iPAPP: study protocol for a multicentre randomised controlled trial comparing safety and efficacy of intravenous paracetamol and indomethacin for the treatment of patent ductus arteriosus in preterm infants.

INTRODUCTION: Patent ductus arteriosus (PDA) causes severe morbidity in premature infants. Although the use of indomethacin is the standard therapy for PDA, it is sometimes not applicable because of its adverse effects, such as renal and platelet dysfunctions. Paracetamol has emerged as an alternative to indomethacin owing to its excellent safety profile in infants. Of the recently reported case series and clinical trials on the use of paracetamol for PDA, there are few reports in Japan on paracetamol use in preterm infants. Furthermore, indications for the use of paracetamol for PDA have not been approved for use in PDA. While the safety of intravenous paracetamol therapy in case series of preterm infants treated for haemodynamically significant PDA (hsPDA) has been reported, studies which were conducted to compare paracetamol to indomethacin are limited. We, therefore, intend to investigate the hypothesis that intravenous administration of paracetamol has superior safety over indomethacin. METHODS AND ANALYSIS: Multicentre open-label randomised controlled trial for intravenous administration of paracetamol for PDA in preterm infants. The inclusion criteria are (1) hsPDA, (2) gestational age from 24 to 34 weeks and birth weight (BW) from 500 to 2000 g, (3) enrolment between 24 hours and 7 days from birth and (4) obtaining parental consent. The primary outcome is renal dysfunction within 48 hours from the last dose of the study drug. Enrolled patients fulfilling all the inclusion criteria are randomly allocated to either intravenous paracetamol or intravenous indomethacin. This trial requires 110 patients. ETHICS AND DISSEMINATION: The clinical trial would follow Japan's Clinical Trials Act. The trial protocol was approved by the Clinical Research Review Board of Saitama Medical University (approval number: 222001). A written informed consent would be obtained from one of the parents. The results are expected to be published in a scientific journal. TRIAL REGISTRATION NUMBER: jRCTs031220386. PROTOCOL VERSION: 31 March 2022, version 1.0.

Extreme Prematurity and Pulmonary Outcomes Program in Saitama: Protocol for a Prospective Multicenter Cohort Study in Japan.

BACKGROUND: Because of the improvements in survival rates for preterm infants, not only the rates of bronchopulmonary dysplasia (BPD) but also those of long-term respiratory complications of premature birth are increasing, resulting in financial and health burdens in developed countries. Thus far, the risk factors of respiratory morbidities in extremely preterm infants remain unknown. Furthermore, the definition and the predictive ability of BPD for long-term respiratory outcomes are yet to be determined. OBJECTIVE: The objective of our study, Extreme Prematurity and Pulmonary Outcomes Program in Saitama, is to develop the diagnostic criteria for BPD and to determine the prognostic factors contributing to the long-term pulmonary outcomes manifesting in extremely preterm infants. METHODS: The Extreme Prematurity and Pulmonary Outcomes Program in Saitama is an observational prospective cohort study performed by a consortium of six neonatal intensive care units (NICUs) in Saitama, Japan. The subjects included in this study are infants (from each clinical center) with gestational ages 22 to 27 weeks. The target is 400 subjects. This study aims to determine the definition of BPD and other perinatal factors that accurately predict the long-term pulmonary outcomes in survivors of extreme prematurity. Moreover, the association between BPD and postprematurity respiratory disease will be investigated using generalized linear models. RESULTS: The protocol and consent forms were evaluated and approved on September 5, 2019, by the Ethics Committee of Saitama Medical Center, Saitama Medical University. Enrollment began on April 1, 2020. It is expected to end on March 31, 2023. The follow-up for 1 year corrected age is expected to continue through the middle of 2024. CONCLUSIONS: The Extreme Prematurity and Pulmonary Outcomes Program in Saitama incorporates aspects of neonatal care in secondary- and tertiary-level NICUs to develop existing research studies on the definition of BPD, objective biomarkers, and outcome measures of respiratory morbidity in extremely preterm infants beyond NICU hospitalization, thereby leading to a novel understanding of the nature and natural history of BPD and potential mechanistic and therapeutic targets in at-risk subjects. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/22948.

Status of and problems concerning neonatal resuscitation in Japan in 2015.

BACKGROUND: The International Liaison Committee on Resuscitation (ILCOR) published Consensus 2015 in October 2015. Thereafter, the Japanese version of neonatal cardiopulmonary resuscitation programs was revised. Prior to the revision, we re-conducted questionnaire surveys in three types of medical facilities in January 2015. METHODS: Targeted groups included (i) 277 training hospitals authorized by the Japanese Society of Perinatal/Neonatal Medicine for training of physicians specialized in perinatal care (neonatology) in January 2015 (training hospitals; response rate, 70.8%); (ii) 459 obstetric hospitals/clinics (response rate, 63.6%); and (iii) 453 midwife clinics (response rate, 60.9%). The survey included systems of neonatal resuscitation, medical equipment and practices, and education systems. The results were compared with that of similar surveys conducted in 2005, 2010 and 2013. RESULTS: Almost all results were generally improved compared with past surveys. In training hospitals, however, the use of oxygen blenders or manometers was not widespread. Only 35% of institutions used continuous positive airway pressure systems frequently, and expert neonatal resuscitation doctors attended all deliveries in only 6% of training centers. In addition, only 71% of training hospitals had brain therapeutic hypothermia facilities. Not all obstetric hospitals/clinics prepared pulse oximeters, and only a few used manometers frequently. Some midwife clinics did not keep warming equipment, and few midwife clinics were equipped with pulse oximeters. In addition, some midwife clinics did not prepare ventilation bags (masks). CONCLUSIONS: The equipment in Japanese delivery rooms is variable. Further efforts need to be made in the distribution of neonatal resuscitation devices and the dissemination of techniques.

Early-infant diagnostic predictors of the neuro-behavioral development after neonatal care.

Multidimensional diagnosis plays a central role in infant developmental care, which leads to the prediction of future disabilities. Information consolidated from objective and subjective, early and late, central and peripheral data may reveal neuro-pathological mechanisms and realize earlier and more precise preventive intervention. In the current study, we retrospectively searched correlating factors to the following neurological and behavioral development of 'Head Control' and 'Roll Over' using multivariate correlation analysis of differ-ent diagnostic domains over age, subject/object information of the patients who were previously admitted in our neonatal intensive care unit (NICU) and could be developmentally followed up in our outpatient clinic. Based on the hematologic and biochemical data, MRI brain anatomy during NICU hospitalization, we characterized all the acquired data distribution from 31 infants with either 'appeared neurologically normal (ANN, n = 21)' or 'appeared neurologically abnormal (ANA, n = 10)' pro tempore, with a physician's clinical judgment before discharge. Besides single factor comparisons between ANN and ANA, we examined their development difference by using the multidimensional information processing, principal component analysis (PCA). The diagnostic predictors of neuro-behavioral development were selected by regression analysis with variable selection. It resulted that hematological and brain anatomical factors seemed correlated to both 'Head Control' and 'Roll Over'. This report suggested certain possibility of the cross-domain translational approach between subjective and objective developmental information through multivariate analyses, with candidate markers preliminarily to be evaluated in further studies.

Two Japanese patients with Leigh syndrome caused by novel SURF1 mutations.

We report two patients with Leigh syndrome that showed a combination of facial dysmorphism and MRI imaging indicating an SURF1 deficiency, which was confirmed by sequence analysis. Case 1 is a 3-year-old girl with failure to thrive and developmental delay. She presented with tachypnea at rest and displayed facial dysmorphism including frontal bossing, lateral displacement of inner canthi, esotropia, maxillary hypoplasia, slightly upturned nostril, and hypertrichosis dominant on the forehead and extremities. Case 2 is an 8-year-old boy with respiratory failure. He had been diagnosed as selective complex IV deficiency. Case 2 displayed facial dysmorphism and hypertrichosis. Since both patients displayed characteristic facial dysmorphism and MRI findings, we sequenced the SURF1 gene and identified two heterozygous mutations; c.49+1 G>T and c.752_753del in Case 1, and homozygous c.743 C>A in Case 2. For patients with Leigh syndrome showing these facial dysmorphism and hypertrichosis, sequence analysis of the SURF1 gene may be useful.