Hello. Thank you for joining me on this Current Concepts webinar on controversies in sepsis. I am Dr. Kelly Cockett and I do want to acknowledge all of the effort of my co-author on this chapter in the Current Concepts book for 2024, Dr. Andrea Braun. I have no disclosures pertinent to this presentation. However, I do want to note that there is a lot of content within the chapter and in the scope of this presentation we will not cover the full scope of that content. So I do highly encourage you to go ahead and read the chapter for further detail. The objectives of this webinar are aligned with that of the chapter in which we will review definitions of sepsis and the resultant impact of the epidemiology, treatment, and research of sepsis. We'll discuss some of the key treatment controversies, specifically with some focus on fluid resuscitation and antibiotic use, and describe additional controversies relating to reporting of sepsis, performance measures, and additional technology and diagnostics as it pertains to sepsis diagnosis and management. As we all know, we are always in a race against time when it comes to sepsis management to provide our patients with the best possible care and outcomes. As we go through the following slides touching on some of what we know and some of the main controversies, you will note that at the bottom of the slide I have referenced which references are pertinent in the chapter and all of those will be available for you at the end of this slide presentation in addition. Please review those for further data and primary study results which are highlighted in more depth in the chapter than we'll have time to do in this talk today. So we will lead off with epidemiology of sepsis, what we know and what we don't. We know that sepsis claims millions of lives every single year and the highest burden of sepsis and sepsis-related deaths occur in low resource and low-income areas. We also have a disproportionate risk for development of sepsis in certain populations such as neonates, pregnancy, and persons living in low resource settings. There's also different patient populations as it pertains to immune status which we'll talk about later in this talk. Epidemiologic studies, however, are really focused on high resource areas and so although we know that we see a high burden of sepsis in low resource low-income areas and that they carry a disproportionate risk, we really don't have a great understanding of the true epidemiology of sepsis in these areas. This results in some significant controversies as it pertains to the epidemiology of sepsis. First, do we really understand the epidemiology if we do not include the highest risk populations simply because they are not the highest resourced? Second, the impact of that epidemiology data is critical as we think about attributable mortality secondary to sepsis. Data shows that attributable mortality is highly variable and that includes issues related to populations that are included in the studies but also it is related to the definitions that have changed over time as to what has been considered sepsis and we will talk about the impact of those definitions and what they are as we continue through this talk. There's also significant controversy as we are coming out of the COVID-19 pandemic on whether or not viral illnesses such as COVID-19 should be included in epidemiologic studies. This is critical because there are differences in the management of viral illnesses and the reality that a pandemic globally is very different than seasonal respiratory viral season. So how do we adjudicate the differences that we see over the last several years in which COVID-19 played a phenomenal role in issues of hospitalization, sepsis, and perhaps a very different syndrome of sepsis than what our standard definitions and guidelines have been focused on? And then finally, we often focus on sepsis studies and in the literature on community onset sepsis or what also could be considered as sepsis present on admission. This is not the same as hospital onset sepsis in which we do see higher mortality in that particular subset of patients, but we do not focus equitably on both. In order to continue to move forward and evolve our care and management of sepsis patients and to improve outcomes, we need to address each of these controversies. As I just mentioned on a prior slide, sepsis definitions are critical when we think about epidemiology and the research, clinical coding, and assessment we have of sepsis patients. And when the definition changes, everything changes. So what's in a name? When we think about definitions, it's important to understand that these truly have changed and impacted much of our epidemiology and other research studies over time and have changed the population and criteria clinically of those considered to have sepsis. So although sepsis has been a syndrome recognized historically for hundreds of years, the true first consensus definitions were adopted in 1991 and that included sepsis, severe sepsis, and septic shock with a long list of clinical criteria. This was further refined by the sepsis 2 definitions in 2001 in which we maintain sepsis, severe sepsis, and septic shock, but severe sepsis at this point transitioned to sepsis with organ dysfunction, secondary to infection. And finally, in 2016, we have the evolution to the current working definitions or our sepsis 3 definitions, which now simplified even further down to sepsis and septic shock and provide the pathophysiologic definition of sepsis being a life-threatening organ dysfunction caused by dysregulated host response to infection and utilizes a sequential organ failure assessment, also known as SOFA score, of two or more in the setting of known or presumed infection to define that organ dysfunction. So it's really important to understand that there was a fundamental change between physiologic derangement based sepsis 1 and sepsis 2 and more specific simplified organ dysfunction based sepsis 3 definitions. When we consider the time of these changing definitions, it really has impacted our ability to assess all of the epidemiology, generalizability, and validity of many of our sepsis research studies and clinical coding for all of these diagnoses. Also of note, we had our first development of surviving sepsis campaign guidelines in 2004 and then the transition into sepsis management bundle performance in 2015. And so again, this has continued to evolve over time and definitions over these time periods matter as we consider when we look back in time at what was guideline-based practice, what were the reporting measures, and how were we all defining sepsis. So with all of this in mind, what controversies do we have? Well first, how do we account for the epidemiologic and research differences over time to these changing definitions? Is sepsis truly a one-size-fits-all syndrome or is our current definition still too simplistic in the realms of advanced individualized and precision medicine? And is it truly validated for all patient populations? I mentioned earlier that most of our studies are truly in higher resourced locations. So is this validated and the same for lower resource areas? Have we included all patient populations such as our immunocompromised or pregnant patients? Or do we continue to need better definitions still? Another controversy is whether or not sepsis 3 prevents early recognition. Is waiting for organ dysfunction via a SOFA score change too late in the process to be the time at which we use that definition? And finally, should different definitions be used clinically versus administratively? Currently, Performance Bundle through CMS uses older definitions and has not fully adopted the newest ones. Is that appropriate if clinically we are working with different definitions when we're considering patient care and patient outcomes? Aligned with that discussion about early sepsis diagnosis and our definitions, we do need to continue to talk about diagnostics and recognizing that we're still not there yet with the best methodology in which to do this. Some key points in screening an early diagnosis is that there remains no gold standard test for the diagnosis of sepsis. Sepsis 3 uses the SOFA score, but there have also been other scores such as Apache scores that have been used. And the usability varies due to the differences in time and variables required. But do we have the right scores in place as we think about these definitions? And again, are they early enough to capture clinical deterioration secondary to sepsis with accuracy? Also, we are seeing increased utilization of early warning systems that may modify the sepsis definitions and integration with artificial intelligence, but none of these are specifically recommended yet in the guidelines. So in the absence of guideline recommended and high evidence-based early recognition systems, we know that we should be integrating these and screening patients per guidelines, but we still don't have the best possible methodology in place. And then there's continued rising evidence on the use of various other clinical factors, including endotypes and phenotypes. There's genomics, metabolomics, different biomarkers that have been studied with some efficacy in sepsis, but none of these have risen to the point of reaching recommendations yet. So when we consider our screening and diagnosis of sepsis at our own institutions, what do we need to think about as far as the controversies? Again, is organ failure too late to screen positive? What are the risks and benefits of misdiagnosis? I think we all can understand missing sepsis and the potential mortality for patients if we have a misdiagnosis there, but if we diagnose patients with sepsis who do not have sepsis secondary to infection, then we miss their alternative medical conditions, we overuse antibiotics, and we may be utilizing fluid and other resuscitative measures inappropriately, and those all could carry different risks to these patients. Again, does sepsis require more nuanced definitions and ultimately diagnostics based on genomics or some of these other factors? And at what point do we consider integrating these into our process, recognizing that none of them have reached the level of a gold standard yet? And finally, what is the role, if any, for biomarkers in sepsis? Even with procalcitonin being heavily studied in sepsis, we still do not have true guideline-driven guidance on how to integrate these effectively in our care of patients as it pertains to screening and diagnosis of sepsis. Transitioning onward more into the management focus of sepsis, we'll move into fluid management. And this is really the Goldilocks of sepsis, where we're still not quite sure what is just right in the management of sepsis. So what does that really entail? The 30 mL per kilo guideline remains a very weak guideline recommendation for septic shock or sepsis-induced hypoperfusion, with really a lack of high quality studies demonstrating what is the right amount of volume for patients with sepsis, specifically, again, those with septic shock or sepsis-induced hypoperfusion. We remain unclear on what may be optimal, liberal or restrictive fluid strategies. And more recent data suggests that either of these may be okay and not change outcomes as much as previously thought, as much of the other sepsis care has evolved. We recognize that there's risks and benefits of IV fluids that do create that Goldilocks phenomenon in care and research has not yet been able to resolve both the volume, the strategy, and if there is one best type of fluid for these patients yet. Individualized assessment of patients, including considerations of fluid dosing for those with obesity and those with pertinent comorbidities, such as chronic kidney disease or congestive heart failure are all key important factors as we consider how we resuscitate patients with IV fluids and whether or not we are over or under resuscitating our patients. We do tend to overestimate the risk of fluids in many of these populations, including those with chronic kidney disease and congestive heart failure, but that doesn't mean that one size fits all across the board for fluid resuscitation. So what fluid is just right? Well, the evidence would say that crystalloids remain better over colloids. Balanced crystalloids more than saline, but which balanced crystalloid is best remains unknown. Lactated ringers, however, is heavily leaned upon and commonly used as a balanced crystalloid due to its availability and cost. So what controversies still remain in fluid management for us to assess? And here again, I really wanna highlight that there is a lot of information in the chapter, so I really encourage you to review that. You will have many of the specific studies and data highlighted there for you. But key controversies remain in how much does fluid resuscitation actually impact outcomes? If liberal versus restrictive are maybe not as impactful as we previously thought, then what is impactful in outcomes? What is the right fluid, the right volume, and the right time for fluid resuscitation and sepsis? All of these remain unknown for us when it comes down to high-level specifics. Should the 30 mL per kilo volume be in performance bundles when we know that it may not be appropriate for all patients and there is little evidence saying that this is actually the optimal amount of volume for patients with sepsis-induced hypoperfusion or septic shock? In obesity, it remains unknown whether we should use actual, adjusted, or ideal body weight for fluid resuscitation. And given the epidemic of obesity, particularly in the United States, this is a critical piece that we need to be considering when we consider sepsis management. And then finally, in general, is there really a best fluid for resuscitation? Yes, we understand that balanced crystalloids have proven to be optimal, but of those balanced crystalloids, is there truly a type of fluid that we really should be using for resuscitation in sepsis? And as we all know, resuscitation is not just about IV fluids. It also includes additional considerations, including vasopressors. So again, not just about the fluids. So let's dive into a little more detail on this topic. So as I mentioned, beyond IV fluids, resuscitation does include vasopressors, the consideration for the need of intravenous access, specifically central venous access, and whether or not there are additional treatments that pertain to resuscitation that should be considered. Norepinephrine has remained the first-line vasopressor recommendation in guidelines, followed by vasopressin and epinephrine. Dopamine has been recommended to be avoided in sepsis based on prior studies. V1 agonists or angiotensin II options are not currently recommended by guidelines, nor are other non-pressor treatments, such as methylene blue. There is some evolving evidence to the potential benefit of some of these medications, or potential adjunctive benefit, as opposed to replacement benefit. However, the data remains early and not at a level enough to be moved into guidelines and recommended for routine practice. A full scope of the additional treatments is beyond the scope of both the chapter and this webinar, but we do touch on several of these within the chapter if you are looking for additional references. And then finally, there's increasing evidence that central venous access may not be required anymore, at least for a period of time. And that would be a fundamental change for many clinicians in the management of sepsis. So what are some of the key controversies that remain in resuscitation and vasopressors? First, should IV fluids be given first or at the same time as vasopressors? Or is there a better timing in which we should utilize IV fluids? Is there a role for vasoactive agents in septic shock that are not vasopressors? Are they superior to norepinephrine or adjunctive in management? And how do we look to study these and integrate these appropriately if in fact they can improve outcomes? And finally, how long can pressors be given via peripheral IV? Guidelines say that we certainly do not need to place a central venous catheter in order to start vasopressors anymore, but the amount of time in which we can safely run vasopressors through a peripheral IV has not yet been established, but continued studies demonstrate that this is likely safer than previously thought and is a viable option for infusion of vasopressors. Optimization of this becomes critical when we think about the potential adverse events of central venous catheters, including development of bloodstream infections and thrombosis, along with vascular damage. Another very key aspect to sepsis management is the use of antibiotics. And really thinking about how we in fact simplify this of killing bugs with drugs, with precision, so that we do this well and effectively for our patients. As we think about antibiotics, we have to recognize that diagnostic uncertainty is critical to antibiotic use in sepsis. When we do not have a gold standard diagnostic test and we are concerned about a high mortality, we will lean into being very aggressive, which can lead to potential overuse of antibiotics or inappropriate use of antibiotics. The most recent guidelines do say that if we have a high likelihood of sepsis or septic shock, we should still focus on giving antibiotics within that first hour. For all else, we have more time in order to really assess the patient, determine whether or not we truly believe this is a sepsis syndrome, and then treat with antibiotics. That timeline is listed in the guidelines as three hours. Delay of antibiotics does increase mortality, but as opposed to the prior teachings that this was an increase in mortality for every single hour of delay, in patients who have sepsis but do not have septic shock, that mortality change really is several hours out and not an hourly impact. Therefore, making the ability to wait those three hours to confirm sepsis and give antibiotics as appropriately as possible with increased precision is a safe way to care for patients. So what are some of the controversies that still remain in antibiotic use? First, what is time zero for the definition of sepsis and for starting antibiotics? This has been incredibly hard to define clinically and administratively to understand when the one-hour time mark or three-hour time mark are happening. So really understanding and refining time zero becomes critically important to adhering to guideline-level management. How do we further address diagnostic uncertainty in the setting of harms secondary to unnecessary antibiotic use? With the rising antimicrobial resistance and the risk of adverse events secondary to antibiotics, this is critical that we are as precise with antibiotic use for the right patients at the right time as possible. And how do we best implement these timelines for antibiotics within one hour versus three hours during our clinical assessments? We all know time is crucial in the emergency room where many of these patients with community-onset sepsis are arriving, in our ICUs as we're managing these patients, and also in the hospital in general for those who develop hospital-onset sepsis. Can we implement this level of care and make it effective and timely so that the right patients get the right medications at the right time? And finally, as we think of all of our assessment of sepsis, from the epidemiology to the diagnosis and diagnostics to the management components, we now also have to address the reporting of sepsis measures and outcomes, and whether these are good, bad, or still undetermined. So at the time of this recording, it really is all still controversy. In the United States, with the SEP1 bundle that we have had in transition from paying for reporting to paying for performance, there's inconsistent data that these bundles actually improve patient outcomes. And there is some concern that, in fact, in a subset of patients, adhering fully to the bundle will result in patient harm. The use of this bundle may increase indiscriminate antibiotic use based on several of the points I made on the prior slides regarding moving quickly, efficiently, and trying to ensure that we're meeting a bundle as opposed to best care of the patient. Again, with the question of, is sepsis really a one-size-fits-all syndrome, which many would argue it is not, should bundles be this rigid? And should we be adhering to them in this level of rigidity, recognizing that they are not a full match to the way patients may optimally be managed? Time zero, again, here is a critical piece because the performance is based on what is defined as time zero. And if there is ambiguity around time zero, then there's ambiguity about the entire reporting process. And finally, should reportable sepsis data be outcomes-based or process-based? What are we most concerned about in this setting? And do we need to continue to advocate for further refinement and adjustment of any reportable sepsis data on the national level to be evidence-based and showing patient outcomes that are meaningful as opposed to showing process components of fluid resuscitation or antibiotic dosing that may or may not always impact outcomes as much of the preceding controversies have highlighted for you? So where do we go from here? At the end of the day, the reality is we still need more data and we need more research in all areas of sepsis, from epidemiology to diagnosis and diagnostics to management and outcomes. We have learned an enormous amount about sepsis to date, but recognizing that there are still significant controversies is critical for all clinicians because blindly adhering to the bundles or blindly adhering to guideline recommendations that may be very weak guidelines really may impede our care to the patient directly in front of us. So continuing to stay up to date on the evolving evidence, the evolving guidelines as they're revisited, any changing definitions, all becomes critical to optimize care for our patients. Again, thank you for your time. And also please remember to check out the chapter in the current concepts book for 2024 for much more detail than I was able to cover in this session today. All references from the book are in the slides that follow.

sepsis management

controversies

definitions

epidemiology

treatment

research