| Background1. Morbidity and mechanism of patent ductus arteriosusPersistent patent ductus arteriosus (PDA) is one of the important early complications after premature birth. The smaller the gestational age and birth weight, the more infants will develop PDA. Four days after birth,10%of preterm infants of more than30weeks’ gestation can be expected to have a persistent PDA, and the rate can reach65%in the infants of less than30weeks’ gestation.60%to70%of preterm infants of less than28weeks’ gestation need to receive medical or surgical therapy for a PDA.30%infants of birth weight less than1500g (very low birth weight, VLBW) have PDA.Furthermore, most infants whose weight less than1000g (extremely low birth weight, ELBW) and gestational age less than27weeks have persistent PDA through all neonatal period,60%of them will been described to have a symptomatic PDA that ultimately leads to medical treatment.Animal experiments and clinical studies showed that PDA can increase the premature mortality and the morbidity of serious complications. So for premature babies, especially VLBW and ELBW infants, most of neonatologists believe the right option is to actively intervene in the PDA to reduce the morbidity of complications and infant mortality.Fetal ductus remains open, connecting the pulmonary artery to the descending aorta. Fetal ductus is regulated by low oxygen tension and high level of prostaglandin, predominantly prostaglandin E2(PGE2) and prostacyclin (PGI2). After birth at term, a postnatal increase in PaO2and a decrease in circulating vasodilators such as PGE2and PGI2will induce constriction of ductus arteriosus smooth muscle cell and, consequently, functional closure of the ductus in newborns. One of the important media on ductus closure is endothelin1(ET-1). Oxygen also induces release of the potent vasoconstrictor ET-1by the ductus, although its role in closure of the DA after birth is controversial.2. Pharmacologic treatment on PDAIn preterm infants, the sensitivity to oxygen induction is reduced; but the sensitivities to PGE2and nitric oxide are relatively higher. Therefore, early in1976, some scholars put forward the application of nonselective cyclooxygenase (COX) inhibitors to inhibit the production of prostaglandins, and thus to improve the rate of premature PDA closure. At present, indomethacin in vein has been recognized as a classic pharmacologic treatment of premature PDA.Indomethacin can significantly decreases renal, mesenteric and cerebral perfusion in the preterm infant, which can lead to adverse effects such as renal function injury and oliguria. In recent years, ibuprofen as the other COX inhibitor gets more and more attention. Studies have shown that intravenous ibuprofen treating on premature PDA is as effective as indomethacin, but has less urine and kidney function damage. But for the treatment timing there has been a hot debate. Some scholars think that the prophylactic use of ibuprofen on the ELBW infants can increase the closure rate of PDA, and such treatment has no obviously increase of side effects. Other studies showed that the prophylactic use of ibuprofen can cause the increases of imminent complications such as intestinal perforation, and increases the unnecessary drug exposure. So whether prophylactic treatment of ibuprofen should be used needs to be studied further.In addition, intravenous Ibuprofen is expensive and there is no intravenous ibuprofen manufactured in China; so maybe oral ibuprofen can be used as a possible alternative. In recent years, more reports about oral ibuprofen treating on premature PDA are surfacing; but most of these studies have limitations such as small sample size, non-double-blind study, non-randomized design and so on. Therefore, most of the neonatologists do not agree on using oral ibuprofen. At present more research is needed to confirm the effectiveness and safety of oral ibuprofen.3. Monitor of PDAStudies have shown that preterm DA has a high rate of spontaneous closure, so some researchers believe that excessive intervention may cause unnecessary drug exposure and suggest that foundation treatment, such as limiting liquid and no drug-intervention, is enough. But given that early combined PDA can certainly increases mortality after premature birth, therefore, we believe that drug intervention, based on strict screening cases and effective predictor of PDA occurrence and development, is clearly a more reliable method.Cardiac ultrasound, a gold standard when it comes to PDA diagnosis, has irreplaceable advantages. Most studies suggest left atrium to aortic root diameter ratio (LA/AO) and DA diameter can be used to predict whether the PDA needs intervention. However, there are a lot of limits of ultrasonic diagnosis, such as expensive equipment and high-level skills to operate; it is difficult to use this diagnosis tool in domestic primary hospitals for onsite screening and tracking. As a result, it is impractical that the heart ultrasound is used as the only index prediction and monitoring mean of treatment response. Clinically, there is an urgent need to find indicators that can be detected with relatively simple and more economic procedures.In recent years, some scholars devoted to the research on the biomarkers which can be used to predict the development of PDA; B-type natriuretic peptide (BNP), N-terminal B-type natriuretic peptide (NT-proBNP) and atrial natriuretic peptide(ANP) have gained more attention. But few studies were published, and no conclusion has been drawn.Objectives1. Evaluation of the efficacy and advantage of oral ibuprofen for the prophylactic treatment of PDA in preterm infants.2. Investigation of the plasma concentrations of NT-proBNP, ET-1, PGE2in the early time of preterm babies, and determination of the best possible biomarkerto predict the presence of PDA based on the above plasma analysis.MethodsProspective, double-blind, randomized controlled trial on103premature neonates with gestational ages less than36weeks who had been treated at the Neonatal Unit of Shandong Provincial Hospital from July to December of2011. They were randomly assigned into three groups. For the prophylactic treatment group, the first dose (10mg/kg) was given within24hours after birth; then the second and third doses (5mg/kg) were given in every24hours afterword.For the conventional treatment group,only infants who had PDA on echocardiogram on the third day after birth were given ibuprofenin at the same dosage of the prophylactic group.5%glucose was given at the same amount every24hours to the infants of the placebo group within24hours after their birth. On the first day, third day and seventh day, echocardiogram was done together with lab tests of NT-proBNP, ET-1and PGE2, blood urea nitrogen, creatinine, blood cell count,and c-reactive protein. Daily physical examinations were conducted to evaluate complications and side effects.Results1. Within the first24hours after birth, the gestational age, birth weight, ultrasound index, and other lab tests of the three groups had no significant difference.2. The babies in the porphylactic group had higher closure rate than those in placebo group on the seventh day (97.14%VS78.38%, P<0.05); however, there was no difference in the prevalence of PDA between the prophylactic treat group and the conventional treatment group (97.14%VS87.10%, P>0.05). Though the closure rate of PDA in the conventional treatment group was higher than that in placebo group, there is no statistical difference (87.10%VS78.38%, P>0.05)3. There was no difference in the prevalence of complications and adverse effects between the three groups (P>0.05).4. Within the first24hours after birth, the diameters of DA of the preterm infants whose ductus could close spontaneously on the third day were smaller than those of the babies whose ductus could not (0.11±0.06VS0.19±0.06, P<0.05)5.The plasma concentrations of NT-proBNP on the third day and seventh day decreased more in the prophylactic treatment group than in the placebo group; moreover, statistical significance occurred(13.27±8.29VS19.41±10.69,9.98±4.14VS13.85±7.19, P<0.05).6. There is no different in the plasma level of ET-1between the three groups.7. But the plasma level of ET-1within24hours was lower in the preterm infants whose ductus could close spontaneously on the third day than those of the infants whose ductus could not (16.74±6.50VS20.65±4.61, P<0.05)8. The plasma level of PGE2decreased with their day ages, but there was no difference among the three groups (P>0.05).ConclusionsIn comparison with the conventional treatment, the1.Prophylactic oral ibuprofen results in less PDA without significant side-effects.2. Prophylactic oral ibuprofen has no significant advantage over the conventional treatment.3. The diameter of ductus arteriosus in the first day may be used to predict PDA development for the preterm infants.4. Prophylactic oral ibuprofen significantly lowers the NT-proBNP level, which can be used as a monitoring biomarker of treatment response. This is the first domestically published finding.5. Another first domestically published finding of this research is that ET-1of the first24hours can possibly be used in the future to estimate the chance of PDA occurrence for the preterm babies; but more investigation of ET-1is needed to solid this notion. |
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