Caffeine as a treatment for perinatal hypoxic-ischemic brain injury - the potential risks and benefits.

It is well established that therapeutic hypothermia improves outcomes for infants with moderate-severe hypoxic-ischemic encephalopathy in high-income counties. However, ~29 % of the infants treated with therpeutic hypothermia still have adverse outcome. Additionally, therapeutic hypothermia is not recommended as a treatment for infants with HIE in low- and middle-income countries. Therefore, there is an urgent need to develop alternative treatments for infants with HIE in middle- and low-income countries, as well as additive treatments to therapeutic hypothermia in high-income countries. Caffeine is widely used as an agent to prevent apnea in preterm infants, and more recently, it has been investigated as a potential neuroprotective treatment for perinatal hypoxic-ischemic brain injury, but the preclinical evidence so far has been mixed. Furthermore, there are concerns that caffeine, which is an adenosine receptor antagonist, could abolish the endogenous neuroprotective effects of adenosine, during and after hypoxia-ischemia. Further studies, particularly in large animal translational models of hypoxic-ischemic brain injury are required to establish the safety and efficacy of caffeine in this setting before conducting large randomized controlled trials.