Differences in the Effects in the Newborn Piglet of Various Nonsteroidal Antiinflammatory Drugs on Cerebral Blood Flow but Not on Cerebrovascular Prostaglandins

Abstract

ABSTRACT. To characterize the role of prostaglandins (PG) in the regulation of basal cerebral blood flow (CBF) in the newborn, we determined the effects of four nonsteroidal antiinflammatory drugs, indomethacin (3 mg/kg, n = 8 and 10 mglkg, n = 5), aspirin (65 mg/kg, n = 6), ibuprofen (30 mg/kg, n = 8), and naproxen (15 mg/kg, n = 6), on CBF, cerebral metabolism, and cerebrovascular PG in conscious 1-to 3-d-old piglets. Drugs and vehicle (n = 8) were injected i.v., and measurements were made 5 min before and 20 and 60 min after injections. Neither the vehicle nor any of the nonsteroidal antiinflammatory drugs exerted significant effects on mean arterial blood pressure and on blood gases and pH. All four drugs, with the exception of indomethacin at the lower dose (3 mg/kg), decreased PG to nearly undetectable levels within 20 min; the low dose of indomethacin caused a small decrease (18-32%) in PG at 60 min. However, the effects of these agents on CBF were diverse. CBF increased after the administration of aspirin, decreased to almost the same extent after both low and high doses of indomethacin, and did not change after the administration of ibuprofen and naproxen. Cerebral metabolic rate for oxygen was increased by aspirin but was unaltered by the other drugs. The data suggest that PG may not play a critical role in the regulation of basal CBF in the newborn animal and that certain nonsteroidal antiinflammatory drugs may have additional actions unrelated to the inhibition of PG synthesis. (Pediatr Res 30: 106-111,1991) Abbreviations PG, prostaglandin CBF, cerebral blood flow BP, blood pressure NSAID, nonsteroidal antiinflammatory drugThe role of PG in the regulation of CBF during various hemodynamic disturbances, such as hypertension, hypotension, hypoxia, and asphyxia, has been reported by various investigators (1-14). However, the significance of PG in the regulation of basal CBF remains controversial (1 5-19). In most studies ex-

Prostaglandin G/H Synthase-2 Is a Major Contributor of Brain Prostaglandins in the Newborn

“…NS-398 reduced prostaglandin concentrations by Ն90% in the brain cortex of the newborn (Fig. 5), comparable with what was observed previously using ibuprofen and indomethacin (42); in contrast, NS-398, decreased brain prostaglandin levels in the juvenile animals only by 26 -30%. In retina where mRNA for PGHS-2 was not detectable (Fig.…”

A meta-analysis of ibuprofen versus indomethacin for closure of patent ductus arteriosus

“…INDO significantly decreases CBF and mitochondrial oxidative function in animals and human newborns [5,16] and inferentially perturbs neuronal function. In contrast, IBU exerts no effect on cerebral and mesenteric blood flow [5,6,20,23,24] and probably has little effect on cerebral perfusion. Whether IBU will prove to have a positive impact on later neurological outcome remains to be seen.…”

Safety and efficacy of ibuprofen versus indomethacin in preterm infants treated for patent ductus arteriosus: a randomised controlled trial

“…INDO (the accepted pharmacological treatment for non-invasive PDA closure in preterm infants) reversibly blocks the cyclo-oxygenase pathway of prostaglandin synthesis [4] which is why it can be expected to have a variety of adverse effects, e.g. renal dysfunction, necrotising enterocolitis, enteric perforation, gastrointestinal and diffuse bleeding.…”

“…The clinical consequences of persistent PDA are related to the degree of left-to-right shunting through the ductus and diastolic steal, leading to a redistribution of blood flow to the organs with localised vasoconstriction, reduced perfusion to the brain, gut and kidney, and Inhibiting prostaglandin synthesis with non-selective blockers of both cyclo-oxygenases 1 and 2 seems effective for the non-surgical closure of patent ductus and, since 1976, indomethacin (INDO) has been widely used with a reported efficacy of 70%-80% [9,12]. Its use raises some concern, however, regarding cerebral, gastrointestinal and renal perfusion [2,4,6,21,22], since INDO causes a decline in cerebral blood flow (CBF) velocity, reduces mitochondrial oxygenation and disrupts cerebrovascular control [7]. Moreover, side-effects such as necrotising enterocolitis or isolated bowel perforation, oliguria and transient renal failure may be encountered [10].…”