Acclimatisation to high altitude (3000-4500 m) over 1-2 weeks is characterised by persistent hyperventilation despite normalised arterial pH. Which mechanism explains this paradox?

• A Carotid body hypersensitisation — chronic hypoxia upregulates HIF-1α in glomus cells, permanently increasing peripheral chemoreceptor gain for O2
• B Central chemoreceptors in the ventral medulla adapt to the new low-CO2 environment and increase their set-point for ventilatory drive
• C Increased 2,3-BPG in red blood cells improves O2 delivery enough to reduce hypoxic drive from peripheral chemoreceptors, allowing hyperventilation to persist
• D Renal excretion of HCO3- (metabolic compensation) reduces CSF and plasma pH toward normal, restoring central chemoreceptor sensitivity to CO2 and allowing sustained hyperventilation at the reduced PaCO2 set-point ✓

Explanation

On initial ascent to altitude, hypoxia stimulates peripheral chemoreceptors (carotid bodies), increasing ventilation and lowering PaCO2 (respiratory alkalosis). This alkalosis initially inhibits central chemoreceptors (which respond to [H+] in CSF), partially resetting ventilatory drive. Over 1-2 weeks, the kidneys excrete HCO3- (renal metabolic compensation), normalising plasma and CSF pH. Now the central chemoreceptors are no longer inhibited by the alkalosis and respond normally to the new, lower PaCO2 set-point. This 'enables' the hypoxic drive from peripheral chemoreceptors to fully express, sustaining hyperventilation. The net result: persistent hyperventilation, normalised pH, but lower PaCO2 and (due to the rightward shift from 2,3-BPG) slightly improved O2 delivery.

Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.

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