All aspects of the study were approved by the ethics committee of Tokushima University (approval number 3755) and were carried out in accordance with the approved guidelines. Because this is a retrospective study, it was difficult to obtain appropriate informed consents from each subject. Therefore, we gained consents using opt-out, which is a way for investigators to give subjects an opportunity for all participants or their guardians to refuse to participate in this study by announcing the detail of this study on the Tokushima University website (http://www.tokushima-hosp.jp/about/disclosure_document.html). The review board of ethics committee of Tokushima University Hospital has approved the way of opt-out consent in this retrospective study.
Inclusion criteria for this study were preterm infants who were inborn at 240/7-316/7 weeks of gestation and were admitted between 2009 and 2018 to the neonatal intensive care unit (NICU) at Tokushima University Hospital. Patients were excluded if any of following was applicable: chromosomal abnormalities, congenital major malformations, outborn, or death prior to 48 h of life. Basic clinical information was extracted from the database in the NICU, and individual medical records were reviewed by multiple authors (MT, ST, OT, and SM).
Fluid therapy starting from the first day of life
Fluid therapy was principally determined based on the judgment of attending physician. Early parenteral AA supplementation was defined as having started within 24 h after birth. Controls were infants supplied with parenteral AA after 24 h of life. The other regimen of fluid therapy on the first of life was also obtained including glucose and gluconate calcium.
The primary outcome was the occurrence of neonatal hyperkalemia. Peak K+ levels during the first 72 h were recorded, and neonatal hyperkalemia was defined as K+ > 6.5 mEq/l with urine output ≥1 ml/kg/h .2,18 Other data for blood examinations were also obtained at the time of the highest serum K+ concentration.
Neurological impairments and morbidites
Neurological impairments were cerebral palsy, mental retardation, attention deficit hyperactivity disorder, autism spectrum disorder, and learning disorder. These neurological impairments were adjudicated by senior pediatricians who were not otherwiseinvolved in this study. Neonatal morbidities were also recorded, including BPD, IVH, PVL, NEC, ligation of PDA, and ROP requiring treatment. BPD was defined as oxygen or respiratory support at a corrected age of 36 weeks. IVH above grade 2 according to the Papile classification was extracted in this study.19
Continuous variables are shown as medians and interquartile ranges, and categorical variables are shown as counts and percentages. The chi-squared test and Fisher’s exact test were used to compare categorical variables appropriately, and the Wilcoxon rank-sumtest was used to compare continuous variables, because all continuous variables were determined to be nonparametric by the Shapiro-Wilk normality test. p<0.05 was considered the threshold for statistical significance. Multivariate analysis were performed with the following explanatory variables: AA supplementation that started within 24 h after birth, risk factors and possible prophylactic management for the occurrence of hyperkalemia determined by clinical relevance and the settings used in previous reports 2,11. These included maternal age, primipara, multiple pregnancy, antenatal steroid, tocolytic agents, cesarean section, delivery before 28 weeks of gestation, non-reassuring fetal status, infant sex, small for gestational age (defined as an infant with weight below the 10th percentile for gestational age and height below the 10th percentile for gestational age),20 Apgar score at 1 min after birth <3, and calendar year (in 5 year intervals). JMP version 15.2 (SAS Institute, Cary, NC) was used for all statistical analyses.
Data and materials used in this study are available upon reasonable request to the corresponding author and under a collaboration agreement.