Early treatment versus expectative management of patent ductus arteriosus in preterm infants: a multicentre, randomised, non-inferiority trial in Europe (BeNeDuctus trial).

BACKGROUND: Much controversy exists about the optimal management of a patent ductus arteriosus (PDA) in preterm infants, especially in those born at a gestational age (GA) less than 28 weeks. No causal relationship has been proven between a (haemodynamically significant) PDA and neonatal complications related to pulmonary hyperperfusion and/or systemic hypoperfusion. Although studies show conflicting results, a common understanding is that medical or surgical treatment of a PDA does not seem to reduce the risk of major neonatal morbidities and mortality. As the PDA might have closed spontaneously, treated children are potentially exposed to iatrogenic adverse effects. A conservative approach is gaining interest worldwide, although convincing evidence to support its use is lacking. METHODS: This multicentre, randomised, non-inferiority trial is conducted in neonatal intensive care units. The study population consists of preterm infants (GA < 28 weeks) with an echocardiographic-confirmed PDA with a transductal diameter > 1.5 mm. Early treatment (between 24 and 72 h postnatal age) with the cyclooxygenase inhibitor (COXi) ibuprofen (IBU) is compared with an expectative management (no intervention intended to close a PDA). The primary outcome is the composite of mortality, and/or necrotising enterocolitis (NEC) Bell stage ≥ IIa, and/or bronchopulmonary dysplasia (BPD) defined as the need for supplemental oxygen, all at a postmenstrual age (PMA) of 36 weeks. Secondary outcome parameters are short term sequelae of cardiovascular failure, comorbidity and adverse events assessed during hospitalization and long-term neurodevelopmental outcome assessed at a corrected age of 2 years. Consequences regarding health economics are evaluated by cost effectiveness analysis and budget impact analysis. DISCUSSION: As a conservative approach is gaining interest, we investigate whether in preterm infants, born at a GA less than 28 weeks, with a PDA an expectative management is non-inferior to early treatment with IBU regarding to the composite outcome of mortality and/or NEC and/or BPD at a PMA of 36 weeks. TRIAL REGISTRATION: This trial is registered with the Dutch Trial Register NTR5479 (registered on 19 October 2015), the registry sponsored by the United States National Library of Medicine Clinicaltrials.gov NCT02884219 (registered May 2016) and the European Clinical Trials Database EudraCT 2017-001376-28 .

Association of Placebo, Indomethacin, Ibuprofen, and Acetaminophen With Closure of Hemodynamically Significant Patent Ductus Arteriosus in Preterm Infants: A Systematic Review and Meta-analysis.

Importance: Despite increasing emphasis on conservative management of patent ductus arteriosus (PDA) in preterm infants, different pharmacotherapeutic interventions are used to treat those developing a hemodynamically significant PDA. Objectives: To estimate the relative likelihood of hemodynamically significant PDA closure with common pharmacotherapeutic interventions and to compare adverse event rates. Data Sources and Study Selection: The databases of MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched from inception until August 15, 2015, and updated on December 31, 2017, along with conference proceedings up to December 2017. Randomized clinical trials that enrolled preterm infants with a gestational age younger than 37 weeks treated with intravenous or oral indomethacin, ibuprofen, or acetaminophen vs each other, placebo, or no treatment for a clinically or echocardiographically diagnosed hemodynamically significant PDA. Data Extraction and Synthesis: Data were independently extracted in pairs by 6 reviewers and synthesized with Bayesian random-effects network meta-analyses. Main Outcomes and Measures: Primary outcome: hemodynamically significant PDA closure; secondary: included surgical closure, mortality, necrotizing enterocolitis, and intraventricular hemorrhage. Results: In 68 randomized clinical trials of 4802 infants, 14 different variations of indomethacin, ibuprofen, or acetaminophen were used as treatment modalities. The overall PDA closure rate was 67.4% (2867 of 4256 infants). A high dose of oral ibuprofen was associated with a significantly higher odds of PDA closure vs a standard dose of intravenous ibuprofen (odds ratio [OR], 3.59; 95% credible interval [CrI], 1.64-8.17; absolute risk difference, 199 [95% CrI, 95-258] more per 1000 infants) and a standard dose of intravenous indomethacin (OR, 2.35 [95% CrI, 1.08-5.31]; absolute risk difference, 124 [95% CrI, 14-188] more per 1000 infants). Based on the ranking statistics, a high dose of oral ibuprofen ranked as the best pharmacotherapeutic option for PDA closure (mean surface under the cumulative ranking [SUCRA] curve, 0.89 [SD, 0.12]) and to prevent surgical PDA ligation (mean SUCRA, 0.98 [SD, 0.08]). There was no significant difference in the odds of mortality, necrotizing enterocolitis, or intraventricular hemorrhage with use of placebo or no treatment compared with any of the other treatment modalities. Conclusions and Relevance: A high dose of oral ibuprofen was associated with a higher likelihood of hemodynamically significant PDA closure vs standard doses of intravenous ibuprofen or intravenous indomethacin; placebo or no treatment did not significantly change the likelihood of mortality, necrotizing enterocolitis, or intraventricular hemorrhage. Trial Registration: PROSPERO Identifier: CRD42015015797.

Hypernatraemia in preterm infants born at less than 27 weeks gestation.

AIMS: To study the incidence of hypernatraemia (plasma sodium >145 mmol/L), identify predisposing factors to and associated complications of hypernatraemia in preterm infants born less than 27 weeks gestation in the first 5 days of life. METHODS: Preterm infants less than 27 week gestation over an 18-month period were studied by retrospective analysis of patient records. Data were collected on gestation, birthweight, sex, antenatal steroid use, phototherapy, incubator humidity, time of transfer to incubator, plasma sodium, urea and creatinine. Actual fluid and sodium intake was calculated for the first 5 days of life. Data were collected on chronic lung disease, patent ductus arteriosus, intraventricular haemorrhage, necrotising enterocolitis and death. RESULTS: In this study 46 (69.7%) of 66 infants studied developed hypernatraemia (>145 mmol/L), occurring most frequently between 24 and 48 h of age. The median gestation of hypernatraemic babies was significantly lower. There was no significant difference in median birthweight, or factors associated with increased insensible water loss between the hypernatraemic and the non-hypernatraemic groups. Fluid intake was significantly higher on days 2, 3 and 4 in the hypernatraemic group. There was no difference in sodium intake between the two groups. More hypernatraemic babies compared with controls developed chronic lung disease, patent ductus arteriosus, significant intraventricular haemorrhage, necrotising enterocolitis and died, but was not significant. CONCLUSION: Hypernatraemia occurs commonly in preterm infants less than 27 weeks gestation and was not associated with significant morbidity. The more immature infants developed hypernatraemia and all cases resolved after increasing fluid intake.

Phototherapy effect on the incidence of patent ductus arteriosus in premature infants: prevention with chest shielding.

Patent ductus arteriosus is common among premature neonates, especially those with birth weights less than 1,500 g. In vitro, room light inhibits the contraction of immature piglet's ductal rings. Because phototherapy is used frequently from the first days of life to treat jaundice in preterm neonates, we compared the occurrence of patent ductus arteriosus among premature infants exposed to this intense light source with those whose chests were shielded. Seventy-four babies with respiratory distress syndrome were randomly assigned to either a treatment group (chest shielded with aluminum foil while on phototherapy, 36 babies) or control group (no shield, 38 babies). All were on radiant warmers, received mechanical ventilation for respiratory distress syndrome, and phototherapy (Air Shields model PTU 78-1) from day 1 of life. Irradiance was maintained at greater than 4.0 microW/cm2/nm in all cases. Although both groups had similar birth weights, gestational ages, severity of respiratory distress syndrome, intravenous fluid intake, and duration of phototherapy, the incidence of patent ductus arteriosus was significantly less in the shield group (shield 11/36 v No shield 23/38; P = .009). Patent ductus arteriosus murmurs developed in shielded patients at a later date, they required less vigorous treatment (ie, indomethacin), and they had shorter hospitalizations (74 v 85 days; P less than .05). The significant reduction of patent ductus arteriosus with shielding suggests that phototherapy may play a role in the occurrence of patent ductus arteriosus in premature infants. Shielding may be a practical method to decrease this common complication should this initial observation be confirmed.

Management of patent ductus arteriosus in the premature infant: indomethacin versus ligation.

A previous report from our institution analyzed the results of pharmacological (indomethacin) closure of patent ductus arteriosus (PDA) in 82 neonates. Closure was achieved in 54 patients. However, gastrointestinal complications occurred in 21, necrotizing enterocolitis in 13, and focal perforation in 8. Overall mortality in the indomethacin group was 40%. This paper compares the results of that pharmacological experience with our subsequent surgical experience with 86 low-birth-weight neonates for whom gestational age, size, illness, and mode of diagnosis were comparable. Mean weight at operation for this study was 1.1 kg; mean gestational age was 29.1 weeks. All infants required endotracheal-assisted ventilation for severe radiographic and clinical hyaline membrane disease. Range-gated Doppler study, retrograde flush aortography, and echocardiographic measurement of the ratio between the left atrium and the aortic root were used to confirm the diagnosis of PDA. Ligation was done in the neonatal intensive care unit using local anesthesia supplemented with morphine. Ventilation was controlled by an inhalation therapist; drug and blood administration were controlled by the infant's nurse. Surgical ligation was employed in all infants except for 7 in whom hemoclip ductal closure was chosen because of extreme instability, coagulopathy, or ductal perforation. There were no operative deaths. Surgical morbidity included ductal perforation (2 patients), wound infection (1), and phrenic nerve injury (1). Necrotizing enterocolitis occurred in 9 patients. The overall mortality was 17%. Patients with preoperative pneumo-thorax had a 32% overall mortality.(ABSTRACT TRUNCATED AT 250 WORDS)