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Caffeine Prevents Prostaglandin E1‐induced Disturbances in Respiratory Neural Control: Therapeutic Implications for Infants Treated for Congenital Heart Disease

Prostaglandin E1 (PGE1) is frequently infused in human neonates with congenital heart disease to maintain ductus arteriosus patency; however this can cause central apnea which may necessitate endotracheal intubation. Caffeine is commonly used in the neonatal intensive care unit as a treatment for apnea of prematurity, and is believed to exert its effects primarily through adenosine receptor antagonism. In a prior study in preterm infants, a higher incidence of intermittent hypoxia events (a surrogate measure of apnea) correlated with an augmented ventilatory response to acute hypoxia (HVR). In the present study we sought to elucidate whether PGE1 enhances the HVR in 10‐day old rats and whether this effect would be prevented via pre‐treatment with caffeine. Rat pups received intraperitoneal injections of PGE1 (1μg/kg) and two hours later the HVR (10% O2, 5 min) was assessed using whole‐body plethysmography. PGE1 increased the HVR relative to saline (control) animals. Pre‐treatment with caffeine (5mg/kg) 1 hour prior to PGE1 injection prevented the increased HVR, as did pre‐treatment with MSX‐3 (100 mg/kg; a selective adenosine 2A antagonist). We propose that PGE1 exerts adenosine‐mediated effects on brainstem mechanisms of respiratory control, which may lead to destabilization of breathing in human infants being treated for congenital heart disease. Caffeine could be a convenient treatment to prevent respiratory instability in infants receiving PGE1 infusions.