Long-Term Effects of Caffeine Therapy for Apnea of Prematurity

Schmidt, Barbara; Roberts, Robin S.; Davis, Peter G; Doyle, Lex W.; Barrington, Keith J.; Ohlsson, Arne; Solimano, Alfonso; Tin, Win

doi:10.1056/nejmoa073679

Cited by 841 publications

(558 citation statements)

References 23 publications

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“…[76][77][78] As a result of these findings there were concerns about the long-term effects of caffeine on brain development. However, results of placebo-controlled multicenter trials showed that caffeine therapy for AOP reduces the incidence of bronchopulmonary dysplasia 79 and improves survival without neurodevelopmental disability in very low birth weight infants. 80 In this regard, the finding of Back et al 81 that caffeine has a protective effect on chronic hypoxia-induced white matter injury is intriguing.…”

Section: Treatment Strategiesmentioning

confidence: 99%

Apnea of prematurity: pathogenesis and management strategies

Mathew

2010

J Perinatol

109

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Apnea of prematurity (AOP) is a significant clinical problem manifested by an unstable respiratory rhythm reflecting the immaturity of respiratory control systems. This review will address the pathogenesis of and treatment strategies for AOP. Although the neuronal mechanisms leading to apnea are still not well understood, recent decades have provided better insight into the generation of the respiratory rhythm and its modulation in the neonate. Ventilatory responses to hypoxia and hypercarbia are impaired and inhibitory reflexes are exaggerated in the neonate. These unique vulnerabilities predispose the neonate to the development of apnea. Treatment strategies attempt to stabilize the respiratory rhythm. Caffeine remains the primary pharmacological treatment modality and is presumed to work through blockade of adenosine receptors A 1 and A 2 . Recent evidences suggest that A 2A receptors may have a greater role than previously thought. AOP typically resolves with maturation suggesting increased myelination of the brainstem.

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Section: Treatment Strategiesmentioning

confidence: 99%

Apnea of prematurity: pathogenesis and management strategies

Mathew

2010

J Perinatol

109

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“…The PK profile of caffeine in neonates is characterized by a volume of distribution of 0.8-0.9 L/kg, which is larger than that of children or adults 4,5) . In addition, the half-life of caffeine in neonates is approximately 72-96 hours, which is longer than that of adults, and is further prolonged with decreased renal function.…”

Section: Introductionmentioning

confidence: 97%

Clinical Pharmacokinetics of Caffeine in Korean Preterm Infants with Apnea of Prematurity

Lim¹,

Son²,

Shin³

et al. 2017

Neonatal Med

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Purpose: Caffeine shows wide interindividual pharmacokinetic (PK) variation, and therapeutic drug monitoring (TDM) may be needed. The PK profile of caffeine in Korean preterm neonates was investigated, and factors influencing the clearance of caffeine were analyzed. Methods: Fifty-nine preterm neonates receiving caffeine for apnea of prematurity were enrolled in the study (gestational age, 29.5±2.2 weeks and birth weight [BW], 1,318±358 g). Caffeine (20 mg/kg) was intravenously administered to each neonate as a loading dose, followed by a maintenance dose of 5-10 mg/kg/d. A total of 190 serum concentrations were measured for population PK analysis and modeling using nonlinear mixed-effects model (NONMEM ® ) software. Results:The mean serum concentration of caffeine was 15.4±4.5 mg/L (range 7.8-33.0 mg/L). High serum concentrations (>20 mg/L) were noted in 36 samples (29%). At the first measurement of serum caffeine, the mean postmenstrual age was 33.9±2.3 weeks, mean BW was 1,802±471 g, mean duration of treatment was 7.4±9.4 days, and mean sampling time after the last dose was 21.8±2.1 hours. In the population PK analysis, the clearance was 0.033 L/h and volume of distribution was 0.371 L. Typical clearance was calculated as 0.0293×(BW/70) 1.33 . Among the subjects receiving 5 mg/kg/d caffeine, the most significant risk factor associated with high serum concentrations (>20 mg/L) was low BW (P=0.024). Conclusion: BW was the only covariate that influenced caffeine clearance in preterm neonates. Preterm neonates with low BW should be carefully monitored for apnea and adverse reactions in addition to undergoing TDM.

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“…A recent study demonstrated that caffeine therapy for very preterm infants is associated with significant reductions in the duration of assisted ventilation, the incidence of patent DA, and the rate of bronchopulmonary dysplasia, by ~10%, and that it reduces the incidence of cerebral palsy as compared with placebo-treated infants (18,19). Although these are very important outcomes, the mechanisms responsible are unknown.…”

mentioning

confidence: 99%

Effects of caffeine on renal and pulmonary function in preterm newborn lambs

et al. 2012

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IntroductIon: administration of caffeine is associated with a reduction in bronchopulmonary dysplasia, assisted ventilation, patent ductus arteriosus (Da), and cerebral palsy in preterm infants, but the mechanisms are unknown. Our aim was to determine the effects of acute caffeine administration on renal and pulmonary functions in preterm lambs. Methods: Lambs were delivered by cesarean section at ~126 d of gestation and ventilated with a tidal volume of 5 ml/ kg, 60 breaths/min and 5 cmh 2 O positive end-expiratory pressure. after 30 min, lambs received 40 mg/kg caffeine i.v. (n = 7) or saline (controls; n = 6) over 30 min and were ventilated for 2 h. results: arterial concentrations of caffeine reached 35.9 ± 7.8 mg/l. Urine output and mean heart rate were significantly higher after caffeine treatment than in controls (5.86 ± 1.95 vs. 0.76 ± 0.94 ml/kg, area under the curve, P = 0.041 and 211 ± 8 vs. 169 ± 15 beats per minute, P < 0.05, respectively). heart rate remained higher for the experimental period. dIscussIon: caffeine did not affect pulmonary artery or Da blood flows or other renal, respiratory, or cardiovascular parameters examined. Neonatal administration of caffeine increased heart rate and urine output but had little effect on pulmonary function in ventilated preterm lambs.

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Long-Term Effects of Caffeine Therapy for Apnea of Prematurity

Abstract: Caffeine therapy for apnea of prematurity improves the rate of survival without neurodevelopmental disability at 18 to 21 months in infants with very low birth weight. (ClinicalTrials.gov number, NCT00182312 [ClinicalTrials.gov].).

Cited by 841 publications

References 23 publications

Apnea of prematurity: pathogenesis and management strategies

Apnea of prematurity: pathogenesis and management strategies

Clinical Pharmacokinetics of Caffeine in Korean Preterm Infants with Apnea of Prematurity

Effects of caffeine on renal and pulmonary function in preterm newborn lambs

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