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

Abstract

A prospective randomized controlled trial was performed to compare the effects of ibuprofen with indomethacin on cerebral hemodynamics measured using near infrared spectroscopy in preterm infants during treatment for patent ductus arteriosus. Infants were randomly assigned to three intravenous doses of either indomethacin (0.20-0.25 mg/kg, 12 hourly) or ibuprofen (5-10 mg/kg, 24 hourly) and also received a dose of saline. The primary end points of the study were the effects of the first dose on cerebral blood flow (CBF) and cerebral blood volume. Fifteen infants received indomethacin and 18 received ibuprofen. The group mean (SD) values for CBF (mL x 100 g(-1) x min(-1)) before and after the first dose of indomethacin were 13.6 (4.1) and 8.3 (3.1), respectively, the change being significant (p<0.001). In contrast, no significant changes in CBF were observed with the first dose of ibuprofen, the respective before and after values being 13.3 (3.2) and 14.9 (4.7) mL x 100 g(-1) x min(-1). The median (interquartile range) value for change in cerebral blood volume (mL/100 g) after the first dose in the indomethacin group was -0.4 (-0.3 to -0.6) and in the ibuprofen group was 0.0 (0.1 to -0.1), the difference between the two groups being significant (p<0.001). Cerebral oxygen delivery changed significantly after the first dose in the indomethacin group but not in the ibuprofen group. Significant reductions in CBF, cerebral blood volume, and cerebral oxygen delivery also occurred after the 24-h dose of indomethacin, but there were no significant changes after the 48-h dose of saline in the indomethacin group or after the 24- and 48-h doses of ibuprofen. The patent ductus arteriosus closure rates after indomethacin and ibuprofen were 93 and 78%, respectively. We conclude that ibuprofen, unlike indomethacin, has no adverse effects on cerebral hemodynamics and appears to mediate patent ductus arteriosus closure.

Treatment of persistent patent ductus arteriosus in preterm infants: time to accept the null hypothesis?

“…Search results and citation lists for prior publications identified 75 randomized-controlled trials of interventions that close a PDA in preterm infants. In 26 trials (five comparing long and short courses of indomethacin, [37][38][39][40][41] 19 comparing indomethacin and ibuprofen, [42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60] and two that included very early crossover to treatment of nonresponders 29,61 ), rates of ductal closure did not differ between treatment assignments, precluding evaluation of effects of ductal closure on other outcomes, so these were excluded. The remaining 49 trials, 36, including 4728 subjects, were deemed potentially informative, as all but one documented substantial reduction in ductal patency after treatment.…”

Ibuprofen Versus Continuous Indomethacin in Premature Neonates With Patent Ductus Arteriosus: Is the Difference in the Mode of Administration?

“…Ibuprofen is also a cyclooxygenase inhibitor, which seems to be equally effective in mediating ductal closure, while minimizing adverse renal effects (11). It has also been reported to have fewer vasoconstrictive side effects (7,8,11) compared with bolus indomethacin. However, both the absence of longterm safety data and uncertainties regarding short-term safety of ibuprofen, including possible interference with bilirubin albumin binding and an increased risk of necrotizing enterocolitis (NEC) and pulmonary hypertension (with ibuprofen tris-hydroxyamino-methane [12]) remain of concern.…”

“…Because it purportedly lacks these side effects, ibuprofen has been proposed as a pharmacologically similar, but therapeutically preferential alternative in the treatment of PDA (5)(6)(7)(8)(9)(10)(11). Ibuprofen is also a cyclooxygenase inhibitor, which seems to be equally effective in mediating ductal closure, while minimizing adverse renal effects (11).…”

Effect of ibuprofen L-lysinate on bilirubin binding to albumin as measured by saturation index and horseradish peroxidase assays

“…[1][2][3][4][5][6][7][8][9][10] Published trials have also demonstrated its better safety and tolerability as compared to indomethacin and its possible role in neonatal therapeutics. [11][12][13] Since the first report of drug-bilirubin interactions in the pathogenesis of kernicterus, the potential for significant drug-bilirubin interactions has become an important consideration in neonatal drug therapy.…”