Ascent to altitude: an integrated cerebrovascular, ventilatory and acid–base response

Intricate relationships exist between arterial blood gases, acid–base balance, cerebral blood flow and ventilatory variables. Central to this phenomenon is the basic carbonic anhydrase equation: CO₂+ H₂O →[H₂CO₃]→[H⁺]+[HCO₃⁻]. As arterial CO₂ increases in the brain and cerebrospinal fluid, it forms carbonic acid and dissociates to hydrogen ions [H⁺]. Respiratory chemoreflex and cerebral blood flow control systems act to protect cerebral and systemic [H⁺] as part of a feedback system, where CO₂/[H⁺] stimulate (1) the respiratory chemoreceptors to increase ventilation, and (2) cerebral arteriolar vasodilatation. In this context, alterations in acid–base in any system will affect the relationship between and [H⁺] (i.e. a greater increase in arterial [H⁺] for a given increase in ), and thereby affect respiratory control. Furthermore, elevated cerebral blood flow allows a ‘washout’ of CO₂ and thus [H⁺] ions, to reduce the ventilatory stimulus and stabilize breathing. Therefore, cerebrovascular responses are in place to adjust [H⁺], thereby affecting respiratory chemoreflex control.

Altering , by varying inspired CO₂ concentrations, permits evaluation of both cerebrovascular and ventilatory responses (termed CO₂ reactivity). Cerebrovascular CO₂ reactivity is a critical homeostatic mechanism to maintain cerebral perfusion and adequate ventilation in acute and chronic conditions. Ascent to high altitude brings about many physiological changes that challenge cerebrovascular and ventilatory mechanisms. Within minutes of exposure to hypoxia at high altitude, cerebral blood flow and ventilation increase, returning to sea-level values after several days. Hyperventilation reduces and increases the [H⁺] of body tissues and fluids. The kidneys respond to respiratory alkalosis by reducing [H⁺] and increasing [HCO₃⁻] excretion to return [H⁺] and cerebral blood flow and ventilation to the normal range. Other buffering mechanisms, such as albumin, phosphate and strong ion concentrations ([Na⁺], [K⁺], [Ca²⁺], [Cl⁻], [lactate⁻]), may also contribute to re-establish acid–base homeostasis (Somogyi et al. 2005). Thus, it is clear that both ventilatory sensitivity and [H⁺] homeostasis contribute to cerebrovascular reactivity; however, few studies have examined this interdependency, or how it is affected by altitude.

Recently, Fan and colleagues published an article in The Journal of Physiology investigating the effect of high altitude ascent on the cerebrovascular CO₂ reactivity and ventilatory sensitivity to CO₂ (Fan et al. 2010). The authors hypothesized that challenges to acid–base balance would explain the cerebrovascular and ventilatory alterations following ascent to high altitude. The authors studied 17 healthy young subjects at sea level and at high altitude (5050 m). To eliminate the acute changes during acclimatization, the ascent was done in two phases; 7 days at 1340 m followed by 8 days of trekking from 2860 m to 5050 m. Experimental data were collected between 2 and 4 days after arrival at 5050 m. Therefore, a total acclimatization period of at least 17–19 days existed between sea level and high altitude measurements. Middle cerebral artery velocity (MCAv, an index of cerebral blood flow) and ventilation were measured during a modified rebreathing protocol to assess both hypocapnic and hypercapnic responsiveness. This rebreathing protocol evaluated the CO₂ responsiveness during hyperoxia, when the peripheral chemoreceptors are silenced, allowing isolated evaluation of the central respiratory chemoreflex. It is worth noting that the authors performed a comprehensive experimental protocol and quality physiological measurements were obtained despite the logistical difficulties of high altitude data collection.

The most salient finding of Fan and colleagues was an increased ventilatory and cerebrovascular CO₂ sensitivity at 5050 m (Fan et al. 2010). Furthermore, both the enhanced ventilatory and cerebrovascular reactivity were associated with alterations in pH and [HCO₃⁻], highlighting the importance of acid–base balance. Taken together, the original findings of Fan and colleagues indicate that the systemic attempt to maintain [H⁺] homeostasis may partially account for the changes in cerebrovascular and ventilatory responsiveness to CO₂ following ascent to high altitude.

Contrary to these results, previous work by the same group demonstrated a lower MCAv reactivity to CO₂ at high altitude (3840 m) compared to sea-level (Ainslie & Burgess, 2008). Despite comparable ventilatory responsiveness to CO₂ at high altitude between these studies, Fan et al. speculate that the Ainslie & Burgess study may represent ‘deacclimatization’ because the subjects were measured after spending 9 days higher than 5000 m prior to the measurement at 3840 m. Interestingly, the authors reported an increase in mean arterial pressure (MAP) change relative to CO₂ at 3840 m, indicating that sympathetic overactivity is also a factor in the integrated response to high altitude (Ainslie & Burgess, 2008). Although intact cerebral autoregulation would prevent MAP-induced changes in MCAv, cerebral autoregulation may be impaired in newcomers to high altitude (Jansen et al. 2000). In the study by Fan et al. cerebrovascular conductance index (CVCi) responsiveness to CO₂ was used to account for the elevated MAP at altitude, and therefore CVCi may be considered an indicator of intrinsic vascular responses to CO₂ (Fan et al. 2010). Baseline MAP and CVCi were not significantly higher at 5050 m (MAP = 81 ± 14 at sea level vs. 90 ± 15 at 5050 m) and the CVCi–CO₂ reactivity slope was not different. It is not known if the CVCi–CO₂ reactivity was associated with acid–base variables. Therefore, despite the baseline differences in MCAv, the microvascular responsiveness (i.e. vascular conductance) was similar at sea level and high altitude when MAP is taken into consideration. Taken together this suggests that enhanced sympathetic nerve activity and impaired autoregulation may complicate the interpretation of cerebrovascular reactivity to CO₂.

Another consideration in the study by Fan and colleagues is that the resting acid–base status at 5050 m indicates respiratory alkalosis, without complete metabolic compensation (pH = 7.47 ± 0.03). It is well established that the ascent to altitude leads to dynamic changes in the acid–base balance, where acute exposure increases ventilation leading to respiratory alkalosis, while chronic exposure forces a systemic compensation (i.e. higher excretion of [HCO₃⁻], increased albumin concentration, etc.), to normalize [H⁺] despite hypoxia and hypocapnia. However, the authors did not report additional correlations with compensatory acid–base variables, despite a significant decrease in the standard basic excess, the non-respiratory component of acid–base imbalances. Because altitude has been shown to increase anion concentrations (albumin, phosphate, etc.), it is possible that other systems will compensate, contributing to altitude-induced changes in ventilatory sensitivity (Somogyi et al. 2005). Nevertheless, Fan and colleagues demonstrated that pH and [HCO₃⁻] are associated with cerebrovascular and ventilatory responsiveness to CO₂, it may partially explain the controversy in the literature between various periods of exposure, and the individual variability in acclimatization to high altitude.

The study by Fan et al. should be interpreted in light of some limitations. The subjects were evaluated after 2–4 days at 5050 m. Because the acid–base compensatory changes are dynamic in the process of acclimatization to altitude, this interval may contribute to the inter-individual variability. Another point to take into consideration is that the authors did not include haemodynamic or acid–base measurements during the initial 7 day acclimatization at 1340 m as they evaluated the subjects once at 5050 m. Therefore these results may not reflect changes observed after acute or chronic exposure to altitude. In addition, due to methodological differences it is difficult to compare the present results to studies reporting serial measurements during acclimatization or chronic exposure to altitude (Brugniaux et al. 2007). However, considering the associations between acid–base and cerebrovascular and ventilatory reactivities, it is possible that the CO₂ responsiveness varies according to adjustments in acid–base to protect [H⁺] during acclimatization to high altitude. For example, newcomers to altitude tend to present lower cerebrovascular and ventilatory responsiveness to CO₂, while subjects in the adaptive process show higher cerebrovascular and ventilatory responsiveness to CO₂, and chronically adapted subjects demonstrate similar responsiveness to lowland dwellers (Brugniaux et al. 2007).

In addition to the considerations described above, several questions regarding the effect of acid–base compensatory variables by other systems on the measurement of cerebrovascular and respiratory responsiveness to CO₂ during exposure to altitude remain. (1) No information was provided regarding symptoms of acute mountain sickness. There is evidence that cerebrovascular reactivity to CO₂ is higher in these subjects (Brugniaux et al. 2007), which suggests a different relationship between the acid–base balance and the CO₂ responsiveness in subjects with acute mountain sickness. (2) The present study demonstrated associations between acid–base and the cerebrovascular and ventilatory responsiveness in healthy sea-level dwellers. Are there similar associations in midland or highland dwellers? This may be important for patients with acid–base disorders such as sleep apnoea or renal disease travelling to or living at higher elevations.

In conclusion, Fan and colleagues are the first to examine the influence of compensatory changes in acid–base variables on the regulation of both cerebrovascular and ventilatory control at sea-level compared to high altitude. The collective results highlight the importance of cerebral blood flow in maintaining [H⁺] homeostasis and respiratory chemoreflex control, and this may have implications to diseases that present acid–base disorders.