TDM is generally considered unnecessary for caffeine treatment of apnea of prematurity in preterm infants. This is because the caffeine concentration at which toxicity occurs is markedly higher than the effective blood-caffeine concentration. Several studies that have previously measured blood-caffeine concentrations have not evaluated doses, as we did in this study [9, 10]. This study demonstrated that the administration of 8 mg/kg/day of caffeine citrate may lead to toxic blood-caffeine concentrations. However, some patients receiving the dose had caffeine concentrations within the normal range. This may be due to individual differences in the excretion of caffeine.
In preterm infants, especially in the neonatal period, urinary metabolic pathways are mainly responsible for caffeine metabolism [11]. In adults, caffeine is metabolized and excreted by hepatic CYP1A2. However, in preterm infants, caffeine is not metabolized because of low CYP1A2 activity. Furthermore, due to reduced reabsorption in the renal tubules, most of the caffeine is excreted unchanged in the urine [11]. Therefore, the lower the urinary excretion, the higher the blood-caffeine concentration. The determinants of urinary excretion are glomerular filtration rate (GFR), renal tubular secretion, and reabsorption in the renal tubule. In preterm infants, most caffeine is not reabsorbed or secreted in the renal tubules. Caffeine excretion is therefore only affected by GFR.[11]. Therefore, the individual differences in serum caffeine concentrations at the same dosage are considered to reflect the differences in GFR. Future studies should evaluate the correlation of GFR with blood-caffeine concentration using serum creatinine and cystatin C, which estimate GFR. It was expected that the lower the gestational age of the infant, the higher the blood-caffeine concentration, because it has been reported that the lower the gestational age, the lower the GFR [12]. However, in this study, there was no significant correlation between blood-caffeine concentrations and gestational age or postmenstrual age. This may be explained by individual differences in GFR due to their treatment course, regardless of gestational age or postmenstrual age. At a dose of ≥ 8 mg/kg, the postmenstrual age was significantly smaller in the toxic concentration group than in the normal group, but the maintenance dose was also significantly higher. Thus, we deduce that a lower postmenstrual age may not be the only risk factor for toxic concentration.
In addition, patients who developed toxicity did not have significant toxic symptoms (e.g., irritability, tachycardia, and polypnea). All reported neonate patients with caffeine intoxication were those who had a single overdose of caffeine [13–15]. It took at least 7 days for the patients in this study to reach blood concentrations of caffeine that may lead to caffeine intoxication. The reason for the lack of obvious symptoms of caffeine intoxication may be the absence of a rapid increase in blood concentrations of caffeine.
A limitation of this study was that the sample size was not planned. This was a pilot study in which stored sera were extensively measured. Therefore, we did not plan the sample size and reported the results for all the samples included in the study. Future studies should include calculations of sample number and further planning. In addition, since this study was an exhaustive survey, the gestational age, the age at the time of caffeine administration, and the duration of caffeine administration varied. From the results of this study, it was found that samples receiving doses ≥ 8 mg/kg/day were likely to exceed the toxic blood-caffeine concentrations. Therefore, we plan to increase the number of samples at doses ≥ 8 mg/kg/day.
It is still unknown whether high blood concentrations of caffeine have an impact on neurological prognosis. However, several studies have reported that high blood concentrations of caffeine are detrimental to brain neurons [16–18]. Therefore, the results show that patients with high blood concentrations of caffeine require long-term developmental follow-up.