Caffeine for Hypoxic-Ischemic Encephalopathy

Hypoxic-ischemic encephalopathy (HIE) due to perinatal asphyxia is common and often fatal. Therapeutic hypothermia reduces mortality and morbidity in infants with HIE. Even with the widespread use of therapeutic hypothermia, ~60% of infants with HIE die or have neurodevelopmental impairment. As a result, there is an urgent, unmet public health need to develop adjuvant therapies to improve survival and neurodevelopmental outcomes in this population. Caffeine may offer neuroprotection for infants with HIE by blocking adenosine receptors in the brain and reducing neuronal cell death. In animal models of HIE, caffeine reduces white matter brain injury. Drugs in the same class as caffeine (i.e., methylxanthines) have been shown to be protective against acute kidney injury in the setting of HIE. However, their safety and efficacy have not been studied in the setting of therapeutic hypothermia and their effect on neurological outcomes is not known. Since these drugs reduce injury to the kidney in infants with HIE, they may also reduce injury to the brain. This phase I study will evaluate the pharmacokinetics, safety, and preliminary effectiveness of caffeine as an adjuvant therapy to improve neurodevelopmental outcomes in infants with HIE.

The first cohort of 9 infants will receive a lower maintenance dose of caffeine. Following a safety review, an additional 9 infants will receive a higher maintenance dose.

AUC0-t defines area under the plasma concentration-time curve (AUC) from administration to the last quantifiable concentration at time t.

7 samples will be collected with the following optimal sampling windows: 0-15 minutes, 30-60 minutes, 1-3 hours, 3-6 hours, 6-12 hours, 12-18 hours, 15 minutes prior to next dose.

Incidence of seizures and necrotizing enterocolitis, which are potential complications of caffeine exposure

Incidence of seizure activity requiring >1 anti-epileptic medication. Necrotizing enterocolitis defined as Bell Stage II or III.

Number of participants with abnormal MRI brain findings based on NICHD Neonatal Research Network score

The NICHD Neonatal Research Network developed and validated an MRI scoring system that categorizes severity of brain injury in the Trial of Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy. Score 0: Normal T2 MRI Score 1A: Minimal cerebral lesions only with involvement of basal ganglia, thalamus Score 1B: Extensive cerebral lesions Score 2A: Basal ganglia thalamic, anterior or posterior limb of internal capsule, or watershed infarction Score 2B: 2A with cerebral lesions Score 3: Hemispheric devastation

Number of participants with a Bayley Scales of Infant Development (BSID-III) cognitive, language, or motor composite score < 85

The BSID--III is a series of measurements to assess the motor (fine and gross), language (receptive and expressive), and cognitive development of infants and toddlers and consists of a series of developmental play tasks. The composite scores are scaled to a metric with a range of 40 to 160, a mean of 100, and a standard deviation of 15. Therefore, children with a composite score < 85 are 1 standard deviation below the mean in that area.

Inclusion Criteria: Documented informed consent from parent or guardian ≥ 36 weeks gestational age at birth Receiving therapeutic hypothermia for a diagnosis of HIE Intravenous (IV) access Postnatal age < 24 hours Exclusion Criteria: Receiving > 1 anti-epileptic drug for seizures Sustained (>4 hours) heart rate > 180 beats per minute Known major congenital anomaly Any condition which would make the participant, in the opinion of the investigator, unsuitable for the study

Deidentified individual data that supports the results will be shared beginning 9 to 36 months following publication provided the investigator who proposes to use the data has approval from an Institutional Review Board (IRB), Independent Ethics Committee (IEC), or Research Ethics Board (REB), as applicable, and executes a data use/sharing agreement with UNC.

Proposals may be submitted up to 36 months following article publication. After 36 months the data will be available in our University's data warehouse but without investigator support other than deposited metadata.

Shankaran S, McDonald SA, Laptook AR, Hintz SR, Barnes PD, Das A, Pappas A, Higgins RD; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Neonatal Magnetic Resonance Imaging Pattern of Brain Injury as a Biomarker of Childhood Outcomes following a Trial of Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy. J Pediatr. 2015 Nov;167(5):987-93.e3. doi: 10.1016/j.jpeds.2015.08.013. Epub 2015 Sep 16.

Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, Fanaroff AA, Poole WK, Wright LL, Higgins RD, Finer NN, Carlo WA, Duara S, Oh W, Cotten CM, Stevenson DK, Stoll BJ, Lemons JA, Guillet R, Jobe AH; National Institute of Child Health and Human Development Neonatal Research Network. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med. 2005 Oct 13;353(15):1574-84. doi: 10.1056/NEJMcps050929.