MRI and Neurodevelopment in Preterm Infants Following Administration of High-Dose Caffeine
Condition: Apnea of Prematurity; Intraventricular Hemorrhage; Brain Injury
MeSH terms: Brain Injuries; Hemorrhage
Study type: Interventional
Phase: Phase 4

Summary: 
      Over the last 30 years the survival rates for babies born prematurely have improved greatly
      with research. As these babies grow up, we have found that many of the premature babies have
      learning and movement problems. The purpose of this research is to learn why premature
      infants are at risk for learning disabilities and movement problems later in childhood and
      whether this is changed by caffeine therapy. Caffeine is often used in premature babies to
      help them to breathe on their own. Nearly all babies born before 30 weeks gestation receive
      caffeine while they are in the neonatal intensive care unit (NICU). Scientists have shown
      that caffeine therapy given to premature babies reduces their disabilities.

      We will use brain monitoring, including electro-encephalogram (EEG) and magnetic resonance
      imaging (MRI) to understand how the brain of a premature baby develops and whether caffeine
      in high doses enhances protection of the developing brain. Just as we monitor the heart and
      lungs to improve our care of premature babies, we wish to monitor the brain so that we can
      understand how to improve our care for the brain.
    

Detailed description: 
      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.
    

Intervention name(s): Caffeine citrate
Intervention type(s): Drug
Intervention description(s): Caffeine to be administered as outlined to compare efficacy of different dosages.
Other intervention name(s): Cafcit
Intervention MeSH terms: Caffeine; Caffeine citrate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention