Pharmacokinetics, dosing exposure and safety of oral ibuprofen in Chinese preterm neonates with patent ductus arteriosus: preliminary report.

Objective – This study was to assess the efficacy and safety of oral ibuprofen and intravenous ibuprofen for the early pharmacological treatment of patent ductus arteriosus (PDA) in preterm infants. Methods – A randomized, single-blinded, controlled study was performed on premature neonates at the neonatal unit tertiary care hospital, from January 2010 to December 2012. The study enrolled 80 preterm infants with gestational age between 28-32 weeks, birth weight ≤ 2000 g, postnatal age 48-96 h, and with echocardiographically confirmed significant PDA (a duct size >1.5 mm). The preterm infants received either intravenous or oral ibuprofen randomly as an initial dose of 10 mg/kg, followed by 5 mg/kg at 24 and 48 h after the first dose (the first treatment course). Serum creatinine (sCr), blood urea nitrogen (BUN) and urine output (UO) were recorded prior to treatment, before each dose and after the first treatment course. Results – Forty patients were treated with oral ibuprofen and 40 with intravenous ibuprofen in this period. There was no difference between treatment groups in demographics or baseline renal function. After the first course of the treatment, the PDA closed in 28 (70%) of the patients assigned to the oral ibuprofen group, versus 23 (57.5%) of those enrolled in the intravenous ibuprofen group (p=0.35). In the evaluation of renal tolerance, none of the patients had oliguria. Moreover, in patients who underwent a second course of intravenous therapy, the urinary output significantly decreased, but the sCr levels after the first and after the second treatment course did not differ significantly from the baseline for each group. 7.5% of the intravenous group underwent surgery, versus 0% of the oral group. (p=0.23) Conclusions – Successful pharmacological closure of PDA can be achieved by the use of ibuprofen orally or intravenously, without statistically significant difference in efficacy and safety between the two treatments. Patients treated with ibuprofen intravenously probably have a much higher risk of undergoing surgery.

Background Patent ductus arteriosus (PDA) is common in very premature infants. Pharmacological closure of PDA with indomethacin, a prostaglandin inhibitor, has remained the mainstay of treatment in premature infants over the last three decades. Intravenous ibuprofen was recently shown to be as effective and to have fewer adverse reaction in preterm infants. If equally effective, then oral ibuprofen for PDA closure would have several important advantages over the intravenous route.This study was designed to assess the efficacy and safety of oral ibuprofen and intravenous ibuprofen for the early pharmacological treatment of PDA in LBW preterm infants with respiratory distress syndrome.MethodsA randomized, single-blinded, controlled study was performed on premature neonates at the neonatal care unit of the University Hospital for Obstetrics and Gynecology”Koco Gliozheni”, Tirana, Albania, from January 2010 to December 2012. The study enrolled 68 preterm infants with gestational age between 28-32 weeks, birth weight ≤ 2000 g, postnatal age 48-96 h, and had echocardiographically confirmed significant PDA. The preterm infants received either intravenous or oral ibuprofen randomly as an initial dose of 10 mg/kg, followed by 5 mg/kg at 24 and 48 h. After the first dose of treatment in both groups, echocardiographic evaluation was performed, to determine the need for a second or third dose. The rate of ductal closure, adverse effects, complications, and the patient’s clinical course were recorded.Results All patients were born after 28 until 32 weeks’ gestation. 36 patients were treated with oral ibuprofen and 32 with intravenous ibuprofen in this period. After the first course of the treatment, the PDA closed in 30 (83.3%) of the patients assigned to the oral ibuprofen group versus 23 (71.8%) of those enrolled in the intravenous ibuprofen group (p = 0.355). There was no difference between treatment groups in demographics or baseline renal function. In the evaluation of renal tolerance, none of the patients had oliguria. There were no significant differences with respect to complications during the stay.Conclusions In low birth weight infants, the rate of early ductal closure with oral ibuprofen is at least as good as with the intravenous route. Oral ibuprofen is associated with fewer adverse effects

Acetaminophen in the Neonatal Intensive Care Unit: Shotgun Approach or Silver Bullet

ObjectiveTo compare the efficacy and safety of oral versus intravenous ibuprofen for the pharmacological closure of patent ductus arteriosus (PDA) in less mature preterm infants.DesignProspective, randomised controlled study.SettingTertiary neonatal intensive...

Objective To evaluate the efficacy and safety of oral ibuprofen for closure of patent ductus arteriosus (PDA) in preterm infants.Methods The related literatures till December 31st,2011 in Cochrane Library,PubMed,EMBASE,Ovid,Springer,China Academic Journal Full-text Database,Wanfang Database,VIP Database and China Biological Medical Literature Database were searched.The inclusion criteria were:(1) the subject of the research was preterm infants with birth weight less than 2500 g and/or gestational age less than 37 weeks; (2) randomized or semirandomized controlled trial; (3) the intervention group received oral ibuprofen,while the control group received oral placebos / intravenous indomethacin or ibuprofen; (4) the main outcome was the failure rate of PDA closure; (5) hemodynamic changes with PDA were detected by ultrasonography.Meta-analysis was performed by Review Manager 4.22 software.Results Eleven randomized controlled trials were included,among which,three were high quality reports.Meta-analysis showed lower failure rate of PDA closure in subjects received oral ibuprofen than in those received placebos orally (RR =0.22,95 ％ CI:0.14-0.35),while the number of infants required operative closure of PDA decreased significantly (RR =0.16,95％ CI:0.03-0.86).Further analysis showed the effect of oral ibuprofen was similar to intravenous indomethacin (RR =0.93,95 ％ CI:0.57-1.53),but better than intravenous ibuprofen (RR=0.42,95％CI:0.26-0.67).However,oral ibuprofen did not reduced the ratio of patients required operation compared with intravenous indomethacin or ibuprofen (RR=0.58,95％CI:0.24-1.41).The incidence of gastrointestinal hemorrhage was higher in oral ibuprofen group than that in placebos(RR=1.99,95％CI:1.13-3.50).The serum level of creatine was lower in oral ibuprofen group than in intravenous indomethacin or ibuprofen group (weighted average=-19.10,95％ CI:-25.12-12.31).Compared with intravenous indomethcin group,less necrotizing enterocolitis cases were identified in oral ibuprofen group,but no statistical significance was found (RR=0.57,95％ CI:0.30-1.09).No long-term outcome was reported in any selected literature.Conclusions Oral ibuprofen for PDA closure in preterm infants appears to be as effective as intravenous or indomethacin,and more effective than intraveous ibuproten.Oral ibuproten represents better safety. Key words: Ductus arteriosus, patent; Ibuprofen; Infant, premature; Indomethacin; Treatment outcome; Meta-analysis

Cost-effectiveness of Oral Versus Intravenous Ibuprofen Therapy in Preterm Infants With Patent Ductus Arteriosus in the Neonatal Intensive Care Setting: A Cohort-based Study

Efficacy and tolerability of enteral formulations of ibuprofen in the treatment of patent ductus arteriosus in preterm infants

Oral Ibuprofen and the Patent Ductus Arteriosus: A New Approach to an Old Problem

ObjectiveTo describe the diagnosis and treatment of patent ductus arteriosus (PDA) in infants born at <32 weeks’ gestational age (GA) in England and Wales between 2010 and 2017.Study designRetrospective cohort...

This overview summarised the evidence from 16 Cochrane Reviews of RCTs regarding the effects of interventions for the prevention and treatment of PDA in preterm infants. Prophylactic indomethacin reduces severe IVH, but does not appear to affect the composite outcome of death or moderate/severe neurodevelopmental disability. Prophylactic ibuprofen probably marginally reduces severe IVH (moderate-certainty evidence), while the evidence is very uncertain on the effect of prophylactic acetaminophen on severe IVH. All available prostaglandin inhibitor drugs appear to be effective in symptomatic PDA closure compared to no treatment (high-certainty evidence for indomethacin; moderate-certainty evidence for ibuprofen; low-certainty evidence for early administration of acetaminophen). Oral ibuprofen appears to be more effective in PDA closure than IV ibuprofen (moderate-certainty evidence). High dose ibuprofen appears to be more effective in PDA closure than standard-dose ibuprofen (moderate-certainty evidence). There are currently two ongoing reviews, one on fluid restriction for symptomatic PDA, and the other on invasive management of PDA in preterm infants.

Premature infants with hemodynamically significant patent ductus arteriosus (HSPDA) have a high risk of developing acute kidney injury (AKI) due to renal hypoperfusion and use of ibuprofen for duct closure. The aim of the study was to evaluate the effect of ibuprofen for the closure of HSPDA on the development of AKI in preterm infants depending on high dose of the drug on the first day of life. 40 preterm infants with HSPDA who were admitted for observation on the first day of life were examined. To close the ductus arteriosus, infants received restrictive therapy. In addition, 32 (80,0%) preterm infants on the first day of life were prescribed ibuprofen: 19 infants – in high dose (20 mg/kg), 13 infants – in standard dose (10 mg/kg). Clinical examination and treatment of preterm infants was carried out according to the generally accepted methods. Echocardiography with Doppler was performed at 5-11 hours of life and then daily to determine the size and hemodynamic significance of patent ductus arteriosus. Diagnosis and stratification of the severity of AKI were performed according to the criteria of neonatal modification of KDIGO, for which the concentration of serum creatinine and diuresis were studied. According to the results of the study, it was established that the frequency of AKI on the third and fifth days of life in preterm infants with HSPDA, who received ibuprofen in a high dose (20 mg/kg) on the first day, was 73.7% and 84.2%, respectively, which is 2.2 (OR=5.6; CI: 1,43-21,95; р&lt;0.02) and 2.5 (OR=10.67; CI: 2.31-49.31; р&lt;0.002) times, more often than in infants without such therapy. High dose of ibuprofen on the first day of life in preterm infants with HSPDA are most often associated with the development of stage I AKI on the third or fifth day of life, which was temporary in one third of patients. The use of a high-dose ibuprofen for HSPDA closure on the first day of life in preterm infants was significantly more often associated with foci of infection in the mother, large duct size and furosemide use.

Patent ductus arteriosus (PDA) complicates the clinical course of preterm infants and increases the risk of adverse outcomes. Indomethacin has been the standard treatment to close a PDA but is associated with renal, gastrointestinal, and cerebral side effects. Ibuprofen has less effect on blood flow velocity to important organs.

After completing this article, readers should be able to: Few aspects of neonatal care have generated as much controversy as the assessment of blood pressure (BP) and need for treatment of perceived abnormalities of this physiologic variable. Familiarity with clinical situations in which BP may be low should allow anticipation of this common clinical problem and timely intervention when such treatment is necessary (Tables 1 and 2). In this article, we review factors that have been shown to have the greatest effect on BP.A direct reading from an indwelling arterial catheter represents the “gold standard” for measuring BP in the neonate, and this method should be used whenever possible. Obviously, arterial access may not always be available, and the ability to monitor BP noninvasively using an oscillometric technique represents a major advancement in neonatal care. The correlation between direct and indirect methods generally has been good. Disparities in results have been related to various factors, including inappropriate cuff width-to-arm ratio or problems with the arterial catheter-transducer system, such as air bubbles or clots. In general, indirect determinations are higher than those obtained directly, often by 3 to 5 mm Hg.The individual contributions of birthweight and gestational age to BP are difficult to delineate. Several groups of investigators have shown that BP at birth is higher in larger, more mature infants. There is evidence that small-for-gestational age infants have lower BPs than do larger babies of comparable gestational age, which suggests that birthweight per se may be more than a marker for increased maturity.Early studies involving large numbers of infants who had a wide range of birthweights and gestational ages demonstrated the significance of both of these variables. In a recent report of a large multicenter study conducted by the Philadelphia Neonatal Blood Pressure Study Group, systolic and diastolic blood pressures were significantly correlated with birthweight (Fig. 1) and gestational age (Fig. 2).Le Flore and associates studied 116 very low-birthweight (VLBW) neonates during the first 72 hours after birth. Following multiple linear regression, both gestational age and birthweight were primary variables predicting mean blood pressure (MBP) during this period. However, gestational age explained more of the variance in MBP during the first 24 hours, with each additional week of gestation increasing MBP by 1.4 mm Hg. Neonates of 24 to 25 weeks’ gestation had an initial MBP of 27±4 mm Hg versus 39±7 mm Hg for neonates at 32 to 33 weeks’ gestation (P≤0.01) (Fig. 3). In contrast, birthweight explained more of the variance in MBP between 25 hours and 72 hours after birth, with each increase of 100 g associated with an increase in MBP of 1.0 mm Hg. The Joint Working Group of the British Association of Perinatal Medicine has recommended that MBP (in mm Hg) be maintained at or above the gestational age of the infant (in weeks). Further investigation is required to establish the safety and efficacy of this approach.As alluded to previously (Fig. 3), MBP increases postnatally in VLBW neonates regardless of gestational age. Zubrow and associates found a similar relationship between BP and postnatal age in infants whose birthweights were 750 to 4,000 g and gestational ages were 22 to 42 weeks (Fig. 4). When the effect of postnatal age on BP was analyzed over a longer period of time, systolic BP was approximately 30 mm Hg higher at the 4-month age-adjusted outpatient examination compared with values at 7 days after birth.The association between advancing birthweight, gestational age, and postnatal age and increases in BP is not understood completely. A discussion of the complex neural, hormonal, and vascular mechanisms that control BP is beyond the scope of this article, but their maturation is a significant consideration. Anatomic relationships may play a role, and decreases in right ventricular pressure after birth may result in improved left ventricular shape and function. Also, it has been shown that urinary prostaglandin E2 and plasma 6-keto-prostaglandin F1alpha (stable metabolite of prostacyclin) decrease during the first 3 postnatal days in preterm neonates. This could result in a rise in vascular tone and increased vascular reactivity. More recently, it has been reported that vascular smooth muscle protein expression and contractility demonstrate functional maturation during development. Thus, the rise in BP during the fetal-neonatal transition may reflect decreases in the activity and synthesis of vasodilators, which are critical to fetal survival, as well as intrinsic changes in vascular smooth muscle function occurring prior to and following birth, both of which appear to be developmentally regulated.Significant hypotension in the neonate can be a reflection of prenatal, intrapartum, or postnatal hemorrhage (Table 1). Fetomaternal, twin-twin, intracranial, subgaleal, and hepatic hemorrhages are the most common types of significant blood loss. Adrenal hemorrhage is a very rare (but reported) cause of severe neonatal hypotension, although the mechanism of subsequent blood pressure instability may be more associated with adrenocortical derangement than significant blood loss. Hemorrhage should be considered in any hypotensive neonate, but it is important to note that the initial physiologic response involves the release of vasoactive substances, such as catecholamines and arginine vasopressin. Hypotension may be a relatively late finding that suggests the presence of acute blood loss. The pre-equilibration hemoglobin and hematocrit values also may be misleading following blood loss.Infusion of cortisol into the sheep fetus results in increased arterial pressure. Several reports have suggested that neonatal BP is higher in preterm infants whose mothers received antenatal steroids to hasten fetal lung maturity. This finding would not be unexpected because previous studies have suggested that sick preterm neonates may have relative adrenocorticosteroid insufficiency. Furthermore, successful treatment with hydrocortisone or dexamethasone, administered because of hypotension refractory to conventional therapies, has been documented.In one study, neonates whose mothers received dexamethasone had higher MBPs during the first 3 days after birth, but this relationship was less clear when adjustment for birthweight was made. After this adjustment, a significant difference in BP was noted only 2 hours following initial treatment with exogenous surfactant. A subsequent study investigated the amount of BP support required by extremely preterm infants (23 to 27 weeks’ gestation) whose mothers did or did not receive antenatal steroids. Infants not exposed to antenatal steroids had lower MBPs from 16 to 48 hours after birth. Furthermore, the use of dopamine was increased in the infants not exposed to antenatal steroids. The reduction in severe intraventricular hemorrhage observed in infants whose mothers received antenatal steroids has been linked to normal BP in those infants. In another study, MBP during the first 24 hours after birth was increased in VLBW infants whose mothers received antenatal steroids, and volume expansion and vasopressor support were decreased in those infants.Conversely, LeFlore and associates reported no differences in BPs among 116 VLBW neonates whose mothers did or did not receive antenatal steroids, and similar results were obtained in another study. Other investigators have reported a tendency for higher mean BP in infants weighing at least 1,000 g whose mothers received antenatal steroids but a tendency for lower MBP in infants weighing less than 1,000 g who were exposed to antenatal steroids. Leviton and colleagues found no difference in the incidence of lowest MBP less than 30 mm Hg in infants whose mothers did or did not receive a complete course of antenatal glucocorticoid prophylaxis.Obviously, further investigation is required to determine the relationship between antenatal steroids and BP. Perhaps in the subset of preterm infants who truly have relative adrenal insufficiency, antenatal steroids may enhance neonatal cardiovascular stability and raise BP, while antenatal steroids have little or no effect on BP in those who have adequate adrenal function.The effect of route of delivery on BP in the neonate has been studied extensively. Several studies in term neonates have indicated that BP in vaginally delivered infants is higher than in those delivered by cesarean section. In general, these studies have attributed the higher BP in the former group to increased catecholamine concentrations and cord blood arginine vasopressin and adrenocorticotropin hormone levels. However, among VLBW infants, blood pressures were similar in infants delivered vaginally and those delivered by cesarean section. Likewise, in the study by Zubrow and associates, which included 106 infants of 32 weeks’ gestational age or younger, stepwise multiple linear regression analysis did not identify route of delivery as a significant determinant of BP variation. Breech delivery has been associated with BP in the lower range of normal. The volume of placental transfusion (as well as postnatal transfusion) also may affect BP.The classic studies of Dawes in newborn monkeys demonstrated that BP initially rises with ongoing asphyxia, but after 5 minutes, it decreases progressively. As emphasized by the American Academy of Pediatrics/American Heart Association Committee on Neonatal Resuscitation, many infants who have birth depression and possibly some degree of hypotension respond to effective positive-pressure ventilation and do not require specific measures to raise BP (see accompanying article on treatment of hypotension).Circulatory changes resulting from apnea in the neonate have been summarized by Miller and Martin. The initial decrease in heart rate is accompanied by a rise in pulse pressure, usually due to an increase in systolic pressure. These events presumably result from increased filling volume associated with bradycardia, which leads to enhanced stroke volume in accordance with Starling’s law. As the severity of apnea and bradycardia increases, BP may decrease, along with a fall in cerebral blood flow velocity. Thus, during prolonged apnea, cerebral perfusion may decrease significantly, placing the infant at risk for brain injury.Infants who have severe respiratory distress syndrome (RDS) may have lower BPs than those observed in healthy preterm neonates or infants who have less severe RDS. An association in infants who have RDS between marked fluctuations in arterial BP and fluctuating cerebral blood-flow velocity has been demonstrated. Also, an association has been reported between acute hypocarbia and marked systemic hypotension.Three aspects of respiratory management in preterm neonates have been shown to affect BP: 1) use of increased airway pressures, given either by constant positive airway pressure (CPAP) or intermittent mandatory ventilation; 2) suctioning of the airway, occasionally accompanied by a fall in diastolic pressure; and 3) instillation of an exogenous surfactant preparation into the airway. Although a number of studies in animals and humans have shown no effect of positive end-expiratory pressure or CPAP on BP, Kluckow and Evans observed a highly significant negative influence of mean airway pressure on MBP in preterm neonates requiring mechanical ventilation. BP fluctuations during mechanical ventilation may be decreased through the use of various methods of synchronized mechanical ventilation.Perlman and Volpe measured arterial BP, cerebral blood-flow velocity, and intracranial pressure in 35 intubated preterm neonates undergoing routine suctioning. MBP increased during suctioning in all but one patient, and these investigators concluded that the observed increases in cerebral blood-flow velocity and intracranial pressure were directly related to the increased blood pressure. Perry and colleagues reported an association between systolic BP above a “stability boundary” and increased periventricular-intraventricular hemorrhage, with BP elevations related temporally to suctioning. In addition to suctioning, BP response to various care procedures, including chest auscultation and physiotherapy, mouth rinsing, diaper changing, and nasogastric feeding, have been studied, and in general, BP responses were biphasic, with a decrease in BP followed by a greater and longer lasting increase.Numerous investigators have studied the physiologic effects of surfactant instillation in neonates, and differences in these reports may be due to dosing or technique of administration. In most studies, any effects on BP were transient. There may be greater hemodynamic effects associated with natural surfactant preparations, perhaps related to their generally more rapid pulmonary effects compared with artificial surfactant preparations.Studies of patent ductus arteriosus (PDA) in animals and preterm human neonates generally have shown significant decreases in diastolic BP. In one study, investigators noted that a diastolic BP of less than 28 mm Hg suggested the presence of PDA, although it is apparent from numerous studies that many normal VLBW neonates actually have mean BPs lower than 28 mm Hg.Among infants whose birthweights were 1,000 to 1,500 g, Evans and Moorcraft found similar BPs in the PDA and nonPDA groups. However, in those whose birthweights were less than 1,000 g, mean systolic and diastolic BPs were lower in infants who had PDA compared with those who did not. Furthermore, these hemodynanic effects could be demonstrated well before the PDA became clinically apparent. These authors cautioned against the use of volume expanders or inotopic agents in this population because these treatments might be counterproductive if the cause of the hypotension is a hemodynamically significant but clinically silent PDA. Furthermore, volume expansion appears to be a risk factor for the development of symptomatic PDA in VLBW neonates. It is apparent that problems with low BP related to PDA, especially diastolic BP, may result in inadequate perfusion of vital organs because of the “vascular steal” phenomenon. Optimum management of this clinical problem, of course, is directed at closure of the PDA rather than increasing the BP by other means.Neonatal sepsis is a common problem that can be devastating in both preterm and term neonates. The complicated pathophysiology of neonatal sepsis involves activation or release of numerous inflammatory and vasoactive substances, and hypotension can be a relatively late finding. The resulting effect on the cardiovascular system can be vasoconstriction, as is seen frequently in term and postterm septic neonates who have pulmonary hypertension or peripheral vasodilation with accompanying cardiomyopathy resulting in profound systemic hypotension (see accompanying article on treatment of hypotension). Necrotizing enterocolitis, which often accompanies sepsis, continues to be a common problem in the neonatal intensive care unit, and neonates who have moderate-to-severe disease very frequently are hypotensive.Maternal smoking may be associated with increases in both systolic and diastolic BP in the neonate, and a direct relationship between neonatal BP and the number of cigarettes smoked has been shown. This effect may persist for at least 12 months. Although maternal hypertension may be a factor associated with higher neonatal BP, this is not reported consistently. Cocaine exposure in utero has been shown to be associated with increased BP on the first day after birth in term neonates, and increased circulating catecholamine concentrations have been demonstrated. Mean arterial pressure was unchanged, but arterial pressure variability was decreased with both pancuronium and pethidine (meperidine). Fentanyl and midazolam may cause hypotension in neonates. Numerous studies have demonstrated that BP may increase and decrease with pneumothorax. Seizure activity may have variable effects on blood pressure. Increased neonatal BP has been documented in infants who have chronic lung disease and receive dexamethasone therapy.The smallest, least mature infants have lower BPs than infants who are larger and more mature. The effect of antenatal steroids, given to the mother when preterm delivery is anticipated, is controversial. Maternal smoking and route of delivery are perinatal factors that can influence neonatal BP. Sepsis and hemorrhage are associated with significant derangements in BP and always must be considered in a hypotensive neonate. PDA may be associated with a significant decrease in diastolic BP.

Background A consensus on the management of patent ductus arteriosus (PDA) in premature neonates remains indefinable. Conservative PDA treatment is based on the premise that in most preterms PDAs spontaneously close before discharge. Ibuprofen has been used for treating PDA, however, no clear guidelines for management have been suggested. Aim of Work The aim of this work is to compare the effect of oral ibuprofen versus placebo on PDA closure in preterm infants less than 34 weeks’ gestation. Methodology This study was conducted on 80 preterm neonates with gestational age ≤ 34 weeks with a hemodynamically significant PDA. They were randomized into a medical treatment group (n = 40) and a placebo group (n = 40). Both groups received conservative PDA therapy in the form of fluid restriction, positive end-expiratory pressure, and/or diuretics. The medical treatment group received oral ibuprofen (at an initial dose of 10 mg/kg/day, followed by 5 mg/kg/day for the next 2 days) and the placebo group received an oral placebo. The open-label option and an extended oral ibuprofen therapy (an offered or a repeated course with the same dose) were only offered if there are concerns over a poor patient condition that was attributed to persistent PDA and only after meeting certain criteria like signs of pulmonary hyperperfusion and/or systemic hypoperfusion. Echocardiography was done on day 1 of recruitment (48-72 hours of age) and was followed up till discharge. The patients were followed up for adverse effects of ibuprofen by serum creatinine and total serum bilirubin after the first course of treatment. Results There was no significant difference in PDA closure rate following the first ibuprofen course (62.5% in the ibuprofen treated group vs 65% in the placebo group, p &amp;gt; 0.05). At discharge time (mean 13.5 days in the ibuprofen group, 14 days in the placebo group), a closure rate of 75% was achieved in both groups, respectively. There was no significant difference in initial serum creatinine levels between the two groups either on day 1 of recruitment or after the first course of the intervention, p &amp;gt; 0.05, respectively. Meanwhile, serum creatinine significantly decreased in both groups after treatment (p-value &amp;lt;0.001, respectively). Also, there was no difference between the two groups in serum bilirubin either on day 1 of recruitment or after the first course of treatment, p &amp;gt; 0.05, respectively. Conclusion Conservative treatment is not inferior to oral ibuprofen therapy in the management of PDA. Oral ibuprofen does not elevate serum creatinine levels or cause hyperbilirubinemia.

A patent ductus arteriosus (PDA) complicates the clinical course of preterm infants, increasing their risks of developing chronic lung disease (CLD), necrotizing enterocolitis (NEC), and intraventricular hemorrhage (IVH). Indomethacin is used as standard therapy to close a PDA, but is associated with reduced blood flow to the brain, kidneys and gut. Ibuprofen, another cyclo-oxygenase inhibitor, may be as effective with fewer side effects. To determine the effectiveness and safety of ibuprofen compared to placebo or no intervention for closing a PDA in preterm and/or low birth weight infants. To determine the effectiveness and safety of ibuprofen compared to other cyclo-oxygenase inhibitors (including indomethacin, mefenamic acid) for closing a PDA in preterm and/or low birth weight infants. Randomized or quasi-randomized controlled trials (RCTs) comparing ibuprofen to placebo or indomethacin or mefenamic acid for therapy of PDA were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2005), MEDLINE (1996 - July 2005), CINAHL (1982 - July 2005), EMBASE (1980 - July 2005), reference lists of published RCTs and abstracts from the Pediatric Academic Societies and the European Society for Pediatric Research meetings published in Pediatric Research (1991 - April 2005). No language restrictions were applied. 1) DESIGN: Randomized or quasi-randomized controlled trials 2) POPULATION: Preterm (< 37 weeks gestational age) or low birth weight infants (< 2500 grams) with a clinically or echocardiographically diagnosed PDA 3) INTERVENTION: Administration of ibuprofen for the closure of PDA 4) OUTCOMES: At least one of the following outcomes were reported: failure to close a PDA, mortality, surgical ligation, intraventricular haemorrhage (IVH), periventricular leukomalacia (PVL), NEC, decreased urine output, retinopathy of prematurity (ROP), chronic lung disease (CLD), sepsis, days on supplementary oxygen. At least two authors worked independently at each step of the original review, then compared results and resolved differences. The current update was conducted by one author (AO). Methodological quality of eligible studies was assessed according to blinding of randomization, of intervention and of outcome assessment, and completeness of follow up. Weighted treatment effects, calculated using RevMan 4.2, included typical relative risk (RR), typical risk difference (RD), number needed to treat (NNT) or harm (NNH), and weighted mean difference (WMD), all with 95% confidence intervals (CI). A fixed effect model was used for meta-analyses. Heterogeneity tests including I(2 )were performed to assess the appropriateness of pooling the data. No study using mefenamic acid was identified. One study compared ibuprofen to placebo but results were not reported unblinded to group. Eleven studies including 620 patients compared the effectiveness of ibuprofen to indomethacin for the closure of a PDA. There was no statistically significant heterogeneity of treatment effect for any of the outcomes. For the primary outcome (failure of ductal closure), there was no statistically significant difference between ibuprofen and indomethacin groups [typical RR 0.96 (95% CI 0.74, 1.25)]. There were no statistically significant differences in mortality, surgical duct ligation, duration of ventilator support, IVH, PVL, NEC, time to full enteral feeds, ROP, sepsis, duration of hospital stay or gastrointestinal bleed. For many of these outcomes the sample size was small and the estimates imprecise. The incidence of decreased urine output (< 1cc/kg/hr) was lower in the ibuprofen group as compared to the indomethacin group [NNT 9 (95% CI 5-14)]. This was the only statistically significant clinical finding favouring ibuprofen. CLD defined as oxygen requirement at 28 days post-natally was statistically significantly more likely to occur in the ibuprofen group [typical RR 1.37 (95% CI 1.01, 1.86); NNH 7 (95% CI 3 - 100)]. There was a similar trend for CLD at 36 weeks corrected gestational age. We found no statistically significant difference in the effectiveness of ibuprofen compared to indomethacin in closing the PDA. Ibuprofen reduces the risk of oliguria. However, ibuprofen may increase the risk for CLD, and pulmonary hypertension has been observed in three infants after prophylactic use of ibuprofen. Based on currently available information ibuprofen does not appear to confer a net benefit over indomethacin for the treatment of a PDA. We conclude that indomethacin should remain the drug of choice for the treatment of a PDA. The most urgent research question to be answered is weather ibuprofen compared to indomethacin confers an improved rate of intact survival (survival without impairment) at 18 months corrected age.