This Podcast Will Kill You - Ep 107 Sepsis: It's a mess

Episode Date: October 11, 2022

Over the years of the podcast, we have often struggled with questions of why: why pathogens act the way they do, why certain people get sick while others don’t, or why we know little about some diseases. This episode is no exception - sepsis certainly inspires many “whys”. But for perhaps the first time on the pod, we find ourselves grappling not only with “why?” but also with “what?”. What, indeed, is sepsis? Ask a dozen doctors and you may get a dozen different answers. Our first goal for this episode is to sift through the various definitions of sepsis and what we know about its pathology to get a firm handle on this deadly consequence of infection. We then turn our sights to a thrilling period of sepsis history - Joseph Lister and his carbolic acid spray - before attempting to address the status of sepsis around the world today. By the end of the episode, your picture of sepsis may not be crystal clear, but hopefully the edges are a little less blurry.And helping us to de-blur the edges of sepsis is the wonderful Katy Grainger, leading sepsis and amputee advocate and on the Board of Directors of Sepsis Alliance, who shares with us her harrowing sepsis experience. You can learn more about Katy’s story and advocacy work by following her on instagram (@katysepsisamputee), TikTok (@katysepsisamputee), Facebook, or by checking out www.sepsis.org. See omnystudio.com/listener for privacy information.

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You're listening to a podcast. So you're doing something else too, like maybe scrolling home listings on Redfin, saving places you like without thinking you'll get them. Because that's what house hunting has become. But Redfin isn't built for endless browsing. It's built to help you find and own a home. home. Redfin agents close twice as many deals as other agents, which means when you find a place you love, you've got a real shot at getting it. Redfin helps turn saved listings into real addresses. Get started at redfin.com. Own the dream. Hi, my name is Katie Granger, and four years ago this

month, I lost seven of my fingertips and both of my lower legs to sepsis. One thing that's interesting about my story is that the reason that it got so severe with me, I actually ended up in septic shock, is because I did not know the signs and symptoms. So when I tell my story, I can't stop myself from kind of highlighting where I made some mistakes. So in September of 2018, I was living in Hawaii with my husband. We were new empty nesters. And I had just gone to visit my kids in California for a week. And my husband had taken that opportunity to go on a fishing trip to very remote Idaho. So I went down to California, hung out with my kids, and then it was time to return back to Hawaii. I got on an airplane, flew home, and when I got

to the airport, this is when I remember noticing that I had this bump on my finger and it was oozing. It was kind of pink, and it had clear fluid coming out of it. So it looked different than anything I'd seen before. So I was on my way home. My house is actually an hour from the airport. It's also an hour from the hospital, which is going to be relevant later on. So I did decide to go by the emergency clinic. When I got there, I showed them the cut and they agreed that it did look infected and looked like it could possibly be MRSA. They took a little swab of it and said, basically, they'd call me in a few days if anything grew out of it. So they gave me a prescription for antibiotics and they said to start taking them if it got worse over the weekend. At the emergency

clinic, when they checked my vital signs, everything was great. So they didn't have any indication that I had subsist at this point. And I really didn't. I just had an infection. So on Saturday morning, I woke up. I hopped in the shower. It was warm there in Hawaii. I was, I was was kind of warm, but I never was registering a fever. So I didn't think there was anything wrong. I did notice that the infection on my finger was getting a little worse, so I went ahead and took an antibiotic. Well, soon thereafter, I threw up. But I just thought it was because I'd taken an antibiotic on an empty stomach, and I wrote it off. But I ended up sleeping through the afternoon and sleeping through the evening. And sometime in the middle of the night, I got up and I probably went

into the bathroom, which is two steps up for my bedroom. And what we think may have happened is that I maybe stood up quickly and low blood pressure in my body caused me to pass out. But what the result was is that I broke my left foot, I sprayed my right ankle, and I had just a mark on my knee where I'd fallen on the floor. So this is a sign for me of mental decline because instead of calling for help like a normal person would, I crawled back in bed. So the next morning was Sunday and I woke up at sunrise, like at the crack of dawn. I could hear the roosters outside. It was still dark. And I don't really remember much. I do know that I texted my friend and I said to my friend, can you take me to the hospital? She asked if we could go to the emergency clinic and I said, no, I have never been so sick.

So my friend took this seriously as one should. She came right down to my house, let herself in, and she found me nearly unresponsive in my bed. We tried to stand up and that's when we realized that my feet hurt. We found out later that it was the break in the one foot. And then I also could have had some nerve pain from some things you're going to hear about in a second. But it was about an hour drive and about 15 minutes out I started crying in the back seat saying, are we there yet? Are we close? My hands and feet are on fire. So she went ahead and called the hospital and let them know that we were coming in. When we got to the hospital, they met us with a gurney. They got me out of the car, loaded me onto it. They took me right into the emergency room and they did the things that they

should do. It took my vital signs. So it turns out that my blood pressure at that point was 50 over 30, which is extremely low. And it's funny because I've read my chart and they said I was conversive and pleasant. And I'm like, well, that's my go-to. I mean, I was faking conversive and pleasant. I also had an increased heart rate and I had low blood oxygen. So they immediately put an oxygen cannula in my nose just to let me breathe oxygen. Later in the day, the oxygen levels got worse and I actually had a mask forcing air into my lungs. So what was happening is that my organs began failing. I stopped urinating. So that was a sign that my kidneys were failing. And it was becoming really clear that I was at the higher levels of sepsis called septic shock. The whole thing with my hands and fingers are on fire is showing that

my circulation at my extremities was very, very bad. And my fingers began turning purple. And so did my toes, although I didn't see them at the beginning. I ended up having a condition later that they diagnosed called disseminated intravascular coagulation. So if this had not happened in the hospital, I would have run out of platelets. So at that point in time, I was on an outer island in Hawaii. We lived on the island of Kauaii. Anyone in Hawaii, if you get sick on an outer island and you get very sick and you need an ICU or you need severe help, they will transport you by air ambulance over to Oahu, which is where Honolulu is. So on Monday morning, a bed became available at the hospital at Queen's Hospital. It was decided that they would fly me over to Honolulu. So they

ended up giving medication to put me in a drug-induced coma. They intubated me and they sent me over to Oahu. When I got there, my husband had actually, thank goodness, had landed on Oahu about an hour before I did, so he was able to meet me at the hospital. So now I have my family with me. When they came out, they told him that I was not stable and that started asking him questions like, does she have a will? And what are her desires if we need to do, you know, if we need to resuscitate? And, but they did say that he should call our children who, again, were in California and have them come because they weren't sure I was going to make it. So my family was by my side for five days as I sat in the ICU or as I laid in the ICU. And, and,

And they were praying over me and watching my hands and feet turn more and more purple up to my wrists and up to my ankles. And it became clear, I think, to them during that week that I was going to lose at least my fingers and toes and likely more than that. On my daughter's 23rd birthday, my oldest daughter's 23rd birthday, which was five days later, I woke up. And when that happened, I saw my husband in front of me and he got right into my face to just let me know he was there and that everything was going to be okay.

I was extremely confused, but one thing that happened is I saw my fingers go in front of my face. And seven my fingertips were black. My thumbs, the tips of my thumbs were black. It looked like I was going to lose all of my fingers. And I was absolutely terrified. I didn't know what had happened. I mean, last I remembered, I was being cheerful talking to people in the hospital. And then I'm waking up and I'm realizing that I can see these clearly dead fingers.

I realize I'm going to lose these fingers. So we spent three weeks at the hospital doing hyperbaric changes. every day and doing nitroglycerin cream on my hands and feet three times a day. It was extremely painful, but we were able to save my hands. Right now I have my hands and most of my fingers up to those seven tips that were black. My thumbs are fine. I have them 100%. I'm really fortunate that that's what my outcome was. At the time, I was really trying hard to save my feet and I was having a hard, as you can imagine, a very hard time admitting that we might not be able to. After three weeks, I finally looked at my husband and said, I understand that we can't save my feet. And I just want to move on to

whatever the next steps are. After, you know, after a couple months, I got the amputations. I did recovery at home. I got my prosthetic legs right around Christmas time. This happened in the middle of September initially. And I was able to stand on them immediately, but it was painful. So I just built up my tolerance to walking around in them just slowly. I stayed in my wheelchair a lot of the time. and anyways, I started getting better and I started realizing I could get my life back. I went and visited my daughter who, she went to Rome for study abroad, and my husband and my best friend arranged for me to go as well. So I got to go visit her like I had always dreamed of doing. And since then, I'm living a really full life. A year later, I was invited onto the board

of directors of sepsis alliance, and now I share my story to spread awareness. Katie, thank you so, so much for being willing to share your story and taking the time to tell your story. It's terrifying. It's terrifying. And thank you, too, for all of the work that you do, raising awareness and sharing your story, not just with us, but with so many people. Yeah. It's amazing. Yeah. Well, hi, I'm Aaron Welsh. And I'm Aaron Alman Updike. And this is, this podcast will kill you. It's a big old episode today. It really, really is. It's a big one. It is. We're covering sepsis, which is not like a one-size-fits-all definition. Oh, I can't wait. I have a whole paragraph called definition. Never had that before. Yeah, it's a big one, but it's also tremendously

important. And I don't think I realized before we started digging into this just how prevalent and scary and kind of still there are a lot of open questions. Oh, Aaron. I feel like all I have are open questions when it comes to sepsis. Yeah, it's going to be probably heavy at times, but it's going to be, I think, a really good episode and really interesting. Yeah. Yeah, for sure. Well, should we start off this episode like we do every other episode? With the quarantini time?

With the quarantini time. What are we drinking this week? We're drinking. Let us spray. I love it. much. I do too. So this is a reference to Joseph Lister and his carbolic acid spray, which will make up a big part of the history section later on in the episode. And I just want to give credit to Doug for giving us the idea to use this as our quarantini title. It is one of my favorites.

It's really fantastic. Thanks, Doug. Erin, what is in lettuce spray? Lettass spray is a delicious little blended cocktail. with cherries and ice cream and lime juice and maybe some whipped cream on top. Oh, and some vodka, if you want to toss that in there. Just casually. Yeah. And we will post the full recipe for Let Us Spray, both the quarantini, as well as the non-alcoholic placebo-a-a-on our website, This Podcast Will Kill You.com, as well as on all of our social media

channels. Any other business, Erin? I don't think so. I think we should just get started because I'm just. I have the feeling this is going to be a big episode. Oh, it's going to be great. We will take a short break and then get into it. Dinner shows up every night, whether you're prepared for it or not.

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now available in Canada too. That's Q-U-I-N-C-E.com slash this podcast to get free shipping and 365-day returns. Quince.com slash this podcast. I think probably more so than any condition or infection or disease that we've covered on this podcast, sepsis is something where the actual definitions of sepsis have changed so many times, even in recent years. So I can't wait to compare like how we identify sepsis today to how we understood it historically. I don't know if I'm going to be going into any of that. Oh, but I bet we'll learn a lot about it. Perhaps. But so what I wanted to start off with was just what are the definitions of sepsis? Because there's kind of a lot floating out there.

So here's one from a 2019 paper. I will quote, quote, sepsis is a medical emergency that describes the body's systemic immunological response to an infectious process that can lead to end-stage organ dysfunction and death. Bum-pum-bum. Another that comes from the third international consensus definitions task force and is kind of the consensus definition known as sepsis three, the third iteration of this, is a bit shorter. Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Okay, that makes sense. Right?

It does. And they go further to then identify a specific subset of sepsis, and that is septic shock, which is a subset of sepsis in which underlying circulatory, cellular, and metabolic abnormalities are severe enough to substantially increase the risk of mortality. Basically, very, very serious and severe. But even that definition of sepsis and septic shock, even though they are considered consensus definitions have changed a lot over time. And even today, that definition doesn't necessarily precisely apply in pediatric populations, which happen to be at

particular risk for sepsis, as we'll talk about later. So because the definitions of sepsis have changed over time, so has the diagnosis or the criteria that are used to diagnose it. And I think that that's kind of the best way to think about sepsis. It is a process, but it's also a diagnosis that's used to kind of triage and determine management if somebody ends up in a hospital setting. Does that make sense? Yeah. And it's interesting that the criteria have changed so much. Like, first of all, why is that? And second of all, how has that affected, this may be like way jumping the gun, but how has that affected more current numbers or being able to compare throughout even the past few decades how our ability to control sepsis has changed?

That is all very important and really good questions. Basically, it's made it difficult. So our numbers on sepsis, as we'll talk about later in this episode, aren't great, especially our understanding of the rates of sepsis and control of sepsis in low and middle income countries. And you do have to kind of take into consideration every study that's done, what were the criteria that were used to identify sepsis versus to rule people out for sepsis or whatever. Yeah. But basically, the definitions have changed in part because of our understanding of sepsis and what the underlying causes are, as well as how we identify it in an emergency setting,

for example. And the truth is there are a whole host of what are often called screening tools that are used to kind of identify in ideally a highly sensitive way what people might either have sepsis or be at high risk for sepsis. One of these screening tools is called SIRS, SIRS. It stands for systemic inflammatory response syndrome. And these criteria are like an increasing or decreased temperature, an increased heart rate, an increased respiratory rate, an increased white blood cell count, or a severely decreased white blood cell count, things like that. So having two of those criteria and a known or suspected source of an infection would, in a lot of cases, rule people in, so make us think this person has sepsis. We're going to call them sepsis until proven otherwise.

There are a lot of other criteria. There's the SOFA, which stands for sequential organ failure assessment, which is mostly based on a list of laboratory values or respiratory status values, to kind of try and determine and triage the degree of organ damage. So getting a certain score on that screening tool, plus having a known or suspected infection would then meet criteria for sepsis. But there are also a lot of others. There's one called News. There's one called Muse. There's likely different versions in different countries that I don't even know about. And so what determines which screening tool you use? Is it just where you are or what hospital you work in? Exactly that. Where you are and what hospital you work in. So I can tell you, we use SERS very often. Serge has a number of detractors and it definitely is not a perfect screening tool. No screening tool is perfect. But it is used very often as one of these possible screening tools. Now, there is an organization, I think you would call it an organization. It's called the Surviving Sepsis Campaign. And it's an international organization that really tries to go through all of the data that we have on sepsis and outcomes of sepsis and come up with a consensus set of guidelines on how to identify, diagnose, and manage.

sepsis in the hospital and ICU setting. And so they have like a set of guidelines and things where they say, you know, this screening tool is not the best and this one is okay and et cetera, et cetera. I have a question. Okay. So about the number of all these screening tools, does that mean that sepsis is difficult to recognize because the symptoms are varied or is it because there are a lot of other things that can look like sepsis and a treatment is different? Yes and both. Okay. Okay. So, yeah, it's hard to tell you exactly what the symptoms of sepsis are because they're incredibly

nonspecific. So in general, according to our definition, people have some sign of an infection. This could be a pneumonia, which tends to be, at least in hospital settings, the most common identified cause of sepsis, but certainly not the only one. It could be like a urinary infection. It could be cellulitis. It could be a tiny cut on your finger. So that could be the initial infection. But then in terms of the other symptoms that you might see, people may or may not have a fever. They may or may not have an elevated heart rate as like a physiologic response to this infection. They may or may not have difficulty breathing or if you put an oxygen meter on them have hypoxia. decrease in their oxygen status. They may or may not already have progressed to the point of hypotension, so decrease blood pressure, which is when you're getting into the point of having septic shock, and we'll get more into that. They may or may not, if you look at laboratory numbers,

have changes in their liver or their kidney function or their platelets. They may or may not have altered mental status or even be unconscious. But it's a really mix. bag and any and all of those signs and symptoms could point to sepsis as a cause, but there are plenty of people that come into a hospital setting or are already in a hospital setting that have many of those signs or symptoms, but do not have sepsis. What do they have? They could have any number of other things. They could have cancer.

They could have just meningitis but not have sepsis. They can have, I mean, anything. Okay. Question. Do the symptoms that somebody has vary more based on who that person is, maybe their age, maybe their history, et cetera, or the infection that has caused or led to sepsis? That's a good question. It's a hard one to answer. I would say there are things that we tend to look out for in certain age groups as an indicator that might make us more worried about sepsis versus.

might make us more worried about something else in like a different age group. For example, altered mental status is one, especially in the elderly, that you might not see as much in younger people with sepsis, though you certainly can. And then, you know, same thing for if they have respiratory symptoms, you might think that they have a predominantly respiratory infection that's the cause of sepsis, but sepsis can lead to respiratory symptoms even if the infection is elsewhere in the body. So it's a... whole mess. I think this might be even more complicated than whatever one has, it's complicated in the title. Right. The episode. I know. And the truth is, like, we have, all we've done is try to define what

sepsis is. Like, that's all we've tried to do. And it's really difficult. But I think that at its core, that short and sweet, like sepsis three definition, organ dysfunction as a result of a combination of both an overwhelming infection, or at least I like to think of it as an overwhelming infection, and a dysregulated immune response to that infection. I think that those things can tell us a lot about the process underlying sepsis, even in the face of the fact that specific criteria to call someone septic might be different at one hospital versus another. So at its core, Sepsis requires first an infection. And this, like I said, can be an infection of literally any body area, cellulitis, pneumonia.

And often we think, I think, classically of sepsis as resulting from a bacterial infection. And some papers even go so far as to say like gram-positive coxye, things like staff and strep, which are common all over our skin, are the most common cause of sepsis-related mortality. Some statistics say that. And then they'll go on to say that gram-negative rods like E. coli, which commonly caused UTIs, are like the second most common cause of sepsis-related mortality. But the thing is that sepsis can be caused by any bacterial infection, true, but also fungal infections and even viral infections. And so then it gets even more complicated because you have culture-negative sepsis,

where you are maybe treating like it's a bacterial infection, but with no evidence of bacteria growing from any body source. Okay. A couple of questions here. I can see your face being like, why did we? Why? No, my brain is like, wait, you have to stop because I have too many questions for you to go on. Number one is what's the breakdown of bacterial versus viral versus fungal and how much of that

is just sort of in the culture negative ones. like we don't know what the sepsis was caused by because we're not detecting any bacteria, but could it still be bacteria? Yeah. We don't know. We don't have great numbers on that in general. 40% of sepsis cases can come back as culture negative. And we have some stats on like the most common sites of infection.

So like 64% of cases, at least that we have numbers on, are starting in the lung, 20% in the abdomen, 15% in the bloodstream, 15% in the genitoneary tract. But that still doesn't tell us that it's necessarily a bacterial infection, though those most commonly are going to be ones that we've identified as bacterial infections. Fungal infections tend to be probably the least common, but the most severe. If you have an overwhelming fungal infection, you're likely very, very, very sick. And viral infections are probably way underdiagnosed. And this is where it gets, both more interesting and so much more complicated, because if you think as an easily recognizable example of COVID-19, the vast majority of people hospitalized, like that ended up in the hospital

or the ICU for COVID-19, would meet many, if not all, of the common criteria that we would use to diagnose sepsis. They're probably tachycardic, their heart rates through the roof. They probably have an oxygen requirement. They may or may not have a low blood pressure. They probably have some evidence of further organ damage like kidney or liver damage. And certainly, they have an overwhelming infection in their lungs and a huge amount of inflammatory response in those lungs causing acute respiratory distress. So people with COVID-19 would, by many definitions or many sets of screening protocols, meet, quote, sepsis criteria. And yet, it's probably only either in an emergency like triage setting or in the very early days of the COVID

pandemic that most of those people were actually classified as having sepsis. Because now on their discharge paperwork, they would be called having COVID-19, right? Because we know that that damage is being wrought by SARS-CoV-2 and our dysregulated immune response to that virus. But instead of calling it sepsis necessarily, we call it COVID-19. And so some people might argue you should still call that sepsis, and some people might argue you shouldn't. So, yeah. I wonder if sepsis in the future is going to be one of those things where people are going to look back and go, you use this catch-all term to describe something, like fever, you know, like we look at fever back in the 1700s. Yeah. Yeah, it's really interesting.

it's a good question. Because a similar thing happens in pediatric populations, and that's part of why sometimes the definition for sepsis in pediatric populations might be a little different than adult populations, because there are so many respiratory viral infections, especially, that children get hospitalized for all the time that might meet some sepsis criteria, but aren't generally classified as sepsis because we know that it's bronchalitis or whatever. Okay, so sepsis is a diagnosis of exclusion? Kind of the opposite. Sepsis is a diagnosis of inclusion. Sepsis is, this is a person who is very sick, and we might not know exactly what they have yet, but they're very, very sick, and they look like they're going to get sicker. So we treat it like sepsis until we can determine if it's something else.

Okay, so using the example of COVID-19, could somebody have severe COVID-19 and then could somebody else have COVID-19 sepsis? Or is sepsis not really directly ever tied to a specific infection? And then how does that impact treatment? Yeah, great questions. Yes, people can have an infection like COVID and still have sepsis. People can also seem to have sepsis initially, but then recover very quickly. And so then you kind of get into the like, you know, did we just treat the sepsis very well at the beginning? And so now they didn't, you know, move on to septic shock, et cetera. So then, I don't know, there's just so much still up in the air when it comes to how you like fully draw that line of is the sepsis or is the sepsis? not sepsis, and I think a lot of that is place dependent. But the treatment does vary, at least according to kind of what we have for now as consensus guidelines when it comes to early identification

and treatment of sepsis. So let's get into a little bit more of like, why do we even have to have this definition of like sepsis and what does that mean what's going on in our bodies? And then we can talk about how we then treat that because of what's happening. Does that make sense? Mm-hmm. Yeah. So while sepsis requires an infection, as we talked about, it is not purely an infection. Not every person with a UTI or a pneumonia or COVID is going to go on to have sepsis. Sepsis is what happens when an infection gets so severe that our immune system reacts to it in such a way as to cause severe damage to one or more of our other organs as a result. And if this process continues unchecked, our immune system and the infection can continue to spiral, which will lead to septic shock

and eventually death. And when you say severe infection, does that mean bacterial load, viral load? What does that mean? Yeah, I don't have an answer as to what that means, because we don't have have an answer as to like, why did that person with a UTI go on to be septic and this person with a UTI didn't? Like two people could have the same viremia and one person could develop substance and the other one may not? Right, because what did their immune system do initially to try and counteract that? Did they suppress it well enough or did they not? Okay. Right?

Did they overreact? Did they underreact? Did they do a little bit of both? Yeah. Okay. I know that's not, I can tell it's not a satisfying answer. That's fine. To talk about septic shock for a quick minute, because it's a really important part of sepsis, we've talked about this concept of shock on the podcast a number of times. Shock is essentially when you aren't getting enough perfusion. You're not getting enough blood flow and therefore oxygen to your organs. So shock is another one of these catch-all definitions. where you can have shock from a whole bunch of different processes, but shock is characterized specifically by hypotension, low, low blood pressure.

And so that means that your organs like your kidneys, your liver, your brain, your heart, they're not getting enough blood and oxygen to function, so they begin to shut down. And that is what leads to death in sepsis. It's multi-organ failure as a result of septic shock. So what exactly is our immune system doing in response to an infection? that eventually results in this all the way down the line, no more blood getting to our organs, not enough oxygen getting to our organs.

Mm-hmm. Yeah. So unsurprisingly, we don't fully understand this mechanism at all, especially when we get into the nitty-gritty details of it. But what we do know is that sepsis is characterized by a very dysregulated response to infection. So what we see is both pro-inflammatory and anti-inflammatory mediators being released at the same time, which we used to think that it was like pro-inflammatory first and then you went through a phase and then you like your immune system shut it down and then went into this anti-inflammatory phase. But it turns out that this is all happening at the same time. It's like our immune system is just on overdrive, just trying to do anything that it can.

It's just like kitchen sinking it. Exactly. One of the major pathways that we think is involved in this severe pro and anti-inflammatory response is this specific group of receptors known as PAMPS, pathogen-associated molecular patterns. And these are like kind of specific antigens, specific sugars or proteins that are present commonly on pathogens like bacteria on their surface that all tend to. to fall into certain patterns. There's one as an example called LPS or lipopolysaccharide. That's one type of

pamp. There's a lot of different like variations that many different types of bacteria might have, but they all have these patterns that lets our immune system recognize, like, and that's one of those LPSs. And then we have these receptors, toe-like receptors that recognize these. And this hugely stimulates our innate immune response, which, tends to be like our first pathway of protection against pathogens. So these receptors see these pamps and they send out alerts and activate both of these systems at the same time. They're stimulating systems to increase the amount of inflammation and at the same time they're stimulating systems that are anti-inflammatory as well. And then those systems, those like pro-inflammatory

actors are releasing cytokines. They're telling the whole rest of our immune system, like, get in gear, bring all the leukocytes, like, tell everyone, this is war. I don't like that analogy, but it's like really good. And it basically like sends our immune system into overdrive. All of this inflammatory process causes vasodilation. So it opens up our blood vessels really wide so that the inflammatory stuff can get to where it's trying to go. And this. inflammation also causes damage to the blood vessel walls and inflammatory changes to the layers of our blood vessel walls so that things can squeeze out and get into tissues to like help heal them. But what this ends up leading to is leaky blood vessels, edema of the tissues, fluid getting out to where it doesn't belong.

And so if that fluid gets into something like our lungs, then that can lead to severe difficulty breathing. called acute respiratory distress syndrome because of fluid filling up your lungs that's supposed to be in your blood vessels. This also leads to a decrease in permeability of your blood brain barrier so then infections can spread to the brain where they maybe couldn't before. And that's all just the inflammatory pathways that are happening during sepsis. Okay, so I have a question about this. this seems like a very maladaptive response to infection. And so is this process, does this whole cascade of inflammatory and anti-inflammatory response,

whatever, is that good in moderation? And is it only in this specific context or certain context that it can be triggered to this, like, massive overdrive that leads to just like, oh, that was too much, buddy, we're, okay, that's it. I think that's kind of a fundamental question that we still have about the underlying pathophysiology of sepsis. And who's at risk for sepsis and why? That's my other question. Yeah. So I know that sepsis can happen to anyone, but why does it seem to happen in the highest rates in elderly people and in young children? So one of the biggest risk factors for sepsis, and I think this is really interesting in the context of a disregulated immune response rather than just thinking of it as like an

overactive immune response is that one of the biggest risk factors for sepsis is immunosuppression. Whether that's primary immunosuppression or a poorly controlled HIV or very elderly, the immune system is just not what it used to be or the very, very young like infants and neonates, don't have like a fully on-boarded immune system yet. Those are the groups that are at highest risk for sepsis. That makes sense. And so, you know, because when you were talking about that inflammatory cascade and just like this overwhelming response, it was reminding me of the 1918 flu and the cytokine storm, but that's a different thing or is it the same thing? Well, that's the thing, right? That's the same thing that we think happens in COVID. Yeah. So is it a different thing or is it actually the same thing? That's what's

happening in sepsis, right? We maybe have a better understanding of the process in very limited disease settings, right? Like, we understand that, okay, maybe it was these particular cytokines in the 1918 pandemic. Maybe it is these particular processes in something like HLH or like other kind of immune-driven disorders. But sepsis, because it's a catch-off, because it's any overwhelming infection that our body is responding to in a dysregulated fashion that's causing this unregulated inflammation. Is it just one process or is it, you know, each case of sepsis is a slightly different process? And is that part of what's making it so difficult to study and to understand?

Whoa, yeah. Whoa. And I'm not even done because there's more. The second consequence of sepsis, besides all of that inflammation, is that all of that inflammation has an interaction with our hemistatic pathways in addition to those inflammatory pathways. So this will be a callback to our hemophilia episode. So all of this inflammation and these inflammatory changes end up causing damage to our endothelial cells, those cells that line. our blood vessels. And we talked in detail in our hemophilia episode about when our blood vessels get damaged, they release something called tissue factor. And tissue factor is one of the first things

that stimulates our coagulation cascade. Coagulation is the process of being able to clot our blood so that we don't bleed out every time that our skin gets cut or a vessel gets cut. So this coagulation cascade, this process, is going to first recruit platelets to come in and plug the holes of that damaged blood vessel. And then tissue factor is going to start the process of activating this whole entire cascade that I'm not going to go back through, but it's factors 7, 8, 9, 5, 4, 10, etc. And this whole process ends up getting activated in, again, a dysregulated way when it comes to sepsis. So what you can end up seeing in a very mild form is just thrombocidopinia, which is a drop in platelets, because those are the first things that come in to plug a hole when we have a hole in

our tissues. But that's mild. If this process continues out of control, it will progress to what's called DIC or disseminated intravascular coagulation, which is basically when this coagulation cascade is underway inside of our blood vessels and ends up forming these little microthrombi, little tiny little clots in our vessels as a result of this coagulation cascade. And these thrombi not only can block off blood vessels by accident, so now you're not getting blood flow to say your fingertips or a part of your brain. And at the same time, because our body, whenever we make a clot, we eventually need to break it down. So when we're forming a whole bunch of clots inside our blood vessels, our body is breaking them down at the same time. We end up using up

all of these coagulation factors. We end up using up all of our platelets to the point where now we can't clot at all so you can end up hemorrhaging. Oh my. And that is DIC. Okay. And this is happening right alongside or is there any sort of, okay, this is just, there's no sequence to the inflammation or not a hard and fast rule? Yeah, exactly. There is not a hard and fast rule and there's not clear sequences. We used to think that there were. We used to think first there's this overwhelming pro-inflammatory response and then our immune system gets suppressed and then the coagulation cascade gets involved. We used to think it was more stepwise. But, But it's not. If you think of it more as a dysregulation, it's that everyone is trying to do something at the same time, but there's no communicators. There's no leaders saying, this is too much, this is too little. We need to work together. It's like everyone's just a free for all. That's at least the way that my brain has tried to understand it. Yeah, yeah, yeah. No, I mean, that makes sense.

Yeah. And then, of course, there's also a fair amount of immune suppression that's happening because of these anti-inflammatory things that are going on. And it tends to be that T-cell lines, and in some cases B-cell lines, more of our specific, like adaptive immune response seems to be suppressed, although aspects of our more non-specific or innate immune responses can also be suppressed. But the problem with this is that it can end up leaving one more susceptible to another infection, a super infection, right? Oh my gosh. Yeah. This is a mess and there is no hard and fast rule to anything. You've summed it up, sepsis. This is a mess. Wow.

The major consequences, of course, I think I've said, are organ failure, septic shock, and death. So this is something that can very quickly progress to a very, very serious emergency situation. So that's why a lot of the definitions of sepsis kind of try to include that in the definition. What is the timeline of that? Like when you say very quickly, what could that be? I mean, it depends on the infection. Okay. So it could be a matter of like hours to days, but not a longer drawn out process than that?

Probably not because once your immune system starts, like once you truly have sepsis, this process is just going to continue unchecked unless you're being managed. So let me finally try and answer some of your questions from before on like, how do we actually treat this? And there are a few, I think, pretty important principles when it comes to management. I will link to the surviving sepsis guidelines from 2021. Those are at least as far as I saw the most recent guidelines. But I will also say, and I'll talk about this more later in the episode, these are imperfect. And they are in a lot of cases based, they say it outright. This is not my words.

They're based on pretty poor quality of data because we just don't have good enough data when it comes to sepsis. But there are a few kind of big, important things. And the first is just identifying people. especially those that are at high risk for septic shock. And so that means using these various criteria to identify people who have sepsis, even if it's early on. The other thing that it means is identifying as quickly as you can the source of infection. And if possible, getting cultures to be able to verify if this is a bacterial infection,

what bacterium it is, or if it's a fungus, what fungus it is. It's also possible to do viral testing in some places, in some areas. But identifying the source of infection and then controlling that source if possible. So if there's an abscess, it needs to be drained. If there's like a necrotizing skin infection, it has to be debreded. If it's an infection from an infected line, like a catheter of some kind, being removed, like finding where the bacteria is seen. seeding from or the infection is seeding from and trying to remove it. And in the vast majority of cases, starting broad spectrum antibiotics, especially if you don't

know what is causing this. And then one of the kind of most well-supported things that tend to happen when someone is identified as having sepsis is fluid resuscitation because it can so quickly progress to septic shock and hypotension, resuscitating with fluids. So like putting in an IV and getting fluids is one of kind of the most well studied, has really good data to support that it improves outcomes and mortality. Question about endotoxins. Oh, yeah. What role do they play? Great question. So endotoxins are often things like that LPS that I talked about. These are can be things that are pathogen associated molecular proteins that our body is recognizing. So that's one of the main pathways that we've

identified that's a likely contributor to the initial development of sepsis. That's like one of the triggers. Exactly. Okay. If we're talking generally about a bacterium. Right, right. So with treatment, what are the mortality rates? They really, really vary place to place and case to case. from some data from maybe about 10 years ago. In Europe, mortality rates from sepsis tended to be about 40% versus about 28% in the U.S., which is massive. Well, it's also interesting too because, you know, like you brought up earlier, what goes on the sheet in terms of diagnosis can also very much affect the mortality rates, yeah. And, you know, in some of those cases, if they use statistical methods to adjust for things like how severe was the disease, then those differences where it seems like, why is sepsis so much more deadly in Europe than the U.S.? If you actually look at like disease severity and sepsis mortality, then there actually wasn't a difference. So it does, I think, in part, come back to how broad this definition is and how it can vary place to place. and overtime.

Yeah. There's very, very many variables. Don't you love it? It's interesting, fascinating, scary. Yeah. So, Erin, has it always been with us? I presume yes. I do too.

I'm not going to talk that much about that aspect of it, but I'll talk about some other ones. Can't wait. And I'll get started right after this break. Anyone who works long hours knows the routine. Wash, sanitize, repeat. By the end of the day, your hands feel like they've been through something. That's why O'Keeffe's Working Hands hand cream is such a relief. It's a concentrated hand cream that is specifically designed to relieve extremely dry, cracked hands caused by constant hand washing and harsh conditions. Working hands creates a protective layer on the

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Just text lift to 3232.32 right. now. Get certified in as little as six weeks and ISSA guarantees you'll get a job. Text lift to 32 32 32 32 32 32 32 32 32 32. The story of sepsis, how do you tell the history of a condition with such varied symptoms? With such varied causes with virtually any viral bacterial or fungal infection able to lead to its development like you talk. about. A condition whose definition and name itself has undergone substantial revision over the past hundred years, and one which we still seem to be struggling to effectively treat or even understand. Obviously, there are many different ways you could go about it. Talk about a particular

bacterial cause or the evolution of treatment strategies or how our understanding and definition of sepsis has changed throughout time. Or maybe you could talk about a big moment in sepsis history. A period when humanity's collective view of the world and how it worked underwent a tremendous and life-saving shift, even if somewhat reluctantly. Okay. And that's my pick for today. Love it. That's what I'm going to do.

Because how could I pass up an opportunity to talk about Joseph Lister and the sanitation revolution? We simply cannot. We cannot. Of course, Lister and his carbolic acid. only make up a small part of the overall history of sepsis, but I wanted to primarily focus on his work today because I think it gives us a fascinating insight into the early days of germ theory

and how we got from germ theory as a ridiculed idea to germ theory as fact and from germ theory as theory to germ theory in practice. And Joseph Lister is really at the heart of so much of that. And I want to mention at the top that most of the info about Lister and those early days of surgery and germ theory, I got from the fantastic book, The Butchering Art by Lindsay Fitzharris. Very great book.

It's truly such a great popular science book that is unput-downable. I highly recommend it to fill in more color and more context and more amazing quotes about the early days of the horrific days of surgery to this story. to this story. Listeners of the podcast and Aaron, you've heard me talk so very much about this time period, but we are covering new ground here, and I honestly think it's one of the most interesting stories yet. But first, let's take a step back to get our bearings with sepsis. Probably could go without saying, but humans in sepsis go way back.

And our recognition of the disease also goes way back to about 20, 700 years ago, when it was first used in a medical context in Homer's poems, in the verb form seppo, meaning I rot. Later, around 400 BCE, the word sepsis was introduced in the Hippocratic texts, meaning, quote, the decomposition of animal or vegetable or organic matter. And this word or variations of it were used extensively in Greek and Roman literature, not just in medical texts, but also classic literature and literature and philosophical writings where it likely held symbolic meaning. Over the next hundreds of years,

it remained in some use, but it seems difficult to say whether that was in the medical sense or in the symbolic sense. And in either case, it's unlikely that the sepsis referred to in most historical texts pre-19th century would always fit the definition that we use today. The modern use of sepsis, more or less, can be traced back to sometime in the early. early 19th century, depending on the language. Also, depending on the definition. This is why I didn't want to go into like the changing definitions of sepsis. It just gets really messy, really fast. And when it was introduced in the early 19th century, it meant putrefaction, often accompanied with the rotting of the body or parts of the body after a wound. And it's really no surprise that it was

around this time that sepsis came into more and more frequent use, as well as other words that were related to sepsis, like septicemia or paemia. Because much of the world was undergoing some pretty drastic changes in terms of urbanization, industrialization, and population growth. And these changes could also be seen in the medical field, namely in the form of hospitals. I talked a bit about the enormous increase in hospitals during this time in the puperal fever episode. Yes. It's go and listen to it. But in case you need a refresher and you don't feel like it, I'm going to set the stage again here.

The late 18th century and early 19th century saw a tremendous growth in hospitals in Europe and in the U.S., mainly as a feature of the cities that were constantly and rapidly growing thanks to industrialization. In contrast with rural areas where doctors would often travel house to house to care for patients, hospitals began to be popular in cities where physicians could just stay put and wait for their many patients to come to them. They could work with other physicians and exchange knowledge, and they could use the people seeking care, many of whom were in lower economic classes, as a teaching opportunity. Prior to the early 1800s, essentially the only requirement for being a surgeon was just calling yourself one. But with the growth in hospitals also came tighter, though still loose by today's standards, regulations for education and training for surgeons. And would-be surgeons had to spend a certain amount of time, say six months or so, learning in hospitals, listening to lectures, performing autopsies or training directly on patients. hospitals were proving to be a tremendous opportunity for the growth and spread of medical knowledge, as well as the growth and spread of pathogenic microbes.

Because these were still the days before germ theory, when it was held that the dirtier the surgeon's hands were the stiffer their coat with dried pus and blood, the more respected they were. I just, it's so yucky. It's horrible to think about. Yeah. The prevailing notion of what caused disease was still my asthma, foul air that contaminated the body and led to infections. How does your coat not be full of foul air? Did it stink? It had to have. That's what's baffling. I don't know. But yeah, these blood and pus encrusted surgical instruments or soiled bed linens, these weren't viewed as dirty or kneading cleaning. It was the bad air in the post-surgical ward that caused the incredibly high mortality rates observed. After all, the site of pus called laudable pus in a wound or surgical site was sought to indicate that the body was healing.

It wasn't something to be worried about. In the first few decades of the 19th century, mortality rates from surgery were as high as you can imagine. But the overall number of surgeries performed was actually fairly low, and that was, was largely due to the lack of anesthesia. Prior to the introduction of Ether in the 1840s, if you had to have surgery of some kind, you either had to take your chances with laughing gas, which could either kill you or not affect you at all, or bite the bullet, or more accurately, the leather strap. The horror of surgeries made many people reluctant to have them unless in cases of dire need, and even made many surgeons reluctant to perform them, or at the very

least, encourage them to cut as quickly as they could. When Ether was first used in 1842 by Crawford Long outside of Athens, Georgia, it was the beginning of a revolution that would transform surgery from a terrifying last resort, where a surgeon had to get in and out as quickly as they could, into a viable option and a burgeoning field of study. With Ether, a surgeon still had to be fast, but they at least had a little more breathing room to make sure they were suturing the right arteries or whatever together. As the miracle of ether became more widely known across the world, the number of surgeries performed climbed up and up and up.

With ether, one enormous barrier to surgeries had been toppled. But the other one, a big one, still remained. Infection. And infections post-surgery loomed bigger and bigger, as Ether became more widely used, since remember, we're still in the days before germ theory. Right. Oof. This is the surgical world that Joseph Lister entered into at the age of 17 in 1844.

Lister was born and raised a Quaker, which meant a simple childhood. No sport, no theater, no frills. Life in general was not about the pursuit of pleasure, but about service and honor of God. Fortunately for little Joseph Lister and the rest of the world, science was considered a worthy pastime, and he had the tools to explore the natural world at his disposal, thanks to his father. Although Lister's father had started his career in the family biz as a wine merchant, over time he became fascinated with the world of microscopes, especially in improving their capabilities through fiddling with this lens or adjusting that angle,

Lister's father's improvements to microscopes earned him great renown, and Lister's childhood home was full of the instruments as well as specimens and books of natural history. Given this upbringing, it's hardly surprising that at the age of 14, Lister decided he wanted to better understand life by becoming a surgeon, which was not welcome news to his family. Oh. At the time, surgeons were not a well-respected bunch. They were seen not so much as educated professionals, but more as crude technicians. To just give you an idea of this, consider that a hospital's chief bug catcher, who was responsible for removing lice from mattresses, was paid more than the hospital's surgeons.

Whoa. Yeah. I mean, that does sound like a difficult job. It sounds like a horrific job, yeah. None of this deterred lister, though. And so in 1844 at age 17, he enrolled in University College London, bringing with him, of course, one of his father's microscopes. He didn't start right away with medical classes, however.

His father realized that if he couldn't dissuade Lister from pursuing surgery, he could at least require that he complete an art degree first, which was effectively a liberal arts degree with courses in history, math, literature, and science. I love that. This was definitely not a requirement or the norm for surgeons in training, but Lister later attributed his ability to make the important connection. connections he did across disease, sanitation, and germ theory to this well-rounded education. Mm-hmm.

The other not required or not normal thing that Lister did was bring his microscope. At the time, microscopes had been around for quite a while. Over 200 years. Wow. I know. I just always forget how early the microscope, like, really came about. It's fascinating. Yeah, it's really impressive. But even though these microscopes had been around for that long of a time, they weren't yet seen as integral to medicine. Instead, they were considered a distraction, a waste of time, or even a threat to the medical community, since they promised answers that physicians could not provide with the naked eye. Yeah. But slowly the tides were turning, as scientists jotted down observations about how some diseases acted on different tissue types rather than or not.

on just the entire body or whole organs, as had been thought. It would still take some time, though, before the value of microscopes in diagnosis and other aspects of medicine was made clear. And so Lister certainly was unusual in owning one, and maybe even more unusual was that he used it. As a senior medical student, Lister was appointed to be a dresser for John Eric Erickson, who was the senior surgeon at University College Hospital. Part of Lister's duties included standing by with a box of supplies to dress wounds during surgery or to change the bandages in post-surgical care.

In 1852, during one of these routine bandage changes, he unraveled the cloth on a patient's seeping, rotting wound and was met with a horrific odor. It was the dreaded hospital gangrene. In the day's pre-germ theory, gangrene was one of the big four exceeding. common hospital infections that cause the most death and disease, with the other three being erysipolis, septicemia, and pyemia, which is a development of pus-filled abscesses. No one knew precisely why hospitals in particular seemed to be so susceptible to these conditions, but they certainly were. You may remember some of the stats about puperal fever in the countryside compared to hospitals

from the puperal fever episode. And here I'm going to do the same thing. but with amputations. Oh, dear. Yeah. For instance, in one year in the countryside, 23 double amputations were performed and seven died, which still seems like a lot.

Mm-hmm, definitely still a lot. Until you compare with the Royal Infirmary of Edinburgh for that same period, 11 double amputations, 10 of whom died. Wow. Mm-hmm. And it wasn't just those seeking care at hospitals that were at risk. Many physicians, surgeons, medical students, and surgical assistants were just the tiniest scalpel slice away from introducing one of these deadly infections into their own bodies. At one hospital, St. Bartholomew's Hospital, over the period from 1843 to 1859, 41 medical students died after developing fatal infections.

Oh, my gosh. And of course, I can't not mention the 300% mortality rate surgery, where the, quote, fastest knife in the West End, Dr. Robert Liston was cutting so quickly that he sliced off his assistant's fingers and then slashed a spectator's coat. The patient and the assistant died of infection, of course, while the spectator died of shock. Or so the story goes. Yeah. Yeah, that possibly true, possibly made up dramatic story aside, the high mortality rate at hospitals and in the cities themselves had come to be expected. Industrial accidents, lack of access to clean water or nutritious foods, crowd diseases, even if you manage to avoid cholera from the contaminated Broad Street pump or tuberculosis from your overcrowded building or arsenic from your wallpaper,

you could just as easily die from septicemia after having the gash on your hand you got at a factory stitched up at the hospital. Deadly infections haunted every hospital wing. And once one appeared, there was not really. anything doctors could do to slow its spread. Within a matter of days, the gangrene that Lister observed in that one patient had swept the entire surgical wards, and Lister was put in charge of wound care. This involved him scraping off the dead decaying tissue from the wounds, and then applying mercury per nitrate, which is both caustic and toxic. An excruciatingly painful process that, thankfully, was done while the patient was under anesthesia.

Lister, observant as always, noticed that the wounds that had been very carefully cleaned and that had received this caustic treatment healed surprisingly well. What was it about this process that prevented the gangrene from getting worse? Maybe the answer wasn't in the air, as many of Lister's contemporaries thought, but in the wound itself. He took some of the pus that he had scraped from patient's wounds and made slides to check out under the microscope. Later, he wrote about what he saw. Quote, I examined microscopically the slough from one of the sores, and I made a sketch of some bodies of pretty uniform size, which I imagined might be the materials morbid substances. The idea that it was probably of parasitic nature was at that early period already present in my mind, end quote. And this is pre-germ theory.

This is pre-germ theory, but I believe that that was. a reflection later on in his life. Okay. But in any case, the seed of a revolutionary idea was planted, but it would take several more years to fully form. Okay. As Lister neared the end of his medical training, he was given awards and accolades in recognition of his exceptional abilities and achievements. But while his professors could see great promise in him, he wasn't so sure. He couldn't decide whether he wanted to go into medicine or.

surgery, so one of his professors recommended he spent some time in Edinburgh with clinical surgeon James Syme. What was supposed to be a month-long stay turned into years as Syme became not only Lister's respected mentor, but eventually father-in-law. In Scotland, he fell back in love with surgery and dove back into the topic that had first grabbed his attention in his surgical training, inflammation in wounds. He spent his free time examined. He spent his free time, examined, more pus and tissue samples under the scope and jotting down any patterns he saw. When did inflammation appear? When did a fever develop? Was fever a good thing or a bad thing? What about inflammation? Did sepsis always come after inflammation or only some of the time? He could only get so far with the

dead and dying tissue he was looking at, so he turned to other living animals to take a closer look, a colony of frogs that he kept at his house. He would injure the their webs in various ways, using heat or chemicals, and then look at what happened to their blood vessels. What these experiments told Lister was that inflammation was a normal part of the healing process, and sepsis didn't necessarily follow. He was getting closer. In 1859, six years after he moved to Edinburgh to work with Sime, Lister, who was then 32, applied for and was given a prominent surgery professorship at the University of Glasgow. Although at the time, the academic atmosphere at Glasgow was conservative, where Edinburgh was daring,

traditional, while Edinburgh lean progressive, new hires like Lister were injecting a bit of freshness into the university, which attracted more and more medical students, students who loved their new professor for his riveting lectures, focus on clarity and modern thinking. alongside his appointment at the university, Lister was also given a position at the city's hospital, which he viewed as essential for connecting theory and practice, demonstrating the procedures that he had lectured about in class. Even though the surgical ward that Lister was assigned to was basically newly constructed, it was already filthy. All the classic infections haunted the wards, the graveyard was constantly overflowing, and there, there was practically nowhere to wash your hands or instruments or bed linens.

Even like the surgical tools that were used were ornately carved, which meant that they were impossible to clean if the surgeon actually attempted to clean it at all. Yeah. I just, I really, I know we talk on this podcast about trying to like separate what we know now from what we knew back then. but like I can't get this one. You know? I know. Like I can't get there.

Like a pus-filled knife? How are you not going to wash that? Because pus was good. It was laudable. Actual like dirt and blood? Come on. I know. I know.

It's very horrible, but interesting to think about. Mm-hmm. Yeah. Lister's house surgeon, get a load of this said, quote, when almost every wound was foul with separation, it seemed natural at the time to postpone the complete cleansing of hands and instruments until the program of dressings and probings had been finished. Basically, what point is there to clean something that's just going to get dirty again? Yeah, all right. Okay. With this attitude, is it any wonder that mortality rates

post-surgery were sky-high. Surgeons weren't being willfully malicious. They simply didn't know any better. But it was still a tragedy to those dying of infection and their loved ones who had to sit by helplessly, as well as to the surgeons who would take great care in treating people only to watch them die of infection a few days later. Lister felt this very keenly. And as a result, he became very invested in trying to prevent these post-surgery deaths, starting with cleanliness. The concept of cleanliness has not remained constant throughout history. Ooh, is that a whole other episode? Yeah, I think it could be.

Nowadays, we may think of a clean hospital room as one that has been sprayed and wiped down with aniseptic, freshly mopped, fresh linens and paper on the bed, sterilized instruments, and so on. In Lister's Day, a clean room was one that had been recently swept and the windows opened. That was basically it. How is it? Because fresh air, yeah. Okay, fresh air. Granted, new ideas were continually being proposed, such as cleanliness and cold water, which held that surgical instruments should be cleaned with water that had been boiled and then allowed to cool.

And the idea behind this was that cold water was supposed to prevent the heat that caused fever and inflammation. Why boil it and then cool it? Great question. I don't know. And of course, Ignaz Semmelweis went further than just washing instruments in cold water. He also famously advocated for better hand washing and instrument washing using a chloride solution. But as we know, he was ridiculed and his ideas did not become widely known until after his death. So Lister didn't hear about him until much later on. Instead, Lister tried out the cleanliness and cold water approach and became increasingly disappointed at the results or lack thereof.

It didn't seem to do anything. He expressed his frustration to his students saying, quote, It is a common observation that when some injury is received without the skin being broken, the patient invariably recovers and that without any severe illness. On the other hand, trouble of the gravest kind is always apt to follow, even in trivial injuries, when a wound of the skin is present. How is this? The man who is able to explain this problem will gain undying fame. I know, end quote. As 1864 drew to a close, Lister was still deep in his depression over the seemingly inevitable death of his patients when a colleague brought some new articles to his attention.

Research involving fermentation and putrefaction, authored by none other than Louis Pasteur. In these articles, Pasteur noted that microscopic rod-shaped organisms were found in spoiled wine, and he believed that they were responsible for the spoilt. But he also looked beyond wine, proposing that these tiny germs were also responsible for certain diseases in humans and other animals. Pestcher's ideas were met with quite a bit of resistance and ridicule from the medical and scientific community, but Lister found them exciting and felt hopeful that the answers he had long been looking for might be found in these articles. To Lister, this concept of germ theory explained why disease appeared after surgery and how it

could be spread from one person to the next all the way down the ward. He wasn't entirely right in his conclusions, believing that it was microbes carried in the air rather than on instruments, for instance, but he was on the right track enough to try out some infection control strategies, namely by attacking these germs after their introduction into the wound. On this, he also turned to pasture, who had demonstrated that these germs could be killed by any no number of different things. Heat or filtration couldn't really be put to practical use for Lister, so he turned towards finding an antiseptic that would kill germs on contact. Again, this was not an entirely new notion. Antiseptics had been used by surgeons for years to irrigate wounds,

but two main things prevented them from being recognized as incredibly powerful sepsis prevention tools. The first was that surgeons typically waited to use the antiseptic on a wound until it was obviously infected, at which point there was little the antiseptic could do because the infection was likely systemic. And second, was that the antiseptics themselves often caused substantial damage to the surrounding skin, allowing for further infection. Because of this, the jury was still out on the value of antiseptics in medicine. Lister wondered if there was more to the story of antiseptics, though, so he decided to test different ones out to see which were the most effective in preventing infection. Instead of waiting for the pus to be freely flowing

and the surrounding skin hot and tight and red with inflammation, he applied the antiseptics prophylactically and waited to see which one did the best. After going through a few that didn't show much promise, he reached for the carbolic acid, aka phenol, remembering that he had heard carbolic acid was sometimes used at sewage works to counteract the smell of rotting liquid waste. Ew. Yeah. He thought, if it can cover up those horrific smells, maybe it'll kill whatever is

putrefying these wounds. And I feel like that was also Semmelweis's train of thought. But yeah. Carbolic acid didn't work that great on the first two people he tried it out on, but the third time was the charm. In August of 1865, 11-year-old James Greenleys was brought to Lister's hospital three hours after his leg had been crushed under a cart. Tibia cracked and jutting through his skin. Oh, yeah.

The wound was already, of course, filthy from the road and from the journey to the hospital, but Lister knew that amputation, which was probably safest in terms of infection, would forever change. this young boy's life. And so he wanted to see what he could do. He put the boy under chloroform and went to work, cleaning out the wound as best he could with dilute carbolic acid and getting the bone reset. And he continued to take meticulous care of the wound over the next days and weeks, carefully cleaning it with carbolic acid and putting some olive oil on as a soother and checking for signs of infection. Six weeks and two days after James Greenleys had been carried into the hospital with his horrifically broken leg, he walked out on his own.

Wow. Yeah. Lister felt that he finally held the key to the hospital infection problem. He continued to try out his carbolic acid technique on other people with compound fractures, with a success rate of 80%, and then moved on to other injuries before he finally felt ready to publish. On March 16th, 1867, two years. after he first began experimenting with carbolic acid, Lister published the first part of a five-part

article in The Lancet describing his findings. Quote, on a new method of treating compound fracture, abscess, etc., with observations on the conditions of separation. This was not only groundbreaking in its support for germ theory, but his articles also provided step-by-step instructions to prevent post-operative infections. the Glasgow Royal Infirmary where Lister worked went from being among the deadliest to the cleanest with the lowest mortality rates. Wow. Lister wrote, quote, I now perform an operation for the removal of a tumor, etc., with a totally different feeling from what I used to have.

In fact, surgery is becoming a different thing altogether, end quote. Wow. I just, it's hard to imagine what a tremendous, like, release. and how much hope that would have inspired, I guess. Like, finally, this isn't a death sentence. Yeah. Yeah. Especially to have, like, dedicated your whole life to something and then finally feel like you can do it and, like, not only have horrific outcomes.

Like, yeah. Yeah. Yeah. I can't even imagine. Yeah. And I have some numbers to back up just how incredible. this was. So 16 of the 35 people that had undergone amputations between 1864 and 1866 before carbolic acid, 16 of those 35 had died, while that number dropped down to only six of 40 between

1867 and 1868 after carbolic acid. Wow. Yeah, it's amazing. And I do just want to point out, because I realize I'm talking mostly about Lister and antiseptic technique in the history of sepsis. And a lot of these post-surgery deaths were due to wound sepsis. Basically, that was caused by an infection that they had gotten from the surgery, not something they came into the hospital with. Right. Yeah. Yeah. As you might expect, Lister's articles weren't immediately accepted with open arms by the medical and surgical community. Shock of all shocks. Shocking, shocking. Though he did seem to have more supporters than someone like Semmelweis.

His old mentor, Syme, was on his side, as were many of Lister's students and Pestewer himself, whom he became close pen pals with. But there was quite a bit of resistance and even ridicule in response to his ideas of antisepsis. most notably from the famous surgeon James Wise Simpson, who had first introduced the use of chloroform as anesthesia and was a big proponent of acupressure for sepsis prevention, which didn't work. Simpson seemed to have a personal vendetta against Lister. Maybe he was frustrated that no one seemed to like acupressure. Maybe he felt protective of his own fame and was jealous of Lister. But there did seem to be a variety of reasons that Simpson and others were so quick. to dismiss Lister's ideas. To some, it seemed like the newest version of,

put this mysterious ointment on it and hope for the best. To others, it was a passing fad. Some believed Lister to be overstating his results, and others dismissed it out of hand due to its reliance on germ theory, which had by no means been widely accepted yet. But perhaps one of the biggest reasons for resisting Lister's ideas

was that if he was right, that meant that these surgeons had been inadvertently causing the deaths of so many of the people that they were supposed to have been helping. Lister fought the disappointment he felt from all this criticism by focusing his efforts on improving surgery in other ways, such as changing the material that the ligatures were made of to catgut, which could be absorbed by the body and reduce the risk of infection. He also concentrated on teaching, realizing that, that, well, if he couldn't convince older generations of doctors of his methods, then he could train the new ones. Over the next few years, years in which so many people continued to die because their surgeons refused to test out Lister's techniques, Lister kept at it, touring across

the U.S. to give talks, where some hospitals, like Mass General, for example, had actually banned Lister's techniques. Wow. And then later it became, they were like the first hospital to make it hospital policy to practice. Wow. And also continuing to publish his results. I hate that this is a lesson in publish, publish, publish, but whatever. It all paid off. The medical community grew to accept Lister's carbolic acid practices in preventing post-surgical infection, and the enormous contribution he made to the field of not just surgery, but all of medicine was recognized in his lifetime, unlike so many of the other people that we talk about on this podcast.

Yeah. Lister spent the rest of his life, showered in awards, accolades, honorary degrees, and was even given the dubious honor of having a hygiene product created in his name. Listerine. Listerine. Oh, my gosh. I don't know if I ever put those two together. Listerine's been around that long?

It was developed by someone who saw his talk, one of Lister's talks in the U.S., and then later, like, the rights to advertise it were sold. And the person who bought them advertised it as a dandruff treatment, a cure for gonorrhea, a floor cleaner, and of course, oral antiseptic. And that's how it came. That's how it has remained. And it wasn't just Listerine that Lister inspired. Lister's antiseptic techniques kicked off a craze for antiseptic products and inspired someone named Robert Wood Johnson, who had also seen Lister speak to join up with his brothers to start a company manufacturing sterile surgical dressings and sutures. They named it Johnson and Johnson. How interesting.

Yeah. Wow. But mouthwash aside, Lister's two biggest legacy, are that he provided an effective means to prevent one of the biggest causes of surgical deaths, which absolutely changed the practice of surgery forever and medicine, period, and also that he demonstrated germ theory in action, which greatly helped it to become accepted or at least more closely examined. With the widespread adoption of Lister's antiseptic practices, hospital sepsis cases,

hospital sepsis cases dropped tremendously over the next decades. Researchers learned more about the underlying pathophysiology of sepsis, such as the role of endotoxins and the immune system response, and they discovered new ways to diagnose and treat the condition. In the 155 years since Lister published his article, we've come so far and learned so much about sepsis, but as we can gather from the biology section, we have still so very far to go.

And I really hope I haven't disappointed anyone too very much by skipping over most of the recent history of sepsis and the changing definitions. But I figured, Erin, that you could at least bring us up to speed with sepsis today. Oh, I can't wait to right after this break. Sepsis today. Aaron, it's a bit of a mess. So in the U.S., in recent years, there are nearly a million sepsis cases admitted to hospitals each year, just in the U.S.

A million. Yeah. And the numbers tend to be on the rise year after year. Huh. Mm-hmm. sepsis is also one of, if not the leading expenses. And I know we've talked about the problem of using like health care expenses, especially in the U.S., because our health care system is so skewed in terms of how much everything costs.

But sepsis costs the U.S. health care system billions and billions of dollars every year. I mean, at the very least, it seems like it would be a good proxy for the number of days that you spend in the hospital, the number of like different specialists that need to see you. Exactly. So as one example from a paper, they cited that in 2013, sepsis cost the U.S. over $24 billion in total hospital expenses, which is 13% of total U.S. hospital costs. Whoa. Even though sepsis accounted for about three and a half percent of hospital stays. So it's disproportionate the cost to the amount of total hospital stays. Wow. Okay.

Because it can be such severe infections. Yeah. When we try to look more globally, I think what we really have to understand is just how underestimate these numbers likely are. Like the true scale of sepsis in the U.S., but also especially in low and middle income countries across the globe, we really don't have a handle on the global burden. A paper from 2017 estimated about 49 million cases worldwide. Wow. And 11 million sepsis-related deaths. if those numbers are accurate, like again, these are estimates, that would be almost 20% of all global deaths. The vast majority of which, it's estimated 85% of those sepsis-related deaths, are in low and middle-income countries that we just aren't getting good data on. Isn't that? It's just so horrific.

Yeah, it truly is. And it's also estimated that almost half of. of all these cases occur among children. So 20 million cases among children and 2.9 million global deaths in children under age 5 is what this paper is estimating. So it's a huge healthcare problem. It's difficult to diagnose. Again, the mortality rate can vary quite a lot. Some papers just that try and estimate it overall say anywhere between 1 in 3 and 1.6.

six people with sepsis can die. And so the World Health Organization has understandably made this a huge, you know, campaign and a priority, as well as the surviving sepsis campaign that I mentioned already. One of the big things that the surviving sepsis campaign tries to do, in addition to raising awareness, is also just gathering data and analyzing that data in a way to try and actually improve outcomes. And one of the big issues with the data that exists so far is that it generally comes from very high-income countries. And so we have to recognize the limitations in how we can interpret and then apply that data to much less resource-rich areas. Right? Yeah. And importantly, all of these kind of campaigns and policies are largely, like I said, trying to improve.

outcomes, as well as improve our recognition of sepsis and how we treat it to reduce morbidity and reduce mortality. Sepsis is something that has likely always been with us and will likely always be with us. And so it's not something that there are a large group saying we should eliminate It's sepsis entirely. That's not realistic goals, at least not at this point. And one I think of the reasons is how little we still understand about sepsis, Erin. It's shocking, but also not shocking. There was a great paper from the Lancet Infectious Disease 2019 that was written by people from the European group on Immunology of Sepsis, EGIS, loved it. And, they were really upfront about their feelings on all of this. They basically were like, look,

the reason that we have all these different definitions and all this controversy of like, is it this criteria or that criteria, etc., it's because we just don't understand the immunology of sepsis. We don't. We do not understand it. And so this article really laid out what they feel, at least, are the major deficits in our understanding and where we should go from here. They did this, by looking at three different stages of sepsis. Before it develops, which is my favorite stage to think about. Very important. Who is at risk? Why are they at risk? What kinds of research do we even need to do to better understand this initial process and these specific risks to be able to actually prevent sepsis to begin with? Maybe change up the animal models we're using? Yes, we don't have good

animal models for sepsis. Then we also have the next stage, the evolution of sepsis. What are these specific immune processes that are underlying this organ damage and how might we use these to better target treatments? There have been a lot, mostly of animal model studies, of like, well, if, you know, IL-10 is involved, let's affect that, like these specific, you know, immune modulators. And the short answer is they don't work, right? Because these are too broad. So anything that we have tried to do to modulate the immune system ends up making things worse rather than better when it comes to sepsis so far. And finally, the third stage post-sepsis. Like what are the consequences of having a severe sepsis infection in the long term? And what can some of these

consequences teach us about the underlying pathology of sepsis. We don't have answers to those, but I think it's just kind of a nice framework to think about where we can go from here. Yeah. I mean, yeah, it's good to have questions. You have to have direction. Exactly. Yeah. So it is going to be very interesting to see how these definitions continue to change. and how treatments then continue to change. I have a question about something you said about numbers going up. Yeah. Is that an increase, is that an apparent increase?

Is that a real increase? What do we think about that? I don't know if we know. Okay. Yeah, I don't know if we know. Is it because of changing definitions? And so are we broadening our definition in order to capture people at an earlier stage to then prevent severe infection or are people actually coming in with sepsis and sicker? I don't have a

great answer to that. Another question I had is if you have had sepsis one time and recovered, are you more likely to develop sepsis a second time? That's a very good question. I think it probably in large part depends on what the inciting factor was. If you, you have cancer and you are immunosuppressed and you end up getting an infection that leads to sepsis and you recover from that. But you still have cancer and you're still immunosuppressed, then yes, you're still at high risk for sepsis. If you, you know, got a cut and a wound that was infected and you ended up with sepsis, but you don't have any other underlying immune conditions that we know of, of course,

there's so much individual immune response differences that we just. just don't know about. It's a good question as to whether you are at higher risk or not. I think we don't probably know enough to know in those instances. Okay, that makes sense. Yeah, great question, though. That's very interesting. Any other questions, Aaron? I mean, a million. Like, do we even know what sepsis is at the end of this? I'm not sure that I do besides, like, a very broad definition, but it seems it seems like a like a moving target. Yeah. And impossible to pin down. Yeah. Right now. Maybe the future. The future holds all the answers. Mm-hmm. For sure. It is also probably interesting to think, though, about so many things now that maybe are more specific

definitions that used to have just been called under a catch-all of sepsis. Uh-huh. Yes. So I do wonder how many other things might come out of our current definition of sepsis. Right. We have a bowl that is sepsis and we can draw out little bits of paper that say, oh, that was actually, I don't know, any of the things, but we now call that something else that is not sepsis. Yeah. Yeah. Interesting. Anyways, sources? Sources. I have a few papers that talk a little bit more about the changing definitions of sepsis and the more recent history of sepsis if you'd like to check those out. But let me just shout out again the fantastic book by Lindsay Fitzherris, The Butchering Art, all about Lister, all about early surgery, all about how germ theory kind of came to save the day

a little bit and Lister. It's such a great read. It is really great. I can also recommend. I had a number of sources, not as many as sometimes because the papers that are I found we're actually really comprehensive just on the overall definitions and what we know so far about the immunology of sepsis. So I will post those as well as the list of all of our sources from every single one of our episodes on our website. This Podcast Will Kill you.com under the

episodes tab. Thank you again so much, Katie, for taking the time to chat and sharing your story. It really means a ton. And we will also link to some more articles that Katie has shared, as well as the Sepsis Alliance website, which is sepsis.org. So be sure to check out the sources for this episode and also the show notes. Thank you also to Bloodmobile, who provides the music for this episode and all of our episodes. And thank you, too, exactly right? And thank you to you, listeners. We hope you enjoyed this episode. Yeah, we hope you found it interesting. What are your burning questions about sepsis? still at the end of this. Let us know. I have a lot. Yeah. And a special thank you, as always,

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