Welcome to the webcast. My name is Craig Coopersmith, I'm the director of the Emory Critical Care Center in Atlanta, Georgia. I will be moderating today's webcast. This webcast recording will be available within five to seven business days via the link on the CAM-LINK website, www.survivingsepsis.org. A few housekeeping items before we get started. There's going to be a question and answer session at the end of the presentation. To submit questions throughout the presentation, type the question or comment into the question box located on your control panel. This presentation is intended for educational purposes. The material presented is related to the recent release of the Surviving Sepsis Campaign Adult Guidelines for the Treatment of Sepsis and Septic Shock. Clinicians should consider the recommendations and ultimately choose the best options for the patients they are caring for based upon the individual patient's clinical status. The full guidelines are published in the journals Critical Care Medicine and Intensive Care Medicine and an executive summary can also be found in Critical Care Medicine. The manuscripts can easily be accessed by visiting www.survivingsepsis.org or by going directly to the journal websites. You are invited to join the Twitter discussion for today's webcast following the hashtag hashtag survivingsepsis. And now I will introduce you to the speakers for today. Our first presenter is Dr. Hallie Prescott. Dr. Prescott is an Associate Professor in Internal Medicine within the Division of Pulmonary and Critical Care Medicine at the University of Michigan Medical Center in Ann Arbor, Michigan, the United States. She also serves as a Core Investigator at the Ann Arbor Veterans Administration Center for Clinical Management Research. Dr. Prescott is a member of the Surviving Sepsis Campaign Steering and Research Committees. She served as a Co-Vice Chair of the Surviving Sepsis Committee Adult Guidelines, which we will discuss in today's webcast. Our second presenter is Dr. Marlies Osterman. Dr. Osterman is a Consultant in Critical Care and Nephrology at Guy's and St. Thomas NHS Foundation Trust in London, England. She also served as a Co-Vice Chair for the Surviving Sepsis Guidelines and is presently a member and contributor to the Surviving Sepsis Research Committee. And now I'll turn things over to begin the presentation. Thanks for the introduction, Craig. It's my honor to be here today. In terms of disclosures, all Surviving Sepsis Campaign activities, task forces, panels, and resulting work products are fully funded by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. We have no financial conflicts of interest. Otherwise, I'm just obliged to tell you that this presentation does not necessarily represent views of my employers, the U.S. government, or the Department of Veteran Affairs. All right. So for today's talk, we'll start out with a quick background on the history and the impact of the Surviving Sepsis Campaign. We'll talk about the structure of the guideline panel. We'll talk about the process by which we determine questions to address in the guidelines and then generate recommendations. And then we'll spend the remainder of the talk on specific recommendations that are new or different compared to the prior guideline in 2016. So first, the history of the Surviving Sepsis Campaign. The Surviving Sepsis Campaign was launched in 2002 and published the first guidelines for sepsis in 2004, which have been updated approximately every four years since then. Over time, the guidelines have become bigger and longer. And so there was a decision made to split off pediatric sepsis. And so specific guidelines to pediatric sepsis were published in 2020, as were guidelines specific to the management of COVID in ICU patients. In addition to publishing guidelines on the management of sepsis, the Surviving Sepsis Campaign also publishes sepsis bundles, which are meant to help implement the guideline recommendations for quality improvement initiatives locally. So the very first sepsis bundles were published in 2004, shortly after the first sepsis guidelines. And those were actually a six and 24-hour management bundle. Those have been updated over time. In 2013, they were updated to a three and six-hour management bundle, and then in 2008 to an hour one management bundle. Again, the guideline bundle, or sorry, the bundles are a separate process from the guidelines, and so are not addressed or updated in this 2021 adult guideline update, but may be updated going forward in the future. There's a large body of literature showing the strong impact the guidelines have in terms of improving care and improving outcomes among patients with sepsis. These are three different examples of studies that have shown increased uptake in process measures and reduced mortality after the implementation of Surviving Sepsis Campaign guideline recommendations. The Surviving Sepsis Campaign guideline involves a large number of people. The guideline has a leadership panel that includes co-chairs and co-vice chairs that are appointed by the two sponsoring societies, the Society of Critical Care Medicine and the European Society of Intensive Care Medicine, as well as a lead methodologist. In addition, there is a conflict of interest management co-chair appointed by each of the professional societies who oversee the conflict of interest management and ensure that nobody with a financial or intellectual conflict of interest is involved in the voting on any individual recommendation. In addition to the guideline leadership, there are about 55 different panel members in the guideline who are assigned to one of six different working groups. And within each working group, there is a group head as well as a lead methodologist who oversees the literature evaluation for questions related to that subgroup. About half of these panel members are appointed by endorsing societies, which are listed at the bottom of the screen, and the other half are selected and appointed by the guideline leadership to sort of round out the expertise within the panel. This surviving sepsis campaign panel has been the most diverse panel. Up on the pie graphs on the left of the chart, we show the locations in the world where our panelists practice, and we also show the breakdown of male versus female members. In addition to the clinical and methodological experts that serve on the panel, new to the 2021 guidelines, we also had a public panel that included 11 public members, patients or family members, to represent patients and family members experiencing sepsis. And those public members worked most directly with the guideline leadership as well as the long-term outcome and goals of care subgroup. So I'll now move on to talk about the process of the guideline development. So there are really two stages. The first is the evaluation of the evidence, and the second is the creation of the recommendations. New to the 2021 guidelines, we started the evaluation of the evidence with a survey of current practices that was sent out to members of the Society of Intensive Care Medicine and the European Society of Intensive Care Medicine, and this was really to help us understand what are areas of practice where there is variation in terms of what is being done, as we felt that those areas where there is marked variation would be more important to address within the guidelines. After that, we identified clinical questions in the PICO format, which is the Patient Intervention Comparison Outcome, and from this list of potential PICO questions, we then identified the most important ones to address within the guideline. Once those questions were identified, we then a priori, ahead of the literature search, prioritized what we thought would be important outcomes to assess for that particular question, and then we commenced with systematic reviews of the literature and meta-analyses where needed. Within the subgroups, evidence profiles were developed for each of the questions, and there was a formal evaluation of the evidence. New to the 2021 guidelines, there was a specific framework used to move from this evidence review to then the development of the guideline recommendations, and that's called the Evidence to Decision Framework that is essentially a worksheet that systematically goes through evaluating the importance of the problem, the desirable and undesirable effects of the intervention, the certainty of the evidence, the balance of effects, because some things may improve one outcome but worse than another, the resources required to deliver the intervention, the cost effectiveness, the equity, and then also the acceptability and feasibility. And only after completing this Evidence to Decision Framework evaluation did we go on to then make draft recommendations within each of the subgroups. We were fortunate to be able to discuss those draft recommendations at an in-person meeting in December of 2019 before the world changed due to the COVID pandemic. After having that in-person meeting where we discussed each of the different draft recommendations, things then went back to the subgroups for potential tweaking or revision, and then were sent out for vote. Again, there was conflict of interest management such that any member with a potential conflict was excluded from the vote on a recommendation-by-recommendation basis. We had pre-specified thresholds to move forward a recommendation, and if a recommendation failed to meet that, we did have a process such that it could then be revised, tweaked. Maybe people were unhappy with the way exactly the recommendation was worded. This could then be sent out for re-vote up to three times to achieve consensus within the guideline panels and inclusion within the guidelines document. There are a number of different types of statements that are included in the guideline. The first are strong recommendations, which come in two different types. One is a best practice statement, and the other is a strong graded statement. Strong graded statements are things where there is a very clear set of, for example, randomized clinical trials that suggest benefit of the intervention, whereas best practice things are recommendations for which it is more difficult to summarize maybe a vast body of literature, and because of this difficulty in formally grading the evaluation, these get classified as best practice statements. Regardless of whether a strong statement is a best practice statement or a strong graded, it will show up in the guidelines as we recommend. For these strong statements, it is expected that all or nearly all informed persons would choose the intervention or that this would be applicable in nearly all contexts. These are the kind of recommendations that should have widespread adoption and would be good for performance assessment. The next type of recommendation are weak recommendation. These are recommendations for which it should really be your default plan, but there might be important variation depending on the specific context. Most informed persons would choose the intervention, maybe two-thirds, but there may still be important variation depending on the specific context. This requires consideration, contextualization, shared decision-making, and for this reason is not optimal as a performance assessment target. Recommendations are more likely to be weak as opposed to strong. When the certainty of evidence is lower, there is close balance between desirable and undesirable effects. There is substantial variation or uncertainty about whether the outcome that is improved is of importance to patients or all patients, and also interventions that require considerable resources are more likely to be weak recommendations. Finally, the last type of statement we make are no-recommendation statements, and those are for questions for which there is insufficient evidence to make a recommendation. So here is a high-level overview of the 93 statements that are made in the 2021 Guideline Update. On the left-hand side, I show the breakdown of different topics, and I'll draw your attention to the Goals of Care and Long-Term Outcomes section. This recommendations related to long-term outcomes are new to this guideline. This has not been something that has been addressed in prior Surviving Sepsis Campaign Guidelines, but as the majority of patients survive hospitalization and many go on to experience poor longer-term outcomes, we felt that it was important to include recommendations related to long-term outcomes. In order to make space for these recommendations, the number of statements related to additional or adjunctive therapies has been decreased compared to prior guidelines. These are specifically fewer recommendations related to things like nutrition or blood transfusion, things which are largely extrapolated from the sort of general management of critically ill patients and not necessarily specific to sepsis. Those recommendations have been decreased in order to make space for recommendations related to long-term outcomes. On the right-hand side, we show the breakdown of statements related to the type of statement. You see that the majority of statements are weak-graded statements. About a third are either strong-graded or best practice statements, and then there's about 10 or 11 no-recommendation statements. I think that this really underscores the need for additional high-quality data to guide the management of patients with sepsis. I'll now move on to walk through each of these different sections of the guideline to highlight some recommendations that are either new or updated compared to the prior guidelines. For screening and resuscitation, there are three different recommendations that I would like to draw attention to. The first recommendation is a new, strong recommendation against using QSOFA as compared to SIRS, NEWS, or MUSE as a single screening tool for sepsis or septic shock. To refresh people's memory, QSOFA is a three-point scale for predicting mortality among patients with suspected infections. This scale comes from an elevated respiratory rate, altered mentation, or a low systolic blood pressure. This was, again, developed to rapidly identify the sickest of the sick patients with potential infection for essentially expedited care. When it was introduced in 2016, with the sepsis definition update, it was introduced under a section titled Screening for Patients Likely to Have Sepsis. And I think that this has led to some confusion as about how QSOFA is meant to be used or integrated into clinical practice. There've been a number of studies that have come out evaluating the performance of QSOFA. And in this systematic review and meta-analysis, they show that QSOFA outperforms SIRS criteria in terms of predicting mortality among patients with infection. That's exactly what it was designed to do. However, it underperforms relative to SIRS criteria in terms of identifying patients with sepsis. This is not a sensitive screening tool. It is not necessarily a specific tool for identifying sepsis either. So this recommendation is really intended to sort of set the record straight in terms of what QSOFA should be used for and encourage hospitals or systems that are using QSOFA alone as a screening tool for sepsis to incorporate additional factors into their screening as QSOFA itself is not sufficient, underperforms relative to other tools in terms of identifying patients with sepsis or septic shock. The next recommendation is a suggestion, a weak recommendation that for patients with sepsis-induced hypoperfusion or septic shock to use at least 30 mLs per kg of intravenous IV crystalloid fluid within the first three hours of resuscitation. This recommendation is similar to what was included in the 2016 guideline. However, it was downgraded from a strong recommendation to a weak recommendation. So to discuss this recommendation, it helps to sort of take a step back and look at the historical context of this recommendation. Earlier guidelines had recommended early goal-directed therapy for resuscitation, but based on the PROMIS process and ARISE trials, this recommendation was essentially simplified to a 30 mL per kg bolus in 2016. And that was really based on the PRISM meta-analysis that looked at the individual patient level data from the PROMIS process and ARISE trial and showed that sort of regardless of which arm patients were in, early goal-directed therapy or usual care, the vast majority of these patients got around 28 mLs per kg of fluid prior to enrollment in the trial and then about an additional two liters of fluid afterwards. So it felt like generally the vast majority of patients are needing at least 30 mLs per kg of fluid bolus for their initial sepsis resuscitation. Additionally, we have some indirect evidence in support of the 30 mL per kg fluid bolus from the study on the right here, this multicenter implementation of a treatment bundle for patients with sepsis and intermediate lactate values. This comes out of the Kaiser Permanente Northern California system where they implemented this sepsis bundle for patients with a lactate of two to four and recommended sepsis bundle in these patients, including a 30 mL per kg fluid bolus. They found that over time with this intervention, more patients received the 30 mL per kg fluid bolus and with that mortality decreased. And specifically mortality decreased most prominently in patients with a history of heart failure or kidney disease for whom we might normally or previously been more hesitant to deliver the full 30 mL per kg fluid bolus. So overall, this kind of body of literature suggests that the default should be to give patients 30 mL per kg fluid bolus who have sepsis-induced hypoperfusion or septic shock. But based on the sort of reassessment of this literature, the panel felt that this qualified as a weak rather than strong recommendation, that there may be individual patient circumstances that would suggest doing a different amount of fluid. Specifically, there are no trials testing an initial 30 mL per kg bolus versus other fluid volumes. Okay, next we have two suggestions regarding the resuscitation and how to guide that. So we suggest that for patients with sepsis or septic shock, we suggest guiding resuscitation to decrease lactate among patients who had an elevated lactate level over not using the lactate level to guide resuscitation. Additionally, we suggest using capillary refill time to guide resuscitation as an adjunct measure of perfusion. So the evidence behind this, there have been previous studies and meta-analyses looking at lactate-guided resuscitation showing that using lactate to target resuscitation is associated with a mortality reduction in these meta-analyses. However, there may be patients for whom lactate cannot be normalized. So overall, based on the evaluation of the literature, the panel issued a suggestion or weak recommendation to use lactate guidance. In terms of capillary refill, there has been a new trial, the Andromeda shock trial published since the last guideline and this randomized patients to using lactate guidance versus capillary refill guidance. There was no difference between those two approaches. However, the point estimate for mortality favored the capillary refill-guided resuscitation. We did not ask this question as an either or, and we don't feel that in practice you can sort of choose either or, you could do both of these things. So we have issued suggestions or weak recommendations to use both of these measures to guide resuscitation, trending lactate to ensure that that is decreasing with your resuscitation, as well as monitoring capillary refill and using that to help make assessments about whether the patient would benefit from additional fluid going forward. All right, I'm next gonna move on to the infection section of the guidelines where there's two recommendations that I'd like to highlight. The first are recommendations related to the timing of antimicrobials. So on the bottom of the slide, I show the 2016 recommendation, which was a strong recommendation to administer IV antimicrobials as soon as possible after recognition and ideally within one hour for both septic shock and for sepsis. And one of the challenges in practice is that often when we're first seeing patients in the emergency department or newly admitting patients to the intensive care unit, it's unclear whether the patient has infection. And so you're left in this tricky situation of like, well, maybe it's sepsis, do I need to give antibiotics within one hour? And so we have reformulated these recommendations to provide additional guidance for when the diagnosis is uncertain. So here we stratify the recommendation based on the certainty of the sepsis diagnosis and also how sick the patient is, specifically whether they are in shock or not. So when that you believe the patient has sepsis, which the language we use here as sepsis is definite or probable, we still recommend just like the 2016 guidelines to administer antimicrobials immediately, ideally within one hour, regardless of whether shock is present or not. However, if this is a patient that's, you know, newly presenting and you're unsure, maybe it's sepsis, but maybe it's something else you're still really getting to handle on the situation. For those patients, we stratify the recommendation based on whether shock is present. So if this is a patient with undifferentiated shock that might be due to sepsis, they are too sick to delay those antimicrobials, it would be associated with potentially significant increase in mortality to delay antimicrobials. For those patients, we recommend administering antimicrobials immediately, ideally with one hour recommendation. However, if shock is not present, we now recommend a rapid assessment of infectious versus non-infectious causes of acute illness, and then to administer antimicrobials within three hours if concern for infection persists and an alternate explanation hasn't been essentially proven or strongly suspected at that point. The idea behind this framework is to still recognize that time to antibiotics is critical, particularly for those sicker patients who present in shock. However, we also know from studies that diagnostic uncertainty related to sepsis is very common in practice. So we're trying to balance those two bodies of literature to ensure that patients with sepsis are getting antibiotics as soon as possible, and these undifferentiated patients who are in shock are getting antibiotics as soon as possible, but providing a window for rapid evaluation in patients with possible sepsis but who aren't in shock. The final recommendation that I will highlight prior to passing this on to my colleague Marlies is this recommendation about stopping antimicrobials. This is not a new recommendation. This was included in the prior guidelines. We include a best practice statement that for adults with suspected sepsis or septic shock but unconfirmed infection, we recommend continuously reevaluating and searching for alternative diagnoses and discontinuing empiric antimicrobials if an alternate cause of illness is demonstrated or strongly suspected. And I want to highlight this because in the prior slide we showed that for patients with possible sepsis and with shock, we recommend giving the antibiotics within an hour. We know that some of those patients are ultimately going to turn out to have other causes for those illnesses, and we want to continuously reevaluate that day by day. And once we find out that actually it's not infection, it's something else that's causing their illness, we should stop the antibiotics. Still, when I practice clinically, I will sometimes have statements said to me like, well, we don't think it's an infection anymore, but we'll just complete a short course of antibiotics. There's no need to complete a short course of antibiotics once infection has been ruled out. And so I just wanted to highlight that we continue to have a recommendation that once an alternative cause of illness has been identified and infection has been ruled out, you can go ahead and stop the antimicrobials. I will go ahead now and pass off to my colleague Marlies to finish the rest of this talk. Thank you, Hallie. It's a great honor to contribute to this important webinar. And like Hallie, I will focus on either revised recommendations or new recommendations in the 2021 guideline. In particular, I will focus on hemodynamic management, fluid therapy, adjunctive therapies, and then recommendations related to long-term outcomes and recovery. Hemodynamic support encompasses fluid therapy and vasopressor support. As in 2016, the 2021 guideline recommends vasopressor, recommends norepinephrine as the first line vasopressor. And it recommends using crystalloids as first line for resuscitation. With regards to the type of crystalloids, there has been a change in the guideline. In 2016, as stated here, the guideline suggested using either balanced crystalloids or saline for fluid resuscitation of patients with sepsis or septic shock. In 2021, the panel felt that there was increasing data in support of balanced solutions. And therefore, they issued a recommendation to use balanced crystalloids instead of normal saline for resuscitation. This recommendation is based on data from numerous randomized controlled trials in the literature, including the SMART trial here on your left. And this was a large randomized controlled single center trial with multiple crossover steps where patients were randomized to either balanced solutions or saline. And in this landmark trial, there was a significantly lower 30-day mortality in patients who received a balanced solution. In addition, there was a significantly lower risk of major adverse kidney events at 30 days. And there was an increased number of vasopressor-free days, again, in patients who have received balanced solutions. However, no cost-effectiveness studies have been conducted so far comparing balanced solutions with saline. And therefore, the panel issued a recommendation in favor of balanced solutions over saline, but it should be considered a weak recommendation. It also needs to be acknowledged that the current guideline, although new and updated, is obviously based on the existing data at the time when the panel convened. And since its publication, new data has already emerged, for instance, the results of the BASIC trial here on your right. And this, the BASIC randomized controlled trial is an even larger trial than SMART. It was conducted in more than 70 ICUs. And again, it compared a balanced solution, in this case, plasmolyte with saline. And in contrast to the SMART trial, the BASIC trial showed no significant difference in 90-day mortality between patients randomized to plasmolyte versus saline. Also, in contrast to SMART, it showed no difference in the incidence of either moderate or severe acute kidney injury. Again, it should also be pointed out that this trial was not only different, but it also enrolled patients who had already received significant amounts of non-study fluid before being admitted to the ICU and before being enrolled in the trial. So clearly, the results of the BASIC trial, but also other ongoing fluid trials will have to be incorporated in future meta-analyses and guidelines. Next slide, please. I quit a bit too fast. The other important new recommendation is a recommendation to consider peripheral administration of vasopressors in order to avoid a delay in restoration of blood pressure. And this is a new recommendation. Again, it is based on existing studies showing that this practice is safe and effective. And it can certainly, in these trials, lead to a shorter time in restoration of target blood pressures and a significantly reduced need or a shorter duration in the need for vasopressors. And the panel felt, therefore, that it was safe and advised the peripheral administration of vasopressors. Obviously, it needs to be acknowledged that this peripheral administration should be kept as short as possible, ideally less than six hours. And for its administration, proximal veins should be used if possible. The next recommendation relates to, again, fluids, and Hallie dealt with fluid administration in the first three hours. Clearly, fluids are an integral component of shock resuscitation. The question is whether we could also recommend a fluid volume beyond the first three hours, in the first 24 hours, for instance. That's an important question because fluids are clearly an important tool to resuscitate patients, but too much fluid is harmful. There's increasing evidence that fluid overload is associated with an increased mortality and worse outcomes. Therefore, the question is whether following initial resuscitation, fluids should be given at reduced doses or, as before, at significantly higher volumes. Having reviewed the evidence, the panel felt and recommended that fluids should only be used in patients with ongoing signs of hypoperfusion and or volume depletion after the initial resuscitation. With regards to the question whether fluid restriction versus a liberal fluid approach could be recommended, the panel was unable to issue a recommendation. And as shown here, when analyzing the data of five pilot randomized control trials, there was no clear sign either way. But it obviously needs to be acknowledged that there are ongoing trials, for instance, the CLASSIC trial or the CLOVIS trial. And certainly the CLASSIC trial, so crystalloid liberal, sorry, conservative versus liberal fluid resuscitation in patients with sepsis, is due to end soon. It will complete recruitment at the end of this month. And soon we will have more data which will inform our clinical practice and will be incorporated in future meta-analyses and guidance. Obviously, again, I want to emphasize that this recommendation is separate from the recommendation which Hallie talked about when she talked about fluid resuscitation in the first three hours. Moving on from hemodynamic support to ventilatory support, the 2021 guideline has a new recommendation dealing with ECMO. And as shown here, the panel suggested to consider ECMO in patients who failed to respond to conventional mechanical ventilation. And this recommendation was based on existing but limited trial data from two trials that looked at ARDS in patients with sepsis. In addition to these two trials, there are also data in meta-analyses. And in summary, the panel felt that this guidance had value, i.e. to consider ECMO in those with ARDS as a result of sepsis in situations where conventional mechanical ventilation had been unsuccessful. Obviously, it was clearly acknowledged that this had to be done in experienced centers with an infrastructure in place to support its use. Undoubtedly, patient selection is very important and undoubtedly more research and more studies are necessary to inform future practice. The another area where guidance changed relates to adjunctive therapies. And I want to highlight the guideline related to corticosteroid use and vitamin C administration. In 2016, the guidelines suggested against the use of intravenous cytoportisone to treat patients with septic shock. However, since then, new data has emerged and new meta-analyses have been performed, which led the panel to a change in the recommendation. And as shown here, the new recommendation suggests to use intravenous corticosteroids in patients with septic shock and an ongoing requirement for vasopressor therapy. And this change was prompted by new data from randomized controlled trials and meta-analyses. And these randomized controlled trials have clearly shown that the addition of intravenous cytoportisone led to a reduction and reduced duration of shock. However, just trying to get back to this previous slide. However, the mortality was not affected by the use of hydrocortisone. And therefore, on balance, the panel felt that the beneficial effects of reducing the duration of shock outweighed potential adverse events and adverse effects of corticosteroids. And therefore, this guidance was issued. The new guideline relates to intravenous vitamin C. In this case, the panel, after having reviewed the data, concluded that there was no role at present for intravenous vitamin C in the treatment of patients with sepsis or septic shock. They meta-analyzed the data of existing studies and, as shown here, there was no clear sign of any benefit. And in the absence of a clear benefit, the panel felt that it was justifiable to issue a recommendation against its use. And then finally, as Halle already mentioned, is a whole new section related to recovery and long-term outcomes. This new section includes 12 new recommendations. And for these recommendations, the input from our patient representatives and families was highly valued. And as soon as the slide moves forward, you can see some new recommendations really dealing with education, patient information, and patient care after discharge from hospital. The guideline suggests offering sepsis education prior to hospital discharge and in the follow-up setting. There's a strong recommendation to screen for economic and social support and make referrals for follow-up where available. The guideline highlights the importance of shared decision-making in discharge planning and highlights the importance of educating patients before they go home and after discharge. As suggested by the panel members, in particular the patient representatives, it was important to highlight the importance of long-term complications and long-term sequelae of sepsis. However, with regards to the specific details of the timing of follow-up or the recommendation with regards to cognitive therapy, at this moment in time, there are no clear data and therefore guidance could not be issued. As you saw in the long-term recommendations, at first glance, they make common sense. But it was felt that they had to be included in this new recommendation and in this new guideline because clinical practice clearly varies. They may also serve as triggers for more research in future. And importantly, based on the feedback from the patient representatives, it was important to highlight this for the long-term outcomes as a very important area of sepsis management. Coming to the end of my presentation, I've shown you some new recommendations, but I've re-highlighted new data which has emerged since its publication. New papers and publications have come out highlighting the fact that there are still many unanswered questions and need for ongoing research. In summary, Hallie and I summarized new changes. We have not talked about recommendations which didn't change. But we'd like to point you to the website where all this information is available. And much more can be found with regards to the background of our recommendations. I'd like to thank you for your attention and now hand over to Craig again who will share the Q&A session. Thank you so much, Hallie and Marlies, for sharing what's new in the Surviving Sepsis Campaign Guidelines. Just as a reminder to everybody listening, questions can be typed into the chat box at any time and we're going to make every effort to address as many as possible. The first question I have is going to go to either one of you. At first, the 2021 changes in the guidelines related to fluid resuscitation remind me of the concept of permissive hypotension developed in military medicine in resuscitation of trauma victims of hemorrhage. Intellectually, is there any connection? Well, that's an interesting question. I think that this concept of permissive hypotension has come into the management of sepsis and distributive shocks such as in the 65 trial, which compared people with targeting a mean arterial pressure greater than 65 versus 60 to 65. The challenge has been that many of the people who are randomized to 60 to 65 actually got greater than 65, so it's hard to know what if you actually got them less than 65. The Surviving Sepsis Campaign still has a recommendation to target a mean arterial pressure greater than 65, but I think that there is this question of, is it safer for some or all patients to allow a lower mean arterial pressure and actually limit the amount of exposure to vasopressors? I think generally there's been this recognition that exposure to more fluids and more vasopressors comes with costs and trying to find what is the bare minimum that we can do that supports our patients without causing extra harm. So I do think this kind of concept of less is more and doing the bare minimum to support our patients without kind of over resuscitating them does have relevance, I think, to some of the literature in sepsis. Marlise, I don't know if you have anything to add to that. I fully agree. I fully agree. There are patients where it's absolutely safe to leave their blood pressure at a lower level. And then there are people for whom 65 is not sufficient. And I think our whole understanding and our knowledge of blood pressure management will hopefully improve. We're obviously hampered by the fact that we look at a mean systemic blood pressure, which tells us absolutely nothing about the perfusion pressures and the microcirculation of individual organs. And there are again there are big differences between the microcirculation and the threshold, for instance, between the brain and the kidney. And I think we need to find tools that help us at the bedside, deciding whether the systemic blood pressure in front of us is sufficient for the individual patient and their organs, and we haven't got them at the moment. Yeah, I think that's a great point right like we target everything, generally to mean arterial pressure for our resuscitation and basal pressures but I believe that was addressed in this research priorities for the surviving sepsis campaign is this question Other targets that can be used to sort of more directly assess whether perfusion is now adequate, as opposed to just this number being at our goal. So, yeah, we don't have that yet but I think going forward. We need more data there. Sorry. I mean the same could probably also apply to fluids and although the, there are new guidance recommends balance solutions over saline. There's still some individual patients saline is the best initial solution because these may be the patients with severe sepsis and dehydration volume depletion from vomiting from large loss of gastric fluids. And again, it's important to look at, at the, at the physiology of the individual patient majority for the majority balance solutions are probably better. The individual ones may just need a bit of saline. So for full disclosure because how he mentioned the research committee and I co chair with Daniel tobacco the research committee of the surviving sepsis campaign. And now I'm going to put each one of you on the spot with a very challenging question from the audience. First for you, Howie. If you have a patient with heart failure, septic shock. How much volume should you get. Yeah, so I think that yeah right that's this million dollar question of this 30 ml per gig fluid bolus I tell my trainees like that's the default that we should be giving the patients the people that I really worry about are not just like all patients with heart failure. It's people who have a severely reduced ejection fraction right like who's EF is 20%, or the people with critical aortic stenosis like those are the patients that make me really worried where I'm like you need to be at bedside like watching the fluid you know only giving it and 250 to 500 ml increments at a time. Kidney failure I worry less about and just like heart failure by chart but you know not a severely reduced EF I worry less about so that's those are the patients where my practice differs from just kind of, you know, being more aggressive with the fluid management is severely reduced ejection fraction or critical aortic stenosis. So the, the group in the early resuscitation stroke screening, dealing with the early resuscitation and screening questions, looked at this, and they, they tried to tease out whether this recommendation 30 minutes per kilo needed to be adjusted and whether And in fairness there is currently no evidence in the data, suggesting that patients with heart failure need always kidney failure or any other forms of failure need less should have less fluid, so it's still as a result of lack of evidence or maybe it is actually okay to give 30 minutes per kilo. That's where the why we still have this is generic guideline, due to lack of evidence for that it's harmful in other patient populations, but it should be looked at the working group look very very hard for evidence to suggest that this may have to be nuanced. There wasn't any. Yeah, I agree. I think the vast majority of people that that's the right volume and it's a much more sort of restrictive population of patients that I get worried about. I think that you know that data out of Kaiser Permanente also showing that you know when they sort of implemented this intermediate lactate bundle that it was actually this kind of, you know, history of heart failure history of kidney disease. That most of patients who kind of fall into those you know having those comorbidities still are going to benefit from a 30 ml per Keg, you know, fluid volume resuscitation. And as we're staying on million dollar or million pounds or million Euro questions. This next one is going to give you Marley for steroids and septic stock, whether there was a quote unquote ongoing shock. What's the timeframe to define ongoing shock. That's a fantastic question, and I do not have the answer. So, and in fantasy, the committee didn't really look at duration of set of steroid therapy. I think Craig is asking like when do you pull the trigger like what qualifies as ongoing shock to initiate those steroids right. So, if you use a data from the adrenal study, then it was anybody on noradrenaline. And it included very low dose noradrenaline and that's where people have argued whether. So the, the guideline recommend refrains from suggesting a threshold. So it's based on adrenal data and the adrenal data included any dose of noradrenaline or, or, or similar vasopressor. In clinical practice. In our practice here in the UK. We use the noradrenaline dose of around point two. And that is to exclude those patients who are just on a vasopressor because to to offset the effects of sedation. And so in clinical practice is generally to use the adrenal trial of, they're still on vasopressors at four hours honestly regardless of the dose, I will initiate steroids, I do always tell my trainees that if you know you've given that initial fluid bolus and you've given them the broad spectrum antibiotics, and they're not started showing signs that they're getting better the first two questions I want them to ask is, is there a source control issue that we haven't controlled. That's correct. Right. And if they've answered those two questions and this patient is, you know, still hypotensive, you know, then I'll initiate the steroids, that's, you know, been been my practice and it's largely just like Marley said, based on the adrenal trial, any dose four hours. Thank you. So, just so you guys know, in the first 45 minutes we got two questions and the last seven minutes we've gotten over 20, and we have six minutes to go so we're going to go relatively rapid fire here. As I scroll through these madly. There is a question about if you're going to give somebody peripheral vaso, if you're going to get somebody vasopressors peripherally, is there a maximum dose. So it's kind of like the million dollar question I mean our recommendation in the guidelines is very conservative it's just saying like to start those vasopressors while you're in the process of putting that central line in. I will tell you that this is a place where there's a lot of like rapid practice evolution and we've surveyed hospitals in Michigan and there's a lot of variation in terms of the specific dosing thresholds, and which vasopressors are allowed, what size of IV what site of IV whether there has to be a protocol in place to like ultrasound that IV, but a lot of hospitals currently are using dose limits. There's not a lot of good data we at Michigan use like half max dose is what you're allowed to give, but clinically we start them there and if anybody's on escalated or not, you know, it's really meant to be as a temporizing measure if they're rapidly getting better great maybe you got away with just two hours of low dose vasopressin and or low dose norepinephrine and avoided a central line, but anybody who's not kind of clearly quickly turning that corner will put in a central line. Okay, so now we have this. I'm sorry. We said we haven't introduced it yet we're still getting used to this recommendation, because we were not allowed to do it. We do it and it works quite well. Again, we're going rapid fire and we're going the exact opposite now. Now we have somebody about norepinephrine and vasopressin, the audience wants to know which one you stop first. So I stopped vasopressin once norepinephrine gets below point two. I don't know why but that's my when I initially initiate vasopressin once vasopressin gets above point two micrograms per gig per minute and I just use the same in reverse. Same. Okay. That's a comment that we're not going to say that though people think you're so awesome. In some of the comments. Let's see. Is there a place for early ward based use of vasoconstrictor boluses, such as terlapressin for alternative purposes. That's a good question, so I can answer this so terlapressin is used in the UK it's licensed, and it is allowed, we can use it on the, on the ward. But that's the only vasopressin allowed on the general ward at the moment. I obviously now have to teach our, my colleagues to that noradrenaline is allowed, but at the moment it's terlapressin on the ward yes for patients with liver disease. You mentioned trending lactate. How often should the lactate be measured. Well, not too frequently because it takes a while to change three to four hours. Is there any recommendation for a hemodynamic goal, using either CVP, or the wedge pressure in steps with your septic shock. There is not, I think that we currently have a recommendation to closely monitor your patient and consider dynamic measures of kind of fluid responsiveness to guide ongoing resuscitation, although I think that generally this is an area where we really need clear guidance like as you guys saw that we did not issue a recommendation regarding these liberal versus conservative fluids management strategies after that initial 30 ml per kg bolus there are studies like in the field right now to look at that but right now we don't have a lot, but no, it's generally dynamic measures over these static things like CVP. Two more quick ones and then we're out of time. What is the ideal rate for maintenance fluids, after initial resuscitation. There is none. It is individual should be individualized and depends on the need of the patient, and that should be assessed using confusion parameters. And that was also addressed in the basics trials, which has come out since our, the guideline but showed no difference in these patients randomized at least in the ICU to faster versus slower and infusions of fluid so I don't think there's any kind of, you know, across the board recommendation that can be made right now, regarding that question. Next question is a very logistically important one, 30 cc per kilo, is that actual body weight or adjusted ideal body weight. Ideal body weight. Good question and clearly there's no correct what I say it's I tell people it should be the same weight as what they're using to do drugs and ventilation. People use the ideal weight, then that it should be the same if people have an estimated weight it's not perfect but they should use one way to do to do all the adjustments drugs, fluids, mechanical ventilation, and then adjust again after assessment. I would love to go on and on and on this is totally awesome but unfortunately our time has run out. And this concludes our Q&A session, I want to thank Dr Prescott and Dr Osterman so much for their presentations today for sharing this important information with our audience. And thank you to all of you, a lot of you for attending. Don't forget to tweet and retweet using the hashtag surviving sepsis. The recording the recorded webcast link will be available at survivingsepsis.org within five to seven business days. Please visit the website to access the guidelines manuscripts and additional resources. This concludes our webcast. Thank you all very much.

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