对乙酰氨基酚和富含血小板血浆治疗早产儿动脉导管未闭的病例对照研究

A case control study of patent ductus arteriosus in preterm infants treated with acetaminophen and platelet-rich plasma

目的探讨对乙酰氨基酚和富含血小板血浆(platelet-rich plasma,PRP)促进早产儿动脉导管闭合的可能机制、有效性和安全性。方法前瞻性选取2016年1月至2018年5月南京中医药大学附属徐州市中心医院新生儿重症监护病房收治的胎龄<34周、存在症状性动脉导管未闭(symptomatic patent ductus arteriosus,sPDA)的早产儿。根据是否有对乙酰氨基酚用药禁忌证分为对乙酰氨基酚组(口服对乙酰氨基酚15 mg/kg,每6 h 1次,共3 d)和PRP初始治疗组(单剂输注PRP 20 ml/kg)。对乙酰氨基酚组治疗3 d后复查超声心动图,结果显示治疗失败患儿给予单剂输注PRP 20 ml/kg,纳入PRP营救治疗组。应用方差分析、t检验、Kruskal-Wallis H法、χ2检验比较各组患儿治疗前及治疗后72 h超声心动图、血小板源性生长因子(platelet-derived growth factors,PDGF)、尿前列腺素E2(prostaglandin E2,PGE2)等检查结果。结果共纳入sPDA早产儿70例,口服对乙酰氨基酚治疗61例,治疗成功41例,成功率为67.2%,3例治疗后动脉导管内径仍≥1.5 mm,但已不满足sPDA诊断标准;PRP初始治疗9例,治疗成功6例,成功率为6/9;两组治疗成功率差异无统计学意义(P=1.000)。PRP营救治疗17例,治疗成功6例,成功率为6/17,低于对乙酰氨基酚治疗成功率,差异有统计学意义(P=0.017)。61例口服对乙酰氨基酚患儿治疗期间发生高胆红素血症22例(36.1%)、上消化道出血5例(8.2%)、便潜血阳性4例(6.6%)、少尿3例(4.9%)、Ⅲ~Ⅳ级脑室内出血1例(1.6%)及≥Ⅱ期坏死性小肠结肠炎1例(1.6%);PRP初始治疗期间发生高胆红素血症3例;PRP营救治疗期间发生高胆红素血症、少尿、Ⅲ~Ⅳ级脑室内出血及≥Ⅱ期坏死性小肠结肠炎各1例。对乙酰氨基酚组治疗后尿PGE2水平较治疗前下降,差异有统计学意义(P<0.001);PRP初始治疗组和PRP营救治疗组治疗后血小板计数和PDGF均较治疗前升高,差异有统计学意义(P<0.05)。结论口服对乙酰氨基酚与输注PRP促进早产儿动脉导管闭合的疗效相似。当sPDA早产儿存在对乙酰氨基酚禁忌证或药物干预失败时,输注PRP可作为备选或营救治疗措施之一。

Objective To study the possible mechanisms, efficacy and safety of acetaminophen and platelet-rich plasma (PRP) on promoting the closure of ductus arteriosus in preterm infants. Method From January 2016 to May 2018, preterm infants (gestational age<34 weeks) with symptomatic patent ductus arteriosus (sPDA) admitted to our neonatal intensive care unit were enrolled prospectively. 15 mg/kg of acetaminophen was orally given every 6 hours for three days (acetaminophen group). If acetaminophen was contraindicated (PRP group) or acetaminophen therapy failed (PRP rescue group), PRP transfusion was given at a single dose of 20 ml/kg. Echocardiogram, platelet-derived growth factors (PDGF) and urinary prostaglandin E2 (PGE2) were examined before and 72 hours after treatment. The data were analyzed using ANOVA, student′s t test, Kruskal-Wallis H method and chi-square test. Result A total of 70 cases were enrolled. 61 cases were treated with acetaminophen. The success rate (67.2%, 41/61) was similar to PRP group (6/9)(P=1.000), and significantly higher than PRP rescue group (6/17)(P=0.017). The complications in acetaminophen group included 22 cases of hyperbilirubinemia (36.1%), 5 cases of upper gastrointestinal hemorrhage (8.2%), 4 cases of positive fecal occult blood test (6.6%), 3 cases of oliguria (4.9%), 1 case of Grade Ⅲ~Ⅳ intraventricular hemorrhage (IVH)(1.6%), and 1 case of ≥Ⅱ stage necrotizing enterocolitis (NEC)(1.6%). A total of 3 cases of hyperbilirubinemia were in PRP group. One case of hyperbilirubinemia, one oliguria, one Grade Ⅲ~Ⅳ IVH and one ≥Ⅱ stage NEC were in PRP rescue group. The urinary PGE2 level in post-treatment was lower than pre-treatment in acetaminophen group (t=6.878, P<0.001). The blood platelet count and PDGF level in post-treatment were higher than pre-treatment in PRP group (t=-2.496,-8.906;P=0.037,<0.001) and PRP rescue group (t=-3.374,-2.503;P=0.004, 0.024). Conclusion Oral acetaminophen and PRP transfusion had similar efficacy in promoting the closure of ductus arteriosus in preterm infants. If oral acetaminophen was contraindicated or failed, PRP transfusion could be one of the candidates for rescue therapy to promote the closure of ductus arteriosus in preterm infants.