Abstracts

Background: Intermittent hypoxia and apnea occur in all preterm babies <32 weeks gestation and may affect drug action, metabolism, disposition and drug dosing such as caffeine.This drug, used in preterm es has a significant impact on major acute neonatal morbidities.Its use is associated with reduction in the duration of mechanical ventilation, incidence of bronchopulmonary dysplasia and retinopathy of prematurity, and improvement of long-term neurodevelopmental outcome.Caffeine is a diuretic and has potent renal effects.However, its effects on vasoactive mediators in the neonatal kidneys under different oxygen environments and intermittent hypoxia remains unclear.Objective: To test the hypothesis that intermittent hypoxia amplifies dose-dependent adverse effects of caffeine on neonatal renal vasoactive mediators and prostanoid biosynthesis.Materials/Methods: Newborn rats were randomized to room air (RA), hyperoxia (50% O 2 ), or IH (50% O 2 with brief episodes of hypoxia, 10% O 2 ) from P0 to P14 during which they received: (1) standard caffeine doses (SCD) of 20 mg/kg IP (loading) on P0; and 5 mg/kg/day IP (maintenance) on P1-P14; (2) high caffeine doses (HiCD) of 80 mg/kg IP on P0 and 20 mg/kg IP on P1-P14; or (3) equivalent volume saline (Sal).At P14, somatic growth, and renal prostanoid production; histopathology; and expression of cyclooxygenases (COX-1&2), prostanoid receptors and aquaporin-4 (AQP-4) were examined.Results: Intermittent Hypoxia (IH) and hyperoxia had significant adverse effects on somatic growth.SCD produced no adverse effects on renal morphology, however IH amplified the detrimental effects of HiCD which produced the most severe renal injury, including marked necrosis and degeneration of the glomeruli and tubular structures.These were associated with increased COX-2 and TP; and decreased FP, IP, DP, and AQP-4 expression.Conclusions: Intermittent hypoxia potentiates the adverse effects of high doses of caffeine on renal prostanoids which are important regulators of renal development and function, suggesting toxicity in the developing kidneys.Its use should be avoided in the setting of IH or neonatal apnea.However, caffeine at standard doses is safe in the preterm neonate who experience frequent arterial oxygen desaturations or IH.