Baclofen and Hypoxia-induced Periodic Ventilation
Condition: CHEYNE Stokes Respiration
MeSH terms: Cheyne-Stokes Respiration; Hypoxia
Study type: Interventional
Phase: Phase 1

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Baclofen; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Breaking tablets of 10 mg of baclofen. Dosage and frequency : 5 mg 3 times a day for 3 days, then 10 mg 3 times a day for 3 days, then 15 mg 3 times a day for 3 days, then 20 mg 3 times a day for 3-5 days, then 15 mg 3 times a day for 1 day, then 10 mg 3 times a day for one day, then 5 mg 3 times a day for one day.; Breaking tablets of 10 mg of placebo. Dosage and frequency : 5 mg 3 times a day for 3 days, then 10 mg 3 times a day for 3 days, then 15 mg 3 times a day for 3 days, then 20 mg 3 times a day for 3-5 days, then 15 mg 3 times a day for 1 day, then 10 mg 3 times a day for one day, then 5 mg 3 times a day for one day.
Intervention MeSH terms: Baclofen
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: CHEYNE Stokes respiration; Periodic ventilation; baclofen; hypoxia; healthy subject