Prophylaxis of patent ductus arteriosus with ibuprofen in preterm infants. Prophylactic ibuprofen versus placebo in very premature infants: a randomised, double-blind, placebo-controlled trial. [Therapeutic effect of early administration of oral ibuprofen in very low birth weight infants with patent ductus arteriosus]. Oral ibuprofen prophylaxis for symptomatic patent ductus arteriosus of prematurity. Prophylactic ibuprofen therapy of patent ductus arteriosus in preterm infants. Timing of patent ductus arteriosus treatment and respiratory outcome in premature infants: a double-blind randomized controlled trial. Prophylaxis of symptomatic patent ductus arteriosus with oral ibuprofen in very low birth weight infants.
The aim of our study was to evaluate whether the prophylactic use of ibuprofen would reduce the incidence of significant patent ductus arteriosus (PDA) and to confirm the effectiveness of ibuprofen as rescue treatment in closing PDA. Eighty preterm infants with gestational age less than 34 wk with infant respiratory distress syndrome (iRDS) were randomized to receive intravenous ibuprofen lysine (10 mg/kg, followed by 5 mg/kg after 24 and 48 h) either within 24 h of life (group A) or after echocardiographic diagnosis of PDA (group B). To evaluate the severity of RDS in each patient, we calculated the initial and highest values of Oxygenation Index (O.I. = mean airway pressure x FiO2 x 100/PaO2) and Ventilatory Index (V.I. = O.I. x mechanical respiratory rate). Other studied variables were ventilatory support, renal function, biochemical and haematological profiles, frequency of bronchopulmonary dysplasia (BPD), intraventricular haemorrhage (IVH), necrotizing enterocolitis (NEC) and retinopathy of prematurity (ROP). On the 3rd day of life, 8% (3/40) of patients of group A and 53% of patients (21/40) of group B (p < 0.0001) developed a significant PDA. Between patients of group B who presented PDA at 3 d of life 90% (19/21) had a closure of ductus arteriosus after ibuprofen treatment. Initial and highest values of O.I. and V.I. were similar in both groups A and B. No significant differences between the groups were observed in regard to respiratory support, renal function and frequency of BPD, IVH, NEC and ROP. Ibuprofen was not associated with adverse effects. Conclusion: Prophylactic treatment with ibuprofen reduces PDA occurrence in preterm infants with iRDS at 3 d of life in comparison with rescue treatment, but both modes are effective in closing the ductus without significant adverse effects. Patent ductus arteriosus is a common complication of prematurity that frequently requires surgical or medical treatment. The benefit of prophylactic treatment by indometacin, a cyclo-oxygenase inhibitor, remains uncertain compared with curative treatment. This benefit could be improved with ibuprofen, another cyclo-oxygenase inhibitor with fewer adverse effects than indometacin on renal, mesenteric, and cerebral perfusion. We aimed to compare prophylactic and curative ibuprofen in the treatment of this abnormality in very premature infants.
                We did a randomised controlled trial in infants younger than 28 weeks of gestation, who were randomly assigned to receive either three doses of ibuprofen or placebo within 6 h of birth. After day 3, symptomatic patent ductus arteriosus was treated first by open curative ibuprofen, then back-up indometacin, surgery, or both. The primary endpoint was need for surgical ligation. Analysis was per protocol.
                The study was stopped prematurely after 135 enrollments because of three cases of severe pulmonary hypertension in the prophylactic group. 65 infants received prophylactic ibuprofen, and 66 received placebo. Prophylaxis reduced the need for surgical ligation from six (9%) to zero (p=0.03), and decreased the rate of severe intraventricular haemorrhage from 15 (23%) to seven (11%) (p=0.10). However, survival was not improved (47 [71%] placebo vs 47 [72%] treatment, p=1.00), because of high frequency of adverse respiratory, renal, and digestive events.
                In premature infants, prophylactic ibuprofen reduces the need for surgical ligation of patent ductus arteriosus, but does not reduce mortality or morbidity. Therefore, it should not be preferred to early curative ibuprofen. To study therapeutic effect and safety of early administration of oral ibuprofen in very low birth weight infants (VLBWIs) with patent ductus arteriosus (PDA).
                A total of 64 symptomatic VLBWIs (within 24 hours after birth) with PDA confirmed by bedside Color Doppler ultrasound were randomly divided into two groups: treatment and control (n=32 each). The treatment group was orally administered ibuprofen within 24 hours after birth at 10 mg/kg, followed 24 hours later by a second dose of 5 mg/kg and 48 hours later by a third dose of 5 mg/kg. The control group was treated with placebo (normal saline) at 1 mL/kg, followed 24 hours later by a second dose of 0.5 mL/kg and 48 hours later by a third dose of 0.5 mL/kg. The therapeutic efficacies and adverse effects in both groups were observed.
                The treatment group showed a significantly higher closure rate of ductus arterious than the control group after one course of treatment (84% vs 41%; P<0.01). The incidence rates of periventricular leukomalacia and bronchopulmonary dysplasia were significantly lower in the treatment group than in the control group (P<0.05). The duration of mechanical ventilation and mean hospitalization time were significantly shorter in the treatment group than in the control group (P<0.05). There were no significant differences in the incidence rates of intraventricular hemorrhage, early pulmonary hemorrhage and necrotizing enterocolitis between the two groups (P>0.05). No obvious adverse effects were observed in both groups.
                Early administration of oral ibuprofen for treatment of PDA in VLBWIs can decrease the incidence rates of some early complications and shorten hospitalization time, but causes no significant adverse effects. The oral suspension form of ibuprofen has been shown to have the same efficacy and safety as indomethacin in the treatment of symptomatic PDA, however its role is still questionable in the prophylaxis of symptomatic PDA.
                1. To assess the efficacy and safety of the drug in the prevention of symptomatic PDA in premature infants. 2. To study its pharmacokinetics-pharmacodynamics relationship.
                A randomized, single-blinded, controlled study was performed on premature neonates with a gestational age between 28-32 weeks, birthweight < or = 1500 grams at the neonatal unit, Queen Sirikit National Institute of Child Health from July 2003 to April 2004. Three doses of ibuprofen suspension or placebo were given 24 hours apart. Clinical evaluation was performed daily until the 28th day of life. Echocardiogram was performed prior to the drug administration, on the 3rd and 7th day of life.
                There were 22 and 20 cases in the ibuprofen and control group respectively. The epidemiologic data between the groups before enrollment showed no significant differences. Prevalence of symptomatic PDA was lower in the ibuprofen than in the control group without any significant side effects (0/22 vs 5/20, p = 0.015 on day 3 and 0/22 vs 6/20, p = 0.006 on day 7). Comparing with the pharmacokinetic study in older children and adult, the present study revealed nearly the same Cmax but longer Tmax and T1/2 in premature neonates.
                Oral ibuprofen suspension could reduce the prevalence of symptomatic PDA without any significant side effects. This study was aimed at evaluating the efficacy of ibuprofen in the prophylaxis of patent ductus arteriosus (PDA) in very preterm neonates and at detecting eventual side-effects. A total of 46 preterm neonates with gestational age under 31 weeks were randomly assigned at 2 h of life: 23 to the prophylaxis group and 23 to the control group. The prophylaxis group received intravenous treatment with ibuprofen lysine (10 mg/kg), followed by 5 mg/kg after 24 h and 48 h. No placebo was given to the control group. No PDA was demonstrated at 72 h of life in 20 of the 23 babies in the ibuprofen group (87%) nor in 7 of the 23 control neonates (30.4%). All neonates with PDA received treatment with indomethacin. One neonate in the prophylaxis group and three in the control group underwent surgical ligation. Prophylaxis with ibuprofen was not associated with any significant side-effect except for food intolerance.
                Ibuprofen prophylaxis seems to be efficient in closing patent ductus arteriosus and in reducing indomethacin treatment. No significant early side-effects were found due to ibuprofen. To determine whether "early" ibuprofen treatment, at the onset of subtle patent ductus arteriosus (PDA) symptoms, would improve respiratory outcome in premature infants compared with "expectant" management, with ibuprofen treatment only when the PDA becomes hemodynamically significant (HS).
                We conducted a randomized double-blind controlled trial of infants with gestational ages 23 to 32 weeks and birth weights 500 to 1250 g who had echocardiography for subtle PDA symptoms (metabolic acidosis, murmur, bounding pulses). Infants were then randomized to "early" treatment (blinded ibuprofen; n = 54) or "expectant management" (blinded placebo, n = 51). If the PDA became HS (pulmonary hemorrhage, hypotension, respiratory deterioration), infants received open label ibuprofen. Infants with HS PDA at enrollment were excluded from the study. Respiratory outcomes and mortality and major morbidities were determined.
                "Early" treatment infants received ibuprofen at median age of 3 days; infants in the "expectant group" in whom HS symptoms developed (20%) received ibuprofen at median of 11 days. A total of 49% of "expectant" infants never required ibuprofen or ligation. No significant differences were found in the primary outcome (days on oxygen [O(2)] during the first 28 days), death, O(2) at 36 weeks, death or O(2) at 36 weeks, intestinal perforation, surgical necrotizing enterocolitis, grades III and IV intracranial hemorrhage, periventricular leukomalacia, sepsis or retinopathy of prematurity.
                Infants with mild signs of PDA do not benefit from early PDA treatment compared with delayed treatment.
                Copyright © 2012 Mosby, Inc. All rights reserved. Patent ductus arteriosus (PDA) is a common cause of mortality and morbidity among very low birth weight infants. Oral ibuprofen suspension has been shown to have the same efficacy and safety as intravenous indomethacin in the prevention and treatment of symptomatic PDA. With lower dosage, the prevalence of side effects may decrease without changes in efficacy.
                To evaluate the efficacy and side effects of low dose ibuprofen suspension for prevention of symptomatic PDA in very low birth weight infants.
                A prospective, double blind, randomized controlled trial was conducted on premature neonates with gestational ages between 28-32 weeks, birth weight 1500 grams or less, at the Neonatal Unit, Queen Sirikit National Institute of Child Health (QSNICH) during October 2005 to October 2006. Only infants who had PDA on echocardiogram were included in the study. Three doses of ibuprofen suspension or placebo were randomly given at the dosage of 10, 5, 5 mg/kg every 24 hours. Daily physical examination, serial laboratory evaluation and echocardiogram were used to evaluate symptomatic PDA, complications and side effects.
                Sixty-two infants were recruited in the study and randomly assigned into the study and control group. The gestational age and birthweight of the 2 groups were similar The prevalence of symptomatic PDA was less in the ibuprofen group than in placebo group (9.86% vs. 35.48%; p = 0.015). There were no differences in the prevalence of complications and adverse effects between the two groups.
                Prophylactic oral ibuprofen suspension at lower dosage results in less symptomatic PDA without significant side-effects.
Prophylactic use of ibuprofen decreased the incidence of PDA, decreased the need for rescue treatment with cyclo-oxygenase inhibitors and decreased the need for surgical closure. In the control group, the PDA closed spontaneously by day three in 58% of the neonates. Prophylactic treatment exposes many infants to a drug that has concerning renal and gastrointestinal side effects without conferring any important short-term benefits and is not recommended. Until long-term follow-up results are published from the trials included in this updated review, no further trials of prophylactic ibuprofen are recommended.