Is alkalosis the dominant factor in hypoxia‐induced cognitive dysfunction?

Exposure to high altitude poses risks for human function and survival. Humans acclimatize to hypoxia by way of highly orchestrated integrative responses acting to defend whole-body homeostasis. An immediate increase in ventilatory drive improves pulmonary gas exchange, serving to limit hypoxaemia. However, hypoxia-induced hyperventilation causes hypocapnia and respiratory alkalosis owing to excessive elimination of carbon dioxide. During acute exposure to hypoxia, cerebral vessels dilate, increasing cerebral blood flow and combating the reduction in arterial oxygen content in hypoxia, thereby maintaining cerebral oxygen delivery. In contrast, hypocapnia mediates constriction of the cerebrovasculature, acting to decrease brain blood flow. The counteractive effect of these opposing stimuli during exposure to hypoxia is an important net determinant of oxygen delivery to the brain, critical for neuronal performance and behaviour. Although it is widely recognized that cognitive function is impaired during exposure to hypoxia, the relative influence of hypoxia and hypocapnia per se is not fully established. In this issue of Experimental Physiology, Friend, Balanos, and Lucas (2019) explore the independent effects of acute normobaric hypoxia and hypocapnia on cerebrovascular haemodynamics and cognitive function. Healthy, young, male participants were exposed to 60 min of poikilocapnic hypoxia (allowing carbon dioxide to decline freely during hypoxic hyperventilation) and, on a separate day, to 60 min of isocapnic hypoxia (with dynamic end-tidal forcing used to clamp carbon dioxide to baseline levels). A subset of participants also performed a 60 min voluntary hyperventilation task during an additional experimental session to establish euoxic hypocapnia. Middle cerebral artery velocity was measured as an index of ‘global’ cerebral blood flow using transcranial Doppler ultrasound. Cognitive tests were performed before and after gas manipulations. Indices of prefrontal cortex tissue perfusion and oxygen saturation were measured using near-infrared spectroscopy in participants exposed to all three ventilatory challenges. Hypoxia increased middle cerebral artery velocity, whereas hypocapnia decreased it. Of interest, the two opposing stimuli counterbalanced one another during poikilocapnic hypoxia such that there was no change in middle cerebral artery velocity from baseline values. Prefrontal cortex (regional) tissue perfusion increased during poikilocapnic and isocapnic hypoxia, but decreased during voluntary hyperventilation; cortical tissue oxygenation index was decreased in all conditions. Poikilocapnic hypoxia and euoxic hypocapnia evoked slower reaction times during single reaction time and five-choice reaction time tests, whereas isocapnic hypoxia had no effect. The decline in cerebral oxygenation was equivalent in hypoxic conditions, suggesting that this was not the principal driver of the difference in cognitive performance between poikilocapnic and isocapnic hypoxia trials. In addition, there was a moderate positive correlation between middle cerebral artery velocity and reaction performance, but prefrontal cerebral tissue perfusion and oxygenation were not correlated with cognitive performance. Surprisingly, there was no effect of the experimental interventions on spatial working memory, which might have been attributable to familiarization during repeated cognitive tests, because the task was not novel. The results contrast with a recent study showing that executive function is impaired after 60 min of poikilocapnic hypoxia in healthy, young, male participants, with evidence of associations between reduced cerebral oxygenation and impaired task accuracy and reaction time (Williams et al., 2019). Thus, it appears that hypocapnia impairs simple cognitive function during hypoxia and normoxia (Friend et al., 2019), extending previous observations by others at high altitude (Dykiert et al., 2010). Importantly, carbon dioxide supplementation during hypoxia was effective in preserving cognitive function, which is consistent with previous findings (van Dorp et al., 2007). One limitation of the study is that the magnitude of hypocapnia differed between challenges, complicating direct comparisons between experimental sessions. Also, assessment of cognitive function during isocapnic hyperpnoea, matching ventilation to levels achieved during voluntary hyperventilation, would provide additional insight and would control for the possibility that the hyperventilation task itself affects cognitive performance by way of distraction or discomfort. Several other methodological limitations associated with the estimation of cerebral blood flow and oxygenation are considered carefully by the authors. Friend et al. (2019) highlight that hypocapnia increases the affinity of haemoglobin for oxygen, which might have decreased the unloading of oxygen to cerebral tissue. However, given that prefrontal cortex tissue oxygenation was not correlated with cognitive performance, and voluntary hyperventilation resulted in a smaller reduction in brain oxygenation than hypoxia, but still resulted in cognitive impairment, it might be that cerebral tissue acid–base disturbance (alkalosis) secondary to hyperventilation was primarily responsible for the slower reaction times. The authors postulate that hypocapnic vasoconstriction might have blunted neurovascular coupling. Hypocapnia profoundly reduces endothelial and astrocytic nitric oxide bioavailability, a key mediator of the neurovascular coupling response. Indeed, hyperventilation-induced hypocapnia was previously shown to suppress the neurovascular coupling response in healthy humans (Szabo et al., 2011). During hypocapnia, it is unclear whether the decreased partial pressure of carbon dioxide or the resultant alkalosis serves as the primary stimulus, but interestingly, neurovascular coupling was found to be intact in acclimatized healthy participants at high altitude, in whom profound hypocapnia was compensated over the course of several days by renal clearance of bicarbonate, restoring near-normal pH (Leacy et al., 2018). Renal compensation would not have occurred in the study by Friend et al. (2019) given the acute nature of the normobaric blood gas stimuli, suggesting that arterial and/or cerebral acid–base status might be the key mediator of the hypoxia-induced cognitive deficits. The important study by Friend et al. (2019) draws focus to the dominant role of carbon dioxide tension and/or acid–base status in shaping cerebrovascular haemodynamics and cognitive performance relevant to the physiology and pathophysiology of acute and chronic exposure to hypoxia in addition to other conditions with concomitant hyperventilation. None declared.

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