The
respiratory stimulant caffeine is the most frequently used
xanthine (
theophylline or
aminophylline) for the treatment of
apnea in premature infants. It decreases but does not eliminate
apnea. In most cases such decreases is insufficient to prevent the use of artificial ventilation.
Progesterone is a
respiratory stimulant in adult mammals including human, and it decreases
sleep apnea in menopausal women. Whether
progesterone as an adjunct to
caffeine therapy could be effective in further reducing the frequency of
apnea in premature infants is not known because its respiratory effect in newborns has not been well studied. Using rat pups at different postnatal ages, we first determined whether the
respiratory stimulant effects of acute
caffeine (10 mg/kg, i.p.) or
progesterone (4 mg/kg i.p.) are age dependent. These studies showed that
caffeine enhances the ventilatory response to
hypoxia in 1 and 4 days-old rats while it decreases
apnea frequency in 12-days-old. In contrast,
progesterone enhances the ventilatory response to
hypoxia in less than 7-days-old but decreases
apnea in 1-day-old rats. Preliminary experiments show that administration of
progesterone (4 mg/kg i.p.) to newborn rats that are chronically treated with
caffeine (mimicking its clinical uses - 7.5 mg/kg once/day by gavage) enhances the
respiratory stimulant effects of
caffeine. Surprisingly, acute injection of
progesterone enhances
apnea frequency and reduces hypoxic ventilatory response in 12-day-old rats.