Theophylline attenuates cerebral hypoxic hyperemia in several adult models and this is thought to be due to receptor-mediated antagonism of adenosine, a proposed mediator of hypoxic hyperemia. This attenuation of hypoxic hyperemia reduces cerebral oxygen delivery and may thus jeopardize cerebral oxidative metabolism. With these considerations in mind, and because theophylline is widely used in neonatal medicine, the present study was designed to investigate the effect of theophylline on regional cerebral blood flow, cerebral oxygen delivery, and cerebral metabolic rate for oxygen during normoxia and hypoxia in the newborn piglet model. In 16 newborn piglets, regional cerebral blood flow (microspheres) increased 250-350% during hypoxia (PaO2 20-30 torr), while cerebral oxygen delivery and cerebral metabolic rate for oxygen were maintained at normoxic levels. Eight of these piglets were then given 10 mg/kg theophylline ethylenediamine intravenously and studies during normoxia and hypoxia were repeated; the remaining eight piglets served as time controls. Regional cerebral blood flow, cerebral oxygen delivery, and cerebral metabolic rate for oxygen during normoxia and hypoxia were not influenced by theophylline, despite plasma theophylline levels of 55-65 mumol/liter, and cerebrospinal fluid theophylline levels of 30-40 mumol/liter. These negative results are reassuring with respect to hypoxic cerebral blood flow control in theophylline-medicated infants. However, they do not support a role for adenosine as a mediator of cerebral hypoxic hyperemia in this model.