CHEYNE Stokes Respiration Clinical Trial
Official title:
Assessment of the Effect of the GABA-B Receptor Agonist, Baclofen, on Hypoxia-induced Periodic Ventilation, in Healthy Subjects
Periodic ventilation that includes CHEYNE Stokes ventilation is a pathological pattern characterized by alternating periods of hyperpneas and apnea-hypopneas. It occurs generally during sleep, at high altitude and in hypoxic conditions in healthy subjects, and in some diseases like congestive heart failure. One study conducted on an animal model suggested that baclofen, a drug already used against spasticity in humans, could also be effective against periodic ventilation. The goal of the study is therefore to assess this hypothesis on hypoxia-induced periodic ventilation in healthy subjects during sleep.
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.
The goal of the project is therefore to assess the effect of baclofen on hypoxia-induced
periodic ventilation in healthy subjects during sleep. This is thus a pathophysiological
study that aimed at demonstrating a concept before a possible clinical trial.
This study is pathophysiological study, conducted in healthy volunteers only.
Methods:
The subjects will sleep in hypoxic conditions, with a level of hypoxia similar to the one
that is found at an altitude of 4000-4500 meters. A this altitude, the partial pressure of
oxygen is approximately 90-100 mmHg. The hypoxic atmosphere will be created in a tent with
an hypoxic generator (EVEREST Summit Hypoxic Generator, Hypoxic Systems, New York, NY, USA).
The electroencephalographic and electrocardiographic signals and the movements of the chest
and of the abdomen will be recorded with a portable polysomnograph. The electromyogram of
the chin and the ELECTRO Oculogram will also be recorded. These signals will permit to
identify the sleep stages. The subjects will ware a face mask connected to a
pneumotachometer for the recording of the ventilatory flow. Gas will also be sampled to
measure the end tidal partial pressure of CO2.
Protocol:
Healthy volunteers will be enrolled after they will have given written informed consent. The
subjects will be asked about their medical history and physical examination will be
performed. Chest X-ray, electrocardiogram and pulmonary function tests will also be
performed.
The subject will be asked not to sleep the night before each recording in hypoxic conditions
(the hypoxic sessions). The recordings will be performed either during a nap in the
afternoon or at night.
A first hypoxic session will be performed to identify the subjects who will develop periodic
ventilation. Only those who will exhibit periodic ventilation during sleep will continue the
study. They will be prescribed either baclofen or placebo (double blind, randomized). The
posology will be progressively increased (over approximately 10 days) to reach 20 mg 3 times
a day, during 3 to 5 days. A second hypoxic session will be performed under this treatment.
Then the posology will be decreased over 3 days and a complete weaning will be performed
during 5 to 10 days. The same protocol will be repeated, either with baclofen or placebo
(depending of the previous run) and a third hypoxic session will be performed. The posology
will then be decreased over 3 days and the study will be considered ended for the subject
after 2 more days of complete weaning.
The maximum duration of the study for one subject will be 63 days.
;
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment
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