RESUMO
OBJECTIVE: To examine the role of endogenous nitric oxide (NO) and endothelin-1 (ET-1) in the pathogenesis of persistent pulmonary hypertension of the newborn (PPHN) and to determine whether inhaled NO, currently under investigation as a new therapy for PPHN, affects plasma concentrations of these vasoactive mediators. METHODS: Circulating ET-1 and cyclic guanosine monophosphate (cGMP) concentrations were measured by radioimmunoassay in 15 healthy term newborn infants and 46 newborn infants with PPHN enrolled in a randomized, controlled trial of inhaled NO. These concentrations were followed up longitudinally and compared between the NO and the conventionally treated group. RESULTS: Concentrations of ET-1 were significantly higher and cGMP concentrations significantly lower in infants with PPHN compared with healthy newborn infants (median ET-1, 28 vs 11 pmol/L; p = 0.0001; median cGMP, 35 vs 61 pmol/ml; p = 0.0001, respectively). ET-1 concentrations showed an upward trend at 1 and 24 hours of treatment and a subsequent decline at recovery in both subgroups of patients, with the most pronounced decrease in the NO group. cGMP concentrations increased significantly only in the NO group, with a peak at 1 hour of treatment (median, 61 pmol/ml). As the dose of NO decreased, cGMP concentrations declined. In contrast, conventionally treated infants manifested no change in cGMP concentrations from baseline until recovery, when a significant decrease was noted (median decrease of 13 pmol/ml; p = 0.002). We did not find a significant difference between ET-1 and cGMP concentrations in infants who required extracorporeal membrane oxygenation compared with those who did not. CONCLUSIONS: PPHN is associated with increased ET-1 and decreased cGMP plasma concentrations, which may contribute to the pathogenesis of the disease. Inhaled NO appears to modulate these mediators during the disease process, suggesting an interaction between ET-1 and NO in vivo.
Assuntos
GMP Cíclico/sangue , Endotelina-1/sangue , Óxido Nítrico/administração & dosagem , Síndrome da Persistência do Padrão de Circulação Fetal/tratamento farmacológico , Administração por Inalação , Feminino , Humanos , Recém-Nascido , Masculino , Óxido Nítrico/fisiologia , Síndrome da Persistência do Padrão de Circulação Fetal/sangueRESUMO
In 100 consecutive neonates with birth weights < or = 2500 gm (range, 540 to 2500 gm; median, 2200 gm), major congenital heart disease (excluding patent ductus arteriosus, isolated atrial septal defect, and ventricular septal defect) was diagnosed between January 1987 and January 1991; 46 had ductus-dependent lesions. Of the 100 neonates, 30 had genetic aberrations or significant associated congenital anomalies. The four most common cardiac diagnoses were tetralogy of Fallot with or without pulmonary atresia (n = 16); coarctation of the aorta (n = 12); transposition of the great arteries (n = 11); and common atrioventricular canal (n = 11). The hospital survival rate for the entire group of 100 neonates was 70%. The patients were separated into three groups on the basis of the time of intervention. Group 1 (early intervention) included 62 infants. These neonates (including 31 with ductus-dependent lesions) had surgical or catheter intervention during the initial hospitalization (median age, 9 days), all at weights < or = 2500 gm. The hospital survival rate was 81% (50/62); survival rates for palliation (78%, 18/23) and for correction (82%, 32/39) were similar. There were 26 neonates in group 2 (late intervention). These neonates did not have surgical intervention during the initial hospitalization. All were managed medically; survivors were discharged and had surgical procedures later (at a median age of 4.3 months). Six neonates (23%) died during medical management; all 20 survivors returned and had surgical procedures, with 90% survival. Overall survival rate for this group was 69% (18/26). The remaining 12 patients (group 3) had complicating features that precluded intervention; none survived. On the basis of these results, we conclude that early intervention, even with corrective surgery, can be performed in low birth weight neonates with an acceptable mortality rate. Prolonged medical therapy to achieve further weight gain did not appear to improve the survival rate.