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Introduction: This podcast is sponsored by Baxter Healthcare Corporation. When you choose Baxter for your CRRT program, you're not only choosing true patient focused treatment with industry leading CRRT technology. You're also selecting a partner dedicated to optimizing your clinical success in treating patients with acute kidney injury. Our commitment to you starts with a program individualized to your facility's needs and provides complete support every step of the way. For more information, visit us at www.Renalacute.com. Baxter Healthcare Corporation has provided funding for this podcast, but all content was developed independently by the presenter. Therefore, the views expressed on the podcast are those of the speaker and should not be attributed to Baxter Healthcare Corporation. For prescription use only for the safe and proper use of this product, please refer to the operator's manual.

Dr. Pamela Peak: Hello and welcome to the Society of Critical Care Medicines, icritical Care Podcast. I'm your host, Dr. Pamela Peak. Today, we'll be talking about severe COVID-19 and sepsis with Dr. Russell Miller, Medical Director of Critical Care at First Health of the Carolinas. Welcome Dr. Miller. Before we start, do you have any disclosures to report?

Dr. Miller: I do not.

Host: Excellent. Thank you so much. All right, now let's look at the goal of this podcast so we can wrap our heads around hitting the objectives for all of the listeners out there, you know, in the current COVID 19 pandemic, which is certainly not abating across the United States, many physicians believe they have to diagnose and treat a novel virus, but patients infected with the COVID Two. This is the SARS Cov Two, and presenting with severe or critical COVID-19 disease have viral sepsis. We need to educate and leverage what we already know about diagnosing and treating viral sepsis. In addition, we can apply what we've learned from sepsis and its sequella inpatients and survivors to support and manage a newly emerging population of COVID-19 patients and survivors. So we already know from the Global Sepsis Alliance that COVID-19 can cause sepsis, and this is an overwhelming life-threatening response to an infection. So Dr. Miller, give us your definition of sepsis, what this is and how this aligns with what goes on with COVID-19?

Dr. Miller: Well, first of all, thank you for having me. I think there are several to make this connection between COVID-19 and sepsis. I think we can make a plain case, perhaps even a theoretical case. And then look at some of the published data that I think you're referencing. From the perspective of a plain case, we know sepsis is a syndromic definition. It is the presence of an infection in the context of sequella, whether that is aberration of vital signs, aberration of mentation, there are various ways of course, to make that definition. Having said, all of that, the plain case is that many of these things are present, including organ failure in COVID just as they are, for example, in pneumococcal sepsis or meningococcal sepsis or fungal infections at times. Sepsis in a sense is well-described and well-accepted in the context of other viral infections, such as influenza. So why would it not be with COVID-19 as well?

Now, there are others who've made this case and make, if you will, this plain case Doctors Taco and Simpson back in July and just made the case and simply described that all of the things that we see in COVID-19 are similar, although perhaps on a different timescale to that, which we see in bacterial and fungal sepsis. And their comment, and I'll leave it as it is. It is logical to conclude that severe COVID-19 is indeed sepsis caused by SARS Covi Two. Now, in addition to that plane case, we have a theoretical case, which is to say that despite all efforts to redefine sepsis in the last several years, sepsis remains, as I said, a clinical syndrome with many presentations and many phenotypes. Sepsis by qSOFA may be less common perhaps in COVID-19 until later in the critical illness, but it still often appears. Respiratory failure is the hallmark, of course, for most of our patients with COVID-19, but kidney failure, brain dysfunction, liver failure, hematologic abnormalities eventually do emerge in some, if not most of our sickest patients.

It is very clear to many people who have cared for now, hundreds, perhaps even more patients individually now, that regardless of the timing that the typical findings of sepsis do eventually emerge whether on admission or during the course of the illness. And certainly by the time of critical illness tends to look like classic sepsis. That is to say cardiac [inaudible05:40] leukocytosis, perhaps less fever if to use the old bone description from the 1990s of and before, of the systemic inflammatory response syndrome. But we still see many of these things emerge during the course of illness. And then finally we have now a fair amount of published data, most observational of course, looking at the initial wave back in January, February, internationally, and then into the United States. And at least conservative estimates would put the incidence of sepsis at least a quarter of hospitalized patients.

Now, I frankly think that's a very conservative estimate. And we also know that 100% of the folks who die from COVID-19 are going to meet criteria for sepsis around the time of their death. So that's a long-winded answer perhaps to your question, but I think it gives, I hope a little bit of perspective from a few different angles as to how sepsis and COVID-19 are in many ways quite synonymous just as with influenza or other types of bacterial or fungal infections.

Host: Yeah, I think you did an absolutely stand-up job of summarizing at a high level, the relationship between severe sepsis and COVID-19. And once again, reiterating some important points, you know, one in three patients who die in the hospital, dive sepsis and the most common cause out of the different types of infections that cause sepsis is pneumonia. And we obviously know that COVID-19 makes a beeline to the lung. Can you help us understand that a little bit better? What is going on with COVID-19 in the lung that can help inform us about why we go from zero to pneumonia with COVID-19?

Dr. Miller: I think the honest answer to that question is no, I can't inform that particularly well. We have certainly observed it. This falls in the category of things we have observed. I don't think we very well understand all of that pathophysiology as with any new disease COVID-19 or SARS Covi Two presents. The challenge of trying to discover how the disease works simultaneous with the massive surge in need to care for patients in front of you. That is a pandemic by definition, of course. And so I think that the basic science behind this and translational science will necessarily lag as it does with many infections. Having said all that we know Coronavirus of non pandemic varieties likes to cause, whether it's common, cold or infections of some other sort, likes to mitigate its symptoms through the lungs, through nasal carriage and then into the lungs. And there's perhaps nothing magical about this disease until you get to the very lengths of it and the effect that it has within the body and specifically within the lungs and all the changes that may occur there in terms of the consistency, perhaps even architecture of the lung.

Host: All right. And that makes sense. There's also the issue of bacterial co-infection, that's leading to severe disease. Talk to us about that. What do you classically see?

Dr. Miller: I think the most common defined infection ultimately ends up being that, which we have been used to seeing with influenza, whether that is a staph infection, staphylococcal infection, or perhaps a streptococcal infection. It turns out COVID-19 likes to find people with lots of comorbidities, of course. And so some of those include structural lung disease. So finding pseudomonas or finding other opportunistic, if you will, pathogens is not entirely surprising. Having said that time course is a little different. I remember back to H1N1, many of the times that we saw patients early in that illness, we were convinced they did indeed have bacterial co-infection early on. With COVID-19, it really feels like, although we get hyped up about needing to use antibiotics early on and treating for co-infections early on really feels like most of these patients just, and I clearly put that in quotes have a viral infection and that the bacterial infection tends to be a subsequent infection, whether that's due to prolonged hospitalization or sort of the culmination of critical illness that we don't particularly well understand pre COVID.

Host: Absolutely. And then obviously other iatrogenic like the use of ventilators, and co-infection obviously that increases, no matter what you try to do, just looking at the therapies themselves. And the extent of the damage is really quite shocking. Really, at the end of the day. You spoke to this, when you were talking about overall organ damage among the patients, it is substantial. What is it severe enough to require drugs, to support the heart and circulation in over 70% of patients. And 30% of patients in one series had evidence of liver injury and 75% had evidence of depressed immune function, overall kidney failure in 20%. I mean, this is very serious and this is something that I think people are just now beginning to understand as they look at what COVID-19 can do. Talk to us about risk factors, the people who are more likely to experience sepsis are whom?

Dr. Miller: Well, I do think that we have a lot to learn about the details. Having said that, what the public data and personal experience among many practicing critical care physicians would lead us to is a recognition of hypertension, simple hypertension. Diabetes. Now we accept that one as a more complicating or bigger risk factor that feels like it should be a bigger risk factor. Morbid or super morbid if you will obesity. And whether that's a combination of restrictive or constrictive chest disease is unclear. Age alone, clearly the data support that age has some effect on at least the survivability and potentially then the severity of the disease. There are a number of risk factors. And I suspect a number that we can't know at this day in time because they are genetic having said that, are those genetic reasons related to race? They sure seem to be, but I don't think in this day, we really yet understand how to tease apart, which are the bigger risk factors, which are the smaller risk factors.

Again, we're inundated, we're dealing with it on a daily basis. To some extent that academic work will have to take a back seat so long as we continue to have heightened awareness and interest in defining and categorizing and better clarifying the true incidents of sepsis here. And I would just like to say as an aside, you know, what a wonderful time, if we could possibly have some sort of early diagnostic marker. I mean, we always clamor for this in our specialty, of course, but what a wonderful time, if we could have an early marker that would give us some ability to detect or predict likely progression to severe disease. And I would argue heightened in COVID is this notion as you allude to of this immune response, it may need to be a marker that's focused on the host immune response, particularly because that may give us the best sense or best predictor of how the body intends to respond in weeks two and three following exposure.

Host: So, you're really talking about something that might pre-stage the cytokine storm?

Dr. Miller: Right.

Host: Yes. And so we could actually almost be able to be proactive about it. And what would you do with a marker that actually showed that potentially cytokine storm is right around the corner? How would you prevent this?

Dr. Miller: Right. Well, I think that's an entirely fair question. And again, perhaps to use your exact term back to you to say, [inaudible 12:15] is exactly that I don't know that we know how to use it today, but I do think as we begin to and continue to have experience and understanding true risk factors, understanding true consequences and different phenotypes of this presentation, I think we'll begin to have that clarity. And if we don't seek now such a marker, then I think we will have missed the opportunity to better delineate this down the line, whether this is a braided kindness or a cytokine storm, or is that really that different? Pardon me? I'm no immunologist, but those things at some point, I think will useful to understand the data supporting direct intervention on the cytokine storm are underwhelming to date, and we really need to better understand it before. And this is hard in 2020, but before jumping all the way through therapeutics, that really have no chance of being successful in my opinion.

Host: All right. So now you're talking about therapeutics. You open that door, let's talk about, we're going to walk right through that one together. Convalescent plasma, dexamethasone, Remdesivir, have a conversation. All right, we have that patient in the ICU. They are septic. What are we doing?

Dr. Miller: Well, I think the first and foremost thing for us to recognize is it's no surprise that the surviving sepsis campaign, the National Institutes of Health, Global Sepsis Alliance, American Thoracic Society, all these organizations, and many others have come together and offer guidelines for management. And they've excepted defacto if you will, that COVID and sepsis care indeed have many parallels. And in short, my opinion is that as many others have suggested, we have to apply what we've learned from treating sepsis and its complications for years to COVID, including importantly, evidence-based supportive therapies. So low tidal volume, mechanical ventilation, appropriate guidance around use of different strategies to mitigate organ dysfunction. So for example, fluid management, to be careful not to injure unnecessarily the lungs or to unnecessarily or unduly cause injury to the kidneys. We have to be thoughtful about standard stuff.

And that's the first, second, third, and perhaps 99th leading explanation, or answer to that question. Once we get beyond all those things, gosh, we all would like to know how to target this disease specifically. And I have faith that we may one day do that. I don't know that anything we have in front of us right now is such a target. The most compelling data perhaps is around dexamethasone or is it really just any steroid? See, there still remain details here that we don't understand. In terms of plasma and Remdesivir. Gosh, the problem with COVID in general has been that we have exposed to the American public, the somewhat intentionally wayward nature of experimental medicine that we find some data and then somebody else finds no data. I think the sum of what the true treatment of COVID will be, can't be known in 2020 as disappointing and fearful as we may be about that. It nonetheless, I think rings true. So we have lots of opportunities, few targets still in 2020.

Host: So, in 2020 speaking of seasonal, we're about ready to walk into flu season. Now, how is this going to complicate things?

Dr. Miller: I think it's going to be complicated on so many levels. Before I get there, though, I would say, and colleagues in New York and other places have experienced this at a scale that I have not. There is a little bit of a notion that when COVID comes in town, other things get out of Dodge and you don't have to be from Kansas to appreciate that remark. I hope the truth is that when we see illness because influenza and COVID and pneumococcal pneumonia have many of the same treatments on a simple level, it doesn't matter. Now, that's the simple level at the much more complex and appropriate level, perhaps is this notion that the appropriate use of PPE, the appropriate use of precautions to prevent ourselves from being exposed and others from being exposed to illnesses that we don't have adequate therapies for. Unlike pneumococcal sepsis, for example, are in a place where we can mitigate that spread and that exposure. So we will have to be mindful of assessing for influenza.

And it turns out just as we've gone through a six-month trial or eight month trial now of looking at different diagnostics for COVID, we still don't have the perfect influenza test either, right? We don't have the perfect test for other viral infections, rhinovirus or any of the enteroviruses. We don't have that perfect test. So it's absolutely going to confound us in the most important way perhaps from, in terms of thinking about how to take precautions, which is on the diagnostic end. It also, however, may have implications on the management side, not the least of which is by volume of patients who may be ill from one, or both or the other illness. And so I think we have an enormous task ahead of us as we enter this next season, not just to understand who has what, but also to understand how do we actively keep patients from getting exposed from one another. And that necessarily requires the most conservative approach that your institution can possibly procure, I suspect.

Host: I don't think there's any question that the issue of physical distancing washing, like you've never seen, sanitizing, the use of masks, etcetera, etcetera, are absolutely foundational to this prevention effort. No question about that. And I'm really glad you brought that up because, you know, we get hung up on a lot of our very expensive interventions here, but really at the end of the day, it'd be nice if we didn't get it in the first place to say the least, and really appreciated your sharing, who you consider to be also at higher risk. I have a question about that, and that is talk to us about gender specificity, because there's an interesting thing going on here with men and women and COVID, both the risk factors for actually contracting the infection and also the post COVID syndrome?

Dr. Miller: Right. So this is very interesting and very fresh of course, in the literature. And that is first, seemingly well understood was that men seem to be at higher risk of mortality than women of finding that perhaps will bear out. It certainly anecdotally does in my practice. At the same time, because two will get you one way or another. It seems at times women seem to be perhaps more susceptible to the long COVID and that has many terms that will change over time I'm sure, but the longer term symptoms associated with COVID. And that is distressing, it is in many ways a parallel to what we've experienced within critical care and come to understand about critical care over the last 20, 30 years or so, which is that it isn't just the critical illness that creates problems.

It is the attempted or indeed recovery from critical illness that is associated with many complications and many opportunities and pitfalls along that way. So yes, there is a gender difference here, how that looks by the time we get additional experience. And I hate to keep saying that it's just that so much of this continues to evolve and seems almost anecdotal until we put enough of the numbers together. I don't know yet. I think it will be interesting to see, and I think it does influence just as it should have been influencing for the last 20 or 30 years, the way in which we prepare survivors of critical illness for the time beyond us, that there will be, or could be consequences long-term that we have to really pay attention to and at least draw attention to as critical care providers.

Host: Absolutely. And that was so well said, I'm working currently with a study at Mount Sinai in New York City, which obviously has seen its share of COVID patients. And interestingly enough, I wonder, big wonder here, because to your point, we're just gathering data as we go along. When it comes to the post COVID syndrome, which is, it seems to be rather long-term, I'm wondering if it's the presence of estrogen? And I'm looking, I'm thinking to myself of the hormonal status of females when they contract the illness, as well as post COVID, whether or not estrogen status plays a role here? I have no idea because I'd love to see the age segmentation of people who are post COVID say for instance, and the ones who are having the worst problem, just anecdotally, it seems as though they seem to trend younger among females in the post COVID syndrome. Like you I'm trolling the evidence-based studies as soon as they come out. And I'm really curious to see where this is going to take us.

Dr. Miller: Yeah, I think we are in an interesting time, for sure. Everybody knows that and interesting in science and in medicine in particular means a time of great opportunity. And I just hope we continue to avail ourselves of those opportunities. You mentioned estrogen, I guess. I wonder since we can't seem to settle this debate about anticoagulation, at least as yet with numerous ongoing studies of course. I wonder if, you know, [inaudible24:30] where's that drug now, does it have a role here? I mean, this was the putative role for it, micro thrombotic inflammatory disease. Where is it now? And you know, whether it's estrogen-based therapy or just estrogen-based association or some specific management related to this micro thrombotic inflammation, wouldn't it be nice to know where we actually stand there?

Host: I love it. And I could sit here and conjecture with you all day because there are so many pieces to this, but you know, something, what you've done today has been fantastic. Everyone, we have been speaking with Dr. Russell Miller, he's the medical director of critical care at First Health of the Carolina's. And today we talked about sepsis and COVID 19, what an interrelationship and what a challenge. This concludes another edition of the icritical Care Podcast. Dr. Miller, we thank you so much for sharing your wisdom and your experience and for the icritical Care Podcast. I'm Dr. Pamela Peak.

Conclusion: This podcast is sponsored by Baxter Healthcare Corporation. When you choose Baxter for your CRRT program, you're not only choosing true patient focused treatment with industry leading CRRT technology. You're also selecting a partner dedicated to optimizing your clinical success in treating patients with acute kidney injury. Our commitment to you starts with a program individualized to your facility's needs and provides complete support every step of the way for more information, visit us at www.renalacute.com. Baxter Healthcare Corporation has provided funding for this podcast, but all content was developed independently by the presenter. Therefore, the views expressed on the podcast are those of the speaker and should not be attributed to Baxter Healthcare Corporation for prescription use only for the safe and proper use of this product. Please refer to the operator's manual. Pamela M. Peak, MD, MPH, FACP, FACSM is a nationally renowned physician scientist expert and thought leader in the field of medicine.

Dr. Peak is a Pew Foundation scholar in nutrition and metabolism. Assistant professor of medicine at the University of Maryland, holds dual Master's Degrees in public health and policy. And Is a fellow of both the American College of Physicians and the American College of Sports Medicine. Dr. Peak has been named one of America's top physicians by the consumer's research council of America. She is a regular in-studio medical commentator for the national networks and an acclaimed TEDx presenter and national keynote speaker. Dr. Peak is a three-time New York Times bestselling author and is a science and health advisor for Apple. The icritical Care Podcast is the copyrighted material of the Society of Critical Care Medicine. And all rights are reserved. Statements of fact and opinion expressed in this podcast are those of authors and participants, and do not imply an opinion or endorsement on the part of the society of critical care medicine, it's officers, volunteers, or members, or that of the podcast commercial supporter.