Standardizing the cerebrovascular response to hypercapnia – increasing the flow of data!

The cerebrovasculature tree is eloquently designed to satisfy the brain's lofty and precise demands for cerebral blood flow (CBF). In humans, there are several known physiological alterations that can influence CBF. Broadly, these are identified as changes in (1) cerebral perfusion pressure, which is defined as the difference between mean arterial pressure and intracranial pressure, (2) autonomic neural activity, (3) local brain tissue metabolism, and (4) the humoral influence of carbon dioxide () and oxygen (Willie, Tzeng, Fisher, & Ainslie, 2014). In some respects, the intact human model is a ‘double-edged’ sword since these mechanism(s) of CBF control are often united and redundant (e.g. changes in systemic blood pressure and sympathetic nerve activity). However, with sufficient creativity and using a variety of both subtle and ‘sledgehammer’ methodologies, this obstacle of human integrative physiology can be overcome. In developing novel experimental approaches, there is the perpetual challenge of methodological consistency. Often overlooked, investigations that explore and advocate methodological regularity are equally important and deserve recognition. In this issue of Experimental Physiology, Burley and colleagues (2020) investigated the effects of stimulus duration on CBF and ventilation. Altering is arguably a ‘sledgehammer’ stressor for assessing cerebrovascular control. To highlight this notion, studies that have measured CBF using duplex ultrasound in the internal carotid and vertebral arteries, and cerebral blood velocity (CBV; a surrogate of CBF) using transcranial Doppler ultrasound in the middle and posterior cerebral arteries have shown that CBF/CBV increases by 3–6%, and decreases by 1–3%, for each mmHg increase or decrease in , respectively (Willie et al., 2014). The mechanism by which influences CBF is attributed to changes in blood pH, which results in cerebral pial vessel (i.e. small arteriolar) vasomotion. There are a wide variety of methodologies available at the hands of physiologists to alter . Some of these methods are simple, such as hyperventilation (to reduce , i.e. hypocapnia), breath-holding, administration of fixed fraction inspired carbon dioxide, and the rebreathing method (these latter methods elevate , i.e. hypercapnia), while other techniques are more sophisticated to alter such as computerized end-tidal gas control. Burley et al. (2020) instrumented their participants (n = 18) with bilateral measurements of the middle cerebral artery velocity using transcranial Doppler ultrasound as a global index of CBF. In a randomized fashion, the participants were administered a fixed fraction of inspired carbon dioxide (5%) via a Douglas bag for 1, 2, 4 and 5 min, and calculated the resulting CBF and minute ventilation response. In addition, the authors compared different data extraction strategies; for example, they averaged 30 and 60 s time bins at the beginning and near the end of each stimulus. The authors concluded that a stimulus of at least 3 min and a 30–60 s data average in the final minute of the stimulus was the best approach to accurately quantify cerebrovascular and ventilatory reactivity to this magnitude of hypercapnia. Although we agree with the authors’ conclusions and commend their comprehensive effort on standardizing this methodology, there are some considerations that should be addressed in future work. While the authors’ results are clearly applicable to young healthy humans, it is yet to be determined if these data are applicable in ageing populations, or in pathology such as pulmonary and cardiac disease. Much of this is due to alterations in the end-tidal-to-arterial gradient – an often overlooked, but extremely significant phenomenon, especially in the context of the current study since the cerebrovasculature is sensitive to even small (i.e. 1–2 mmHg) alterations in . In the investigation by Burley and colleagues (and many others), the partial pressure of end-tidal CO2 () was used as a surrogate for the partial pressure of arterial CO2 (). In most physiological circumstances this assumption is valid; however, even slight alterations to this gradient have been shown to impact the CBF and ventilatory response to (Tymko et al., 2016). At rest, the end-tidal to arterial gradient (calculated as − ) is typically non-existent, or positive; however, it has on occasion been reported as being negative. This gradient can be altered with changes in body position, ageing, exercise, breathing frequencies and during administration (Robbins, Conway, Cunningham, Khamnei, & Paterson, 1990). To further elaborate on the latter, during hypercapnia a high concentration of CO2 occupies physiological deadspace during inspiration, and mixes with alveolar gas during expiration, which inflates to a greater extent than . Although some correction algorithms have been previously derived to account for these gradients during hypercapnia (Peebles et al., 2007; Tymko et al., 2016), they have yet to be fully validated. In future studies, these gradients should be carefully considered, especially across different populations (sex, age, pathology, etc.) and when stressors are combined (e.g. exercise and hypercapnia). In addition, it is important to acknowledge the limitations of transcranial Doppler ultrasound, which assumes that the diameter of the intracranial cerebral artery remains unchanged. More recent evidence indicates this is not likely to be the case, and particularly during changes in blood pressure and (Hoiland & Ainslie, 2016), where transcranial Doppler ultrasound underestimates and overestimates true CBF during hypercapnia and hypocapnia, respectively. Nonetheless, the majority of physiologists accept that if carefully conducted, transcranial Doppler ultrasound can be a valuable tool to measure CBF in large intracranial conduit vessels under certain conditions. These experimental concerns, although acknowledged by the authors, should also be addressed in future studies. The research investigation by Burley and colleagues is a crucial step in clarifying methodology criteria for studies focused on understanding the complex regulation of CBF and the control of breathing, and as such should be viewed in high regard. M.M.T. is supported by a natural sciences and engineering research council of Canada (NSERC) post-doctoral grant. C.D.S. is funded by a NSERC discovery and Heart and Stroke grant. None declared.

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