Good morning, everyone. My name is Jerry Zimmerman, and my co-chair is Dr. Andy Rhodes. And this is the moment you've all been waiting for. This is the session that will provide a face-to-face rollout of the long-anticipated international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children. We have four esteemed speakers who know what they're talking about and have managed an incredible amount of work for this project. Tex Kassoun hails from Children's Hospital in Vancouver, British Columbia. We know Tex as a past president of WIFPICS, and I think basically as an ambassador to sepsis and critical care around the world. Pierre Tesseris is a professor of pediatrics from SACLA University in Paris. He is the current president of the European Society of Pediatric and Neonatal Intensive Care. And Pierre's real focus on sepsis relates to biochemistry, molecular biology, and immunology. Waleed Al-Hazani is an associate professor at McMaster University in Canada. And we were fortunate to get him into this group as he is an expert on methodology, and he will be telling you about the methodology. He has extensive experience and leadership in both the guide as well as the grade methodologies working groups. And then Scott Weiss from CHOP is, along with Tex, one of the co-chairs for the Pediatric Surviving Sepsis Campaign, an associate professor at the University of Pennsylvania, as you know, the PI and the Sprout study. And in addition to this, Scott is also very interested in the biochemistry and metabolism around sepsis. This is our schedule for this morning. It's tight. I would ask that all the speakers try to stay on track so that we can stay on schedule and have time for questions at the end. And then my last comment is right here. I would like to see, in this session, a Twitter frenzy. The paper, as you may know, has unprecedented social media exposure, and we'd like to see the same thing for this session. So please use these hashtags, and let's extend this discussion around the world. So Andy, no, I will introduce the first speakers, who will be Pierre, as well as Tex, who will be providing us the introduction and the rationale for the guidelines. Thank you so much for this very nice presentation. First of all, I would like to thank both the Society of Critical Care Medicine as well as the European Society of Intensive Care Medicine for the support for this very important work. So I will start this presentation with rapid disclosure. I have some disclosure, but not relevant to this talk. So what's the purpose of those recommendations? Clearly, these are the new guidelines that were not intended to update or iterate prior documents. So this is really important. Instead, we decided that we needed to provide some strong evidence-based approach to the management of septic shock as well as to sepsis-associated organ dysfunction by using a very comprehensive and transparent methodological approach by a panel with geographic and professional diversity. And I have to say, we reached this objective thanks to the support of both societies. So in terms of funding, as I said, this work was supported by both DSICM and SCCM. And there was no external funding sources that were used for the development of those guidelines. The conflict of interest were reviewed according to the American College of Critical Care Medicine guidelines development policies. What were the resources in the health care system? Recommendations, in fact, were developed based on evidence but without consideration of the availability of resources. And this is especially important because based on our own, each of us' experience, we know that application of those guidelines may be difficult based on the local resources. We agree, we acknowledge the variation within and across health care system and geographic region that we determine the practical application of those guidelines as well as recommendation for those guidelines are based on the best current evidence but cannot replace clinicians' decision making. In terms of contribution, it was a three, almost four years dedicated work of 51 professional physician nurses from 11 countries. So this is an outstanding achievement. This is, in my knowledge, the first time in pediatric which such a wide experience panels from all around the world. There was parent representative, three methodologists, as well as six group heads. Sponsoring organization contribute to the liaison and expertise. And I would thanks both societies and especially Lori for her help. I have to acknowledge Dr. Mark Peters, who's the ESIC co-vice chair who couldn't be present today for his invaluable participation and work for the development of those guidelines, as well as all my colleagues. In addition, we have to acknowledge the appreciation of extended to the following guidelines by 13 endorsing organizations that are listed just in front of you. What are the rationale for the guidelines? So those guidelines are dedicated for who? Mainly to provide guidance for clinicians, all of you, caring for children, including infants, school-age children, and adolescents with septic shock and sepsis with associated organ dysfunction. Where? Mostly in hospital, for sure, but also in emergency room and acute care settings. For what? Mostly, and most importantly, to guide, inform practice rather than define standard of care. So I will pass the last words to Tex, who will give you why now. Thank you. Thanks very much, Pierre. And thank you very much, Mr. Chairman, Jerry, and Andy, for having us here. I think this question really needs no answer. In fact, when you heard early on from Sapna, the Ultrametrics Court, this paper has already produced a number of views worldwide already. In the 99th percentile, I think she said, of some 14 million articles. In fact, my colleagues in Latin America, within matter of hours, translated this into Spanish already. We know that sepsis is a leading cause of ICU and hospital admission across the world. And for the first time, we have some data now that came just at the right time from the IHME, the Institute of Health Metrics and Evaluation Global Burden of Disease Study, that showed that sepsis in children across the world at 25 million cases approximately. And of those, there are about 3 to 4 million deaths in children, which is quite high still. The other thing is, while mortality varies across the world, it may be low in high resource areas. It's up to 50% in many areas. So you have a 50-50 chance of dying if you come to some of these institutions. We will talk more about the issue of severity, risk factors, et cetera. Morbidity is very high, as also shown by Jerry's seminal work, which he's presented. This is from the Global Burden of Disease Study, showing that if we look at it carefully, the highest incidence of sepsis by age groups is in the pediatric age group. You can see that worldwide. So children bear the biggest burden across the world, more than half of the cases of sepsis, both from primary infections and other things. So there's a heavy societal burden. We know that disability-adjusted life years is heavily weighted towards children. And the life years lost also is heavily weighted to children. And the fact the economic impact to societies is one of the things that policymakers would like to pay attention to. Matthew Born, a Harvard economist, said that infectious diseases steal human resources. And I think it takes it mostly from children. So there are a lot of reasons why this is very good now. The other rationale for the guidelines is that most of these deaths occur very early on. Even in poor countries or rich countries, by the time they come to the door of the institutions, although in low-income countries they may arrive later, most die very early on. And hence, if we can get care as quickly as possible, we have a better chance of making inroads and outcome survival and also decreasing disability. So I think we can save lives for the identification. Now, I stand here representing the group. But behind me, I wish I could bring everyone on stage. We have a team of over 50 professionals, as you heard about. And for every one of these sections which we had, we had group heads. You can see recognition and management of infection. Lauren, who could not be here now, did stellar work there. David Inwall, who led the hemodynamics and resuscitation group. Heidi, Lori, the ventilation group. Endocrine and metabolic therapies, Michael Agus, Simon Nadal for adjunctive therapies. And the research priorities, Robert Tasker is leading that. That's still under. While we have listed some of the research priorities, there's more work to be done in those areas. But without these individuals, we could have never achieved what we have done. Overall, the final document that you will see, the panel provides 77 statements. It is very humbling to work on these groups because the strong recommendations, we only have six strong recommendations. And that shows to a certain extent the paucity of the literature and how much more we have to do. Weak recommendations are 49. And best practice statements, nine. Best practice statements or where we have no recommendations, we felt that sometime we may have to give some sort of guidance because it would be a disservice to our community if we did not. And hence, we put in practice statements. And Waleed will give some idea more of the methodology and how we got to that. The research priorities, we are in the five of 49. And we are categorizing them in further things. So it is a very comprehensive document that at least right now summarizes the best state of the art, the best evidence we have. And the magic now beyond this, as you will hear more as we go on, is to contextualize it and it makes sense in different resources. Thank you very much. Thank you, Pierre. Thank you, Tex, for a fantastic introduction to this session. But also, thank you very much for your immense leadership over the last few years because bringing this panel together has really been quite challenging. But also, you've done it in a fantastic way. Clearly, the most important part of a guidelines approach is understanding the methodology. I'm really pleased that Waleed's going to join us up on the podium and describe the methodology. Waleed, I think it's fair to say, is probably one of the most eminent methodologists now in the world in guidelines. He seems to be on every guideline. And it's really a pleasure to listen to Waleed and to work with him. So please. Thank you, Andy, for the kind introduction. Hello, everyone. It's a great pleasure to be here today. These are my disclosures. I am the chair of the guide group, which provides methodology support to several international guidelines. I'm also a member of the great working group in which most of the methodology talk will be based on the great approach. The objectives of this talk would be to have an overview of the methodology that we use in the surviving sepsis and the children surviving sepsis campaign guideline. And also, more importantly, is to understand the language and the implications of recommendations. I think we're all familiar with the GOPSAT approach, the Older Methodology of Guideline Development. And GOPSAT stands for Good Old Boys Sitting Around a Table. What I'm going to talk about today is summarized in this slide. So I'm going to try to take you step by step in the next 13 and 1 1⁄2 minutes. The first step that we take before issuing a recommendation is to form the PICO question, or the question that we need to answer. The questions that we postulated in the guidelines were formed based on few sources. One was the adult surviving sepsis guidelines was a starting point. However, each of the five subgroups and the panel in those groups have discussed and weighed in according to the priority of clinicians and patients, and tried to prioritize questions that actually matters for practitioners. We ended up with 67 PICO questions. And when I say PICO, I mean the P stands for Population, Intervention, Comparator, and the Outcome. So you can see each question was very explicit. We know exactly what population we're looking at and what kind of interventions. The next step would be to come up with a list of outcomes and prioritize those outcomes. And the way to do this, or the way we used in this panel, was to survey the panelists. So the panelists will come up with a list of outcomes that they think that are important or relevant. We survey the panels and ask them to rate the importance of outcome on a scale from 1 to 9. We also sought input from patient representatives. What outcomes matter to you as a patient? And hopefully, we retained outcomes that are patient-centered, and they are critical for decision-making. By this process, we used a systematic approach to selecting the outcomes rather than, OK, let's look at the outcomes that were reported in each of the studies. So now we have formulated the question. We've prioritized the outcomes. The next step is, let's look at the evidence. So we conducted systematic reviews for each PICO question. We had excellent help from professional librarians. We included only English studies and with no data restriction. That's just for feasibility. And we searched a minimum of two large databases, so pretty comprehensive reviews. And what I like about this guideline is the hybrid approach in which panel members with support of methodologists conducted these reviews. And this table just shows the relative contribution of the panel members and methodologists to each of the steps, like screening, selection of the articles, risk-advised assessment, data abstraction when relevant, quantitative, and qualitative summary. So a ton of work for each question. And after identifying the relevant evidence or studies, we have to summarize the evidence. And this is where methodologists, again, shout out to my colleagues, Dr. Mark Nunley and Karen Chung, who both were excellent methodologists in these guidelines and did a lot of work. And so we perform meta-analyses or quantitative summary of the evidence when feasible, or qualitatively summarize the evidence if that's not possible. So now we've formed the questions, prioritized the outcomes, looked for the evidence, summarized the evidence. So we have the estimates in front of us. The next step is, what is the quality of evidence, or how confident we are about those estimates? And again, this is done based on the GRADE approach. As a general rule of thumb, so here I'm not going to talk about the details of GRADE. There is another workshop going on actually simultaneously that talks about this in detail. But the general rule of thumb, body of evidence that is based on randomized controlled trials start as high-quality evidence, while body of evidence from observational studies start at low-quality evidence. However, at the end of the GRADE assessment, you may end up with completely different assessment of the body of evidence based on certain criteria. And the implications or the meaning of the different levels of quality of evidence that could range anywhere between very low to high, it just reflect how confident we are about the estimates reflecting the truth. So it's kind of a scale ranging anywhere between being super confident, very confident about the evidence, to really you have no clue if this is the truth or not. So a quick example. As I said, RCTs start at high-quality evidence. Observational studies start at low-quality evidence. When you look at RCTs, there are certain criteria that you can use to assess the rigor and the quality of the evidence. However, if there are issues with risk of bias, this high-quality evidence could drop to moderate. Or if there is issues with indirectness, it could even drop to low. So your confidence would change depending on problems with certain categories of GRADE. When you look at observational studies, again, it could go both ways. But also, there are upgrading criteria. So for example, if there is a large treatment effect in a low-risk of bias observational study, sure enough, you can upgrade the quality of evidence to moderate. And I hope you guys can see this slide. But the intent here, not to go through this in detail, this is evidence profile. So for each of the recommendations that were graded, you will find in the appendix a table that summarizes the GRADE quality assessment for each of the outcomes and the estimates that we used to issue the recommendation. And I hope you can see here. Probably you can see it on the bigger screen. But you can see that there are a lot of different criteria but you can see that we assess the quality of evidence for each of the outcomes. And as you can see, some of the outcomes were judged to be at low quality evidence. And one of the outcomes was moderate quality of evidence because the contributing evidence to each of the outcomes may differ. The problems that we talked about with the GRADE approach also may differ in the assessment. So this is one of the merits of using the GRADE approach in which the assessment is also at the outcome level. Again, we're still talking about just what happens with a single recommendation. One of the interesting challenges that I found with the children guideline is the decision whether to use direct or indirect evidence. Given the fact there's not too many high quality RCTs available published in the literature, we always were faced with the question, okay, should we use indirect evidence? Should we look at observational studies or what to do? So we developed a framework that is also available in the published manuscript that only allows groups to follow the same process when we select the indirect evidence. I'm not gonna go through it in detail now because we don't have time, but I just wanna make sure that you guys are aware that this actually exists and it being followed in the recommendations. Back to my favorite slide. So we've been through all this journey from the PICO, systematic review, grading, and now the panel members who are smiley here, but in real life, not too much smiles. But the plan now is to move from evidence to recommendation. Well, one would think we have the quality of evidence, what else we need? High quality evidence means strong recommendation all the time. As it turns out, there are several factors that we should look at. And each of the groups have looked at all these factors, including, sorry, the cost, values of preferences, risk and benefit, feasibility, acceptability, all these variables using what is known as the evidence to decision framework. So this framework allows the panel members to discuss each of those components. And we had several teleconferences, again, for each of the PICO questions, for each of the evidence tables to come up with the final decision. And it's gonna look something like this at the end. So we have a table that summarizes the judgments of the panel members and after discussion and deliberation, what do they think about the influence of each of those variables on the final recommendation? And then finally, the moment of truth is to make the recommendation. So it's not like people sitting in one room and saying, okay, what do you think? Should we issue a strong recommendation for this intervention or not? It actually was following a very strict and systematic approach. Once the subgroups have proposed initial recommendations, we had a two-day meeting in Hamilton and the panel went through every single recommendation in detail and the groups took feedback and they rewarded the recommendations. And then finally, we send the recommendations electronically to the full panel who are not conflicted to vote on the recommendations. We had very strict voting criteria. So we need at least 75% of the panel to respond and more than 80% or more agreement, which it's very, very strict, I have to say. If you haven't paid attention so far, please pay attention now, because this is one of the most challenging areas. We need to speak the same language. I find the grade language is more methodology-oriented. So I'll try to explain it in the next few slides, which hopefully set the stage for my colleagues when they're discussing the recommendation so everybody's on the same page. So when the desirable consequences clearly outweighs the undesirable consequences, I know one would be inclined to issue a strong recommendation for this intervention. When the desirable consequences and the undesirable consequences probably close to each other or maybe the desirable consequences probably outweighs the undesirable consequences, one might be inclined to issue a weak recommendation. And the way we worded strong recommendation, we used the term we recommend. So once you see we recommend, that implies a strong recommendation. As an analogy, you must do it or you must avoid it. And when you say we suggest, we're talking about a weak recommendation. It's like a suggestion. And I'll talk about the implications in one second. So that's an example of a strong recommendation. I highlighted the important components. You see the word we recommend reflects strong recommendation and usually it's based on moderate or high quality evidence. In some instances, low quality evidence could result in a strong recommendation, but I'm not gonna go through this now. We don't have time. A weak recommendation, that's another example, starts with the word we suggest and again, implies a weak or conditional recommendation and usually it's based on low or very low quality evidence. So what does that mean? What does that mean when I say a strong recommendation or a weak recommendation? The implications for patients, a strong recommendation means that most individuals who are faced with this situation would wanna use the recommended course of action and only a minority or very small proportion would not. As opposed to a weak recommendation when yeah, majority of people may say, okay, I'll use it, but there will still be many who would say, no, thank you. So it's subject to values and preferences and other variables. For clinicians, the same. Most clinicians in a strong recommendation would use the recommended course of action. They should ask themselves if they don't follow the recommendation, why I'm not following it? There have to be a really good reason why not. As opposed to a weak recommendation which is subject to patients or families values and preferences and other patient related variables. And these are extremely important because people tend to hear the word recommendation, first thing clicked into their mind that everybody has to follow this recommendation. You have to always look at the strength of the recommendation. For policymakers, a strong recommendation can be adopted as a policy in some institutions as opposed to weak recommendation shouldn't be adopted policies will likely vary according to local context. Also, I want to grab your attention about best practice statements. And there are certain criteria that we use to issue a best practice statement that also implies a strong recommendation. Again, I don't have time to go through the details of this. And a clear example for best practice statement, should I examine my patient every day? There is no evidence to look at this, but we know that the desirable consequences is clearly favorable. So one would say, we recommend you examine your patient every day. So that's an example of a best practice statement. So if you see that throughout the guideline document, you have to know that we used strict criteria that was proposed by the Great Working Group. The remarks are meant to clarify some important aspects of the recommendation. So if there's a recommendation has a remark section with it, please read it so we can understand the context of the recommendation. The last thing I want to touch on, there were instances where the evidence did not allow us to generate recommendations. So two options, whether we say, well, we could not generate recommendations because the evidence didn't help us and leave it as this, or we could add a little bit extra piece of information by surveying the panel member and then describing to readers, well, this is what our panel are using in practice. So they are not recommendations, they are not associated with a strength or direction, it's just a descriptive statement. Thank you for listening. And if you have any questions, feel free to ask at the end or email me directly and feel free to follow me on Twitter as well. Thank you. Thank you, Waleed. So next we will call to the podium, Scott Weiss, who will discuss antimicrobials and source control. Thank you very much and good morning. I have no relevant disclosures, except to say that I'm going to summarize some of the key recommendations and Pierre will do the same. Because of time limitations, we're not going to be able to provide an exhaustive summary of the evidence that went into each recommendation. And so we're going to show some examples of where the data kind of led us to the recommendation, but for more exhaustive and complete rationale, refer you to the published manuscript and the supplemental tables and figures in that document. So for screening and management, we suggest implementing systematic screening for timely recognition of septic shock and other sepsis associated organ dysfunction, which is a weak recommendation based on very low quality of evidence. And we recommend implementing a protocol for the management of children with septic shock or other sepsis associated organ dysfunction, which is a best practice statement. And for screening, the recommendation was based on data such as this one example from my institution, the Children's Hospital of Philadelphia, where implementation of a screen for sepsis for all patients who present to the ED, which was started here, led to a decrease in the proportion of missed sepsis cases from 17% to less than 5%. An example of why we issued a best practice statement about formulating a protocol for management of sepsis at each institution is from this paper published from New York State, which demonstrated that a simple protocol that included three elements was associated with a reduced adjusted odds ratio of mortality. Another example where these two approaches have been combined is from the University of Utah, where the implementation of a screen as well as a simple bundle that included rapid antibiotics and fluid administration was associated with an adjusted odds ratio of 0.2 for death among over 1300 children who presented to an ED with septic shock. We were unable to issue a recommendation about using blood lactate to stratify children with suspected septic shock or other sepsis associated organ dysfunction into low versus high risk of having septic shock or sepsis. And I wanna clarify here that the point of this lack of recommendation is solely related to children who have suspicion of sepsis and whether lactate is useful to help determine whether or not they actually do or do not have sepsis or septic shock. We have another recommendation about using lactate to guide management, which will be discussed in a bit. We do recommend obtaining blood cultures before the initiation of antimicrobial therapy, as long as this will not substantially delay antimicrobial administration, and this is a best practice statement. For children who have septic shock that is clinically identified, we recommend starting antimicrobial therapy as soon as possible, and ideally within one hour of recommendation. And this is a strong recommendation, although based on low quality of evidence. In contrast, for children who have sepsis but without shock, we suggest starting antimicrobial therapy as soon as possible after appropriate evaluation and within three hours of the initial suspicion of sepsis. And that is a weak recommendation, again, based on low quality of evidence. So let me try to explain why these two recommendations. So for children who have clinically identified shock for whom a diagnosis should be able to be made based on physical exam findings without the need for additional laboratory evidence, there are two studies that inform this recommendation. And there was a strong suggestion of benefits for administration of antibiotics within one hour of the recognition of shock. And so that led to that recommendation, although the panel did acknowledge that a dichotomous cut point was not entirely clear, but felt that the one hour recommendation was supported by the literature and is likely to be beneficial to children. For those children, however, who have suspicion of sepsis, but do not have clinical evidence of shock, additional laboratory testing may be necessary to confirm the diagnosis. And here we consider the problem of over-administration of antibiotics, which is potentially harmful for the individual patient as well as the greater public health. And so the same two studies were able to inform this recommendation. And so in the first study, which was a small single center study, we noted a dose response increase in the risk of mortality with each hour delay from onset of sepsis here. And in the second study, a larger study out of New York State, multi-centered, which did show a benefit of early administration of antibiotics. But when you delve deeper into the data, there was not a strong difference between those patients who received antibiotics within one hour and those patients who received antibiotics within three hours. And so in order to balance the competing priorities of being able to accurately administer antibiotics to those who need it, for children, again, who do not have shock, we recommend an expedited diagnostic evaluation. If your evaluation confirms sepsis or the patient develops shock in the interim, then antibiotics should be administered as soon as possible. And ideally that's within three hours of your initial suspicion. We recommend empiric broad-spectrum therapy with one or more antimicrobials to cover all likely pathogens. And again, that's a best practice statement. And specifically for those children without immune compromise or high risk for multidrug-resistant pathogens, we suggest against routine use of empiric multidrug therapy, instead suggesting that clinicians choose broad-spectrum monotherapy. But for those children who have immune compromise or are at high risk for multidrug-resistant pathogens, we suggest empiric multidrug therapy as a weak recommendation based on low quality of evidence. And so why those recommendations? These are based largely on a meta-analysis of over 7,000 patients that included children which showed no benefit for routine use of multidrug therapy for either mortality or treatment failure. And in a meta-analysis of three trials of high-risk children with febrile neutropenia, there was no evidence for use of multidrug therapy related to treatment failure. However, several studies have demonstrated an association of increased adverse effects with routine use of multidrug therapy. As an example, vancomycin and piperacillin-tazobactam combination is associated with an increased risk of acute kidney injury in children. So then when do we recommend use of multidrug antimicrobial therapy? Well, in children who have sepsis or septic shock, if one needs to expand the spectrum of coverage, you may need to use empiric multidrug therapy. So for example, that's adding a glycopeptide or an aminoglycoside, although one would prefer that we use broad-spectrum monotherapy instead, if possible. If there's a high risk of antimicrobial resistance in the community or the hospital in which you're treating that patient, you might need to consider expanding your coverage, again, to include a glycopeptide like vancomycin or an aminoglycoside. The rate of, or the level of antimicrobial resistance for concerning pathogen is not clear, but the evidence suggests that if the prevalence of antimicrobial resistance is somewhere around 10%, that might be reasonable to start thinking about multidrug coverage, and again, for children who have immune compromise who present with septic shock. We do not routinely recommend for use of multidrug therapy for the purposes solely of synergy or so-called double coverage when those three above categories are not present. In terms of antimicrobial stewardship, we had several recommendations, including narrowing antimicrobial therapy as soon as possible once additional data are available, daily assessment for de-escalation of antimicrobial therapy, and we also recommend determining the duration of antimicrobial therapy based on the individual patient and their circumstances rather than on a set time period of seven or 10 days. If no pathogen is identified, we recommend narrowing or stopping empiric antimicrobial therapy as soon as possible in conjunction with consultation from infectious disease specialists. For source control, we recommend instituting source control procedures as soon as possible after a diagnosis of infection amenable to a source control procedure is made. There was not sufficient data to recommend a specific time period in which this should occur. We also recommend removal of intravascular devices that are confirmed to be the source of sepsis or septic shock after other vascular access has been established, and depending on the pathogen and risk benefits of the surgical procedure for that particular patient. And so there was insufficient evidence to make a broad recommendation, and so these decisions need to be individualized to the patient depending on the pathogen and the other circumstances of that patient's condition. So in summary, we recommend implementing systematic screening for sepsis and a management algorithm that's tailored to local resources, ideally using these guidelines as the basis for formulating that protocol, but having a protocol that takes into account local resource availability and workflow processes. Clinicians should prioritize early broad-spectrum antibiotics and source control for shock, or for those patients without shock, as soon as an expedited evaluation supports that sepsis-associated organ dysfunction is present. We recommend narrowing or stopping antimicrobial therapy as soon as possible based on the patient's clinical condition and available microbiological data. Thank you. Thank you, Scott. Our next speaker, Pierre, is gonna take us through the hemodynamic resuscitation recommendations. This is probably the most tricky part. Okay, hemodynamic resuscitation in terms of fluid and vasopressor, what are the guidelines? And so, during the next 10 minutes, I will not get in the detail basis of all those recommendations, because most of you are aware of the current literature on it, but I will really focus and be mostly specific on the recommendation that the guidelines sort out. What about fluid resuscitation? Basically, we have to admit that depending on the healthcare system and the availability of ICU, there might be some difference. Even though, initially, I told you that we didn't consider the system, healthcare system, for making the analysis, clearly, for the interpretation of the data, we needed to consider those two aspects. Over the first hour is suggested clearly also in line with the other recommendation as well as the way we will administer the bolus based on the clinical markers of our cardiac output as well as the signs of fluid overload. The full point is the regular assessment, mostly clinical assessment, regular assessment as well as advanced hemodynamic reassessment. So I will get more deeply in the recommendation now. So first it really depends on the expert panel consider that really depends on the availability of an ICU in the environment. So if there is an ICU we suggest the administration of up to 40 to 60 mils per kilo in bolus of 10 to 20 per bolus of the first hour. If there is no ICU in the absence of hypotension and it's a strong recommendation we recommend against bolus fluid administration and this is important. It's one of the strong recommendation of the guidelines. If ICU are not available but the patient has hypotension we suggest administration of up to 40 to 60 mils per kilo in 10 to 20 mils per kilo per bolus over the first hour and this is a weak recommendation. Whatever the setting it's clear that fluid administration should be guided by frequent reassessment of the clinical markers as well as sterile blood lactate and advanced hemodynamic monitoring. I will go to those points later on. So which solution? So this one was pretty easy. We suggest using crystalloids rather than albumin for the initial resuscitation of children with septic shock and other sepsis associated organ dysfunction and we suggest using balanced crystalloids rather than normal saline. Starches and gelatin another strong recommendation against the use of starches in the acute resuscitation of children with septic shock and other sepsis associated organ dysfunction but this is not a surprise for you. We suggest against the use of gelatin in the resuscitation of children with septic shock or other sepsis associated organ dysfunction. Hemodynamic monitoring. So this is a very important part because as you know one of the of the key point in the other recommendation is the emphasis on the necessity to have advanced monitoring and to regularly re-evaluate the response to fluids and to vasopressor. An important point for the pediatric guidelines is that we get rid of the cold warm septic shock categorization based solely on the clinical parameters. So this is extremely important and I think it's a major advance. Advanced monitoring of hemodynamic variables to guide resuscitation as well as lactate trend. We will discuss it later on. So we suggest not using bedside clinical site in isolation to characterize septic shock as warm or cold as I said. We suggest using advanced hemodynamic variables when available. Clearly it depends on the setting. It depends on the local ICU ability to develop or have access to advanced monitoring. In addition to bedside clinical variables to guide resuscitation either the fluids as well as the vasopressors as we'll see. We suggest using trends in blood lactate levels. Also we have no clear recommendation for using lactate as an initial risk stratification. Clearly we suggest using the trends in addition to clinical assessment to guide resuscitation in those very serious patients. Vasoactive medication. This is another important modification or recommendation. Clearly the point is in regards to use of epinephrine or norepinephrine as preferred vasoactive drugs. Again I will insist using advanced hemodynamic monitoring of cardiac ultrasound either with cardiac ultrasound or individual patient physiology. Vasopressin and vasoactive drugs titration is mandatory. So clearly dopamine is not recommended anymore. We suggest using epinephrine rather than dopamine. We suggest using norepinephrine rather than dopamine. But we were unable to issue any recommendation for a specific first-line vasoactive infusion treatment with septic shock. But in our practice both epinephrine or norepinephrine can be selected as a first line. Vascular access. The question of peripheral vascular access. We were unable to issue a recommendation about where to initiate vasoactive agent. Although that in our practice we all agree that we can use peripheral line if central venous access is not immediately available. We suggest either adding vasopressin or further titrating catecholamine in children with septic shock. But always using advanced monitoring to evaluate the response. In summary, four points. Adapt volume resuscitation to the care of the setting. To the care setting. Clinical variables of cardiac output as well as advanced hemodynamic monitoring. It makes a lot of sense but it needed to be said. Adapt vasoactive resuscitation to regular assessment of clinical variables. Still very important. As well as cardiac output evaluation through advanced hemodynamic monitoring. No starches, epinephrine or norepinephrine should be privileged. Thank you. Thank You Pierre and I will call back to the podium Scott Weiss who will discuss mechanical ventilation. Thank you. So this is a summary of the key recommendations around mechanical ventilation and nutrition. Nothing to disclose. So we were unable to issue a recommendation about whether or not to intubate children with fluid refractory catecholamine resistant shock because they had shock and without other indications for intubation. When decision is made to intubate we suggest not to use etomidate as an induction agent when intubating children with septic shock or other sepsis associated organ dysfunction as a weak recommendation based on low quality of evidence. A summary of that evidence is from two observational pediatric studies where etomidate was associated with increased mortality when those two studies were combined as well as indirect adult data which shows a high risk of adrenal suppression with the use of even a single dose of etomidate. We further suggest trying non-invasive mechanical ventilation in children with sepsis induced pediatric acute respiratory distress syndrome or PARDS without a clear indication for intubation and who are responding to initial resuscitation. Again a weak recommendation based on low quality of evidence. And that summary is here. Three studies combined together showed a significant improvement when non-invasive ventilation was used over early intubation again in children who were responding to initial resuscitation and didn't have other hard indications for intubation. In children who have sepsis associated PARDS we further suggest a strategy using a high PEEP, a weak recommendation based on low quality of evidence. We were not able to define what exactly high PEEP means but in general that means being more aggressive with PEEP using levels often greater than 10 to 15 especially in children who require an FIO2 of 60% or more. We suggest trial a trial of prone positioning as a weak recommendation based on low quality of evidence. Again this is for children who have severe PARDS. An early and temporary neuromuscular blockade as a weak recommendation based on very low quality of evidence mostly indirect from adults but some some pediatric data supports that this may be beneficial. Again we were not able to issue a recommendation about how long to use neuromuscular blockade but most studies have that have been associated with benefit have used 24 to 48 hours of early neuromuscular blockade. We recommend against the routine use of inhaled nitric oxide in all children with sepsis associated PARDS as a strong recommendation but we suggest trialing inhaled nitric oxide as a rescue therapy in the subset of children who have refractory hypoxemia after other oxygenation strategies have been optimized and that's a weak recommendation based on moderate quality of evidence. To summarize here so you can see there's no benefit signal for mortality but those patients who received inhaled nitric oxide had more vent free days as well as a decrease in their oxygenation index suggesting that it's at least provides some physiologic advantage temporarily and so potentially is useful as a rescue strategy for severe hypoxemia unresponsive to other management strategies. We could not suggest for or against the use of recruitment maneuvers in children with sepsis PARDS and refractory hypoxemia and we were not able to issue a recommendation as to whether high-frequency oscillatory ventilation is beneficial over conventional ventilation in children with sepsis induced PARDS. For nutrition we suggest enteral nutrition as the preferred method of feeding and when enteral nutrition cannot be adequately advanced we suggest that parenteral nutrition may be withheld in the first seven days of PICU admission as a weak recommendation based on moderate quality of evidence and the latter part of this suggestion is based largely on the data from the papanic trial which studied over 1,400 PICU patients and showed that late initiation of PN after day seven was associated with lower incidence of new infections as well as a faster rate of discharge from the ICU and a trend towards higher survival. We further suggest not withholding enteral feeding solely based on the use of vasoactive inotropic medications as a weak recommendation based on low quality of evidence and this is an important caveat to this is that enteral feeding is really not thought to be contraindicated after adequate hemodynamic resuscitation when you're no longer escalating doses of vasoactive agents regardless of the level of vasoactive agents that you ultimately settle out on. Further suggest that when enteral feeds are administered in a route that cannot be done through regular feeding that we preferentially suggest use of a gastric tube rather than a post pyloric feeding tube as a weak recommendation based on low quality of evidence and we suggest against routine measurement of both gastric residual volumes and the routine use of prokinetic agents to treat feeding intolerance in children. And again this is routine use for individual patients this may be helpful but for routine use not overall thought to be helpful. And then finally we suggest against the use of the following nutritional supplements and adjuncts selenium, glutamine, arginine, zinc, thiamine, vitamin C and vitamin D and the vitamin D suggestion is only for acute use patients who are documented to be vitamin D deficient. We still recommend general nutritional repletion but again this recommendation is based on rapid acute repletion for all patients with septic shock and these are all weak recommendations based on low or very low quality of evidence. I want to take one moment to comment specifically on the thiamine and vitamin C recommendations. Since the formulation of these recommendations there have been several new studies that have been published and these recommendations were based largely on the absence of pediatric data to inform these the use of these therapies in children with sepsis or septic shock. So in the last year or so there's been several adult studies and a couple of randomized controlled trials as well as two pediatric studies. One from my institution was a small study that suggested that thiamine administration may be useful as a metabolic rescue for children who have persistent hyperlactateemia despite evidence of otherwise adequate resuscitation. And a more recent study was a single-center retrospective observational study out of Lori Children's published a few weeks ago in the Blue Journal and this was a study of initially over 500 children some of whom received hydrocortisone ascorbic acid and thiamine or HAT therapy some of whom received hydrocortisone only and some of whom received neither and this was done by clinician preference not in a randomized fashion. This study showed a mortality benefit in propensity mass analysis for the use of HAT therapy and while this study was intriguing and well conducted and certainly worthy of follow-up it's notable that only 8% of the eligible patients received HAT therapy. There was no mortality benefits in the unmatched analysis and the matched analysis only included about 20% of the total number of patients with a surprisingly high mortality rate in the patients who did not receive HAT therapy. The panel was reconvened to discuss this new data as well as several studies in adults and there was overwhelming agreement that our current suggestion against the routine use of thiamine and vitamin C for all children with septic shock or sepsis associated organ dysfunction is still appropriate. However I do acknowledge that two of our research recommendations are for further randomized trials to investigate this as a promising therapy. So in summary it's important to individualize timing of intubation, avoid automated use, and use high PEEP, proning, and brief neuromuscular blockade of strategies for severe sepsis-induced PARDS, to prioritize early enteral feeding preferably through the gastric route after hemodynamic stability has been achieved, whether or not that hemodynamic stability is achieved with or without use of vasoactive infusions, and there's currently insufficient evidence for routine recommendation for the addition of several nutritional supplements. Thank you. Thank you Scott. I'd like to ask Pierre to come back up to the podium again now. Pierre's going to talk to us about some of the adjunctive therapies. Yeah, thank you. One more before the bundles. All right, adjunct therapy recommendation highlights. If there is one word to introduce this topic is we have to say that as pediatricians we are always very innovative in terms of finding out new therapies in septic shock, but at some point we have difficulties to prove it using controlled studies, but this should encourage us to move forward to those directions. So, again, some disclosure. Corticoids. Well, it's a tricky question. It brings a lot of discussion within the panel, but basically we all agree to suggest against the use of hydrocortisone if the patient was hemodynamically stabilized with fluid recitation vasopressors, but I will say in Europe, we say that it's a neutral answer, like a Swiss answer regarding use of IV hydrocortisone is either if your patient is not stabilized with fluid recitation of vasopressor, the panel recommends either the use or not the use of hydrocortisone. So this is a Swiss answer. What about endocrine and metabolic? We recommend against. Another very strong recommendation, the use of insulin therapy in patient with a target blood glucose below 140 milligrams per deciliter or 7.8 millimoles, but we were unable to issue a recommendation regarding what blood glucose range we should focus, but clearly, in our practice, target blood glucose level below 10 millimoles per liter should be reached. Calcium. We are unable to issue a recommendation of whether to target normal calcium agent with septic shock or sepsis-associated organ dysfunction, but again, in our practice, normal calcium level for children with septic shock should be recommended. We suggest against the use of L-tyroxine in children with septic shock, as well as we suggest either using or not using anti-operatic therapy to treat fever on those patients. So it was not, it was a Swiss panel, probably. Anyway, blood product. We suggest against transfusion of red blood cells in patient with an hemoglobin level greater or equal to 7 grams per deciliter if it is hemodimatically stabilized. However, we cannot make any recommendation with the red blood cell transfusion threshold for critically ill children with unstable septic shock. Again, for blood product, more specifically focused on platelets, and I think it's an important modification, evolution of the recommendation. We suggest against the prophylactic platelet transfusion based solely on platelets level in non-bleeding children with septic shock. In addition, we suggest against the use of prophylactic plasma transfusion in non-bleeding patients. Plasmatic change. I know that many of you are using regularly plasmatic change in septic shock patients, and I did hear some comments in the LA yesterday, but we suggest against using plasmatic change in children with septic shock or other associated organ dysfunction without thrombocytopenia-associated middle organ failure. But we all agree that we cannot suggest for or against the use of plasma exchange in children with septic shock or other associated sepsis organ dysfunction with TAMOF. Renal replacement therapy. This is one of the points that were tricky. We suggest using CRT to prevent or treat fluid overload in those patients, but we suggest against the use of high-volume hemifiltration over standard therapy hemifiltration in patients and children with septic shock. Another point that where pediatrician, where innovation came from pediatrics, is the use of extracorporeal life supports, either VV or VA. So we suggest using VV ECMO in children with sepsis-induced PRDS and refractory hypoxemia. It's a weak recommendation. As well as we suggest using VA ECMO as a rescue therapy in children with septic shock only if refractory. Immunoglobulin, stress ulcer prophylaxis. So first immunoglobulin, we suggest against the routine use of IV immune globulin in children with septic shock. But considering that some of the patients may benefit of the use of IV immunoglobulin, such in patients with toxic shock syndrome, necrotizing fasciitis, primary humoral immunodeficiency, or low document IV circulating IVIG. Regarding stress ulcer prophylaxis, globally we suggest against the use of those drugs in critically ill children with septic shock. Deep vein thrombosis prophylaxis, again against routine use of DVP, but we acknowledge that in some patients the risk may overweight, the benefit may overweight the risk in very specific populations, such in teenagers, obesity, cancer, multiple medical conditions, such renal cardiac disease. So in summary, IV hydrocortisone in unstable septic shock, neither recommended or not recommended. No tight glucose strategy, no systematic blood transfusion, platelet administration, or plasma. Probably or not PEX for time off, it's an open question. CRT for fluid overload, no high flow hemifiltration in septic shock patients. VE and VA ECMO is suggested in specific conditions. No IVIG except special indication I previously mentioned, and no stress ulcer, systematic stress ulcer therapy, nor DVT prophylaxis in patients without risk factors. Thank you. Thank you Pierre, and now I will call to the podium Tex Kissoon, who will discuss the application of these guidelines in resource poor settings. Thanks very much Jerry. This is one of the difficult tasks. When we started this process, we sort of pledged to the group that while the guidelines are going to be have great fidelity to the evidence, the best evidence we have, I think that we recognized very early on the importance of context, and in fact when we look at the adult guidelines, the studies have shown that only 2% of African ICUs were able to enact the entire guidelines. So this is a work in progress, and what I'm going to say here is really the plans that we have. This plan is informed, has sort of been informed in my mind, but I haven't spent time in those many of those places, and obviously my colleagues like Andrew, who is sitting here, who has really helped sort of challenge some of my assumptions. Now, as you heard before, the recommendations were developed without consideration of availability of resources, and the only one except the fluid resuscitation, and I think that was deliberate in our part because of the implication of the issue of fluid when there's no advanced supports, and in fact when we look at the studies, obviously the FEAST trial casts a big shadow as far as the approach to fluid management in resource-poor areas, but there are other reasons to adapt the guideline to resources, and it will depend on several things. We have profiles that are different in different countries with different pathogens, different sort of geography, get into healthcare systems that are much later. There are non-resilient health systems where there's difficulty in obtaining many of the tests that we do, and obviously the overarching thing is resources, and inequity poses a big problem in many areas of the world, so when we talk about the guidelines, if we use the present contemporary guidelines we have, I sort of hazard to guess that it will not be able to be used in many areas. So the practical application is very important, and I'd like to stress this is not only in sub-Saharan Africa or Southern Asia where about 85 to 90 percent of the children with sepsis die. I think this is also in high-income countries. Look at Canada, and up northern Canada we are working with some of the very same assumptions and the same methods that we've used in Uganda. We know again, with my colleagues telling me again, in southern United States, but across the country, wherever you are outside the major centers, the same problems would occur, and I would suggest that we'll have to grapple with the sort of the thorny issue of adapting these guidelines even for centers outside the centers. And this study, this is the IHME global burden of disease for the first report on sepsis in the world, and this by itself, the method that we use, but how we got to it is a long story, but this slide shows age standardized sepsis incidence versus socio-demographic index, and socio-demographic index is really an indication of really the sort of wealth in the society. It's for the rate education and income, etc. And one can see that the incidence is very high in these countries, which are mostly in sub-Saharan Africa and Asia, whereas the rich countries, United States, Canada, Europe, the incidence of sepsis is a lot lower, and even within that, you have great dichotomy. So the SDI can be used not only looking at countries as a whole, but you can get more granular into various regions, and in some areas of the world, the IHME is getting to that, which would show us that there is a marked difference in incidence of sepsis, and if we look at the resources, the resources are going to be very low there. Again, the mortality rate, you can see the stark differences, less death in these areas, whereas in the lower socio-demographic indices, there's a lot more mortality, and this shows the reason why it is very important if we want to make the best bang with these guidelines, we have to contextualize it for these reasons. Well, look at the pyramid of the importance. In Europe, North America has a similar age structure, male and blue, female and the red side, but age distribution of patients, and one can see that there are less kids here. Not surprisingly, when we look at Africa, sub-Saharan Africa, you can see the distribution. In many countries, more than half the population is under 16 years of age, so contextualize it to be used in those areas is a really weighty task that we have to do. We look at beta-lactamase producing enterobacter, and we look at colonization or sort of resistance organisms. It varies widely, even within sub-Saharan Africa, and again, in Asia, it's the very same thing, so again, when we give these guidelines, we can say give antimicrobial agents, but as Scott had spoken about, the choices of antimicrobial agents, it would vary depending on these. In many cases, they have scant laboratory sort of support. So, all of us in the panel accepted the fact that the guidelines is a general scheme of best practice, but translation is going to depend on the availability of local health resources, but the other factors that are mentioned. We also know that when we look, it is very humbling, as I said before, to look at the amount of knowledge we have, and more so in poor areas, and in fact, a few years ago in the Lancet Commission on Infectious Disease stated quite clearly that what we can do for the poorest of the poor is that we have to look at both getting basic knowledge of basic mechanisms, but the science of delivery, implementation science, and we need, for these guidelines to work, we need research to test the adaptation of the interventions in local area. We also need to look at environmental scans in readiness to take your patients with sepsis. We need to look at the issue of whether there's the drugs, personnel, whether the guidelines are in place there. We have to look at throttle points or points of weakness in the system, because non-resilient healthcare system plagues most of the low and middle-income countries, and in potential solutions. The question is, who needs to be in a working group? Well, this is a sort of work in progress. I know the WHO is very much interested in helping with this, which gave us a great boost. WFPCS, the World Federation, is much interested, as well as our colleagues who worked on this. But we need broad international and multi-professional representation from not only critical care, intensive care, emergency medicine, anesthesia, neonatology, infectious disease, etc. But I think we also need parents and families, those are recipients of care. We need not only the anthropologists and psychologists, because how do you enact these guidelines in situations where we have the local medicine man and those sort of things have great influence? So it takes wide ranges of society to really get these guidelines in a position where it could be used very effectively in those areas. And I think that this will, the working groups, while we may have the co-op working groups among medical teams, etc., getting the policy makers very early on from the ground floor is the only way that it can be adopted. For instance, countries still follow the ETAT, IHME guidelines, etc. So panelists will be recruited from a wide range of areas, including diversity to sex, race, and geography, etc., to work on this. We will extract themes from the guidelines, and we will align the guidelines with priorities from community and country. We look at development of methodology, and that would be helped by Waleed, who has some robust techniques to do that, to make sure that everyone can contextualize the guidelines in their world. Because one size will not fit all, and when we talk about low- and middle-income countries, you can have contemporary care within the same institution with what we call third-world diseases or poverty in the same institution, for instance, Andrews Institution. So in summary, we need to adapt the guidelines to the resources available, but we also need to give people stretch goals to the extent that what we put in place is, I'd like to see that when the next iteration comes, we are not in the same position saying that, you know, this is a lot of people. We would have made progress and use advocacy as a big push with incorporation of the guidelines to various settings. Thank you very much. So, Tex, thank you very much. I'd like you to stay at the podium, if you can. And I'd like you to stay up at the podium, and you're going to present this next talk on algorithm and bundle presentation. I think this, to me, is one of the really important parts of this session, because this is what, to the bedside clinician, makes the guidelines real and alive and tangible, and they can begin to understand what you're saying in real-life practice. So please, I'm looking forward to hearing about your algorithm and bundle. Thank you very much. To me, in fact, you say the important part gets me nervous. I'll start stumbling over my words. Now, this algorithm and bundle is the distillation of all that we have put together. You've heard Waleed talk about methodology. We've heard Pierre and Scott, as to the various recommendations. And the fact is this, I thought this would be easy, but it's one of the most difficult things to distill all this information into this algorithm. It took many iterations to get where we are, and it is not perfect. It does not have everything in great detail, but it is not meant to be. It is a graphic representation, and I trust that people will use it in their own settings by sort of using it as a guide. And if those who would like to get more information will need to go back to the original document. Now, in putting this algorithm together, we took note of the difficulty we had in discussing the issue of antimicrobial agents, when to give antimicrobial agents, and sort of balancing that with antimicrobial resistance, when to give fluids, and balancing it with how much fluids you give and where you give these fluids, etc. And Scott summarized it very nicely in saying that, okay, there are kids who will come in with septic shock, and once we recognize septic shock, the evidence really points to the fact that we need to jump and treat reasonably quickly. So you will see what is different here is that the guidelines are divided into two parts. One, the child is obvious in septic shock, and the other, where sepsis is suspected, septic shock is not yet apparent. Now, the one hour clock here is intended that we need to start these elements. Now, I know this caused a lot of... we learned from the adult guidelines. I know Andy and Laura, they came to our session, and they really sort of crystallized our thought as to where they stubbed their toes, so we did not have to stub our toes that often, although we did at times. So the reason is that, so in one hour, the intention was to start these elements. It was not intended that the administration of, say, fluids would be completed in one hour. So the elements here are, you start and obtain vascular access, you get a blood culture, and remember Scott said the blood culture, if you cannot get it, especially in small children, it should not delay the antibiotic agent, given the antibiotic agent. We measure lactate, not as an index of categorizing severity of the disease, but it may follow therapy. We also give administer fluid in those who need it, and obviously we start inotropic agents if shock persists. So these are the elements that need to be started when someone comes in septic shock. Now, those whose sepsis is suspected, we have the luxury of time, right, and we suggested, based on the data that Scott presented, that three hours is a reasonable time for him to evaluate this patient, do an expedited evaluation, and if shock intervenes, they then follow their one-hour pathway. But once diagnosis is complete, and if there's sepsis-associated organ dysfunction, they would be given the same therapy. Now, so these, I think this clarifies it, and this made it very well for us, in that the other societies, as you heard, the societies that endorsed our guidelines, they were sort of endorsed this also, which I think sort of was an indication of the thought and the clarity and listening to what the concerns of others were. You heard about the issue of respiratory support, assess the patient for respiratory distress syndrome, and then this continuous assessment, infection control being very important, source control, and fluid and vasoactive titration, and advanced hemodynamic monitoring, came to what Pierre had said, that in this sort of case, we needed to really not only use our clinical senses and a traditional warm and cold shock, but we may have to use other modes of monitoring to determine the robustness of their cardiovascular support. We spoke about hydrocortisone, we spoke about other therapies that can be given, avoiding the hypoglycemia, which was very important in these patients, and nutritional support, as you heard, a gastric tube as early as we can, the issue of VV and VA support for these patients, depending on whether it was purely in parts, or if there was a failure of cardiac failure, also an unremitting shock. So these were the sort of basic guidelines there, and what we thought that we would give a little more context is to the issue of fluid and these therapies, because that is where, as I said, we had a lot of discussion, in which there is great angst. So fluid and vasoactive and inotropic management, you heard about the issue of the choice of vasoactive agents, previous guidelines where dopamine was sort of recommended, because it was common practice, and now we have some evidence and we felt that epinephrine and norepinephrine are preferred choices. So in healthcare system with intensive care, we divided into those without intensive care, and the reason for that, when we spoke about intensive care, we spoke about advanced support, the ability to provide respiratory support for patients, because we know overzealous fluid resuscitation can tip them over, and if there's no respiratory ability to support the respiration, we would have sort of determined outcome because of iatrogenesis. So in those areas with intensive care support, we said about abnormal perfusion with or without hypotension. So this is the cases where we say we have the kid who comes in tachycardia, cool periphery, CNS, sort of abnormalities, et cetera, with the possibility of an infection. And in those cases, we still recommend giving a fluid, 10 to 20 mLs per kilo aliquots, up to 60 mLs. But every 10 to 20 mLs kilo that is given, the most important thing is the continuous monitoring of the patients, continuous reassessment of the patients to determine whether the fluid is making a difference because we have seen, and there's some work, not published, that given fluid, you may tip the patient over if there's myocardial dysfunction that is undiagnosed early on. Or on the other hand, more fluid may be needed. So we felt that once you go, decide to go beyond 40, we need to reassess again and assess cardiac function. And cardiac function in the world with resources, there would be several other methods. We'll have the ultrasound on the bedside is one form of it. But then, obviously, we have other methods of looking at judging myocardial function. Then we said, consider now the inotropic support and you give, if there's myocardial dysfunction, you can start epinephrine or no epinephrine if shock persists. Now, the thorny issues came on the side where there was without great intensive care support. And this is where the evidence diverge. And as I said, there is the FEAST trial, which is a very robust trial. It was done in poor resource areas. It did not give us much guidance on the issue of those children who had hypotension because there was a small number. It was a little over 50 with hypertension. So if we look at abnormal perfusion with hypotension, what was done at the time is a smaller amount of fluids, 10 to 20 mLs per kilo, but over a longer period of time. And once we get beyond 40 mLs per kilo, then we suggest starting inotropes a little earlier. Now, the issue of fluid resuscitation in resource-poor areas was discussed at length at the WHO. In fact, we met there for over a week. And it was amazing to see the various opinions that came out with fluid. And I know this has been a thorny issue since then, but we came to the accommodation that there should be a reasonably wide range. So individuals have a choice in the matter. You can give 10 mL per kilo of fluid as Ebola, so you can give 20 mL per kilo, and you can give it between 30 to 60 minutes. That was the WHO recommendation. So that is without hypotension. Sorry, with hypotension, this is what we recommend. In those with abnormal perfusion without hypotension, and maybe I can digress and tell you what we meant by hypotension. You can see it's written here. The blood pressure sort of criteria dependent on age. And these blood pressure criteria was the evidence we had from the FEAST trial in patients with hypotension in sub-Saharan Africa. The point is that if you look at PALS guidelines, there are different sort of threshold levels, but we felt it more prudent with the evidence to use these levels. When we spoke about the WHO criteria for hypotension, where you cannot measure blood pressure, it is three of these things. It is really cold extremities, prolonged capillary refill greater than three minutes, and fast pulse. And if you have two of these, it does not constitute shock. You've got to have all three. That's the WHO criteria. So when we have abnormal perfusion without hypotension, we strongly recommend do not give bolus fluids. These patients can be put on ongoing maintenance fluids, except for diarrheal diseases, which was not addressed in the FEAST trial. And there are certain subpopulations. We know, for instance, if you look at literature on dengue fever, dengue fever, the benefits were tremendous with fluids, large volume of fluid. So there are subgroups, whereas malaria, it was not that beneficial. Again, we start maintenance fluid. We monitor hemodynamic closely, bearing in mind that we may not have the sophisticated method to do that. And we consider vasoactive support if available early on. So if shock is resolved from these things, perfusion-infused, then you consider maintenance fluid. You do not give more fluid boluses, and you continue monitoring the patient. And again, the antimicrobial agents that you use in this area would be determined clearly by the local resistance pattern, the local organisms that is available. And I think that's all for this. Thank you very much. Stop there. Thank you. I'd like to provide the opportunity for the audience to ask questions. I don't see other mic. Yes. If you come to the front, there is at least one microphone down here. Sapna, did we get any questions on Twitter? Yes, you did. All right. So the first question was the, at the bottom of the bundle. It has this asterisk. This is hydrocortisone may cause benefit or harm. So there was a question from Twitter. What is a bedside clinician supposed to do with that information? All right, I get voted to answer that question, I suppose. So, the wording on that recommendation was slightly different than some of the other recommendations where we said we couldn't issue a recommendation. And instead of not issuing a recommendation at all, we said it's reasonable to either use or not use, which essentially you could say is the same thing. But it's slightly different in that either approach is right now supported by the evidence. There's no direct pediatric evidence of benefits. And there are low quality, well done, but in the GRADE approach, low quality observational studies that suggest harm. And that harm may be for certain subsets of patients, we're not yet sure. So, that decision needs to be individualized, but either decision is appropriate. And so, if your preference is to use hydrocortisone at the moment, that is supported by the guidelines. And if your preference is to not use hydrocortisone, that too is supported by the current level of evidence. And that speaks to the need for better evidence so that we can provide a more structured guideline that could be, you know, more easily applied at the bedside. And just, can I add one more thing that relates to research priorities from the endocrine group. This is the first one, and that is, doesn't relate to the bedside clinician, but maintain equipoise on the question and support clinical trials that address this question. So, if I could now open these guidelines up to questions from the audience. Perhaps, if I could ask you just to introduce yourself before you ask the question and then keep the question nice and succinct. Okay, my name is Dr. William Norbert, and I'm a pediatric intensivist from Texas. And I would like to congratulate you on a very good job of coordinating and concisely coming down to recommendations regarding sepsis management. However, this is the best arrangement of the chairs on the Titanic that I've ever seen. And I don't think other people can do it better. But the Titanic still sinks. You have nothing new. Over the past four years at this convention, I have had a booth which has presented an option in fluid management to this group. And I am still in hopes that someone will take up my project that clearly alters the prognosis and outcome in the treatment of sepsis. We have nothing new in 20 years. Talk to me. No, thanks very much. I think, as I said before, it's really humbling to see how little we have. And as I said, when we look at the fluid approaches, the most robust study that we have, whether we believe it or not, or whether we feel there are warts in the evidence, is the FEAST trial. It was well conducted and it has sort of been defended in various different fora. In the rich countries or countries with high resources, we have not had any of those trials. And I would echo what you're saying. If you have an idea and you can convince our colleagues to really get on board with it in North America, where you are here, or across the pond, both sides, I think that would be a good idea. Ron Sanders. I'm a pediatric intensivist in Arkansas Children's Hospital. And outstanding work from my perspective, particularly the emphasis on looking out for fluid overload is long overdue. I know we're all aware of that, but emphasizing that is important. My question is, I hear your recommendation with regards to it's okay to feed when you're on basal actives if it's only basal actives alone. Has the panel thought, for instance, and this wasn't directly addressed, perhaps if escalator or unchanged lactase should change our approach with regards to feeding in children on basal actives? Yeah. Does anybody want to take it? Okay. The issue of lactate, we discussed that at length, too. As you know, we said that if we have a lactate, we will use a lactate to sort of follow therapy. Okay? We cannot use it to judge the level of shock or the sort of severity of organ dysfunction. I don't think there is any evidence. You know, as I said, again, we don't have much evidence for it. It doesn't mean that it doesn't exist and it shouldn't be considered. And I think that would be left to individual practice, because one would intuitively think that if the lactate is not going down, that we are not resolving the shock, right? But we don't have the evidence to say, well, at this point, just stop feed. I don't know if any panel member had anything else. Lactate is a complicated molecule that in sepsis we often think of as an indication of insufficient oxygen delivery and aerobic respiration, but it's much more complicated than that. Initially, that probably is the majority of the patients we're talking about. But over time, I think the reasons for persistence of elevated lactate diverge. And so if the reason a child has an elevated lactate is due to testinal ischemia, then feeding is contraindicated. And that's clearly outlined in the guidelines that these recommendations apply to children who don't have other reasons why feeding, actually, is contraindicated. But for children who have either primary or acquired mitochondrial dysfunction or other issues with clearance of lactate without evidence of ongoing tissue perfusion abnormalities, then there's no evidence right now that feeding is harmful. And in fact, it may actually be helpful in some of those patients. So I think the persistence of lactate needs to be separated from the initial elevated lactate that we see as we're engaging in the initial resuscitation efforts of shock. Thank you. If I can add some point, I think it's clear that we have to consider those recommendations, the guidelines or the related guidelines that are based on the strongest and the strongest evidence in the literature that all of us know. And we know that there is published retrospective series, a lot of patients where we look at the kinetics of lactate. And in our daily practice, we use it. That's why there was this discussion regarding the use of the kinetics or not, and regarding the lactate as a stratification. I'm not sure that in the future it might change. But for now, we have also trust our own experience and the literature, even though it's not high or high level. Thank you. Pierre? Hello. I'm Susan Morris. I'm a pediatric intensivist in Huntsville, Alabama. And my question is about initial antibiotic therapy. So I was a resident and fellow in the mid-2000s when community-acquired MRSA was a big thing, previously healthy kids coming in in septic shock. So when you say single antibiotic broad-spectrum therapy, are you referring to not using Venk at all to start with, or starting it and then taking it off after 48 hours, or just, I guess I just want clarification. Yeah. Thanks for the opportunity to clarify. So if you're caring for children in an area where there's a high prevalence of MRSA, or resistant pneumococcus, for example, then empiric therapy with vancomycin probably makes sense. And that would be an area where you probably should add that as multidrug therapy. That goes to that second point, that if the patient is being treated with either a personal history of multidrug-resistant pathogens or an area where the prevalence is more than 10%, and that's kind of a guesstimate of where the threshold should be, then multidrug therapy is probably beneficial. And if that's MRSA, then vancomycin should be included as part of that initial regimen. Hello. I am Arun Baranwal. I am working in an academic PSU in India. So my question is regarding the fluid therapy related to resource-constrained setting. So what we have done is we have just divided the settings in two groups. One is the low-income, and another is high-income. And the low-income recommendation is basically being informed by the FEAST trial, right? But there are a lot many situations or countries where we are falling into middle-income group, like something like India. So where you have a lot of, like situation is not like the FEAST clinical setting, you can give fluid, you can assess clinically, you can give fluid, you can give inotropes, and you can give hand ventilation, but there is no ICU bed. So while they are getting shifted to ICU, they are getting ventilated on hand by the parents in emergency room for significant time, and that may range anything between one to 12 hours. So whether that not giving fluid to a hypotensive, not hypotensive child will be really applicable in those setting as well. That is one. And number two, when we are targeting, when we are dosing, creating a dose for fluid therapy, we are saying that it should be according to ideal body weight. I think that may be fine for the obese patient, because that fluid is not going to go to the subcutaneous fat. But as far as malnourished children are concerned, if we are dosing fluid according to ideal body weight, don't you think that it will be more for them, considering the fact that they might be having nutritional and anemic cardiomyopathy as well? Thanks. Thanks, Arun. Good to see you. Now, that is what keeps me up at night. The issue of when we speak about low and middle income or low and high resource setting, I think that it's really a false dichotomy. In your institution, you'll get contemporary care, right? And right next to it, you may have no care. In Canada, it's the same sort of thing. Across sub-Saharan Africa, Andrew does complex cardiac surgery and separate conjoined twins. You go down and emerge from diarrhea and pneumonia. So that's why we talk about context. And when I say context, I don't think that we can even operationalize these guidelines to say that in this country or even in this region is going to be used. I think it depends. So for instance, in your institution, right, you would probably be using a high resource setting guideline. But just down the road, about five kilometers, they may be using a different setting, right? And then the practical thing of context matters. Because if you're saying that you can ventilate, hand ventilate someone for 12 hours, that is important to put into the context to say that we don't have ICU support, but we can tide these patients over this period of time. And I know the studies we did in India with Hindu in South India and Chennai, we showed also in the whole context at a time that if you had to hand ventilate someone more than six hours, the outcome was 50-50 for shock as compared to if you hand ventilated them for less and they got a ventilator. So it's a very, very difficult issue. And that is what I think that what we will do is, and I'm relying heavily on the wisdom of my colleagues across the world, like yourself, and Waleed with his methodology, to say here are some broad brush strokes what you can do. Here are the operational things you can do, as we did back with India again, where we said these are the monitoring issues you can have from low resource center to high resource center. These are the therapies you can offer. These are the different outcomes you may have in those things. So I don't know. And I would turn the question around with a malnourished kids because I didn't get the full thing you're saying. What would you recommend? I think. No, what I said is considering ideal body weight in malnourished children. Suppose one year old baby who is weighing just seven kilo. I see. And we are dosing fluid according to 10 kilo. I see. I see what you're saying. Probably that will be too much for that. Yeah, sure. Agreed. I think that the malnourished kid, obviously, most guidelines are 90-10 rule. And same as the WHO, ETAT, and IMCI, for the malnourished kids, you are going to be a lot more cautious. So I agree with you. And in fact, when you look at the FEAST trial, the outcome where the kids who died, many have died from cardiovascular collapse. So I think that we have to think about that very carefully. I raised the first question just because this statement, this guideline, will be start getting used as a Bible or Gita in all these centers. And I heard people saying that in emergency room, even if it is of standard of my institution, don't give fluid until the child is having hypotension. I think that kind of statement should not be, is not acceptable. That is what you mean. So even if, like in our institution, we are hand ventilating, so the idea should not go as if child has to be hypotensive before they receive fluid. OK. All right. Thank you. Hi, Allie Maddox, Children's Colorado. I was interested, at the beginning of the talk, you presented that you had a patient and family members that were evaluated to determine what kind of outcomes are most important to them to really think about patient-centered outcomes. It seems like most of these studies are derived from mortality and resolution of organ failure. But I was curious if those investigations drove any of these recommendations or even future research interests. Yeah. Talk about future research interests? Well, just in the discussions with the patients and the families, did that, were any outcomes derived from that discussion? Yeah, the family was involved in, from the beginning, in all discussions. What they chose, because as you notice, even among ourselves, the discussion of this was very dense and technical in a lot of different ways. The family said, at the end, they did not want to be involved in the technical aspects of evaluating data, et cetera. They would talk to us in the end when it came to the recommendations and those things. And I think that that's where they sort of gave their output and preference. I don't think they sort of spoke in terms of what research ideas, but I may be mistaken, if you recall. Yeah. Actually, it's a very interesting point, because when we, it's very difficult to ask the opinion of the public members and the family members regarding the outcomes, because is there some specific outcomes related to the family in regards to guidelines, recommendations for sepsis management? So they did acknowledge that, and the text said they were very uncomfortable regarding the very technical approach of those guidelines. But still, it's an open issue that might need to be treated for the next ones. Thank you. Did you have patient or public representatives from high income settings or both high income and low income settings? High. Just high? Okay. Good morning. Dwight Bailey from Levine Children's Hospital in Charlotte, North Carolina. I'm a pediatric intensivist there. Understanding the FDA and the European EMA approval of synthetic angiotensin 2, or Giapreza, in the adult population, and the growing adult literature data through ATHOS-3 trial and others in the refractory vasodilatory shock population. Also understanding the lack of, or less, much less data in the pediatric population. But also thinking through the multimodal approach of vasoactive therapy and septic shock and the potential benefit by tackling other mechanistic opportunities, particularly through the red angiotensin aldosterone system that would be utilized through an angiotensin 2 or Giapreza approach. I'd like to know the panel's thoughts on the potential use down the road, sooner or later for synthetic angiotensin 2 in that specific vasodilatory refractory shock population. Yeah. Thanks. I can take it. So basically, there is two questions. The first one is the use of angiotensin 2. Initially, when we started the process for these pediatric guidelines, one of the main aim was to, even though it was not necessary, one of the main aim was to try to find a way to do not have any contradictory approach with the adult recommendation. But also considering that to do some recommendation, we may need some pediatric strong study outlining the effect. So as you know, for the angiotensin, it's only the adult studies. There is ongoing pediatric studies. So that's why we didn't approach this issue. But you are perfectly right regarding the fact that we may have discussed a little more regarding other approaches, myocardial function support, you know, dilators, whatever. It's difficult based on the current literature to have very strict positioning. That's why we very deliberately consider that it should be, it is recommended, not very, very weak recommendation, but it is recommended to evaluate the use of those drugs mostly based on the evaluation of hemodynamic parameters, what basically we all do in our practice. So it's not close to norepinephrine and epinephrine, but it's also open to other drugs without names. We didn't namely mention angiotensin 2. We didn't mention phosphodiesterase inhibitors, but mostly looking after a full hemodynamic evaluation. Okay, thank you. Thank you very much for your excellent effort. Abdullah Sherif from Saudi Arabia, pediatric intensivist. Now, in the previous guidelines, the blood sugar level and the ionized calcium has been addressed in the first 15 minutes to be monitored. Now, our observation and the mortality review of patients, especially newborn and infants, when they have hemoglicemia, the mortality is 100%. Even if they have the whole stiffs of guidelines has been done accurately with fluid boluses and atrophic support, and I don't see it here. Number two, fistrial is a problem rather than a good evidence because it has been applied to a certain patient population. Most of them were having malaria. So, the organism also is an issue as a causative agent. So, to generalize a guideline or a recommendation based on precision medicine is a problem for me, so I don't understand this one. Other issues that the blood pressure level, you know, in the infants and newborn, circulatory dysfunction can be without hypotension. Hypotension is a very late sign. So, giving fluid boluses early in this age group may be important. So, I think guidelines should be certified according to the age group. Again, for the blood pressure level, I mean, when I was in Canada and in tertiary care living in Saudi Arabia, it was different when I come back to Mecca because the patient population is different. We have in Mecca the patient population from different poor countries. They are either illegally or legally staying in Mecca, and the blood pressure level was very variable. You may have a blood pressure that you consider it low for some children, but it can be normal. So, you have a low blood pressure, but everything is good. Perfusion is good, cardiac function is good, and the patient is looking very well. So, now we are trying to make a study for the norms of the blood pressure and the diversity of patient population. Now, as you have mentioned that the sepsis in pediatric age group is very high, more than the adult. Now, I have a problem in Saudi Arabia because I have been assigned to look after pediatric sepsis project improvement in the Ministry of Health. But then I found myself alone in the adult group, and then we have a problem with the collection of data because I consider different age group, and we have done a conference in September two years ago, and I have presented the preliminary data. The people who are represented if the WHO was from adult side. So, there was no support actually for the pediatric group because one of my recommendations was to have a separate pediatric group to look for the pediatric sepsis in Saudi Arabia. Now, my questions for the guidelines, and then I think what is your plan for spreading your communication and collection more data from the Middle East countries and North Africa because if I remember 2016, the global epidemiology of pediatric sepsis, there was no data actually from the Middle East and North Africa. So, what is your question? Because we are running out of time, really, if you can sort of summarize quickly. Yeah, so the guidelines is very clear. The other thing that how you are going to improve the research and the collection of data regarding pediatric sepsis. Okay. So, thanks very much. So, what we're going to do, we said there were 49 recommendations for research that was proposed, and what we're saying that we're taking those 49, and we are then now putting through a Delphi process to look at feasibility, whether there's funding, whether there's patient population, the relevance of the research, et cetera, and doing a weighted scale, and then we will sort of provide that data to anyone who decides to work in an area. I think in any area in the world, as I said before, there is very little research in the resource-poor areas of the world, and as the Lancet Commission rightly pointed out, the science of delivery is important, implementation science of what we know works very well already, but also doing simple other research to get to the basic mechanism of the various types of diseases. So, I understand everything you're saying. I fully agree with it, but it's a problem that we have to, obviously, advocate long term for different areas to address the issue and put these things in context. Okay. Thank you. Hi, my name is Ahmed. I'm one of the ICU fellows at McMaster Children's Hospital. So, my question regarding the definition of septic shock. So, as per the paper, they refer to 2016 guidelines, which is sepsis in the presence of cardiovascular with metabolic and cellular dysfunction. So, my question is regarding those patients who come to the door of eMERGE with hypotension, but after one or two boluses of fluids, their blood pressure improved. So, is there will be considered as patient with septic shock? And my next clarification will be regarding the sepsis three guidelines, which have more clarification regarding the definition of sepsis with the presence of SOFA and, again, the definition of septic shock if the child requires vasoactive medications. So, the question, where is the definition between whatever has been published here and from sepsis three and, again, for the future research studies? So, thank you for the question. I want to clarify that the sepsis three, purpose of sepsis three was to define an operationalized sepsis in adults. The purpose of the surviving sepsis campaign is to provide recommendations about the management of sepsis in adults and now in children. It was beyond the scope of this panel to consider changes to the definition for pediatric sepsis or septic shock or severe sepsis. There's an ongoing effort separate from the surviving sepsis campaign to tackle that very issue. But the purpose here was to address the management, not the definition. Yeah. So, quick question. We are, as Scott said, have a panel working on the definition and hopefully in the next few years we'll have something. Good morning. My name is Deborah Maka. I'm the PICU pharmacist at Advent Health for Children. You delineated out the fluid recommendations based on whether there's an ICU present or not. What if a patient is coming from a place without a pediatric ICU but is being transported for longer than an hour to one? Has there been any recommendations in terms of amount or rates of fluid administration in those cases? Okay. My guess is that we can consider, because it will be a medical transfer, retrieval, so we might consider it's ICU. I'm just going to make a general comment. It is very difficult to issue recommendations that would fit every possible clinical scenario. So, the intention of guidelines is to give some guidance on the average patients that you see in daily practice, also to give some hints to clinicians in which context they should be focused on and which not. I can come up now, I'm an adult intensivist, but I can come up now with like five different scenarios where, okay, what are you going to do in this scenario? What are you going to do this? And in these extreme cases, when clinicians think, for good reason, that the recommendation does not apply to the patient, then use your clinical judgment. Okay. Last two questions, if I may. Nice and quick. Okay. Lynn Quintos, Pediatric Critical Care, from New York, turn quality officer. So, I think my first question went away because it's based on conceptual definition, because we acknowledge the intent of the panel, which is management guidelines. But it is somehow difficult when the algorithm starts with recognition and how the term applies. So, we'd work forward. We will hope that there are consideration also for the non-SEARS subset of children, because there are now publications on the subset of children presenting with non-SEARS porcepis, and how do we account for them? Because they might be at higher risk. And my second question relates to quality, because there are now state, we are from New York State and other states following, in terms of regulation. And to be able to make recommendations and compare outcome, do we have a, I guess, a universal or a consensus of what quality indicators we're following to be able to compare study? I think, go ahead, Scott. So, regarding the first question, I think you raised a very important problem, and again, one that another task force is addressing. It was just simply beyond the scope of what we could do to consider that body of literature and to make recommendations about what are the best criteria to recognize septic shock. So, I realize that's a limitation and perhaps somewhat frustrating, but there is an ongoing effort to address that problem specifically, which will hopefully work in concert with these guidelines when that's available. In terms of quality indicators, so I think Waleed, in his introduction, presented that strong recommendations that would be appropriate to use as quality indicators. And we only had eight strong recommendations, so I can refer you back to those to look at the indicators to use for sort of quality metrics. One of those was antibiotics within one hour for those patients who have septic shock. And we carefully write in the rationale for that, that we, for pragmatic reasons, we chose one hour, but that there's no biological reason why a one-hour cut point is the gold standard at the current time with the current evidence. And so, when it gets antibiotics within 55 minutes, probably doesn't have a different outcome from 65 minutes. And so, we actually recommend using time to antibiotics as a metric rather than a dichotomous cut point, which says you've either met or failed compliance with some metric that's somewhat arbitrary. Yeah, so it seems that the process indicator are more articulated than the outcome measure, like mortality and, I guess, other patient-centered outcome at this point. Thank you for the comment. I think that sounds reasonable. Lee, last question. Lee Polakoff, Hasbro Children's Hospital. And I want to thank everybody for just the seminal work, and not only for pediatric intensivists, but for community providers when they see children that are not traditionally trained in pediatrics, and now they have a rubric for taking care of these patients before they're sent to referral institutions. Two questions. Several migrations away from the ACCM guidelines from 2017. First of which is titration away from MAP goals. I know, Scott, we spoke about it last night. So, I was wondering if you could expound upon that. And secondarily, the issue of low cardiac output stayed in the initial nivino dilators or phosphorus inhibitors. The data is initially presented in the 80s of low cardiac output, LV dysfunction. And then, obviously, in the 90s, it's been demonstrated in pediatrics. So, after the initiation of vasopressors, thoughts then about, if too much afterload, how to balance the circulation with those adjunctive agents in the setting of, again, this low cardiac output state? Sure. So regarding there's no there was no it was insufficient data to come up with a recommended blood pressure target. And so we issued an in a practice statement where we surveyed the panelists and about half the panelists targeted about the 50th percentile for age and height and about 50 percent of the panel targeted fifth percentile for age and height. So somewhere in between seems reasonable based on what the panelists do. But as an area of unclear evidence and so you know it's hard to issue a recommendation about a goal blood pressure guideline. The data on use of I know dilators is also similarly insufficient to issue a guideline and so we should enter a practice statement for that as well. And many of the panelists do use I know dilators when there's evidence of ongoing myocardial dysfunction with increased systemic vascular resistance after initial you know gentle fluid resuscitation and other catecholamines support. There's just not sufficient data to issue a recommendation based on it. But many of the panelists do practice that way and it's just probably reasonable with close hemodynamic monitoring. Actually we did a survey within the European Society Pediatric Intensive Care looking at the practice in regards to the 2016 recommendation. We found out that about 90 percent were using norepinephrine or epinephrine but something like 40 to 50 percent were using hyaluronidine dilators in their practice. So the message is if we can evaluate hemodynamically those patients I think everything is correct. So thank you. It's my privilege to be able to sum up this session. So I'd just like to say, Scott, Waleed, Pierre, and Tex, thank you for your fascinating and excellent presentations. Thank you for staying on time. Thank you for you, the audience, for staying with us. And thank you for all of the questions. I think it's these debates that's gonna really move the literature forward. And perhaps on behalf of Scott, Waleed, Pierre, and Tex, and the whole of the panel, all 51 members, a huge thank you and gratitude to the work you've done because it's fantastic. And I think it's really, really important. So thank you very much. Thank you.

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