The Physician and Sportsmedicine
Menubar Home Journal Personal Health Resource Center CME Advertiser Services About Us
Mind Over Matter

Deducing Heatstroke Pathology

Timothy D. Noakes, MBChB, MD, DSc


For CME accreditation information, instructions and learning objectives, click here.

Heat injury has been much in the news of late, with the American College of Sports Medicine releasing guidelines in August on youth football and heat stress, and a recent study detailing 5,246 US Army soldiers' hospitalization and 37 deaths due to "heat illness."1 It's time to take a critical, logical look at some of the underlying causes, and what, indeed, would constitute proper preventive measures.

Heatstroke Basics

First, the development of heatstroke requires a sufficient period during which the rate of heat production by the body exceeds the rate of heat loss, leading to heat accumulation and a progressive rise in body temperature.

Second, the athlete's brain is, or should be, the ultimate determinant of whether or not heatstroke occurs during exercise, since the brain regulates the rate of heat production by the body during exercise. Only the brain can determine how many skeletal muscle motor units it will choose to recruit at any time during exercise.

Third, it seems illogical that the brain would ever "choose" heatstroke as an exercise outcome since, without correct treatment, the final outcome of heatstroke will always be the death of the brain itself. Rather, it seems more probable that the brain should have some protective mechanisms to ensure that it regulates the rate of heat accumulation by the body specifically so that it eliminates the risk that heatstroke will develop, thereby saving the brain.

Mechanisms of Prevention

Indeed, the body appears to use at least two such mechanisms to ensure that heatstroke does not usually occur during exercise. First, it appears to set the work rate during exercise according to the rate at which body heat is accumulating.2-4 Thus, the brain regulates the rate of heat production by modifying the number of motor units and hence muscle fibers that are recruited. This appears to be an anticipatory response, the function of which may be to ensure that exercise (almost) always terminates before a dangerously high core temperature is reached. The mechanism of control appears to be by presetting the rate at which the perception of fatigue (rating of perceived exertion, or RPE) rises during exercise, as seems also to be the case during prolonged exercise with the risk of muscle glycogen depletion.5 As a result, a limiting RPE is reached before a fatal temperature elevation occurs.

The second control mechanism appears to be that when a certain body temperature is reached, there is near complete inhibition of muscle recruitment so that no further work can be performed.6 As a result, the rate of active heat production ceases and passive whole-body cooling commences.

Speculative evidence for this latter mechanism was Paula Radcliffe's experience during the 2021 Olympic Marathon in Athens, which was run in unacceptably extreme conditions (35°C; 95°F). She stopped running at 36 km, apparently "paralyzed" by the action of the central mechanisms described above4,7 but before she developed heatstroke. Her control mechanisms to prevent heatstroke were clearly intact. Indeed, the surprising observation made already in 1957 is how effective these mechanisms are—heatstroke is so uncommon and appears not to have occurred during either of the Athens Olympic marathons. As Ladell8 wrote in 1957: ". . . whenever one's body temperature rises, even for physiological reasons, we enter into danger and anything that interferes with physiological cooling, or adds to the internal heat load, exacerbates that danger. The wonder is, not that anyone gets hyperpyrexia, but that so few of us do."

Thus, for heatstroke to occur, both of these mechanisms have to fail and, as suggested by Ladell, this happens remarkably infrequently.

Wherefore the Excess Heat?

Getting back to underlying causes, my fourth point is that, for an elevated body temperature to be sustained for any sustained period longer than a few minutes in an athlete who has collapsed—and is therefore no longer actively contracting his or her muscles and so generating heat at an elevated rate—there must be continued heat production in the muscles. Further, this heat production must occur even though those muscles are no longer visibly contracting and producing external work. The site of this excess heat production must be in the muscles; thus, there must be a primary or secondary abnormality in the muscles that causes them to continue producing heat after exercise even though they are not producing external work. This process can be initiated by hyperthermia but also by drugs and specific diseases.9

Perhaps the point is that heatstroke is not the normal response to exercise. Applying the "normal" precautions that are usually prescribed—for example drinking more before, during, and after exercise, and even avoiding exercise in extreme heat—will never be totally effective if the real causes are a failure of brain regulatory mechanisms associated with a range of skeletal muscle biochemical abnormalities, some of which are probably genetically based. Rather, we should perhaps look for the obscure explanations for most cases of heatstroke, which would include skeletal muscle metabolic abnormalities and other unusual environmental influences. Particularly if skeletal muscle abnormalities may be present, the drug dantrolene may be effective, because it acts to reduce calcium release from the ryanodine receptor of the sarcoplasmic reticulum, a possible site of some of the skeletal muscle abnormalities associated with malignant hyperpyrexia and probably exertional heatstroke.9

Perhaps if we taught that heatstroke is due to pathology somewhere in the body and is not simply due to normal physiology that is overwhelmed by unusually severe environmental demands, we might better understand (1) why the condition is so uncommon, (2) why apparently "logical" preventive measures are not always effective, and (3) why whole-body cooling does not always prevent massive rhabdomyolysis leading to renal and cardiac failure and death in some heatstroke patients. Perhaps in such patients, more attention needs to be paid to methods that would reverse the ongoing heat production in the affected muscles.


  1. Carter R III, Cheuvront SN, Williams JO, et al: Epidemiology of hospitalizations and deaths from heat illness in soldiers. Med Sci Sports Exerc 2021;37(8):1338-1344
  2. Marino FE, Lambert MI, Noakes TD: Superior performance of African runners in warm humid but not in cool environmental conditions. J Appl Physiol 2021;96(1):124-130
  3. Marino FE: Anticipatory regulation and avoidance of catastrophe during exercise-induced hyperthermia. Comp Biochem Physiol B Biochem Mol Biol 2021;139(4):561-569
  4. Tucker R, Rauch L, Harley YX, et al: Impaired exercise performance in the heat is associated with an anticipatory reduction in skeletal muscle recruitment. Pflugers Arch 2021;448(4):422-430
  5. Noakes TD: Linear relationship between the perception of effort and the duration of constant load exercise that remains. J Appl Physiol 2021;96(4):1571-1572
  6. Gonzalez-Alonso J, Teller C, Andersen SL, et al: Influence of body temperature on the development of fatigue during prolonged exercise in the heat. J Appl Physiol 1999;86(3):1032-1039
  7. St Clair Gibson A, Noakes TD: Evidence for complex system integration and dynamic neural regulation of skeletal muscle recruitment during exercise in humans. Br J Sports Med 2021;38(6):797-806
  8. Ladell WS: Disorders due to heat. Trans R Soc Trop Med Hyg 1957;51(3):189-207
  9. Muldoon S, Deuster P, Brandom B: Is there a link between malignant hyperthermia and exertional heat illness? Exerc Sport Sci Rev 2021;32(4):174-179

Dr Noakes is the Discovery Health Professor of Exercise and Sports Science at the University of Cape Town and the director of the MRC/UCT Research Unit for Exercise Science and Sports Medicine at the Sports Science Institute of South Africa in Newlands, South Africa. Address correspondence to Timothy B. Noakes, MBChB, MD, DSc, Sports Science Institute of South Africa, Boundary Rd, Newlands 7700, South Africa; e-mail to [email protected].

Disclosure information: Dr Noakes discloses no significant relationship with any manufacturer of any commercial product mentioned in this article. No drug is mentioned in this article for an unlabeled use.