Therapeutic drug monitoring is generally unnecessary in caffeine treatment for apnea of prematurity, as serum caffeine concentrations in preterm infants are normally markedly lower than those at which caffeine intoxication occurs. However, several studies have reported preterm infants having developed toxicity. This retrospective observational study, conducted at a tertiary center in Kagawa, Japan, aimed to evaluate the correlation between the maintenance dose and serum caffeine concentrations and determine the maintenance dose leading to suggested toxic caffeine levels. We included 24 preterm infants (gestational age, 27 ± 2.9 weeks; body weight, 991 ± 297 g) who were treated with caffeine citrate for apnea of prematurity between 2018 and 2021, and 272 samples were analyzed. Our primary outcome measure was the maintenance dose leading to suggested toxic caffeine levels. We found a positive correlation between caffeine dose and serum caffeine concentrations (p < 0.05, r = 0.72). At doses of ≥ 8 mg/kg/day, 15% (16/109) of patients had serum caffeine concentrations above the suggested toxic levels. Patients who receive doses ≥ 8 mg/kg/day risk reaching the suggested toxic serum caffeine levels. It remains unclear whether suggested toxic caffeine concentrations are detrimental to neurological prognosis. Further investigation is required to understand the clinical effects/outcomes of high serum levels of caffeine and to obtain long-term neurodevelopmental follow-up data.

Cerebral haemodynamics during the immediate transition period in neonates may differ depending on whether delivery is vaginal or by caesarean section. However, these differences have never been confirmed by near-infrared time-resolved spectroscopy (TRS). Therefore, the purpose of this study was to compare cerebral blood volume (CBV) and cerebral haemoglobin oxygen saturation (ScO2) between healthy term neonates by mode of delivery. Subjects were 31 healthy term neonates who did not require resuscitation. Thirteen neonates were delivered vaginally (VD group) and 18 were delivered by elective caesarean section (CS group). Absolute oxyhaemoglobin, deoxyhaemoglobin, and total haemoglobin concentrations were measured continuously by TRS; oxyHb × 100/totalHb (ScO2) (%) and CBV (mL/100 g brain tissue) were also calculated. Measurements were started as soon as possible after birth, obtained from 1 to 2 min after birth, and continued until 15 min after birth. CBV was significantly higher in the VD group than in the CS group in the 4 min after birth but not thereafter. There were no significant between-group differences in ScO2 and SpO2. These findings indicate that there is a difference in cerebral haemodynamic patterns in the first 4 min after delivery between term neonates by mode of delivery when CBV is monitored by TRS.

Therapeutic drug monitoring (TDM) is generally unnecessary in caffeine therapy for apnea of prematurity because the normal blood-caffeine concentrations of preterm infants are markedly lower than those at which caffeine intoxication occurs. However, several reports have mentioned preterm infants developing toxicity. In this retrospective observational study, conducted at a tertiary center in Kagawa, Japan, we evaluated the correlation between the maintenance dose and blood-caffeine concentrations and determined the maintenance dose leading to toxic caffeine concentrations.. Preterm infants were treated with caffeine citrate for apnea of prematurity between 2018 and 2021. Our primary outcome measure was the maintenance dose leading to toxic caffeine concentrations. Twenty-four preterm infants (gestational age, 27 ± 2.9 weeks; body weight, 991 ± 297 g) were included, and 272 samples were collected for analysis. The caffeine dose and blood-caffeine concentration were positively correlated (p < 0.05, r = 0.72). At doses of ≥ 8 mg/kg/day, 15% (16/109) of patients had a blood-caffeine concentration above the toxic concentration. Patients who receive doses of ≥ 8 mg/kg/day are at risk of reaching the toxic blood-caffeine concentration. Although it is unknown whether toxic caffeine concentrations are detrimental to neurological prognosis, the administration of high-dose (≥ 8 mg/kg/day) caffeine may require TDM to prevent blood-caffeine concentrations from reaching toxic levels.