Fever
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Welcome friends and family to another episode, because that's the only people listening to the podcast, another episode of Dr. Matt and Dr. Mike's Medical Podcast. I'm your host, Dr. Mike Todorovich, and I'm joined today by my co-host, Bernard Fanning. How are you, Bernard? Statistically, nine out of 10 injections are in vain.

Oh, nice, nice. Very good. I'd like to know what that 10th one is in. Maybe intramuscular. Thank you, my friend and foe, depending on the day, Dr. Matthew Barton. Are you good? It's getting hot in here. Next part. Next part, please. We may have a fever. All right. Okay. I was sure it was half off, but fair enough.

We are talking about Fever, not the song, you know, You Give Me Fever. There's a lot of songs about fever. That's a good one, right? Michael Bublé's version of Fever is very good, I have to admit. We're going to talk about- Woman on Fire? What's that? There's Sex on Fire by Kings of Leon. My daughter, Zarina, was singing it the other day because I think they were playing it at daycare.

Alicia Keys? Oh, yeah. My something's on fire. I don't know. What did they say? What did she say? Zarina was singing it wrong. She mentioned fire in it. I could tell by the tune that all the words were otherwise incorrect. That's my kids. My kids love listening to the Macarena and they say macaroni instead of Macarena. Macaroni.

I don't correct them. I don't know the lyrics to Macarena either. The whole thing's in Spanish, isn't it? Or Portuguese? Something like that. All right. Fever. I think we should begin by defining a fever. Can you do that for us? How quickly do you want it defined? Well, you're talking, so let's do it in another three seconds. All right. I will do it accurately and then in clinical practice. How's that? Is that okay? Don't ask me, mate. All right.

All right, so fever, if you want to be accurate, is an elevation in core body temperature above the daily normal range. Now, it's important to note that our body temperature isn't static through the day. It's diurnal, so it will be different. So you're cooler in the morning, hotter in the afternoon. Thanks. So technically speaking, on average, if you are 37 point – now, I'm not going to do Fahrenheit today, I'm sorry –

If you're 37.2 degrees Celsius in the morning, that would probably constitute a fever. Whereas if you're 37.7 and above in the afternoon, that would be a fever. But that's too difficult, right? Yeah. So we generally say in clinical practice, anything above 38 degrees Celsius, which I think is about 100, 101 Fahrenheit, there you go, would be fever.

Right. But... There's a lot of buts there. Now, okay. Well, let me put my butt into this. So we've taken the temperature rectally. That's right. Which is weird because you've used the same thermometer for rectal. Oh, do you want to tell you a quick story about that? Okay, go on. So I worked with a neurosurgeon and doing some clinical research.

And he did an early stint of his neurosurgery career in Johns Hopkins. Yeah. Johns Hopkins. Johns. Johns Hopkins, yeah. Yeah. And he was working there for some time, but he mentioned that one day he noticed that there was two thermometers. Two thermometers? Two thermometers. Yeah. And I think he said they were wall-mounted. Right. And he didn't know that there was two, and he asked the –

nurse, why are there two thermometers? And she said, well, one is orally, one's rectally. And he's like, right, right. Which I knew earlier. I was just going to say, really think that they should be labeled. Really think they should be labeled. So you've said that, okay, we've got our body temperature changes throughout the day. Just with that though.

Rectal would be a core temperature, which is much more accurate at measuring body temperature than orally, which is peripherally, like under the arm. Fair point. Or under the tongue. Yeah. So that would be preferably a core temperature is better to measure than would peripherally. But not always practical. Superficially. That's right. So you've said that our body temperature is a little bit cooler in the morning than in the evening. So there's variability there.

and you just said that generally over 38 degrees might be considered a fever. However, what is the difference? Because I know that I can reach 38 degrees after a workout. So would you call that having a fever? No.

So that would then be another term we use called hyperthermia. Not to be confused with hypothermia. Correct. Hyper is low, hyper is high. Now that would be probably falling more into conditions like heat illness, which is again a spectrum of seriousness where if you were to, well, you're just retaining heat basically. So that can be by a multitude of factors, by exertion,

or ambient temperature increase, or both together. And if you're retaining heat, so your body isn't efficient enough to dissipate heat, you're retaining heat, which is now increasing your temperature, but the big difference here is it's not via a fever-based mechanism. A fever-based mechanism of temperature, high temperature, is you've changed the set point in your hypothalamus.

Yes. So a transient hypothermia, which you might get through exercise, isn't a problem necessarily if you can cool yourself off. However, a fever is generally due to some sort of pathological condition.

or scenario, generally speaking, where the set point of your thermostat has changed. It depends on what you call pathological because to a certain degree you would say it's homeostatic. Yes. Only if it's starting to move into disease forming outcomes. Good point. Okay. Because you would say fever is part of your immune system.

It's an innate immune response, physiological immune response, which is reacting to something that it's perceiving as not a good thing happening in the body. Yes. So let's first talk about temperature homeostasis, so how we normally regulate body temperature. And the way, so I've said before and I'll say it again, probably the most important concept from my perspective for anybody to understand about medicine is homeostasis.

Because it's all about every single function within your body has a range in which it's happy, healthy, normal functioning range. If it's too low...

illness. Too high, illness. So take anything. You could take blood sugar levels, right? There's a happy, healthy range. Too low, not good, hypoglycemic. Too high, hypoglycemic, not good. Same with breathing rate, heart rate, all these types of things, right? And that includes our temperature. So we do have a temperature range. It's not a single temperature. You said before that throughout the day generally fluctuates from 37.2 to 37.8-ish, I think you said.

And that's probably generally the happy, healthy range-ish plus or minus, you know, point something of a degree, okay? So when your body temperature goes up,

This might happen due to exercise or it's a hot day, you're sitting in the car and you haven't worn the windows down and it's summer or whatever it might be, your body temperature goes up and there are receptors that pick up, called thermoreceptors that pick up the increase in temperature. It sends that signal to your brain, specifically the hypothalamus and the hypothalamus has a thermostat just like your air conditioning system has a thermostat that you've set it at which says, hey, 37 degrees, that's where I want to be.

And that signal, if it says, hey, we're above 37 degrees, your body goes, oh, I need to bring it back down. That's called negative feedback. It says, what can I do to make this hot body, which is how I've often been defined, how can I make this hot body cool again? Cool again. Yeah. And you know, there's four...

kind of heat dissipation mechanisms that the body can employ okay so i'm i'm the brain i'm the hypothalamus i've just picked up from my thermoreceptors in my skin and peripheries i go hey it's too hot i need to cool myself down again i know i've got four things i can do what's the first thing i might do well it's only really it's only really one that we employ okay

I'm glad that you mentioned that there's three more. But I'm just saying from a heat loss point of view, there's four things physically from a physics standpoint that can be employed. Okay. So let's just, before you talk about all four, hypothalamus is now needing to make a decision to cool itself down. What does it do?

So what does it do for the body? Yeah. Okay. So it will say, well, we need to get this core heat out into the periphery to be lost into the ambient environment, into the room. And where is the core heat sitting? I guess you'd say in your organs, in your blood, in your blood vessels, you know.

The inner part of you. Yeah, so your circulatory system is probably the best and easiest way to transport and dissipate that heat. So what's one of the things that the hypothalamus makes its decision on and on how it can get rid of this excess heat? So it would activate the vasomotor center, which then tells...

Neurons that control blood vessels to dilate. Tell them to relax. Blood vessels open up. The wider they open... More blood flow to the periphery. Okay. And so that would be one of the first mechanisms out of the four, which would be...

You call it transference. So you bring in heat to a surface, which then can be transferred into the room. What else can the hypothalamus do? Now, this is the big one. This is the most important one for humans to cool ourselves. It instructs... Hop in the fridge. Yeah. Well, that's another mechanism. That's behavioral. But this one is, it tells sweat glands in your skin to start to secrete...

Water or, you know, sweaty fluid. Yeah. And that then goes onto your skin and then that –

So this is the strongest one. This is evaporation. Yeah. And that evaporation process. So as the water molecules break from each other, it's a, what is it? Exothermic reaction, which is a cooling reaction. And it cools the surface of the skin and that's where the blood is. And so now you're transferring coolness into the blood that hopefully it's taken to the

core regions to cool it down. Yep. Okay. So they're the major ways that the hypothalamus can... But behaviour would be huge. Behaviour would be big. So you stop exercising, you sit in a cool room, put the fan on so that's convection. Yep. Stop the radiation, which is direct heat from the sun. Evaporation's the strongest...

the most efficient way to cool yourself. And that's why it's hard in humidity because you can't break the water molecule because it's too humid. Yes. So that's why you generally have problems with cooling in high humid climates. So we vasodilate and we sweat. What were the other ones that you were saying? Vasodilation, sweat. Yeah, that's about all. No, no, I'm just talking about the mechanisms. The four mechanisms of losing heat is through...

Evaporation. Yeah. Radiation. Yeah. Convection. Yeah. And transfer. Transference. So they would be like, if you wanted to utilize those processes in a room, you would turn the fans on that's utilizing convection and

you would put the air conditioner on. That's changing the temperature so it transfers the heat easier. Evaporation is sweat and radiation, you get out away from the sun. Okay, cool. All right, so that's how we... A lot of that's behaviourally. Okay, now let's maybe be faster on the next one because that's cooling down. But sometimes when the external temperature's too low and our...

body heat gets transferred through those mechanisms to the atmosphere and we actually get too cold, our core temperature drops below that 37.2 or 37 degrees.

We then need to try and maintain or generate heat. So same thing. Thermoreceptors detect the drop in temperature. The hypothalamus makes a decision. And then what does the hypothalamus decide it wants to do? Same thing. Activates neurons of the vasomotor center. But in this case, it tells neurons to go to blood vessels and constrict them. Okay. Moving them away from the surface of the skin. So you won't get blood flow to skin. Yeah. That's why you go white. Yeah.

And you'll maybe employ the skin to do goosebumps. So that's the, at the end of hair, a rectopilla, which kind of makes the bumpy things in your skin, which probably doesn't do a huge amount, but holds, the thought is it holds air molecules closer to the skin, which works kind of like a,

Yeah, and between the hairs holds the heat between the hairs. Like you said, like a wetsuit. But the other thing is it stimulates the skeletal muscles to contract and relax very quickly. Contract, relax, contract, relax, contract, relax. That's what we call shivering. Yeah, but even before that, like the shivering apparently isn't a huge one in terms of retaining heat. A bigger one- That would be generating heat. They would. They would.

but it would be a non-shivering thermogenesis. So that would actually go to, it would instruct fat cells. Brown fat?

Brown fat more so in infants. We don't really know in adults how much we have and where it is. We have ideas that, you know, I think it's in like between the shoulder blades and kind of the neck area, but not to the extent of how children and infants employ brown fat. Right. Okay. So what it does... Breaks the fat down? No, it uncouples the electron transport chain in adipose tissue. So instead of...

being efficient in producing ATP, it changes it and kind of uncouples it. So instead of making ATP, it makes heat.

Right. You know how like when you explain the ATPase synthase process and the electron transport chain, it's like turbine spinning. Yeah. It's like you're spinning the turbine with nothing going through it and it's just generating heat. Okay. Okay. That's interesting. That's kind of the practice of say hibernating bears. That's how they keep warm in a cave whilst they're sleeping. I wonder if that produces a lot of erective oxygen species.

You can ask. I'll ask about it next time I see it. Okay, so when the temperature drops, the hypothalamus, the decision it makes is to vasoconstrict, keeping the temperature close within the body, so maintaining it, a

Erecta pili, so a hair stand on end to maintain the heat between the hairs at the surface of the skin, tells the skeletal muscles to contract and relax quickly to generate heat and then to uncouple the electron transport chain within the fat, or at least the brown fat potentially, to generate heat through that mechanism. Yeah, and just, I came across a number just by shunting blood

and doing a bit of non-shivering thermogenesis, that will raise the body temperature by two degrees. Very interesting. Now, the reason why we're saying this is because when you have a fever and you change that set point, your body might recruit some of these functions to try and

Because it's thinking it needs to maintain homeostasis, right? Now, we'll get to that point in a sec. But something we need to realize is that there is that thermostat set point for temperature in the hypothalamus. And that set point can change. Just like if you walk into a room and the air conditioner is set at, again, we're going to do

metric system here. We're going to do Celsius, 23 degrees Celsius. The air conditioner said at 23 degrees. You might walk in and go, that's too hot. I'm going to drop it down to 21. So now what the air conditioner senses is that, oh, 23 degrees is too hot. I need to be at 21. So I'm going to cool the room down. Or if you walk into that room at 23, you go, it's too cold. And you turn up to 25, it now thinks 23 is too cold and pumps out heat. The body does the same thing. It recruits those mechanisms when the thermostat changes. So

Let's talk about how we can change that thermostat. What are the chemicals called? So in a fever context, one side point I'll just put here is you can have a condition called a hypothalamic fever. A hypothalamic fever. Which is a fever that has come about through abnormal function of the hypothalamus. So there could be head injury, there could be hemorrhage, there could be tumour, she

...gummers growing in that region, and that causes the hypothalamus to become dysfunctional. But that's got nothing to do outside the hypothalamus. It's due to a dysfunction in the hypothalamus. This is relatively rare, and it's more likely to cause actually the opposite direction, hypo, not hyperthermia. Okay.

Yeah, because my thought would be it becomes dysfunctional. That's right. Less active. So it probably doesn't have a set point necessarily. Okay. So now we're working in the context of fever only. And the common causes. The common causes. So what changes the set point generally?

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So these fire generators can be... It's a good song. Who used to sing that? Firestarter. Firestarter.

I think there's going to be a lot of people yelling at us. Because he died a couple of years ago, the lead singer of The Prodigy. The Prodigy. Yeah. Sorry. Okay. Go on. So pyrogens are just chemicals that can change the set point of the hypothalamus. Right. Okay. And now they come in two forms. They're either exogenous. From outside. Or endogenous. From inside. That's it. Okay. So...

Do you want me to start with the exogenous ones? Or do you want to talk about the mechanism of how they do it? No, no, no. I think that, yeah, the mechanism of how they just broadly do it. Because effectively, these pyrogens, which aren't just one chemical. No. For example...

So exogenous, just broadly. Two main ones. They're either what we call a lipopolysaccharide, which comes from gram-negative bacteria. So that's something that's intrinsic within the cell membrane of the bacteria. Okay, so bacterial infection. Well, the other one is also a bacteria, but it's exotoxin. So it's produced by a gram-positive bacteria, which is sometimes...

or excreted as a defense mechanism or something else. What about viral pyrogens and fungal pyrogens? Yeah, I'm not sure intrinsically or endogenously they do it or it's our immune system's response to them. Oh, gotcha, gotcha, gotcha. Yeah, okay. But those as independent structures are actually exogenously pyrogens. Gotcha, that makes sense. So if you were to get exotoxin and just inject it into someone's blood

they would actually get a fever. Yes, or endotoxin. Or an endotoxin, yeah. Right, okay. So what ends up happening is, for example, this endotoxin like lipopolysaccharide, like Matt said, which is part of the outer membrane of gram-negative bacteria...

Once that's in the body, in the bloodstream, it travels to the hypothalamus and it triggers the synthesis of something we've spoken about many times in the past, prostaglandins. One particular type called PGE2. And PGE2 is the remote for the air conditioning system, right? Yes. It sets the temperature. And so when you have these pyrogens, such as lipopolysaccharides, in the bloodstream, it says, hey, let's increase the set point.

Now, instead of being set at 37 degrees, you might be set at, as an example, 39 degrees. Now, your body thinks that 39 degrees is where it needs to be as its normal temperature, which means you, currently at 37 degrees, you're too cold. You need to warm up. Your blood vessels constrict. You start shivering. You get very pale.

And your body temperature starts to go up. And behaviorally, you want to put more clothes on or get in the blankets. Exactly. And your body temperature goes up. Now,

all the other pyrogens, whether they're exogenous or endogenous, work the same way pretty much in that they trigger the synthesis of PGE2. So can you give us some examples of other pyrogens? Just as one final side point, which was an interesting point I came across, was an exogenous and exotoxin, which can be released by some...

like Staph aureus, okay, it leads to a syndrome called toxic shock syndrome, which is potentially lethal. Now that commonly can be associated with tampon use. So the way that...

I guess it retains blood within the vagina, which then becomes toxic if a bacteria is grown in it. Now, what it can do is release an exotoxin. Now, this is what I found interesting, is normally when you have an immune reaction, your immune response would activate...

0.01% of T cells in that response. But in this toxic shock syndrome, 20% of T cells are activated. So you have this massive cytokine storm leading to initially rash, massive fever,

and then it leads to multi-organ failure. And that's from the exotoxins from these bacteria. And they're sometimes referred to as super antigens. Super antigens, that's right. So that's kind of how the microbes can lead to pyrogen and then the fever. But then in most cases, what's going to happen is

When the body senses something abnormal, particularly the immune cells, so these would be things like neutrophils, macrophages, things like that that are picking up the initial...

something's not right here, they need to communicate between each other. So what they will do is they have certain communicating chemicals. Now the ones that are relating to fever would be interleukin-1, interleukin-6. Interleukin just means between white. Leukin is white, between white blood cells. And tumor necrosis factor alpha. They're the big three chemicals

cytokines that you would call them. Can I talk about what stimulates them? Yep. Okay, so...

So you said about the exogenous. So if we start with that exogenous that you spoke about, yeah, lipopolysaccharides out a membrane of gram-negative bacteria. It's released when bacteria replicate or they lyse and they're split. That can trigger the PGE2. You can have from gram-positive bacteria, the cell wall, so peptidoglycans, for example, they can again be released during bacterial growth or immune-mediated lysis.

You can have just bacterial DNA itself can stimulate like toll-like receptors. Macrophages, right? Yeah, within the body. You can have the super antigens that you spoke about before. You can also have viral pyrogens. So when viruses replicate, they're detected by immune cells in the body. So again, like toll-like receptors, for example, or pattern recognition receptors.

And that triggers the immune system to then trigger PG. But my question here is, is it now more so the endogenous that's causing the fever than the actual...

Unlike, say, the LPS, the lipopolysaccharides, which can directly act on the hypothalamus to raise the temperature, are what we're talking about now more so the immune system's response to the microorganisms and their products? Yes, I think it's still classified as exogenous because the initiating factor came from outside. So I...

I would classify bacteria, viruses, fungi and parasitic stimuli to be exogenous even if the way it increases the...

in the hypothalamus is through triggering the body's own immune system. Okay. Right? So yeah, they're the exogenous ones, right? But then the endogenous, like you were saying before. So of the cytokines, you can have, like you said, interleukins, tumor necrosis factor, right? And even interferons. So interleukin 1, that's activated by macrophages and monocytes and dendritic cells. And they can be even stimulated by the lipopolysaccharides or bacterial toxins. Okay.

You can have sepsis as well and other infections can do it. Tumor necrosis factor, macrophages, monocytes, again, LPS, lipopolysaccharides, viral bacterial soil components can do it. Also, autoimmune diseases can trigger tumor necrosis factor. Interleukin-6, infections, chronic inflammation, malignancies can do it.

Then you've got hormonal mediators. So you can even have like, uh,

just systemic inflammation or tissue injury that directly stimulates the synthesis of prostaglandins, right? You can have non-microbial pyrogens. So you can have just tissue injury, burn, ischemia, cancer, right? You can have autoimmune diseases like lupus, drugs, even certain drug administrations and infusions can stimulate the immune system. But at the end of the day, I think the point we're trying to make here is that

Regardless, all roads lead to Rome and Rome is the hypothalamus and PGE2. And so if we can limit PGE2 synthesis, you can effectively limit fever, but we'll get to limiting that in a sec. So knowing all these different stimuli causing fever,

what do you think is the next thing we should understand about fever? Should we discuss whether, like, what is the point? Why is fever even coming about? So you can say, okay, we've got an infection or damage to tissue in the body. The thermostat has changed. It's gone up. We now get very hot. Our core body temperature gets very hot. Why? Why have we evolved this mechanism? Is it something that

and it's not beneficial or is it potentially beneficial? What do we know? Yeah, so the fever response is a physiological response that sits in the arm of the immune system known as the innate immune system, which is a nonspecific response to...

A problem that's going wrong in the body. First line of defense. First line. Well, it's the first arm, but probably you'd say the second line after the barriers. Gotcha. So inflammation would be in the same category as fever. It's a physiology. It's a process. Yeah. That's...

demonstrating that something happened in the body that needs to be rectified. Now, one arm or one function of the fever would be making the environment a little less suitable for pathogens. When we say pathogens, they're disease-forming microbes. Now, remember, all the pathogens that... All the microbes that become pathogens, because we're full of microbes. Yeah. You know, we arguably have as many microbes on us as cells. Right.

I know that's debated, but generally speaking, you'd probably say one-to-one. And this would be all over our skin, all through our respiratory tract, all the way through our gastrointestinal tract. Now, they're living there symbolically...

To give us benefit, but also we're giving it benefit. Now, it's only when some of them become rogue or they get an opportunity to come into the body that they can then start to cause disease. Opportunistic. But if they are causing disease, they're usually microbes that like to live in our physiological temperature.

So they won't want to live at 10 degrees. They won't want to live necessarily at 40 degrees. They want to live at 37 degrees. So it is... Perfect for them. Yeah. It's... Why can't I remember? What's the name of the three bears?

Goldilocks. Goldilocks. So they have their own Goldilocks. That's right. Right. So just by changing the temperature by two degrees, it make it harder on them to reproduce and become too active. Question. Yeah. 37 degrees is also our optimal body temperature. So is this a battle of attrition? Well, probably the best evidence that I've come across...

is a temperature is a good thing for your immune system. I'm sorry, an increase in temperature is a good thing for your immune system to a point where it's now starting to cause dysfunction to your body. So if it's getting too hot and starting to cool, because remember, once you get, let's just say ballpark around 39 degrees, you're starting to possibly interact with

protein structures called denaturing. And that can start to cause problems with functions of cells and things in the body. Proteins fold at 37 degrees and any... I mean...

Crack an egg on a hot plate and yes, your body's not getting to that temperature, but the protein goes from being translucent or transparent, you know, the albumin to being white because it's denatured. It's unfolded due to a temperature change. And so effectively you can have your proteins unfold. So my thought would be that as the temperature goes up,

It's becoming not a great environment for pathogenic cells to live in, but also probably not an ideal environment for our cells to grow in either. Yet, as temperature goes up, we also see an increase in the function of something. Enzymes. Right. Enzymes work faster at high temperatures. So would you say that that is part of the...

Yeah, so because it's a part of the immune system, it would arguably make the immune system or the immune response more efficient. So the processes of what's... To a point. To a point. So the immune system is starting to become more active. So the white blood cells become probably more active the way that they...

can phagocytose, which means gobble up things that are kind of not supposed to be there or damaged cells or debris of cells. They can be more efficient at a slightly higher temperature. The way that they communicate between each of the cytokines becomes more efficient. The way that you produce more antibodies becomes more efficient. The way you produce certain proteins from the liver. What?

Just a whole host of things probably become more efficient as we get hotter. So that is probably why it's suggested mitigating or stopping a fever straight away may not be the best thing you can do. But as it's getting approaching the 39 degrees and below, then it's probably going to cause...

detrimental effects on the body where you may want to intervene and drop the temperature because otherwise it's going to cause a problem to the host. So when people ask, is a fever good or bad? The answer is yes. It's both. And it depends. So the increase in temperature can also help enhance our immune function and

which is good for, like I said, phagocytosis and immune cell proliferation and so forth. It can inhibit the pathogenic growth as well.

But it also is going to in some way potentially, especially if maintained or gets too high, be detrimental to us. As I said, it's a process that's employed by the immune system as is inflammation. Would you say to people that whenever you get inflammation, you need to stop it? No, because it plays an important role for neutralizing the problem,

getting rid of the problem and being part of the cleanup and the healing. So if you were to stop every single inflammatory response in the body, it would probably not be great. But if the inflammatory response becomes exaggerated so much that now it's causing disease or disorder or so much pain that you can't sleep or function, then yes, you want to intervene.

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Generally, its suppression would be recommended by a healthcare physician or healthcare professional when it's leading to discomfort or complications or particular issues. And probably particularly with children, infants, where they are already not suppressed but their... What would you say? Their resilience in temperature regulation is already immature and by putting the fever into the mix that they...

Just like the elderly don't have the capacity to, in a homeostatic range, hold it at a safe range like, say, an adult would. And that could be a problem. Like a lot of things, fever may be less beneficial in those certain populations.

And that's why you see with infants they can get heat-induced or fever-induced convulsions which can cause brain injury. This is why, again, it's really important to seek your healthcare professional, go see your GP if you or a loved one has a fever to determine what is the best course of action because there is no one-size-fits-all approach to it. Fevers can be beneficial and they can also be harmful.

And those two things can simultaneously exist, which is hard for people because they just want to know a clear-cut answer about fevers. Yes, they can be okay. They can also not be okay. So no, and again, there's no recommendation here as to what you should do when you have a fever. That's what the conversation between you and your healthcare provider, that's that conversation you need to have. We're not advocating or condoning or condemning anything.

What we need to talk about, Matt, is how do healthcare professionals generally manage fevers? Because we know that prostaglandins,

PGE2 is what is being synthesized by COX enzymes. We've spoken about COX enzymes before. They synthesize prostaglandins that can be regulatory, housekeeping, maintain gut lining, help maintain blood pressure, renal perfusion of blood and oxygen and nutrients. But also you can have prostaglandins that are stimulated through infection, inflammation, fever, which PGE2 I know is a part of that process. It can be stimulated to be released.

And there are enzymes called COX enzymes that synthesize these prostaglandins. So I know that there's a range of drugs out there that can be used to inhibit these COX enzymes. So are these drugs used to reduce fever? Yeah. So, I mean, I think you basically answered it. I haven't said what any of these drugs are. Okay. Okay.

So I guess the first thing just to be aware of that fever is a symptom. I mean, you can measure it through a thermometer. So that arguably is a sign. But

It's an experience internally. So that is something that needs to be understood and investigated. And as we said, fever is generated by pyrogens, which can be internally and externally generated, right? And that then can be for the physician, for the health professional,

it can be investigated to see, well, what is the category of cause that's leading to this fever? And like you alluded to when you were explaining the different pyrogens, by far the most common cause of fever is an infectious-based mechanism or category. So infections would be the most common, whether it's bacteria, viruses, fungi, parasites as examples, right? Yeah.

But then you have some other less frequent but still common causes of fever. Malignancy, as you mentioned.

Anything with the immune system being over-exaggerated, so that could be autoimmune, auto-inflammatory. So the health profession is trying to figure out, well, what's the root cause of the fever? Because you don't want to just necessarily band-aid it and just turn it off. You want to say, what's the underlying reason for it? Another very common one is clot-based. So if you have deep vein thrombosis or some kind of clots in blood vessels, they intrinsically can release cytokines, which can...

can lead to a fever. So I think from a health professional standpoint, understanding where the fever is stemming from, if it's an ongoing thing that's causing problem to the person, then you're trying to figure out what's the basis of it. And then the investigations would go accordingly. But at the same time, you want to, just as you would with pain, you want to bring it, mitigate it. So the person's at a certain level of comfort that they're not

They can sleep at night. They're not highly anxious, et cetera, et cetera. So there's certain medications that can be employed to negate the production of those prostaglandins to then have an effect on the hypothalamus. Now, as you said, the hypothalamus is using prostaglandins as its primary kind of chemical set point regulator. Yeah.

Any drug that can play around with prostaglandins arguably would be effective in temperature. These could be the common NSAIDs like ibuprofen, aspirin, maybe, aspirin.

Maybe not the first line, but arguably in its mechanism, it will be antipyretic. But probably the most well-tolerated and the most commonly used is paracetamol or acetaminophen. Yeah. Tylenol, Panadol. Most well-tolerated. They're all different drugs. Best for children because of the risk of Rice syndrome with aspirin. NSAIDs probably have hyaluronic acid.

side effect profile with gastrointestinal upsets and renal issues. So paracetamol generally would be considered the first line of treatment for adults and children for antipyretic effects. And let me just clarify when you said renal issues, generally that's within a population of pre-existing renal disease. Yeah. That's right. Or medications that are already straining the

Or nephrotoxic. So if you already were taking medications, as you may be doing when you have an infection, you might be taking an antibiotic that is nephrotoxic. So you don't want to add more nephrotoxic agents to the mix, which you can. And you might be sitting here listening going, then how the hell do I know what I should take? That's why you go see your healthcare provider. I know a lot of people go, oh, I don't want to do that. I just want to get an answer from people on a podcast. It's not going to happen. We can't give you an answer.

It's not how it works. Matt, is there anything else? The only thing I'll just add in the mix is the elderly have a diminished fever response. Meaning? So, I mean, they could have an infection on board. Most commonly would be a UTI or a respiratory-based infection. So, they're the two big ones that would likely impact elderly people, particularly if they're in an aged care facility. So...

Let's just say they have an infection on board. For a healthy adult, the immune system would be kicking in, releasing cytokines. Now fever's turned on. Elderly, they have a suppressed immune response. So now the infection has taken quite serious hold, but there's not enough cytokines to generate a fever response. So from a fever standpoint, they don't seem to be sick anymore.

But when the fever finally comes on, they may be so established in their infection that they're very, very unwell, which can lead to pneumonia or a UTI that becomes sepsis. And then that can be lethal. So fever's not always super active at all.

No, accurate, as a means of dictating the severity of the infection. Yes, or even in that instance, the stage of the infection. Yes. And just for people, if you want to understand a little bit more about the age-related changes that can occur to the body that

for example, Matt alluded to, that's called Reduction in Physiological Reserve. And I think we're going to do an episode at some point on physiological reserve and the changes that can happen with age. But that, Matthew and friends, is what was the topic again? Fever, everybody. Yes. Not hypothermia, fever. Fever. You give me fever.

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