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In a Resource-Limited Setting, Is Oral Ibuprofen Effective for Closure of a Patent Ductus Arteriosus in a Preterm Neonate?

In a Resource-Limited Setting, Is Oral Ibuprofen Effective for Closure of a Patent Ductus... SCENARIO You are a paediatric resident working in the neonatal unit of a referral hospital in Rwanda, East Africa. During your morning round, you see an infant weighing 1.2 kg and of 28 weeks’ gestation, who is now 7 days old. On examination, there is a loud machinery murmur heard over the precordium in association with easy-to-feel, bounding, femoral pulses. There is no cyanosis, and saturations are within normal limits. You diagnose a patent ductus arteriosus (PDA). Echocardiography is not available. On reviewing the patient records, you note that these clinical findings have been present for 2 days and that the previous team has restricted fluid intake for this infant. Within the past 48 h, the infant has developed signs of respiratory distress with increased respiratory rate and recessions. A plain chest radiograph has ruled out respiratory infection. You therefore consider treating the PDA. Owing to supply chain problems, you frequently do not have access to intravenous (IV) indomethacin or ibuprofen. These medicines are also financially burdensome for the families you treat. Surgical closure of PDA is not available. WHAT IS ALREADY KNOWN? In the foetus, the ductus arteriosus connects the aorta and pulmonary artery allowing the majority of the right ventricular output to bypass the lungs. The ductus normally closes in the first few days of life, but in preterm infants, this may be delayed with risk of PDA being inversely proportional to gestational age. A PDA is defined as such if the ductus does not close by 72 h of life [1]. PDA is a common problem in small preterm infants with 65 and 25% of infants weighing <1000 g and 1000–1500 g having a PDA, respectively, of which current trends suggest 85 and 70% requiring treatment, respectively [1]; this is currently the question of a large multicentre trial [2]. In many infants, the natural evolution of PDA is a spontaneous closure. This is more likely if PDA is ≤1.55 mm in diameter or in more mature infants (>1000 g or >28 weeks of gestation) [2]. There are many clinical sequelae of a PDA, including chronic lung disease, pulmonary haemorrhage, renal hypo-perfusion, necrotizing enterocolitis (NEC), intraventricular haemorrhage (IVH) and mortality [2, 3]. PDA is diagnosed clinically but, where available, may be confirmed with an echocardiogram, which also allows for an assessment of the size of the PDA as well as excluding pulmonary hypertension or a duct dependent congenital heart defect. Treatment of a PDA is initially conservative with fluid restriction. One of the challenges of fluid restriction is maintaining adequate nutrition [4]. This is especially pertinent in resource-limited settings, where total parental nutrition is usually not available. Diuretics are also occasionally used. Indomethacin is used as staRepodard therapy to close a PDA but is associated with reduced blood flow to several organs. Cyclooxygenase (COX) inhibitors such as ibuprofen or indomethacin are frequently used as standard medical therapy but can be associated with their own complications, reduced renal function, NEC, etc. [4, 5]. Contraindications to COX inhibitors include reduced renal function, oliguria, thrombocytopenia, bleeding or coagulopathy, NEC, marked unconjugated hyperbilirubinemia, a duct-dependent cardiac lesion and infection [6]. Ibuprofen is typically given in IV form. However, in the resource-limited setting, the IV preparation is expensive and/or unavailable, and therefore, oral ibuprofen could be advantageous. STRUCTURED CLINICAL QUESTION In a preterm newborn with a PDA in a resource-limited setting (patient), is oral ibuprofen (intervention) as effective (non-inferior) as IV/oral indomethacin or IV ibuprofen (controls) for PDA closure (primary outcome) and safety profile (secondary outcome)? OPTIMAL STUDY DESIGN In this question, we are interested to know if there is ‘non-inferiority’ between two treatment options (i.e. they have similar action and effectiveness). The comparison is between an established treatment (indomethacin) and an alternative (oral ibuprofen). An equivalence or non-inferiority study could be used to answer this question [7]. FULL SEARCH DESCRIPTION A literature search was performed (18 September 2017) using the search terms described (see Table 1). We excluded papers not published in the languages of the authors (English and French) along with papers measuring surrogate markers (e.g. cerebral blood flow). We searched the databases PubMed and Cochrane, and this revealed 16 and 4 results, respectively, of which 3 and 2 were relevant. The ‘developing country’ search string was removed and this revealed 227 and 95 results, respectively, of which 19 and 11 were relevant. A search of the reference lists of the relevant papers was performed and found a further six relevant papers. Three papers [1, 5, 8] were systematic reviews including a Cochrane systematic review (SR) [5]. Neuman’s SR [8] was superseded and therefore excluded. Looma [1] and Ohlsson [5] were both included, as they described syntheses of different papers and different subgroups. Articles included in these syntheses were removed from our appraisal table. Once duplicates were removed, six relevant papers have been reviewed here (see Table 2). Table 1 Search terms (italics if MeSH) (Ductus arteriosus, patent OR patent ductus OR ductus arteriosus OR PDA) AND (Ibuprofen OR brufen) AND (Indomethacin OR indometacin) AND (Developing countries OR developing country OR countries, developing OR nations, developing OR developing nations OR poverty OR resource poor country OR low-income country OR low-income country OR resource poor country OR Global health OR third word OR India OR Africa OR Asia OR South America OR Papua New Guinea OR Asia-Pacific) (Ductus arteriosus, patent OR patent ductus OR ductus arteriosus OR PDA) AND (Ibuprofen OR brufen) AND (Indomethacin OR indometacin) AND (Developing countries OR developing country OR countries, developing OR nations, developing OR developing nations OR poverty OR resource poor country OR low-income country OR low-income country OR resource poor country OR Global health OR third word OR India OR Africa OR Asia OR South America OR Papua New Guinea OR Asia-Pacific) Table 1 Search terms (italics if MeSH) (Ductus arteriosus, patent OR patent ductus OR ductus arteriosus OR PDA) AND (Ibuprofen OR brufen) AND (Indomethacin OR indometacin) AND (Developing countries OR developing country OR countries, developing OR nations, developing OR developing nations OR poverty OR resource poor country OR low-income country OR low-income country OR resource poor country OR Global health OR third word OR India OR Africa OR Asia OR South America OR Papua New Guinea OR Asia-Pacific) (Ductus arteriosus, patent OR patent ductus OR ductus arteriosus OR PDA) AND (Ibuprofen OR brufen) AND (Indomethacin OR indometacin) AND (Developing countries OR developing country OR countries, developing OR nations, developing OR developing nations OR poverty OR resource poor country OR low-income country OR low-income country OR resource poor country OR Global health OR third word OR India OR Africa OR Asia OR South America OR Papua New Guinea OR Asia-Pacific) Table 2 Evidence summary table Author, date, citation, country (economy) Study type (Oxford CEBM level of evidence) [22] Study group population and comparisons Key outcomes Key result Appraisal comments Olgun, 2017 [23] Turkey (UMIE) Single-centre, non-controlled, retrospective PDA in 134 of 576 infants. In total, 100 given repeated oral ibuprofen Effectiveness (PDA closure): Course 1: 67/94 (71.3%) Course 2: 11/27 (40.7%) Course 3: 5/14 (35.7%) The cumulative closure rate was 71% (Course 1), 83% (Course 2) and 88% (Course 3) (Cochran’s Q = 25.1, p <0.001) Retrospective, non-controlled study giving no data on if ibuprofen is superior to other therapeutic options Safety: Three (3%) infants experience thrombocytopenia, renal dysfunction or both during the first course Gulack, 2015 [12] USA (HIE) Multi-centre (165 units), retrospective cohort study. Data extracted from a prospectively collected patient database (Level 2b) Ibuprofen (N = 1177) vs. indomethacin (N = 5172)No description of whether IV or oral preparations Effectiveness: (OR < 1.0 favours ibuprofen) Multivariable logistic regression adjusted analysis: Closure rate: No data Surgical ligation: OR = 1.10 (0.87, 1.37) Not included in the Loomba or Ohlsson systematic reviews Clear description of study cohort Power analysis included (5400 infants to give 80% power for 3.75% absolute difference) Patient’s identified by treatment with ibuprofen/indomethacin, rather than as having PDA diagnosis No access to echocardiographic data to give initial size of PDA or to confirm PDA closure Safety: Multivariable logistic regression adjusted analysis: Death before discharge: OR = 1.10 (CI: 0.82 to 1.47) Rise in creatinine: OR = 1.16 (0.87 to 1.54) Loomba, 2015 [1] SR of mixed nations and economies (LMIE = 1, UMIE = 2, HIE = 5) SR with MA of 22 papers (n = 1583) (Level 1a-) Sub-analysis of six papers [11, 24–28] comparing oral ibuprofen (n = 193) vs. IV indomethacin (n = 219) Effectiveness: (OR < 1.0 favours oral ibuprofen) Significant heterogeneity was not present (chi-squared = 0.76, p = 0.51, I2 = 0%) Closure rate: OR = 0.76 (CI: 0.50−1.18) Surgical ligation: OR = 0.78 (CI: 0.45−1.37) Cochrane Handbook for SR of Interventions was used for quality evaluation Bias was assessed using the Cochrane Risk of Bias Tool Publication bias was assessed qualitatively using forest plots for endpoints with 10 or more studies included Heterogeneity between studies was identified using chi-square and I2 tests Safety: NEC: OR = 0.60 (CI: 0.30−1.24) Gastrointestinal bleeding: OR = 0.62 (CI: 0.31−1.27) Bronchopulmonary dysplasia: OR = 0.80 (CI: 0.47−1.36) Change in serum creatinine (mean difference −0.03, CI: −0.11−0.05) Sub-analysis of two papers [10, 29] comparing oral ibuprofen (n = 58) vs. oral (n = 45) indomethacin Effectiveness: Heterogeneity was not present (chi-squared = 0.45, p = 0.50, I2 = 0%) Closure rate: OR 0.90 (CI: 0.40 to 2.00). Safety: Change in serum creatinine favouring ibuprofen: mean difference −0.10 (CI−0.13 to−0.07) Ohlsson, 2015 [5] SR of mixed nations and economies (LMIE = 2, UMIE = 9, HIE = 1) Cochrane SR with MA (Level 1a-) of 33 studies (n = 2190) Planned subgroup analysis of eight studies [10, 24, 28–33] comparing oral ibuprofen (n = 145) vs. IV or oral indomethacin (n = 127) Effectiveness: (RR < 1.0 favours oral ibuprofen) Closure failure: RR = 0.96 (CI: 0.73−1.27) Surgical closure: RR = 0.93 (CI: 0.50−1.74) Well-designed systematic review Only randomized or quasi-randomized controlled trials included Subgroup analysis was planned No subgroup analysis regarding resource poor environments A single paper was described looking at ‘early’ or ‘expectant’ management of a PDA. This found no statistically significant difference between the early vs. the expectant group for mortality or CLD at 36 weeks [24] Safety: Mortality: −0.10 (CI−0.20 to 0.00) NEC: RR = 0.41 (CI 0.23−0.73) Plasma creatinine: mean difference −0.51 (CI: −6.04, 5.01) IVH: RR = 0.90 (CI: 0.45−1.83) Intestinal perforation: RR = 0.24 (CI: 0.03−1.95) Gastrointestinal bleed: RR = 2.80 (CI: 0.48−16.45) Oliguria: RR = 0.0 (CI: −0.10 to 0.10) Planned subgroup analysis of four studies [35–38] comparing oral ibuprofen (n = 156) compared with IV ibuprofen (n = 148) Effectiveness Closure failure: RR = 0.41 (CI: 0.27−0.64)Surgical closure: RR = 0.35 (CI: 0.1−1.17) Safety NEC: RR = 0.86 (CI: 0.35−2.15) Intestinal perforation: RR = 0.32 (CI: 0.01−7.48) Gastrointestinal bleed: RR = 2.89 (0.12−69.24) Plasma creatinine: mean difference −22.47 (CI: −32.40 to−12.53) Oliguria: RR = 0.14 (CI: 0.01−2.66) Cheriff, 2007 [39] UMIE Non-controlled pilot study (Level 4) Oral ibuprofen (n = 40). No comparison group Effectiveness Ductal closure in 38/40 (95%) of infants. Surgical closure in 1/40 (2.5%) A small pilot study No control group Safety NEC: 3/40 (7.5%) Gastrointestinal bleed: 2/40 (5%) Renal impairment: 0/40 Tatli, 2004 [13] Turkey (UMIE) Case report (Level 4) Two infants Safety Both newborns had sudden abdominal distension without prodromal and radiological findings of NEC Small case series with a significant complication Heyman, 2003 [40] Israel (HIE) Non-controlled pilot study (Level 4) Oral ibuprofen (n = 22). No comparison group Effectiveness Ductal closure in 21/22 (96%) of infants. No reopening of the ductus after closure had been achieved A small pilot study to identify dosing regimen Good inclusion criteria described for external validity Good description of neonatal care Safety No difference in serum creatinine pre- and post-treatment Author, date, citation, country (economy) Study type (Oxford CEBM level of evidence) [22] Study group population and comparisons Key outcomes Key result Appraisal comments Olgun, 2017 [23] Turkey (UMIE) Single-centre, non-controlled, retrospective PDA in 134 of 576 infants. In total, 100 given repeated oral ibuprofen Effectiveness (PDA closure): Course 1: 67/94 (71.3%) Course 2: 11/27 (40.7%) Course 3: 5/14 (35.7%) The cumulative closure rate was 71% (Course 1), 83% (Course 2) and 88% (Course 3) (Cochran’s Q = 25.1, p <0.001) Retrospective, non-controlled study giving no data on if ibuprofen is superior to other therapeutic options Safety: Three (3%) infants experience thrombocytopenia, renal dysfunction or both during the first course Gulack, 2015 [12] USA (HIE) Multi-centre (165 units), retrospective cohort study. Data extracted from a prospectively collected patient database (Level 2b) Ibuprofen (N = 1177) vs. indomethacin (N = 5172)No description of whether IV or oral preparations Effectiveness: (OR < 1.0 favours ibuprofen) Multivariable logistic regression adjusted analysis: Closure rate: No data Surgical ligation: OR = 1.10 (0.87, 1.37) Not included in the Loomba or Ohlsson systematic reviews Clear description of study cohort Power analysis included (5400 infants to give 80% power for 3.75% absolute difference) Patient’s identified by treatment with ibuprofen/indomethacin, rather than as having PDA diagnosis No access to echocardiographic data to give initial size of PDA or to confirm PDA closure Safety: Multivariable logistic regression adjusted analysis: Death before discharge: OR = 1.10 (CI: 0.82 to 1.47) Rise in creatinine: OR = 1.16 (0.87 to 1.54) Loomba, 2015 [1] SR of mixed nations and economies (LMIE = 1, UMIE = 2, HIE = 5) SR with MA of 22 papers (n = 1583) (Level 1a-) Sub-analysis of six papers [11, 24–28] comparing oral ibuprofen (n = 193) vs. IV indomethacin (n = 219) Effectiveness: (OR < 1.0 favours oral ibuprofen) Significant heterogeneity was not present (chi-squared = 0.76, p = 0.51, I2 = 0%) Closure rate: OR = 0.76 (CI: 0.50−1.18) Surgical ligation: OR = 0.78 (CI: 0.45−1.37) Cochrane Handbook for SR of Interventions was used for quality evaluation Bias was assessed using the Cochrane Risk of Bias Tool Publication bias was assessed qualitatively using forest plots for endpoints with 10 or more studies included Heterogeneity between studies was identified using chi-square and I2 tests Safety: NEC: OR = 0.60 (CI: 0.30−1.24) Gastrointestinal bleeding: OR = 0.62 (CI: 0.31−1.27) Bronchopulmonary dysplasia: OR = 0.80 (CI: 0.47−1.36) Change in serum creatinine (mean difference −0.03, CI: −0.11−0.05) Sub-analysis of two papers [10, 29] comparing oral ibuprofen (n = 58) vs. oral (n = 45) indomethacin Effectiveness: Heterogeneity was not present (chi-squared = 0.45, p = 0.50, I2 = 0%) Closure rate: OR 0.90 (CI: 0.40 to 2.00). Safety: Change in serum creatinine favouring ibuprofen: mean difference −0.10 (CI−0.13 to−0.07) Ohlsson, 2015 [5] SR of mixed nations and economies (LMIE = 2, UMIE = 9, HIE = 1) Cochrane SR with MA (Level 1a-) of 33 studies (n = 2190) Planned subgroup analysis of eight studies [10, 24, 28–33] comparing oral ibuprofen (n = 145) vs. IV or oral indomethacin (n = 127) Effectiveness: (RR < 1.0 favours oral ibuprofen) Closure failure: RR = 0.96 (CI: 0.73−1.27) Surgical closure: RR = 0.93 (CI: 0.50−1.74) Well-designed systematic review Only randomized or quasi-randomized controlled trials included Subgroup analysis was planned No subgroup analysis regarding resource poor environments A single paper was described looking at ‘early’ or ‘expectant’ management of a PDA. This found no statistically significant difference between the early vs. the expectant group for mortality or CLD at 36 weeks [24] Safety: Mortality: −0.10 (CI−0.20 to 0.00) NEC: RR = 0.41 (CI 0.23−0.73) Plasma creatinine: mean difference −0.51 (CI: −6.04, 5.01) IVH: RR = 0.90 (CI: 0.45−1.83) Intestinal perforation: RR = 0.24 (CI: 0.03−1.95) Gastrointestinal bleed: RR = 2.80 (CI: 0.48−16.45) Oliguria: RR = 0.0 (CI: −0.10 to 0.10) Planned subgroup analysis of four studies [35–38] comparing oral ibuprofen (n = 156) compared with IV ibuprofen (n = 148) Effectiveness Closure failure: RR = 0.41 (CI: 0.27−0.64)Surgical closure: RR = 0.35 (CI: 0.1−1.17) Safety NEC: RR = 0.86 (CI: 0.35−2.15) Intestinal perforation: RR = 0.32 (CI: 0.01−7.48) Gastrointestinal bleed: RR = 2.89 (0.12−69.24) Plasma creatinine: mean difference −22.47 (CI: −32.40 to−12.53) Oliguria: RR = 0.14 (CI: 0.01−2.66) Cheriff, 2007 [39] UMIE Non-controlled pilot study (Level 4) Oral ibuprofen (n = 40). No comparison group Effectiveness Ductal closure in 38/40 (95%) of infants. Surgical closure in 1/40 (2.5%) A small pilot study No control group Safety NEC: 3/40 (7.5%) Gastrointestinal bleed: 2/40 (5%) Renal impairment: 0/40 Tatli, 2004 [13] Turkey (UMIE) Case report (Level 4) Two infants Safety Both newborns had sudden abdominal distension without prodromal and radiological findings of NEC Small case series with a significant complication Heyman, 2003 [40] Israel (HIE) Non-controlled pilot study (Level 4) Oral ibuprofen (n = 22). No comparison group Effectiveness Ductal closure in 21/22 (96%) of infants. No reopening of the ductus after closure had been achieved A small pilot study to identify dosing regimen Good inclusion criteria described for external validity Good description of neonatal care Safety No difference in serum creatinine pre- and post-treatment Note: Income Group (World Bank) [41]: low-income economy (LIE), lower-middle-income economy (LMIE), upper-middle-income economy (UMIE), high-income economy (HIE). Table 2 Evidence summary table Author, date, citation, country (economy) Study type (Oxford CEBM level of evidence) [22] Study group population and comparisons Key outcomes Key result Appraisal comments Olgun, 2017 [23] Turkey (UMIE) Single-centre, non-controlled, retrospective PDA in 134 of 576 infants. In total, 100 given repeated oral ibuprofen Effectiveness (PDA closure): Course 1: 67/94 (71.3%) Course 2: 11/27 (40.7%) Course 3: 5/14 (35.7%) The cumulative closure rate was 71% (Course 1), 83% (Course 2) and 88% (Course 3) (Cochran’s Q = 25.1, p <0.001) Retrospective, non-controlled study giving no data on if ibuprofen is superior to other therapeutic options Safety: Three (3%) infants experience thrombocytopenia, renal dysfunction or both during the first course Gulack, 2015 [12] USA (HIE) Multi-centre (165 units), retrospective cohort study. Data extracted from a prospectively collected patient database (Level 2b) Ibuprofen (N = 1177) vs. indomethacin (N = 5172)No description of whether IV or oral preparations Effectiveness: (OR < 1.0 favours ibuprofen) Multivariable logistic regression adjusted analysis: Closure rate: No data Surgical ligation: OR = 1.10 (0.87, 1.37) Not included in the Loomba or Ohlsson systematic reviews Clear description of study cohort Power analysis included (5400 infants to give 80% power for 3.75% absolute difference) Patient’s identified by treatment with ibuprofen/indomethacin, rather than as having PDA diagnosis No access to echocardiographic data to give initial size of PDA or to confirm PDA closure Safety: Multivariable logistic regression adjusted analysis: Death before discharge: OR = 1.10 (CI: 0.82 to 1.47) Rise in creatinine: OR = 1.16 (0.87 to 1.54) Loomba, 2015 [1] SR of mixed nations and economies (LMIE = 1, UMIE = 2, HIE = 5) SR with MA of 22 papers (n = 1583) (Level 1a-) Sub-analysis of six papers [11, 24–28] comparing oral ibuprofen (n = 193) vs. IV indomethacin (n = 219) Effectiveness: (OR < 1.0 favours oral ibuprofen) Significant heterogeneity was not present (chi-squared = 0.76, p = 0.51, I2 = 0%) Closure rate: OR = 0.76 (CI: 0.50−1.18) Surgical ligation: OR = 0.78 (CI: 0.45−1.37) Cochrane Handbook for SR of Interventions was used for quality evaluation Bias was assessed using the Cochrane Risk of Bias Tool Publication bias was assessed qualitatively using forest plots for endpoints with 10 or more studies included Heterogeneity between studies was identified using chi-square and I2 tests Safety: NEC: OR = 0.60 (CI: 0.30−1.24) Gastrointestinal bleeding: OR = 0.62 (CI: 0.31−1.27) Bronchopulmonary dysplasia: OR = 0.80 (CI: 0.47−1.36) Change in serum creatinine (mean difference −0.03, CI: −0.11−0.05) Sub-analysis of two papers [10, 29] comparing oral ibuprofen (n = 58) vs. oral (n = 45) indomethacin Effectiveness: Heterogeneity was not present (chi-squared = 0.45, p = 0.50, I2 = 0%) Closure rate: OR 0.90 (CI: 0.40 to 2.00). Safety: Change in serum creatinine favouring ibuprofen: mean difference −0.10 (CI−0.13 to−0.07) Ohlsson, 2015 [5] SR of mixed nations and economies (LMIE = 2, UMIE = 9, HIE = 1) Cochrane SR with MA (Level 1a-) of 33 studies (n = 2190) Planned subgroup analysis of eight studies [10, 24, 28–33] comparing oral ibuprofen (n = 145) vs. IV or oral indomethacin (n = 127) Effectiveness: (RR < 1.0 favours oral ibuprofen) Closure failure: RR = 0.96 (CI: 0.73−1.27) Surgical closure: RR = 0.93 (CI: 0.50−1.74) Well-designed systematic review Only randomized or quasi-randomized controlled trials included Subgroup analysis was planned No subgroup analysis regarding resource poor environments A single paper was described looking at ‘early’ or ‘expectant’ management of a PDA. This found no statistically significant difference between the early vs. the expectant group for mortality or CLD at 36 weeks [24] Safety: Mortality: −0.10 (CI−0.20 to 0.00) NEC: RR = 0.41 (CI 0.23−0.73) Plasma creatinine: mean difference −0.51 (CI: −6.04, 5.01) IVH: RR = 0.90 (CI: 0.45−1.83) Intestinal perforation: RR = 0.24 (CI: 0.03−1.95) Gastrointestinal bleed: RR = 2.80 (CI: 0.48−16.45) Oliguria: RR = 0.0 (CI: −0.10 to 0.10) Planned subgroup analysis of four studies [35–38] comparing oral ibuprofen (n = 156) compared with IV ibuprofen (n = 148) Effectiveness Closure failure: RR = 0.41 (CI: 0.27−0.64)Surgical closure: RR = 0.35 (CI: 0.1−1.17) Safety NEC: RR = 0.86 (CI: 0.35−2.15) Intestinal perforation: RR = 0.32 (CI: 0.01−7.48) Gastrointestinal bleed: RR = 2.89 (0.12−69.24) Plasma creatinine: mean difference −22.47 (CI: −32.40 to−12.53) Oliguria: RR = 0.14 (CI: 0.01−2.66) Cheriff, 2007 [39] UMIE Non-controlled pilot study (Level 4) Oral ibuprofen (n = 40). No comparison group Effectiveness Ductal closure in 38/40 (95%) of infants. Surgical closure in 1/40 (2.5%) A small pilot study No control group Safety NEC: 3/40 (7.5%) Gastrointestinal bleed: 2/40 (5%) Renal impairment: 0/40 Tatli, 2004 [13] Turkey (UMIE) Case report (Level 4) Two infants Safety Both newborns had sudden abdominal distension without prodromal and radiological findings of NEC Small case series with a significant complication Heyman, 2003 [40] Israel (HIE) Non-controlled pilot study (Level 4) Oral ibuprofen (n = 22). No comparison group Effectiveness Ductal closure in 21/22 (96%) of infants. No reopening of the ductus after closure had been achieved A small pilot study to identify dosing regimen Good inclusion criteria described for external validity Good description of neonatal care Safety No difference in serum creatinine pre- and post-treatment Author, date, citation, country (economy) Study type (Oxford CEBM level of evidence) [22] Study group population and comparisons Key outcomes Key result Appraisal comments Olgun, 2017 [23] Turkey (UMIE) Single-centre, non-controlled, retrospective PDA in 134 of 576 infants. In total, 100 given repeated oral ibuprofen Effectiveness (PDA closure): Course 1: 67/94 (71.3%) Course 2: 11/27 (40.7%) Course 3: 5/14 (35.7%) The cumulative closure rate was 71% (Course 1), 83% (Course 2) and 88% (Course 3) (Cochran’s Q = 25.1, p <0.001) Retrospective, non-controlled study giving no data on if ibuprofen is superior to other therapeutic options Safety: Three (3%) infants experience thrombocytopenia, renal dysfunction or both during the first course Gulack, 2015 [12] USA (HIE) Multi-centre (165 units), retrospective cohort study. Data extracted from a prospectively collected patient database (Level 2b) Ibuprofen (N = 1177) vs. indomethacin (N = 5172)No description of whether IV or oral preparations Effectiveness: (OR < 1.0 favours ibuprofen) Multivariable logistic regression adjusted analysis: Closure rate: No data Surgical ligation: OR = 1.10 (0.87, 1.37) Not included in the Loomba or Ohlsson systematic reviews Clear description of study cohort Power analysis included (5400 infants to give 80% power for 3.75% absolute difference) Patient’s identified by treatment with ibuprofen/indomethacin, rather than as having PDA diagnosis No access to echocardiographic data to give initial size of PDA or to confirm PDA closure Safety: Multivariable logistic regression adjusted analysis: Death before discharge: OR = 1.10 (CI: 0.82 to 1.47) Rise in creatinine: OR = 1.16 (0.87 to 1.54) Loomba, 2015 [1] SR of mixed nations and economies (LMIE = 1, UMIE = 2, HIE = 5) SR with MA of 22 papers (n = 1583) (Level 1a-) Sub-analysis of six papers [11, 24–28] comparing oral ibuprofen (n = 193) vs. IV indomethacin (n = 219) Effectiveness: (OR < 1.0 favours oral ibuprofen) Significant heterogeneity was not present (chi-squared = 0.76, p = 0.51, I2 = 0%) Closure rate: OR = 0.76 (CI: 0.50−1.18) Surgical ligation: OR = 0.78 (CI: 0.45−1.37) Cochrane Handbook for SR of Interventions was used for quality evaluation Bias was assessed using the Cochrane Risk of Bias Tool Publication bias was assessed qualitatively using forest plots for endpoints with 10 or more studies included Heterogeneity between studies was identified using chi-square and I2 tests Safety: NEC: OR = 0.60 (CI: 0.30−1.24) Gastrointestinal bleeding: OR = 0.62 (CI: 0.31−1.27) Bronchopulmonary dysplasia: OR = 0.80 (CI: 0.47−1.36) Change in serum creatinine (mean difference −0.03, CI: −0.11−0.05) Sub-analysis of two papers [10, 29] comparing oral ibuprofen (n = 58) vs. oral (n = 45) indomethacin Effectiveness: Heterogeneity was not present (chi-squared = 0.45, p = 0.50, I2 = 0%) Closure rate: OR 0.90 (CI: 0.40 to 2.00). Safety: Change in serum creatinine favouring ibuprofen: mean difference −0.10 (CI−0.13 to−0.07) Ohlsson, 2015 [5] SR of mixed nations and economies (LMIE = 2, UMIE = 9, HIE = 1) Cochrane SR with MA (Level 1a-) of 33 studies (n = 2190) Planned subgroup analysis of eight studies [10, 24, 28–33] comparing oral ibuprofen (n = 145) vs. IV or oral indomethacin (n = 127) Effectiveness: (RR < 1.0 favours oral ibuprofen) Closure failure: RR = 0.96 (CI: 0.73−1.27) Surgical closure: RR = 0.93 (CI: 0.50−1.74) Well-designed systematic review Only randomized or quasi-randomized controlled trials included Subgroup analysis was planned No subgroup analysis regarding resource poor environments A single paper was described looking at ‘early’ or ‘expectant’ management of a PDA. This found no statistically significant difference between the early vs. the expectant group for mortality or CLD at 36 weeks [24] Safety: Mortality: −0.10 (CI−0.20 to 0.00) NEC: RR = 0.41 (CI 0.23−0.73) Plasma creatinine: mean difference −0.51 (CI: −6.04, 5.01) IVH: RR = 0.90 (CI: 0.45−1.83) Intestinal perforation: RR = 0.24 (CI: 0.03−1.95) Gastrointestinal bleed: RR = 2.80 (CI: 0.48−16.45) Oliguria: RR = 0.0 (CI: −0.10 to 0.10) Planned subgroup analysis of four studies [35–38] comparing oral ibuprofen (n = 156) compared with IV ibuprofen (n = 148) Effectiveness Closure failure: RR = 0.41 (CI: 0.27−0.64)Surgical closure: RR = 0.35 (CI: 0.1−1.17) Safety NEC: RR = 0.86 (CI: 0.35−2.15) Intestinal perforation: RR = 0.32 (CI: 0.01−7.48) Gastrointestinal bleed: RR = 2.89 (0.12−69.24) Plasma creatinine: mean difference −22.47 (CI: −32.40 to−12.53) Oliguria: RR = 0.14 (CI: 0.01−2.66) Cheriff, 2007 [39] UMIE Non-controlled pilot study (Level 4) Oral ibuprofen (n = 40). No comparison group Effectiveness Ductal closure in 38/40 (95%) of infants. Surgical closure in 1/40 (2.5%) A small pilot study No control group Safety NEC: 3/40 (7.5%) Gastrointestinal bleed: 2/40 (5%) Renal impairment: 0/40 Tatli, 2004 [13] Turkey (UMIE) Case report (Level 4) Two infants Safety Both newborns had sudden abdominal distension without prodromal and radiological findings of NEC Small case series with a significant complication Heyman, 2003 [40] Israel (HIE) Non-controlled pilot study (Level 4) Oral ibuprofen (n = 22). No comparison group Effectiveness Ductal closure in 21/22 (96%) of infants. No reopening of the ductus after closure had been achieved A small pilot study to identify dosing regimen Good inclusion criteria described for external validity Good description of neonatal care Safety No difference in serum creatinine pre- and post-treatment Note: Income Group (World Bank) [41]: low-income economy (LIE), lower-middle-income economy (LMIE), upper-middle-income economy (UMIE), high-income economy (HIE). ASK A STATISTICIAN Loomba describes no heterogeneity in their systematic review. In systematic reviews, heterogeneity is the variability or differences between studies in the estimates of effects. Heterogeneity should be differentiated as ‘statistical heterogeneity’ (differences in the reported effects), ‘methodological heterogeneity’ (differences in study design) and ‘clinical heterogeneity’ (differences between studies in key characteristics of the participants, interventions or outcome measures). See Bandolier EBM glossary [9]. COMMENTARY When treating this newborn, one of the first questions the clinician will need to ask is whether the PDA is clinically significant? If so, then treatment certainly can be considered, as this infant is at risk of the PDA not closing spontaneously (see above). This is especially important in many resource-limited settings, where there is a lack of long-term respiratory support whilst awaiting spontaneous closure. These papers reveal a selection of small non-randomized and randomized studies, which have been summated in two large systematic reviews [1, 5] including a Cochrane review [5]. Ibuprofen is effective, and this is well established in these papers. Throughout, equivalence of effectiveness was demonstrated. However, the lack of statistically significant difference between groups does not necessarily indicate that there is no difference. The group sizes were small in all the papers including the meta-analysed (MA) data in the systematic reviews. Yadav [10] and Yang [11] both performed pre-study power analyses with a clinically relevant ‘difference’ of 25% (with 80% power) resulting in sample sizes of n = 35 and n = 24, respectively. Considering PDA is known to be a relatively common problem in neonates, with significant implications, one has to consider if a ‘difference’ of 25% is adequate to determine superiority. Gulack [12] described 3.75% absolute difference as an adequate marker, with a power analysis revealing a requirement of 5400 infants to give 80% power to determine equivalence in rates of important outcomes such as death and/or requirement of surgical ligation. Regarding safety, it is well established that there are risks associated with COX inhibitors. The systematic reviews and the large cohort study [12] find no evidence that ibuprofen has significantly more complications when compared with either oral or IV indomethacin. In a subgroup analysis of their Cochrane systematic review, Ohlsson [5] described fewer transient side effects on the kidneys and reduced the risk of NEC when comparing oral ibuprofen with IV ibuprofen. Ohlsson and Loomba did not include the large multicentre, retrospective cohort study by Gulack [12], which was not available at the time of MA. Gulack studied 1177 infants treated with ibuprofen and 5172 infants treated with indomethacin and initially found a higher rate of complications with ibuprofen. However, multivariable analysis of the same data revealed no significant differences in any negative outcomes, including death. Noteworthy to interpretation related to our PICO question, Gulack did not describe a subgroup analysis for oral and IV preparations. Tatli [13] reported two cases of spontaneous intestinal perforation (SIP) in two infants treated with oral ibuprofen. SIP affects 3% of all Very-low Birth Weight newborns and therefore is not a rare entity [13]. Both systematic reviews looked at gastrointestinal complications such as NEC, SIP and bleeding. There is no evidence that oral ibuprofen has a higher incidence of these complications, with Ohlsson [5] finding that oral ibuprofen leads to less NEC then IV or oral indomethacin [risk ratio (RR) = 0.41, confidence interval (CI): 0.23−0.73], though this finding was not repeated in Loomba’s paper [odds ratio (OR) = 0.60, CI: 0.30−1.24). Globally, prematurity continues to be a significant cause of mortality and identifying cheap, effective and safe treatments for common neonatal problems, such as PDA, is a priority. In this case, there are important financial, logistical and practical considerations. Oral ibuprofen costs $2 per 100 ml bottle (100 mg/5 ml) and is easily available, compared with $345 and $60 for a three-dose course of IV ibuprofen and indomethacin, respectively [14]. In Rwanda, gross national income is $700 [15]. These costs therefore offer a significant financial challenge to many families who already face the cost of care of a premature infant. Logistically, IV preparations are often not available, and therefore, clinicians need robust evidence that oro-gastric preparations are effective and safe in this vulnerable group of patients. Finally, in considering the practical issues, IV preparations are burdensome in a resource-limited setting, as they require an IV cannula to be sited for three doses (24 h apart), which adds to cost whilst also requiring a skilled practitioner for insertion in a preterm infant. The IV cannula also requires monitoring for extravasation, and the siting of a cannula increases the infection risk in the infant, and is therefore not without risk. AT THE BEDSIDE: APPLYING THE EVIDENCE Once the clinician has determined that the PDA is clinically significant and that treatment should be considered, then ibuprofen is as effective as indomethacin for PDA closure with oro-gastric administration of ibuprofen appearing as effective as Intravenous (IV) administration (Grade A); oral ibuprofen appears to be as safe as IV/oral indomethacin or IV ibuprofen (Grade A); and oral ibuprofen may have fewer transient side effects on the kidneys and reduced the risk of NEC compared with IV ibuprofen (Grade B). WHAT NEXT Paracetamol is now regularly used as the agent of choice for PDA closure or for cases when COX inhibitors are contraindicated (e.g. thrombocytopenia, bleeding, renal impairment, etc.) [16]. A future journal club Best Evidence Topic comparing paracetamol with ibuprofen would be of assistance to clinicians striving to choose the most appropriate therapy for these infants. A further pertinent question to consider is whether the use of any pharmacological agent to close a PDA benefits the infant or should the clinician wait for the ductus to close itself without intervention? This is a question that is gaining momentum [17, 18], and trends suggest that, year-in-year-out, clinicians are treating fewer cases of PDA [19–21]. The National Perinatal Epidemiology Group (NPEU) is currently recruiting patients as part of a multicentre, masked, randomized placebo-controlled parallel group trial (‘OSCAR study’) in extremely preterm babies to determine short- and long-term health and economic outcomes of active treatment (with ibuprofen) vs. no treatment (placebo) [2]. This study is aiming to recruit 730 extremely preterm babies over an 82-month period and will provide the best evidence available to answer this question, with meaningful, clinically relevant outcomes. This journal club awaits the results with anticipation. References 1 Loomba R , Nijhawan K. Ibuprofen versus indomethacin for medical closure of the patent arterial duct: a pooled analysis by route of administration . CurēUs 2015 ; 7 : e274 . http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4494534&tool=pmcentrez&rendertype=abstract Google Scholar PubMed 2 NPEU . Protocol | Baby-OSCAR (Outcome after Selective Early Treatment for Closure of Patent Ductus Arteriosus in Preterm Babies) [Internet]. 2016https://www.npeu.ox.ac.uk/baby-oscar/protocol [18 September 2017, date last accessed]. 3 Uptodate.com. Clinical manifestations and diagnosis of patent Ductus Arteriosus in term infants, children, and adults [Internet]. https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-patent-ductus-arteriosus-in-term-infants-children-and-adults?source=search_result&search=clinical manifestations of PDA&selectedTitle=1∼150 [18 September 2017, date last accessed]. 4 Harish Madhava MS , Settle P. Fluid restriction for symptomatic patent Ductus Arteriosus in preterm infants. In: Cochrane Database of Systematic Reviews . John Wiley & Sons, Ltd ; 2009 . doi: 10.1002/14651858.CD007800. 5 Ohlsson A , Rajneesh W , Shah Sachin S. Ibuprofen for the treatment of patent Ductus Arteriosus in preterm or low birth weight (or both) infants , 2015 . http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD003481.pub6/abstract 6 Uptodate.com . Management of patent Ductus Arteriosus [Internet], 2016 . https://www.uptodate.com/contents/management-of-patent-ductus-arteriosus [16 June 2016, date last accessed]. 7 Walker E , Nowacki AS. Understanding equivalence and noninferiority testing . J Gen Intern Med 2011 ; 26 : 192 – 6 . Google Scholar Crossref Search ADS PubMed 8 Neumann R , Schulzke SM , Bührer C. Oral ibuprofen versus intravenous ibuprofen or intravenous indomethacin for the treatment of patent Ductus Arteriosus in preterm infants: a systematic review and meta-analysis . 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Spontaneous intestinal perforation after oral ibuprofen treatment of patent Ductus Arteriosus in two very-low-birthweight infants . Acta Paediatr 2004 ; 93 : 999 – 1001 . Google Scholar Crossref Search ADS PubMed 14 Royal Pharmaceutical Society . MedicinesComplete [Internet]. https://www.medicinescomplete.com/about/%0D [17 September 2017, date last accessed]. 15 The World Bank . Rwanda | Data [Internet], 2016 . http://data.worldbank.org/country/rwanda [5 May 2016, date last accessed]. 16 Terrin G , Conte F , Oncel MY , et al. Paracetamol for the treatment of patent Ductus Arteriosus in preterm neonates: a systematic review and meta-analysis . Arch Dis Child Fetal Neonatal Ed 2016 ; 101 : F127 – 36 . Google Scholar Crossref Search ADS PubMed 17 Benitz WE , Bhombal S. The use of non-steroidal anti-inflammatory drugs for patent Ductus Arteriosus closure in preterm infants . Semin Fetal Neonatal Med 2017 ; 22 : 302 – 7 . 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The pharmacological treatment of patent ductus arteriosus in premature infants with respiratory distress syndrome: oral ibuprofen vs. indomethacin . Korean J Pediatr 2008 ; 51 : 956 – 63 . Google Scholar Crossref Search ADS 27 Sivanandan S , Bali V , Soraisham AS , et al. Effectiveness and safety of indomethacin versus ibuprofen for the treatment of patent ductus arteriosus in preterm infants . Am J Perinatol 2013 ; 30 : 745 – 50 . Google Scholar Crossref Search ADS PubMed 28 Chotigeat U , Jirapapa K , Layangkool T. A comparison of oral ibuprofen and intravenous indomethacin for closure of patent ductus arteriosus in preterm infants . J Med Assoc Thai 2003 ; 86 : S563 – 9 . Google Scholar PubMed 29 Pourarian S , Pishva N , Madani A , et al. Comparison of oral ibuprofen and indomethacin on closure of patent ductus arteriosus in preterm infants . East Mediterr Health J 2008 ; 14 : 360 – 5 . Google Scholar PubMed 30 Akisu M , Ozyurek M , Dorak C , et al. 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All rights reserved. For Permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Tropical Pediatrics Oxford University Press

In a Resource-Limited Setting, Is Oral Ibuprofen Effective for Closure of a Patent Ductus Arteriosus in a Preterm Neonate?

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Abstract

SCENARIO You are a paediatric resident working in the neonatal unit of a referral hospital in Rwanda, East Africa. During your morning round, you see an infant weighing 1.2 kg and of 28 weeks’ gestation, who is now 7 days old. On examination, there is a loud machinery murmur heard over the precordium in association with easy-to-feel, bounding, femoral pulses. There is no cyanosis, and saturations are within normal limits. You diagnose a patent ductus arteriosus (PDA). Echocardiography is not available. On reviewing the patient records, you note that these clinical findings have been present for 2 days and that the previous team has restricted fluid intake for this infant. Within the past 48 h, the infant has developed signs of respiratory distress with increased respiratory rate and recessions. A plain chest radiograph has ruled out respiratory infection. You therefore consider treating the PDA. Owing to supply chain problems, you frequently do not have access to intravenous (IV) indomethacin or ibuprofen. These medicines are also financially burdensome for the families you treat. Surgical closure of PDA is not available. WHAT IS ALREADY KNOWN? In the foetus, the ductus arteriosus connects the aorta and pulmonary artery allowing the majority of the right ventricular output to bypass the lungs. The ductus normally closes in the first few days of life, but in preterm infants, this may be delayed with risk of PDA being inversely proportional to gestational age. A PDA is defined as such if the ductus does not close by 72 h of life [1]. PDA is a common problem in small preterm infants with 65 and 25% of infants weighing <1000 g and 1000–1500 g having a PDA, respectively, of which current trends suggest 85 and 70% requiring treatment, respectively [1]; this is currently the question of a large multicentre trial [2]. In many infants, the natural evolution of PDA is a spontaneous closure. This is more likely if PDA is ≤1.55 mm in diameter or in more mature infants (>1000 g or >28 weeks of gestation) [2]. There are many clinical sequelae of a PDA, including chronic lung disease, pulmonary haemorrhage, renal hypo-perfusion, necrotizing enterocolitis (NEC), intraventricular haemorrhage (IVH) and mortality [2, 3]. PDA is diagnosed clinically but, where available, may be confirmed with an echocardiogram, which also allows for an assessment of the size of the PDA as well as excluding pulmonary hypertension or a duct dependent congenital heart defect. Treatment of a PDA is initially conservative with fluid restriction. One of the challenges of fluid restriction is maintaining adequate nutrition [4]. This is especially pertinent in resource-limited settings, where total parental nutrition is usually not available. Diuretics are also occasionally used. Indomethacin is used as staRepodard therapy to close a PDA but is associated with reduced blood flow to several organs. Cyclooxygenase (COX) inhibitors such as ibuprofen or indomethacin are frequently used as standard medical therapy but can be associated with their own complications, reduced renal function, NEC, etc. [4, 5]. Contraindications to COX inhibitors include reduced renal function, oliguria, thrombocytopenia, bleeding or coagulopathy, NEC, marked unconjugated hyperbilirubinemia, a duct-dependent cardiac lesion and infection [6]. Ibuprofen is typically given in IV form. However, in the resource-limited setting, the IV preparation is expensive and/or unavailable, and therefore, oral ibuprofen could be advantageous. STRUCTURED CLINICAL QUESTION In a preterm newborn with a PDA in a resource-limited setting (patient), is oral ibuprofen (intervention) as effective (non-inferior) as IV/oral indomethacin or IV ibuprofen (controls) for PDA closure (primary outcome) and safety profile (secondary outcome)? OPTIMAL STUDY DESIGN In this question, we are interested to know if there is ‘non-inferiority’ between two treatment options (i.e. they have similar action and effectiveness). The comparison is between an established treatment (indomethacin) and an alternative (oral ibuprofen). An equivalence or non-inferiority study could be used to answer this question [7]. FULL SEARCH DESCRIPTION A literature search was performed (18 September 2017) using the search terms described (see Table 1). We excluded papers not published in the languages of the authors (English and French) along with papers measuring surrogate markers (e.g. cerebral blood flow). We searched the databases PubMed and Cochrane, and this revealed 16 and 4 results, respectively, of which 3 and 2 were relevant. The ‘developing country’ search string was removed and this revealed 227 and 95 results, respectively, of which 19 and 11 were relevant. A search of the reference lists of the relevant papers was performed and found a further six relevant papers. Three papers [1, 5, 8] were systematic reviews including a Cochrane systematic review (SR) [5]. Neuman’s SR [8] was superseded and therefore excluded. Looma [1] and Ohlsson [5] were both included, as they described syntheses of different papers and different subgroups. Articles included in these syntheses were removed from our appraisal table. Once duplicates were removed, six relevant papers have been reviewed here (see Table 2). Table 1 Search terms (italics if MeSH) (Ductus arteriosus, patent OR patent ductus OR ductus arteriosus OR PDA) AND (Ibuprofen OR brufen) AND (Indomethacin OR indometacin) AND (Developing countries OR developing country OR countries, developing OR nations, developing OR developing nations OR poverty OR resource poor country OR low-income country OR low-income country OR resource poor country OR Global health OR third word OR India OR Africa OR Asia OR South America OR Papua New Guinea OR Asia-Pacific) (Ductus arteriosus, patent OR patent ductus OR ductus arteriosus OR PDA) AND (Ibuprofen OR brufen) AND (Indomethacin OR indometacin) AND (Developing countries OR developing country OR countries, developing OR nations, developing OR developing nations OR poverty OR resource poor country OR low-income country OR low-income country OR resource poor country OR Global health OR third word OR India OR Africa OR Asia OR South America OR Papua New Guinea OR Asia-Pacific) Table 1 Search terms (italics if MeSH) (Ductus arteriosus, patent OR patent ductus OR ductus arteriosus OR PDA) AND (Ibuprofen OR brufen) AND (Indomethacin OR indometacin) AND (Developing countries OR developing country OR countries, developing OR nations, developing OR developing nations OR poverty OR resource poor country OR low-income country OR low-income country OR resource poor country OR Global health OR third word OR India OR Africa OR Asia OR South America OR Papua New Guinea OR Asia-Pacific) (Ductus arteriosus, patent OR patent ductus OR ductus arteriosus OR PDA) AND (Ibuprofen OR brufen) AND (Indomethacin OR indometacin) AND (Developing countries OR developing country OR countries, developing OR nations, developing OR developing nations OR poverty OR resource poor country OR low-income country OR low-income country OR resource poor country OR Global health OR third word OR India OR Africa OR Asia OR South America OR Papua New Guinea OR Asia-Pacific) Table 2 Evidence summary table Author, date, citation, country (economy) Study type (Oxford CEBM level of evidence) [22] Study group population and comparisons Key outcomes Key result Appraisal comments Olgun, 2017 [23] Turkey (UMIE) Single-centre, non-controlled, retrospective PDA in 134 of 576 infants. In total, 100 given repeated oral ibuprofen Effectiveness (PDA closure): Course 1: 67/94 (71.3%) Course 2: 11/27 (40.7%) Course 3: 5/14 (35.7%) The cumulative closure rate was 71% (Course 1), 83% (Course 2) and 88% (Course 3) (Cochran’s Q = 25.1, p <0.001) Retrospective, non-controlled study giving no data on if ibuprofen is superior to other therapeutic options Safety: Three (3%) infants experience thrombocytopenia, renal dysfunction or both during the first course Gulack, 2015 [12] USA (HIE) Multi-centre (165 units), retrospective cohort study. Data extracted from a prospectively collected patient database (Level 2b) Ibuprofen (N = 1177) vs. indomethacin (N = 5172)No description of whether IV or oral preparations Effectiveness: (OR < 1.0 favours ibuprofen) Multivariable logistic regression adjusted analysis: Closure rate: No data Surgical ligation: OR = 1.10 (0.87, 1.37) Not included in the Loomba or Ohlsson systematic reviews Clear description of study cohort Power analysis included (5400 infants to give 80% power for 3.75% absolute difference) Patient’s identified by treatment with ibuprofen/indomethacin, rather than as having PDA diagnosis No access to echocardiographic data to give initial size of PDA or to confirm PDA closure Safety: Multivariable logistic regression adjusted analysis: Death before discharge: OR = 1.10 (CI: 0.82 to 1.47) Rise in creatinine: OR = 1.16 (0.87 to 1.54) Loomba, 2015 [1] SR of mixed nations and economies (LMIE = 1, UMIE = 2, HIE = 5) SR with MA of 22 papers (n = 1583) (Level 1a-) Sub-analysis of six papers [11, 24–28] comparing oral ibuprofen (n = 193) vs. IV indomethacin (n = 219) Effectiveness: (OR < 1.0 favours oral ibuprofen) Significant heterogeneity was not present (chi-squared = 0.76, p = 0.51, I2 = 0%) Closure rate: OR = 0.76 (CI: 0.50−1.18) Surgical ligation: OR = 0.78 (CI: 0.45−1.37) Cochrane Handbook for SR of Interventions was used for quality evaluation Bias was assessed using the Cochrane Risk of Bias Tool Publication bias was assessed qualitatively using forest plots for endpoints with 10 or more studies included Heterogeneity between studies was identified using chi-square and I2 tests Safety: NEC: OR = 0.60 (CI: 0.30−1.24) Gastrointestinal bleeding: OR = 0.62 (CI: 0.31−1.27) Bronchopulmonary dysplasia: OR = 0.80 (CI: 0.47−1.36) Change in serum creatinine (mean difference −0.03, CI: −0.11−0.05) Sub-analysis of two papers [10, 29] comparing oral ibuprofen (n = 58) vs. oral (n = 45) indomethacin Effectiveness: Heterogeneity was not present (chi-squared = 0.45, p = 0.50, I2 = 0%) Closure rate: OR 0.90 (CI: 0.40 to 2.00). Safety: Change in serum creatinine favouring ibuprofen: mean difference −0.10 (CI−0.13 to−0.07) Ohlsson, 2015 [5] SR of mixed nations and economies (LMIE = 2, UMIE = 9, HIE = 1) Cochrane SR with MA (Level 1a-) of 33 studies (n = 2190) Planned subgroup analysis of eight studies [10, 24, 28–33] comparing oral ibuprofen (n = 145) vs. IV or oral indomethacin (n = 127) Effectiveness: (RR < 1.0 favours oral ibuprofen) Closure failure: RR = 0.96 (CI: 0.73−1.27) Surgical closure: RR = 0.93 (CI: 0.50−1.74) Well-designed systematic review Only randomized or quasi-randomized controlled trials included Subgroup analysis was planned No subgroup analysis regarding resource poor environments A single paper was described looking at ‘early’ or ‘expectant’ management of a PDA. This found no statistically significant difference between the early vs. the expectant group for mortality or CLD at 36 weeks [24] Safety: Mortality: −0.10 (CI−0.20 to 0.00) NEC: RR = 0.41 (CI 0.23−0.73) Plasma creatinine: mean difference −0.51 (CI: −6.04, 5.01) IVH: RR = 0.90 (CI: 0.45−1.83) Intestinal perforation: RR = 0.24 (CI: 0.03−1.95) Gastrointestinal bleed: RR = 2.80 (CI: 0.48−16.45) Oliguria: RR = 0.0 (CI: −0.10 to 0.10) Planned subgroup analysis of four studies [35–38] comparing oral ibuprofen (n = 156) compared with IV ibuprofen (n = 148) Effectiveness Closure failure: RR = 0.41 (CI: 0.27−0.64)Surgical closure: RR = 0.35 (CI: 0.1−1.17) Safety NEC: RR = 0.86 (CI: 0.35−2.15) Intestinal perforation: RR = 0.32 (CI: 0.01−7.48) Gastrointestinal bleed: RR = 2.89 (0.12−69.24) Plasma creatinine: mean difference −22.47 (CI: −32.40 to−12.53) Oliguria: RR = 0.14 (CI: 0.01−2.66) Cheriff, 2007 [39] UMIE Non-controlled pilot study (Level 4) Oral ibuprofen (n = 40). No comparison group Effectiveness Ductal closure in 38/40 (95%) of infants. Surgical closure in 1/40 (2.5%) A small pilot study No control group Safety NEC: 3/40 (7.5%) Gastrointestinal bleed: 2/40 (5%) Renal impairment: 0/40 Tatli, 2004 [13] Turkey (UMIE) Case report (Level 4) Two infants Safety Both newborns had sudden abdominal distension without prodromal and radiological findings of NEC Small case series with a significant complication Heyman, 2003 [40] Israel (HIE) Non-controlled pilot study (Level 4) Oral ibuprofen (n = 22). No comparison group Effectiveness Ductal closure in 21/22 (96%) of infants. No reopening of the ductus after closure had been achieved A small pilot study to identify dosing regimen Good inclusion criteria described for external validity Good description of neonatal care Safety No difference in serum creatinine pre- and post-treatment Author, date, citation, country (economy) Study type (Oxford CEBM level of evidence) [22] Study group population and comparisons Key outcomes Key result Appraisal comments Olgun, 2017 [23] Turkey (UMIE) Single-centre, non-controlled, retrospective PDA in 134 of 576 infants. In total, 100 given repeated oral ibuprofen Effectiveness (PDA closure): Course 1: 67/94 (71.3%) Course 2: 11/27 (40.7%) Course 3: 5/14 (35.7%) The cumulative closure rate was 71% (Course 1), 83% (Course 2) and 88% (Course 3) (Cochran’s Q = 25.1, p <0.001) Retrospective, non-controlled study giving no data on if ibuprofen is superior to other therapeutic options Safety: Three (3%) infants experience thrombocytopenia, renal dysfunction or both during the first course Gulack, 2015 [12] USA (HIE) Multi-centre (165 units), retrospective cohort study. Data extracted from a prospectively collected patient database (Level 2b) Ibuprofen (N = 1177) vs. indomethacin (N = 5172)No description of whether IV or oral preparations Effectiveness: (OR < 1.0 favours ibuprofen) Multivariable logistic regression adjusted analysis: Closure rate: No data Surgical ligation: OR = 1.10 (0.87, 1.37) Not included in the Loomba or Ohlsson systematic reviews Clear description of study cohort Power analysis included (5400 infants to give 80% power for 3.75% absolute difference) Patient’s identified by treatment with ibuprofen/indomethacin, rather than as having PDA diagnosis No access to echocardiographic data to give initial size of PDA or to confirm PDA closure Safety: Multivariable logistic regression adjusted analysis: Death before discharge: OR = 1.10 (CI: 0.82 to 1.47) Rise in creatinine: OR = 1.16 (0.87 to 1.54) Loomba, 2015 [1] SR of mixed nations and economies (LMIE = 1, UMIE = 2, HIE = 5) SR with MA of 22 papers (n = 1583) (Level 1a-) Sub-analysis of six papers [11, 24–28] comparing oral ibuprofen (n = 193) vs. IV indomethacin (n = 219) Effectiveness: (OR < 1.0 favours oral ibuprofen) Significant heterogeneity was not present (chi-squared = 0.76, p = 0.51, I2 = 0%) Closure rate: OR = 0.76 (CI: 0.50−1.18) Surgical ligation: OR = 0.78 (CI: 0.45−1.37) Cochrane Handbook for SR of Interventions was used for quality evaluation Bias was assessed using the Cochrane Risk of Bias Tool Publication bias was assessed qualitatively using forest plots for endpoints with 10 or more studies included Heterogeneity between studies was identified using chi-square and I2 tests Safety: NEC: OR = 0.60 (CI: 0.30−1.24) Gastrointestinal bleeding: OR = 0.62 (CI: 0.31−1.27) Bronchopulmonary dysplasia: OR = 0.80 (CI: 0.47−1.36) Change in serum creatinine (mean difference −0.03, CI: −0.11−0.05) Sub-analysis of two papers [10, 29] comparing oral ibuprofen (n = 58) vs. oral (n = 45) indomethacin Effectiveness: Heterogeneity was not present (chi-squared = 0.45, p = 0.50, I2 = 0%) Closure rate: OR 0.90 (CI: 0.40 to 2.00). Safety: Change in serum creatinine favouring ibuprofen: mean difference −0.10 (CI−0.13 to−0.07) Ohlsson, 2015 [5] SR of mixed nations and economies (LMIE = 2, UMIE = 9, HIE = 1) Cochrane SR with MA (Level 1a-) of 33 studies (n = 2190) Planned subgroup analysis of eight studies [10, 24, 28–33] comparing oral ibuprofen (n = 145) vs. IV or oral indomethacin (n = 127) Effectiveness: (RR < 1.0 favours oral ibuprofen) Closure failure: RR = 0.96 (CI: 0.73−1.27) Surgical closure: RR = 0.93 (CI: 0.50−1.74) Well-designed systematic review Only randomized or quasi-randomized controlled trials included Subgroup analysis was planned No subgroup analysis regarding resource poor environments A single paper was described looking at ‘early’ or ‘expectant’ management of a PDA. This found no statistically significant difference between the early vs. the expectant group for mortality or CLD at 36 weeks [24] Safety: Mortality: −0.10 (CI−0.20 to 0.00) NEC: RR = 0.41 (CI 0.23−0.73) Plasma creatinine: mean difference −0.51 (CI: −6.04, 5.01) IVH: RR = 0.90 (CI: 0.45−1.83) Intestinal perforation: RR = 0.24 (CI: 0.03−1.95) Gastrointestinal bleed: RR = 2.80 (CI: 0.48−16.45) Oliguria: RR = 0.0 (CI: −0.10 to 0.10) Planned subgroup analysis of four studies [35–38] comparing oral ibuprofen (n = 156) compared with IV ibuprofen (n = 148) Effectiveness Closure failure: RR = 0.41 (CI: 0.27−0.64)Surgical closure: RR = 0.35 (CI: 0.1−1.17) Safety NEC: RR = 0.86 (CI: 0.35−2.15) Intestinal perforation: RR = 0.32 (CI: 0.01−7.48) Gastrointestinal bleed: RR = 2.89 (0.12−69.24) Plasma creatinine: mean difference −22.47 (CI: −32.40 to−12.53) Oliguria: RR = 0.14 (CI: 0.01−2.66) Cheriff, 2007 [39] UMIE Non-controlled pilot study (Level 4) Oral ibuprofen (n = 40). No comparison group Effectiveness Ductal closure in 38/40 (95%) of infants. Surgical closure in 1/40 (2.5%) A small pilot study No control group Safety NEC: 3/40 (7.5%) Gastrointestinal bleed: 2/40 (5%) Renal impairment: 0/40 Tatli, 2004 [13] Turkey (UMIE) Case report (Level 4) Two infants Safety Both newborns had sudden abdominal distension without prodromal and radiological findings of NEC Small case series with a significant complication Heyman, 2003 [40] Israel (HIE) Non-controlled pilot study (Level 4) Oral ibuprofen (n = 22). No comparison group Effectiveness Ductal closure in 21/22 (96%) of infants. No reopening of the ductus after closure had been achieved A small pilot study to identify dosing regimen Good inclusion criteria described for external validity Good description of neonatal care Safety No difference in serum creatinine pre- and post-treatment Note: Income Group (World Bank) [41]: low-income economy (LIE), lower-middle-income economy (LMIE), upper-middle-income economy (UMIE), high-income economy (HIE). Table 2 Evidence summary table Author, date, citation, country (economy) Study type (Oxford CEBM level of evidence) [22] Study group population and comparisons Key outcomes Key result Appraisal comments Olgun, 2017 [23] Turkey (UMIE) Single-centre, non-controlled, retrospective PDA in 134 of 576 infants. In total, 100 given repeated oral ibuprofen Effectiveness (PDA closure): Course 1: 67/94 (71.3%) Course 2: 11/27 (40.7%) Course 3: 5/14 (35.7%) The cumulative closure rate was 71% (Course 1), 83% (Course 2) and 88% (Course 3) (Cochran’s Q = 25.1, p <0.001) Retrospective, non-controlled study giving no data on if ibuprofen is superior to other therapeutic options Safety: Three (3%) infants experience thrombocytopenia, renal dysfunction or both during the first course Gulack, 2015 [12] USA (HIE) Multi-centre (165 units), retrospective cohort study. Data extracted from a prospectively collected patient database (Level 2b) Ibuprofen (N = 1177) vs. indomethacin (N = 5172)No description of whether IV or oral preparations Effectiveness: (OR < 1.0 favours ibuprofen) Multivariable logistic regression adjusted analysis: Closure rate: No data Surgical ligation: OR = 1.10 (0.87, 1.37) Not included in the Loomba or Ohlsson systematic reviews Clear description of study cohort Power analysis included (5400 infants to give 80% power for 3.75% absolute difference) Patient’s identified by treatment with ibuprofen/indomethacin, rather than as having PDA diagnosis No access to echocardiographic data to give initial size of PDA or to confirm PDA closure Safety: Multivariable logistic regression adjusted analysis: Death before discharge: OR = 1.10 (CI: 0.82 to 1.47) Rise in creatinine: OR = 1.16 (0.87 to 1.54) Loomba, 2015 [1] SR of mixed nations and economies (LMIE = 1, UMIE = 2, HIE = 5) SR with MA of 22 papers (n = 1583) (Level 1a-) Sub-analysis of six papers [11, 24–28] comparing oral ibuprofen (n = 193) vs. IV indomethacin (n = 219) Effectiveness: (OR < 1.0 favours oral ibuprofen) Significant heterogeneity was not present (chi-squared = 0.76, p = 0.51, I2 = 0%) Closure rate: OR = 0.76 (CI: 0.50−1.18) Surgical ligation: OR = 0.78 (CI: 0.45−1.37) Cochrane Handbook for SR of Interventions was used for quality evaluation Bias was assessed using the Cochrane Risk of Bias Tool Publication bias was assessed qualitatively using forest plots for endpoints with 10 or more studies included Heterogeneity between studies was identified using chi-square and I2 tests Safety: NEC: OR = 0.60 (CI: 0.30−1.24) Gastrointestinal bleeding: OR = 0.62 (CI: 0.31−1.27) Bronchopulmonary dysplasia: OR = 0.80 (CI: 0.47−1.36) Change in serum creatinine (mean difference −0.03, CI: −0.11−0.05) Sub-analysis of two papers [10, 29] comparing oral ibuprofen (n = 58) vs. oral (n = 45) indomethacin Effectiveness: Heterogeneity was not present (chi-squared = 0.45, p = 0.50, I2 = 0%) Closure rate: OR 0.90 (CI: 0.40 to 2.00). Safety: Change in serum creatinine favouring ibuprofen: mean difference −0.10 (CI−0.13 to−0.07) Ohlsson, 2015 [5] SR of mixed nations and economies (LMIE = 2, UMIE = 9, HIE = 1) Cochrane SR with MA (Level 1a-) of 33 studies (n = 2190) Planned subgroup analysis of eight studies [10, 24, 28–33] comparing oral ibuprofen (n = 145) vs. IV or oral indomethacin (n = 127) Effectiveness: (RR < 1.0 favours oral ibuprofen) Closure failure: RR = 0.96 (CI: 0.73−1.27) Surgical closure: RR = 0.93 (CI: 0.50−1.74) Well-designed systematic review Only randomized or quasi-randomized controlled trials included Subgroup analysis was planned No subgroup analysis regarding resource poor environments A single paper was described looking at ‘early’ or ‘expectant’ management of a PDA. This found no statistically significant difference between the early vs. the expectant group for mortality or CLD at 36 weeks [24] Safety: Mortality: −0.10 (CI−0.20 to 0.00) NEC: RR = 0.41 (CI 0.23−0.73) Plasma creatinine: mean difference −0.51 (CI: −6.04, 5.01) IVH: RR = 0.90 (CI: 0.45−1.83) Intestinal perforation: RR = 0.24 (CI: 0.03−1.95) Gastrointestinal bleed: RR = 2.80 (CI: 0.48−16.45) Oliguria: RR = 0.0 (CI: −0.10 to 0.10) Planned subgroup analysis of four studies [35–38] comparing oral ibuprofen (n = 156) compared with IV ibuprofen (n = 148) Effectiveness Closure failure: RR = 0.41 (CI: 0.27−0.64)Surgical closure: RR = 0.35 (CI: 0.1−1.17) Safety NEC: RR = 0.86 (CI: 0.35−2.15) Intestinal perforation: RR = 0.32 (CI: 0.01−7.48) Gastrointestinal bleed: RR = 2.89 (0.12−69.24) Plasma creatinine: mean difference −22.47 (CI: −32.40 to−12.53) Oliguria: RR = 0.14 (CI: 0.01−2.66) Cheriff, 2007 [39] UMIE Non-controlled pilot study (Level 4) Oral ibuprofen (n = 40). No comparison group Effectiveness Ductal closure in 38/40 (95%) of infants. Surgical closure in 1/40 (2.5%) A small pilot study No control group Safety NEC: 3/40 (7.5%) Gastrointestinal bleed: 2/40 (5%) Renal impairment: 0/40 Tatli, 2004 [13] Turkey (UMIE) Case report (Level 4) Two infants Safety Both newborns had sudden abdominal distension without prodromal and radiological findings of NEC Small case series with a significant complication Heyman, 2003 [40] Israel (HIE) Non-controlled pilot study (Level 4) Oral ibuprofen (n = 22). No comparison group Effectiveness Ductal closure in 21/22 (96%) of infants. No reopening of the ductus after closure had been achieved A small pilot study to identify dosing regimen Good inclusion criteria described for external validity Good description of neonatal care Safety No difference in serum creatinine pre- and post-treatment Author, date, citation, country (economy) Study type (Oxford CEBM level of evidence) [22] Study group population and comparisons Key outcomes Key result Appraisal comments Olgun, 2017 [23] Turkey (UMIE) Single-centre, non-controlled, retrospective PDA in 134 of 576 infants. In total, 100 given repeated oral ibuprofen Effectiveness (PDA closure): Course 1: 67/94 (71.3%) Course 2: 11/27 (40.7%) Course 3: 5/14 (35.7%) The cumulative closure rate was 71% (Course 1), 83% (Course 2) and 88% (Course 3) (Cochran’s Q = 25.1, p <0.001) Retrospective, non-controlled study giving no data on if ibuprofen is superior to other therapeutic options Safety: Three (3%) infants experience thrombocytopenia, renal dysfunction or both during the first course Gulack, 2015 [12] USA (HIE) Multi-centre (165 units), retrospective cohort study. Data extracted from a prospectively collected patient database (Level 2b) Ibuprofen (N = 1177) vs. indomethacin (N = 5172)No description of whether IV or oral preparations Effectiveness: (OR < 1.0 favours ibuprofen) Multivariable logistic regression adjusted analysis: Closure rate: No data Surgical ligation: OR = 1.10 (0.87, 1.37) Not included in the Loomba or Ohlsson systematic reviews Clear description of study cohort Power analysis included (5400 infants to give 80% power for 3.75% absolute difference) Patient’s identified by treatment with ibuprofen/indomethacin, rather than as having PDA diagnosis No access to echocardiographic data to give initial size of PDA or to confirm PDA closure Safety: Multivariable logistic regression adjusted analysis: Death before discharge: OR = 1.10 (CI: 0.82 to 1.47) Rise in creatinine: OR = 1.16 (0.87 to 1.54) Loomba, 2015 [1] SR of mixed nations and economies (LMIE = 1, UMIE = 2, HIE = 5) SR with MA of 22 papers (n = 1583) (Level 1a-) Sub-analysis of six papers [11, 24–28] comparing oral ibuprofen (n = 193) vs. IV indomethacin (n = 219) Effectiveness: (OR < 1.0 favours oral ibuprofen) Significant heterogeneity was not present (chi-squared = 0.76, p = 0.51, I2 = 0%) Closure rate: OR = 0.76 (CI: 0.50−1.18) Surgical ligation: OR = 0.78 (CI: 0.45−1.37) Cochrane Handbook for SR of Interventions was used for quality evaluation Bias was assessed using the Cochrane Risk of Bias Tool Publication bias was assessed qualitatively using forest plots for endpoints with 10 or more studies included Heterogeneity between studies was identified using chi-square and I2 tests Safety: NEC: OR = 0.60 (CI: 0.30−1.24) Gastrointestinal bleeding: OR = 0.62 (CI: 0.31−1.27) Bronchopulmonary dysplasia: OR = 0.80 (CI: 0.47−1.36) Change in serum creatinine (mean difference −0.03, CI: −0.11−0.05) Sub-analysis of two papers [10, 29] comparing oral ibuprofen (n = 58) vs. oral (n = 45) indomethacin Effectiveness: Heterogeneity was not present (chi-squared = 0.45, p = 0.50, I2 = 0%) Closure rate: OR 0.90 (CI: 0.40 to 2.00). Safety: Change in serum creatinine favouring ibuprofen: mean difference −0.10 (CI−0.13 to−0.07) Ohlsson, 2015 [5] SR of mixed nations and economies (LMIE = 2, UMIE = 9, HIE = 1) Cochrane SR with MA (Level 1a-) of 33 studies (n = 2190) Planned subgroup analysis of eight studies [10, 24, 28–33] comparing oral ibuprofen (n = 145) vs. IV or oral indomethacin (n = 127) Effectiveness: (RR < 1.0 favours oral ibuprofen) Closure failure: RR = 0.96 (CI: 0.73−1.27) Surgical closure: RR = 0.93 (CI: 0.50−1.74) Well-designed systematic review Only randomized or quasi-randomized controlled trials included Subgroup analysis was planned No subgroup analysis regarding resource poor environments A single paper was described looking at ‘early’ or ‘expectant’ management of a PDA. This found no statistically significant difference between the early vs. the expectant group for mortality or CLD at 36 weeks [24] Safety: Mortality: −0.10 (CI−0.20 to 0.00) NEC: RR = 0.41 (CI 0.23−0.73) Plasma creatinine: mean difference −0.51 (CI: −6.04, 5.01) IVH: RR = 0.90 (CI: 0.45−1.83) Intestinal perforation: RR = 0.24 (CI: 0.03−1.95) Gastrointestinal bleed: RR = 2.80 (CI: 0.48−16.45) Oliguria: RR = 0.0 (CI: −0.10 to 0.10) Planned subgroup analysis of four studies [35–38] comparing oral ibuprofen (n = 156) compared with IV ibuprofen (n = 148) Effectiveness Closure failure: RR = 0.41 (CI: 0.27−0.64)Surgical closure: RR = 0.35 (CI: 0.1−1.17) Safety NEC: RR = 0.86 (CI: 0.35−2.15) Intestinal perforation: RR = 0.32 (CI: 0.01−7.48) Gastrointestinal bleed: RR = 2.89 (0.12−69.24) Plasma creatinine: mean difference −22.47 (CI: −32.40 to−12.53) Oliguria: RR = 0.14 (CI: 0.01−2.66) Cheriff, 2007 [39] UMIE Non-controlled pilot study (Level 4) Oral ibuprofen (n = 40). No comparison group Effectiveness Ductal closure in 38/40 (95%) of infants. Surgical closure in 1/40 (2.5%) A small pilot study No control group Safety NEC: 3/40 (7.5%) Gastrointestinal bleed: 2/40 (5%) Renal impairment: 0/40 Tatli, 2004 [13] Turkey (UMIE) Case report (Level 4) Two infants Safety Both newborns had sudden abdominal distension without prodromal and radiological findings of NEC Small case series with a significant complication Heyman, 2003 [40] Israel (HIE) Non-controlled pilot study (Level 4) Oral ibuprofen (n = 22). No comparison group Effectiveness Ductal closure in 21/22 (96%) of infants. No reopening of the ductus after closure had been achieved A small pilot study to identify dosing regimen Good inclusion criteria described for external validity Good description of neonatal care Safety No difference in serum creatinine pre- and post-treatment Note: Income Group (World Bank) [41]: low-income economy (LIE), lower-middle-income economy (LMIE), upper-middle-income economy (UMIE), high-income economy (HIE). ASK A STATISTICIAN Loomba describes no heterogeneity in their systematic review. In systematic reviews, heterogeneity is the variability or differences between studies in the estimates of effects. Heterogeneity should be differentiated as ‘statistical heterogeneity’ (differences in the reported effects), ‘methodological heterogeneity’ (differences in study design) and ‘clinical heterogeneity’ (differences between studies in key characteristics of the participants, interventions or outcome measures). See Bandolier EBM glossary [9]. COMMENTARY When treating this newborn, one of the first questions the clinician will need to ask is whether the PDA is clinically significant? If so, then treatment certainly can be considered, as this infant is at risk of the PDA not closing spontaneously (see above). This is especially important in many resource-limited settings, where there is a lack of long-term respiratory support whilst awaiting spontaneous closure. These papers reveal a selection of small non-randomized and randomized studies, which have been summated in two large systematic reviews [1, 5] including a Cochrane review [5]. Ibuprofen is effective, and this is well established in these papers. Throughout, equivalence of effectiveness was demonstrated. However, the lack of statistically significant difference between groups does not necessarily indicate that there is no difference. The group sizes were small in all the papers including the meta-analysed (MA) data in the systematic reviews. Yadav [10] and Yang [11] both performed pre-study power analyses with a clinically relevant ‘difference’ of 25% (with 80% power) resulting in sample sizes of n = 35 and n = 24, respectively. Considering PDA is known to be a relatively common problem in neonates, with significant implications, one has to consider if a ‘difference’ of 25% is adequate to determine superiority. Gulack [12] described 3.75% absolute difference as an adequate marker, with a power analysis revealing a requirement of 5400 infants to give 80% power to determine equivalence in rates of important outcomes such as death and/or requirement of surgical ligation. Regarding safety, it is well established that there are risks associated with COX inhibitors. The systematic reviews and the large cohort study [12] find no evidence that ibuprofen has significantly more complications when compared with either oral or IV indomethacin. In a subgroup analysis of their Cochrane systematic review, Ohlsson [5] described fewer transient side effects on the kidneys and reduced the risk of NEC when comparing oral ibuprofen with IV ibuprofen. Ohlsson and Loomba did not include the large multicentre, retrospective cohort study by Gulack [12], which was not available at the time of MA. Gulack studied 1177 infants treated with ibuprofen and 5172 infants treated with indomethacin and initially found a higher rate of complications with ibuprofen. However, multivariable analysis of the same data revealed no significant differences in any negative outcomes, including death. Noteworthy to interpretation related to our PICO question, Gulack did not describe a subgroup analysis for oral and IV preparations. Tatli [13] reported two cases of spontaneous intestinal perforation (SIP) in two infants treated with oral ibuprofen. SIP affects 3% of all Very-low Birth Weight newborns and therefore is not a rare entity [13]. Both systematic reviews looked at gastrointestinal complications such as NEC, SIP and bleeding. There is no evidence that oral ibuprofen has a higher incidence of these complications, with Ohlsson [5] finding that oral ibuprofen leads to less NEC then IV or oral indomethacin [risk ratio (RR) = 0.41, confidence interval (CI): 0.23−0.73], though this finding was not repeated in Loomba’s paper [odds ratio (OR) = 0.60, CI: 0.30−1.24). Globally, prematurity continues to be a significant cause of mortality and identifying cheap, effective and safe treatments for common neonatal problems, such as PDA, is a priority. In this case, there are important financial, logistical and practical considerations. Oral ibuprofen costs $2 per 100 ml bottle (100 mg/5 ml) and is easily available, compared with $345 and $60 for a three-dose course of IV ibuprofen and indomethacin, respectively [14]. In Rwanda, gross national income is $700 [15]. These costs therefore offer a significant financial challenge to many families who already face the cost of care of a premature infant. Logistically, IV preparations are often not available, and therefore, clinicians need robust evidence that oro-gastric preparations are effective and safe in this vulnerable group of patients. Finally, in considering the practical issues, IV preparations are burdensome in a resource-limited setting, as they require an IV cannula to be sited for three doses (24 h apart), which adds to cost whilst also requiring a skilled practitioner for insertion in a preterm infant. The IV cannula also requires monitoring for extravasation, and the siting of a cannula increases the infection risk in the infant, and is therefore not without risk. AT THE BEDSIDE: APPLYING THE EVIDENCE Once the clinician has determined that the PDA is clinically significant and that treatment should be considered, then ibuprofen is as effective as indomethacin for PDA closure with oro-gastric administration of ibuprofen appearing as effective as Intravenous (IV) administration (Grade A); oral ibuprofen appears to be as safe as IV/oral indomethacin or IV ibuprofen (Grade A); and oral ibuprofen may have fewer transient side effects on the kidneys and reduced the risk of NEC compared with IV ibuprofen (Grade B). WHAT NEXT Paracetamol is now regularly used as the agent of choice for PDA closure or for cases when COX inhibitors are contraindicated (e.g. thrombocytopenia, bleeding, renal impairment, etc.) [16]. A future journal club Best Evidence Topic comparing paracetamol with ibuprofen would be of assistance to clinicians striving to choose the most appropriate therapy for these infants. A further pertinent question to consider is whether the use of any pharmacological agent to close a PDA benefits the infant or should the clinician wait for the ductus to close itself without intervention? This is a question that is gaining momentum [17, 18], and trends suggest that, year-in-year-out, clinicians are treating fewer cases of PDA [19–21]. The National Perinatal Epidemiology Group (NPEU) is currently recruiting patients as part of a multicentre, masked, randomized placebo-controlled parallel group trial (‘OSCAR study’) in extremely preterm babies to determine short- and long-term health and economic outcomes of active treatment (with ibuprofen) vs. no treatment (placebo) [2]. This study is aiming to recruit 730 extremely preterm babies over an 82-month period and will provide the best evidence available to answer this question, with meaningful, clinically relevant outcomes. This journal club awaits the results with anticipation. References 1 Loomba R , Nijhawan K. 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Journal of Tropical Pediatrics – Oxford University Press

Published: Oct 1, 2018

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