Mechanisms of thermoregulation

This chapter seems directly relevant to the very last word of Section R1(ii) of the 2023 CICM Primary Syllabus, which expects the trainees to "explain the mechanisms by which normal body temperature is maintained and regulated". It has appeared several times in the past papers, with Question 9 from the first paper of 2021 and Question 19 from the first paper of 2018 both asking directly about it. The pass rate of 50something percent threatens the prospective candidates with the possibility of repeated appearance for such SAQs. Moreover it seems like some kind of core knowledge that an intensivist should have, considering our tendency to meddle with human temperature.

  • Thermoregulation is a sensor-integrator-effector system
  • Sensors: peripheral and central
    • Peripheral sensors are nociceptive neurons that express temperature-activated transient receptor potential (TTRP) cation channels; report to the hypothalamus via the lateral spinothalamic tract
    • Central sensors are temperature-sensitive neurons in the preoptic area of the hypothalamus, which sense core temperature 
  • Integrator is the preoptic area of the hypothalamus
  • Effectors are skin, skeletal muscle, sweat glands, and brown adipose tissue  
    • Skin vasodilation and vasoconstriction can alter skin blood flow to increase or decrease convection between core and periphery
    • Piloerection is of minimal importance in humans, but in furred mammals increases the thickness of the insulating air layer  
    • Non-shivering thermogenesis by muscle and brown adipose tissue mostly due to futile proton leak through the inner mitochondrial membrane which uncouples oxidative phosphorylation from ATP synthesis 
    • Shivering, involuntary muscle contractions which produce heat through the hydrolysis of ATP
    • Hypeventilation (and panting in animals), to increase evaporative heat loss via the upper respiratory tract 
    • Behavioural changes, eg. shelter or warmth-seeking, exercise 
    • Sweating - quantitatively the most important - usuing the latent heat of vaporisation of sweat (2.4 kJ per gram of sweat at 30°C)

A topic like this really calls for a single definitive resource which somebody can quickly skim before their test, and for that, it is difficult to go past "Physiology of thermoregulation" by Andrea Kurz (2008) or Patapoutian et al (2003).

Peripheral temperature receptors

The sensory mechanism for heat is mediate by temperature-activated transient receptor potential (TTRP) cation channels which are activated by changes in temperature (and capsaicin, and occasionally also low pH). Several receptor populations exist, with different temperature range sensitivities (eg. there are "cool" receoptors and "hot" receptors). Generally, the threshold for "uncomfortably hot" is about 42 ºC, though some higher-temperature receptors  fire only at 52 ºC.

For contrast:

Thermosensory neurons are mostly polymodal nociceptors that can detect all kinds of chemical and mechanical stimuli, but also some unique neurons that respond only to temperature. They connect via large myelinated Aδ fibres and thin unmyelinated C fibres to cell bodies in the dorsal root ganglion. Their distribution is mostly cutanous and mucosal, but thermoreceptors are also present in the viscera, muscle tissue, airways, blood vessels and spinal cord (at least among animals).

Central temperature sensors

The hypothalamus is the central thermostat that receives peripheral thermal sensory information and commands thermogenesis. It is also true that it directly senses temperature via TTRP receptors, specifically TRPM2 receptors which are expressed on a subpopulation of neurons in the preoptic area. How exactly these two inputs are handled and prioritised remains to be fully established, but it seems as if the hypothalamic thermosensory neurons are also the neurons that act to integrate the peripheral input. Moreover hypothalamic temperature trumps peripheral temperature, which seems to suggest that core temperature is favoured as the most important parameter to conserve; for example when  Hemingway et al (1940) directly heated the hypothalami of dogs held in a room cool enough to produce shivering, the shivering was completely abolished. Which would in all fairness make sense. The blood supply of the hypothalamus is abundant and sufficiently direct, via the Circle of Willis straight from the core organs, and that blood (one should expect) had not undergone any sort of extensive cooling on its way up the neck, so hypothalamic temperature should usually be closely representative of the core. 

Temperature regulation by the hypothalamus

Without trying to paraphrase the works of Boulant and Hammel, and without imposing yet more pointless detail or elaborate diagrams on the reader, the "central processor" mechanisms of the hypothalamus can be summarised as follows:

  • Temperature-sensitive neurons receive inputs from peripheral receptors, and also sense the core temperature themselves
  • Temperature-insensitive hypothalamic neurons do not receive temperature information, and produce a reference signal which is probably the homeostatic setpoint for temperature.
  • These two groups of neurons send mutually antagonistic synaptic inputs to effector neurons controlling various thermoregulatory responses
  • The net effect of these is to adjust the firing rate of warm effector and cold effector neurons.
  • These effector neurons then activate or deactivate all the diverse thermoregulatory mechanisms that are discussed in more detail below.
  • Apart from the hypothalamus, a hierarchy of lower structures exists in the brainstem and spine which can, to a lower and cruder degree, sense temperature changes and effect thermoregulatory responses.

The net effect of all the inputs is therefore a constant tonic output to these effector mechanisms which is regulated up or down depending on the needs of the organism. This is the "hypothalamic set-point" for temperature, which in reality is not a point but rather a diffuse and flexible range over which active thermoregulatory responses are dormant. 

Effector processes that regulate temperature

So, we finally arrive at the central question of this chapter, namely the mechanisms by which normal body temperature is maintained and regulated. As mentioned somewhere high above, endothermic organisms exist dangerously close to the upper limits of protein thermotolerance, which means cooling mechanisms need to be much more active and effective than heating mechanisms. This probably seems ridiculous unless one thinks about it, but in fact it is true: humans routinely trespass their thermoneutral zone only because of extensive behavioural modifications, which extend all the way to things like space suits that allow survival at close to absolute zero and ablative reentry plating that allows survival at 1650 °C. Without these refinements we would be dependent on non-behavioural thermoeffector responses, which would limit our range of tolerated temperatures considerably. The early pre-fire hominins, even with their luxurious body hair, were basically restricted to the warm stable climate of tropical and sub-tropical Africa. From here we will focus on the non-behavioural mechanisms of thermoregulation, in order in which they are usually recruited, starting from cold adaptation responses (which are of greatest interest to the intensivist because they contain responses to both fever and therapeutic hypothermia). Wherever possible, the section will contain a link to the excellent Handbook of Clinical Neurology (2018), of which the entire 156th volume was dedicated to the processes of temperature regulation.

Thermoeffector responses to cold

It appears that the thermoeffector responses in humans are recruited in an orderly manner, according to their physiological cost. It requires more effort to shiver than it does to vasoconstrict a few arterioles, and calories are precious, especially when one considers the finite energy supply of our distant ancestors. 

Skin vasoconstriction

The blood vessel network of the skin is the one peripheral circulatory system that was sufficiently monofunctional to be left out of the regional circulation section of the cardiovascular collection. The other reason for this was that the only SAQ on this subject was Question 6 from the second paper of 2007, which asked for the role of the skin in thermoregulation. Johnson & Kellog (2018) and Charkoudian (2003) were the better resources to inform the summary that follows, and it is mainly focused on creating a solid answer for Question 6.

In summary, the skin is the surface which radiates convects and conducts heat, as it forms the barrier between the warm heat-producing core and the open system that is the environment. From this, it follows that the transfer of heat from the core to the skin is an essential step for the transfer of heat out of the body. Skin blood flow is therefore the most important component of this heat transfer process, considering that we have already discussed how excellent the subcutaneous fat is as an insulator.

Or have we? Perhaps that should have come first. In the order of recruiting the least energy-expensive cold resistance mechanisms first, one could not fail to mention subcutaneous fat, as it is a zero-cost system which provides constant protection from the cold by simply sitting there in the space between the skin and muscle. Its insulating properties are not the primary purpose of this layer; it's supposed to be where we store our long-term metabolic fuel substrate, to mobilise during periods of prolonged fasting which seem to have been a dominant feature of the upright ape lifestyle in the Pleistocene. 

Pond (1992) goes into a lot more detail than is necessary for this section, and for our purpose it will suffice to note that animals of many different clades survive the Arctic and Antarctic by having developed unrelated but homologous fat deposits in their subcutaneous tissues, but these are not much different from similar deposits from temperate zone animals, especially ones which experience long periods of starvation punctuated by episodes of plenty. It is especially true of carnivores who feed intensively and fatten rapidly during (for example) the brief Siberian summer. The fat deposits created in this fashion last into the winter and serve a dual role of both being insulators and being an excellent space to store excess food. 

How good is this fat as an insulator? Speakman (2018) answers this question by presenting a table of thermal conductivity measurements as a means of a comparison between different tissue types. To help the reader scroll past it faster, the values themselves are probably immaterial, but the range of values is interesting. The most conductive tissue is the heart (heart of the rat, apparently), and the least conductive was adipose, with pig fat being the most insulating, and human fat being not far behind the blubber of the harp seal. 

Thermal conductivity of different tissues from Speakman (2018)

It is of course unfair for us to compare ourselves to aquatic organisms as for them conductive heat transfer is a much greater problem, and passive insulation would probably be the only sustainable mechanism of preventing excessive heat loss into the icy water. The harp seal (Pagophilus groenlandicus) is a beast that lives in frozen seas with surface temperatures routinely around 0 ºC and for this reason these animals are often up to 58% blubber in crossectional area, with subcutaneous adipose deposits enveloping the entire animal in a continuous layer. Humans have no need for such passive heat engineering, being terrestrial organisms blanketed in nicely insulating air, and anyway preferring to skin and wear the insulation of other animals, but we do have something of a nutritional catastrophe of our own making, and so become well insulated despite our best intentions. It is therefore essential to deliver blood through and around this layer, to perfuse the skin with blood from the core, thereby allowing heat to be convectively delivered to a surface that can transfer it to the outside world. Which is a terrible circuitous way of coming back to the circulatory system of the skin. 

The regional circulation of the skin

The resting blood flow of the skin is approximately 250 mL/min in the thermoneutral zone. Considering that this organ weighs about 3-4 kg in the normal adult, or up to 16% of the total body mass if one includes the fatty panniculus (around 11kg), that makes it look extremely low maintenance, compared to organs like the liver and kidneys. The attentive reader would respond to this remark with the correct assertion that unlike those other organs, the skin doesn't do much, and so requires little blood flow for its own internal purposes. Considering that the skin cells themselves are metabolically rather ascetic, requiring not much more than 0.20-0.25 ml/min/100g of oxygen, and moreover that the metabolic requirements of the stratum corneum to a depth of of 0.25–0.40 mm are fully satisfied by direct diffusion of atmospheric oxygen, it is no wonder that the skin has a low baseline demand for blood flow. That amount of oxygen is contained in 1.86ml of fully oxygenated blood with a haemoglobin of 100g/L, which means that theoretically you could perfuse your whole skin and subcutaneous fat with only 205 ml/min of blood. At minimum, it is probably even less than this - down to a total whole-body skin blood flow of around 20ml/min, according to Agache (2004).  At maximum  John Johnson et al (1986) and Johnson & Kellog (2010) report experimentally measured flow rates of up to 300-400ml/min/100g, which would be something like 9-16L/min, in which case it would dominate the cardiac output demands of the body.  The skin is therefore capable of expanding its blood flow over three orders of magnitude, which is not something that can be said of any other vascular system except for skeletal muscle. 

The control of this regional circulatory network falls to the autonomic (sympathetic) nervous system, which supplies the arterioles of the skin. This is a rare scenario where the sympathetic efferents do both functions, i.e. they can vasoconstrict and vasodilate. The constriction is a familiar α1 effect, and the dilation is a curious cholinergic process, mediated by M1 muscarinic receptors but still via sympathetic nerve endings that release acetylcholine. This dual activity is present everywhere except for glabrous skin, "glabrous" meaning hairless or smooth and referring to the lips, the soles of the feet and the palms. These areas are only innervated by sympathetic vasoconstrictor nerves, but these nerves supply arteriovenous anastomotic conduits which can massively increase the blood flow through these vascular territories, making them into effective radiators. In the non-glabrous skin the active vasodilator system is responsible for the increased blood flow. This system is not normally active, i.e. there is no constant vasodilator tone, which means cold and clammy is the default setting. 

Cooling of the extremities or the core results in vasoconstriction. This is mediated by numerous mechanisms:

  • Centrally driven α1-mediated noradrenergic vasoconstriction
  • Translocation of  α2c adrenoceptors to the smooth muscle surface membrane, which is a local temperature-mediated  effect
  • Locally driven α1-mediated noradrenergic vasoconstriction (nerves talking to nerves, bypassing the central nervous system - this is a form of reflex neurogenic vasoconstriction)
  • Nitric oxide synthase inhibition, which occurs largely due to the effects of decreased temperature on that enzyme

The upshot of these processes is a decrease in the delivery of the warmed blood to the periphery, where the resulting cooling of the exterior surfaces becomes instrumental to the reduced heat transfer, which fundamentally requires a temperature gradient. If the skin and the environment were exactly the same temperature, no heat transfer would occur by any of the mechanisms. In cold environments evaporative heat transfer by sweating would not be a significant contributor, and in basically all circumstances conductive heat loss contributes minimally also, which means vasoconstriction mainly affects convective and radiative heat loss. How much this contributes is difficult to estimate; its obviously an imperfect system, so some heat transfer will still occur, but we assume it will be minimised compared to what it might have been if this regulatory  system was not in place.  When Colin & Houdas (1967) undressed fifteen people and exposed them to chilling cold air (12.5 ºC), the temperature of their skin dropped to 25 ºC, but their radiative and convective heat losses still increased by about 200kJ/m2/hr (as compared to being surrounded by air with a temperature of 35 ºC). 

Piloerection

Being largely hairless over most of their body surface, humans get basically nothing from piloerection as a thermoregulatory mechanism, and it is mentioned here only because it still happens in humans, and because in 2007 CICM examiners noted that "credit was also given for mentioning piloerection, particularly if candidates went on to explain why this might be useful". The implication here was that to only mention was not enough. 

Piloerection in mammals has the effect of increasing the thickness of the layer of motionless insulating air around the animal, creating an excellent layer of insulation. It seems to be a privilege of larger  furry animals, as smaller ones haven't the frame or bearing for long fur, and must instead resort to insane metabolic rates or periods of torpor. Large mammals from cold regions (eg. Bison bison) tend to have more sparse hair because it is longer and therefore creates a thick coat with only about 1000-2000 hairs per cm2,  and small mammals from cold regions tend to have a larger number of shorter hairs (eg.  Dicrostonyx groenlandicus, with almost 20,000 hairs per cm2). Humans, with a normal hair density of 75 follicles per cm2 of chest surface, are obviously losers here. We seem to retain piloerection mainly because of relaxed selection, i.e.  in evolutionary terms the development of hairlessness was extremely recent (2.0-1.5 million years ago) and there has not been enough time for this useless trait to disappear because there is no survival disadvantage from having it. Considering that humans seem to be completely free from the effects of natural selection more generally, we should expect to have this vestigialised system for a while. For now it remains mostly useful as one of the tests of the autonomic nervous system function

Non-shivering thermogenesis  by muscle

Muscle is a major resource for heat production owing to the structure of muscle, which are rich in mitochondria and calcium pumps, both of which are essential for this porces. Blondin & Haman (2018) describe this in more detail than is required by the ICU trainee. The most important points are:

  • It is distinct from shivering, as the EMG activity can be silent, even as the heat production is increased
  • It has two main mechanisms:
    • Mitochondrial proton leak, which can be increased by various "uncoupling proteins", and which is also responsible for the increased thermogenesis that occurs in brown adipose tissue
    • SERCA pump cycling, which basically involves shuttling calcium back and forth between the layers of the sarcolemma, burning ATP in the process. The use of ATP by SERCA can account for 40–50% of resting skeletal muscle metabolic rate and can be leveraged to increase this rate of ATP consumption, thereby increasing heat production. The uncontrolled version of this mechanism is responsible for the heat excess of malignant hyperthermia.

The amount of heat produced by this can be considerable, considering that skeletal muscle contributes a large fraction to the total body mass. When Blondin et al (2017) explored the responses of nine men exposed to 10 ºC over for weeks, they found that the basal metabolic rate of muscle increased by a factor of about 2.6 before the onset of actual shivering.

Brown adipose tissue thermogenesis

Apart from muscle, the next most quantitatively important source of facultative adaptive heat production is brown adipose tissue. This method is the change produced by chronic exposure to cold, and represents a long term adaptation to conditions of increased demand. Nedergaard & Cannon (2018) describe this as the effect of autonomic stimulation, specifically an adrenergic effect mediated via the β3 receptors. The cellular mechanisms are the same as described for the non-shivering thermogenesis of muscle, i.e. by uncoupling the electron transport chain from the production of ATP via unique porin protein that increases the permeability of the mitochondrial membrane to protons. The resulting increase in the rate of fatty acid oxidation is the mechanism for increased heat production, as fatty acid oxidation yields something like 39 kJ/g of heat. In fact brown adipose tissue is so geared for this that it is nearly devoid of ATP synthase.

In the adult this tissue is present as depots which can be easily identified on PET scans because of their increased uptake of metabolic substrate. It is seen in a distinct fascial plane in the neck, superficial and lateral to the sternocleidomastoid muscles. It can extend inferiorly between the subscapularis and pectoralis muscles, and down the paraspinal spaces of the chest along the aorta towards the adrenal glands and kidneys. The graphical representation of this distribution mapped by Brooks et al (2017) is probably more explanatory:

Distribution of brown adipose tissue, from Brooks et al (2017)

This may seem like huge thick tracts of brown fat, but in fact the total amount of this stuff in an adult is only about 300-400g at the most, and usually much less. In lean men, the mapping study by Brooks et al found about 330ml was the usual volume, or around 1.5% of the total body mass. That this is all you need would seem remarkable if one did not take into account the massive potential for heat production in this tissue; according to Symonds (2013) it can produce up to 300 W/kg of heat when maximally stimulated. Even if only 1/3rd of a kilogram of such tissue exists in a normal 70kg adult, the total output of heat from those 330g would be approximately the same as the heat output from the rest of the organism. 

Surely, one must ask - what is the metabolic cost of this ridiculous excess? It is not trivial. When Heim & Hull (1966) perfused the brown fat of cute newborn rabbits with raw noradrenaline, the oxygen consumption jumped from 9.3ml/100g to 60ml/100g, and the blood flow tripled. Comparing this with the oxygen demand of other metabolically active organs listed around this site is informative:

Oxygen demand by organs and tissues
Organ/tissue O2 consumption in ml/100g/min
Heart (arrested) 2
Brain 3.8
Kidney 4
Liver 6
Heart (at rest) 8
Brown adipose tissue 9.3
Brown adipose tissue (maximum stimulation) 60
Heart (at maximum inotropy) 90

If that seems like an excellent mechanism to lose some weight, one is reminded that normal brown adipose tissue does not have noradrenaline funnelled directly into it, and even if it did the maximum total amount of energy expenditure would be modest in obese patients because they tend to have less of this type of fat. Because this tissue consumes mainly its own stored fatty acids, only 10% of its metabolic substrate comes from the rest of the organism, and short-term energy consumption only ends up being something like 100 kcal/day. Some studies are more optimistic. For example, when normal humans receive high dose mirabegron (roughly four times the usual dose of this β3 agonist), the apparent increase in metabolic activity seemed to be higher than what would be expected (about 200 kcal/day). When van Marken Lichtenbelt et al chilled several healthy men down to 16 ºC, they reported an increase of their basal metabolic rate by up to 30%, which they attributed to the brown fat. 

Shivering

The end phase of the recruitment process that brings all the thermoeffector mechanisms together, shivering is an extremely effective method of increasing body heat production from metabolic substrate without having to perform tedious repetitive gym exercises.  In general shivering shares the same mechanism for heat production with non-shivering thermogenesis by muscle, which is the repetitive activity of ATP hydrolysis in the service of moving calcium ions around. The net energy demands of muscle during heavy exercise, and the relative inefficiency of its use of metabolic substrate, both mean that the whole body becomes a heat generator, with a variable capacity to generate heat that depends on the intensity of the exercise.  The following table was constructed from Potter et al (2017) and Cramer et al (2022)  to give the reader some appreciation of the magnitude of this energy output. 

Heat Produced by Exercise and Shivering
Exercise/activity Heat (W)
Resting (no activity) 100
Relaxed standing 150
Walking slowly 180
Bicycling at ~ 18 kph 400
Running at ~8 kph 800
Running at  16 kph 1500
Seizures Probably around 1000
Shivering, maximum ~500

The increase in body heat resulting from exercise is significant. Elite cyclists in the UCI Road Cycling World Championship measured core temperatures up to 41.5 ºC after 45 minutes of riding in the Qatari heat (and interestingly medal-winners had the highest core temperatures). Experimental primate models of epilepsy resulted in core temperatures rising to 42 ºC after ninety minutes of generalised seizures. These increases in temperature were occurring in robust organisms with intact thermoregulatory systems, i.e. in spite of all the work done by their heat dissipation mechanisms. In short, exercising muscle is an excellent source of heat, which makes it a good resource for the endotherm organism trying to stay warm. This is probably why shivering is a technique common to all endotherms, probably because muscle is the largest proportion of their body mass, and is extremely recruitable, in the sense that it can increase its metabolic activity massively if asked. 

What is shivering? It is involuntary muscle contraction with increased tone, which resembles the normal postural activity of skeletal muscles. Small motor units are recruited first, and then larger and larger ones are brought into play in a smooth crescendo of increasing activity, which manifests as muscle rigidity and tremor.  In humans the most important muscle groups are the larger ones, with proximal legs and trunk producing most of the heat, and arm muscles contributing relatively little. Interestingly, coarser tremor and more visible vibration is not necessarily the sign of more intense thermogenesis, as all it really means is that the motor units are more coordinated (Hohtola, 2004).

The exact kind of shivering (rhythm, intensity, etc) appears to be determined at the spinal cord level, probably according to some kind of proprioceptive feedback loop, but nobody really seems to know what circuitry underlies this process. Its heat production appears to be throttled at about five times the total metabolic rate, i.e. continued cooling beyond the point where this level of shivering is seen (usually about 35 ºC) does not yield any greater muscle activity, muscle metabolic rates or heat production. In fact beyond 31 ºC shivering tends to decrease, and severely hypothermic individuals do not shiver at all. 

How is this shivering different from febrile rigors

It's not, reader. It's the exact same thing. It occurs at normothermia and is the effect of the hypothalamus having selected a higher body temperature setpoint in response to infection, which then motivated thermoeffector mechanisms to increase the body temperature. 

Thermoeffector responses to heat

The mechanisms designed to dissipate heat are more active and have a higher capacity to change heat transfer than the mechanisms designed to increase heat production and decrease heat loss, probably because hyperthermia is more rapidly fatal than hypothermia for the hot bird or mammal. We already live at the distant edge of the normal temperature range for protein tertiary structure integrity and further heating would be poorly tolerated by the molecular mechanisms we rely on. The importance of the thermoeffector responses to heat would therefore seem like something that requires a long discussion, but in fact is the shortest part of this chapter, mostly because it is at the very end, and all the work of explaining the important concepts has already been done. 

Skin vasodilation

As the regional circulation of the skin already enjoys a lot of attention elsewhere, it will suffice to offer the reader a definitive reference (Francisco & Minson, 2018) and summarise that the convection of warm blood from the core of the body to the cool surface can increase massively by means of cutaneous vasodilation, and could soak up something like 70% of the cardiac output. This brings the cool external surface close to core temperature, and this is a crucial step in increasing heat loss, because broadly speaking the rate of heat loss is proportional to the temperature gradient between the body surface and the external environment. Conduction being usually trivial, air convection being out of one's control, and radiative heat loss being difficult to scale, the biggest contribution made by cutaneous vasodilation is via increasing the heat available to evaporate sweat. 

Sweating

Heat lost by the evaporation of sweat is by far the most important mechanism of heat transfer, and has the capacity to scale massively, as rates of  sweat production of 2000 ml/hr and even up to 4000ml/hr are reported in the literature.   The properties and contents of sweat are discussed elsewhere, and for the purposes of this section its most important characteristic is its latent heat of vaporization.  Gagnon & Crandall (2018) give a value of 2426 J per gram of sweat at 30°C, which could theoretically dissipate as much as 1700 W of heat if all of that 2000g of sweat is efficiently vapourised. Realistically this maximum  is never achieved because sweat does not form neatly and ends up soaking into clothes or dripping away without evaporation, so the maximum rate of heat loss in the clothed human is probably much lower. 

Panting and thermal hyperpnoea

Respiratory heat loss is a mechanism of heat transfer, but humans do not seem to activate this mechanism to regulate their temperature as much as other species. To be clear, panting is distinct from normal tachypnoea. It can be characterised as a pattern of breathing which is specifically aimed at increasing the ventilation of anatomical dead space, increasing the rate of evaporative heat loss by increasing air convection over the heat and moisture exchange surfaces of the upper airways. This usually looks like rapid shallow breathing with small tidal volumes at a respiratory rate of something like 200-300, distinct from the kind of hyperventilation one sees during exercise, and usually not associated with major changes in gas exchange. 

Hyperthermic humans don't do this, but they do increase their minute volume (Robertshaw, 2006), and in fact this seems to be a common thing for both panting and non-panting animals. The magnitude of the change is given by experiments such Gaudio & Abramson (1968), who reported that an increase in core temperature by 1°C resulted in an increase in minute volume by 35%, with a proportionate fall in PaCO2 from 44 to 33 mmHg. That the CO2 drops is informative: this increase in ventilation is obviously not merely trying to keep up with some kind of increase in metabolic activity resulting from the increased temperature.  Iampietro et al (1966) heated some healthy volunteers to rectal tem,eratures of around 39.2 °C and recorded pH values around 7.60 and PaCO2 as low as 20 mmHg.  White (2018) reviewed the available data and concluded that on balance of the evidence we should probably regard this "thermal hyperpnoea" as a thermoregulatory response. 

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