some were not involved, but basically what they wanted was to cover a wide range of things that were not covered in the previous guidelines as well, and of course, various aspects of diversity were taken into consideration. And it was a very simple process, actually, that we followed, and what each member was asked to do was to submit five research questions on any subject that they felt would improve the understanding of sepsis. So, all the members of the team would submit this, and then the task force explicitly, you know, sort of told them to pick the topics that they felt were most important from the entire lot, and this was, again, not restricted to any particular area or not restricted to, you know, the previous, what was already covered or not covered by the previous guidelines, and the expectation was that this kind of open-ended process would lead to research questions spanning over a broad spectrum, especially of unanswered essential questions related to sepsis. So, this is the kind of flow diagram, looks a little complicated, but it was a really simple process. There were 81 questions that were put together by this group and there were many overlaps, so they were, you know, removed, and finally, there were 34 clinical questions and there were 10 basic science questions, and then the members of the committee, they voted, and from these questions, we got five top clinical questions and top five basic science questions, and the remaining 34 questions were not considered as a top, but they were also included in the research priorities, but not as top priorities. They were only five and five from the clinical questions as well as the basic research. So, these were the top research priorities, five top clinical research priorities, and five from basic sciences. I won't go through each of them, but I'll just tell you the kind of, the way in which they are described. So, each of these, you know, the research priorities, there is, you know, first we've described what is known about the topic, and then we talk about what are the gaps in knowledge, including a critique of whatever evidence that exists about this and future directions in which the research should progress, and again, they are listed not in order of the importance, but in the order of, you know, the patient management. So, I'll just put you through one of them, not all the five, because then I'll take a very long time and I want to have enough time for discussion. So, the first clinical question was, what is the best strategy for screening and identification of patients with sepsis? And can predictive modeling be used in real time to assist recognition of sepsis? So, it's important to know what we know so far. So, in the 2021 Iteration of Surviving Sepsis Guidelines, they recommended that healthcare systems have performance improvement programs for sepsis, including screening. Identification is crucial, since any delay in treatment is associated with outcomes, as we know, and identification requires the recognition of infection, the acute organ dysfunction and determination, and also that this is due to a dysregulated host response. So, it's really, really important for us to know, and we know that we have many screening tools that are available in our mentorium for predicting this kind of clinical deterioration, you know, and also poor outcomes. However, many have utility and each is associated with, they have some limitation or the other. So, this was an important, you know, to know further about this and to do research. So, the real gaps in the knowledge are the best screening tool for sepsis is still unknown. And this is really important for us, because we're gonna manage it if we know that this is sepsis in the first place. And without standard diagnosing of infection, sepsis, or dysregulated host response, or organ dysfunction, both accurate and generalizable, it will be very difficult to create them. And despite the interest and the growth in automated sepsis screening models, we have many of them, high quality evidence of the benefit over routine care is actually lacking. So, future directions would be, of course, that we need studies to determine whether these various sepsis algorithms that are generalizable to different, especially this electronic health records have accurate sensitivity, specificity, and also positive predictive value to be incorporated in the clinical workflow. And we need studies to test if these automated sepsis algorithms improve outcomes compared to routine care. And these studies should not only be large scale observation studies, but it's important that we also do prospective randomized control trials to add value to the algorithm. And what was recommended is that these RCTs should be designed as cluster randomized control trials and randomized units within the hospital to have both alert in live mode and silent mode and comparing these outcomes. So that means including the patient-related outcomes, but also the impact of this on various healthcare systems. So based on this, various recommendations for various questions that needed to be addressed were given that what defines a death-regulated host response, how should sepsis algorithms be trained, and what should be used as the gold standard, how are automated sepsis screening best implemented into clinical workflow? When implemented well, can automated sepsis screening to algorithms actually improve care processes and also outcomes as compared to the usual care? And more importantly, how is sepsis screening best implemented in the low resource settings? So this is just an example of how each clinical question and also the basic research questions was addressed. I won't go through each of them, but I'll just talk about the other four, the important clinical ones. The second question was what causes organ injury and dysregulated dysfunction in sepsis? How should it be defined, and how can it be detected? And there were various, there were three parts to this, and the first part was what causes organ injury and dysfunction in sepsis? Then we had a second part that do we know, how can we identify this organ dysfunction? And the third mark was that can blood biomarkers, the various biomarkers that we have, can they be used to improve our understanding of what is happening? So if we could have something that could tell us real time about the effect of, on the tissue, the cells and the tissues with this ongoing sepsis, if we could know this real time, that would really be useful and the way forward for research to progress in this area. And this was, the third question was on fluid resuscitation, and this was the part that I was involved in, and should it be individualized initially and beyond? So the many, many unanswered questions in this domain, and 3A is what is the optimal fluid management, not only in the first 24 hours, but also going further, and for these patients who present with hypotension and hyperperfusion, and as we know in the, even the last iteration of surviving sepsis guidelines, we talk about giving 30 mils per kg of fluid for the initial resuscitation, and this is based on one retrospective study. So whether we can use this all one size fits approach, or we should have a more individualized approach, what is the best hemodynamic tool? Should we look at fluid responsiveness to predict, you know, the requirement for fluid and individualize our care? If we use fluid responsiveness, there are various tests, and which test, which one is better over the others? And, you know, which one can predict the fluid responsiveness better? And which is the best fluid for the initial resuscitation? We all use crystalloids, but should we be using, you know, balanced solutions, or should we be using saline? Many, many unanswered questions in terms of individualized resuscitation. The fourth question, was the best vasopressor approach for treating the different phases of shock? Even with vasopressors, there are many unanswered questions. What should be the target for the vasopressor therapy? For example, the mean arterial pressure, or should it be organ-specific pressure, or should we be looking at the diastolic pressure? And what are the strategies to optimize your vasopressor therapy to improve the outcomes? So when should you initiate the vasopressor? Should you give fluids and then start the vasopressors if there's no response, or co-administration of vasopressors? And in what circumstances can the vasopressor be delivered peripherally? And what is the role of epinephrine or adrenaline? Can you use adrenaline? And this is an important question in resource-limited settings, where it's, you know, adrenaline is cheaper and readily available. And for patient with septic shock receiving norepinephrine and vasopressin, which drug should be weaned off first? Should you stop your norepinephrine first, or should you stop your vasopressin versus? These are very important clinical questions for which we really don't have the answer. And the fifth top clinical question was, that can a personalized precision medicine approach identify optimal therapies for improving patient outcomes? And there were also top basic science priorities. I'm not going to go through each of them, but many looking at various aspects of sepsis, how we can, you know, improve the animal models that we use and make them resemble as closely to humans, because we're using them as surrogates for various therapies that we're using in humans, aren't we? And how can we, you know, our outcomes be maximized, correlation between the animal models and in sepsis, and therefore use appropriate tools in both? And various other, you know, points were identified, and these were the five top basic research questions. In addition to that, there were many other clinical priorities. The remaining 34 were also included, and this has also been detailed. I won't go into this, but should you have separate, for immunocompromised patients, should there be separate recommendations? Should we be looking at sepsis outcomes in obese patients differently? So there were very different perspectives that were given, and more towards an individualized approach and not a one-size-fits-all approach towards sepsis. So these have been outlined. I won't go into details in the interest of time. And there were also other basic science priorities that have been enlisted in this paper. And if you look at the last iteration, in 2018, we had a similar SSE research committee was formulated, a joint committee by SICM and SCCM, and they also identified six clinical priorities that have been enumerated here in the 2018 guidelines that were published. And if you look at the progress that has occurred since this 2018, there has been significant progress that has been made for each of these questions that have been enumerated. However, it's very interesting that four of the top five clinical priorities in the new surviving sepsis guidelines, four of them are actually from the previous iteration of the 2018 guidelines. And this is not really surprising because when you have multiple studies have been performed, and this has changed the way we manage sepsis, nevertheless, when you have used a concept of precision medicine, it means with near certainty, you can't have a one size fits all approach. And sepsis, of course, as we know, is a heterogeneous entity and continuing to ask the big picture questions will guide the future of sepsis and the care. And this necessitates that every time you ask one question is answered, this will follow with many other questions from the same domain. So these were the basic research questions that were asked in 2018. And although the few basic research questions have translated into improved outcomes, the majority of the basic science priorities have changed from 2018. The question related to microbiome represents the only one that is repeated from 2018 to this iteration of the research priorities. And this may be because the combination of questions has actually changed with the change in the committees and between the previous iterations of the guidelines. So I'll just conclude by my last two slides. So if you look at the general limitation of this kind of process of having the research priorities, now, of course, one of the inherent limitations is there is subjectivity, of course, in the process. And this panel was composed of intensivists. So not all, intensivists are not the only ones who manage sepsis, right? There are non-intensivists who manage sepsis, but they were not included. And some countries had higher representation. Sadly, Africa was not represented. And significantly less is known about sepsis management in resource-limited settings. Though the kind of questions that were used were independent of the practice setting, we know that there will be differences in high and low resource settings. And this, of course, needs to be incorporated in the future, you know, iterations. And most importantly, that the committee did acknowledge that in order that some elements of the research agenda ultimately reach to the patient, there are pragmatic elements in its success. And therefore, it's very important to include explicitly link the research performance to implementation science, if you really want to get it at the bedside. So I'd just like to summarize by saying that this surviving sepsis research priorities actually is designed to be a catalyst for the research that's required in sepsis. And the knowledge that is advanced in the incorporation with various iterations of the surviving sepsis campaign guideline has actually allowed us to have evidence-based recommendations for the management. However, we all acknowledge that there are research gaps and they remove, and these are the, you know, therefore we cannot have very strong recommendations. And the priorities that have been identified represent a kind of roadmap for research in sepsis and septic shock in the future. And the hope really is that this document spurs international research on sepsis, both to change clinical guidance in the near future and also to answer more basic questions that will hopefully spear the discovery and innovation and can be translated into fundamental breakthroughs in sepsis. And with that, I thank you very much for your attention. Thank you.

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