The role of acid‐base balance in cerebrovascular and ventilatory responses to CO₂ during 10 h normobaric hypoxia

Hyperventilation-induced alterations in acid-base buffering play a crucial role in resetting the cerebrovascular and ventilatory control during high-altitude acclimatisation. This study examines the relationship between cerebrovascular CO₂ reactivity, ventilatory CO₂ sensitivity and acid-base balance during a 10 h hypoxic exposure. We assessed resting venous pH and bicarbonate concentrations [HCO₃ ^-], middle cerebral artery velocity (MCAv; transcranial Doppler ultrasound) and ventilatory ( <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics> <mml:msub><mml:mover><mml:mi>V</mml:mi> <mml:mo>̇</mml:mo></mml:mover> <mml:mi>E</mml:mi></mml:msub> <mml:annotation>$\dot{V}_{\mathrm{E}}$</mml:annotation></mml:semantics> </mml:math> ) responses during hyperoxic rebreathing in 27 healthy individuals (13 females) at 0, 2, 4 and 8 h of 10 h exposures to normobaric normoxia (fraction of inspired O₂ ( <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics><mml:msub><mml:mi>F</mml:mi> <mml:mrow><mml:mi>I</mml:mi> <mml:msub><mml:mi>O</mml:mi> <mml:mn>2</mml:mn></mml:msub> </mml:mrow> </mml:msub> <mml:annotation>${F_{{\mathrm{I}}{{\mathrm{O}}_2}}}$</mml:annotation></mml:semantics> </mml:math> ): 0.21) and normobaric hypoxia ( <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics><mml:msub><mml:mi>F</mml:mi> <mml:mrow><mml:mi>I</mml:mi> <mml:msub><mml:mi>O</mml:mi> <mml:mn>2</mml:mn></mml:msub> </mml:mrow> </mml:msub> <mml:annotation>${F_{{\mathrm{I}}{{\mathrm{O}}_2}}}$</mml:annotation></mml:semantics> </mml:math> : 0.117, simulated altitude of 5000 m) in a randomised, single-blinded manner. The MCAv- and <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics> <mml:msub><mml:mover><mml:mi>V</mml:mi> <mml:mo>̇</mml:mo></mml:mover> <mml:mi>E</mml:mi></mml:msub> <mml:annotation>$\dot{V}_{\mathrm{E}}$</mml:annotation></mml:semantics> </mml:math> -CO₂ relationships were analysed using sigmoidal and segmental linear regression fitting, respectively. Compared to normoxia hypoxia progressively increased venous pH and decreased venous [HCO₃ ^-] throughout the 10 h exposure (P < 0.001 for both). We observed a progressive decrease in the ventilatory recruitment threshold (VRT) with hypoxia across the day (d = 0.9, P < 0.001 vs. normoxia), along with an increased <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:semantics> <mml:msub><mml:mover><mml:mi>V</mml:mi> <mml:mo>̇</mml:mo></mml:mover> <mml:mi>E</mml:mi></mml:msub> <mml:annotation>$\dot{V}_{\mathrm{E}}$</mml:annotation></mml:semantics> </mml:math> -CO₂ slope by ∼0.4 l/min/mmHg (d = 0.3, P = 0.039). The slope of the MCAv-CO₂ response was moderately increased with hypoxia by 0.5 cm/s/mmHg across all time points (d = 0.5, P = 0.006), whereas the midpoint of the MCAv-CO₂ response was unchanged (P = 0.401). Our data support the role of altered blood acid-base buffering in the resetting of the ventilatory CO₂ sensitivity to a lower operating point. Because we did not observe a concurrent leftward shift in the MCAv-CO₂ response, we attribute this to the lagging compensation of respiratory alkalosis within the cerebrospinal fluid compartment. KEY POINTS: Acid-base balance plays an important role in the control of cerebral blood flow and ventilation, but the compensation of hypoxia-induced respiratory alkalosis in cerebrospinal fluid is slower than that within the arterial compartment. In this study we hypothesized that the rates of resetting between the cerebrovascular and ventilatory responsiveness to CO₂ would be different during 10 h exposure to normobaric hypoxia. We found a progressive leftward shift in the ventilatory response to hyperoxic rebreathing, which appears to be linked to changes in blood acid-base balance during early hypoxic exposure. In contrast we did not observe a resetting of cerebrovascular response to CO₂ during the 10 h exposure period. Our data demonstrate a dissociation in the rate of resetting between the cerebrovascular and ventilatory responsiveness to CO₂ during early hypoxic exposure. We speculate that these differences are due to the slower compensatory metabolic acidosis in the cerebrospinal fluid compared to the arterial/venous compartments.