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支气管肺发育不良的预防策略
Prevention of bronchopulmonary dysplasia: current strategies
随着近代新生儿学的持续发展和极早早产儿存活率的不断改善，支气管肺发育不良（bronchopulmonary dysplasia,BPD）的定义发生了重大变化。BPD已不再是半个世纪前Nothway等学者提出的因高浓度氧及高压力通气导致的严重呼吸衰竭。新BPD更多发生在极早早产儿中，以损伤发育中的肺及肺血管而产生程度较轻却持续的呼吸问题为表现。由于影响肺及肺血管发育的因素贯穿早产儿产前生后的整个过程，因此对新BPD有效的预防策略应当包含多个角度，共同促进早产儿肺及肺血管的正常发育。近年来，BPD的预防在很多方面都取得了一定的进展，本文在此对部分策略做简单介绍。
产前糖皮质激素的应用可增加早产儿肺表面活性物质生成，减少新生儿呼吸窘迫综合征（respiratorydistress syndrome,RDS）的发生，但我们并未发现其对BPD的预防作用。这多半由于产前使用糖皮质激素明显增加了具有BPD高危风险的极早早产儿的存活率。绒毛膜羊膜炎的预防及治疗与BPD发生之间的关系目前仍存在争议。
早产儿窒息复苏中氧浓度的选择与BPD发生率的关系仍无定论，在新的可靠的证据发表前，窒息复苏中选择适中的氧浓度并持续进行血氧饱和度监测是当下最佳的选择。合适的经皮血氧饱和度目标区间对早产儿后续氧疗的指导意义重大。三项新生儿领域最大规模的RCT比较了目标经皮氧饱和度在不同区间（85%~89% vs 91%~95%）对早产儿病死率和发病率的影响。两项研究发现较低的经皮氧饱和度目标区间可显著降低BPD的发生，但其中一项研究同时发现病死率也明显增高。整合全部三项研究的荟萃分析，也同样证实了这样的趋势。
肺表面活性物质的应用并未减少BPD的发生，这可能与常规肺表面活性物质治疗需要气管插管和正压通气，而这样的操作会增加早产儿肺损伤有关。正因为此，越来越多的学者开始研究无创给予肺表面活性物质是否会减少BPD发生率，目前的初步结果是让人欣喜的，但仍有待更进一步的大规模RCT证实。此外，给予长时间机械通气的早产儿晚期补充肺表面活性物质理论上可能会减少BPD的发生，但基于该理论的两项RCT均未发现有意义的结果。
多项研究均未证实早产儿早期应用经鼻持续气道正压通气（NCPAP）可减少BPD的发生，但整合这些研究的荟萃分析却提示了可能的预防作用。与NCPAP相比，无创正压通气（NIPPV）可有效减少早产儿拔管失败的发生，但并未直接影响BPD发生率。无创呼吸支持首选NIPPV可能可减少BPD的发生，但这样的预防作用在近年来的数项RCT中并未得到证实。经鼻高流量氧疗（HFNC）是近年来研究较多的无创呼吸支持模式，目前暂无HFNC在极早早产儿中的研究数据，对于胎龄大于28周的早产儿HFNC对BPD的预防作用可能弱于NCPAP。
允许性高碳酸血症是减少机械通气造成肺损伤的保护策略之一，但其对BPD的保护作用缺乏研究支持。近来的一项RCT显示，允许性高碳酸血症反而可能增加BPD的发生。最新的荟萃分析提示与压力控制通气模式相比，容量目标通气策略可能对BPD有预防作用。而另一项荟萃分析则提示高频震荡通气（HFOV）也可能会减少BPD的发生，不过该分析纳入的研究同质性较差而缺乏足够的说服力。众所周知，机械通气上机时间与BPD的发生高度相关。理论上而言，任何有效的撤机策略都应当减少BPD的发生率，但目前该理论仍缺乏可靠的临床研究证据支持。
尽管持续左向右分流的动脉导管未必有可能对肺造成损伤，但目前缺乏其与BPD发生的直接证据。当下医学界对于极早早产儿动脉导管未闭的预防策略、临床症状评估、管理方案等均存在较大争议，在更全面、更有效统一的PDA管理方案出现前，动脉导管的管理可能仍需结合早产儿具体情况进行个体化考量。
母乳喂养可有效减少BPD的发生。尽管目前仍缺少大规模的临床研究证实营养策略对BPD的预防作用。但理论上而言，在避免过多液体摄入的前提下，通过提供充足的宏量元素和微量元素来减少早产儿生后生长迟缓的发生，从而预防BPD的发生是可行的。
各种药物对BPD的预防作用也是近年来临床研究和实践的热点。比如越来越多的新生儿医生开始在机械通气的早产儿中应用咖啡因以预防BPD的发生，但目前这样的做法仍缺乏强有力的循证医学证据支持。生后给予地塞米松可减少BPD的发生，但需警惕其对早产儿神经系统发育的影响。尽管氢化可的松对BPD也有预防作用，对神经系统发育的影响也弱于地塞米松，但有增加胃肠穿孔的风险。值得注意的是，已有研究证实小剂量氢化可的松在减少极早早产儿BPD发生的同时，并没有增加胃肠穿孔的风险。目前一项NICHD主持的大规模RCT正在探究晚期应用氢化可的松是否可以减少持续呼吸衰竭早产儿BPD的发生，改善其神经发育转归。有研究证实在肺表面活性物质治疗的同时，直接气管给予布地奈德，可显著减少BPD的发生率。但布地奈德临床应用预防BPD仍有待更多的研究明确其远期影响。
除甲基黄嘌呤和糖皮质激素类药物外，最新的荟萃分析提示补充维生素A可减少BPD的发生。但由于补充维生素A需要频繁的肌肉注射、成本较高、供应量也有限，大规模的临床应用存在诸多限制。一氧化氮对BPD的预防作用存在争议，而且预防效果还可能由于人种的不同而不同。利尿剂在早产儿中应用广泛，尽管其可短期改善肺顺应性，减少早产儿对呼吸支持和氧疗的依赖，但目前仍无可靠的证据证实利尿剂可降低BPD的发生率。早产儿解脲脲原体的呼吸道定植与BPD的发生相关，应用大环内脂类抗生素治疗可能可降低BPD的发生，但目前仍缺乏其对早产儿影响的全面评估，也缺少对合适剂量的考证。
大量动物实验证实干细胞及人克拉拉细胞蛋白（CC10）等新兴的治疗方法可改善肺损伤，理论上对BPD也有预防作用，但其安全性、有效性及合适的剂量仍有待进一步研究。
很显然，除非相关的研究有奇迹般的突破，否则BPD仍将继续威胁早产儿的健康。未来对于BPD的预防应是产前干预与生后治疗并重，通过多种途径减少肺损伤以及异常修复的发生，共同促进肺泡和血管的正常发育。
Bronchopulmonary dysplasia (BPD) is one of the few diseases affecting premature infants that have continued to evolve since its first description about half a century ago. The current form of BPD, a more benign and protracted respiratory failure in extremely preterm infants, is in contrast to the original presentation of severe respiratory failure with high mortality in larger premature infants. This new BPD is end result of complex interplay of various antenatal and postnatal factors causing lung injury and subsequent abnormal repair leading to altered alveolar and vascular development. The change in clinical and pathologic picture of BPD over time has resulted in new challenges in developing strategies for its prevention and management. While some of these strategies like Vitamin A supplementation, caffeine and volume targeted ventilation have stood the test of time, others like postnatal steroids are being reexamined with great interest in last few years. It is quite clear that BPD is unlikely to be eliminated unless some miraculous strategy cures prematurity. The future of BPD prevention will probably be a combination of antenatal and postnatal strategies acting on multiple pathways to minimize lung injury and abnormal repair as well as promote normal alveolar and vascular development.
Bronchopulmonary dysplasia / Prevention / Strategy / Premature infant
Bronchopulmonary dysplasia / Prevention / Strategy / Premature infant
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