MRI and Neurodevelopment in Preterm Infants Following Administration of High-Dose Caffeine
| Status: | Completed |
|---|---|
| Conditions: | Hospital, Neurology, Pulmonary |
| Therapuetic Areas: | Neurology, Pulmonary / Respiratory Diseases, Other |
| Healthy: | No |
| Age Range: | Any |
| Updated: | 4/21/2016 |
| Start Date: | November 2008 |
| End Date: | December 2015 |
Magnetic Resonance Imaging and Neurodevelopmental Outcomes in Preterm Infants Following Administration of High-Dose Caffeine - A Pilot Study
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.
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.
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.
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.
Inclusion Criteria:
- Preterm infants from 24 to 30 weeks completed PMA admitted to the neonatal intensive
care unit (NICU) at St. Louis Children's Hospital. The estimated post menstrual age
will be provided by the obstetrical records and compared with a Dubowitz exam at
admission. The provided PMA will be used unless the Dubowitz exam has a discrepancy
of greater or equal to 2 weeks, where then the Dubowitz age will be used.
- Infants must be recruited within the first 24 hours of life.
Exclusion Criteria:
- Infants over 30 weeks gestation.
- Infants who are moribund with severe sepsis, in respiratory failure, or have severe
brain injury present in the first 24 hours of life. This would be defined as
physiologic instability requiring >80% FiO2 for 6 hours and/or more than 2 inotropic
drugs (excluding hydrocortisone), or in the attending or recruiting physicians'
opinion the infant is likely to die within 24 hours or would not tolerate any
handling for the protocol.
- Infants must not have received any doses of caffeine citrate prior to enrollment.
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