Randomized Double-Blind Controlled Trial Comparing the Effects of Ibuprofen with Indomethacin on Cerebral Hemodynamics in Preterm Infants with Patent Ductus Arteriosus

New apparatus was made whereby indices of cerebral oxygenation and haemodynamics in sick newborn infants could be quantified by near infrared (NIR) spectrophotometry and displayed instantaneously at the cotside. The indices included oxygenated haemoglobin, reduced haemoglobin, oxidised cytochrome aa3, and total haemoglobin concentration: cerebral blood volume, mixed cerebral venous saturation, and changes in cerebral blood flow were then derived. Striking changes were observed in response to alterations in arterial oxygen saturation and carbon dioxide tension and to tilting of the infant. Abnormal responses were detected in cerebral oedema following birth asphyxia, patent ductus arteriosus, and cystic encephalomalacia. NIR spectrophotometry provides valuable quantitative data at the cotside for the management of sick infants and for exploring the pathophysiology of damage to the brain.

Among 3559 newborn infants with birth weight less than 1750 gm, 421 developing a hemodynamically significant patent ductus arteriosus were entered into a randomized trial to evaluate the role of indomethacin in the management of PDA. Indomethacin given concurrently with usual medical therapy at the time of diagnosis resulted in ductal closure in 79%, versus 35% with placebo (P less than 0.001). Indomethacin as backup to usual medical treatment resulted in similar closure rates. To assess overall effects through hospital discharge, three management strategies were compared. Although mortality did not differ significantly, infants given indomethacin only if usual therapy failed (strategy 2) had a lower incidence of bleeding than those to whom indomethacin was given with initial medical therapy (strategy 1) and lower rates of pneumothorax and retrolental fibroplasia than those to whom no indomethacin was administered, with surgery the only backup to medical therapy (strategy 3). Thus the administration of indomethacin only when medical treatment fails appears to be the preferable approach for the management of symptomatic PDA in premature infants.

The use of indomethacin as a tocolytic agent in pregnant women appears to be accompanied by a low incidence of neonatal complications. However, the neonatal effects of indomethacin have been studied primarily in infants born after 32 weeks' gestation. This study was designed to examine the incidence of neonatal complications in very premature infants. We identified 57 infants delivered at or before 30 weeks' gestation whose mothers had been treated with indomethacin for preterm labor and matched them with 57 infants whose mothers had not received indomethacin. The infants in the two groups were matched for sex, gestational age at delivery (mean [+/- SD], 27.6 +/- 2.0 weeks), exposure to betamethasone for 24 hours or more before delivery, and rupture of membranes 24 hours or more before delivery. There were no significant differences between the two groups in birth weight, Apgar scores, cord-blood gas values, frequency of multiple gestation, or incidence of respiratory distress syndrome. The proportion of infants who required exogenous surfactant was similar, as were ventilator settings at 24 hours, the incidence of chronic lung disease, and the incidence of sepsis. The infants exposed to indomethacin had a lower urine output and higher serum creatinine concentrations during the first three days after delivery. More indomethacin-exposed infants had necrotizing enterocolitis (29 percent vs. 8 percent, P = 0.005), intracranial hemorrhage grade II to IV (28 percent vs. 9 percent, P = 0.02), and patent ductus arteriosus (62 percent, vs. 44 percent, P = 0.05). More indomethacin-exposed infants with a patent ductus arteriosus required surgical ligation because of either a lack of initial response or a reopening of the duct after postnatal indomethacin therapy (50 percent vs. 20 percent of the unexposed infants, P = 0.05). Antenatal indomethacin therapy for preterm labor appears to increase the risk of serious neonatal complications in infants born at or before 30 weeks' gestation.