Abstract
Introduction Apnea of prematurity (AOP) is a clinical manifestation of an immature control of breathing in preterm infants. Caffeine therapy is the cornerstone of pharmacologic treatment for AOP, and is among the most frequently used medications in preterm infants. Although caffeine has been well studied in trials as well as in popPK studies, the daily clinical application may be different. The aim of this study is to describe current clinical use and dosing of caffeine and to evaluate effectiveness of this therapy.
Methods We performed a retrospective cohort study in preterm infants born before 30 weeks of gestation, admitted to the NICU of the Erasmus MC Rotterdam in the period of January 2018 to December 2021. Patients were included if they received treatment with caffeine base during their admission. The primary outcome of our study was treatment failure, defined as the need for an additional caffeine loading dose or co-treatment with doxapram.
Results A total of 554 patients with a median gestational age (GA) of 27 (IQR 26 to 28) weeks and a median birthweight of 980 (IQR 781 to 1200) grams were included in this study. The median caffeine maintenance dose per patient was 5.30 mg/kg/day, range 4.14 to 7.45. Caffeine treatment failed in 278 patients (50%), leading to one or more additional loading doses in 277 patients and co-treatment with doxapram in 99 patients. The median postnatal age at time of treatment failure was 18 days (IQR 7 to 33 days). In patients with a GA of <=27 weeks, treatment failed in the majority of patients. No correlation was found between postnatal age or birthweight and the caffeine maintenance dose at the time of treatment failure as would have been expected based on pharmacokinetic maturation.
Conclusion A high amount of caffeine is used in clinical practice to treat AOP, with relatively low effectivity, especially in the most extreme preterm infants. This in contrast to what would be expected based on pharmacological maturation and related kinetics. This suggests either an inversed age-related caffeine PK/PD relationship, with higher exposures needed in the smaller infants, or overexposure because of treatment resistant apnea. This might result in an unnecessarily high amount of caffeine given to this vulnerable group of extremely premature infants.
