Physiological responses to hyperthermia

This chapter is theoretically relevant to Section R1(iv) of the 2017 CICM Primary Syllabus, which expects the trainees to "explain the physiological responses when a person is subjected to hypothermia and hyperthermia". Specifically, the discussion in this chapter will focus on the topic of hyperthermia (as distinct from fever). It is not a topic that has ever been asked about in the primary exam, because in contrast to hypothermia, there is basically no scientific reason for ICU patients to ever have their temperature increased above the normal range.

In summary:

Hyperthermia is core temperature above the range specified for the normal active state of the species.

Fever is hyperthermia resulting from intact homeostatic responses.

Both have the same functional effects:

  • Metabolic rate increases by 8-10% for every degree, which results in increased nutrient, oxygen, and ventilation requirements
  • Increased minute volume due to the above as well as thermal hyperpnoea, leading to respiratory alkalosis
  • Increased PaO2 (by 5mmHg) and increased PaCO(by 2mmHg) per each degree above  37°C due to decreased gas solubility
  • Decreased affinity of haemoglobin for oxygen (right shift)
  • Increased cardiac output (heart rate and stroke volume)
  • Decreased CVP and systemic vascular resistance due to vasodilation
  • Redistribution of blood flow to skin (up to 50-70% of the cardiac output)
    • Renal hepatic and splanchnic blood flow are sacrificed; thus:
    • Decreased glomerular filtration and impaired renal drug clearance
    • Decreased hepatic drug clearance (hepatic blood flow decreases by 50-75%)
    • Capillary endothelial dysfunction leading to increased permeability and third-space fluid shifts
  • Cognitive impairment, ranging from confusion to coma, with decreased seizure threshold
  • Fluid shifts and electrolyte losses due to sweat and capillary leak, resulting in haemoconcentration and hypokalemia
  • Impaired intestinal motility, persistent ileus even with short exposure
  • Increased gastrointestinal mucosal permeability, decreased barrier function which leads to bacterial translocation and endotoxemia
  • Hypercoagulabiliuty of blood,  leading to disseminated intravascular coagulation and widespread haemorrhages, small and large
  • Improved immune cell function (signalling, migration, recruitment from marrow, phagocytic activity, etc)
  • Impaired microbial growth for some pathogens, S.pneumoniae, T.pallidum, C.neoformans, but not for others (eg. Aspergillus)

The critical thermal limits ("the minimal high deep-body temperature that is lethal") for humans seems to be a sustained temperature of 41.5-42 ºC (hours), or short exposure to a core temperature of >45-46 ºC

Considering that basically every senior academic seems to have written a hypothermia review at some stage or another, it is remarkable how little literature there is dealing with hyperthermia. Simon (1993) is probably the last time anyone wrote about this in a big name journal. For the majority of the points below, no single paper was enough, and information had to be scraped together from multiple dispersed sources. Without reciting the entire bibliography, notable recommendations would have to include Pinksy et al (2006) for the ABG effects, Loring Rowell (2011) for the cardiovascular responses, Walter & Carraretto (2016) for the neurological effects, Hashim (2010) for the fluids and electrolytes, and Chapman et al (2021) for the renal consequences.

Definition of hyperthermia

The IUPS  Commission for Thermal Physiology defines hyperthermia as follows:

Hyperthermia: The condition of a temperature regulator when core temperature is above its range specified for the normal active state of the species.

This official definition leaves some room for improvement. "The condition of a temperature regulator" might sound weird (are they talking about the hypothalamus?) but in fact refers to another IUPS CTP definition, where a "temperature regulator" is "an organism which regulates its body temperature to some extent by autonomic and/or behavioral processes." The "normal active state of the species" seems to be an addendum necessary for the term to be applicable to poikilotherm species who may enter states of torpor or hibernation, which are not "active" states, but this is not defined anywhere else in the IUPS document. However, many authors seem to borrow this definition and cite IUPS. Others create their own, often using specific temperature values, and usually without specifying that the core temperature is referred to:

  • "A body temperature greater than 40 ºC" - Wasserman et al, 2017
  • "Elevation of temperature to a supraphysiologic level ... temperatures between 40° and 45°C". - Dewhirst et al, 2003
  • A temperature above 37.5 °C, "because physiologic responses to elevated temperature are present at this level"- Schroeck et al, 2016
  • "Hyperthermia exists if body temperature during homeostatic conditions rises above the normal range", or perhaps it is "a rise in core temperature more than 2°C per hour or more than 0.5°C over 15 minutes" - Vu, 2007
  • "... considered as a rise in core body temperature >38.3°C in humans" - Thorne et al (2020), who misquoited the definition of fever from Laupland, 2009

In short, the CICM exam candidates should not make any specific efforts to define hyperthermia beyond "temperature higher than normal", and in a fair universe the CICM examiners should not ask them to make any such effort. 

How is hypothermia distinct from fever?

One possible way to use a definition to look bad in a written exam answer is to confuse hyperthermia with fever. There is a distinction between these terms, and some authors do draw attention to it.

From Sajadi et al (2017)

"Fever is a regulated rise in core temperature in response to a physiologic threat to the host, while hyperthermia is defined as a disturbance in temperature regulation when core temperature is above the normal range."

Or, via Boron & Bouelpaep (2017, p.1202),

"Fever is a regulated elevation of core temperature induced by the central thermoregulatory system itself."

Or, perhaps the best one, from a 1993 NEJM article:

"A variety of disorders can elevate body temperature; those resulting from thermoregulatory failure are properly called hyperthermia, whereas those resulting from intact homeostatic responses are categorized as fever."

There is probably no better way rephrase this. The bottom line is that fever is an intentional response of the organism to some kind of stress which required the temperature to be elevated, and normal thermoeffector mechanisms are responsible for the increase in temperature, whereas hyperthermia is an increase in temperature which occurs in spite of opposing thermoeffector responses, or in their absence.

Conceptual framework for the discussion of hyperthermia

Broadly the effects of anything can be defined in terms of "what the thing does to the body" and "what the body does in response to the thing", but in the case of hypothermia and hyperthermia these clear boundaries are blurred and smudged to the point where it becomes impossible to separate causes and effects. Does hypothermia decrease the metabolic rate? Yes, but it causes shivering and non-shivering thermogenesis, so the metabolic rate ... is increased? Or does it remain the same? The reader is gently redirected from these totally reasonable questions with the reassurance that the mechanisms of thermoregulation are discussed in detail elsewhere, and they are dealt with in a way that lets this page unfocus from the compensatory responses as much as possible. Still, they are mentioned wherever it is necessary, hopefully in a way that does not dominate the discussion. 

  • Hyperthermia causes thermoregulatory responses which are intended to restore the temperature back to normal
  • Hyperthermia also has physiological consequences which are unrelated to thermoregulatory responses (eg. the increased metabolic rate)
  • Some of these responses and consequences (eg. tachycardia, increased oxygen demand) are unproductive and can be regarded as pathological under specific circumstances (eg. coronary artery disease, traumatic brain injury)
  • The raised temperature has effects on cellular and organ function which are generally pathological, except where they help the immune system
  • Failure or exaggerated performance of heat-related regulatory processes also has pathological effects (eg. like where a lot of the clinical features of heat stroke are due to an excessive systemic inflammatory response)

The transition from adaptive changes, to maladaptive ones, and then to their failure and to unmitigated heat stress, can be represented as a continuum along a temperature scale, and this is what we will attempt to do at every stage along this discussion.

The effect of hyperthermia on metabolic rate

The Law of Arrhenius dictates that the rate of reactions should proceed faster with increasing temperature, and so in the same way that hypothermia depresses metabolic activity, so hyperthermia should increase it. The specific equation involved predicts an exponential rate of increase. For reactions in beakers, this relationship is probably some kind of eye-pleasing parabola, but for organic reactions occurring inside living organisms the rate of rise terminates at a plateau and then drops steeply with increasing temperature as critical metabolic enzymes become denatured by the heat. The graphical representation of this, sometimes referred to as a thermal performance curve, would look like this diagram, adorned with exam-answer-satisfying labels:

A typical thermal performance curve, labelled diagram

This is obviously much easier to observe in ectotherms, who are at the mercy of the ambient temperature and are therefore have all of their characteristics mostly described by this curve. Specifically, when one sees this in the literature, the y axis is usually labelled something like "fitness" and the graph describes population survival over a range of environmental temperatures. Endotherms, with their advanced thermoregulatory mechanisms, tend to keep their core temperature in a narrow range, and so do not tend to obey this rule (if you use the ecological fitness definition of thermal performance), but if the core temperature is altered, and a specific parameter is being observed (eg. the metabolic rate or the performance of some specific enzyme), a similar relationship is revealed. When McQueen (1975) boiled some human lactate dehydrogenase (obtained from human cadavers), this is what he got:

lactate dehydrogenase thermal performance curve from McQueen (1975)

The reader who is able to effortlessly read temperatures in the Kelvin scale will instantly note that lactate dehydrogenase seems to function optimally in the range of 31-41 ºC, with peak activity at about 36.8 ºC and loses its affinity for its substrate with increasing temperature, becoming comically useless at 46 ºC. The molecular mechanisms behind this are mostly related to the need for constant barely-keeping-yourself-together instability in enzyme systems, which can only function if their tertiary structure is highly flexible and capable of changing with a minimal investment of energy. Adding too much energy to such a system will result in a change in this tertiary structure, and a (usually) reversible loss of function. 

So what does this mean for the metabolic rate of endotherms whose core temperature is raised? An often quoted factoid about hypothermia holds that for every degree call in temperature, the metabolic rate decreases by 6%. Something similar is said of rising temperature, and the data to support it is also derived from anaesthetised dogs. When Iwasaka et al (1992) heated their subjects to 43 ºC, they observed a sustained increase in their rate of metabolism, at a rate of about 8-10% for every degree:

The rate of metabolism here being measured by oxygen consumption begs the question about how hyperthermia affects nutritional requirements. This deserves some additional attention.

The effect of hyperthermia on nutrient metabolism

Critically ill patients with hyperthermia are often accused of being "hypermetabolic", a term that is loosely applied to explain the increased need for nutrition in this population. The scientific basis for this assertion is surprisingly shaky, even by the standards of Intensive Care physiology which frequently accepts a 1950s paper with measurements from three dead pigs as sufficient support. For example, when Miles et al (2006) reviewed contemporary works for any evidence of an association between fever and hypermetabolism, they discovered that the majority of the published works  excluded febrile patients from their analysis. Some data, however, are available, and they are very interesting. For example, though it may be difficult to separate the effects of fever from the effects of critical illness,  Frankenfield et al (1997) were able to compare metabolic rate multipliers (in %) for trauma, surgery and medical patients, as follows:

metabolic rates of febrile and afebrile ICU patients from Frankenfield et al, 19971

"Fever" in this context was a core temperature of around 38.1-38.5 ºC on average, i.e. a rise in the metabolic rate by about 10-20% for every degree of temperature was observed. Considering that nutrition trials in the second and third decade of the 21st century have yielded mainly negative results, the reader may be forgiven for scoffing at the idea of titrating one's caloric goals to match predicted expenditure.

Effect of hyperthermia on pharmacokinetics and pharmacodynamics

From the above, it follows that if the metabolic rate of nutritional substrates is increased, then surely the rate of metabolic clearance for drugs and toxins will be increased, considering especially that in hypothermia these processes are depressed in a temperature-dependent manner. An excellent review by Vanakoski & Seppälä (1998) addresses this matter, though the readers are cautioned that the study is Finnish and therefore mostly concerned with the pharmacokinetic effects of a sauna. In fact there does not appear to be any drug known to man that has not been fed to partially clothed Finnish löylynottajat under experimental conditions. Setting this imagery aside, a few salient points can be borrowed from this resource:

  • Absorption of drugs may be increased, especially from skin sites which suddenly enjoy a massive increase in regional blood flow. However gastrointestinal absorption is largely unaffected. 
  • Distribution may be decreased, i.e. the apparent volumes occupied by the drugs may be reduced because of haemoconcentration (as fluid losses tend to be higher in hyperthermia), but this has nothing unique about it, and is the same sort of volume contraction one may see in any other sort of dehydration.
  • Metabolism by the liver is affected by two main factors:
    • Liver blood flow seems to be reduced markedly (by 50-75%!) with prolonged high-temperature heat exposure.
    • Liver enzyme activity is variably affected. The Arrhenius relationship suggests that there should be some increase in the rate of enzyme-mediated reactions, but not all CYP450 enzymes obey this rule.  Kojima et al (2023) determined that the activity of CYP3A4 and CYP2C19 was reduced to 74-58% from normothermic values, whereas activity of other isoforms (eg. CYP2C9) had increased up to 131%.
    • The net effect of most of these changes leads to decreased drug clearance, and most of all decreased drug clearance of drugs which are metabolised by high-affiity systems and which therefore have their rate of clearance determined by hepatic blood flow.
  • Renal elimination is pushed mostly in the direction of "less", as the result of circulating volume changes which fool the kidneys into conserving water and therefore reduce the glomerular filtration rate. Data from experiments where volume loss was controlled for do not seem to demonstrate any major change in the rate of renal elimination. 

The results of all these largely negative investigations into the pharmacological effects of hyperthermia need to be considered in the context of their subject population, who were mostly healthy young volunteers. Apart from increased skin blood flow and therefore increased drug absorption from patches and creams one cannot really make a big deal about the effects of hyperthermia on drug pharmacology. The pragmatic intensivist would have to conclude that individual organ-failure-related variations in pharmacokinetics which are associated with critical illness would probably play a far greater role.

As for the other half of all pharmacology, the heading "effect of hyperthermia on pharmacodynamics" cannot even be raised to a h2 tag level of  importance because there is no literature on the subject. Still, we can make guesses from first principles. One may surmise from what is known about the effects of temperature on complex protein systems that excessive heat will disturb the tertiary structure of a protein, and considering that most drug targets are proteins of one sort or another, the affinity of the target for the drug will steeply decrease with rising temperature. There do not appear to be any studies to support this, even from the cruel dark ages of critical care physiology.

The effect of hyperthermia on respiratory function

Considering what we just discussed about the effects of increasing temperature on the metabolic rate, it would make sense for CO2 to rise, and for the minute volume to increase. Increased metabolic substrate use translates into increased CO2 production in a familiar relationship (0.8) and so we could expect the minute volume to increase proportionally. In fact it increases even more than that, as mammals seem to have a thermal hyperpnoea response (White, 2006) which is a thermoregulatory mechanism distinct from panting, and which increases respiratory heat transfer. In fact arterial CO2 tends to actually drop, illustrating that this increased respiratory drive is disconnected from the normal mechanisms of CO2 and pH regulation. It seems to go rather low:  Iampietro et al (1966) recorded pH values around 7.60 and PaCO2 as low as 20 mmHg in healthy volunteers who were heated  to a rectal temperature of around 39.2 °C in a dry heat chamber with an air temperature of 54.4 °C. From these data, we can generate two take-home messages for the intensivist:

  • Minute volume of conscious hyperthermic patients will increase, disproportionately to the increase in their metabolic rate, and will produce a respiratory alkalosis which is an entirely normal phenomenon.
  • Minute volume of mechanically ventilated patients will need to be increased, if they are on a mandatory mode, to compensate for the increased CO2 production - but only by about 8-10% for every degree of hyperthermia.

At this stage one should probably also bring up the temperature-related changes in gas solubility, which brings us to:

The effect of hyperthermia on blood gas analysis

This section is preambled with the caveat that the changes will be minor because the range of clinically relevant raised temperatures is small. Consider that we routinely cool people by 15 degrees, but we never heat them by 15 degrees, mostly because even a temperature increase by 4 degrees from baseline is lifethreatening. The changes in gas solubility which occur over this range are therefore modest. Still, it is worth remembering that gas solubility in water decreases with temperature, wj=hich pushes up the partial pressure.

Tremey & Vigue (2004) give an excellent account of this, but their l’interprétation des gaz du sang is  only available to the reader fluent in French. The uncultured English must resort to primary sources such as Gordon Darling and Shea (1949) who measured each other's blood gases using ancient steampunk equipment and experimentally confirmed the physiological changes listed in the points above. The adorable diagram from their paper is offered here as a monument to them and their other subjects, of whom "five received physically induced fever for neurosyphilis and one, for a non-specific iritis". 

Hyperthermic oxygen haemoglobin dissociation curves from Gordon Darling and Shea (1949)

A less specific but more comprehensive resource is Pinsky et al (2006), cited here mainly because the author wanted to steal their gas solubility diagram:

gas solubility with temperature from Pinsky et al (2006)

In summary:

The effect of hyperthermia on the circulation

The circulatory system is heavily involved in the thermoregulatory response to hyperthermia, and it is difficult to separate this from the direct effects of hyperthermia on cardiac and vascular function. Fortunately, these effects are never separated clinically either. 

The objective changes of both were observed and recorded by Pettigrew et al (1974) in a series of nightmarish experiments aimed to establish "the safety, or otherwise" of extreme hyperthermia (for the management of cancer). Their experimental setup was described as follows:

"The patient is prernedicated with promethazine hydrochloride, narcotized with intravenous barbiturates and then curarized. He is sealed in a large polythene bag and placed in a specially constructed bath. Paraffin wax (melting point, 43-46 ºC) heated to 50 ºC is pumped into the bath around the sealed bag. The wax solidifies around the patient, forming an insulating layer. Ventilation is maintained through an insulated endotracheal tube with an enriched oxygen mixture heated to 80ºC. This is the temperature at the top of the tube, where the closed-circuit adapter meets the endotracheal tube fitting. It falls to 45-55 ºC at the lower end, i.e. near the carina... dry gas at this temperature does not damage the lungs. The body temperature is raised by between 3 and 6 Centrigrade degrees/hour, depending on body weight."

This method is reproduced here mainly because it confronts the reader with the full horror of early  hyperthermia research, and not necessarily to make use of their findings. Though seventy such immersions were performed and recorded, the data they collected was not as comprehensive as some earlier experiments by Rowell et al (1969) and Rowell et al (1974) which were so impressive that they were lightly molested with Photoshop and displayed below with minimal modification:

cardiovascular responses to hyperthermia from Rowell et al, 1969

A diagram of some regional ciculatory changes from later experiments is also helpful:

Regional circulatory changes with heat stress from Rowell et al (1974).jpg

Loring Rowell was the primary investigator here in the sixties and seventies, notably having subjected himself to the heat before his  experimental subjects to determine the maximum water temperature that could be tolerated for the duration of the experiment (anything beyond 47.5 ºC was apparently so painful that he could not inflict it on his undergrad volunteers). The same man, many years later a Professor Emeritus at the University of Washington, wrote an excellent entry for Comprehensive Physiology where the cardiovascular responses to heat stress are detailed. From this paper, the following points can be summarised:

Normal (thermoregulatory) circulatory changes in response to hyperthermia:

  • Global circulatory changes:
    • Cardiac output is markedly increased (both stroke volume and heart rate increase, but the heart rate increases by about 50% whereas the stroke volume only goes up by about 10%)
    • Arterial blood pressure increases as the result, but not by very much.
    • CVP decreases
    • Systemic vascular resistance decreases 
    • Total blood volume gradually decreases as the result of volume loss via sweat and tachypnoea
  • Regional circulatory changes
    • Up to 50-70% of the cardiac output is redirected to the cutaneous circulation (4L/min/m2 of body surface, or 400ml/100g of skin, which resembles the normal blood flow of the kidneys).
    • This is mediated by sympathetic cutaneous vasodilation
    • Blood flow is redirected from other regional circulations: renal blood flow and splanchnic blood flow are sacrificed
    • Cerebral blood flow is reduced, but this is mainly due to the reduced PaCO2 (Nelson et al, 2011)

These normal adaptive changes are obviously replaced by very abnormal maladaptive ones when the temperature continues to increase. Marchand & Gin (2022) detail the pathophysiology of these in their opening paragraphs. To summarise, the increased fluid losses ultimately produce hypovolemia. With the circulation maximally vasodilated and the cardiac output already maximally increased, the usual systemic responses to volume loss are ineffective, and organ perfusion starts to suffer, i.e. shock develops. 

Severe hyperthermia and heat stroke lead to the development of haemoprrhagic lesions in the myocardium, including "subepicardial, intramuscular, subendocardial, or even intravalvular". Some of these from the autopsy series by Malamud et al (1946) were sufficiently massive to produce symptoms of cardiac failure, purely by enough extravasation of blood into the walls of the left ventricle. 

An interesting side issue raised by autopsy studies of heat stroke victims is the development of late shock due to adrenal insufficiency, precipitated by adrenal cortical haemorrhage. "Early coalescence of lipid droplets in the zona fasciculata" are observed within even three hours of high temperature exposure, according to Gore & Isaacson (1949),  followed by oedema and then what looks like acute necrosis and haemorrhage.This resembles the sort of widespread haemorrhagic change that occurs in the central nervous system of these patients, which is a convenient transition to:

The effect of hyperthermia on neurological and cognitive function

The end stages of heat stroke are usually cerebral oedema multiple small cerebral haemorrhages, according to findings from the brains of heat stroke victims reported by Malamud et al (1946). Before these final events the progression of hyperthermia neurological dysfunction is through various stages of poor cognition and confusion, all the way to coma and seizures. Considering what was just discussed about the rate of reactions and increased metabolic substrate use, one might expect neurotransmitters to work harder with hyperthermia, but in fact overall the effects of higher temperature on the CNS are deleterious. A core temperature as low as 38.8 °C can produce measurable cognitive dysfunction. Walter & Carraretto (2016) report on the most important effects, which can be summarised as follows:

  • Poor short term memory
  • Impaired processing of information
  • Inattention
  • Decreased seizure threshold

Severe hyperthermia, i.e heat stroke, will obviously have even more serious and potentially irreversible consequences. Basim Yaqub, recording his findings from heat stroke victims during a 1987 pilgrimage to Mecca, reported profound coma among many of the patients, including the reversible loss of brainstem reflexes. Pupils were constricted in all of the patients. Some, i.e. those not profoundly comatose, exhibited "automatism" such as "chewing, swallowing, and lip smacking", which recalls the features of non-convulsive status epilepticus. 

The effects of hyperthermia on body fluids and electrolytes

One may separate the effects of hyperthermia on the body fluid compartments into those volumes lost  to various thermoregulatory shenanigans such as sweat, and those lost by redistribution to some kind of stupid third compartment where the fluid can no longer serve its original purpose. For the latter, the shift can be considerable. When Eschel et al (2001) boiled several monkeys at 42 ºC, their haematocrit increased from 35% to 45% over two hours, which could be attributed to the movement of fluid into various suddenly permeable potential spaces. Haemoserous fluid was abundant in the pleural and peritoneal cavities. The extent of the haemoconcentration resembles what is seen in pancreatitis. The movement of the fluid into the dilated peripheries empties the central vascular spaces and produces the reduction in CVP reported in the graphs above, which can be represented in terms of an increased "unstressed volume".

This sideways movement of fluid does not usually disturb the electrolytes overmuch, but electrolytes are still generally lost via urine and sweat. From the horror experiments of Pettigrew et al (1974), as well as numerous similar others, we can estimate the quantities of these losses. Specifically for the linked experiment series, the wax-encased subjects lost about 500ml/hr of body water as sweat and 50ml/hr as urine, with corresponding sodium and chloride loss of 45 mmol/hr, and a potassium loss of 4 mmol/hr. The potassium depletion through losses is also exacerbated by the hyperadrenergic state which develops in hyperthermia, which results in the intracellular movement of potassium due to increased Na+/K+ ATPase activity (Hashim, 2010). The hypokalemia then gives way to hyperkalemia and rising serum phosphate when rhabdomyolysis develops in advanced heat stroke. Speaking of which:

The effects of hyperthermia on renal function

The kidneys, as the recipients of a large proportion of the cardiac output and the main governors of the fluid and electrolyte balance, are under considerable stress under conditions of hyperthermia. Even if the hypovolemia and rhabdomyolysis are controlled for, renal function declines with hyperthermia. A classical study by Kanter (1961) raised the core temperature of anaesthetised dogs to 43 ºC and observed that their glomerular filtration rate declined even when their body fluid volume was well-maintained with intravenous fluids. The reasons for this, the author concluded in the basis of some renal blood flow measurements, was a failure of the normal renal blood flow autoregulation: renal vascular resistance increased even though the blood pressure and cardiac output decreased in the later stages of hyperthermia. With more time passing, this reduced perfusion begins to cause damage; autopsies of American soldiers who suffered heat stroke during the Second World War revealed changes suggestive of acute tubular necrosis (Malamud et al, 1946).

The effects of hyperthermia on liver function

When the skin blood flow increases by several factors of magnitude, the blood flow to the splanchnic circulation has to decrease, making the liver a loser. When Hall et al (1980) induced malignant hyperthermia in pigs, their hepatic blood flow had reduced by 75% at 41.2°C. This is probably a dominant factor underlying the wildly elevated LFTs one tends to observe in patients suffering from heat stroke after a couple of days of ICU stay. Hepatocellular damage only seems to occur with prolonged exposure to high heat, and tends to be associated with microthrombosis, i.e. not only sluggish blood flow is to blame, but also stasis and endothelial dysfunction. But before it becomes ischaemic and clogged with microthrombi, the liver valiantly tries to still take part in the whole-body stress response, for example by responding to the sympathetic storm by increasing glycogenolysis and releasing glucose, and by trying to increase the rate of lactate uptake. Thorne et al (2020) detail all sort of other molecular responses which are probably of less interest to the intensivist, except where they affect the fate of transplant livers.

The effects of hyperthermia on gastrointestinal function

If the liver, a notably important citizen of the abdomen, is starved of blood flow when the body becomes preoccupied with perfusing the skin, then surely the gastrointestinal tract must fare even worse. Who could be digesting anything in this heat anyway, one might pant. Surely there is better use for that blood flow. Indeed, the GIT is shortchanged in this situation, which might seem like a really useful adaptive strategy, but which ultimately turns into a serious problem which threatens to destroy the entire organism. The reason for this is increased intestinal permeability. 

The emergence of unfavourable gastrointestinal effects of heat is rather quick: in Eschel's boiled monkeys, the gut became adynamic over the first two hours, developing an ileus. More disturbingly, the effect appears to be irreversible after a couple of hours of exposure. One does not need to heat the entire body - ICU patients recovering from hyperthermic intraperitoneal chemotherapy tend to have prolonged ileus even after regional heating.  The entric nervous system seems to be the main point of failure: when Burke et al (2011) cooked some mouse ileum, they found that specifically the failure of normal acetylcholine release mechanism was the thing that did not recover been after normothermia is reestablished. 

If the heat stress continues, the next stages are characterised by gastrointestinal haemorrhage and the loss of barrier function, which is thought to be responsible for much of the disastrous organ system effects seen in heat stroke. The profound widespread "endothelitis" seen in severe hyperthermia is thought to be at least partly attributed to the translocation of gut organisms into the portal circulation, and the failure of the overheated liver to clear a sufficient amount of endotoxin. The central role of this in the final stages of hyperthermia is supported by the findings of Bouchama et al (1991) who found abundant lipopolysaccharide in the blood of heat stroke victims.

The effects of hyperthermia on coagulation

Microthrombosis and haemorrhage at all scales seems to be the main process underlying organ pathology in heat stroke and hyperthermia. To bring an irrelevant digresson from history via the excellent paper by Marcel Levi (2018), we are moved to recall the experience of James Raymond Wellsted, a terrible white person who wrote a book describing his travel to Baghdad in 1840. He described events during a heatwave where heatstroke patients were treated on board of his military vessel, with such profounbd bleeding diathesis that "the decks of the ship Liverpool … resembled a slaughterhouse, so numerous were the bleeding patients."

A dominant feature of all the autopsy series of heat stroke seem to be haemorrhages, both petechial and much larger, which can be attributed to DIC. Al-Mashhadani et al (1994), reporting on Hajjis with heat stroke, presented a picture of consumptive coagulopathy with all the cardinal features of DIC which the authors attributed to a widespread activation of haemostatic mechanisms by the injured capillary endothelium. Fajardo & Prionas (1994) discuss this in some detail, though focusing mostly on the benefits of this circulatory injury for hyperthermia-assisted cancer therapy. In short, hyperthermia causes reduced secretion of antithrombotic factors such as tPA, and increases the exposure of the bloodstream to the subendothelium. The hypercoagulable state produced by this tends to cause thrombosis wherever there is even trivial stasis (eg. the liver) and the consumption of clotting factors then leads to a loss of overall clotting function and widespread petechial haemorrhage.

But the haematology nerd will point out that these are changes in clotting function mainly due to the denuded angry endothelium, i.e. we are really describing a widespread "endothelitis" rather than clotting dysfunction per se. Clotting function, they may argue, remains essentially normal, it's just reacting (normally) to a bizarre situation where all the endothelium suddenly becomes thrombogenic. Indeed, they may be correct, at least insofar as the heating of raw blood is concerned. When it is not being led astray by the inflammatory rhetoric of a disgruntled endothelium, whole blood seems to tolerate temperatures all the way up to 49 ºC, according to studies by Herron et al (1997)

Beyond 51-52 ºC, the investigators detected some features of haemolysis, but the red cells mostly kept themselves together well into the high 50s and osmotic fragility did not properly develop until 60 ºC. Astonishly, the haemoglobin molecule remained relatively functional even beyond this temperature, and did not undergo the sort of spontaneous depolymerization the one might expect. Though the authors called for a relaxation of the normal guidelines and advocated for the increased warming of blood being returned to the trauma patient, most healthcare industry blood-warming apparatus is limited to an upper range of 42-43 ºC by non-user-modifiable safety locks. 

The effects of hyperthermia on the immune system

The effect of self-induced hyperthermia on bacterial survival can be broadly summarised as "you yourself will overheat and die before the bacteria even notice". Most microorganisms of relevance to man are extremely resistant to changes in temperature and are generally able to survive a much larger range of temperatures than the host. For some examples from Huus & Ley (2021):

  • C.difficile is equally happy at 37 ºC and 41 ºC
  • E.coli is basically an extremophile and grows happily in a range between 8 ºC and 48 ºC
  • Aspergillus fumigatus is perfectly happy at 60 ºC
  • P.aeruginosa actually increases in pathogenicity as temperature increases, and seems to have some enzymes which are maximally efficient at 45 ºC

Still, one might argue that the very fact that the hypothalamus steers our metabolism towards fever during an infection should suggest to the reader that there must surely be some kind of benefit. It would be insanely wasteful otherwise, from the viewpoint of metabolic resources. It costs 834.4 kJ of energy to raise the temperature of a 70kg body by 4 °C, which is about 200 kcal, and no self-respecting organism would ever waste so much nutrient. And all self-respecting organisms seem to have this - the febrile response is ubiquitous among vertebrates (even ectothermic oneseg. amphibians) as well as invertebrates, down to the evolutionary fork in the road that separated annelids and arthropods from the vertebrate phylogeny. In other words the last common ancestor that couldn't  mount a fever was something soft and vaguely bilaterian, burrowed in the silt of a Pre-Cambian sea. The reason for this random digression is to impress on the reader that fever must have some noticeable evolutionary advantage, because otherwise it would not be present in every complex living thing. For humans, these advantages can be broadly divided into "antimicrobial" and "immunomodulatory". 

Antimicrobial effects of hyperthermia

Yes, contradicting what was said literally two paragraphs above, some microorganisms are actually rather sensitive to heat, and would be affected by fever. For the majority these are zoonotic pathogens which are sufficiently institutionalised to being the parasites of specific organisms that their temperature preference range is somewhere outside that of the human (but not too far, otherwise they would not find us to be suitable hosts). For example, Mycobacterim leprae much prefers the body temperature of its usual host (the armadillo), which is around 35 °C, and for this reason prefers to infect the cooler extremities of the human. Other notable examples include:

  • S.pnemoniae, which seems to stop growing at 41.0 °C
  • Treponema pallidum, which is so sensitive to heat that induced hyperthermia was actually therapeutic for sufferers of syphilis. Bessemans (1938), reflecting on his experiences over the 1920s, recalled that "our curiosity was aroused because treponemata in cultures and emulsions were killed by temperatures which were compatible with life in man". 
  • Neisseria gonococcus, which was similarly treated with hyperthermia
  • Cryptococcus neoformans, which was frustratingly difficult to introduce into rabbit brains because of their high (39ish) baseline core temperature

Additionally, hyperthermia disables the organisms that rely on the effector processes of the host for replication, such a viruses. Famously, André Lwoff (1959) found that he was able to extract 250 times less poliovirus from cell cultures incubated at 40.0 °C., as compared to normal body temperature.

Immunomodulatory effects of hyperthermia

The complexity of the immune system being bewildering to the author, all attempts to discuss it in any detail make him feel like a fraud and impostor, and so the reader is hurried towards authoritative references like Evans et al (2015) or  Frey et al (2012). What follows is an oversimplification designed to help the reader appear knowledgeable by repeating the insights of these experts:

  • Effects of fever on innate immunity
    • Increased recruitment of neutrophils from the bone marrow
    • Increased neutrophil migration to local sites of infection
    • Increased activity of NK cells
    • Increased bacterial clearance by resident tissue macrophages
    • Increased migration of dendritic cells to lymphoid tissues
  • Effects of fever on adaptive immunity
    • Increased activity of antigen-presenting dendritic cells
    • Increased circulation of lymphocytes through lymphoid tissue
    • Increased T cell proliferation
    • Lower threshold for T cell signalling

It's obviously not all sunshine and roses: 

  • Systemic hyperthermia can lead to an exaggerated systemic inflammatory response that is clearly unproductive (leading as it does to multiorgan system failure)
  • Increased localisation of neutrophils to sensitive tissues (eg. lungs) can increase the local damage there (i.e. worsen ARDS)
  • Temperatures above the normal febrile range impair neutrophil accumulation and function

Following from this last point, as well as these historical records of heating patients to take advantage of the narrow temperature range acceptable to a pathogen, raises the question: what narrow temperature range is acceptable to the human host, and for how long is it possible to safely exceed it? 

Critical thermal limits

The term "critical thermal limit" or " thermal tolerance limit" is unlikely to ever appear in any critical care exam, as it is mostly seen in ecological literature. It is generally used to describe the upper and lower boundaries for normal organism function, which for most species are highly preserved across large taxonomic groupings, suggesting that we all had very limited opportunities to evolve beyond our ancestral temperature niches - what Bennett et al (2021) call "deep time climate legacies". 

Unfortunately,  the conventional definition of critical thermal limits is so macabre that it fits very poorly into the medical context. Though it broadly describes the abilities of the organism to remain normally active under thermal stress, the manner in which it is measured has discoloured the definition, mostly because the determination of these limits involves some kind of deliberate cruelty, like heating the animal until the point of physiological failure. For example, Terblanche et al (2007) lists horrors like "knockdown, loss of righting response, onset of muscle spasms" referring to the detection of thermal limits for tsetse flies. Among humans, who tend to perform more complex tasks than tsetse flies, death would surely be a more robust endpoint than the onset of "unorganised locomotion" (which may not seem like an authentic boundary because it may represent the endpoint of a normal Saturday night for some of the readers).  A broader more human-applicable version of the definition would therefore have to be:

 

Critical thermal limit: "the minimal high deep-body temperature that is lethal"

Note the focus on "deep-body temperature". The critical limits for surface and environmental temperature are much harder to pin down because of robust thermoregulatory mechanisms, which will vary in their effectiveness depending on the person and the environment, of which the most potent is sweating. The best parameter to describe the environmental survival threshold for humans is therefore the temperature of adiabatic saturation or the the wet bulb temperature, i.e. the temperature at which the air is the same temperature as the skin and the relative humidity is 100%, making it impossible to lose heat by evaporation (as the heat transfer into the body is in equilibrium with the heat transferred out). This thermal limit is about 35 ºC, because that is the usual temperature of the human skin surface, and we will probably see sustained periods of this temperature over the equatorial regions after the world finishes doing a capitalism. 

If the thermoregulatory mechanisms fail, the body becomes a net importer of heat, and the core temperature will rise. From the fact that humans already exist at the upper thermal boundary for protein stability, one might surmise that even a comparatively small increase in temperature is likely to be tolerated very poorly. Indeed, it appears that something like 42.0 °C is the upper limit of core body temperature beyond which dangerous organ system effects begin to develop (though the data is not especially robust because what we know about this critical upper limit for humans comes from terrible case reports and records of well-meaning interventional systemic hyperthermia, which seemed to come in and out of vogue during the twentieth century).  With various careful risk mitigation strategies, it may be possible to survive this kind of hyperthermia, but probably not for very long. For example, Bynum et al (1978) detail the sustained survival of several anaesthetised patients heated to a core temperature of 41.6-42.0 °C for the duration of an hour, but at the end of this two out of five developed deranged LFTs. 

How high can you go? The reader familiar with Deranged Physiology will surely be expecting this chapter to be capstoned with some preposterous case report, and Suchard (2007) does not disappoint. They detailed the apparently uncomplicated survival of a young man whose decision to swallow 100 dose-units of contraband methamphetamine was followed first by some heroic efforts to evade the police ("a chase ensued, and he was apprehended by police while running around the roof of one building and attempting to jump to another roof") and then by a similarly heroic rectal temperature of 45.0 ºC. The emergency services were able to correct this back down to 38.1°C after one hundred minutes of ice-pack cooling, which probably accounts for his uneventful discharge on day 5, into the care of his long-suffering wife. An even higher core temperature (46.5 °C) is recorded by Slovis et al (1982), measured in a victim of heat stroke. Both patients had very unhappy organs and would have surely died without aggressive treatment, which suggests that these temperature values are likely representative of some kind of maximum for our species.

But what about other species? We are certainly not the highest achiever when it comes to hyperthermia tolerance. The red-billed quelea (Quelea quelea) is comfortable with a core temperature of 43-44 ºC at rest and  routinely exceeds 48 ºC during flight up to a maximum of around 49.1 ºC, which is probably as high as a terrestrial vertebrate is likely to go. Metazoans in general seem to max out at something like 60 ºC , judging by the thermal tolerance limits of deep sea hydrothermal vent animals. Specifically one very warm alvinnelid worm (Alvinella pompejana) lives at a sustained core body temperature of close to 60 ºC and can briefly tolerate immersion of its tail in water up to 80 ºC, which is roughly the correct air temperature of a proper Finnish sauna. Vitrified tardigrades of course can survive temperatures up to 110 ºC, but this cannot be held up as an upper range for anything because they are in a state of anhydrobiosis and therefore not strictly speaking alive. In terms of remaining "alive", i.e. reproducing and carrying on other vital activities, the upper boundary for living things on Earth appears to be something like 122 ºC, which is a comfortable temperature for Methanopyrus kandleri (a rod-shaped archaeobacterium from some hydrothermal vents in the Gulf of California); though some astrobiologists theorise that this may stretch all the way up to 150 ºC in organisms which remain to be discovered.

Heat tolerance characteristics of human tissues

Because 12-150 ºC is the temperature one would usually use to braise a nice bourguignon, the next most sensible questions are of course "how does Methanopyrus live like that without its proteins becoming verkackten" and "why are human tissues so thermofragile". Human organs and tissues are much less tolerant to heat than the cell components of Methanopyrus.  Yarmolenko et al (2011) presented some data using CEM43 (cumulative equivalent minutes at 43 °C) to describe the threshold values for some of the main players:

  • Brain: 1-2 CEM43
  • Bone: 15 CEM43
  • Bone marrow: 20 CEM43
  • Kidneys: 20 CEM43
  • Skin: 20-40 CEM43
  • Eye: 40 CEM 43
  • Muscle: 40-80 CEM43
  • Bladder: 80 CEM43
  • Small intestine: 80 CEM43
  • Liver: 80-320 CEM43

For the majority of these values, the findings come from papers where hyperthermia is used to destroy some tumour cells, and the key issue determining the success of the treatment is the functional survival of the surrounding organ. The temperatures to which they were heated was therefore mostly modest. In contrast, much higher temperatures tend to be used when we do not have any interest in ongoing functional survival of the tissue being heated (eg. where it is at the end of a diathermy probe, and in the path of the surgeon who is on their way to something deeper and more interesting). For example, during fulguration (an archaic term borrowing from for sheet lighting) the destruction of tissues is in fact the goal, and the temperature required for this is around 60-90 ºC. The tissues are desiccated by this sort of heat, leaving them dead but largely structurally intact, which may be desirable if the tissue is (for example) bleeding diffusely, or invaded with cancer cells. Higher temperatures (over 100 ºC) result in the boiling of cell water and the rupture of the cells, which produces the desired cutting effect.

The diathermy knife itself tends to heat up to as high as 400 C in the process, which is much higher than the temperature of burning literature. This begs the question, how does the wound surface not combust and generate paperwork for the department? Reader, it sometimes does, but the patient is usually not the one on fire.  Operating rooms contain abundant ignitable materials apart from oxygen, such as polyvinyl airway tubing, linen, cotton sponges, skin prep alcohol and anaesthetic gas.  These tend to be the source of fuel. Human tissues are rather difficult to encourage into flame, as most of the composition of a living body is water, and the rest is not readily combustible. Situations in which human tissue participates in the fire are thankfully uncommon and largely limited to the territory of forensic pathology. Without creating the proper conditions for nightmares, one gently redirects the reader's attention from such references as DeHaan (2012), whose experiments explored the properties of human tissues as a fuel source in a house fire ("could support combustion for 6-7 hours", apparently), or Bohnert et al (1998), who recorded the course of the observable changes of human bodies during cremation until they achieved Zermürbungspunkt, the point at which ashes disintegrate. That stage is reached about 50-80 minutes into the process of cremation which usually takes place at a temperature somewhat below that of a typical house fire (encouragingly detailed guidelines from the ACCA recommend 650-900 ºC as an industry standard). In contrast, a typical Australian bushfire can reach 1100 ºC, the temperature at which even teeth become irreversibly and unrecognisably damaged, and also the temperature at which biological waste is supposed to be incinerated (as this leaves behind no recognisable volatile organic compounds and vitrifies the remaining material into a form which is chemically inert). Unlike the chapter on hypothermia, where the absolute zero was a convenient barrier in the path of further frivolous digressions, this chapter only has the Planck temperature as a limit (1.416785×1032 Kelvins), but to head in that direction seems pointless to even this easily distracted author, as anything organic is generally disassembled into constituent atoms above 1500-2000 ºC, leaving behind only steel and titanium prostheses. 

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