Transcription:

Dr. Michael Smith: Hello and welcome, I'm your host, Dr. Michael Smith. Today we're going to talk about a sepsis quality improvement program with Dr. Erkan Hassan, who's the Cofounder and Chief Clinical Officer of the Sepsis Program Optimization Service and Dr. Roy Davis, the Chief Medical Officer of Immune Express. Dr. Davis, I wanted to start with you. We know sepsis requires a quick diagnosis, right? Quick Identification. Treatment has to begin quickly. So why is this topic about an improvement program so important?

Dr. Davis: I think what we'd like to do over the next 20 minutes is sort of review some of the challenges in the diagnosis and management, which are major from the standpoint of sepsis and use those to develop a coordinated effective and functional clinical quality program for the management of sepsis. I think we can briefly review some of the human and economic impact of sepsis, discuss some of the challenges that this gives the clinician, and then review some of the new laboratory and diagnostic approaches that may help this process and make an early diagnosis and enclosure the primary elements of a QI program.

Host: You know, Dr. Davis, you mentioned something there very interesting about the human and economic impact of sepsis. Tell us a little bit about what that means.

Dr. Hassan: Yeah, I'd be happy to. I, you know, the sepsis still remains the leading cause of deaths, not only in the US but also worldwide. Some of the latest statistics I saw was 1.7 million cases of sepsis in the US with over 270,000 related deaths per year, and on a worldwide basis what's commonly quoted is about 30 million cases of sepsis. It was quoted about 6 million deaths a year, but in January there was a recent update to that that demonstrates about 11 million deaths per year from sepsis, which now if you use that number, then that exceeds cancer as sepsis being a leading cause of death, greater than cancer cases of death. And recently Dr. Buchman reviewed the largest Medicare set of data from 2012 to 2018 and analyzing that data in a very detailed approach saw a 40% increase in hospitalized cases with true estimated costs of about 41 and a half billion dollars of sepsis to the US.

Host: I think those are beyond what most people realize when they think about sepsis and the impact that it can have. You know, Dr. Hassan sticking with you as clinicians, diagnosis and treatment of sepsis is tough. It's fraught with challenges and barriers. What do you think are some of the biggest challenges that providers face?

Dr. Hassan: You know, that's a really good question and, and there's so many that we could spend an hour talking on each one of those. I'll try to summarize those as I see them in my bias. I think that number one, as you indicated, there's no single clear definition of sepsis. And sepsis is really a clinical diagnosis and there have been three consensus conferences on sepsis starting in 1991 where the original SIRS definition started. And then there was another one 10 years later in 2021, and another one 15 years later in 2015, so the definition of sepsis keeps changing over this timeframe. Secondly, the bundles are relatively new starting in 2005 and those have changed over time. Another big challenge I think is the window between onset of sepsis and the identification is oftentimes delayed and some of the data represents that every hour that goes by increases the likelihood of death by 5%.

So that gap in that window between onset of symptoms and actual identification, one of the elements is the elements of sepsis management. And as we said that the bundles are relatively new things and there's some challenges in those primarily as I see it, some questions that arise in terms of are the bundles all or none? Right now it's all or none. If you miss one element, there's no partial credit. You missed the whole bundle. But the question in my mind becomes, are there certain items more important than others that we're starting to learn about with that? And then secondly, in terms of evidence supporting these recommendations have reasonably openly challenged in the literature. And so that's another challenge that we have to deal with sepsis.

Host: Yeah. So you mentioned that window of identification and the beginning of treatment is so important. Right? So as you said that the longer that takes, the greater the risk of mortality with sepsis. Why do you think in your expertise, Dr. Hassan, that there's evolving definitions of sepsis? Where are those differences coming from?

Dr. Hassan: I think that the differences of the definitions of sepsis, you know, back in 1991 when Roger Bone started with the first consensus that came up with the SIRS criteria, you got to remember what kind of technology, and care we were providing back in without the tools that we have today. So SIRS, the systemic inflammatory response syndrome and two out of four SIRS was rather novel, but it's very nonspecific. And that's sort of the, some of the issues with that. And I think that serves criteria is still prevalent today. But it uses, because it's primary, it's simple to remember, but it's very nonspecific. I mean, I get SIRS walking up a couple of flights of steps and it's, it uses actual cut points. So for example, a temperature of 38, above 38 centigrade gives you, it meets SIRS criteria. Does that mean that a temperature of 37.9 Is not sepsis but a temperature of 38.1 is. And so I'm not sure there's a complete cut point like that. And you know, I read an interesting thing the other day. If you want to start a fight, you ask an intensivist, an ED doc, and an ID specialist and then nephrologists to talk about sepsis.

Host: Yeah, I know, I totally get that and agree with that because at the end of the day when you're at the bedside of somebody in an ICU, you don't have time to debate these kind of end point questions, right? You have to make a decision that could be life or death. This is why I think this is such an important conversation. How do we improve the sepsis quality programs? And so I want to ask both of you, Dr. Davis, we can start with you. What does an effective sepsis program require?

Dr. Davis: I think one of the major challenges to developing an effective sepsis program is that initial diagnosis process, that early identification there is an unmet need there. We presently don't have a rapid sensitive or reliable diagnostic that provides the physician with actionable results. We have a number of current diagnostic processes that multiple and nonspecific, for example, Erkan just mention the SIRS criteria. And as you work up a patient in the ER, you use the of criteria, they're part of your diagnostic process but they don't say sepsis or not sepsis. And that's what we lack. So we use search criteria, we use lactate levels, CBCs, whole bunch of tests that are really nonspecific but drive you towards a possible diagnostic process. We also draw blood cultures, which are drawn up slow. They have a long turnaround time up to 72 hours before you get a result. So they're not rapid or reliable. They approach with multiple false positives and false negatives. And I think that is a major unmet need from that standpoint. We need a specific diagnostic that drives the physician to a clinical decision process. And without that, it's very hard to set up a quality improvement program that is directly related to sepsis. And so we use bundles to help us get to that diagnosis.

Host: Dr. Davis, you bring up a really good point. The bundling of these different tests that we can do is critical because listen, when I was in medical school, this is back in the mid nineties. I remember specifically, if you can't culture something out of the blood, it's not sepsis. And obviously that's not true because those tests aren't all that great, right, Dr. Davis?

Dr. Davis: That's sort of considered the gold standard, but it's a very poor gold standard. When you look at the studies that have shown that in patients with septic shock, 40% have positive blood cultures, overall sepsis diagnosis, anywhere from 10 to 30% have a positive blood culture. So you have 60% of patients who get discharged with a diagnosis of sepsis with no positive blood culture. So it's a very poor gold standard. There are changes coming with regards to detection of DNA pathogenic DNA in the bloodstream that may help us shorten that time from a pathogen standpoint, but it's still one very expensive, two massive equipment requirements from a standpoint of cost. And so that changes that process, but we cultures are really not the turnaround time process that we need.

Host: But Dr. Davis culturing a pathogen from the blood, is that still really going to be the gold standard? So if we can get some tests that can quickly, like as you said, DNA for instance, pinpoint a pathogen in the blood, is that still the gold standard or are there other things being developed that might get us to a quicker diagnosis of sepsis?

Dr. Davis: Yeah, I think there are a number of approaches being taken. I think that because of the pathogen process being fought with concerns, for example, we have multiple episodes of bacteremia every day we brush our teeth, we get bacteria in our bloodstream. Would these tests pick up that DNA? And would say, yes, you have pathogen in your bloodstream. So I think that there's that approach with that difficulty. And so over the last few years multiple people have been in, researchers have been investigating the use of biomarkers. We've been using biomarkers for some time. For example, we all know C reactive protein, a sign of inflammation, but not a sepsis diagnostic. The same applies to such things as procalcitonin. Procalcitonin is being used in a number of cases to demonstrate bacterial inflammation. Again, it's not a diagnosis of sepsis. It just says that you have a bacteria that is causing inflammatory response.

The other thing with procalcitonin is it also increases as you have severe disease, not necessarily severe sepsis disease, but severe inflammatory disease. So as you measure your Apache or Q Sofa, which is a sign of severity of illness, the procalcitonin follows that up. That's really hindered the diagnosis because it's elevated because I have severe and non bacterial sepsis that doesn't give me a good onset. So we've been looking at these biomarkers for some time. As we look further, we're seeing people starting to look at much more specific processes with regards to biomarkers and investigating the host response because sepsis has a obviously deregulated immune response and organ failure, we get a host response as related to that process. And so people have been looking at various host response processes that are much more specific from that standpoint. For example, a recent article came out looking at the monocyte distribution with, it's been shown that as the patient develops increasing sepsis, the monocyte distribution increases.

And it's, again, not a specific test for sepsis, but an inflammatory marker that adds to that list of sepsis diagnostics that we have. The most recent process is to start looking at host response specifically looking at RNA and the development of a host response specific for sepsis. And those are multiple people are looking at that from a research standpoint. Presently there's only one FDA approved diagnostic that has specific for sepsis. It reports the probability of sepsis and it looks at four MRNA signatures in white cells. And these increase or decrease depending on the patient's septic response and the report gives out a positive sepsis report with the probability of sepsis being reported in a percentage increase. It has a very high negative predictive value, which is what you want. And so this test scores hepatocyte lab and as being evaluated for a point of care process in the near future.

Host: And you know, Dr. Davis, I want to come back to you and talk a little bit more about the biomarkers, but I wanted to allow Dr. Hassan to speak into this a little bit too. We're talking about what does an effective sepsis program require and Dr. Hassan, I know you've talked about screening. What does a typical patient look like that might have sepsis? Can you tell us a little bit more about the screening of patients for sepsis?

Dr. Hassan: Well yeah, that's a good question and let me answer your first question initially of what does a program look like? The program in my mind needs to have two very large components. One is the plan creation and the second is the plan implementation. And I think critical to that is sepsis in my mind is a team sport and there have been a number of solutions that address only one area. As you mentioned screening, and we'll talk about that in a moment, but there's solutions that address screening, there's solutions that address diagnosis, there are solutions that address prognosis, there are solutions that address the bundle elements, but a real comprehensive sepsis program needs to be entail all of that. And it starts with a team approach and you need to have everybody from, you know, the ED, the lab pharmacy, the, the ED floor ICU med director, the nurse managers, the bedside nurses from all those sites, respiratory therapy, nurse educators, it takes a village, it takes a whole team to address this. And so you need to start with that and you need to define exactly how you're going to build a program. And it does start with screening.

One of the things, sepsis screening still remains a daunting challenge because it's very nonspecific. And like I said, SIRS was established in 1991. It's easy to remember, very nonspecific. Most of the sepsis screening tools are, have a high sensitivity and a low specificity. But what we're really trying to get to is early sepsis identification. And really the goal should be every patient get screened every day, every shift. So that doesn't really get done I don't think because it's so labor intensive and even when you automate it, it's still, it's not a sepsis program per se because that only addresses the screening part of it. So who is going to do the screening? What tool are you going to use to screen? Are you going to use different tools in the ED versus the floor versus the ICU? How is the diagnosis really made? How do you escalate a controversy? How do you activate? Some places use specific sepsis teams, some do not. How do you track the bundle elements and how do you track the timing of those? All of those come into play in developing a sepsis program and then then we have to talk about implementation, which am I answering your question, Dr. Smith?

Host: Yeah, this is great. I want to talk more about implementation of all this, as you mentioned, I'm going to just back up for one second because you said something that kind of caught my attention. You mentioned that some hospital centers, and I assume probably the ones with the largest ICU units have essentially a sepsis team, a group of nurses, nurse practitioners and physicians that are up to date on a lot of this. How important is that for more and more hospitals, community hospitals to have a team that's trained to as best they can with what we have out there to identify sepsis?

Dr. Hassan: You know, I think it really relates to how well your sepsis program overall is. Obviously I think communication is key. Creating a good substance program, overarching program and implementation of that really requires that everyone understands their individual roles and responsibilities, that they do only what they can do, and that training and education follows that. But everyone needs to understand their role and responsibility and what they need to do. And so if that is functioning in all the departments, in all these team members, in all these locations that we talked about, you may not need a sepsis team. The sepsis team's kind of in response to our rapid response team of a specialized site. And sometimes people are busy doing other things. They may not be able to leave the bedside of what they're doing and go to that. But that's part of the decision process that needs to occur in building this program as to what the best way to provide that care is. Is it better to have a select team of individuals do it? Typically what I found is when you first start a sepsis program, there's some things that fall through the crack and it's not because people just aren't doing what they're supposed to be doing, but they didn't understand or forgot their complete roles and responsibilities and reeducating resolves that.

Host: Yeah. Do you think Dr. Hassan that I mean at least hospitals, County hospitals, city hospitals that have a decent size ICU, should they have at least in place specific people that are going to collect the data, store the data and communicate that data?

Dr. Hassan: Yeah, I think that's really key. Obviously, you know, the old adage of if you don't measure it, you can't improve it. And so you need to be able to really centralize that. And I think the data and the presentation of that data needs to be not just to the hospital administration but to the bedside clinical folks as well. If they don't know how well they're doing, how can they improve. So I think it needs to go in in all directions.

Dr. Davis: As you put that process in regards to the data, having been the chief medical officer in a large hospital system and then without having that data to go back to the department of medicine and the department of emergency medicine and report those data processes, it's very hard to drive improvement. So I support that process. And also we're driven now by the joint commission and CMS. They require that data for you to get either paid or certified. So the data is driving this process.

Host: Dr. Davis, I do want to go back to you. I want to talk about biomarkers just quickly here. I'm going to, I hate to do this. I'm going to put you on the spot a little bit. Dr. Davis, cause you have so much experience actually you know, working at the bedside with all these different biomarkers. You mentioned several of them and when you bundle all this together, I know that's important, but I want to just talk about what do you think really are the top three, four, five biomarkers that physicians at the bedside need to be testing and need to be acutely aware of?

Dr. Davis: Yeah, I think that from two ways that is driven. One is in the emergency room, it might be slightly different from the patient on the floor because that patient on the floor may have had some of the tests that you would order already done that morning because they're post-surgical or some other reasons. But I think there are a number of biomarkers that we use to help make the diagnosis, but they're made jointly together, for example, a C reactive protein, lactate, the use of Serrate in some places still being used, but in a micro sense. And then your white count with your [inaudible] and your banding system process or add together to help make that diagnosis. The presence of the monocyte distribution, which is becoming available now on the Coulter counter. So it's very easy test to run. It's done with your CBC. That will help. These are all additive processes, none is specifically diagnostic. The addition of a turnaround time tested one hour that is much more diagnostic with regards to that is the host response process. And I think you'll find that as that becomes available in the clinical arena, they will add that to those. So I think you're looking at a CBC diff, we still draw up blood culture because she needed to have a blood culture. If you can get it because you might have some different organism grow. The Lactaids, the C reactive protein, the differential, and then the addition of specific biomarkers like monocyte distribution with and the new silicide lab will add to that process.

Host: Yeah. Yeah. H1ost response. You think that's where we're headed in the future? Understanding more how the patient is responding.

Dr. Davis: Yeah. I think if you look at a recent review in clinical microbiology and infection talked about personalized medicine from the standpoint of that and they talked about host response quite a lot. And in fact, one of the several recommendations was that as we look at sepsis and the host response and delivering the appropriate care, we need to have much more evaluation of how host responses and how we can look at biomarkers that will drive that personalized approach.

Dr. Hassan: Let me follow up on it. I think that's a really good point. I mean I think guidelines are valuable as an aid, but we really need to personalize the care. I mean these sepsis patients, the sepsis response really is individualized based on your immunologic response. So treatment has to be individualized. I think the precision medicine for sepsis is not there yet, but we're in that direction, and the initial evidence of biomarkers I think are encouraging not only in terms of a diagnostic tool but also as prognostic indicators of what direction your patient's going to go.

Dr. Davis: And perhaps even the therapeutic drug driving process because your treatment of sepsis might be different to mine because of my host response. And I think if we took it at what's happening with COVID, we've seen markedly different presentations and markedly different people of the same disease.

Host: Yeah. And we're starting to appreciate that across the board, right. From cancers to autoimmune disorders. There may be a common denominator for some of these processes, but ultimately how the host responds is very personalized and different and it's going to require medicine to keep up with that. Right.

Dr. Davis: That's for sure. I think that a 10 to 15 years from now they're going to be saying what the hang were you doing?

Host: Yeah, listen. But isn't that the beauty of science and medicine? You got to get, things are constantly evolved. I mean, if anybody ever tells you they know the absolute answer, I'd move on. Right. I don't think anybody ever knows the absolute answer. Dr. Hassan, I do want to back up just for a second with you because you know, you were talking a lot about screening and data collection, communication. Any thoughts or advice about how a medical center can create a sepsis quality program and how they implement that and how do they assess it as well?

Dr. Hassan: Good question. So there's three ways that you can do implement a sepsis program. You can implement it with education only programs, which consists of lectures, meetings, various educational training materials. That's one. Number two, you can do a process intervention only program, which is aimed at decreasing the variability of care with things like predefined order sets, various specific screening tools, clinical decision support, that type of thing. Or number three, which is the best, is really a combination of both. And a really good sepsis implementation plan has both the educational component and the process intervention. And that's actually been shown to improve survival. It's been shown to improve bundle compliance. And it's also at the most recent SCCM meeting this past year shown to improve, there was an abstract that showed, improved compliant with the CMS Step one measures. Went from 53% to 81% by using both of those. And we haven't even talked about the CMS quality measures yet.

Host: Where are we going to go with all of this? Where are we going to go with all these guidelines and is there ever going to be a consensus in all this or is that asking too much, Dr. Hassan?

Dr. Hassan: I think the answer to this really is guidelines. As I said earlier, guidelines are valuable as an aid, but I would not follow guidelines as a treatment plan. Guidelines. They need to be personalized to your patient and because you, you need to address the guidelines that have been put out by the various associations and societies and whatnot, but they're a starting point and they're a pathway. They're not a calendar and so you need to see how your patient and their individualized responses both to their response to sepsis as well as to response to treatment with that. And I think hopefully the biomarkers will help with that. We don't have that yet, but precision medicine in terms of identifying what specific markers according to the individualized physiologic response of the patient is going to help us in terms of specific treatment for a specific patient, but that's the future that I see, but we're not there yet.

Host: Dr. Hassan, Dr. Davis, I think this podcast right here is a great starting point for us to have more conversations. There's just so much more that we could talk about. So Dr. Davis, I'm going to give you 30 seconds in summary, what do you want physicians, hospital staff, nurses to understand about a quality sepsis program?

Dr. Davis: I think that from my standpoint, it's driven by what Erkan said. Two things, education and data process collection process, and that drives it and use it, and use it to make changes as you go along. It's not cookbook medicine, it's process medicine that can be personalized and implemented appropriately.

Host: Nice. Good job, Dr. Hassan, your summary?

Dr. Hassan: I think it's getting everybody on the same page and getting everyone to decrease the variability of care. From the point they hit the ED door to the time that they go home and I think we need a comprehensive approach. Early identification, early intervention is going to be the key. The best way to get there is with a team approach to really address these patients.

Host: Doctors, thank you for joining me today. I'm Dr. Mike. Thanks for listening.