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Frostbite: From Napoleonic era treatments to the first FDA approved frostbite drug
Dominique Jean Larrey lived quite a life. He was born in 1766, and at the age of 13, had to walk from his home in a French village to study in the city of Toulouse. That journey was 70 miles, and yes, he walked it. That would be important much later in his life, when he found himself walking through the bitter cold in Russia as the Chief Surgeon of Napoleon's army. During that time, Napoleon's troops had to contend with the reality of Russian cold and temperatures that got as low as -37 degrees Celsius, which is about -35 Fahrenheit.
Larrey attributed his ability to withstand the cold to his walking. But many of the soldiers around him wound up with frostbite, and to treat them, Larrey suggested slowly rewarming the affected area and rubbing it with snow. Frostbite treatment has been on quite the journey since then, and it was just earlier this year that the FDA approved the first drug to treat frostbite in the US, which is exciting news for the doctors who see cases of frostbite and for patients who are often left with the horrific reality of amputation.
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Dominique Jean Leray lived quite a life. He was born in 1766, and at the age of 13, he had to walk from his home in a French village to study in the city of Toulouse. That journey was 70 miles, and, yes, he walked it. That would be important much later in his life, when he found himself walking through the bitter cold in Russia as the chief surgeon of Napoleon's army. In the meantime, though, loret was busy he was winning awards for his academics, including a medal for his thesis on bones, sailing to Newfoundland as an assistant naval surgeon, leading medical students in an attack against the Bastille, and advancing battlefield medical care by inventing the flying ambulance, a wagon that held all the medical necessities and staff to help soldiers on the battlefield, so they wouldn't have to wait for the fighting to end to get care.
Speaker 2:And then, in 1812, napoleon decided to invade Russia. It's hard to find good records for this, but it's estimated that Napoleon started out with an army of around 500,000 soldiers. By the end of the year, he would retreat with only 20,000 having survived. This was obviously not the outcome Napoleon had expected when he crossed the Neman River that June. The army had been prepared for a much faster victory, which meant they were dressed for warm weather, but there were cold rains that summer, and when victory didn't come quickly, napoleon's troops had to contend with the reality of Russian cold and temperatures that got as low as negative 37 degrees Celsius, which is about negative 35 Fahrenheit.
Speaker 1:Luray attributed his ability to withstand the cold to his walking, but many of the soldiers around him wound up with frostbite, and to treat them, luray suggested slowly rewarming the affected area and rubbing it with snow. Frostbite treatment has been on quite the journey since then, and it was just earlier this year that the FDA approved the first drug to treat frostbite in the US, which is exciting news for the doctors who see cases of frostbite.
Speaker 3:When winter comes, we all gear up for frostbite season, because what that means to us is that we're just going to deal with a lot of amputations.
Speaker 1:That's Lucy Wibbenmeyer, a clinical professor of surgery at the University of Iowa. We reached out to her because for many of us in the Northern Hemisphere things are starting to get cold, but frostbite is also starting to make appearances in places where you might not expect it.
Speaker 3:Frostbite, with climate change, has really started affecting more southern areas. I'm giving a talk shortly in South Carolina because they wanted to hear about it. San Diego I gave a talk to because they had some frostbite issues, and then, of course, texas had horrible frostbite and more people died during that cold exposure than died during their recent hurricane. So more sites, not restricted to our little group, are calling out and asking what do we do with frostbite? Because frostbite is so different from anything else you'll treat and it does require a little bit different skill set.
Speaker 1:Hello and welcome to Tiny Matters, a science podcast about the little things that have a big impact on society, past and present. I'm Deboki Chakravarti and I'm joined by my co-host, sam Jones.
Speaker 2:Today, on Tiny Matters, we're going to be talking about frostbite, which, as an aside, is perfect timing, because today in DC it is in the 20s, it's cold. Yeah, it's a harsh reality that winter is here, yep. So we're going to talk about frostbite what it is and the journey that frostbite treatment has been on since the Napoleonic era. We're also going to cover some of the exciting work that scientists and doctors are doing to improve frostbite treatment and also that promising drug that the FDA approved just last year. Okay, so what causes frostbite?
Speaker 4:Frostbite happens when tissues freeze after prolonged exposure to extreme cold. So, to protect your vital organs, your body essentially prioritizes blood flow to the core and reduces flow to the extremities like your fingers, toes, your nose and your ears.
Speaker 2:That's Rachel Nygaard, a faculty researcher at Hennepin Medical Center in Minnesota and the Hennepin Healthcare Research Institute in the Department of Surgery. She explained to Deboki and me that there are two different types of frostbite. The first is contact frostbite.
Speaker 4:Contact frostbite happens when you come into you're touching something that's very, very cold, so this can be a hyper-cold metal of some sort or the ground, and so that acts much more like a superficial burn. It can become a very deep burn if the contact continues or if it's a very low temperature. You see it a lot more in industrial injury, where you're around different chemicals or metals that are hyper-cooled.
Speaker 1:But the type of frostbite we'll be focusing on today happens due to atmospheric cooling. So it's cold out and maybe you're skiing or you're driving somewhere and your car breaks down. As you stay out in the cold, your body starts to cool down. Lucy explained it to us in terms of what happens if, say, your hand is exposed to cold weather.
Speaker 3:What happens at first is your body will constrict the blood flow to your fingers and then, as the cold proceeds, the constriction will go from your fingers to your hand to your arm, Before you get total shutdown of blood flow to those areas. However, you get alternating constriction and dilation of the blood vessels, and that's called the hunting reflux.
Speaker 1:The hunting reflux, or the hunting response, is thought to be a way that our body has adapted to cold temperatures. The amount of blood flowing to your fingers and toes oscillates, sometimes going down and then sometimes going back up, which might then help maintain the tissues in that area. But if you're out in the cold long enough, that response will stop, leading to total constriction of blood flow.
Speaker 2:That already sounds not so great, but frostbite is a two-step injury and that's just the first step where, to protect itself, the body has to prioritize where it's sending blood, through a process called vasoconstriction, where blood vessels narrow, restricting blood from flowing to the limbs.
Speaker 4:And while this helps conserve heat, it also deprives those areas of oxygen, causing ischemia. So as the exposure to the cold continues, ice crystals actually start to form outside of the cells in your body and this draws water outside of the cells, which causes dehydration. And if the freezing then persists, ice forms inside the cells, damaging the cellular structure, leading to cell death.
Speaker 1:That all sounds awful, but hopefully at some point your body will warm up and that should fix all of your problems right. Wrong, rewarming is very important, but unfortunately it also causes damage, because the return of blood flow triggers inflammation.
Speaker 3:When you get back into a warm environment, you have a reperfusion phase and that's when blood is restored and it's intensely painful and if it's not treated appropriately, you can have re-clotting of those vessels and then the tissue will actually get black and that's what we call necrosis, and will become necrotic. And oftentimes we also refer to that as dry gangrene, where the digits just look mummified and they're black.
Speaker 2:Your risk of frostbite and its severity is linked to a number of factors, but the main risk factor is your exposure to extreme cold. So that could be everything from being a winter sports enthusiast to traveling during a winter storm and dealing with car troubles, but Rachel and Lucy both told us that a large population that's at risk for frostbite are people who lack secure housing. Any of these factors make treating frostbite a challenge, because they can delay a patient's ability to get treatment.
Speaker 4:The key thing with the medical treatments for frostbite injury is it's really dependent on the timing of the injury. So there's a critical window that occurs after the tissue is rewarmed, when treatment needs to happen. So the goal is to minimize what's called warm ischemia time. That is essentially the time when you've been warmed up and that tissue is still not getting oxygen. So, as you can imagine, you know, the longer that your tissue is being deprived of oxygen because of blood clots in that area, the worse the ultimate injury is going to be, because as your tissue is continued to be poorly perfused, then more and more cells in those areas are going to die. So in one study we found that with each hour, delay in treatment resulted in 28% decrease in tissue salvage.
Speaker 2:Thankfully, the treatment that patients received today looks a bit different from Larea's treatment rubbing snow on frostbite but there was some basis to his ideas. At the time, luray realized that the soldiers who were warming up near a fire often ended up with gangrene, where tissue starts to die. So using snow was thought to lower the chances of that happening, and this slow method of rewarming would continue to be the generally accepted practice for a while. But over a century later, in the 1930s, ussr scientists tested out the idea that rapid rewarming might actually be better, though their work wasn't read more widely until it was later translated into English.
Speaker 1:And across history, war has often meant frostbite. During World War II there were about 70,000 frostbite cases in Americans and across history, war has often meant frostbite. During World War II there were about 70,000 frostbite cases in Americans and with the urgency of war and more research, an increasing number of scientists would report on the value of rapid rewarming instead of slower methods. But the man who gets much of the credit for shaping modern frostbite treatment is William Mills, a doctor practicing in Anchorage, alaska, where he saw a lot of frostbite cases With his colleagues. Mills would go on to publish a series of studies in 1960 and 1961 that established a rapid rewarming protocol.
Speaker 3:So those extremities, anything that's frostbitten, is placed in a circulating water bath that's anywhere between 40 to 42 degrees. The key is first getting a container, and this is hard to do in emergency rooms, as you can imagine. First getting a container and then making sure that it's swishing around, that you maintain the temperature at 40 and 42 degrees. So that's hard.
Speaker 1:That's 40 to 42 degrees Celsius, which is 104 to 107.6 degrees Fahrenheit, which is pretty warm.
Speaker 2:Today, frostbite is usually treated in burn centers, and when it comes to figuring out how severe a patient's frostbite is, rachel told us that doctors have a few options.
Speaker 4:First is just the clinical assessment of the injury, where doctors assess things like skin color, temperature, sensation. However, frostbite does evolve over time and what you initially see may not reveal the full extent of the injury, and that's where imaging comes in these imaging tools include things like bone scans that can help doctors evaluate blood flow in the tissue.
Speaker 4:And this provides a much clearer picture of what's happening at that time to evaluate how much tissue has been impacted by frostbite. So you generally have two different types of severity. So you have the superficial type of injury and this affects just the outer skin layers. It's treated with warm water, rewarming, some pain relief and some wound care. So generally those people are going to heal and are going to have very few complications. Then you have the more deep frostbite and this is severe frostbite that affects muscles, tendons, even bones.
Speaker 2:Treating this deeper frostbite requires more interventions, which we'll talk about in a minute, but it can also end up requiring amputation to get rid of the dead tissue.
Speaker 4:The biggest thing is. Frostbite treatments focus on acting quickly to minimize the tissue damage. So your first step is to protect the area from cold exposure and avoid thawing the tissue. If you're still at risk for refreezing Because the freezing, thawing and refreezing causes even worse damage to the injured tissue Rewarming will happen, and it's the most critical step. It's typically done in warm water baths, and while this is effective, it can be painful, so you have to make sure that you have some pain management. Typically, you want to do this in warm water as quickly as tolerable and you want to make sure that you're not rewarming with a fire, because when you have frostbite injury, you lose sensation in those areas, so you could end up actually with a flame burn on the tissue that doesn't have a return of sensation yet, and so that's doubly bad.
Speaker 1:And alongside rapid rewarming, doctors have made further improvements to frostbite treatment using drugs that can help improve blood flow while also reducing clots and inflammation.
Speaker 4:We use clot-busting drugs called thrombolytics, which are similar to what they use for strokes, to reduce and prevent clot formation in the tissue. We also use vasodilators like iliprost to help open up the blood vessels, some anti-inflammatory medications like ibuprofen or aspirin to reduce inflammation, and then usually some longer-term anticoagulants to prevent new clots from forming in the damaged vasculature.
Speaker 1:Rachel mentioned a drug called Iloprost. This is the drug that the FDA actually approved this past year. Iloprost was developed in the 1980s and it's been used to treat diseases like Raynaud's, where blood flow to the extremities is limited, and in 1994, an article was published in the Lancet reporting its use to treat frostbite.
Speaker 3:So it's been 30 years between that initial report and its approval by the FDA, and Lucy told us that this approval is thrilling, and the thing that we're excited about with IslaProst is it seems to be a little more forgiving in terms of the time to start, so it seems that it's effective if you start before 24 hours and it can also be given for days after that, up to like six days, and, like I said, we're all really excited to use it. We have no experience in the US, so we're relying on the experience of our European colleagues.
Speaker 1:And remember timing is critical when it comes to frostbite treatment. Rachel told us that in one study they found that each hour delay in treatment led to a 28% decrease in tissue salvage. Another major challenge is assessing just how severe an injury is.
Speaker 4:Clinical exams can be subjective and often the ability to evaluate frostbite injury severity just visually and clinically depends a lot on how experienced you are in seeing frostbite. Injury Severity just visually and clinically depends a lot on how experienced you are in seeing frostbite. Frostbite's a relatively rare condition so not every clinician has experience or has even seen frostbite. And the imaging tools that we use, like bone scans and angiography, they aren't available at all hospitals so that kind of uncertainty in the urgency of care can delay treatment, I think it really starts with knowing what you're looking at, because no one's used to looking at frostbitten extremities.
Speaker 3:They're just so different. I mean, like I said first, when you'll see a patient, the appendage that's frozen, like the finger, the toe, the hand, the foot, will appear white and waxy and firm and then, once it gets rewarmed, it is anywhere between pink and that's going to be full recovery to dusky or cyanotic.
Speaker 1:Cyanotic is when your skin turns a bluish, purplish color because of the lack of oxygen.
Speaker 3:But the unique thing with frostbite is it can change, and if it's not treated with thrombolytics in a timely fashion, or if it's not you know, soon it will be isoprost you'll see necrosis set in and that can happen. It's quite horrifying that happens in about a week or two weeks where it just starts turning black. And then you have to know that usually we don't operate right away. There used to be a saying frostbite in January, operate in June. Now that's not quite the case anymore. We don't usually wait that long, but it's certainly not a disease where you have frostbite in January and you operate mid-January. We usually push it out, probably about a month or a little bit more, because sometimes you'll get recovery and so it's really hard to tell if that tissue is going to come back and recover and actually what's happening is it's recovering underneath that necrosis and the necrosis then will lift off. So sometimes it's hard to tell exactly what's going to recover what's not so.
Speaker 1:frostbite is tricky to treat, and compounding all of these issues is the fact that it's also hard to do research on. There isn't a great animal model to work with, and frostbite itself is a seasonal disease with sample sizes that are so small that it can be hard to make really strong conclusions about how to best pursue any kind of treatment. So I asked Lucy what it's like to treat something like frostbite, where you have to work with a lot less information than you'd like, especially when the stakes are so high and people are facing potentially losing limbs.
Speaker 3:Having limited knowledge doesn't really increase your confidence that much, and that's hard, I mean, as physicians, oftentimes we have to fill in the blanks. I mean I hate to have to say that, but not everything is studied. I mean, every patient is really unique. Everyone's not like a little cookie cutter, and so in some regards we do this all the time. But there's some diseases, like frostbite, that you're like, oh my goodness, we just have to be able to study this, because there's got to be a way we could actually save this finger or save this toe. And so, yeah, it's sad that we don't have the information that we need to really give everyone optimal care.
Speaker 2:But, of course, scientists and doctors are working to improve frostbite treatment. Scientists and doctors like Rachel and Lucy, and their findings are making a difference. Rachel told us about a study where they looked at the importance of the time between when patients went through rewarming to when they received thrombolytics, those clot-busting drugs that we talked about before it was about eight hours usually on average and we got it down to about four and a half hours.
Speaker 4:And I know a lot of centers have really prioritized and kind of changed their protocols to make sure that people know that this is a limb-saving, potentially intervention.
Speaker 1:Rachel and Lucy are also heading up a study funded by the Department of Defense that's coordinating the experiences of 14 burn centers across North America to figure out how to treat frostbite and standardized care.
Speaker 3:We're super excited about this study for one Frostbite just really hasn't gotten enough attention, and it's a horrific disease when it happens, so we're just super excited that we can now study this.
Speaker 1:Among their goals, they want to learn more about the importance of timing in delivering thrombolytics and the role of visual assessments in frostbite treatment, as well as to evaluate the ability to deliver treatments to patients who are in remote areas and might not be able to get to a burn center. The hope is that this study will help fill in the gaps left by previous research.
Speaker 3:We have studies that involve maybe up to 500 patients and these studies have been going on since 1990, and there's only 500 patients that have been studied. They show across the board that thrombolytics cut the amputation rate in half. However, they've all used different definitions and so it kind of makes the literature kind of murky and hard to interpret, and so this will be a study that we hope will be definitive in showing that, yes, thrombolytics work and, yes, you need to get those patients to hospitals that can actually do thrombolytics and save their fingers and their toes.
Speaker 2:Their study is going to be taking place over five years. This year is the first, which makes this upcoming winter a big deal for them. So in the meantime, we wanted to know what do Rachel and Lucy think are the most urgent aspects of diagnosing and treating frostbite?
Speaker 4:My biggest one really is how reliably we can determine which tissue is at risk early in the injury, and so I think that's just such a key question because it drives treatment. So if we can figure out a good way to evaluate it in as low of a tech way as humanly possible that will allow for evaluation at more rural centers in the field, all of those things and potentially at least then triage like yep, this looks severe, so we need to send them on for more intensive treatment, or no, this looks like it's going to be a superficial injury, so they should be okay at this smaller hospital or for the military, depending on where they are in the world.
Speaker 3:One thing that has changed is just the need to get the knowledge out about time as tissue. Time can save fingers and toes and that information has to be everywhere. Somehow it has got to reach the patients. It's got to reach the shelters that some of them go to, it's got to reach the outside emergency rooms that they may go to, and then they may just sit and wait all night for a bed and people not realize that time is tissue. So I think the public announcements, the public knowledge has to get out there.
Speaker 1:I think it's my turn. I think you're right. This is going to last for like one more episode maybe at most. After that, we're forgetting, we're back to how it's always been, oh for sure yeah.
Speaker 1:Well, today I have one of my classic long article recommendations that I just think is a really interesting read, and this is an article in the Atlantic by Daniel Engberg that's called the Business School Scandal that Just Keeps Getting Bigger. Some of you might remember there was this researcher, a professor at Harvard Business School, who was studying honesty, only to end up accused of academic fraud. I think there's like the inherent dramatic irony of that. Yeah, like really got a lot of attention, and I think also a big part of that is something that this article talks about is the fact that a lot of these business school researchers are doing research that is really, I guess, like marketable. One thing they said are like the TED Talks. Even the article itself talks about the fact that in the Atlantic they often have business professors getting interviewed and every person who was interviewed for this article is someone who's been interviewed for another article. Like there's just inherent marketability associated with research that comes out of these places.
Speaker 1:So it got a lot of attention, and this article is about the fallout from that reveal and how it's affected other researchers associated with this work, and really it's just kind of about like the whole can of worms that comes with having your work questioned and like then trying to prove that your other work is also fine, like well, that was bad, but the rest of my stuff is good, but like, maybe sometimes that also doesn't go the way that you expect it to.
Speaker 1:And so this is a really long article and I think it's worth it, partly because I am a sucker for petty human drama and there's plenty of that in there. But I think also a lot of it is about the nitty gritty details of setting up experiments and where things can go wrong, and I think that's just great to remember because, again, like, at the core of this story is research that is very, very marketable and I'm not saying that you should distrust research that makes it into the headlines, because obviously a lot of that research is based on work that is not necessarily fraudulent. But it is good to think about what are the caveats that can exist around how this work is done and just like have a sense for some of the criticisms that exist within academia, within these research communities, and you know, coming from like a bio background, like I think we have a sense for like some of that within our respective research fields that we worked in, but it's always good to like kind of see what that looks like in other fields.
Speaker 2:I think also just following these kinds of stories and trying to understand conflict of interest and thinking about a legitimate study design and statistical significance and, again, like, who's involved in the study, what do they seek to gain from it? It can be very complicated, so I think it's that's like a form of literacy in itself. I think like that ability to evaluate these kinds of things. Yep, definitely so. My tiny show and tell is about how it was just found that Florida panthers appear not to be susceptible to chronic wasting disease that's found in infected deer. So chronic wasting disease. It is caused by misfolded proteins called prions. We have an episode on prions that I can link to in the episode description, but one of the things that we learned in that episode was these prion diseases. So these diseases caused by these misfolded proteins called prions include things like chronic wasting disease, which you often see in deer elk, a few other animals in particular, and it's very similar to BSE, so bovine spongiform encephalopathy, aka mad cow really devastating diseases and communicable right. So like these are infectious diseases. If you haven't listened to the episode like the big concern with chronic wasting disease is animals, including humans, that maybe eat deer and eat certain parts of the central nervous system maybe they're not getting just the meat from the rest of the animal are then exposed to prions and that's very dangerous. So there's a lot of concern about other animals and I know that when it came to BSE, aka mad cow, there were cats that were affected. Prions in infected either sheep or cow, I can't remember at that point.
Speaker 2:Tissue got into cat food that was then sold and distributed and people's household cats got prion disease, which was really sad. Dogs didn't, which was interesting. So I thought that this was kind of fascinating because Florida panthers are, of course, large cats. So I thought it was kind of fascinating because Florida panthers are, of course, large cats, so I thought it was kind of interesting that they don't seem to actually be getting chronic wasting disease and it's great news for the Florida panther because it can really wipe out a population. It's really really really dangerous. It's just one of those little things where I saw and I was like, huh, interesting. So household cats are susceptible to prion diseases, but maybe the panther isn't.
Speaker 1:Yeah, also, this is like really revealing of my own ignorance, because I was kind of like huh, florida has panthers.
Speaker 2:So the Florida panther is one of two native cat species in Florida.
Speaker 1:Yeah, so just for anyone else who is similarly confused, they're not a species that ended up in Florida through poor exotic wildlife management.
Speaker 2:Yeah, no, no, no, they're supposed to be there. Yeah, we're just happy they're not all getting these prion diseases. But I thought that was kind of like a cool callback to something that we talked about, I don't know, a year and a half ago at this point. Maybe even longer. Yeah, it's possible it was even longer. But yeah, prion diseases are terrifying. They make me really nervous. So the less that it's able to spread, the better. Yep for sure. Well, good job, Florida Panthers. Yeah, nice work, Florida Panthers. Thanks for tuning in to this week's episode of Tiny Matters, a podcast brought to you by the American Chemical Society and produced by Multitude. This week's script was written by Deboki and was edited by me, Sam Jones and by Michael David. It was fact-checked by Michelle Boucher.
Speaker 1:Sam is also our executive producer. The Tiny Matters theme and episode sound design is by Michael Simonelli and the Charts and Leisure team.
Speaker 2:Thanks so much to Lucy Wibbenmeyer and Rachel Nygaard for joining us. A reminder that we have a newsletter Sign up for updates on new Tiny Matters episodes, video clips from interviews, a sneak peek at upcoming episodes and other science content we think you'll really like. We'll see you next time.
