Study registrations and Ethics consideration
The study was approved by the Ethics Committee of Children's Hospital of Chongqing Medical University and registered at http://www.chictr.org.cn. (ID: ChiCTR1900026980) (registration time: Oct-27, 2019). The study was performed in accordance with the approved guidelines and regulations of the participating institutions.
Study Design and Participants.
This was a retrospective study conducted in the neonatal intensive care unit (NICU), Children's Hospital of Chongqing Medical University from Jan-1, 2017 to July-30, 2018.
Eligibility requirements for neonates were as follows: (1) The gestational age was less than 37 weeks and admitted to NICU in 24 h after birth; (2) These neonates were initially diagnosed with RDS. Exclusion criteria were: (1) major congenital anomalies; (2) chromosomal abnormalities; (3) neuromuscular diseases; (4) upper respiratory tract abnormalities.
Diagnosis of neonatal RDS
The diagnosis criteria of RDS was based on clinical manifestations and chest X-ray findings. The clinical signs and symptoms of RDS were respiratory distress, tachypnea, nasal flaring, groan, and cyanosis appear within 24 h after birth, as well as beneficial response to pulmonary surfactant and/or lung recruitment strategies. The other criteria include the typical X-ray picture of a grain shadow, air bronchogram or white lung [3].
Diagnosis of neonatal ARDS.
The diagnosis of ARDS was according to the criteria established by pediatric acute lung injury consensus conference group in 2015 [6] and Montreux conference in 2017 [4], which mainly included: (1) A known or suspected clinical insult-associated acute onset within one week; (2) Exclusion of transient tachypnea of newborn (TTN), RDS, or congenital anomalies as a primary current acute respiratory condition. (3) Chest imaging changes cannot be explained by local effusions, atelectasis, RDS, TTN, or congenital anomalies; (4) Exclusion: edema induced by acute heart failure, fluid overload; (5) Oxygen index (OI) ≥4 should be used to diagnose ARDS for patients receiving noninvasive and invasive ventilation.
Definition of the transition from RDS to RDS and ARDS
Definition of the transition from RDS to RDS and ARDS must fulfill both the following conditions: 1. The first diagnosis in the first 24 h after birth was RDS; 2. The preterm infants were diagnosed with both RDS and ARDS within one week after birth;
The administration of surfactant replacement and caffeine citrate.
When the neonate was admitted to the NICU and had fulfilled the entry criteria, pulmonary surfactant (Curosurf, Chiesi Pharmaceuticals, Parma, Italy) was administered with a dosage of 200 mg/kg as a rescue treatment using the INSURE (intubation-surfactant-extubation) technique of surfactant administration if an infant needed FiO2>0.40 to maintain the targeted SpO2 with 90%-95%. The intervals of surfactant administration were 6 to 12 hours without more than four doses allowed, and the second and later dose was 100 mg/kg.
Also, these preterm infants received a loading dose of 20 mg/kg caffeine citrate and a maintenance dose of 10 mg/kg/d until 34 weeks of GA. Other care was at the discretion of the attending neonatologist.
Definition of PRF.
Four individual PRF were analyzed in the present study, including ICP, HDCP, GDM, and pernicious placenta previa (PPP). Diagnosis of PRF were consistent with recommendations and guidelines from international consensus files [10] and Chinese Medical Association [11-14]. The preterm infants with RDS were considered to be with PRF as long as having one or more individual PRF. The diagnosis of BPD is consistent with definition of BPD [15].
Evaluation of primary and secondary outcomes.
The primary outcomes were: 1) to report the effects of PRF on the transition from RDS to RDS and ARDS in preterm infants, and 2) to clarify whether stayed in RDS, as compared with transition to RDS and ARDS, is associated with the decreased incidence of BPD. And the secondary outcomes is mortality and other complications.
Data Collection
The clinical data of all enrolled neonates were collected in standardized case report forms, including gender, gestational age, birth weight, Apgar score, administration of surfactant, respiratory mode, PRF, death, BPD, retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), and so on.
Sample Size Estimation.
The sample size estimation was calculated by PASS software (2008 v8.0.3). According to previous studies [16], the incidence of RDS in newborns from ICP was about 28%. Our previous study have indicated that the incidence of severe RDS in newborns from ICP was about 7% [9], the incidence of ARDS was therefore thought to no less than 7%, if the severe RDS was considered as ARDS. With 80% power and a 2-sided significance level of 0.05, 21 neonates would be needed at least in RDS and ARDS conversion group. According to the nature of cohort study, the number in the RDS group was usually not less than RDS and ARDS conversion group, so at least 42 neonates would be needed in preterm infants from ICP. In the present study, four PRF were included, the total number was therefore 168. Actually, during the study period, 269 preterm infants were enrolled. Therefore, the actual sample size was more than theoretical need.
Statistical analysis.
Continuous variables, expressed as mean ± standard deviation, were compared using independent samples t test. Categorical variables were compared using the χ2 test or the Fisher’s test. The predefined BPD subgroups were: mild, moderate and severe BPD. To further assess the effects of surfactant administration on the rate of BPD between the two groups, use of surfactant were divided into three subgroups: zero, one and two of surfactant. Subgroup analyses were conducted for the primary outcome. All analyses were carried out using computer software (SPSS 16.0 for windows). A p-value less than 0.05 was regarded as statistically significant.