| BACKGROUNDDuctus arteriosus, which connects the descending aorta to the pulmonary artery, will closes spontaneously as arterial ligament after birth result from a postnatal increase in PaO2 and a decrease in circulating vasodilators such as PGE2 and PGI2. Most full term infants’ductus arteriosus will close spontaneously, but premature infants are not. Because of poor ductus arteriosus smooth muscle development, more sensitivity to vasodilators of premature infants and ineffective oxygen-mediated constriction in ductus arteriosus, ductus arteriosus fail to generate the hypoxic zone by insufficient constriction prevents it true anatomic closure which make ductus arteriosus of premature infants remain open. Consequently, patent ductus arteriosus (PDA) is more common in premature infants than full term infants. There is a negative linear correlation between birth weight and gestational age. And the lower birth weight and gestational age, the higher rate of PDA.Left-to-right shunting between descending aorta and pulmonary artery through the ductus arteriosus leads to volume overload, systemic hypoperfusion and pulmonary overcirculation that would influence on growth and health of infants. Although premature infants with mild left-to-right shunting may remain asymptomatic, with time of increasing shunting of ductus arteriosus may lead to symptoms, including feeding intolerance, hyperhidrosis, anhelation, systolic or continuous murmur at the left sterna edge, increased precordial impulse, bounding peripheral pulses and chest radiographic shows pulmonary congestion or cardiomegaly with increased pulmonary flow. Premature infants with PDA symptoms, which called symptomatic patent ductus arteriosus (sPDA), are susceptible to volume overload, hypoperfusion of vital organs and resultant additional short-term comorbidities such as heart failure, intraventricular hemorrhage (IVH) and neonatal necrotizing enterocolitis (NEC). What’s more, some professors reported that long-term comorbidities of premature infants such as chronic lung disease (CLD) and periventricular leukomalacia (PVL) are associated with sPDA.Because of short-term and long-term complications of sPDA, nonselective cyclooxygenase (COX) inhibitors are widely used for closure of patent ductus arteriosus in premature infants who are failed to close ductus by fluid restriction and respiratory support to avoid surgical ligation. However, there are side effects of COX inhibitors included indomethacin and ibuprofen, which influence on digestive system, nervous system and renal system of premature infants who are easier hurt by diseases because of immature. There are prophylactic treatment and symptomatic treatment for premature infants to close ductus arteriosus by nonselective cyclooxygenase (COX) inhibitors. However, two methods have its disadvantages. Prophylactic treatment may make patients whom ductus closes spontaneously exposed to the risk of significant side effects from over-treatment. Symptomatic treatment for premature infants may expose patients to pulmonary overcirculation, heart volume overload and long-term ventilation that would induce CLD, cardiac dysfunction, retinopathy of prematurity, etc. Therefore, timing of treating is important. It is advantage to close ductus by nonselective cyclooxygenase (COX) inhibitors for premature infants who must develop to sPDA, because it may decrease incidence of overtreatment and complication of sPDA. Hence, it’s important to predict sPDA to establish clinical project of sPDA treatment.Recently, brain natriuretic peptide (BNP) has become one of biochemical makers for predicting sPDA of premature infants. Domestic and foreign scholars had intensive study BNP since 1988 when Tetsuji Sudoh discovered it. BNP is synthesized and released mostly by ventricular myocardium in response to pressure or volume expansion and pressure load of heart. The measurement of plasma BNP levels are used in adult patients in the diagnosis of congestive heart failure. In healthy neonates, BNP level will increase at the 1st day of life and return to normal levels and become stable after that day, because the transition from fetal to neonatal circulation is accompanied by an increase of pulmonary blood flow lead to an increase in ventricular volume and pressure load and the function of renal clearance become immature. Pulmonary hypertension, sepsis and apnea will influence on the levels of BNP. In sPDA premature infants, BNP levels will increase. Byung MC et al reported that the sPDA group had significantly higher plasma BNP concentration on the third day after birth compared to control group. The area under the receiver operator characteristic curve for the detection of sPDA was high:0.997 (95% confidence interval:0.991-1.004). The best cutoff of BNP concentration for the diagnosis of sPDA was determined to be 1110 pg/mL (sensitivity:100%; specificity:95.3%). Multiple studies have showed that BNP can be the quantitative index for shunt volume. Byung MC et al reported that positive correlation between the levels of BNP and the ratio of the left atrial to aortic root diameter (LA/AO) which reflected shunt of ductus arteriosus (r=0.726; P<0.001). Joon Sik Ki et al also showed that the levels of BNP were correlated with LA/AO (r=0.812; P<0.001).NT-proBNP is similar to BNP. BNP is synthesized as a pre-proBNP; it is cleaved to proBNP. ProBNP is further cleaved into the biologically active BNP, which only keep 24h at room temperature and with a half-life of 20 minutes, and the inactive fragment, amino-terminal pro-brain natriuretic peptide (NT-proBNP) which can keep 72h at room temperature and has a longer half-life of 120 minutes. BNP and NT-proBNP are cleaned by kidney. BNP and NT-proBNP are released from ventricular myocardium at the rate of 1:1. Therefore, NT-proBNP may take a place of BNP to as a maker of predicting sPDA, assessing cardiac function and quantitating shunt volume of ductus arteriosus.There are few domestic literatures to investigate the relationship between NT-proBNP and ultrasonic parameters and the value of NT-proBNP predict sPDA. Our subject analyzes the clinical feature of sPDA prospectively. To investigate the relationship between NT-proBNP and ultrasonic parameters, identify the best cut-off level of NT-proBNP for predicting sPDA.OBJECTIVE1. To investigate the value of clinical features in predicting sPDA.2. To determine the correlation between plasma NT-proBNP and echocardio-graphic assessment of ductal shunting.3. To study the value of NT-proBNP in predicting sPDA in preterm infants that born at≤32 weeks’ gestational age and identify the best cut-off level of NT-proBNP.METHODSThe preterm infants admitted to hospital within 24 hours of life, born at a gestational age (GA) of≤32 weeks and diagnosed with PDA by echocardiography within 48 hours after birth between June 2014 and April 2015 were selected as subjects. General information (gestational age, birth weight, gender, birth date, admission time, way of birth and Apgar score, etc) and diseases (RDS, NEC, IVH, pneumonia, etc) happen during their hospitalization were recorded. Fluid intake of preterm infants before diagnosed sPDA and whether using pulmonary surfactant were also recorded. Preterm infants’ clinical manifestations (breathing condition, heart murmur, increased precordial impulse, bounding peripheral pulses, blood pressure, and chest radiography) were observed, and serum NT-proBNP levels were measured and echocardiography was performed to measure the diameter of ductus arteriosus, direction of ductus arteriosus flow and the value of LA/AO at 3 and 5 days after birth. The infants were divided into sPDA group and asymptomatic PDA (asPDA) group based on their clinical manifestations and the results of echocardiography.Statistical Analyses:Data was analyzed by SPSS20.0. Investigating the value of clinical features in predicting sPDA. Means and standard deviations (SD) were used to described measurement data of normally distributed values, the comparison of two groups which are equal variance using t-test and which are unequal variances using Wilcoxon rank sum test. Non-normal distribution values of measurement data were described by Medians and quartile, difference between two groups using Wilcoxon rank sum test. Enumeration data were described with frequencies and proportions. Chi-square test and Fisher’s exact test was used to compare enumeration data. The correlations between NT-proBNP levels and echocardiographic indices were analyzed by bivariate correlation analysis. Serum NT-proBNP levels were compared between the two groups. The receiver operator characteristic (ROC) curve was applied to determine the sensitivity and specificity of serum NT-proBNP in the prediction of sPDA. A P value of<0.05 was considered significant.RESULTSA total of 69 preterm infants were enrolled in this study, with 13 infants in the sPDA group (sPDA group,9 male,4 female; mean GA:30.0±1.7 weeks; mean birth weight:1367±249 g) and 56 infants in the asPDA group (asPDA group,32 male,24 female; mean GA:30.8±1.4 weeks; mean birth weight:1454±265 g).In sPDA group, preterm infants became symptomatic at 2-7 day of life (mean 3.7 day) and diagnosed sPDA at 7-16 day of life (mean 11 day). Clinical symptoms of 11 sPDA preterm infants were improved after treated by ibuprofen, seven of their ductus had closed and four of their ductus’diameter had reduced. Serum NT-proBNP levels were positively correlated with the diameter of the arterial duct and LA/AO at 3 and 5 day of life (at 3 day of life:r=0.856, P<0.05; r=0.713, P<0.05; at 5 day of life:r=0.528, P<0.05; r=0.721, P<0.05). At 3 and 5 days after birth, the NT-proBNP levels in the sPDA group were significantly higher than those in the asPDA group (P<0.05). The area under the ROC curve (AUC) for the prediction of sPDA by NT-proBNP levels at 3 days after birth was 0.949 (95% CI:0.892-1.000; P<0.001), with a cut-off value of 27035 pg/mL (yueden’s index:0.869, sensitivity:92.3%; specificity:94.6%, positive predictive value:80.0%, negative predictive value:98.1%); the AUC for the prediction of sPDA by NT-proBNP levels at 5 days after birth was 0.924 (95% CI: 0.848-1.000; P<0.001), with a cut-off value of 6411 pg/mL (yueden’s index:0.852, sensitivity:92.3%; specificity:92.9%, positive predictive value:75.0%, negative predictive value:98.1%).CONCLUSIONIf diagnosed sPDA only by clinical features might delay treatment, which may expose patients to pulmonary overcirculation and heart volume overload for long time and influence prognosis.NT-proBNP may be the quantitative index for shunt volume.Serum NT-proBNP levels at 3 and 5 days after birth may help to predict sPDA in preterm infants born at a gestational age (GA) of≤32 weeks. The best cut-off value to predict sPDA at 3 and 5 days after birth are 27 035 pg/mL and 6411 pg/mL, respectively. |
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