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Blunted cerebrovascular CO2 reactivity to satisfy the hungry heat stressed brain

The high relative metabolic rate of brain tissue, paired with an exceptionally restricted capacity for substrate storage (e.g. <10% non-oxidative metabolism), necessitates tight regulation of cerebral oxygen delivery (CDO2 = cerebral blood flow × arterial oxygen content). The balance between cerebral metabolic rate of oxygen (CMRO2 ; heat gain) and cerebral blood flow (CBF; heat loss) governs cerebral heat balance (Fig. 1A). High resting CMRO2 relative to brain mass (e.g. 3.5 ml O2/100 g brain/min) in excess of CBF contributes to cerebral heat gain; therefore, cerebral temperature is typically warmer than average core temperature (Tc) as indicated by the cerebral arterial to venous blood temperature difference of approximately 0.3–0.5°C (Bain et al. 2015). The inherent biological tissue response to temperature changes (Q10 effect) explains the progressive increases in CMRO2 with heat stress; at least in humans, cerebral tissue corresponds to an estimatedQ10 of 2–3; e.g. CMRO2 reportedly increases by 20% at +1.5–2°C (Bain et al. 2020). Overall, CBF is typically reduced with +1–2°C elevations in Tc during passive heat stress – a response principally regulated via hyperventilatory-evoked reductions in arterial PCO2 (PaCO2 ) and subsequent cerebrovascular vasoconstriction (Bain et al. 2015). Although heat-induced panting is effective to increase respiratory convective/evaporative heat loss in animals, any heat loss from the human respiratory tract is trivial versus the exceptional ability of the skin to dissipate heat and importantly this hyperventilatory response contributes to reductions in CBF that adversely affect cerebral heat loss (Bain et al. 2015). Alternatively, reductions in cerebrovascular sensitivity to changes in PaCO2 during heat stress are likely an advantageous response to avert marked reductions in CDO2 (expected due to thermal hyperventilation), regulate heat balance and support the elevated CMRO2 . In a recent issue of The Journal of Physiology an elegant and ambitious study by Gibbons and colleagues (2021) investigated the changes in volumetric CBF regulation (via duplex ultrasound) with incremental heat strain to thermal tolerance or 40°C via (1) passive hot-water immersion (spa); (2) passive hot, humid air exposure (sauna); and (3) cycling exercise with and without CO2 restoration. At thermal tolerance, CBF was reduced by 30% in the sauna; however, it was unchanged with the spa or exercise. It is noteworthy that cerebrovascular CO2 reactivity to hypocapnia (via spontaneous thermally-mediated hyperventilation) was universally reduced by approximately 50% across all conditions at thermal tolerance (e.g. range −20% to −75%; Fig. 1B). Although there is no convincing evidence to date that thermal hyperventilation per se contributes to improved heat balance in humans, these novel data by Gibbons and colleagues (2021) are indicative that the compensatory reduction in cerebrovascular CO2 reactivity at thermal tolerance is likely necessary to regulate CBF and support the conceivably elevated CMRO2 at +2–2.5°C (Fig. 1B). For example, assuming a Q10 of 2–3, it is estimated that CMRO2 would be increased by 20–25% at +2–2.5°C in the current study (Bain et al. 2020). Importantly, recent data indicate that increases in CMRO2 with severe passive heat stress are independent of arterial pH/PaCO2 (i.e. via respiratory alkalosis) (Bain et al. 2020); therefore, it is expected that CMRO2 would be elevated with heat stress in all conditions. Taken together, these results illustrate the disparity between the relatively linear increase in CMRO2 (via the Q10 effect) at thermal tolerance and the exponential reduction in PaCO2 via thermal hyperventilation in the passive heat stress conditions. These changes, collectively, would explain the necessary reduction in cerebrovascular sensitivity to PaCO2 to preserve CDO2 and suppress heat gain (Fig. 1C). The competing influence of heat stress on increases in CMRO2 is typically insufficient at regulating CBF due to the prevailing hyperventilatory-induced reductions in PaCO2 . It is interesting to consider whether the 15.5% reduction in resting systemic arterial blood pressure in the spa condition contributed to the marked 75% reduction in cerebrovascular CO2 reactivity; e.g. the same relative change in CBF with a threefold larger reduction in PETCO2 versus exercise (albeit not statistically different; Fig. 5C of Gibbons et al. 2021). These data are supported by classic work by Harper and Glass (1965) who showed that substantial hypotension effectively overrules the vasoconstrictive ability of the cerebrovasculature to respond to reductions in PaCO2 (Harper & Glass, 1965). It is likely that the severely attenuated cerebrovascular CO2 reactivity during the spa condition was exacerbated by hypotension; i.e. although hypotension per se reportedly does not reduce CBF in the face of elevated CMRO2 (Bain et al. 2020), the favourable reduction in cerebrovascular CO2 reactivity is at least in part attributable to blood pressure. Lastly, localized cerebral ischaemia with severe heat stress may lead to release of vasodilatory substances (e.g. adenosine, nitric oxide, hydroxyl radical) that would help explain the attenuated vasoconstrictive response to reductions in PaCO2 (Nelson et al. 1992). These results by Gibbons and colleagues (2021) provide novel evidence that reductions in cerebrovascular CO2 reactivity per se likely contribute favourably to CBF regulation during severe heat stress. Additionally, as reductions in