Running title: Air hunger potency of hypoxia Corresponding Author:

Anecdotal observations suggest hypoxia does not elicit dyspnea. An opposing view is that any stimulus to medullary respiratory centers generates dyspnea via corollary discharge to higher centers; absence of dyspnea during low inspired PO2 may result from increased ventilation and hypocapnia. We hypothesized that, with fixed ventilation, hypoxia and hypercapnia generate equal dyspnea when matched by ventilatory drive. Steady-state levels of hypoxic normocapnia (PETO2=60-40torr) and hypercapnic hyperoxia (PETCO2=40-50torr) were induced in naïve subjects when free-breathing and during fixed mechanical ventilation. In a separate experiment, normocapnic hypoxia and normoxic hypercapnia, matched by ventilation in free-breathing trials, were presented to experienced subjects breathing with constrained rate and tidal volume. Air hunger was rated every 30s on a VAS. Air hunger/PETO2 curves rose sharply at PETO2<50torr. Air hunger was not different between matched stimuli (p>0.05). Hypercapnia had unpleasant non-respiratory effects but was otherwise perceptually indistinguishable from hypoxia. We conclude that hypoxia and hypercapnia have equal potency for air hunger when matched by ventilatory drive. Air hunger may therefore arise via brainstem respiratory drive. Key words: visual analog scale; human; perception; adverse ECG effects; steady state; shortness of breath; breathlessnes