Integration of cerebrovascular CO2reactivity and chemoreflex control of breathing: mechanisms of regulation, measurement, and interpretation

Abstract

Cerebral blood flow (CBF) and its distribution are highly sensitive to changes in the partial pressure of arterial CO2(PaCO2). This physiological response, termed cerebrovascular CO2reactivity, is a vital homeostatic function that helps regulate and maintain central pH and, therefore, affects the respiratory central chemoreceptor stimulus. CBF increases with hypercapnia to wash out CO2from brain tissue, thereby attenuating the rise in central Pco2, whereas hypocapnia causes cerebral vasoconstriction, which reduces CBF and attenuates the fall of brain tissue Pco2. Cerebrovascular reactivity and ventilatory response to PaCO2are therefore tightly linked, so that the regulation of CBF has an important role in stabilizing breathing during fluctuating levels of chemical stimuli. Indeed, recent reports indicate that cerebrovascular responsiveness to CO2, primarily via its effects at the level of the central chemoreceptors, is an important determinant of eupneic and hypercapnic ventilatory responsiveness in otherwise healthy humans during wakefulness, sleep, and exercise and at high altitude. In particular, reductions in cerebrovascular responsiveness to CO2that provoke an increase in the gain of the chemoreflex control of breathing may underpin breathing instability during central sleep apnea in patients with congestive heart failure and on ascent to high altitude. In this review, we summarize the major factors that regulate CBF to emphasize the integrated mechanisms, in addition to PaCO2, that control CBF. We discuss in detail the assessment and interpretation of cerebrovascular reactivity to CO2. Next, we provide a detailed update on the integration of the role of cerebrovascular CO2reactivity and CBF in regulation of chemoreflex control of breathing in health and disease. Finally, we describe the use of a newly developed steady-state modeling approach to examine the effects of changes in CBF on the chemoreflex control of breathing and suggest avenues for future research.