A LC–MS/MS method for the quantification of caffeine, betamethasone, clonidine and furosemide in cerebrospinal fluid of preterm infants

Background: Newborns, admitted to the Neonatal Intensive Care Unit (NICU), are exposed to a large number of medications, the majority of which are not labeled for use in infants, especially in preterm newborns, because clinical trials on their benefits and harms are lacking. There is a huge gap in knowledge on pharmacokinetic (PK) data in sick preterm infants, including that of drug penetration to cerebrospinal fluid (CSF). One of the issues is related to the lack of reliable analytical methods for the measurement of drugs in CSF. Methods: In this paper we describe a specific and sensitive LC–MS/MS method for the simultaneous quantification in CSF of four commonly prescribed drugs in NICUs: caffeine, betamethasone, clonidine and furosemide. Results: The method was validated following EMA guidelines and applied to several CSF samples of preterm infants with post-hemorrhagic ventricular dilatation in which a ventricular access device was applied. The range of the concentrations of the four drugs measured in the CSF was wide. Conclusions: Our method can be considered useful for further clinical studies to describe the PK aspects of these drugs in neonatal medicine.