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Kevin J. Tracey, MD: [00:00:00] Patients chose to enter the clinical study of vagus nerve stimulation rather than going down a continuing checklist of biologics. And And why is that? Well, it’s because the biologics have black box warnings. That means the side effects are so serious that you can. Get sepsis from immunosuppression, or you can get cancer or you can have other problems.

So patients prefer to actually try the vagus nerve therapy, and as I said, about 75% of them had a significant lasting improvement. This 

Nicole Kupchik: is the sepsis spectrum, a podcast about antimicrobial resistance, sepsis, and how to expect the unexpected in your practice.

[sponsor message]: Sepsis Alliance gratefully acknowledges the monetary support provided by Vantive for this podcast series.

Kimberly Emanuel: My name is Kimberly and I am a sepsis survivor. My story begins by waking up from a [00:01:00] long sleep, um, that is all I recall as waking up and being told. Of my sepsis survival, um, events and the trials that I experienced, um, after being in the hospital for nearly a month, um, when I awoke, I was told that I had gone into severe sepsis shock as a result of having an unknown or undiagnosed kidney stone.

I remember preparing for my 50th birthday, getting excited about having, um, a photo shoot. And having a, a birthday party, um, in the time that I was in a medically induced coma that I had in fact suffered a cardiac arrest, I was down for about five minutes. I had two brain aneurysms or strokes. Every major body system was failing and, um, we just did not know how [00:02:00] devastating a sepsis diagnosis would be when I woke up.

I noticed that my hands and my feet were, uh, hard. They were cold to the touch. Um, I was unable to move them and they were beginning to curl. The last doctor that I was able to visit was my vascular doctor, and at that time, that’s when he explained to me that I had, um, dry gangrene. I had all four of my limbs amputated.

I know that each stage of my recovery, I had a whole host of doctors and nurses and specialists who saw me, but then they didn’t see me. They never saw what happened after I was discharged or after I was released. And I wanna just say that sepsis is such a devastating disease. After my amputation, I was fitted for prosthetics.

I worked very hard to get in prosthetics and to master them. I did suffer two strokes and, uh, [00:03:00] fortunately I had no debilitating results of those strokes. But it has left me very aware of the fact that sepsis is something that destroys body systems and has, has devastating effects every step of the way.

My recovery was, um, profound and remarkable because of. The cutting edge and new treatment options that are made that are made available because of sepsis research and because of sepsis advocates.

Nicole Kupchik: Hi everyone, and welcome to the sepsis spectrum. I’m Nicole Kupchik, critical care nurse, clinical nurse specialist, and you are a guide through the unpredictable world of sepsis, or as we like to call this season, sepsis and multiorgan dysfunction syndrome. The story we just heard was Kimberly Manuel, a survivor who woke up from a coma to find her body, life, and world completely changed.

She unfortunately suffered [00:04:00] so much from septic shock, cardiac arrest, to strokes to the loss of all four limbs, and yet she stood again, no small part. Thanks to modern medicine, relentless research and sheer determination. I think Kimberly’s story captures something profound. We often touch on is that sepsis isn’t just a battle in the bloodstream.

It’s a storm that reaches the brain. It alters consciousness, cognition, and identity itself. Even when patients survive, their minds may still be fighting to find their way back, and their body does its best to do the same. That very discourse. One of the brain and immune system being constantly in conversation is where today’s guest has reshaped medical science.

Dr. Kevin Tracy, president and CEO of the Feinstein Institutes for Medical Research at Northwell Health. A pioneer of vagus nerve research and author [00:05:00] of the Great Nerve. Dr. Tracy’s work bridges inflammation and neuroscience, revealing a fascinating communication network within the body. Notably a specific reflex control of immunity by the nervous system known as the inflammatory reflex.

A process where the nervous system literally talks back to the immune system sending electrical signals that can calm inflammation. His discoveries have played a crucial role in launching the field of bioelectric medicine and have transformed how we think about treating disease, especially through the therapeutic use of vagus nerve stimulation.

I can’t wait for you to hear this one. Dr. Tracy and I are about to have a wide ranging exploration of the interconnected natures of the brain, autonomic nervous system and immune system in sepsis. We’ll be right back with Dr. Kevin Tracy.[00:06:00] 

Hi, and welcome to the show. I am so excited today to be joined by Dr. Kevin Tracy. He has done so much work specifically on the vagus nerve and the vagus nerves role in inflammation. So welcome to the show, Dr. Tracy. Thanks for having me on. It’s great to be here. The work you have done in research is so incredibly impressive, and you’ve made so many ties to different inflammatory markers, the vagus nerve to sepsis.

So can you give the audience a rundown of just the research that you’ve been doing and the focus. 

Kevin J. Tracey, MD: For the past 40 years or so, I’ve been fascinated by the basic mechanisms of inflammation and sepsis, and it really started when I was training as a neurosurgeon in 1985 and, and a young patient named Janice died in my arms of septic shock and we couldn’t explain it.

I, uh, essentially have been in the laboratory since then, [00:07:00] essentially since. The summer of 1985, and what my colleagues and I at the Feinstein Institute at Northwell Health have discovered in the last 20 years or so, is the mechanisms, the signals by which the brain can shut down inflammation by sending signals through the vagus nerve.

And this is, this has opened, uh, uh, the possibilities to using a recent FDA approved device to actually treat rheumatoid arthritis. Patients now by, by, by suppressing their inflammation without immunosuppressing the patient. So there’s a lot, there’s a lot to unpack in that little, uh, introduction, and I look forward to covering that ground with you.

Nicole Kupchik: Well, and you know, we know sepsis is, we know it causes so many issues and we know inflammation is kind of the root of a lot of the issues It does cause So let’s just, I, I would love to dive in on this whole idea of the, the role of the vagus nerve in inflammation. [00:08:00] ’cause I’ll be honest, I’m not really up to speed on like what the literature is showing and, and its role.

So let’s, let’s just start from that perspective. So what is the role of the vagus nerve in, in sepsis and inflammation? 

Kevin J. Tracey, MD: The vagus nerve, uh, is, let’s, let’s start with some basic definitions first, perhaps like what is the vagus nerve? So the vagus nerve is a paired structure. You actually have two of them, like two kidneys or two thumbs, and it runs from your brain down your neck, across your chest, into your abdomen, and along its path, it sends out branches.

To all the organs that you never think about all day long. So the, the, the reason the, the vagus nerve carry signals back and forth from your organs to your brain and your brain to your organs is because these, these signals are, are the basis of reflexes that keep your organs functioning in balance.

When we have, when we have organs functioning in balance, we call that [00:09:00] homeostasis or health. And what happens during sepsis. Is organs functions become essentially dis dysfunctional. They, they don’t, they don’t function in harmony. And what’s become a fascinating field of, of inquiry is the role of the vagus nerve, which is the fight or flight.

Rest and digest autonomic nervous system components. So let, let’s talk about that for another minute. The, the autonomic nervous system as in autonomy, like self-governing, the autonomic nervous system is the part of the nervous system that you can’t control. Voluntarily. You can play the piano, you can walk and chew gum.

That’s the, the voluntary nervous system. The involuntary or autonomic nervous system includes the fight or flight or sympathetic nervous system and the rest and digest or parasympathetic nervous system. And most of the parasympathetic, [00:10:00] rest and digest nervous system signals are actually carried in the vagus nerves.

So that’s sort of a, a, a basic primer of, of what the vagus. Nerve does in controlling the reflexes to your organs, and, and most of what I said has been known for a hundred years or more. What, what’s relatively new is understanding how those signals in the vagus nerve actually control your inflammatory response or your cytokine storm as well.

Nicole Kupchik: Okay, well, let’s, let’s just dive into that because I think a lot of times we, when we see patients in septic shock, we often think of the sympathetic nervous system being on overdrive and releasing catecholamines so that you know, the, you know, hypothetically that their organs are preserved. But you’re saying that there’s actually, the parasympathetic system is playing a gigantic role in inflammation.

So let’s dive in. How is this working? 

Kevin J. Tracey, MD: Both of those systems are actually, um, activated during conditions that, uh, [00:11:00] you might think of. So let’s do an easy one exercise. When you exercise, your heart rate goes up, your blood pressure goes up, your respirations go up, and, and, and it’s as if you’re running away from the, from the, from the predator, from the, from the tiger.

And that, and, and people classically attribute that to fight or flight. Responses, which that, that’s what you see. That’s what we can measure. What’s fascinating is if you study sheep, and this has been done in a, in a study a a year or two ago out of New Zealand, a beautiful study studying, exercising sheep, uh, they, they made some measures that you could really only do in, in a laboratory.

You couldn’t really do this in, uh, in people short of, in, in an operating room. And what they found in these sheep. Was that not only when the sheep were running uphill on a treadmill, not only was there a fight or flight, uh, increase or, or response, but there was also a rest and digest response occurring at the same time.

And [00:12:00] to prove this, they measured the signals in the vagus nerve, which were increased. And they measured the effects of blocking those signals or cutting the vagus nerve. And what they saw was actually a worsening of, of athletic performance. They saw decreased cardiac output and they saw decreased blood flow in the coronary arteries.

So what does that mean? It means that although you can’t see the effects of the vagus nerve, which would normally slow the heart because the fight or flight response is sort of. Overwhelming. The, the, the ability to see the slowing of the heart rate, the slowing effect on cardiac filling, which occurs when the vagus nerve is firing at the same time as fight or flight, is actually really important and beneficial to the exercise response, the hypothesis, the theory, the thing that can be studied in sepsis.

Is, what is the influence of combined sympathetic and parasympathetic signals in the sepsis patient? Right now, the textbook would [00:13:00] say if one system comes on, like fight or flight, then the other system goes off that they act in opposition, but by the example and several others that I, that I didn’t go into, uh, today with you, but by the example I just gave, the evidence says it’s not.

Necessarily one on the other off, they can actually, they can actually be functioning together for the benefit of a, of a better outcome. 

Nicole Kupchik: And that’s something very different than we’ve been taught. Now, what’s interesting to me is there’s been some newer literature popping up about the use of beta blockers in sepsis.

Okay. So is the whole idea then that we’re just allowing for that parasympathetic system to be turned on a little more, or. How did, how, where is that connection? 

Kevin J. Tracey, MD: The, the, it’s not as simple as, as, uh, assigning an effect to a single drug or a single drug target. 

Nicole Kupchik: Well, we’ve, well, we’ve tried that with sepsis for years and we’ve realized it.

You’re right. It doesn’t 

Kevin J. Tracey, MD: work, right. Well, exactly [00:14:00] right. So let’s look, let’s look further in at the vagus nerve. I said you have two. You actually have a hundred thousand vagus nerve fibers on each side of your neck. So that means you have 200,000 vagus nerve fibers. My colleagues and I have have shown in laboratory studies and to some extent in clinical studies as well, is that when you drive signals down the vagus nerve to the spleen, those signals inhibit the production of cytokine storm by white blood cells monocytes.

Are either in the spleen, resident to the spleen, or passing through the spleen. And the spleen gets 20% of cardiac output every minute. So this is a way where you can have a signal from a few neurons in the brainstem, travel down the vagus nerve and be amplified so it can influence the circulating white blood cells.

For hours and hours after just a couple of minutes of electrical stimulation. Now all those effects are mediated by we estimate as few as a few [00:15:00] hundred, or perhaps a few thousand vagus nerve fibers out of the 200,000, and they culminate on a neurotransmitter called acetylcholine, which is actually made not only by the vagus neurons.

We’re talking about, but also by, uh, a white blood cell, a lymphocyte that actually makes acetylcholine in this, in this nerve circuit. So when someone talks about the effects of a single drug, say, say, uh, enderol or, or, or beta blockers. Those drugs diffuse everywhere in the body that they can get. They pass through your bloodstream and they, they saturate or they can prevent the activity of norepinephrine signaling through beta receptors on all kinds of different organs.

Your heart, your liver, your spleen, uh, your lungs. When, when you drive a signal down the vagus nerve into the spleen, you can actually target the effects on cytokine storm. [00:16:00] Slow it down without turning it off a hundred percent, without necessarily targeting targeting effects in other organs. And so this, this we call bioelectronic medicine, and it’s really the, the topic of, of a book that I wrote called The Great Nerve, which is frankly what, what Galen used to refer to the vagus nerve as the great nerve.

Nicole Kupchik: How do we make this connection clinically to human beings? Because you, I mean, we’ve, you’ve been able to show in animal models that these nervous systems actually work in concert and they’re not independent of each other. Um, so what does that look like in a human? So let’s say we’ve got a patient who’s septic or in septic shock.

Can we make the bridge to humans? Is that a little too early? Or how do you feel about that? 

Kevin J. Tracey, MD: We’ve made the bridge in humans through patients with rheumatoid arthritis and an and also inflammatory bowel disease. And the way we’ve done that to begin is to implant vagus nerve [00:17:00] stimulating devices, uh, implanted in clinical trials in Europe and, and most recently at a clinical trial that was completed last year.

The trial study today. Device that was developed by a company called Setpoint Medical. Full disclosure, I co-founded that company in 2007. I’m no longer an insider to the company, although I still am a consultant to it. Those trials showed quite convincingly. A couple things. First, uh, the pi, the original pilot studies done in Europe.

Showed a significant clinical benefit in patients with either Crohn’s disease or rheumatoid arthritis. And second, the larger clinical trial completed in the US as a pivotal a registration trial, which led to FDA approval a few weeks ago, actually showed that in patients with severe rheumatoid arthritis, so these are patients who are taking drugs called biologics like anti TNF and anti IL one, or JAKs, which are JAK stat inhibitors.

These are [00:18:00] very powerful immunosuppressing drugs. Those patients taking those drugs who are still having symptoms of rheumatoid arthritis, were able to be enrolled in the trial. The company needed 250 or so patients in their trial. They had 30, almost 30,000 applications. Wow. So the, so the demand from the patients to enter the trial, an experimental trial that involves a surgery.

Oh, it was very high. Now the surgery is a surgery in the left neck about, uh, through an incision about an inch and a half long, and implant a device that’s about the size of a multivitamin. And this device sits on the vagus nerve and delivers a small amount of current, about 400 micro amps for one minute a day.

Many of the patients slept through the therapy ’cause it, it was programmed to fire at about four 30 in the morning and the results were very, very striking. About 75% of the patient has significant benefit, [00:19:00] uh, within one year, and that benefit persists. We know from other studies for many years. So I’ve had that real good fortune of meeting some patients in that trial and in the previous trials, and I’ve met a few patients who take no medication, have no longer have any symptoms despite the seriousness of their symptoms before, and their only therapy is, is vagus nerve stimulation.

It’s really, it’s really remarkable. Yeah, it’s really remarkable. 

Nicole Kupchik: They’ve gotten off the biologics or, yeah. Wow. Some of ’em, not all of them, but, or at least, 

Kevin J. Tracey, MD: I mean, even if you can decrease the dose, that’s, well, a lot of them have gotten off the biologics. Many of them remember, these patients weren’t having benefit from the biologics.

They, and they were, they were, they were taking these drugs in the hope of either getting benefit in the future and or persisting going from one biologic to the next what? What turned out to be the case was that patients chose to enter the clinical study of vagus [00:20:00] nerve stimulation rather than going down a continuing checklist of biologics.

And And why is that? Well, it’s because the biologics have black box warnings. That means the side effects are so serious that you can get sepsis from immunosuppression or you can get cancer or you can have other problems. So patients preferred to actually try the vagus nerve therapy, and as I said, about 75% of them had a, had a significant lasting, lasting improvement.

That’s pretty impressive. All 

Nicole Kupchik: right, well listen, we’re gonna go to break and when we come back to break, what I wanna do is take this a step further and talk about how potentially in the future could this be used in sepsis.

Are you a healthcare professional who wants to stay ahead of the curve? Visit sepsis podcast.org to learn more about how you can receive free CME and nursing CE credits. By listening to or watching the sepsis spectrum. It’s our way of supporting you and together [00:21:00] better understanding the ever evolving world of sepsis care.

And now back to the show.

Well, welcome back from the break. We are now gonna chat a bit about just the kind of the connection between sepsis and a lot of the neuro encephalopathies and effects on the brain that we see from inflammation, and we’re gonna talk a little bit about how patients become immunocompromised. All right, so.

Dr. Tracy, let’s just jump in and chat about that. We know that sepsis has profound effects on the brain, and what are your thoughts about the role of sepsis its effects on the brain and inflammation? 

Kevin J. Tracey, MD: Inflammation plays a critical, uh, part to, uh, influencing how, how the brain responds to the, to, to, to its environment.

So if you [00:22:00] start really, really simply there, there’s overwhelming evidence now. That cytokines, things like IL one and and TNF produced in the body can affect the brain to affect how the animal or the patient feels. So, so for instance, if you inject a mouse with IL one. It will develop what we call sickness behavior.

It’ll run into the corner of the cage. It’ll huddle up, it’ll look sick. It will avoid eating, it’ll avoid playing, and it, it, it, it, uh, has the, the classic signs, if you will, of early sepsis in a mouse. Now, if, if I were to inject you with cy with cytokines, you would also develop sickness behavior. In fact, we know this, uh, because.

Either from clinical research studies where patients have been, uh, volunteered to be injected with cytokines or from some treatment studies where some cancer patients are [00:23:00] treated by infusion of cytokines. Those, those patients, they will get a fever, they will get nausea, they will get severe fatigue, they will get myalgias and ache, aches and pains, and some of them will become clinically depressed.

And in fact, many of these patients now knowing they have to be. Receiving a cytokine infusion for their cancer, for instance, many of them will be pretreated with an antidepressant in the hopes of minimizing. So what do we learn from that? Um, what we, what we, what we can take as, as a fact is that cytokines can produce, if you will, uh, depression.

It can also affect your ability. To learn, in addition to depressing your emotional affect, it can impair your ability to concentrate and learn. So from the simple comment you made comes this complex story of how do, how do cytokines have all these effects on, on the brain? And obviously the, the answer is it’s complicated.

You, you know, the brain is, is com [00:24:00] comprised of human brain of what, a hundred billion neurons or so, but there are trillions. Of connections between these a hundred billion neurons. And so cytokines can influence not only, and not just cytokines, molecules produce during inflammation that, that contribute to or cause the, the inflammation, those molecules change the way neurons function.

And when you change the way neurons in the brain function, you change the way, uh, you change how you feel. 

Nicole Kupchik: Well, and you know, clinically we have really had to do so much education with frontline. Healthcare providers about this neuro encephalopathy that we see and you know, and it’s just, I, I mentioned this in another episode, but it was just, it’s kind of interesting.

We have like, for example. 76-year-old female who presents with a urinary tract infection and she’s pleasantly confused. And then we label her as dementia. When she doesn’t have dementia. She’s gotten encephalopathy from sepsis. And, um, and it’s, it’s fascinating ’cause when I [00:25:00] first learned about sepsis, I was never taught about this.

And, and it is absolutely profound what we see. People are so tired and lethargic and confused. So it sounds like those connections, at least in research, were, we’re tr starting to figure out why this is happening. 

Kevin J. Tracey, MD: Research is done in a, in a reductionist way. So we try to dive deeper and deeper into rabbit holes to identify mechanisms of action.

And so that’s sort of the state we’re in now. Um, I it’s, the field broadly would be called neuroimmunology. It’s the study of. Looking at the role of neuroscience mechanisms and immunological mechanisms contributing to, to things like the encephalopathy, encephalopathy of sepsis or the, the depression or cognitive, uh, impairment that occurs in sepsis.

And what we’ve learned will s will surprise some of your listeners. So for instance, in the mouse experiment I told you about when, when you inject [00:26:00] IL one in the mouse and the mouse gets the sickness behavior, if you cut the vagus nerve in them. In those mice, they don’t get sickness behavior. So what does that mean?

That means that the IL one in the body is activating signals that are traveling up the vagus nerve. And the arrival of those signals in the brain is what’s turning on the, the brain, uh, responses. The brain neural networks that control the onset of the sickness behavior. And this is true also, um, for other molecules that you can inject into the body of the mouse and.

Cause signals to travel up the vagus nerve to change the way the brain is functioning. Another molecule that requires the vagus nerve to, uh, mediate its effects is actually, are actually the GLP ones and very few. I was gonna 

Nicole Kupchik: ask about those. Okay. Let’s chat because this is interesting, right? 

Kevin J. Tracey, MD: Very few people realize this.

Uh, I, I, I’ve recently been talking at a panel with a bunch of physician and scientific colleagues and they were surprised to hear [00:27:00] this too. So if you. Inject a mouse with GLP ones. The mouse will, will have anorexia, eat less and will have a drop in. Its its blood glucose, which is how these molecules were originally developed was to be for diabetes.

Well, when, when the investigators cut the vagus nerves in those mice and you have to cut the vagus nerves down in the abdomen, if you cut it up in the neck, uh, it’s lethal. When they cut the vagus nerve in the abdomen and injected the glp, the mice did not have anorexia and they did not get the hypoglycemia.

Now, the, to prove that this is also true in humans, a uh, a surgeon, a surgeon researcher in the UK actually repeated the experiment in humans who were having gastric, uh. Stomach cancer surgery, gastric cancer surgery. And, and what he showed was that when he treated patients pre-op with GLP ones, they had anorexia and, and decreased, [00:28:00] um, blood sugar.

But when he cut their vagus nerves and repeated the exact same experiment in the exact same people post-op, now they did not have anorexia and they did not have hypoglycemia when they, when he gave them GLP once. That just shows you how complex this is because the vagus nerve has. As I said, 200,000 fibers, 80% of them are sensory, and so the amount of information that’s, that’s traveling from your patient that you mentioned before with the urinary tract infection where there’s inflammation in her bladder, potentially maybe her ureters, maybe all the way up into her kidneys, that amount of inflammation is creating information, information which is traveling up the vagus nerve as electrical signals.

Which changed the way the brain works, and all of a sudden now you, you go from this simple idea of a few white blood cells in the urine to an incredibly complicated neurological response in the brain. 

Nicole Kupchik: I mean, it’s, it’s [00:29:00] absolutely fascinating. I think the thing I’ve come to realize, I mean I’m 33 over three decades into this career, is that the more we learn, the more we realize we have yet to learn.

Right. I mean, so, okay. One other thing I wanted to chat about is, so you’ve talked about the role of the vagus nerve in inflammation or maybe even. Possibly decreasing inflammation. You’ve been able to show that. So do you, if you had a crystal ball or, or let’s say you’re the director of a research program, which you are the director of a research program.

Okay. So let’s say you had a crystal ball or you could at least drive, um, research, what is that gonna look like? Connecting the vagus nerve and inflammation to sepsis. 

Kevin J. Tracey, MD: We will need a, a new definitions and new understandings of sepsis before I think we make significant inroads in, in treating it [00:30:00] Where we are today is we have a very good understanding that neurons traveling in the vagus nerve from the brain to the spleen can reduce the amount of cytokines produced during acute cytokine storm.

So the kind of cytokine storm that’s activated, for instance, by giving bacterial endotoxin or a lipopolysaccharide, we understand a great deal about those mechanisms and we’re able to apply it to conditions, like I said before, rheumatoid arthritis in in humans. But we’re not exactly sure what else is happening.

So in the case of rheumatoid arthritis. Other things happening include the fact that vagus nerve stimulation can increase the release of resolvins, resolvins, or molecules that accelerate the resolution of inflammation. There’s also evidence that vagus nerve signals can change the balance between osteoclasts and osteoblasts.

Those are the cells that destroy the joint [00:31:00] in rheumatoid arthritis or actually can rebuild it. So. How these would apply to sepsis, uh, remains an open research question. Now, the good news is that in animals, we and others laboratories around the world have studied vagus nerve stimulation in animals with.

Bacterial endotoxemia and in animals with bacterial sepsis caused by either colitis or by sequel ligation and puncture, or by infusing bacteria and causing infections in these animals. And we have seen some positive results, but the issue will be trying to apply these acute. Studies in mice that are very genetically homogeneous to patients who are not homogeneous genetically or in any other way, and in fact, to patients who come in at all various stages of their sepsis.

And here’s, here’s where it gets really interesting and complicated. So if you look back at, at COVID, [00:32:00] there’s a lot of evidence from the, from, from some of the COVID induced sepsis, if you will. That patients with severe COVID often had damage to their vagus nerves. And this was seen at autopsy in careful autopsy studies out of Spain.

But it was also seen in patients who survived and had, uh, sophisticated ultrasound and MRI imaging of their vagus nerves. And what they saw was not only damage to the vagus nerve, uh, from in inflammation in and around the nerve, but also in some patients they actually found virus in. The COVID virus, the SARS virus in, in the vagus nerve.

Now, if you damage the vagus nerve during the course of sepsis, either the inflammation damages it or the infection, what you, that’s like cutting the brakes on your car. So it it, it raises a whole new, new question. Is the damage to the vagus nerve actually contributing to or allowing the overproduction of cytokine storm?

So the, the number of [00:33:00] questions is, is, is lengthy and it’s almost like we need a reset on some of our definitions, what is necessary and sufficient. To cause various aspects of sepsis and, and, and what, where can we, where can we turn for new answers? I think we’re positioned to do that now, and I think you will see future clinical trials of vagus nerve stimulation and sepsis.

And I, uh, uh, you know, I encourage my colleagues to do this research, but to do it slowly and carefully and in a way that is hypothesis driven in. Well controlled randomized clinical trials, not like you find on the internet today with billions of web impressions, with do this, that, or the other thing for your vagus nerve and everything will be fine.

It’s not that simple. 

Nicole Kupchik: Yeah. Well, and I think if we’ve learned anything from research and sepsis is that, A, it’s complicated, and B, there’s not a silver bullet. We’ve just, we’ve, we’ve learned that. Right. Okay. So I have one more question for you before we end the show. Do you feel, [00:34:00] now this is, again, super like hypothesis, uh, generating question here.

Do you feel there is a role of GLP one’s acutely in sepsis? 

Kevin J. Tracey, MD: It’s a fair question that’s being studied right now. There’s a sense, I think by, by some, again, from the, from the billions of web impressions and social media postings, you can find there’s a sense that it’s, uh, that it’s snake oil and some sort of holy grail.

The reality will be somewhere in between the fact that it’s. That, that it, that there’s so much hope and promise for it, uh, at one extreme and at the other extreme that nobody should take it ’cause we don’t know all of its side effects. Somewhere in the middle will be the answer. I, I fully expect. I think the challenge will, with sepsis and, and, and putting GLP in the context of sepsis will be the same challenge we’ve had from the early days of cytokine biology back in the, the late eighties and, uh, early 1990s.

And the challenge is actually very simple. Uh, just because two [00:35:00] people have elevated heart rates, uh, elevated body temperature and an abnormal white count doesn’t mean they have sepsis. If I told you one of them just ran a marathon and the other one has a perforated appendix, you’d have a totally different view of, of those two patients.

The, the problem we have today is. If you wanted to do the study, you propose of using GLP one in patient A, B, C, or D. We don’t even have, today, we don’t even have the language to separate them into comparable patient groups. And so it’s, we’re still, we’re still back to base basics. I, I argue actually strongly that.

We have, uh, we have to be very careful about definitions and so something as simple as inflammation. What is inflammation? Well, it’s the heat, the redness, the pain, and the swelling that you see when you have an infection in your arm or when you sprain your ankle. That’s what Galen taught us 2000 years ago.

Fine, but. When I look at, uh, at a patient with myocarditis [00:36:00] and sepsis and I look in their heart at autopsy, I don’t see redness. It’s, there’s, there’s no heat and swelling. You know, what you see in a patient like that might be, and, and, and maybe there’s a few extra white blood cells, and you might see a upregulation of the production of some cytokines, TNF or IL one or something.

But is that really the same as what Galen was talking about? We almost need new definitions. Organ by organ and patient by patient. And until we can sort of figure that out, then, then it’s really hard. Gonna be hard to design the clinical trials to develop the therapies. It’s not so much that we’re missing a magic bullet, it’s it we’re missing basic definitions.

Nicole Kupchik: Yeah. Wow. 

Kevin J. Tracey, MD: Well, if, if anything 

Nicole Kupchik: we’ve learned it is complex. So Well, I wanna thank you for being here today. I am just so appreciative of people like you who are willing to just go out there. Do the research because we know that it’s definitely gonna help future, future generations of [00:37:00] people who experience sepsis.

So thanks again for being here today. 

Kevin J. Tracey, MD: Oh, thank you for having me on. But I, I think. You know, I thank you for your kind words, but I, I’ve spent the last 40 years doing what I love to do, working with brilliant colleagues, doing research, trying to find answers that might help people. But you know, the people who who deserve the real gratitude and and praise from all of us are the patients.

’cause they don’t choose to get sick. And many of them participate in clinical trials and, and they suffer through what they suffer through because they have to, not because, like me, I. They, I get to do what I love to do, so, so it’s, it’s the patience that I’m grateful for. 

Nicole Kupchik: I would a hundred percent agree with you 

Kevin J. Tracey, MD: on that as well.

Nicole Kupchik: That was a really interesting episode with Dr. Kevin Tracy. I honestly had no idea that this was even a thing where your vagus nerve was playing such a [00:38:00] role with your immune system in sepsis. And I, I’m honestly, I’m very fascinated to see what happens in the. Couple decades to see where this goes and if perhaps we can kind of make that bridge from research into patient care.

It’s gonna be fascinating to see, you know, where that goes. But, um, I just wanna thank you for joining me on today’s episode of the Sepsis Spectrum. If you have a story you want me to read on air, visit www dot human content. Dot com slash sepsis. Speaking of which, here’s a submission we received from Haley b.

I am 28 years old and survived severe septic shock in 2020 at the age of 23 from a misdiagnosed ruptured appendix. I’m based in Toronto, Canada. Was misdiagnosed by two separate hospitals who had assumed I was dealing with menstrual pain and female related issues. My blood pressure [00:39:00] dropped to 50 over 30, and I was rushed to the hospital for a third time where I underwent a laparotomy and multiple blood transfusions.

I was on a ventilator for a week and in the ICU for 45 days. I underwent many months of recovery, including physical rehab and treating my mental health for PTSD and post sepsis syndrome. I have since recovered, but have lingering chronic fatigue and scarring on my abdomen. I love sharing my story to encourage patient advocacy and the misconception of young, healthy individuals.

Not being at risk of developing sepsis. Well, Haley, I wanna thank you for sharing your story because I think it is a big misconception that young people don’t get as sick as perhaps an elderly person who’s got pneumonia or urinary tract infection. And I think your [00:40:00] story is telling of the long-term effects that can happen.

And this was something as. What we call air quote, simple as an ruptured appendix, which we know can be quite complex when it ruptures. And so you know, Haley, thank you again for sharing your story. If you have a story you want me to read on the air, visit www.human-content.com/set. And if you’re enjoying the sepsis spectrum, we wanna hear about it.

Please leave review wherever you’re enjoying this podcast. It helps a ton. You can also reach me and our awesome team@infoatsepsis.org or visit sepsis podcast.org to share any stories of your own or questions, concerns, or episode ideas. To learn more about Sepsis Alliance, visit sepsis.org. The sepsis spectrum is brought to you by Sepsis Alliance.

I’m your host, Nicole Kupchik. Our executive producers are Alice Strickland, Hannah Sass, Claudia Orth, and Alex Colvin. Our producers are Aron Korney, Rob Goldman, Shahnti [00:41:00] Brook, and me Nicole Kupchik. Our post-production producer is Sundus Hassan Nooli. Our editor and engineer is Jason Portizo, and our music is by Omer Ben-Zvi.

To learn about Sepsis Alliance’s podcast, legal disclaimer and compliance policies. You can visit sepsis podcast.org/disclaimers. The sepsis spectrum is a human content and sepsis alliance production.

Thanks for watching. I hope you’re enjoying the sepsis spectrum. Leave a comment below and let me know if you want to binge some more episodes. Just click that playlist right over there and if you’re feeling super generous today, give this video a like, subscribe if you haven’t hit the bell. All the things.

And of course you can also listen on the go wherever you get your podcast. Bye.