Objective To examine whether a more conservative approach to PDA treatment is associated with an increase or decrease in morbidity compared with an approach of early PDA ligation. Study design In 1/2005 we changed our approach to infants (≤27 weeks gestation) that failed indomethacin treatment. We changed from an early surgical approach (where feedings were stopped and all PDAs were ligated)(Period 1:1/99-12/04, n=216) to a more conservative approach (feedings continued and PDAs were ligated only if cardiopulmonary compromise developed)(Period 2:1/05-8/09, n=180). All infants in both periods received prophylactic indomethacin. Results The two periods had similar rates of perinatal/neonatal risk factors and indomethacin failures (24%); ventilator management and feeding advance protocols also were similar between the two periods. The conservative approach was associated with decreased rates of ductus ligation (72% versus 100%, p<0.05). Even though infants were exposed to larger PDA shunts for longer durations in the conservative treatment period, the rates of BPD, Sepsis, ROP, Neurological Injury, and Death did not change; their overall rate of NEC was significantly lower. Conclusions These findings support the need for new controlled, randomized trials to reexamine the benefits and risks of different approaches to PDA treatment.
Objective To test the hypothesis that infants who are just being introduced to enteral feedings will advance to full enteral nutrition at a faster rate if they receive “trophic” (15 ml/kg/day) enteral feedings while receiving indomethacin or ibuprofen treatment for patent ductus arteriosus (PDA). Study design Infants were eligible for the study if they were 231/7 – 306/7 weeks gestation, weighed 401–1250 g at birth, received maximum enteral volumes ≤60 ml/kg/day and were about to be treated with indomethacin or ibuprofen. A standardized “feeding advance regimen” and guidelines for managing feeding intolerance were followed at each site (n=13). Results Infants (n=177; 26.3±1.9 wks (±SD) gestation) were randomized at 6.5±3.9 days to receive “trophic” feeds (“feeding” group, n=81: indomethacin=80%, ibuprofen=20%) or no feeds (“fasting (npo)” group, n=96: indomethacin=75%, ibuprofen=25%) during the drug administration period. Maximum daily enteral volumes prior to study entry were 14±15 ml/kg/day. After drug treatment, infants randomized to the “feeding” arm required fewer days to reach the study’s feeding volume endpoint (120 ml/kg/day). Although the enteral feeding endpoint was reached at an earlier postnatal age, the age at which central venous lines were removed did not differ between the two groups. There were no differences between the two groups in the incidence of infection, necrotizing enterocolitis, spontaneous intestinal perforation or other neonatal morbidities. Conclusion Infants required less time to reach the feeding volume endpoint if they were given “trophic” enteral feedings when they received indomethacin or ibuprofen treatments.
We hypothesized that there is a significant relationship between a neonatologist's belief that feedings must be stopped in the presence of a patent ductus arteriosus (PDA) and his or her willingness to ligate a PDA. We administered the same survey questionnaire to two separate populations of neonatologists to assess their beliefs regarding PDA treatment practices. Although >90% of U.S. and non-U.S. neonatologists reported that they would ligate a PDA when infants with birth weights <900 g required mechanical ventilation (and indomethacin was contraindicated or had failed to close the PDA), U.S. neonatologists reported that they were significantly more likely to ligate a PDA when less respiratory support was required. U.S. neonatologists were also more likely to stop feedings when a PDA was present. The reported likelihood that a neonatologist would ligate a PDA in infants who did not require mechanical ventilation was significantly increased if the neonatologist believed that feedings had to be stopped because of the PDA. After controlling for the belief that "feedings must be stopped in the presence of a PDA," the significant difference between U.S. and non-U.S. neonatologists, in their reported desire to ligate infants who did not require mechanical ventilation, was no longer present.
Three independent risk factors (immature gestation, absence of antenatal glucocorticoid exposure, and presence of the rs2817399(A) allele of the gene TFAP2B) are associated with patent ductus arteriosus (PDAs) that fail to close during prostaglandin inhibition. We hypothesized that these three factors may affect a common set of genes that increase the risk of persistent PDA after birth. We studied baboon ductus from term, preterm, and glucocorticoid-treated preterm fetuses and found that both immature gestation and absence of antenatal glucocorticoid exposure decreased RNA expression of calcium-and potassium-channel genes involved in oxygen-induced constriction, and phosphodiesterase genes (that modulate cAMP/cGMP signaling). Ductus obtained from second trimester human pregnancies were genotyped for TFAP2B polymorphisms. When present, the rs2817399(A) allele also was associated with decreased expression of calcium-and potassium-channel genes. In contrast, alleles of two other TFAP2B polymorphisms, rs2817419(G) and rs2635727(T), which are not related to the incidence of PDA after birth, had no effect on RNA expression. In conclusion, three calcium-and potassium-channel genes (CACNA1G/ alpha1G, CACNB2/CaL-beta2, and KCNA2/Kv1.2) were similarly affected by each of the PDA risk factors. We speculate that these channels may play a significant role in closing the preterm ductus during prostaglandin inhibition and may be potential targets for future pharmacologic manipulations. (Pediatr Res 68: 292-297, 2010) I n contrast with the full term newborn, preterm infants frequently fail to close their ductus arteriosus after birth. Persistent ductus patency alters mesenteric blood flow, impairs pulmonary mechanics, increases the risk of pulmonary hemorrhage, and prolongs the need for mechanical ventilation (1,2).In preterm infants, persistent ductus patency appears to be the result of alterations in the balance between developmentally regulated vasoconstricting and vasodilating pathways. Alterations in prostaglandin signaling seem to account for most persistent patent ductus arteriosus (PDA); 70% of preterm infants will close their PDA when prostaglandin production is inhibited by indomethacin or ibuprofen. However, approximately 30% of PDAs are the result of factors that are independent of prostaglandin signaling. In these infants, the PDAs fail to close when prostaglandin production is inhibited (3,4). Discovering the pathways that prevent ductus closure (when prostaglandin signaling is not involved) may lead to the development of new therapeutic approaches.We recently identified three perinatal/neonatal risk factors that are independent of each other and predict the presence of PDAs that fail to close when prostaglandin signaling is inhibited (5): 1) immature gestation at birth, 2) absence of antenatal glucocorticoid exposure, and 3) racial/genetic variation (5). We hypothesized that these environmental (immature gestation and absence of antenatal glucocorticoid exposure) and genetic risk factors may be associat...
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