Assessment of the Effect of the GABA-B Receptor Agonist, Baclofen, on Hypoxia-induced Periodic Ventilation, in Healthy Subjects

Rationale of the study:

Periodic ventilation, often called CHEYNE Stokes ventilation, results from a dysfunction of the mechanisms of the control of breathing. In this type of ventilation, alternating periods of hyperventilation and apneas and/or hypoventilation replace the normal regular pattern of breathing. Periodic ventilation occurs preferentially during sleep. It is responsible for decreases in arterial saturation in oxygen and for sleep fragmentation. There is currently no consensual treatment but non-invasive nocturnal mechanical ventilation is often used to bring the ventilatory pattern back to normal.

Periodic ventilation occurs in various conditions, the most frequent being cardiac failure. It also occurs in healthy subjects exposed to hypoxia or at high altitude.

The pathophysiology of periodic breathing remains poorly understood. Our hypothesis regarding the mechanisms of this abnormal ventilatory pattern is based on comparative physiology. Periodic ventilation is indeed the usual ventilatory pattern of many lower vertebrates. Moreover, even isolated in VITRO, the tadpole brainstem still produces a periodic ventilatory rhythm, characterized by clusters of ventilatory discharges. In this model, the agonist of the GABA-B receptor, the baclofen, transforms the periodic pattern into a regular one. Of note, the baclofen is already used in the treatment of some human diseases, especially against spasticity.

The hypothesis of the research project assumes that periodic ventilation in humans results from a neural reconfiguration of the networks that command breathing, leading them to produce an ancestral behavior. It also assumes that the baclofen woul reverse this phenomenon as it does in the model of the tadpole isolated brainstem.