Caffeine Citrate for the Treatment of Apnea of Prematurity

Marcia L. Buck, Pharm.D., FCCP; Kristi N. Hofer, Pharm.D.; Michelle W. McCarthy, Pharm.D.


Pediatr Pharm. 2008;14(6) 

In This Article

Mechanism of Action

Caffeine (1,3,7-trimethylxanthine) acts as an antagonist to endogenous adenosine at A1 and A2 receptor subtypes. It inhibits phosphodiesterase, leading to increased levels of cyclic AMP and stimulation of the central nervous system (CNS). Caffeine relaxes bronchial smooth muscle, stimulates cardiac muscle, and acts as a mild diuretic. In infants with apnea, caffeine is believed to work by stimulating the central respiratory center, decreasing the carbon dioxide threshold and increasing the response to hypercapnea. Caffeine may also increase skeletal muscle tone and decrease diaphragmatic fatigue, aiding respiratory effort.[1,8,9]

The pharmacokinetic profile of caffeine in infants has been evaluated in several studies. Caffeine is well absorbed after oral administration, with a bioavailability approaching 100%. In neonates, a 20 mg/kg caffeine citrate dose produces peak serum concentrations of 6 to 10 mcg/mL, with an average time to peak of 30 minutes to 2 hours. Absorption does not appear to be affected by administration with feedings. Caffeine is widely distributed throughout the body, with a mean volume of distribution of 0.8 to 0.97 L/kg in neonates (compared to 0.6 L/kg in adults). It rapidly crosses the blood-brain barrier, achieving concentrations in the cerebrospinal fluid equal to serum concentrations.[8,9,10,11,12]

Caffeine is metabolized in the liver by cytochrome P450 1A2 (CYP1A2), as well as CYP2E1 and CYP3A3/4. Approximately 3 to 10% of a caffeine dose is converted to theophylline. In clinical trials, the mean elimination half-life of caffeine has been correlated to postconceptional age, postnatal age, and weight, reflecting the development of CYP1A2 activity in the growing infant. In preterm neonates, the half-life of caffeine is approximately 72 to 96 hours (range 40 to 231 hours). By 9 months of age, the half life has declined to approximately 5 hours, similar to that observed in adults. Likewise, the rate of caffeine clearance increases with age, from an average of 5 to 9 mL/hr/kg in neonates to 94 mL/hr/kg in adults.[8,9,10,11,12]


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