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Sepsis - Beyond the guidelines
1.3k Plays29 days ago
In a recent episode, Dr. Sergio Zanotti discussed the 2026 iteration of the Surviving Sepsis Guidelines. In this episode, the discussion continues, focusing on important aspects beyond clinical guidelines. He is joined by Dr. Andre Kalil, a physician specializing in critical care and infectious diseases. Dr. Kalil is a Professor in the Division of Infectious Diseases and Director of Transplant Infectious Diseases at the University of Nebraska Medical Center (UNMC). Dr. Kalil is a prolific author and has participated in several IDSA/SCCM Clinical Guidelines and has written extensively on critical care and infectious disease topics.
Additional resources:
Surviving sepsis campaign 2026 guidelines | Critical Matters
Sepsis. M Singer, et al. The Lancet 2026.
Books mentioned in this episode:
Curious: The Desire to Know and Why Your Life Depends on It. By Ian Leslie.
Recommended
Transcript
Introduction and Episode Overview
00:00:06
Speaker
Welcome to Critical Matters, a sound podcast covering a broad range of topics related to the practice of intensive care medicine. Sound provides comprehensive critical care programs to hospitals across the country.
00:00:19
Speaker
To learn more about our programs and career opportunities, visit www.soundphysicians.com. And now your host, Dr. Sergio Zanotti.
00:00:32
Speaker
Sepsis is the leading cause of mortality in hospitalized patients and affects millions of patients worldwide. In a recent episode of Critical Matters, we discussed the last version of surviving sepsis guidelines.
00:00:44
Speaker
In today's episode, we will discuss sepsis beyond
Introduction of Dr. Andre Khalil
00:00:47
Speaker
the guidelines. Our guest is Dr. Andre Khalil. a physician specializing in critical care and infectious disease. Dr. Khalil is a professor in the Division of Infectious Disease and Director of Transplant Infectious Disease at the University of Nebraska Medical Center.
00:01:02
Speaker
A renowned clinician, educator, and researcher, Dr. Khalil has received numerous distinctions, including the 2021 Scientist Laureate Award at the University of Nebraska Medical Center. Dr. Khalil is a prolific author and has participated in several IDSA SECM clinical guidelines and has written extensively on critical care and infectious disease topics.
00:01:22
Speaker
He recently co-authored a wonderful seminar on sepsis published in The Lancet.
Critique of Sepsis Syndrome Framework
00:01:27
Speaker
Andrei, welcome back to Critical Matters. Thanks so much, Sergei. Always, always a great pleasure to be with you.
00:01:34
Speaker
But we were discussing before the recording how it's important sometimes to dive a little bit deeper beyond guidelines into diseases and syndromes and also talking about the importance of recognizing where there's opportunity for improvement, recognizing some of the shortcomings of trials, of evidence, of guidelines, but ultimately really being focused on building positive momentum to care better for our patients. So I would like to start with the whole concept of the sepsis syndrome. A lot of people have criticized it as being a syndrome. From my perspective, it's inadequate in some respects, yet it seems that it's a framework that is still needed and helpful. What are your thoughts on this?
00:02:15
Speaker
Thank you for the question, Sergio. So, the you know, I mean, we we we have to be realistic. I mean, ah there is no medical syndrome in any field, that you know, critical care, infectious disease, oncology, yeah ah you know, at any field. that that That would be perfect, correct? I mean, it's it's the reason why we have syndromes is because... you know, we we are still lagging into understanding accurately the ah the, you know, kind of the precision that we need in order to sometimes to tackle some of this challenge. However,
00:02:49
Speaker
and the The reason why we utilize syndromes is because with the syndromes, we can narrow down the ah the possibilities that are really critical for us to you know have a proper decision making at the bedside. And through the syndrome, then we can kind of go further. and and and try to understand exactly what's happened with each one of our patients. So it's clearly far from ideal. ah Sepsis syndrome has many, many issues in terms of a lacking a specificity and and being overly sensitive and in many settings. but
00:03:27
Speaker
But the reality is that if we're going to take at face value the syndrome and not really try to transport that syndrome to your patient population, where you live, where you practice, then likely the syndrome is going to be even less useful. So correct so I think we have to understand the limitations of the syndrome. and utilize what can be of benefits to us and to our patients by utilizing this syndrome. So yeah, it is a flawed syndrome. It is a flawed definition like any syndrome. But without that you know without that definition, without at least the basic definition, our job would be way more complicated and likely would be much less beneficial to patients. So I think this is a good start, it's a good beginning. And I think through that, we're gonna talk a little more in the next 20, 30 minutes, and how can we go from that syndrome to make our you know our diagnostics and our therapeutic more accurate to our patients. And so it is it is something that we are evolving, we are changing, we're improving, and honestly, the sepsis syndrome, probably is going to be much changed, you know, five, 10 years from now, 20 years from now. And it's a good thing. It's a good thing because it means it's evolving and it's improving and um and and that's okay. So I think that's that's where we sit today. And and I'm sure that we're going to just keep improving.
Defining Sepsis in Practice
00:04:48
Speaker
Without going into details, into the multiple iterations of consensus guideline definitions, and from a practical standpoint, Andrรฉ, how do you define sepsis?
00:05:00
Speaker
From a practical standpoint, so we at this point, you know, based on the SEPSI-3 definition, it's, you know, these are patients patients that we have a suspicion of infection and we have a a a increasing or a worsening of organ failure in conjunction with the suspect with the suspicion of infection. like Sepsis 3 use the SOFA, some countries like UK use NEWS2, so different scores. So the bottom line is if you have somebody, and this is really important because nowadays in RICUs we deal with a lot of patients with chronic pre-existing conditions, chronic organ failure. So, you know, I mean, we you know we admit, you know, I mean, a large proportion of patients with chronic heart failure, chronic renal failure, chronic liver failure. And so this is a little different from like 20, 30 years ago in which we didn't have a lot of these patients didn't survive that long to make to the ICU. So we have, we have today because of the advances in medicine, we have patients surviving and with quality of life, and despite the fact they have chronic organ failure or chronic immune suppression, you know, survivor of, you know surviving post-cancer chemotherapy, transplant so forth. So these patients,
00:06:08
Speaker
actually will, ah yeah you know, they will have sometimes pre-existing organ failures. And this is important to mention because most of the sepsis definitions, including SOFA and use, they, yeah you know, they are based on ah organ dysfunction.
00:06:26
Speaker
and And so even though the organ dysfunction is is important, you have to take into account that, you know, what's the baseline organ dysfunction of these patients. And so let's say if you have somebody that lives with, you know, with a chronic cranial failure with a creatinine of 1.9, and the patients coming to you know to our ICU or to our ER with a suspicion of sepsis in which we we define you know a suspicion of infection with highly ah probable that the patient has a progressive organs function secondary to some immunos regulation. you want to see a organ dysfunction that is above the baseline. Let's say if the patient had a creatinine 1.9, definitely you want to see somebody that's now is going to show a creatinine of 2.5 or 2.8.
00:07:14
Speaker
Or if the patient had a, let's say, ah you know a chronic lung failure, and normally you know runs at home with, say let's say, a nasal cannula of two liters,
00:07:26
Speaker
and the patient now comes to your hospital and the patient has a, you know, has more hypoxia and requiring a non-invasive or or or some other types of respiratory support that is much more than a patient was in in their home. So these are the situations where I think that it's important for us to emphasize.
00:07:43
Speaker
The change from baseline can be changed from no organ dysfunction. It can be changed from somebody that had organ dysfunction. So this is critical because otherwise, We're going to be like fooling ourselves with patients that that we believe that they have organ dysfunction related to the infection, but actually organ dysfunction is just related to the baseline, you know, physiological state of the patient. So this is why it is very important for us to, you know, to kind of understand the definition definition in a way that we can put the patient perspective as well.
00:08:12
Speaker
Excellent. So to summarize, really, it's thinking of infection and the presence of either new or worsening organ failure. As intensivists, I always would argue that our expertise is in managing multi-organ failure. So this should be right down than our alley. In terms of epidemiology, Andre, any comments on the epidemiology at a worldwide and basis, but also specifically in the U.S.?
Global Sepsis Statistics and Challenges
00:08:40
Speaker
Yeah, so, you know, the data, you know, the data last few years keep coming and showing very clearly that we are dealing with close to 50 million cases a year, you know, in the planet. And the mortality, you know, something in the range of 12, 10 to 12 million people, you know, are dying from this. So the point is impressive how prevalent sepsis is all over the planet.
00:09:05
Speaker
What's interesting is that the, ah ah you know, when you look at least the data based on this large electronic, um ah you know, medical records, electronic databases, we tend to see sometimes studies showing a a increasing prevalence of sepsis in the US with decreasing mortality and in some of the low-middle income countries we tend to see more data showing a decreasing rate of sepsis with still with a very high mortality and so it's it's interesting how when you see this I think okay what's happening here this is a little weird you know i mean it's we are seeing these discrepancies here
00:09:48
Speaker
And, yeah you know, I think that most most of the discrepancies because the ah ah in the U.S. and in Canada and some of the Western European countries where we are now having a a much better resources and much better infrastructure to take care of these patients, we are meeting patients to the ICU that actually have a a higher risk of developing sepsis patients that are survivor from, you know, let's say from cancer chemotherapy, from transplants or or some other, you know, comorbidity or immune disease. And so it's not unusual in the electronic medical records to see sometimes a higher description of sepsis, even though these are just patients that actually have a chronic medical medical illnesses and pre-existing disorders. So it's in some ways, it seems to me that
00:10:35
Speaker
Most of the developed countries and the high income countries, they have a inflation of the rate, mostly related to the way that we're capturing this data. and And in part because of the high tech and the and the long survival of some patients with autoimmunocompromised or comorbidities. So it maybe it's mix of both.
00:10:57
Speaker
in the ah in the low middle income countries, we are lacking we are really lacking a lot of data. We really need more data. And I think this is a huge problem that we face all over the planet because the lack of data end up leading us to make assumptions. And ah and you know making assumptions about specific large regions and countries it gets very dicey and very dangerous. and For instance, you can have way more heterogeneity in a low, medium-income country in ICUs. You can go from ICU to the other in matter of just, you know, one mile and and and see massive differences of resources, of healthcare personnel in the ICU, technicians, nurses, and respiratory therapies, whatever. So the point is,
00:11:45
Speaker
We've got to be careful when you know we make these comparisons because part of the problem that we're facing today with the diversity of you know prevalence of sepsis and diversity of mortality in part is related to the challenge of collecting this data and in part is related to the incredible heterogeneity of a yeah resources and limitations that goes through different regions in different countries.
00:12:15
Speaker
Excellent.
Factors in Sepsis Progression
00:12:16
Speaker
In terms of why some patients with infections end up developing organ failure and sepsis and others don't, could you comment on the risk factors for this progression?
00:12:28
Speaker
Yeah, no, it's very important, Sergio. I think that the you know the it's this is probably one of the most ah challenging factors that we have today because you know we have we've developed a lot of you know really incredible technology in terms of trying to understand the pathophysiology of these patients. We are still you know still in the beginning of the learning curve, but I think we are starting to understand much better at the situation. so there are so There are several factors here that are are critical for us to understand who is going to progress to a more severe picture of, you know, seps and septic shock compared to who is not. So several factors. um
00:13:10
Speaker
The number one that i want to bring is, and and i I brought this to point, a short editorial that I wrote with a couple of colleagues of mine at Ford Intensive Care Medicine just last year. We we titled as a sub-phenotypes and phenotypes as a way to reduce sepsis heterogeneity, hyper hope that the editorial was trying to understand, you know, who are, you know, how can we define which patients are really at at higher or lower risk of developing and progressing this dysregulated kind of sepsis response.
00:13:44
Speaker
So the first thing that we comment, and I'll bring this, and we will comment also in this sepsis paper in Lancet, is, you know, the microbial heterogeneity, correct? So the microbe, it's going to vary about the type. Let's say if you have a sepsis from Staph aureus, likely going to have a different approach compared to a sepsis from, let's say, E. coli.
00:14:05
Speaker
Why? Because Staph aureus, it is a bacteria that tends to have a more metastatic infection tends to have more organ invasion than let's say equalize. So there's something particular about the bacteria and so that the host will matter but the bacteria has ah very very intrinsic properties that you have to put in perspective.
00:14:24
Speaker
The second thing on on on the microbe perspective is the burden, Serge. And this is something that I'm i'm dreaming of is that we yeah that we can develop techniques in which we can actually measure and the burden of the infection at the diagnostic moment. So, you know, nowadays you have, let's say you do, you know, you do like, say, PCRs or we do blood cultures, And and usually it's just you know a qualitative process, correct? So you just say, okay, you have, you know you have let's say, Eucalysepsis, Eclipsella sepsis, and that's what you know, correct? So it this is not enough for us. you know For us, being the bedside in the ICU,
00:15:06
Speaker
we need to know the burden of this infection because a patient that has, let's say, you know, 100 million copies of Klebsiella pneumonia in the blood will have a different progression of the natural history history of sepsis compared to a patient that has 100,000 copies. It's just this simple fact that the burden of the infection will ah will, you know, will change the host immune response because when you have such a high burden of infection, becomes way more difficult for our immune system to deal with that, you know, impressive burden. And and that means we're going to become more vulnerable to to develop a and progress to septic shock. And I'll give an example. If you're a 25-year-old with... let's say, with a 10 million copies of Klebsia in your blood, you're going to have a different answer compared to somebody that is a 75-year-old with you know chronic heart failure, hypertension, and chronic renal failure. Because, again, it's simply the fact that if the host is dealing with the same amount of bugs, but the host already has some vulnerable immune ah dysfunction, and this host is gonna be way more vulnerable to progress progress septic shock than somebody that does not have the same comorbidities. So the key point here is that the bacteria matters, the amount of bacteria matters,
00:16:28
Speaker
ah The host, ah as we just talked about, the host is going to be also critical to define the progression of sepsis. So if you have a host that is young, normally it's going to have a more a robust immune response. It's normal and it's expected in somebody that is much older because we we we have something called immunosenticense. Immunosenticense is...
00:16:50
Speaker
you know, the aging of our immune system. Every day that we wake up, our immune system is a little bit weaker. And, you know, and that's that's progressive for the rest of our lives. There is no way back. And so the point is, the older we are, the more vulnerable we are to to have progression of infection to sepsis and septic shock.
00:17:09
Speaker
If you have comorbidities that affect your immune system, and remember, you know you can have one organ failure. yeah You don't need to have two or three or four. You can have simply, I mean, let's make that very simple. You have one organ failure. All your or yeah all the auto organs are perfect, let's say, even though this is not unusual because most people have some kind of some degree of multi-organ failure if they have one organ failure. But let's assume that you have specifically one organ failure. Remember, for every organ failure that you have, you have a very defective immune system in that organ. Because sometimes we forget that each one of our organs have actually different immune regulation. So we we think about immune system as a whole body immune system, but this is just one part of the of the scenario here, because you have to think that the kidneys and the hearts and the lungs, they have a very distinct immune defense, and and they will be affected different from other organs.
00:18:02
Speaker
So this is the host perspective. The last thing i want to talk about the host search, it's really important because it's a huge part of my population, my hospital, my ICU is the immunocompromised population. and These patients that already have history of, let's say, solid organ transplants, stem cell, you know cancer chemotherapy, these patients will have way less manifestations of sepsis that normally we'd expect. They're going to progress in a much more silent way. I'll give an example.
00:18:31
Speaker
We had a couple of studies done in the past in our University of Nebraska, in which we are trying to understand just kind of the clinical presentation of these patients and turn out that most of these patients don't have any fever. They don't have even leukocytosis when they're immune compromised. So if you don't have leukocytosis, you don't have fever, likely the patient himself or herself is not gonna be even aware that infection is progressing until they come to the hospital and then they get into the ER and they're in shock. Now we get called to see the patient the ER and the patient literally in shock. You do a CBC, the white count is 6,000, temperature is normal.
00:19:07
Speaker
So, you know, that's kind of go against, you know, kind of the, you know, the traditional teaching that you should have some signs of infection. A lot of times the signs are not there. So that means you have to be way careful aware and they have a much lower threshold to diagnose seps in these patients. and And again, these patients will become more vulnerable, not only because they're going to have the lack of diagnosis in the early process, but also because they will not be able to stop even a burden of infection that's not that high, correct? So you don't need a huge burden of infection. You can have literally a you know, a quote unquote mild, you know, urinary tract infection. end up in the ICU with depressors, correct? so So the point is, this is not even a high-burden infection, but if you're that immune compromised, you have to put in perspective that there is no mild. So a mild UTI in 35-year-old woman be a you know a disaster for woman that has had, let's say, you know, a stem cell transplant just a few months ago. So the point is, when you look at this patient's at the bedside, you have to put in perspective the type of infection, the type of bacteria, the burden of the infection, and in the host, and the host understanding at that moment, who is your host? Because once you connect the host with the the source of the infection, you're gonna be able to approach this patient in a much more individualized, in a much more accurate way. so i joke I joke with my residents and my fellows that you know we are one of the rare, maybe the only specialist that actually have to treat two organisms at the same time. We have to treat the microorganism and the macroorganism, you know basically the human organism and the microbial organism. Because a lot of other you know specialists, they treat one organ, let's say a cardiologist treat the heart, your nephrologist treat the kidney.
00:20:59
Speaker
But if you're working in the ICU with all these patients, you end up having to actually tackle two different organisms at the same time. I like that. In terms of pathophysiology, Andre, we could obviously spend a long time talking about this and going deep.
Sepsis Pathophysiology
00:21:13
Speaker
And you did mention already some of the impact of the host and the the immune or the dysregulated immune response and its impact on different organs. Any other important current and mechanisms, understanding of mechanisms that you want to mention?
00:21:30
Speaker
Yeah. So, Serge, I think that we are we are moving slowly towards pathophysiology uh really trying to kind of sub phenotype or endotype there's all kinds of different terms and if you ask people that really do a lot of the bench they're going to have different definitions for this so we we as clinicians and clinician scientists we we you know we tend sometimes simplify these things but the reality is you know sub phenotype and typing are ways to really it basically brings some kind of biological signatures that will help us to be more accurate treating our patients. So I'll give an example of some that you've lived through and I lived through throughout these years. So sometimes you're going have, let's say, patients with a septic shock with a massive coagulation disturbance. They're going to have, you know, out of the blue, going have, they're going to be very thromocytopenic with a high PT and high INR. And if you can measure in your hospital, you can look for antithermin 3 or protein C, they're going to be very low. So these patients,
00:22:26
Speaker
these patients are going to be like having a massive coagulation disturbances related to the sepsis. And this, again, these patients are probably going to be 20, 30% of the patients that we see on regular basis. But if you identify these patients early, likely we're going to tackle the pathophysiology of the coagulation as part of the immune defense, correct? So coagulation is part how we defend ourselves against these bugs, but if the coagulation gets completely dysregulated part of our immune dysregulation, then we're gonna have potentially, we're gonna have um you know alternatives, treatment alternatives that's gonna be really focused on bringing a coagulation to a more regulated process. The same way,
00:23:08
Speaker
surgeon Now we know we have phenotypes, subphenotypes, a study published in Lancet just recently, i think in March, April of this year, showing that maybe there a specific biomarkers at the bedside that can help us to understand which patients could benefit from immune modulation. this this I think this study was in Lancet Reservatory Medicine. They talked about potentially using um um a procalcitonin, interleukin-6, and S3 biomarkers that were, you know, were predictive of progressing sepsis and potentially responding to immune modulation. so I think that, again, these are going to be trying to understand which which of these patients have a some degree of inflammatory dysregulation that can be amenable and can be treatable treat, as we say, you know something that can be treated with a very accurate you know tools.
00:24:08
Speaker
So I think that the way we are seeing today, Serge, is we are learning more about both the inflammatory and the coagulation cascades, and then some people are doing some work in metabolomics and proteomics. I think my hope is that understanding that pathophysiology the way we understand it today we're gonna be able to develop ah treatments that are gonna be very accurate for this specific regulations because you know the old fashioned approach of you know giving steroids to everyone, giving whatever you have in your hands to everyone, likely that you know yeah we're gonna cause more damage than than than good because we we saw that. yeah yeah mean you know I think you remember, this is 23 years ago when when you know I remember when I was in medical school, you know people ah You know, people that had the label of sepsis and they still literally were getting one two grams of sulomadrin. And they're not even in shock. And and that was that was the standard of care for many, many years, correct? so and And because, you know, that was that was the physiology of the day. That was what people thought. That was the physiology of the day, correct? So everyone is inflamed. Everyone should get high-dose steroids.
00:25:14
Speaker
and Another 10 years passed by with the randomized clinical trials to figure out that actually this high-dose solomadro or any high-dose steroids were being harmed for increased mortality. And that was banned from most of the ICUs in the world until the the early 2000 with the French studies in which they they start to look for low-dose steroids to see if that potentially in patients with septic shock, and not only patients with sepsis, and they start to kind of change and the gear in terms of being a little more you know a little more precise and and trying to and understand which patients potentially could have benefits from immunomodulation. But the point is, you know going for with one tool for everyone, we already learned it doesn't work. We already learned that can be harmful. And so you know from here you forward, we're going to have to really be way more accurate, way more specific in understanding the pathophysiology to actually develop new treatments.
00:26:10
Speaker
Perfect. and And obviously this also, when you look in in hindsight, right, explains why applying these broad immunosuppressant or immunomodulatory therapies doesn't work in a large population of very heterogeneous, like you said, phenotypes and sub-phenotypes.
Role of Biomarkers in Diagnosis
00:26:28
Speaker
and And ultimately, like you said, moving towards understanding what's going on with each individual patient and trying to use a modulation of of those responses might be the the way of the future. But let's ah let's go back to the bedside and talk about some of the clinical interventions that we have to implement today to our patients.
00:26:48
Speaker
And as I mentioned, we had a previous episode with a lot of the guidelines, but I want to get a little bit more of the nuanced interpretation from your perspective, Andrade. And let's start with diagnosis.
00:27:00
Speaker
and What's the role of biomarkers and what is ah the current state of the art for diagnosis from your perspective? Yeah, so, Sergei, this is so critical. i mean, without without good diagnosis, you know it's you know, it's very hard for us to do what we need to do to improve, ah you know, the survival of our patients. It's really important. And, and you know, I'll give an example that i was and was in Europe just few months ago in a meeting, and and I was quite surprised to learn that actually there are many many, many countries, and this is both in West and Eastern Europe, in which people
00:27:37
Speaker
the micro lab of these hospitals is outsourced in order to save costs. And we see that little bit here in the US in a very country, very community, very small areas in the countryside as well, because they don't have the means of a micro lab. I get it, you're in a small place, in a village or in a small city with a few thousand people, they're going to have to outsource some of these tests. I still don't understand, but I was very surprised to see that many of the European countries outsourcing even in places that have, you know, high population density, you know, in big cities. So what's the problem with this? The problem with this is, Sergio, that if you're going to send a blood culture to, you know, you suspect sepsis in your ER, in your ICU, and you send a blood cloture, the blood cloture is gonna have to literally be in a bus or an airplane to another place. Right there, you know, even if you have the proper bottles and the proper collection, you everything correct. it's going to take hours for that sample to arrive in a lab, to be processed in the lab, because the lab is outside your hospital.
00:28:49
Speaker
and And what I've noticed talking to people is that, and I've seen that in any place, including here in South America and Europe, is that the report of this outsourced micro lab is going to take much longer than if you had a lab in your in your hospital. So you say, well, what's what's the big deal? Well, the big deal is that people are having way longer time to have a a result from a blood cloture. It doesn't mean it could be sputum cloture, it could be, you know, it could be a urinary cloture, whatever it is, it's simple.
00:29:20
Speaker
So the time that's taking is much longer. Second of all, what I've also been very impressed when I go out and and talk about sepsis and and and and in utilization of, you know, rapid utilization of antibiotics is that that the the time to blood culture positivity is not being reported in a lot of these outsourced labs. They just don't report. let's say you have a patient that, let's say have a patient in ICU today with multiple lines in septic shock,
00:29:53
Speaker
very ill, and you you don't know if the patient is is is septic because of a line infection or because of something else. You collect blood cultures from the lines, you collect blood cultures from peripheral vein, as we actually indicate in the SCC, MADSA, fever and and and guide fever guidelines. that We already had a a podcast together before about this. Very important to know the time to positivity because that helps you to understand if it is it is a situation in which the line has to be removed or not.
00:30:22
Speaker
You're not going to have it. You're not going to have They're going to just report whenever the culture turns positive. You're not to have People don't have even that that kind of very basic, simple thing that you do if you had a micro-leadment hospital. So I think we have to you know we have to we have to emphasize, Sergio, that the fundamentals didn't change. The fundamentals are... you need a you need a rapid and precise diagnosis of the infection. This is never gonna change.
00:30:50
Speaker
This is never ever gonna change. And I bring that to every meeting I talk about. do You have to make the efforts to have a micro lab that's gonna be responsive to you. If it is a micro lab in your hostel, if it is outsourced, you have to have the access to, a quick access to the results and you have to understand how long it's taking for these cultures to grow.
00:31:11
Speaker
So that's the first thing. and And we are talking about burden of infection, Sergeant. I mean, you know, and yeah yeah i'm just last week I had a patient that literally and you grew intrabacter in five hours after collecting blood cloture in the yard before even a patient hit the ICU.
00:31:25
Speaker
Five hours was passed for the patient. You could clearly, yeah you know, went fast septic shock. I mean, it's that, you know, that this is a situation where the patient had a very high burden of infection that, you know, it made the entire team, the ICU team, the yard team to be much more aggressive and responsive to the situation than somebody that, you know, maybe is going to take 24 hours to grow something because of a low bacterial burden. So all these things are very important. Now, talking about biomarkers, because, you know, we could talk forever, but I'll try to just in a couple of minutes bring a little bit of what, you know what we have today. So today is still pretty much, I would say that, yeah you know, the the things that we have in our in arsenal, most of the places, not every place, but most of the places are going to be,
00:32:07
Speaker
white blood count, you know, with a differential neutrophiles, bands and so forth and playlets. So a CBC and that's still very important, still useful. Not alone doing anything might be important as a complement. You're going to have a lactate as you know, as is indicated by the Survive Caps guideline. But remember,
00:32:28
Speaker
Remember, very important, lactate and it you know it can be elevated for many, many reasons other than hyperperfusion or other than shock. So if you do not really try to understand the potential reasons for lactate acidosis, you may end up treating hyperperfusion when the patient does not have hyperperfusion, right? So this is, and and potentially you're going cause harm to the patient by giving more fluids and more peresters. So lactate alone is not a great tool. Lactate has to be in the context of what is the clinical situation and what are the potential reasons for having lactate elevation, other than hyperperfusion. Very, very important. A third of the patients can have lactate elevation without shock and you know, a third of the patients can have septic shock without any lactate elevation. You could have, you can have actually a no lactate elevation and being in severe septic shock from infection. So again,
00:33:21
Speaker
it is alone is not gonna do much for you. And then the other two biomarkers that are used differently in different countries, the C-reactive protein and the procalcitonin. Both are, you know, if they are normal when you're seeing the patient at the bedside, they're useless. They don't do anything for you because they can be normal in patients with a severe infection and even severe septic shock. So the first CRP, the first procal that you're gonna do It can simply yeah you know can simply basically reveal that the marker did not have enough time to elevate, to be to a level where it can you know be useful at the bedside.
00:34:00
Speaker
What these biomarkers can help, the same with lactates, the same with Procal, the same with the CRP, is that you measure serially, correct? So you want to you you want to make ah you want to make several measurements of these biomarkers to try to understand the trend of these biomarkers.
00:34:15
Speaker
If you see a lactate going up, up and up without stopping, you're going to be, you know, it's going to be much more informative than a lactate that does not change at all. The same with the Procal, the same with the CRP. So understanding the kinetics of this biomarkers and how the kinetics really inform you at the bedside it's critical. So I think the lesson of the biomarkers today is that they they have to really be, you know, they have to be in the context of the situation that you are for each one of these patients. If you simplify the biomarkers by just calling, you know, norm and abnormal, ah likely youre you're going to miss the diagnosis or you're going to be treating things that actually are non-infection that are elevating some of these biomarkers and that require different treatments. So biomarkers, even if we develop, let's say, surgeon, very great tools, you know very specific biological signatures, different tools. Remember, biology is is overlaps a lot. So you can have IL-6 elevation. six elevation it can have ah you know all these biomarkers cytokine elevation for reasons that there are infection as well. So even when we even when we reach the points to have some of these subphenotypes, phenotypes at a bedside, what I think is going to be marvelous,
00:35:30
Speaker
Still, that's going to require us clinicians to actually put in the context of each one of our patients. If we don't do that, likely we're not going to make the progress that we should.
00:35:41
Speaker
Perfect.
Antibiotic Use in Sepsis Treatment
00:35:42
Speaker
As we move into management, and I want to focus on antibiotics. And really what I would like to hear, Andre, is your your approach to ah rational antibiotic use. And the two things that I'm always trying to balance is how broad and how quick.
00:36:03
Speaker
And based on what do you make those decisions? So, you know, Serge, the thing that... and and got me really, it kind of changed my mind dramatically about the use of antibiotics, it was in 2015.
00:36:18
Speaker
i know that sounds like too long ago when we talk about these years. 2015, we published a study in which and me and a couple of my ICU colleagues here in a stat station tried to understand the differences between um early goal therapy, ah the difference between observational studies and RCTs because in 2015, it was the year just a year or two after ARRIs and the process trials were were published. And ah and and and in and the promise were three RCTs that basically did not show benefits of early goal therapy. So the the goal of this study was just trying to understand what was happening with early goal in the 2000s and why the observational studies were so positive ah from the usual, the the first 2001, the many re-reviewed study. And and the the three RCTs done 10 years later were flat negative. And so so it was much more a... a scientific curiosity, you know, we're trying to understand what was different. So we dissect each one of the studies, the RCTs, the artificial studies, and try to understand the hemodynamics, the amount of fluids, the the the amount of hypoxia, the, you know, and the response to the fluids and immunitarial pressure, the whole thing, right? So hemodynamics and antibiotics, we look for everything, blood transfusion, vasopressors.
00:37:46
Speaker
So With, you know, with literally with a, you know, over 10,000 patients looking to all this, we we found something that was a complete surprise that the observation studies that had the the usual, the pre and post. So in my ICU, before I start early go and after early go, the, you know, survival was improved, but the RCTs didn't improve. We found that the only thing that justified a difference between observation studies and RCT was timed antibiotics.
00:38:15
Speaker
So in the observation studies, the time to initiation of antibiotics, it was significantly shorter, faster when they, you know, they provide the bundle, the early goal bundle. So compared to before when the ICU didn't have that. And in the RCTs, the time and to initiation of antibiotics was identical between control and and the early goal and bundle arms. So in the RCTs, they didn't show mortality difference because timed antibiotics was identical. In the observation studies, it showed improved survival with the ah the early goals simply because the antibiotics were given early. So that that to me
00:38:53
Speaker
It was a shift change for me in 2015 because I realized, you know, as an infectious disease and a critical care doc, I always believed antibiotics were super important.
00:39:05
Speaker
But after 2015, I realized that they are more than super important. and They are hyper, uber important. So it's really impressive. So, ah and what we learned in the last 10 years, Sergio, is that actually, you know, we...
00:39:21
Speaker
The speed is critical. The spectrum is going to be really based on where you live. So if you live, I'll give an example. great I'll give you an example. very pre Last week I had a patient that had a infection. a Basically we had a rapid diagnosis, the culture grew fast, the we had the PCR of the culture.
00:39:43
Speaker
and and and And we had a suspicion that this patient had a specific microorganism, a specific bacteria that based on our University of Nebraska antibiogram, it is a bug that normally tends to be resistant to the usual antibiotics that you use for ah for the empirical forceps and septic shock. So with that, with knowing that bug and knowing the antibiogram of my hospital, in my ICUs, I was able to say, you know what, I'm going to have to be broader than usual. I'm going to have to be more aggressive than usual because because if if it is the bug that normally we see at my hospital, at my ICU, I may end up missing the treatment if I just use the standard antibiotics that normally use and was the right decision to do because it turns out that the bug that grew was a little more resistant than we expected based on the antibiogram. So
00:40:39
Speaker
Why I'm saying that? I'm saying that, Sergei, because it you know I really believe that being broad, when you have understanding of your you know your ah biome in your hospital, in your ICU, you have a nice understanding of your ecology, it makes much more sense. If you live in an area with no resistance to you know a lot of these antibiotics, like let's say some Nordic countries have very low resistance to let's say pneumococcus, they tend to be sensitive to penicillin. A lot of there, if you're going to ICU in some of the Nordic countries, they're treating the Mococcal sepsis with penicillin.
00:41:12
Speaker
If you come to Nebraska, if you come to the US, you can't. And mostly, you know, because because if somebody is that ill, septic shock Mococcal, chances are that penicillin is not gonna cut the deal because they're gonna be resistant. So we live in an area in which we have a different ecology. So understanding your ecology is gonna make you much more accurate about how aggressive we're be in in the broad, in the spectrum of antibiotics.
00:41:36
Speaker
But the initiation to me is critical for every hour In the same study that I mentioned to you in 2015, we noticed that for every hour that we delay antibiotics in patient septic shock, the mortality was pretty much going up in in terms of relative terms, in terms of 18%, was very similar to the Kumari study done in 2006 in Canada. So again, different studies, different populations, 10 years later,
00:42:00
Speaker
Same results. So the bottom line is septic shock and in which you have a high suspicion of infection. For every hour that you delay your antibiotics, you're going to really increase significantly mortality of your patients. So it's really important.
00:42:14
Speaker
When it comes to severe sepsis, well, we don't call more severe sepsis. When it comes sepsis without shock, and this is what, you know, the guidelines, the surviving sepsis, what I agree with the guidelines is that You know, you have a little more time for diagnosis. You have a little more time to just, ah you know, kind of be aggressive with the antibiotic because you you don't know even if the patient has infection. So go ahead and, you know, try to, you know, try to get, you know some tests that going to help you to understand. Let's say if you suspect maybe the patient has pulmonary embolism or the patient has some other non-infectious disease, do some other tests, do some, do like an angiogram, whatever you believe that's going to be important.
00:42:49
Speaker
before you you know you just give like tons of antibiotics to a patient. Because remember, giving antibiotics to the patient without having a proper diagnosis has you know two major harmful effects. One is that you may miss the diagnosis that actually could kill the patient. Let's say if the patient has a pulmonary embolism, may treat a pneumonia, the patient is not, i me um you know, the patient likely is not going to survive, is not going to do well if you give antibiotics. Antibiotics are not going to treat pulmonary embolism, right? Second of all, the antibiotics have side effects. Major side effects can be an issue for a patient, especially if the patient is critically ill. So you may give side effects and you may not treat the actual etiology of the the shock of the patient. So that's why it's very important if if the patient is not critically ill, it's not that critically we have a little time, and the patient is not in shock yet, and you have you're not clear if this patient has infection.
00:43:40
Speaker
you can definitely spend another two or three hours, four hours trying to understand more if it is a situation in which you should use empirical antibiotics or not. So I think that's a reasonable recommendation from the guidelines, and I do agree that in practice.
00:43:53
Speaker
And and ah and as ah as a rule of thumb for our audience, the way I interpret all this is beyond what the guidelines say and some of the arguments and pushback on on on time. The reality is that the sicker your patient is, the quicker you have to intervene with antibiotics.
00:44:10
Speaker
And the lower your certainty of having an infection is going to be accepted. On the other hand, when you start the antibiotics, right, again, ah Think about the sort of and source of infection. Where do you think the infection is from?
00:44:24
Speaker
Think about the individual patient, like you mentioned earlier, the host characteristics, and understand your antibiogram. And I do believe that's a point worth emphasizing, Andre, because...
00:44:35
Speaker
With your ID hat, you live and die by the antibiogram. But I would argue that a lot of our critical care colleagues, including myself, are not as familiar or don't use their antibiograms to the full of its potential at their ICUs.
00:44:50
Speaker
yeah I agree 100% with you, Serge. I mean, it's you're making a very good point. I think that, yeah you know, I think it is something that's missing a lot of ICUs is the ah more objective understanding of the utilization of antibiogram. So what we do here, we have every six months, we update our antibiogram here, and we we have little pocket, you know, like little pocket things, just literally you just put in your lab coat and you carry with you 24-7. It's just a very small little thing in which you just open, and you see the you see the bug and you see the ah the antibacterial in front of you. So that stuff to me, it's marvelous. And and i mean up to me, it's something that should be done in every single ICU, in every single place in this planet. But I know we are far from reaching that, out but I think, you know, the fact that we're still not there doesn't mean that you shouldn't be there. So I think we should keep aiming to to have this more widespread.
00:45:45
Speaker
Excellent. as we As we move forward and and try to close, Andre, we're not going to talk about hemodynamic support.
Importance of Timely Source Control
00:45:53
Speaker
That's, I think, a story for another day, but I really wanted to hit on the antibiotic discussion.
00:45:59
Speaker
Any comments on source control? Yeah, so, Serge, I'm so i'm glad to be brought this up, Serge, because the you know sometimes we get so focused on antibiotics and ah and you know and and we we really cannot forget the source control because the source control means it's a great way for you to understand the burden of the infection, correct? So let's say if you have somebody with a large intra-abdominal abscess,
00:46:27
Speaker
ah as a likely source of the sepsis or the septic shock. You can give all antibiotics in the world, you can give the broadest and the fastest antibiotics in the world, all you're gonna do is potentially minimize the spread of the infection, but you're not gonna be able to eradicate the infection, correct? So you have to drain that abscess because most antibiotics are gonna have a very hard time to reach levels inside the abscess that are gonna be able to eliminate that infection.
00:46:57
Speaker
So there are plenty of studies showing today, and I'd say in the last 10 years, there plenty of studies showing that the adequate and and the timely control of the source impacts in the survival of our patients with sepsis and septic shock. so The way I try always to think is, okay, you know, i'm I'm being pretty smart about choosing the antibiotics and and and timing the antibiotics, and I have to be as smart as controlling the source. If the source requires some kind of device removal, line me I'll give an example. I remember like today, Sergei, it was about a year ago. it was Saturday night. It was 10 p.m.
00:47:39
Speaker
When I got called to see a patient on the floor that had staphores, bacteremia, and the patient was already in two vasopressors who have been transferred to the ICU, and the patient had a dialysis catheter. It was Saturday, 10 p.m. It was a permanent catheter, and let me tell i you, know I said, you know we're going to have to remove this catheter. And because the patient was was a young patient, septic shock, very ill,
00:48:02
Speaker
And I remember like today, at the moment we got that catheter out, it was, you could count, was a linear progression of decreasing vasopressors, decreasing fluids. By the morning, Sunday morning, she was off everything. and And so, you know, these things are dramatic because this is what it is. It was a patient that really needed a source control. If that line was not removed on Saturday night, you know, it's very possible it shouldn't survive through the Sunday.
00:48:28
Speaker
the burden of the infection was too high. So absolutely with you, Serge, I'm glad you brought this up because i think source control has to be at the same level of choice of antibiotics when it comes to controlling sepsis and septic shock.
Recommended Reading: 'Curious' by Ian Leslie
00:48:42
Speaker
Excellent. Well, Andre, you've been on the on the podcast before. And as we close, you know that we like to ask a couple of questions unrelated to the clinical topic. Obviously, there's a lot more we can talk about sepsis. And we definitely will have you back on the podcast to talk about this and another other topics. But I would like to ask you about books. We talked about books last time. But have there been any other books that you've read recently that have an impact on you?
00:49:07
Speaker
um yeah Yeah, it's it's I'll tell something, you know, interesting. ah Usually, you know, I try to always think about reading new books. But a few weeks ago, I decided to be, you know what you know, when you go through your, you know, your little library home and you start to look for, it you know, just things, you know, just to change a little bit gears and I found an old book. I'm not sure how old it is, but I actually, I brought it because I thought it was fascinating. I think was published in, me see, give you the date, Sergio. It was published in
00:49:41
Speaker
in 2014. Interesting. um i decided I decided to reread this book. It's a book called Curious. um And the title is Curious. And it says, The Desire to Know and Why Your Future Depends on It.
00:49:55
Speaker
And the author is called young Ian Leslie. I-A-N Leslie, L-E-S-L-I-E. It's a fascinating book. I'm i'm rereading. I'm i'm just ah halfway through again. And I read, i read you know, about 11 years ago.
00:50:09
Speaker
And I'm going to read just, if you don't mind, just for, you know, 30 seconds, I'm going to read a yeah couple of sentences from the book because it illustrates the beauty of of what the book tries to say. Perfect. yeah It says...
00:50:25
Speaker
yeah So it says the the attraction to every you know this attraction to everything novel is what the scientists we studied call Diversive Curiosity.
00:50:36
Speaker
Diversive curiosity is essential to exploring mind. You know, like, ah you know, when you get, you know, you see headlines and tweets and blog posts and apps and new things and news. And, you know, it's all these flashy things. Everything is, you know, around us. And again, this this book is 11 years old. I mean, today we have way more, you know, um kind of a diverse ways to to get to get to know things. So, diversive curiosity is essential to an exploring mind.
00:51:06
Speaker
It opens our eyes to new and undiscovered, encouraging us to seek out new experiences and meet new people. But unless it's allowed to deepen and mature, it can become a futile waste of energy and time, dragging us from one object to have attention to another without reaping insight from any.
00:51:27
Speaker
Unfettered curiosity is wonderful. Unchanneled curiosity is not. When diversity curiosity is entrained, When it's transformed into a quest for knowledge and understanding, it nourishes This deeper, more disciplined and effortful type of curiosity is called curiosity.
00:51:49
Speaker
epistemic curiosity. And it is it is this that I want to bring to you, Serge, because epistemic curiosity is that kind of deep, that deepened curiosity that we all, you know, we all we all just just crave to know more, to learn more, to you know, it's kind of when you talk to each other, to know about each other when we talk to our patients, when we read a book, when we try to understand in the pathophysiology of the disease, All these things that just triggered this great feeling on us of of earning, of of learning, of of being even more curious because you just read something that triggers something so exciting to you. So that's why I'm bringing to you. I think this is this is how we can be better clinicians, how we can we be better scientists is is just, you know, being curious is is a huge, huge deal. And I do praise that. And that's why I went back and I'm rereading this book.
00:52:45
Speaker
I love it. And i really, in today's age where everything seems to be soundbites, TikToks and posts, I always say that having a broad curiosity obviously is important, but also remind ourselves that going deep sometimes is extremely valuable as well. And I think, Andre, this is a great reflection.
00:53:06
Speaker
I was going to ask you about what would you want to leave our audience, but I think this is perfect and a perfect place to stop. I really appreciate your time, your expertise. And like I said earlier, I look forward to having you back on the podcast.
00:53:21
Speaker
Thanks so much for invitation, Sergio. It was a pleasure always talking to you. i learned a lot you through our conversation as well. And good luck with everything. Thank you. Thank you for listening to Critical Matters, a sound podcast.
00:53:35
Speaker
Make sure to subscribe to Critical Matters on Apple or Google Podcasts and share with your network. Sound's transforming the way critical care is provided in hospitals across the country.
00:53:45
Speaker
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