| Background The ductus arteriosus (DA) is a normal pathway to connecting to the descending aorta and the pulmonary artery during fetal period. Usually, the function closure of neonatal infants’DA occurswithin 24 hours after birth, and anatomically completed closure occurs within one to three months.Patent ductus arteriosus (PDA), a common congenital heart disease due to the abnormal in closure system of DA, its incidence is one of the highest congenital heart malformations. The PDA incidence in preterm infants with gestational age (GA) less than 32 weeks is more than 30%, significantly higher than the incidence in full-term newborns which is only 0.2%. With smaller gestational age and lower birth weight, the incidence of PDA is higher, which highly results from the descending ability to combine the DA and vasoactive substances, and the immature of DA contraction and remodeling system and other factors.The hemodynamie significant patent ductus arteriosus (hsPDA), with continuous shunt of DA,can easily induceincluding the increase of cardiopulmonary blood volume which may result in congestive heart failure and even death, the decrease of systemic blood volume, the decrease of blood and oxygen supply to the brain which may result in intracranial hemorrhage or white matter damage and etc. Even the infants survive, sequelae may occur including cerebral palsy, epilepsy, developmental retardation of motor nerve. Currently, conservative drug treatment is commonly used in preterm PDA treatment. But when the infants with PDA fail in treated with conservative treatment,and extubationis a must even after giving appropriate anti-heart failure treatment, in these cases, DA surgical ligation is the main treatment to get the infants out of ventilator. So far, the natural process of PDA development in preterm infantsis remaining totally unclear.it is still controversial regarding the risk factors which have contributedto PDA developing to hsPDA, and the diagnostic criteria of hsPDA.And regarding the requirementof PDA drug treatment, surgical intervention, selection of drugs, the time of surgical intervention, there is big disagreementamong both domestic scholars and foreign scholars.Color Doppler ultrasound is the critical measure to determine whether the ductus arteriosus (DA)is close or open, but it is difficult to fully reflect the hemodynamic changein the PDA.By using B-type brain natriuretic peptide (BNP), a biomarker,with only a simple blood test can easily, quickly and accurately reflect the hemodynamic change.This test uses a prospective study method, by measuring plasma BNP level in preterm infants,to study the clinical value of the early development of hsPDA of the preterm infants,to summarizethe relevant factors which have contributed to the changeof plasma BNP of the preterm infantswith PDA in this region. A multivariate analysis with possible risk factors is performed to discover the factors including BNP and other associated disease in premature infants that have affected PDA.Hemodynamics change and respiratory disorder likely occurs in the premature infants with hsPDA, and hsPDA is relevantwith intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), pulmonary hemorrhage (PH), bronchopulmonary dysplasia (BPD) / chronic lung disease (CLD), retiopathy of multiple comorbidities prematurity(ROP),death and other complication.To improve the survival rate of premature infants and reducethe incidence of sequelae,optimal threshold value is determined based on the receiver operating characteristiccurve (ROC), and early identification of hsPDA has been carried out by combining echocardiography and CVD score, and premere intervention indicationsof ibuprofen drugs treatment and surgery have been established for our hospital.Methods Aprospective observational study was preformed to the extremely premature infantswho were in our hospital, between April 2014 and December 2014, with a gestational age ≤ 32 weeks, birth weight < 1500g, age ≤ 24 hours. The patients are divided into two groups. hsPDA group, with 89 infants with hsPDA, determined by the first echocardiographyafter birth and degree of cardiovascular dysfunction using a scoresystem(CVDscore), i.e., use cardiac ultrasound to determine the presence of PDA and CVD score ≥ 3. Control group, with 64 infants,including infants with PDA or without PDA, clearly indicated by ultrasound but CVD score<3. According to different DA closure condition and different treatment, hsPDA group is divided into the following subgroups:1. according to DA was closedor not after the first course of drug and requirement of surgery,37 patients of 89are classified as drugs-sensitive group, and 26 patients of 89 are classified as drugs-insensitive group; 2. According to DA was closed by conservative drugs treatment (regardless of the course of drug treatment) or by surgery,44 patients of 89 whose DA were closed by onlydrugs treatment are classified as one group,10 patients of 89 whose DA failed to closebyonlydrugs treatment are classified as one group, and 9patients of 89 whose DA were closed by combination treatment of drugs and surgery are classified as one group.0.5-1ml whole blood were collected for BNP measurementthrough arterial or venous access fromall the patients who were admitted to hospital on 1 day,3days,7 days after their birth, and from hsPDA group when it is 24 hours after each drug treatment or 24 hours prior to surgical intervention, and 24 hours,3 days and 7 daysafter their surgery. Statistical analysis was performed by using IBM SPSS Statistics version 19.0.The data are divided into measurement data and enumeration data according to its nature. Abnormal distribution of measurement data are expressed by the median (interquartile range) (M (IQR)).Non-parametric tests (Mann-WhitneyU test) are used in the comparisonbetween two groups.Multiple independent sample nonparametric tests (K Independent Samples Test) are used in the comparison among multiple groups. The plasma BNP levelcomes out as abnormal distribution, the results are expressed in median (interquartile range) (M (IQR)); Spearman rank correlation is used to compare the two variables associated with echocardiographic indicators; and Spearman partial correlation analysis is used to carry out analyze of the factors which affect the level of BNP. α= 0.05 is consideredas test standard, and P<0.05 indicates statistically significant differences.Results In this prospective observational study, the BNP level of plasma was determined asmeasurement data of non-normal, namely the skewness distribution.According to the double variables of Spearman rank correlation analysis to both of the ultrasonic indicators and the plasma BNP levels of the lstday after the birth of 153 patients in this study, there was a rank correlation between the vessel diameter size and the plasma BNP levels, but this correlation was not close (rs= 0.37, P< 0.001). At the same time, the plasma BNP level did not have the rank correlation with the ejection fraction, left atrial/aortic sinus, pulmonary artery flow velocity, diameter of left ventricle or pulmonary artery diameter (P> 0.05).For the prematureinfants, according to the double variables of Spearman rank correlation analysis to the birth asphyxia, serum creatinine and urea nitrogen with the plasma BNP peak value within the 1st week after birth,the plasma BNP peak value was correlated with either birth asphyxia,but not very closed(rs=0.029, P<0.029; rs=0.158, P=0.018),while it did not have rank correlation with theserum creatinine or urea nitrogen(P>0.05)。After the baseline analysis on the clinical data of hsPDA group and the control group, differences were shown in the gestational age:There were no significant differences in the plasma BNP levels between the hsPDA group and the control group on the 1st,3rd and 7th day after the birth when the gestational age was fewer than 28 weeks (median were 352.5 pg/ml VS365 pg/ml,189.1 pg/ml VS70.2 pg/ml,52.4 pg/ml VS71.2 pg/ml separately, P> 0.05).However, when GA came to 28 weeks to 30 weeks, there wereobvious differences of plasma BNP levelsbetween the hsPDA group and the control group on the 1st,3rdand 7th day after the birth(median374 pg/ml VS162.9 pg/ml,277 pg/ml VS68.8 pg/ml,75.5 pg/ml VS17.3 pg/ml separately, P< 0.05). What’s more, the difference of plasma BNP level between the hsPDA group and the control group on the 1st,3rd and 7th daywas significant when the GA came to 30 weeks to 32 (median:756 pg/ml VS 182.5 pg/ml, 178 pg/ml VS62.2 pg/ml,114 pg/ml VS 18.05 pg/ml, P< 0.05).Characteristics of the work curve, namely the ROC curve, was analyzed according to the plasma BNP levels on the 1st,3rd and 7th dayseparately and the area under the curve were 0.751, 0.819 and 0.736 respectively, which showed that the area under the curve of the 3rdday plasma BNP level was the largest, implying that the plasma BNP levels on the 3rd day after the birth were of the most diagnostic significance in hsPDA diagnosis.Besides,except the influence of GA, for VLBW, with an ultrasonic clear DA and a CVD of 3 points or more, the plasma BNP levels on the3rdday could be diagnosable forhsPDAin a concentration of 143.85 pg/ml, with a sensitivity of 0.786, 0.804 for specifity, prompting that intervention treatment is needed.In the comparison of the plasma BNP levels on the 3rdday and 24 hours after drug treatment between the drug sensitive group and the drug non-sensitive group, the area under the ROC curve are 0.763 and 0.801 respectively, P< 0.05, both of which are of diagnostic value.In addition,the area under the ROC curveof the plasma BNP levels at 24 hours after drug treatment was the largest, implying that a diagnosis significance for the diagnostic efficacy of drug treatment for the first time. When BNP levels was 157 pg/ml, with a sensitivity of 0.786 and a 0.939 for specifity, prompting thatmedication treatment was not sensitive and continual drug use or intervention surgery were needed.For the comparison ofthe plasma BNP levels among the drug closed group, the drug has not closed group and the drug combining surgery group, the 1st day,3rdday and the 24 hours after the first time course of medicine, the 3rd day drawn the most significantly difference among the plasma BNP levels (median:209.5 pg/ml VS 168 pg/ml VS 663 pg/ml), so we analyzed the ROC curve of the 3rdday plasma BNP level and found thatthe area under the curve was0.762, with the 95% CI (0.613,0.613) and P= 0.058, drawing a conclusion of no diagnostic significance.In our observation, plasma BNP levels of the drug combining surgery group were significantly higher than the drug closed group or the drug has not closed group,which might be associated with the amount of surgical sample cases that was too small.Conclusion In this region there is a correlation between the vessel diameter size and the plasma BNP levels of VLBW, thus theplasma BNP levels may beof sensitive and specificdiagnostic value to hsPDA. In the hsPDA group and the control group, the plasma BNP levels on the 3rd day after the birth were of the most diagnostic significance in hsPDA diagnosis, much more valuable than the 1st or 7th day. Furthermore, VLBW, with an ultrasonic clear DA and a CVD of 3 points or more, other than thegestational age, can be diagnosed as hsPDA in a concentration ofplasma BNP at 143.85pg/ml, prompting that intervention treatment is needed.In addition, plasma BNP levels differ in gestational ages as followed. When gestational age is between 28 to 30 weeks, the safety range of BNP level on the 3rd day is under 218 pg/ml, which indicates that drug therapy is temporarily needless without obvious clinical symptoms whenthe plasma BNP concentration isunder218 pg/ml. However, when the plasma BNP concentration has come to218 pg/ml,intervention treatment can be processed according to the CVD score and the ultrasonographyfeatures. WhenGA is between30to 32 weeks, the safety range of BNP level on the 3rd day is under 153.3pg/ml,which indicates that drug therapy is temporarily needless without obvious clinical symptoms whenthe plasma BNP concentration is under 153.3pg/ml. However, when the plasma BNP concentration has come to153.3pg/ml, intervention treatment can be processed according to the CVD score and the ultrasonographyfeatures.For VLBW,who are born under 28 weeks, seen as super immature infants for their immature tissue and organ development, it’s limited to detect the ventricularrsecretion of BNP. In addition the sample size is small, which leads to prospective studies on larger sample size.In addition, when the plasma BNP levels arrive to 157pg/mlat the 24 hours after the first course of medication treatment, it takes the consideration that the drug is not sensitive, whatever GA or CVD score, prompting the need for further interventionof drug or surgery. Last but not the least, the plasma BNP levels on the 3rd day of the simple drug treatment group, regardless of the courses or whether get closed by ultrasonic detection, are much lower than those of the drug combined surgery treatment group. However the ROC curve analysisis 0.162,P=0.058,considering the small sample size, calling for further in-depth study. |
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