The Effect of Theophylline on Regional Cerebral Blood Flow Responses to Hypoxia in Newborn Piglets

Abstract

ABSTRACT. 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 mav thus ieo~ardize cerebral oxidative metabolism. With these con~de~ations 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 (Pa02 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 pmol/liter, and cerebrospinal fluid theophylline levels of 30-40 pmol/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. (Pediatr Res 21: 573-578, 1987) Abbreviations CBF, cerebral blood flow COD, cerebral oxygen delivery CMR02, cerebral metabolic rate for oxygen MAP, mean arterial pressure SSP, sagittal sinus pressure CPP, cerebral perfusion pressure ANOVA, analysis of variance Theophylline is used widely in neonatal medicine, its uses include the treatment of apnea of prematurity (1, 2), the treatment of bronchopulmonary dysplasia (3), and the facilitation of weaning from mechanical ventilation (4-6). Several studies in adult models have shown that theophylline attenuates CBF re-

Effect of Caffeine on Cerebral Blood Flow Velocity in Preterm Infants

“…On the contrary, using the newborn piglet un der conditions of controlled ventilation to maintain a constant Pco2> Stonestreet et al [5] showed that a therapeutic dose of ami nophylline (6 mg/kg) did not alter CBF. McPhee and Maxwell [8] confirmed these findings with theophylline (10 mg/kg) in the same animal model.…”

“…CBF was measured with either the xenon-133 inhala tion technique, or the xenon-133 intracarot id injection method [6,7]. In contrast to adults, Stonestreet et al [5] and McPhee and Maxwell [8] found no effect of aminophyl line and theophylline, respectively, on CBF (measured by microspheres) in the newborn animal.…”

Brain Hemodynamic Changes in Preterm Infants after Maintenance Dose Caffeine and Aminophylline Treatment

“…These results apparently differ from previously studies that found that aminophylline [4,[6][7][8][9] and theophylline [5] significantly reduce CBF [5,[7][8][9] and CBF velocity [4,6]. Nonetheless, the study design of these papers is very different from ours: (1) loading doses of aminophylline (or theophylline) were administered to the patients; (2) some studies evaluated CBF [5,[7][8][9] and others evaluated CBF velocity [4,6]; (3) some studies were performed by cerebral Doppler ultrasounds [4,6], others by xenon clearance technique [5,7], or by NIRS [8,9]; (4) none of them provided continuous monitoring of cerebral hemodynamics that was able to show transient and slight changes, and (5) there is wide variability in the study period. In particular, Bucher et al [9] applied NIRS from 10 min before to 20 min after administration of aminophylline, while in the remaining studies data collection started 60 min after drug administration or later, and none of them investigated possible changes during this initial unrecorded period.…”

The Contribution of δ1- and δ2-Opioid Receptors to Hypoxia-Induced Pial Artery Dilation in the Newborn Pig

“…In new born pigs, for instance, hypoxia increased brain in terstitial fluid adenosine concentration (Park et ai. , 1987), but hypoxia-induced hyperemia was not di minished by theophylline (McPhee and Maxwell, 1987). Similar differences concerning the role of prostaglandins in hypoxia-induced cerebrovasodila tion have also been noted.…”