Caffeine for Neuroprotection in Birth-Related Brain Injury

Research Question Can intravenous caffeine improve brain recovery in babies with birth-related brain injury (hypoxic-ischaemic encephalopathy; HIE)? I will test the hypothesis that caffeine increases proton magnetic resonance (MR) spectroscopy thalamic N-acetylaspartate concentrations ([NAA]) and reduces the time to normalisation of amplitude-integrated electroencephalography (aEEG) in babies with moderate or severe HIE undergoing cooling therapy. Background In the UK, HIE affects 1–2 per 1,000 live births — approximately 800 babies annually. Around 30% of affected babies either die shortly after birth or develop serious long-term complications, including cerebral palsy, epilepsy, and sensory impairments. The lifetime care cost for a child with severe brain injury can reach £20 million, with NHS litigation costs exceeding £2.9 billion annually. Among 25 neuroprotective therapies evaluated in preclinical studies, caffeine has shown the most promise, with evidence suggesting greater efficacy than cooling therapy, the current standard care. Aims The primary aim is to assess whether caffeine alongside cooling therapy, compared with cooling alone, increases thalamic [NAA] at 1–2 weeks in newborn babies with moderate or severe HIE. Secondary aims include assessing brain injury on conventional MR imaging and time to aEEG normalisation. Methods Sixty-five newborn babies (?36 weeks’ gestation and aged <6 hours) will be recruited from six NHS hospitals within the NIHR-funded Cooling in Mild Encephalopathy (COMET) platform. Babies will be randomised 1:1 to receive either intravenous caffeine citrate (20 mg/kg loading dose, followed by 10 mg/kg at 24 and 48 hours) alongside cooling therapy or cooling therapy alone. All babies will undergo continuous aEEG monitoring for the first three days after birth. MR spectroscopy will be performed between days 7–10 using a harmonised protocol and analysed with SPANT to measure thalamic [NAA], with assessors masked to treatment allocation. Conventional MR images will be scored using a validated system, also masked to allocation. The primary outcome is mean thalamic [NAA] (mmol/kg/wet weight). Secondary outcomes include evidence of brain injury on conventional MRI and age at aEEG normalisation. Timeline The 36-month fellowship will include nine months for approvals and set-up, 22 months for recruitment, and five months for data analysis and dissemination. Knowledge Mobilisation and Impact This proposal was developed in collaboration with parents of babies with HIE, the charities HOPE for HIE and PEEPS, clinical teams across participating sites, and with input from industry partners, trialists, supervisors, and mentors, all of whom will continue to contribute throughout the project. Knowledge mobilisation will involve direct communication with parents and the public through meetings, newsletters, social media, and presentations at national and international conferences. Findings will be published in peer-reviewed journals. Research Inclusion Site selection reflects the UK’s diversity in geography, ethnicity, and socioeconomic background. Inclusive recruitment will be supported through translated materials, access to interpreters, and tailored communication strategies. Parental and public involvement is embedded in the study design, costed accordingly, and will be actively monitored throughout the project.