Studies in premature animals suggest that 1) prolonged tight, constriction of the ductus arteriosus is necessary for permanent anatomic closure and 2) endogenous nitric oxide (NO) and prostaglandins both play a role i...Studies in premature animals suggest that 1) prolonged tight, constriction of the ductus arteriosus is necessary for permanent anatomic closure and 2) endogenous nitric oxide (NO) and prostaglandins both play a role in ductus patency. We hypothesized that combination therapy with an NO synthase (NOS) inhibitor [NG- monomethyl- L- argini- ne (L- NMMA)] and indomethacin would produce tighter ductus constriction than indomethacin alone. Therefore, we conducted a phase I and II study of combined treatment with indomethacin and L- NMMA in newborns born at < 28 weeks’ gestation who had persistent ductus flow by Doppler after an initial three- dose prophylactic indomethacin course (0.2, 0.1, 0.1 mg/kg/24 h) . Twelve infants were treated with the combined treatment protocol [three additional indomethacin doses (0.1 mg/kg/24 h)- plus a 72- hour L- NMMA infusion]. Thirty- eight newborns received three additional indomethacin doses (without LNMMA) and served as a comparison group. Ninety- two percent (11/12) of the combined treatment group had tight ductus constriction with elimination of Doppler flow. In contrast, only 42% (16/38) of the comparison group had a similar degree of constriction. L- NMMA infusions were limited in dose and duration by acute side effects. Doses of 10- 20 mg/kg/h increased serum creatinine and systemic blood pressure. At 5 mg/kg/h, serum creatinine was stable but systemic hypertension still limited L- NMMA dose. We conclude that combined inhibition of NO and prostaglandin synthesis increased the degree of ductus constriction in newborns born at < 28 weeks’ gestation. However, the combined administration of L- NMMA and indomethacin was limited by acute side effects in this treatment protocol.展开更多
Fetal tracheal occlusion (TO) was developed in an attempt to enhance prenatal lung growth and improve survival in fetuses with severe congenital diaphragmatic hernia (CDH). We conducted a randomized, controlled clinic...Fetal tracheal occlusion (TO) was developed in an attempt to enhance prenatal lung growth and improve survival in fetuses with severe congenital diaphragmatic hernia (CDH). We conducted a randomized, controlled clinical trial in 24 fetuses with severe left CDH (liver herniated into the thorax and low lungto-head ratio) to compare survival after endoscopic fetal TO vs standard perinatal care (control) and prospectively followed up the 16 survivors (9 control, 7 TO) to compare neurodevelopmental, respiratory, surgical, growth, and nutritional outcomes. At 1 and 2 years old, subjects underwent evaluation consisting of medical and neurological history and physical, developmental testing, nutritional assessment, oxygen saturation and pulmonary function testing, chest radiograph, and echocardiogram. Growth and developmental measures were corrected for prematurity. Data were analyzed by Mann-Whitney rank sum test, Fisher’ s exact test, and logistic and linear regression. Infants with TO were significantly more premature at birth (control vs TO, 37.4 ± 1.0 vs 31.1 ± 1.7 weeks; P < .01). Growth failure (z score for weight < 2 SDs below mean) was severe in both groups at 1 year of age (control vs TO, 56% vs 86% ; P = .31). There was considerable catch-up growth by age 2 years (growth failure: control vs TO, 22% vs 33% ; P =.19). There were no differences in other growth parameters. There were also no differences in neurodevelopmental outcome at 1 and 2 years. Supplemental oxygen at hospital discharge was a significant predictor of worse neurodevelopmental outcome at 1 and 2 years old (P =.05 and P =.02, respectively). Hearing loss requiring amplification has been diagnosed in 44% of the group (control vs TO, 44% vs 43% ; P = 1.0). In this group of infants with severe CDH, there were no differences in outcome at 2 years old despite significant prematurity in the TO group. Oxygen supplementation at hospital discharge identified the most vulnerable group with respect to neurodevelopmental outcome, but all infants had significant growth failure, and hearing impairment is a substantial problem in this population. Severe CDH carries significant risk of chronic morbidity.展开更多
文摘Studies in premature animals suggest that 1) prolonged tight, constriction of the ductus arteriosus is necessary for permanent anatomic closure and 2) endogenous nitric oxide (NO) and prostaglandins both play a role in ductus patency. We hypothesized that combination therapy with an NO synthase (NOS) inhibitor [NG- monomethyl- L- argini- ne (L- NMMA)] and indomethacin would produce tighter ductus constriction than indomethacin alone. Therefore, we conducted a phase I and II study of combined treatment with indomethacin and L- NMMA in newborns born at < 28 weeks’ gestation who had persistent ductus flow by Doppler after an initial three- dose prophylactic indomethacin course (0.2, 0.1, 0.1 mg/kg/24 h) . Twelve infants were treated with the combined treatment protocol [three additional indomethacin doses (0.1 mg/kg/24 h)- plus a 72- hour L- NMMA infusion]. Thirty- eight newborns received three additional indomethacin doses (without LNMMA) and served as a comparison group. Ninety- two percent (11/12) of the combined treatment group had tight ductus constriction with elimination of Doppler flow. In contrast, only 42% (16/38) of the comparison group had a similar degree of constriction. L- NMMA infusions were limited in dose and duration by acute side effects. Doses of 10- 20 mg/kg/h increased serum creatinine and systemic blood pressure. At 5 mg/kg/h, serum creatinine was stable but systemic hypertension still limited L- NMMA dose. We conclude that combined inhibition of NO and prostaglandin synthesis increased the degree of ductus constriction in newborns born at < 28 weeks’ gestation. However, the combined administration of L- NMMA and indomethacin was limited by acute side effects in this treatment protocol.
文摘Fetal tracheal occlusion (TO) was developed in an attempt to enhance prenatal lung growth and improve survival in fetuses with severe congenital diaphragmatic hernia (CDH). We conducted a randomized, controlled clinical trial in 24 fetuses with severe left CDH (liver herniated into the thorax and low lungto-head ratio) to compare survival after endoscopic fetal TO vs standard perinatal care (control) and prospectively followed up the 16 survivors (9 control, 7 TO) to compare neurodevelopmental, respiratory, surgical, growth, and nutritional outcomes. At 1 and 2 years old, subjects underwent evaluation consisting of medical and neurological history and physical, developmental testing, nutritional assessment, oxygen saturation and pulmonary function testing, chest radiograph, and echocardiogram. Growth and developmental measures were corrected for prematurity. Data were analyzed by Mann-Whitney rank sum test, Fisher’ s exact test, and logistic and linear regression. Infants with TO were significantly more premature at birth (control vs TO, 37.4 ± 1.0 vs 31.1 ± 1.7 weeks; P < .01). Growth failure (z score for weight < 2 SDs below mean) was severe in both groups at 1 year of age (control vs TO, 56% vs 86% ; P = .31). There was considerable catch-up growth by age 2 years (growth failure: control vs TO, 22% vs 33% ; P =.19). There were no differences in other growth parameters. There were also no differences in neurodevelopmental outcome at 1 and 2 years. Supplemental oxygen at hospital discharge was a significant predictor of worse neurodevelopmental outcome at 1 and 2 years old (P =.05 and P =.02, respectively). Hearing loss requiring amplification has been diagnosed in 44% of the group (control vs TO, 44% vs 43% ; P = 1.0). In this group of infants with severe CDH, there were no differences in outcome at 2 years old despite significant prematurity in the TO group. Oxygen supplementation at hospital discharge identified the most vulnerable group with respect to neurodevelopmental outcome, but all infants had significant growth failure, and hearing impairment is a substantial problem in this population. Severe CDH carries significant risk of chronic morbidity.
