High on altitude: new attitudes toward human cerebral blood flow regulation and altitude acclimatization

Abstract

Travel to high altitude for the lowland dweller unmasks a complicated array of physiological mechanisms responsible for acclimatization (Dempsey & Forster, 1982). First, the reduction in both the barometric pressure and the arterial partial pressure for oxygen () stimulates an increase in ventilation, the magnitude of which depends upon the individual ventilatory sensitivity to hypoxia. Then, the arterial partial pressure for carbon dioxide () is decreased due to hypoxic hyperventilation resulting in respiratory alkalosis. As time at altitude increases over the next 1–2 weeks, acid–base balance is normalized by renal excretion of bicarbonate, and is improved by increases in the ventilatory sensitivity to hypoxia and polycythaemia. This simplified overview of altitude acclimatization highlights two major controlling factors for cerebral blood flow (CBF): (1) changes in arterial blood gases (i.e. and ) and (2) changes in pH. The brain, notably a vital organ, relies upon an adequate supply of blood and delivery of oxygen for its normal operation. Therefore, CBF is regulated not only to maintain oxygen delivery but also to maintain cerebral tissue pH (or cerebral spinal fluid (CSF) pH). Interestingly, the cerebral circulation is relatively insensitive to hypoxia, only increasing CBF when reaches levels <50 mmHg. Conversely, CBF is highly sensitive to changes in (and pH), decreasing CBF during hypocapnia and increasing CBF with hypercapnia. This property of the cerebral circulation may dampen changes in CSF pH and provides a unique point of respiratory integration. It can be appreciated that oscillations in CSF pH in the region responsible for central chemoreception would directly affect ventilation. Taking this one step further, the individual magnitude of the cerebrovascular response to CO2 may impact the ventilatory sensitivity to CO2 (Xie et al. 2006). The implications of this interaction may relate to the stability of ventilation and possibly include the unstable breathing observed during sleep at high altitude and in patients with sleep apnoea or congestive heart failure. These concepts, briefly described herein, form the basis of what may lead to a greater appreciation and understanding of the mechanisms responsible for determining and adjusting cerebral blood flow during travel to high altitude. Further, these concepts may provide important insight into cerebral blood flow regulation in patients with chronic respiratory disease. In this issue of The Journal of Physiology, Lucas et al. (2011) travelled to the base of the world's tallest mountain with specialized laboratory equipment to investigate three important questions: First, during acclimatization to high altitude, do the changes in CBF relate to the changes in the balance of arterial blood gases (i.e. the ratio of /)? Second, does high-altitude acclimatization alter cerebral vascular CO2 reactivity? And finally, is there an interaction between CBF CO2 reactivity and CO2 ventilatory sensitivity? To address these, they measured arterial blood gases, ventilation and CBF velocity at sea level and during 2 weeks at high altitude (5050 meters). They also assessed the cerebral vascular response to hypocapnia, hypercapnia, and the ventilatory response to hypercapnia and hypoxia. CBF increased with initial arrival at altitude and normalized after 1 week at altitude, a finding that was related to the balance in arterial blood gases (i.e. /) and explained about 40% of the variability in CBF. A low / ratio indicates a greater degree of hypoxic vasodilatation for a given hypocapnic stimulus. As the ventilatory response to hypoxia increases with one's stay at altitude so too does the / ratio, suggesting a decrease in hypoxic-induced dilatation and a greater degree of hypocapnic-induced constriction. Assessing the ratio of / at high altitude and linking it to changes in cerebral blood flow is a novel feature of this study. Lucas et al. (2011) also report higher hypocapnic CBF sensitivity and decreased hypercapnic CBF sensitivity upon arrival at high altitude, which is consistent with other reports (Jansen et al. 1999). The authors suggest that this may be the result of increased muscle sympathetic activation or increased cerebral sympathetic activation. However, could it also be a mechanism designed to minimize changes in CSF pH? At altitude, arterial pH and CSF pH are increased (Dempsey et al. 1974). An increase in CSF pH can interfere with brain function (and ventilatory control). A decrease in vasodilatory capacity will prevent further washout of CSF hydrogen ions (minimizing the increase in pH), and an increase in vasoconstrictor capacity will help to maintain or normalize CSF pH. In summary, Lucas et al. (2011) found that (1) CBF regulation at high altitude is largely explained by the balance in arterial blood gases; (2) the reactivity of the cerebral circulation is altered in both the hypocapnic and hypercapnic range; and (3) the changes in CBF reactivity are linked to changes in ventilatory sensitivity. These findings are important as they highlight integration between cerebral vascular regulation and respiratory control, and they contribute to our knowledge of ventilatory instability not only at high altitude but also in patients suffering from congestive heart failure and sleep apnoea. It is unclear, however, as to which physiological mechanisms explain the remaining variability in CBF during altitude acclimatization. What is the mechanism and function for changes in CBF reactivity? Is it related to cerebral sympathetic activation or changes in CSF pH? Finally, can this new knowledge be applied to stabilize breathing at high altitude and in patients with ventilatory instabilities?