Apnea is defined as a cessation of breathing for twenty seconds or greater, or as a brief episode if associated with bradycardia, cyanosis, or pallor. Recurrent apnea of prematurity occurs in up to 85% of infants born under 1000g. Standard treatment of care for apnea of prematurity is the administration of methylxanthines, specifically caffeine citrate, as a respiratory stimulant. This class of pharmacotherapy is a nonselective inhibitor of adenosine receptors. Adenosine inhibits respiratory neural output both directly and through interactions with another inhibitor of respiratory control, GABA. Adenosine A1 receptors are also thought to play a role in hypoxia-induced brain injury, and features of perinatal white matter injury have been observed in rodents treated with A1AR agonists during early postnatal life. By inhibiting adenosine effects, caffeine may play a role in preventing white matter injury. Recently, caffeine therapy for apnea of prematurity has been shown to improve the rate of survival without neurodevelopmental disability at 18 to 21 months, reduce the incidence of cerebral palsy, and reduce the incidence of cognitive delay in infants with very low birth weight.
In the last five years, multiple trials have studied the effects of using higher doses of caffeine citrate in the treatment of apnea of prematurity. Steer compared the efficacy of three dosing regimens of caffeine citrate (3, 15, and 30 mg/kg) and found that higher doses of caffeine correlated with less documented apnea and less time with oxygen saturations \<85%. The effectiveness of higher caffeine doses was confirmed when Scanlon showed that a loading dose of 50 mg/kg of caffeine citrate is more effective in reducing apneic episodes within eight hours than a caffeine citrate loading dose of 25 mg/kg. Studies evaluating the long-term neurologic effects of higher doses of methylxanthines, however, have resulted in conflicting conclusions. For patients at 12 months of corrected gestational age, Steer found a higher incidence of major disabilities in the low dose caffeine group compared with the high-dose group (18% to 7.5%). Conversely, Davis reported a higher incidence of cerebral palsy in 14 year old children with birth weight below 1501g who were treated with theophylline in the newborn period than prematurely born infants without methylxanthine treatment (13% to 1.6%).
Recent advances in magnetic resonance imaging (MRI) have allowed for new techniques in visualizing brain injury and development in preterm infants by non-invasive means. Diffusion tensor imaging (DTI) is a modality of MRI that measures the translational motion of water within tissue, or "apparent diffusion." If the direction of diffusion is hindered more in one direction than another, the water motion is considered anisotropic. Water apparent diffusion in mature white matter is highly anisotropic; the directionally averaged water apparent diffusion coefficient (ADC) has been referenced at 1.0-2.0 x 10\^-3 mm2/s for the infant brain, 0.8 x 10\^-3 mm2/s for the adult brain. Normative values obtained by DTI have been shown to be a sensitive indicator for white and gray matter development and complexity. Both Dyet and Woodward have been able to correlate abnormal white matter signals on brain MRI in preterm infants with subsequent impairment in cognitive, motor, and neurosensory outcomes.
As caffeine use in the CAPT study has been demonstrated in low doses commenced around 3 days of life to have a positive impact on neurodevelopmental outcomes at 18 to 21 months, it would be beneficial to understand the effects of a higher dose of caffeine on both short- and long-term outcomes with an emphasis on the prevention of brain injury (intraventricular hemorrhage and white matter injury) and the improvement of neurodevelopmental development.
Thus, we propose a randomized controlled trial of high-dose versus standard low-dose caffeine therapy postulating that high doses of caffeine citrate will have beneficial effects on both short- and long-term neurologic outcomes.
