The Effects of Caffeine on the Preterm Sheep Ductus Arteriosus

Abstract

Caffeine and other methyl xanthines are widely used in the neonatal period. A recent, randomized, placebo-controlled, multicenter trial found that infants who were randomly assigned to caffeine treatment had less need for pharmacologic and/or surgical closure of a patent ductus arteriosus (PDA). We hypothesized that the decreased need for pharmacologic and surgical closure of the PDA after caffeine treatment might be due to a direct effect of caffeine on ductus contractility. We examined preterm fetal lamb ductus arteriosus (from 24 fetuses, 105 Ϯ 4 d of gestation, term ϭ 147 d), in vitro to determine the direct effects of caffeine on the isometric tension of the ductus arteriosus. Caffeine (0.003-0.3 mM) had no direct effect on ductus arteriosus tension, nor did it affect the contractile response of the ductus arteriosus to increasing oxygen concentrations. Caffeine's lack of effect was observed in both the presence and absence of indomethacin and N g -nitro-L-arginine methyl ester (L-NAME) (inhibitors of prostaglandin and nitric oxide production). In conclusion, we found no evidence of a direct effect of therapeutic caffeine concentrations on ductus contractility. ) (1-10), in vivo studies suggest that postnatal constriction is primarily determined by a shift in the balance between oxygen (a ductus constrictor) and prostaglandins and nitric oxide (ductus dilators) (11,12). Alterations in antenatal glucocorticoid concentrations and postnatal pulmonary vascular resistance also play roles in in vivo ductus constriction (13,14).Recently, a randomized, placebo-controlled, multicenter trial was performed to evaluate the effects of caffeine administration in preterm infants (15). Infants were enrolled in the trial during the first 10 d after birth, and the primary goal of the study was to evaluate the long-term effects of caffeine on neurodevelopmental outcome. An unexpected finding of the study was that infants who were randomly assigned to caffeine treatment had less need for pharmacologic and/or surgical closure of a PDA.Caffeine has been found to directly affect several of the signaling molecules that are involved in ductus constriction: it increases cAMP by inhibiting cyclic nucleotide phosphodiesterase (16); it releases Ca 2ϩ from the endoplasmic reticulum by binding to the ryanodine receptor (17); it inhibits both prostaglandin production (18) and activity (19) and inhibits adenosine activity by binding to its receptors (20). At therapeutic concentrations, caffeine's effects appear to be due primarily to antagonism of the adenosine receptor (21).In this study, we hypothesized that the decreased need for pharmacologic and surgical closure of the PDA after caffeine treatment might be due to a direct effect of caffeine on ductus contractility. To examine this hypothesis, we studied the effects of caffeine on the isolated preterm fetal sheep ductus arteriosus. METHODSPreterm fetal lambs (mixed Western breed: 105 Ϯ 4 d of gestation, term ϭ 147) were delivered by cesarean section and anesthetized with keta...

Effects of caffeine on renal and pulmonary function in preterm newborn lambs

“…Our findings are consistent with those of a recent study demonstrating that, in isolated DA from fetal sheep, caffeine had no direct effect on vessel contractility (33). The temporal changes in PBF and DA blood flow we observed are consistent with our previous studies, which have shown that immediately after birth retrograde flow (left-to-right shunting) through the DA contributes to the increase in PBF.…”

Patent ductus arteriosus hemodynamics in very premature infants treated with poractant alfa or beractant for respiratory distress syndrome

“…27,28 Our findings are analogous to improved pulmonary status and lesser need for PDA treatment in infants treated with early caffeine treatment, 29 where no direct effect of caffeine on periductal ductal smooth muscle constriction was demonstrable. 30 The primary weaknesses of this study were the small sample size, open label design and high rate of PDAs in the beractant group. This is a highly selected population of very premature infants who were mechanically ventilated for RDS, infants with the greatest risk of developing the morbidities of prematurity, including PDAs and chronic lung disease.…”

Early caffeine therapy and clinical outcomes in extremely preterm infants

“…Although caffeine may also affect several signaling molecules involved in ductal constriction, investigations on this effect are still inconclusive. [24][25][26] Possibly, improved respiratory morbidity in the neonate reduces the likelihood of a PDA requiring treatment, although the management of pharmacological and surgical ductal closure remains a controversial area of practice. 27 The physiologic effects of caffeine may increase the success of early initial continuous positive airway pressure therapy or facilitate weaning from the ventilator and result in a reduction of endotracheal ventilation and protection against associated lung injury.…”