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Original article

Oral versus intravenous ibuprofen for patent ductus arteriosus closure: a randomised controlled trial in extremely low birthweight infants Omer Erdeve,1 Sadık Yurttutan,1 Nahide Altug,2 Ramazan Ozdemir,1 Tulin Gokmen,1 Ugur Dilmen,1 Serife Suna Oguz,1 Nurdan Uras1 1Division

of Neonatology, Zekai Tahir Burak Maternity Teaching Hospital, Ankara, Turkey 2Pediatric Cardiology, Zekai Tahir Burak Maternity Teaching Hospital, Ankara, Turkey Correspondence to Omer Erdeve, 312 Ulusoy City, 16B/46, 2432. Cadde Agacseven Sokak, 06810, Cayyolu, Ankara, Turkey; [email protected] Received 26 June 2011 Accepted 2 November 2011 Published Online First 5 December 2011

ABSTRACT Objective To compare the efficacy and safety of oral versus intravenous ibuprofen for the pharmacological closure of patent ductus arteriosus (PDA) in less mature preterm infants. Design Prospective, randomised controlled study. Setting Tertiary neonatal intensive care unit. Patients and interventions The study enrolled 80 preterm infants with gestational age ≤28 weeks, birth weight <1000 g, postnatal age 48 to 96 h, and had echocardiographically confirmed significant PDA. Seventy extremely low birthweight (ELBW) 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. Main outcome measures The success rate and the safety of the drugs in ELBW preterm infants were the major outcomes. Results PDA closure rate was significantly higher with oral ibuprofen (83.3% vs 61.7%) after the first course of the treatment (p=0.04). Although the primary closure rate was marginally higher in the oral ibuprofen group, the need for a second course of ibuprofen during the whole hospitalisation was similar between groups: 11 of 36 in oral versus 15 of 34 in intravenous groups (p=0.24) because of a higher reopening rate in the oral group. In addition to no increase in side effects with oral ibuprofen use, the need for postnatal steroid use for chronic lung disease was significantly lower in oral ibuprofen group (p=0.001). Conclusions Oral ibuprofen is as effective as intravenous ibuprofen for PDA closure even in ELBW infants.

INTRODUCTION The persistence of a patent ductus arteriosus (PDA) in preterm infants complicates their clinical course and contributes to increased morbidity. Treatment options in the closure of PDA include pharmacological therapy and surgical ligation. Pharmacological closure of PDA can be achieved with cyclooxygenase inhibitors which block the conversion of arachidonic acid to prostaglandins.1–3 Indomethacin to close the PDA is one of the few drugs developed specifically for preterm infants. However, treatment with indomethacin is associated with adverse reactions such as reduced renal, mesenteric and cerebral perfusion.4 More recently, a related drug, ibuprofen, was approved for the indication of PDA closure in preterm infants, and unlike Arch Dis Child Fetal Neonatal Ed 2012;97:F279–F283. doi:10.1136/archdischild-2011-300532

What is already known on this topic ▶

▶

Oral ibuprofen is more effective than intravenous ibuprofen in the closure of PDA in VLBW preterm infants. There is a lack of data on its efficacy and safety in ELBW preterm infants who constitute the majority of patients with ductal patency in developed countries.

What this study adds ▶

▶

First course oral ibuprofen is more effective than intravenous ibuprofen for PDA closure even in ELBW preterm infants. Oral ibuprofen use for ductal closure may have a potential effect on the severity of developing chronic lung disease

indomethacin, ibuprofen does not affect the basal cerebral blood flow and has fewer effects on renal haemodynamics. Ibuprofen has a potential interference with the bilirubin binding to albumin which may cause the risk of hyperbilirubinaemia. The unique aspect is that both of these are in a solution for intravenous use. The intravenous preparations of indomethacin and ibuprofen are available only in some medically resource-rich countries and at exorbitant prices. However, oral indomethacin and ibuprofen are widely available as very inexpensive pills and liquids worldwide. The availability and lower cost of oral ibuprofen have led many physicians, especially in the developing countries, to prefer this treatment for the closure of PDA.4–11 A recent randomised controlled trial demonstrated that oral ibuprofen more effectively closed the PDA than did intravenous ibuprofen, and there were no complications associated with the oral treatment. However, the infants had mean birth weights of about 1200 g and only 10% of them were ≤28 weeks’ gestation, and thus were larger than many of the treated extremely preterm infants in the developed countries.11 Therefore, we decided to conduct a prospective, randomised trial in less mature infants to compare the efficacy and safety of oral ibuprofen to intravenous ibuprofen in the pharmacological closure of PDA. F279

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Original article METHODS The study was conducted in the neonatal intensive care unit (NICU) of Zekai Tahir Burak Maternity Teaching Hospital, Ankara, Turkey, between January 2010 and February 2011. This unit has 150 incubators and serves as a referral Level III NICU with about 4000 newborn admissions per year. This trial was approved by the local ethics committee, and infants were enrolled in the study after written parental consent. The study enrolled 80 preterm infants with a gestational age ≤28 weeks, birth weight <1000 g, postnatal age 48–96 h and one of the following echocardiographical criteria of a duct size >1.5 mm: a left atrium-to-aorta ratio >1.5, left-to-right shunting of blood, end-diastolic reversal of blood flow in the aorta or poor cardiac function in addition to the signs of PDA.11 Twodimensional colour Doppler echocardiography was performed using a GE Vivid 7 Pro, 10S transducer (GE Healthcare, Salt Lake City, Utah, USA). Exclusion criteria were the major congenital abnormalities, right-to-left ductal shunting, life-threatening infection, grade 3 or 4 intraventricular haemorrhage, urine output of less than 1 ml/kg/h during the preceding 8 h, serum creatinine level >1.6 mg/dl, platelet count <60 000/mm3, tendency to bleed, hyperbilirubinaemia requiring exchange transfusion and persistent pulmonary hypertension. Before and 24 h after treatment, all patients were evaluated with a complete blood count, renal function tests (serum creatinine, blood urea nitrogen and sodium levels, and urine output), bilirubin level, cranial ultrasonography and echocardiography. The patients were randomly assigned to a treatment group by means of cards in sequentially numbered sealed opaque envelopes. Each enrolled patient received either intravenous ibuprofen (Pedea, Orphan Europe, Paris, France) or oral ibuprofen (Pedifen, Atafarm, Istanbul, Turkey) at an initial dose of 10 mg/kg, followed by 5 mg/kg at 24 and 48 h. Intravenous ibuprofen was infused over a 15-min period with a syringe pump, and the line was subsequently flushed with saline. Oral ibuprofen (312 mOsmol/l and stabilised with propyl parapen, methyl parapen and sodium benzoate) was given

Figure 1 F280

via an orogastric tube, which was flushed with 1 ml of sterile water to ensure the delivery of the drug. Infants were tried to be fed only with breastmilk starting from the fi rst day of life and all infants continued their current enteral feeding during the treatment. Daily oral intake received at the time of treatment start of the fi rst ibuprofen course ranged between 20 and 40 ml/kg for patients in both groups. One day after the third treatment, an echocardiographical evaluation was performed by a paediatric cardiologist who was blinded to the treatment group to determine the success of the treatment and the need for a second course via the same route. Patients who had minimal ductal shunting were followed up regularly by a neonatologist or paediatric cardiologist. Patients who achieved PDA closure but had signs and symptoms of reopening later during the hospitalisation were re-evaluated by echocardiography and treated according to their echocardiographical fi ndings in addition to clinical condition. For all patients enrolled in the study, the fluid intake was begun at 70–80 ml/kg per day and increased by increments of 10–20 ml/kg each day, to a maximum of 150 ml/kg per day. Hypotension was treated with dopamine for cases in which fluid treatment had failed. Ventilation was supported according to the severity of respiratory distress, using nasal continuous positive airway pressure or mechanical ventilation. The patients were given penicillin G and netilmicin on admission, if required. The success rate which was defi ned as closed duct on control echocardiography after the completed course and the safety of the drugs in extremely low birthweight (ELBW) preterm infants were the major outcomes of the study. Secondary outcomes included the need for the retreatment or surgical ligation of the PDA (performed for patients who had haemodynamically significant PDA after two completed courses of medical treatment); mode and duration of ventilation; increase in the serum bilirubin level after treatment; the rates of ductal reopening, surfactant treatment, pneumothorax, pulmonary haemorrhage, pulmonary hypertension, chronic lung disease (CLD), intraventricular haemorrhage (grades I–IV), necrotising

Flow chart of the study. Arch Dis Child Fetal Neonatal Ed 2012;97:F279–F283. doi:10.1136/archdischild-2011-300532

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Original article Table 1 Demographic data of both groups Birth weight, mean±SD (g) Gestational age, mean±SD (weeks) Male, n (%) Caesarean delivery, n (%) Prenatal steroids, n (%) Premature rupture of membrane >18 h, n (%) APGAR 1, median (min–max) APGAR 5, median (min–max) Surfactant for respiratory distress syndrome, n (%) Caffeine treatment, n (%) Patients with ductal size >1.5 mm and LA:Ao ratio >1.5, n (%)

Oral (n=36)

IV (n=34)

p

892±117 26.4±1.1 20 (55.6) 31 (86.1) 25 (69.4) 9 (25) 5 (1–7) 7 (3–9) 27 (75) 36 (100) 25 (69.4)

872±123 26.3±1.3 13 (38.1) 27 (79.4) 27 (79.4) 10 (29.4) 4 (1–7) 7 (4–9) 30 (88.2) 33 (97.1) 26 (76.5)

0.48 0.50 0.14 0.45 0.34 0.67 0.17 0.28 0.15 0.30 0.50

LA:Ao, left atrium-to-aorta ratio.

Table 2

Evaluation of renal function tests and bilirubin level after first course of treatment Intravenous ibuprofen

Oral ibuprofen

Measurement

Before

After

p

Before

After

p

p*

Blood urea nitrogen (mg/dl) Plasma creatinine (mg/dl) Plasma bilirubin (mg/dl) Plasma sodium (mmol/l) Urine output (ml/kg/h)

79.3±28.4 0.79±0.27 5.2±2.7 140±6.4 3.2±1

79.9±37.2 0.76±0.22 4.4±1.7 138±6.9 2.8±0.8

0.91 0.64 0.03 0.05 0.06

61.8±33.9 0.68±0.24 5.4±2.5 140±6.5 2.9±0.7

65.2±31.7 0.69±.026 5.1±2.9 137±7 3±0.7

0.53 0.96 0.48 0.12 0.44

0.07 0.16 0.21 0.95 0.39

*p value for after treatment measurements between groups.

enterocolitis (NEC) (any stage, according to Bell classification), intestinal perforation, gastrointestinal bleeding, retinopathy of prematurity (ROP) (according to the International Classification), defi nite sepsis (clinical symptoms and signs of sepsis and a positive blood bacterial culture) and death. CLD was defi ned as a persistent oxygen requirement at 36 weeks postmenstrual age. A physiological test was used to confi rm the need for oxygen at the time when CLD was being diagnosed. Infants with moderate dependency on oxygen at 36 weeks postmenstrual age (<30% oxygen) were challenged with room air breathing to determine whether the supplemental oxygen was in fact needed. Patients who demonstrated ≥30% oxygen requirement and/or positive pressure at 36 weeks postmenstrual age (severe CLD) were treated by dexamethasone.

Statistical analysis According to our one-sided hypothesis, we calculated that a study group of at least 62 patients would be necessary for the study to be able to detect a difference of at least 25 percentage points in the closure rate between the oral ibuprofen and the intravenous ibuprofen groups, assuming a closure rate of 65% with intravenous ibuprofen, with a p value of 0.05 and a power of 80%.9 11 The data are presented as mean±SD, frequency or percentage. Paired-samples t test and independent-samples t test were used for continuous variables; the χ2 test was used for categorical variables. Logistic regression analysis was used to determine the effects of gestational age, preterm premature rupture of the membrane, the presence of early onset sepsis and the application route of the drug on the risk for a second course of the treatment.

RESULTS During the study period, 207 ELBW preterm infants of gestational age ≤28 weeks were admitted to our NICU. Twelve of the 92 ELBW preterm infants who had significant PDA were

excluded before enrollment (figure 1). The study randomly assigned 80 preterm infants using cards in sealed opaque envelopes. The entire study protocol was completed for 70 patients because of exclusions for various reasons (figure 1). Baseline characteristics were similar between the two groups in the fi rst 96 h (table 1). After the fi rst course of the treatment, the PDA closed in 30 (83.3%) of the patients assigned to the oral ibuprofen group versus 21 (61.7%) of those enrolled in the intravenous ibuprofen group (p=0.04). Six patients (16.6%) in the oral ibuprofen group required a second course of drug therapy, compared with 13 (38.2%) in the intravenous ibuprofen group after the fi rst evaluation (p=0.012). The mean gestational ages of patients who did not respond to the treatment did not differ between oral (26.4±1.1 weeks) and intravenous (26.3±1.2 weeks) groups (p=0.76). According to the results of a logistic regression analysis, only the application route of the drug was a risk factor for a second course of treatment (OR=3.2; 95% CI 1.06 to 9.8, p=0.04). Although the primary closure rate was marginally higher in the oral ibuprofen group, the need for a second course of ibuprofen during the whole hospitalisation was similar between groups: 11 of 36 in oral versus 15 of 34 in intravenous groups (p=0.24) because of a higher reopening rate in the oral group. The cumulative closure rates were high in both groups, and only one patient each in the oral (2.7%) and intravenous (2.9%) groups had surgical ligation. In the evaluation of renal tolerance, none of the patients had oliguria. Renal function test results before and after the fi rst and second courses of each drug did not differ significantly within or between the groups (table 2). There were decreases in the bilirubin level (5.2±2.7 to 4.4±1.7, p=0.03) in the fi rst course and in sodium level (133±5.8 to 130±7.2, p=0.01) in the second course of intravenous ibuprofen. Although CLD rates were similar, the only secondary outcome that was significantly different between the two groups was the need for postnatal steroid use for CLD (p=0.01, table 3)

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Original article Table 3

Safety outcomes and adverse events after oral and intravenous treatments Oral (n=36)

Duration of hospitalisation, mean±SD (days) Necrotising enterocolitis, n (%) Spontaneous intestinal perforation, n (%) Gastrointestinal bleeding, n (%) Sepsis, n (%) Duration n-CPAP, median (range) (days) Duration mechanical ventilatior, median (range) (days) Increase in the grade of intraventricular haemorrhage, n (%) Pneumothorax, n (%) Pulmonary haemorrhage, n (%) Pulmonary hypertension Chronic lung disease *, n (%) Postnatal steroid use for severe chronic lung disease, n (%) ROP required laser treatment†, n (%) Death, n (%)

73.7±24.2 2(5.6) – – 11(30.6) 5 (0–25) 2 (0–25) 5 (13.9) 2 (5.6) – – 17 (47.2) 8 (22.2) 5 (12.9) 2 (5.6)

IV (n=34) 79.6±21.4 3(8.8) 1 (2.9) – 17(50) 5 (0–30) 3 (0–25) 4 (11.8) 2 (5.9) 3 (8.8) – 19 (55.9) 17 (50) 6 (17.6) 1 (2.9)

p 0.28 0.59 0.30 – 0.09 0.64 0.09 0.79 0.95 0.07 – 0.46 0.01 0.64 0.58

*Patients with moderate (oxygen requirement<30%) to severe (oxygen requirement≥30% ±positive pressure support) chronic lung disease at postmenstrual 36th week or discharge, whichever comes first. †Patients with prethreshold type I ROP or progressed to threshold disease received laser photocoagulation treatment. n-CPAP, nasal continuous positive airway pressure; ROP, retinopathy of prematurity.

DISCUSSION Given the reduction in the side effects noted in meta-analysis, ibuprofen currently appears to be the drug of choice.4 However, the unavailability of intravenous ibuprofen in certain regions of world and the availability of inexpensive oral preparations have led to the off-label nasogastric administration of oral ibuprofen in preterm infants with PDA. 2 5–11 The evidence supporting the off-label use of oral ibuprofen for PDA in ELBW preterm infants was weak. Well-designed, appropriately powered pharmacological and controlled clinical studies were needed before the use of oral ibuprofen could be recommended.2 In two recent randomised controlled studies, oral ibuprofen was more effective than intravenous ibuprofen for ductal closure in very low birthweight (VLBW) preterm infants, but both studies consisted of only 10–25% of patients who were born ≤28 weeks’ gestation.9 11 On the other hand, although 29% of NICUs in Europe reported the use of oral ibuprofen for ductal closure, still there has been lack of sufficient data on its use in ELBW preterm infants.12 Being a pioneer one, our study was designed with sufficient power for determining whether oral and intravenous ibuprofen treatments are equally efficacious and safe in PDA closure. The results demonstrated that oral ibuprofen was more effective for the closure of PDA with one course of treatment. Slower absorbtion with oral ibuprofen than with intravenous ibuprofen, and the longer half-life probably prolong the time of contact with the ductus, leading to a higher response rate.13 14 In addition, the oral form was as safe as the intravenous form in terms of renal tolerance, hyperbilirubinaemia, gastrointestinal perforation or bleeding, NEC, intraventricular haemorrhage, CLD and pulmonary hypertension. The rates of closure in the intravenous and oral ibuprofen groups in our study were consistent with previously reported studies. 5–11 There are only two previous studies comparing oral and intravenous ibuprofen that enrolled VLBW preterm infants. Both of them demonstrated that the rate of ductal closure tended to be higher in the oral ibuprofen group.9 11 In addition to the study by Cherif et al,9 Gokmen et al11 increased the number of randomised infants and expanded the information about the safety and efficacy of oral ibuprofen in more mature VLBW infants. Now, this study expands our information F282

especially about the efficacy of oral ibuprofen in very preterm infants who are the major concern for PDA closure.15 16 Although renal failure at rates ranging from 6.8% to 57% has been reported with intravenous ibuprofen, similar to our study renal failure has not been reported in any study using oral ibuprofen. 5–11 17–19 Tiker et al20 and Erdeve et al21 reported anecdotal observations of transient renal impairment in VLBW infants given a complete course of oral ibuprofen, and both reported that the cases recovered on follow-up. Gokmen et al11 investigated renal tolerance in detail using cys-C levels to examine the adverse renal side effects with ibuprofen use. Although there was an increase in cys-C levels in the oral ibuprofen group, this increase was not high enough to be of importance. Since renal tolerability of ibuprofen on renal function in the neonate is a major argument in favour of its use in the treatment of PDA 22, this study expands our information about the safety and efficacy of oral ibuprofen in more immature ELBW infants. But depending on the power of the study on complications, we believe that renal function of infants receiving ibuprofen should be carefully monitored and drugs that are eliminated by glomerular fi ltration handled cautiously during this period.11 22 23 NEC, sepsis, pneumothorax, CLD and ROP were less common with oral ibuprofen than with intravenous delivery in ELBW infants, but the differences were not statistically significant. These data showed similarity with the results obtained from VLBW preterm infants. 5–11 The major gastrointestinal concerns about the oral route are gastrointestinal bleeding, NEC and bowel perforation. 5–11 24 Only one patient in intravenous group developed spontaneous intestinal perforation (SIP), and there were no significant differences in the other side effects between the treatment groups. The rates of NEC reported with intravenous ibuprofen vary from 4.5% to 17%. 5–11 In this study, NEC occurred in 8.8% of the intravenous group and in 5.6% of the oral group. In a retrospective review of 102 preterm infants who were treated by intravenous ibuprofen, Rao et al25 demonstrated that 8.8% of preterm infants developed SIP. The authors concluded that infants at lower gestational age were at risk of SIP when treated early with intravenous ibuprofen for symptomatic PDA. Tatli et al24 reported two cases of SIP after oral ibuprofen treatment for PDA in two preterm infants,

Arch Dis Child Fetal Neonatal Ed 2012;97:F279–F283. doi:10.1136/archdischild-2011-300532

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Original article but they did not state the osmolality and pH of the suspension used. In published, randomised clinical trials, no case of gastrointestinal bleeding has been reported with intravenous ibuprofen. In a pool of 151 patients treated with oral ibuprofen, gastrointestinal bleeding was reported in 19 cases (12.6%). 5–10 A recent meta-analysis reported that oral ibuprofen for the prevention of PDA in preterm and/or low birthweight infants showed an increased risk of gastrointestinal bleeding. 26 In this study, gastrointestinal bleeding did not develop in both ibuprofen groups. We suggest that gastrointestinal irritation may be due to the method of administration of the oral drug. Essentially, almost all patients with defi ned PDA were medically treated. Requirement of surgical ligation was present for only one patient in each groups. Richards et al27 reported that a second course of intravenous ibuprofen may be effective in closing PDA in even the most preterm infant. On the other hand, Tefft 28 reported that the incidence of PDA ligation among VLBW infants decreased after adoption of an early ibuprofen treatment protocol. In combination with previous studies, the efficacy of ibuprofen in our study group suggests that ibuprofen has potential in decreasing the rate of surgical ligation even in ELBW preterm infants. Although CLD rates did not show differences in both groups, the need for steroid treatment at postmenstrual 36th week was lower in oral ibuprofen groups. This demonstrates the effect of the oral ibuprofen on the severity of CLD. It was demonstrated that ibuprofen-induced ductal closure improved pulmonary mechanics and increased alveolar surface area in animal models compared with persistent PDA. 29 Shorter durations of respiratory support depending on the higher ductal closure rate in the fi rst course of oral ibuprofen may also have affected pulmonary mechanics in our group. There is still a need for investigation for whether prophylactic and/or symptomatic PDA therapy will cause substantial improvement in outcomes such as CLD. Our study had few limitations. First, the intervention was not completely blinded. No attempt to blind treatment intervention by giving an oral placebo to the intravenous ibuprofen group and an intravenous placebo to the oral ibuprofen group was made. Caretakers were therefore not blinded to the intervention, and this might have made an effect towards the overestimation of the treatment effect. However, the most important outcome – PDA closure or not – was made by a cardiologist who was blinded to the treatment groups. Second, safety parameters should have been defi ned more clearly before the study started to prevent overestimation in evaluation. Third, we did not investigate the possible side effects of preservatives such as sodium benzoate used in the oral ibuprofen in preterm infants. However, although oral ibuprofen is used commonly in some parts of the world, no harm has been reported related to sodium benzoate in newborns.

CONCLUSION This study is the fi rst one comparing oral ibuprofen versus intravenous ibuprofen in immature preterm infants. Oral ibuprofen seems to be a safe alternative for the closure of PDA in ELBW preterm infants with additional potential effect on the severity of CLD. Future studies should be designed to explore the effects on improvements in CLD in addition to the bioavailability related to oral formulation in this patient group. Acknowledgements The authors thank F Emre Canpolat for his help in the statistical analysis.

Ethics approval Zekai Tahir Burak Local Ethics Committee. Provenanace and peer review Not commissioned; externally peer reviewed.

REFERENCES 1.

2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29.

Competing interests None. Arch Dis Child Fetal Neonatal Ed 2012;97:F279–F283. doi:10.1136/archdischild-2011-300532

Noori S. Patent ductus arteriosus in the preterm infant: to treat or not to treat? J Perinatol 2010;30:S31–7. Gouyon JB, Kibleur Y. Efficacy and tolerability of enteral formulations of ibuprofen in the treatment of patent ductus arteriosus in preterm infants. Clin Ther 2010;32:1740–8. Hermes-De Santis ER, Clymann RI. Patent ductus arteriosus: pathophysiology and management. J Perinatol 2006;26:14–18. Ohlsson A, Walia R, Shah SS. Ibuprofen for the treatment of patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database Syst Rev 2010;4:CD003481. Heyman E, Morag I, Batash D, et al. Closure of patent ductus arteriosus with oral ibuprofen suspension in premature newborns: a pilot study. Pediatrics 2003;112:e354. Cherif A, Jabnoun S, Khrouf N. Oral ibuprofen in early curative closure of patent ductus arteriosus in very premature infants. Am J Perinatol 2007;24:339–45. Aly H, Lotfy W, Badrawi N, et al. Oral Ibuprofen and ductus arteriosus in premature infants: a randomized pilot study. Am J Perinatol 2007;24:267–70. Lee SJ, KimJY, Park EA, et al. The pharmacological treatment of patent ductus arteriosus in premature infants with respiratory distress syndrome: oral ibuprofen vs. indomethacin. Korean J Pediatr 2008;9:956–63. Cherif A, Khrouf N, Jabnoun S, et al. Randomized pilot study comparing oral ibuprofen with intravenous ibuprofen in very low birth weight infants with patent ductus arteriosus. Pediatrics 2008;122:e1256–61. Erdeve O, Gokmen T, Altug N, et al. Oral versus intravenous ibuprofen: which is better in closure of patent ductus arteriosus? Pediatrics 2009;123:e763. Gokmen T, Erdeve O, Altug N, et al. Efficacy and safety of oral versus intravenous ibuprofen in very low birth weight preterm infants with patent ductus arteriosus. J Pediatr 2011;158:549–554.e1. Guimarães H, Rocha G, Tomé T, et al. Non-steroid anti-inflammatory drugs in the treatment of patent ductus arteriosus in European newborns. J Matern Fetal Neonatal Med 2009;22 (Suppl 3):77–80. Raju NV, Bharadwaj RA, Thomas R, et al. Ibuprofen use to reduce the incidence and severity of bronchopulmonary dysplasia: a pilot study. J Perinatol 2000;20:13–16. Sharma PK, Garg SK, Narang A. Pharmacokinetics of oral ibuprofen in premature infants. J Clin Pharmacol 2003;43:968–73. Nemerofsky SL, Parravicini E, Bateman D, et al. The ductus arteriosus rarely requires treatment in infants >1000 grams. Am J Perinatol 2008;25:661–6. Koch J, Hensley G, Roy L, et al. Prevalence of spontaneous closure of the ductus arteriosus in neonates at a birth weight of 1000 grams or less. Pediatrics 2006;117:1113–21. Van Overmeire B, Smets K, Lecoutere D, et al. A comparison of ibuprofen and indomethacin for closure of patent ductus arteriosus. N Engl J Med 2000;343:674–81. Varvarigou A, Bardin CL, Beharry K, et al. Early ibuprofen administration to prevent patent ductus arteriosus in premature newborn infants. JAMA 1996;275:539–44. De Carolis MP, Romagnoli C, Polimeni V, et al. Prophylactic ibuprofen therapy of patent ductus arteriosus in preterm infants. Eur J Pediatr 2000;159:364–8. Tiker F, Yildirim SV. Acute renal impairment after oral ibuprofen for medical closure of patent ductus arteriosus. Indian Pediatr 2007;44:54–5. Erdeve O, Sarici SU, Sari E, et al. Oral-ibuprofen-induced acute renal failure in a preterm infant. Pediatr Nephrol 2008;23:1565–7. Fanos V, Antonucci R, Zaffanello M. Ibuprofen and acute kidney injury in the newborn. Turk J Pediatr 2010;52:231–8. Vieux R, Desandes R, Boubred F, et al. Ibuprofen in very preterm infants impairs renal function for the first month of life. Pediatr Nephrol 2010;25:267–74. Tatli MM, Kumral A, Duman N, et al. Spontaneous intestinal perforation after oral ibuprofen treatment of patent ductus arteriosus in two very-low birth weight infants. Acta Paediatr 2004;93:999–1001. Rao R, Bryowsky K, Mao J, et al. Gastrointestinal complications associated with ibuprofen therapy for patent ductus arteriosus. J Perinatol 2011;31:465–70. Ohlsson A, Shah SS. Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database Syst Rev 2011;7:CD004213. Richards J, Johnson A, Fox G, et al. A second course of ibuprofen is effective in the closure of a clinically significant PDA in ELBW infants. Pediatrics 2009;124:e287–93. Tefft RG. The impact of an early ibuprofen treatment protocol on the incidence of surgical ligation of the ductus arteriosus. Am J Perinatol 2010;27:83–90. Waleh N, McCurnin DC, Yoder BA, et al. Patent ductus arteriosus ligation alters pulmonary gene expression in preterm baboons. Pediatr Res 2011;69:212–16.

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Oral versus intravenous ibuprofen for patent ductus arteriosus closure: a randomised controlled trial in extremely low birthweight infants Omer Erdeve, Sadik Yurttutan, Nahide Altug, et al. Arch Dis Child Fetal Neonatal Ed 2012 97: F279-F283 originally published online December 5, 2011

doi: 10.1136/archdischild-2011-300532

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