Using the Doppler technique, the effect of therapeutic doses of indomethacin on the cerebral blood flow velocity (CBFV) of anterior cerebral arteries was studied in 13 preterm infants with patent ductus arteriosus. The first intravenous injection of indomethacin (0.2 mg/kg, group 1, n = 10) induced a significant decrease in the area under the velocity curve at 15 min (––22%), which was sustained until 120 min (––28%, p < 0.005). In contrast, no significant change in CBFV occurred after the third dose (group 2, n = 7). In both groups, capillary blood gases, mean arterial blood pressure, and heart rate remained stable throughout the study. In 5 mechanically ventilated infants, the increase in CBFV secondary to suctioning was significantly attenuated after the first dose of indomethacin (p < 0.02) but not after the third (p = 0.56). Thus, an initial dose of indomethacin may attenuate CBFV increases secondary to clinical manipulations in the preterm newborn.

This study investigated the role of adenosine in the regulation of neonatal cerebral blood flow (CBF) during moderate (arterial PO2 = 47 +/- 9 Torr) and severe (arterial PO2 = 25 +/- 4 Torr) hypoxia. Twenty-eight anesthetized and ventilated newborn piglets were assigned to four groups: 8 were injected intravenously with the vehicle (controls, group 1); 13 received an intravenous injection of 8-phenyltheophylline (8-PT), a potent adenosine receptor blocker, either 4 mg/kg (group 2, n = 6, mean cerebrospinal fluid (CSF) levels less than 1 mg/l) or 8 mg/kg (group 3, n = 7, mean CSF levels less than 3.5 mg/l); and 7 received an intracerebroventricular injection of 10 micrograms 8-PT (group 4). During normoxia, CBF was not altered by vehicle or 8-PT injections. In group 1, 10 min of moderate and severe hypoxia increased total CBF by 112 +/- 36 and 176 +/- 28% (SE), respectively. Compared with controls, the cerebral hyperemia during moderate hypoxia was not altered in group 2, attenuated in group 3 (to 53 +/- 13%, P = NS), and completely blocked in group 4 (P less than 0.01). CBF increase secondary to severe hypoxia was attenuated only in group 4 (74 +/- 29%, P less than 0.05). CSF concentrations of adenosine and adenosine metabolites measured by high-performance liquid chromatography increased during hypoxia. Arterial O2 content was inversely correlated (P less than 0.005) to maximal CSF levels of adenosine (r = 0.73), inosine (r = 0.87), and hypoxanthine (r = 0.80).(ABSTRACT TRUNCATED AT 250 WORDS)

Caffeine and doxapram are two respiratory stimulants used in the treatment of apnea in newborns. When used concurrently, these drugs may produce interactive effects on the control of breathing in the newborn. The ventilatory effects of these drugs, given alone or together, were measured during 150 min of drug infusion in two groups of awake lambs 2-5 days old. The first group (n = 5) received a caffeine loading dose of 10 mg/kg followed by a maintenance dose of 0.1 mg/kg/h and incremental doses of doxapram: 0.25, 0.5, 1.25 and 2.5 mg/kg/30 min. The second group (n = 5) received a doxapram loading dose of 5.5 mg/kg followed by a maintenance dose of 1 mg/kg/h and incremental doses of caffeine: 2.5, 5.0, 7.5 and 10.0 mg/kg/30min. In the first group, ventilation increased after the caffeine loading dose from 566 ± 55 to 680 ± 74 ml/kg/min (plasma caffeine = 14.7 ± 1.6 mg/l) and progressively increased with the addition of incremental doses of doxapram upto 1,000 ± 108 ml/kg/min at 2.5 mg/kg of doxapram (p < 0.001 compared to baseline and caffeine loading dose). In contrast, in the second group, the doxapram loading dose markedly increased ventilation from 582 ± 50 to 936 ± 75 (p < 0.002 and p < 0.04 compared to caffeine loading dose) at plasma doxapram of 5.3 ± 0.8 mg/l, but incremental doses of caffeine had no effects. We conclude that doxapram exerts a brisk and powerful respiratory stimulant effect and produces an additional dose-dependent ventilatory response when added to caffeine.

The effects of the prostaglandins (PG) PGE(1), PGE(2), PGF(2α) and PGI(2), and of indomethacin on cerebral blood flow (CBF) and cerebral metabolic rate for O(2) (CMRO(2)) were studied in 60 1-to 3-day-old conscious piglets. Effects of PGs in indomethacin-treated animals were also measured. CBF was measured by radiolabelled microspheres prior to and 45 s after intracarotid bolus injections of 0.1 -10 μg/kg PGE(1) and 0.01-1 μg/kg PGE(2), PGF(2α) and PGI(2). PGE(1) decreased CBF by 30% at the dose of 0.1 μg/kg and increased it by 39.5% (n = 6) at the higher dose of 10 μg/kg. PGE(2) (n = 6) increased CBF at all doses administered. PGF(2α) (0.01 μg/kg, n = 8), which is a potent cerebral vasoconstrictor in adults, and PGI(2) (0.1 μg/kg, n = 6) significantly increased CBF in newborn piglets (p < 0.05). CMRO(2) correlated with CBF in all groups of animals, except for those injected with PGI(2). Indomethacin (3 mg/kg i.v.) decreased CBF by 39% (p < 0.01, n = 6). This effect was partially reversed by PGI(2), but not by PGE(1) and PGF(2α). Sagittal venous blood and arterial-sagittal venous blood differences in concentrations of PGF(2α), but not of PGE and 6-keto-PGF(1α), correlated weakly but positively (r = 0.4, p < 0.05) with CBF in indomethacin-treated piglets. These data indicate that PGs exert significant effects on cerebral circulation in the newborn. Primary PGs are principally cerebral vasodilators and are devoid of vasoconstrictive effects in the newborn, except for PGE(1) which produces vasoconstriction at low dose (0.1 μg/kg). Thus, we speculate that a relative deficiency in cerebral vasoconstrictor effect of PGs may contribute to the reduced upper limit of the CBF autoregulatory range of the newborn.