Olivier Baud1, Laure Maury2, Florence Lebail3, Duksha Ramful4, Fatima El Moussawi5, Claire Nicaise6, Véronique Zupan-Simunek7, Anne Coursol8, Alain Beuchée9, Pascal Bolot10, Pierre Andrini11, Damir Mohamed12, Corinne Alberti12. 1. Neonatal Intensive Care Unit, Assistance Publique-Hôpitaux de Paris, Centre Hospitalier Universitaire Robert Debré, Université Paris Diderot, Sorbonne Paris Cité, INSERM U1141, Paris, France. Electronic address: olivier.baud@rdb.aphp.fr. 2. Neonatal Intensive Care Unit, Assistance Publique-Hôpitaux de Paris, Centre Hospitalier Universitaire Robert Debré, Université Paris Diderot, Sorbonne Paris Cité, INSERM U1141, Paris, France. 3. Neonatal Intensive Care Unit, Centre Hospitalier Corbeil-Essonnes, Sud Francilien, France. 4. Neonatal and Pediatric Intensive Care Unit, CHR Saint-Denis, La Réunion, France. 5. Neonatal Intensive Care Unit, Centre Hospitalier Intercommunal de Poissy, Poissy, France. 6. Neonatal Intensive Care Unit, Assistance Publique-Hôpitaux de Marseille, Centre Hospitalier Universitaire Hôpital Nord, Marseille, France. 7. Neonatal Intensive Care Unit, Assistance Publique-Hôpitaux de Paris, Centre Hospitalier Universitaire Antoine Béclère, Paris, France. 8. Neonatal intensive care unit, Centre Hospitalier de Pontoise, France. 9. Neonatal Intensive Care Unit, Centre Hospitalier Universitaire Rennes, France. 10. Neonatal Intensive Care Unit, Centre Hospitalier de Saint-Denis, France. 11. Neonatal Intensive Care Unit, Centre Hospitalier Universitaire Grenoble, France. 12. Unit of Clinical Epidemiology, Assistance Publique-Hôpitaux de Paris, Centre Hospitalier Universitaire Robert Debré, Université Paris Diderot, Sorbonne Paris-Cité, INSERM U1123 and CIC-EC 1426, Paris, France.
Abstract
BACKGROUND: Bronchopulmonary dysplasia, a major complication of extreme prematurity, has few treatment options. Postnatal steroid use is controversial, but low-dose hydrocortisone might prevent the harmful effects of inflammation on the developing lung. In this study, we aimed to assess whether low-dose hydrocortisone improved survival without bronchopulmonary dysplasia in extremely preterm infants. METHODS: In this double-blind, placebo-controlled, randomised trial done at 21 French tertiary-care neonatal intensive care units (NICUs), we randomly assigned (1:1), via a secure study website, extremely preterm infants inborn (born in a maternity ward at the same site as the NICU) at less than 28 weeks of gestation to receive either intravenous low-dose hydrocortisone or placebo during the first 10 postnatal days. Infants randomly assigned to the hydrocortisone group received 1 mg/kg of hydrocortisone hemisuccinate per day divided into two doses per day for 7 days, followed by one dose of 0·5 mg/kg per day for 3 days. Randomisation was stratified by gestational age and all infants were enrolled by 24 h after birth. Study investigators, parents, and patients were masked to treatment allocation. The primary outcome was survival without bronchopulmonary dysplasia at 36 weeks of postmenstrual age. We used a sequential analytical design, based on intention to treat, to avoid prolonging the trial after either efficacy or futility had been established. This trial is registered with ClinicalTrial.gov, number NCT00623740. FINDINGS:1072 neonates were screened between May 25, 2008, and Jan 31, 2014, of which 523 were randomly assigned (256hydrocortisone, 267 placebo). 255 infants onhydrocortisone and 266 on placebo were included in analyses after parents withdrew consent for one child in each group. Of the 255 infants assigned tohydrocortisone, 153 (60%) survived without bronchopulmonary dysplasia, compared with 136 (51%) of 266 infants assigned to placebo (odds ratio [OR] adjusted for gestational age group and interim analyses 1·48, 95% CI 1·02-2·16, p=0·04). The number of patients needed to treat to gain one bronchopulmonary dysplasia-free survival was 12 (95% CI 6-200). Sepsis rate was not significantly different in the study population as a whole, but subgroup analyses showed a higher rate only in infants born at 24-25 weeks gestational age who were treated with hydrocortisone (30 [40%] of 83 vs 21 [23%] of 90 infants; sub-hazard ratio 1·87, 95% CI 1·09-3·21, p=0·02). Other potential adverse events, including notably gastrointestinal perforation, did not differ significantly between groups. INTERPRETATION: In extremely preterm infants, the rate of survival without bronchopulmonary dysplasia at 36 weeks of postmenstrual age was significantly increased by prophylactic low-dose hydrocortisone. This strategy, based on a physiological rationale, could lead to substantial improvements in the management of the most premature neonates. FUNDING: Assistance Publique-Hôpitaux de Paris.
RCT Entities:
BACKGROUND:Bronchopulmonary dysplasia, a major complication of extreme prematurity, has few treatment options. Postnatal steroid use is controversial, but low-dosehydrocortisone might prevent the harmful effects of inflammation on the developing lung. In this study, we aimed to assess whether low-dosehydrocortisone improved survival without bronchopulmonary dysplasia in extremely preterm infants. METHODS: In this double-blind, placebo-controlled, randomised trial done at 21 French tertiary-care neonatal intensive care units (NICUs), we randomly assigned (1:1), via a secure study website, extremely preterm infantsinborn (born in a maternity ward at the same site as the NICU) at less than 28 weeks of gestation to receive either intravenous low-dosehydrocortisone or placebo during the first 10 postnatal days. Infants randomly assigned to the hydrocortisone group received 1 mg/kg of hydrocortisone hemisuccinate per day divided into two doses per day for 7 days, followed by one dose of 0·5 mg/kg per day for 3 days. Randomisation was stratified by gestational age and all infants were enrolled by 24 h after birth. Study investigators, parents, and patients were masked to treatment allocation. The primary outcome was survival without bronchopulmonary dysplasia at 36 weeks of postmenstrual age. We used a sequential analytical design, based on intention to treat, to avoid prolonging the trial after either efficacy or futility had been established. This trial is registered with ClinicalTrial.gov, number NCT00623740. FINDINGS: 1072 neonates were screened between May 25, 2008, and Jan 31, 2014, of which 523 were randomly assigned (256 hydrocortisone, 267 placebo). 255 infants on hydrocortisone and 266 on placebo were included in analyses after parents withdrew consent for one child in each group. Of the 255 infants assigned to hydrocortisone, 153 (60%) survived without bronchopulmonary dysplasia, compared with 136 (51%) of 266 infants assigned to placebo (odds ratio [OR] adjusted for gestational age group and interim analyses 1·48, 95% CI 1·02-2·16, p=0·04). The number of patients needed to treat to gain one bronchopulmonary dysplasia-free survival was 12 (95% CI 6-200). Sepsis rate was not significantly different in the study population as a whole, but subgroup analyses showed a higher rate only in infants born at 24-25 weeks gestational age who were treated with hydrocortisone (30 [40%] of 83 vs 21 [23%] of 90 infants; sub-hazard ratio 1·87, 95% CI 1·09-3·21, p=0·02). Other potential adverse events, including notably gastrointestinal perforation, did not differ significantly between groups. INTERPRETATION: In extremely preterm infants, the rate of survival without bronchopulmonary dysplasia at 36 weeks of postmenstrual age was significantly increased by prophylactic low-dosehydrocortisone. This strategy, based on a physiological rationale, could lead to substantial improvements in the management of the most premature neonates. FUNDING: Assistance Publique-Hôpitaux de Paris.
Authors: A Kugelman; M Peniakov; S Zangen; Y Shiff; A Riskin; A Iofe; I Shoris; D Bader; S Arnon Journal: J Perinatol Date: 2016-10-13 Impact factor: 2.521
Authors: Rosemary D Higgins; Alan H Jobe; Marion Koso-Thomas; Eduardo Bancalari; Rose M Viscardi; Tina V Hartert; Rita M Ryan; Suhas G Kallapur; Robin H Steinhorn; Girija G Konduri; Stephanie D Davis; Bernard Thebaud; Ronald I Clyman; Joseph M Collaco; Camilia R Martin; Jason C Woods; Neil N Finer; Tonse N K Raju Journal: J Pediatr Date: 2018-03-16 Impact factor: 4.406