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   复旦学报(医学版)  2023, Vol. 50 Issue (3): 405-411      DOI: 10.3969/j.issn.1672-8467.2023.03.012
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新生儿缺氧缺血性脑病中喂养困难的临床特征和高危因素分析
钱天阳 , 高婷 , 邱寒 , 张鹏 , 程国强 , 王来栓     
国家卫生和健康委员会新生儿疾病重点实验室/复旦大学附属儿科医院新生儿科 上海 201102
摘要目的 探究新生儿缺氧缺血性脑病(hypoxic-ischemic encephalopathy,HIE)喂养困难的临床特征以及高危因素。方法 本研究为病例对照研究,纳入复旦大学附属儿科医院2013年1月—2021年9月NICU住院的所有HIE新生儿。根据喂养困难标准分为喂养困难和无喂养困难两组。采集患儿暴露因素和临床检查评分,行单因素分析和Logistic回归分析探究HIE患儿喂养困难的临床特征以及高危因素。结果 收治270例HIE患儿,共计176例HIE患儿纳入本研究,其中喂养困难组72例(40.9%),无喂养困难组104例(59.1%)。HIE患儿喂养困难组住院天数长于无喂养困难组[19天(15,29.75) vs. 12天(10,15),P < 0.001];喂养困难组死亡率高于无喂养困难组(5% vs. 0,P=0.027)。喂养困难组患儿合并新生儿惊厥(25% vs. 12.5%,P=0.044)、新生儿败血症(33.3% vs. 7.3%,P=0.019)、新生儿肺炎(30.6% vs. 17.3%,P=0.045)、呼吸衰竭(31.9% vs. 17.3%,P=0.030)的比例高于无喂养困难组。喂养困难组患儿接受机械通气的比例明显高于无喂养困难组(80.6% vs. 41.39%,P < 0.001),且接受机械通气天数更长[4.5天(1,9) vs. 0天(0,2),P < 0.001]。喂养困难组接受亚低温治疗的比例显著低于无喂养困难组(38.9% vs. 72.1%,P < 0.001)。Logistic回归分析示:HIE患儿接受亚低温治疗降低喂养困难风险(OR:0.290,95%CI:0.118~0.715,P=0.007);机械通气时间越长,患儿发生喂养困难风险越高(OR:1.384,95%CI:1.184~1.618,P < 0.001);HIE临床分度越严重,患儿发生喂养困难的风险越高(OR:3.029,95%CI:1.279~7.174,P=0.012)。结论 HIE患儿发生喂养困难的高危因素主要有接受长时间机械通气、高HIE临床分度、未接受亚低温治疗。应尽可能为具有指征的HIE患儿行亚低温治疗。
关键词新生儿    缺氧缺血性脑病(HIE)    喂养困难    高危因素    临床特征    
Clinical characteristic and risk factors for feeding difficulties in neonates with hypoxic-ischemic encephalopathy
QIAN Tian-yang , GAO Ting , QIU Han , ZHANG Peng , CHENG Guo-qiang , WANG Lai-shuan     
National Health Commission (NHC) Key Laboratory of Neonatal Diseases/Department of Neonatology, Children's Hospital, Fudan University, Shanghai 201102, China
Abstract: Objective To investigate the clinical characteristic and high-risk factors of feeding difficulties (FD) in neonates with hypoxic-ischemic encephalopathy (HIE). Methods This is a single center case-control study. We enrolled all the HIE neonates hospitalized in NICU from Jan 2013 to Sep 2021 in Children's Hospital of Fudan University. The included neonates were divided into feeding difficulties (FD) group and non-feeding difficulties (NFD) group according to diagnostic criteria. The exposure factors and clinical examination scores were collected and analyzed. Univariate analysis and logistic regression analysis were performed to investigate the high-risk factors and clinical characteristic of FD in neonates with HIE. Results A total of 270 neonates met the HIE inclusion criteria, of which 176 neonates were included in the analysis, and 72 (40.9%) had FD and 104 (59.1%) had NFD. The hospital stay in the FD group was longer than that in the NFD group [19 days (15, 29.75) vs.12 days (10, 15), P < 0.001]; the FD group mortality was higher than NFD group (5% vs. 0, P=0.027). The proportion of neonates in the FD group with neonatal convulsions (25% vs.12.5%, P=0.044), neonatal sepsis (33.3% vs. 17.3%, P=0.019), neonatal pneumonia (30.6% vs.17.3%, P=0.045), neonatal respiratory failure (31.9% vs. 17.3%, P=0.030) were higher than that in the NFD group. The proportion of neonates receiving mechanical ventilation in the FD group was significantly higher than that in the NFD group (80.6% vs. 41.39%, P < 0.001), and the days of receiving mechanical ventilation was longer [4.5 days (1, 9) vs. 0 days (0, 2), P < 0.001]. The proportion of neonates receiving therapeutic hypothermia (TH) in the FD group was significantly lower than that in the NFD group (38.9% vs.72.1%, P < 0.001). Logistic regression analysis showed that receiving TH reduced the odds of FD (OR: 0.290, 95%CI: 0.118-0.715, P=0.007), the longer the mechanical ventilation (OR: 1.384, 95%CI: 1.184-1.618, P < 0.001) and the more serious the HIE (OR: 3.029, 95%CI: 1.279-7.174, P=0.012), the higher the odds of FD. Conclusion High-risk factors for FD in neonates with HIE included: receiving prolonged mechanical ventilation, sever HIE clinical grade, and not receiving TH. TH should be performed as far as possible in neonates with indications.
Key words: neonatus    hypoxic-ischemic encephalopathy (HIE)    feeding difficulties    high-risk factors    clinical characteristic    

喂养问题被认为是新生儿期面临的一个重要且具有挑战性的问题,美国儿科学会将独立经口喂养推荐为高危婴儿出院标准之一。新生儿缺氧缺血性脑病(hypoxic-ischemic encephalopathy,HIE)患儿由于大脑不同程度的受损,导致自主吮吸、吞咽、呼吸、消化等一系列神经肌肉失去精密协调能力,从而出现一系列喂养困难相关的问题。HIE患儿的喂养困难加剧了护理难度,许多患儿在新生儿期需要接受侵入性静脉营养或鼻饲喂养,甚至在出院后仍需长期的鼻饲喂养,直接影响到后期神经发育过程,给患儿及家庭带来了沉重负担。此外,延迟的完全口服喂养影响了母亲与患儿亲密关系的早期建立,不利于母亲及婴儿的身心健康 [1]

本文探究HIE新生儿喂养困难的临床特征和高危因素,以便一线工作人员尽早识别和发现并及早干预。我们假设更严重的出生缺血缺氧事件、更多的临床疾病暴露、一些具有争议的治疗措施可能会是HIE患儿喂养困难的高危因素。

资料和方法

研究设计  本研究为单中心回顾性病例对照研究。纳入2013年1月1日—2021年9月30日在复旦大学附属儿科医院新生儿科入院的所有HIE患儿。根据喂养困难标准,将患儿分为喂养困难组和无喂养困难组。轻度HIE、中度HIE、重度HIE判别根据HIE临床分度[2]851。采集各组患儿暴露因素(出生资料、母亲产科特征、NICU病程、MRI评分、脑电图检查、出院结局等)分析HIE患儿喂养困难的临床特征和高危因素。

本研究中患者身份匿名、权益不被侵犯,入院时已经获得知情同意,因此豁免伦理批准。

研究方法

喂养困难标准  参考黄瑛等[3]的标准并作修改,有以下情况之一被认为喂养困难。不能完成吞咽动作需要鼻饲喂养且:(1)频繁呕吐 > 3次/天,或(2)在完成全量喂养(150~180)mL-1·kg-1·d-1前有3天以上出现奶量不增或反而减少,或(3)鼻饲配方奶胃潴留量 > 前次喂养的1/3。此外,将生后15天仍不能全量经口喂养自定义为喂养困难。

HIE纳入标准  纳入HIE患儿诊断标准参考第五版《实用新生儿学》[2]850-851:(1)临产时或产时存在导致胎儿和新生儿急性缺血缺氧的病因;(2)新生儿生后短时间内出现相应的神经系统表现,至少持续24 h以上;(3)辅助检查证实有急性缺血缺氧后相应改变。

排除标准  (1)胎龄 < 35周或胎龄不详;(2)遗传代谢病或染色体异常;(3)消化道畸形;(4)患儿放弃治疗出院,无法获取暴露因素和结局。

亚低温治疗新生儿HIE的选择标准  参考亚低温治疗新生儿缺氧缺血性脑病方案(2011)[4],亚低温治疗新生儿HIE的选择标准为:胎龄≥36周和出生体重≥2 500 g,并且同时存在下列情况:(1)有胎儿宫内窘迫的证据;(2)有新生儿窒息的证据;(3)有新生儿HIE或aEEG脑功能监测异常的证据。

HIE新生儿机械通气指征  参考2010年英国《新生儿缺氧缺血性脑病临床管理指南》[5]:反复肤色苍白伴惊厥、呼吸衰竭、对氧的需求增加、呼吸性酸中毒进行性加重[如Pa(CO2) > 8 kPa、氧体积分数 > 500 mL/L]。

数据采集  从复旦大学附属儿科医院病例系统收集数据如下:患儿出生资料、母亲产科特征、NICU病程、MRI评分、脑电图检查、出院结局等。

部分暴露因素定义说明  (1)早产:胎龄 < 37周;(2)过期产:胎龄≥42周;(3)高龄产妇:母亲年龄≥35周岁;(4)羊水异常:羊水污染、血性羊水;(5)脐带异常:脐带高度螺旋、脐带脱垂、脐带血管外露、脐带高度水肿;(6)胎盘异常:胎盘早剥、胎盘钙化、前置胎盘、帆状胎盘。

MRI评分、新生儿脑电图分级  参考已发表文献中的方法[6],评估4个方面的脑损伤:(1)深部灰质评分(丘脑、基底神经节、内囊后肢、脑干、中央旁皮层和海马);(2)大脑白质/皮质评分(皮质、大脑白质、视放射、胼胝体、点状白质病变、实质出血);(3)小脑评分(小脑、小脑出血);(4)评估有无脑室内出血或硬膜下出血或静脉窦血栓,无评0分,有评1分。对每个项目的损伤程度进行评分:无损伤评0分,< 50%的局限性损伤评1分,≥50%的广泛性损伤评2分;单侧损伤评1分,双侧损伤评2分。将4个子评分相加计算MRI总评分。总评分越高,说明损伤越严重。MRI评分有高职称放射科医师独立盲法完成。新生儿脑电图正常、轻度异常、中度异常、重度异常分级参考第五版《实用新生儿学》[2]252-257

统计学分析  使用SPSS 21.0统计软件进行统计分析。采用t检验和Mann Whitney U检验比较连续变量;采用χ2检验比较分类变量。采用二分类Logistic回归分析,通过计算比值比和回归系数建立回归方程。P < 0.05为差异有统计学意义。

结果

一般情况  符合纳入标准的HIE患儿共270例:排除21例胎龄 < 35周或胎龄不详;排除13例遗传代谢病或染色体异常;排除15例消化道畸形;排除45例因放弃治疗出院导致无法提取暴露因素。共余176例纳入分析:其中喂养困难者72例(40.9%),无喂养困难者104例(59.1%)。

两组患儿的一般情况对比见表 1。两组患儿在性别、出生胎龄、出生体重、Apgar评分方面差异无统计学意义。喂养困难组有4例(5%)在NICU住院期间死亡,显著高于无喂养困难组0死亡(P=0.027)。喂养困难组中位住院天数19天,最长住院130天;无喂养困难组中位住院天数12天,最长住院39天,喂养困难显著延长了患儿NICU住院天数(P < 0.001)。分析产科特征:两组患儿在剖宫产、羊水异常、宫内窘迫、胎膜早破、子宫疾病、脐带异常、母亲产前/产时发热、母亲子痫前期、妊娠高血压、妊娠糖尿病方面差异无统计学意义(P > 0.05)。

表 1 喂养困难与无喂养困难组一般情况对比 Tab 1 Comparison of baseline between the FD group and NFD group
Parameters n FD (n=72) NFD (n=104) P
Male 113 48 (66.7%) 65 (62.5%) 0.633
Premature infant/Postterm infant 10 5 (7.0%) 5 (4.8%) 0.529
Birth weight (g)a 175 3186±581 3192±443 0.972
Apgar-1 min 171 70 (97.2%) 101 (97.1%) 0.135
  0-3 113 50 (71.4%) 63 (62.4%)
  4-7 57 19 (27.1%) 38 (37.6%)
  8-10 1 1 (1.4%) 0 (0)
Apgar-5 min 165 68 (94.4%) 97 (93.3%) 0.071
  0-3 32 19 (27.9%) 13 (13.4%)
  4-7 93 35 (51.5%) 58 (59.8%)
  8-10 40 14 (20.6%) 26 (26.8%)
NICU death 4 4 (5%) 0 (0) 0.027
Hospital stay(d)b 175 19 (15,29.75) 12 (10,15) < 0.001
Caesarean delivery 78 34 (47.2%) 44 (42.3%) 0.540
Abnormal amniotic fluid 77 31 (43.1%) 46 (48.4) 0.540
Fetal distress 71 29 (40.3%) 42 (40.4%) 0.870
Premature rupture of membranes 32 9 (12.5%) 23 (22.1%) 0.116
Abnormal umbilical cord 17 3 (5.0%) 14 (14.9%) 0.275
Abnormal placenta 26 11 (19.6%) 15 (17.9%) 0.827
Mother had fever before/during delivery 17 3 (4.2%) 14 (13.5%) 0.066
Preeclampsia 3 2 (2.8%) 10 (0.1%) 0.702
Gestational hypertension 5 2 (2.8%) 3 (2.9%) 1.000
Gestational diabetes 19 5 (6.9%) 14 (13.5%) 0.220
a:Data is represented by mean±SD;b:Data is represented by M (P25,P75);Counting data is represented by n (%).

两组患儿临床疾病暴露与治疗措施暴露差异

我们分析了两组患儿的临床疾病暴露差异(表 2)。喂养困难组轻度HIE 0例,中度HIE 19例(26.4%),重度HIE 48例(66.7%),不详5例(6.9%);无喂养困难组轻度HIE 5例(4.8%),中度HIE 59例(56.7%),重度HIE 40例(38.5%)。两组患儿HIE严重程度差异有统计学意义(P < 0.001)。喂养困难组患儿合并新生儿惊厥(25% vs. 12.5%,P=0.044)、新生儿败血症(33.3% vs. 17.3%,P=0.019)、新生儿肺炎(30.6% vs. 17.3%,P=0.045)、呼吸衰竭(31.9% vs. 17.3%,P=0.030)的比例更高。两组患儿在合并新生儿颅内非创伤性出血、气胸、电解质紊乱、低血糖症、应激性高血糖、代谢性酸中毒、房缺、动脉导管未闭、肺动脉高压、多器官功能衰竭、肝肾功能异常方面差异无统计学意义。回顾两组患儿治疗措施,两组患儿在接受气管插管方面差异不显著。喂养困难组患儿接受机械通气的比例较无喂养困难组明显更高(80.6% vs. 41.39%,P < 0.001),且接受机械通气天数更长[4.5天(1,9) vs. 0天(0,2),P < 0.001]。喂养困难组接受亚低温治疗的比例显著低于无喂养困难组(38.9% vs. 72.1%,P < 0.001),两组患儿在开始亚低温治疗时机方面差异不显著。

表 2 喂养困难与无喂养困难组临床疾病暴露与治疗措施暴露对比 Tab 2 Comparison of clinical disease exposure and treatment exposure between the FD group and NFD group  
[M(P25, P75)or n(%)]
Parameters n FD (n=72) NFD (n=104) P
Clinical grade of HIE 176 72 (100) 104 (100) < 0.001
  Mild HIE 5 0 (0) 5 (4.8)
  Moderate HIE 78 19 (26.4) 59 (56.7)
  Sever HIE 88 48 (66.7) 40 (38.5)
  Unknown 5 5 (6.9) 0 (0)
Fetal intracranial nontraumatic hemorrhage 52 20 (27.8) 32 (30.8) 0.738
Neonatal convulsions 31 18 (25) 13 (12.5) 0.044
Neonatal sepsis 42 24 (33.3) 18 (17.3) 0.019
Neonatal pneumonia 40 22 (30.6) 18 (17.3) 0.045
Neonatal respiratory failure 41 23 (31.9) 18 (17.3) 0.030
Pneumothorax 17 7 (9.7) 10 (9.6) 1.000
Electrolyte disorder 40 19 (12.5) 21 (20.2) 0.364
Hypoglycemia 21 7 (9.7) 14 (13.5) 0.489
Stress hyperglycemia 29 13 (4.2) 16 (15.4) 0.682
Metabolic acidosis 74 24 (33.3) 50 (48.1) 0.063
Atrial septal defect 117 45 (6.9) 72 (69.2) 0.417
Patent ductus arteriosus 86 30 (41.7) 56 (53.8) 0.127
Pulmonary arterial hypertension 37 16 (22.2) 21 (20.2) 0.851
Myocardial damage 37 15 (20.8) 22 (21.2) 1.000
Neonatal shock 7 4 (5.6) 3 (2.9) 0.446
Multiple organ dysfunction syndrome 17 9 (12.5) 8 (7.69) 0.310
Abnormal renal function 9 4 (5.6) 5 (4.8) 1.000
Abnormal liver function 13 7 (9.7) 6 (5.8) 0.385
Endotracheal intubation 137 59 (81) 78 (75) 0.081
Mechanical ventilation 101 58 (80.6) 43 (41.39) < 0.001
Day of mechanical ventilation(d) 158 4.5 (1,9) 0 (0,2) < 0.001
Nasal oxygen catheter 106 43 (59.7) 63 (60.6) 1.000
therapeutic hypothermia 103 28 (38.9) 75 (72.1) < 0.001
Postnatal hours of therapeutic hypothermia(h) 96 4 h (2.5,4.5) 3.5 h (2.5,4) 0.275

两组患儿出生1周内MRI评分、脑电图结果分析  分析两组患儿在出生1周内的MRI评分和脑电图(表 3)。喂养困难组共有65位新生儿接受了MRI检查,其中9位患儿(9.2%)未见明显异常,喂养困难组MRI总评分中值12分,最高29分;无喂养困难组共有98位新生儿接受了MRI检查,其中38位患儿未见明显异常(38.8%),无喂养困难组MRI总评分中值得分2分,最高28分;两组患儿MRI总评分差异有统计学意义(P < 0.001)。分析4个子项目,深部灰质评分占比相较于白质皮层、小脑、出血高。分析新生儿脑电结果:喂养困难组患儿脑电重度异常比例高(43.3%),无喂养困难组患儿轻中度异常(67.5%)比例高,少数重度异常(15.0%)。两组患儿脑电图分级差异有统计学意义(P < 0.001)。

表 3 喂养困难与无喂养困难组头颅MRI和脑电图比较 Tab 3 Comparison of MRI and aEEG between the FD group and NFD group  
[M(P25, P75) or n(%)]
Parameters n FD (n =72) NFD (n =104) P
MRI total score 163 12 (3,17) 2 (1,5) < 0.001
  Deep grey matter 163 8 (0,12) 0 (0,0)
  Cerebral white matter/cortex 163 3 (0,6) 0 (0,4)
  Cerebellum 163 0 (0,0) 0 (0,0)
  Presence of intraventricular or subdural hemorrhages 163 0 (0,1) 0 (0,1)
aEEG 140 60 (83.3) 80 (76.9) < 0.001
  Normal 17 3 (5.0) 14 (17.5)
  Mild abnormal 39 13 (21.6) 26 (32.5)
  Moderate abnormal 46 18 (30.0) 28 (35.0)
  Sever abnormal 38 26 (43.3) 12 (15.0)

HIE新生儿喂养困难高危因素分析  将通过共线性诊断且单因素分析P < 0.05的变量(新生儿惊厥、新生儿败血症、新生儿肺炎、新生儿呼吸衰竭、HIE分度、亚低温治疗、机械通气天数)纳入Logistic回归分析(输入法),计算OR及回归系数,建立相应的回归方程(表 4),HIE患儿接受亚低温治疗可降低喂养困难风险(OR:0.290,95%CI:0.118~0.715,P=0.007);机械通气时间越长,患儿发生喂养困难风险越高(OR:1.384,95%CI:1.184~1.618,P < 0.001);HIE临床分度越严重,患儿发生喂养困难风险越高(OR:3.029,95%CI:1.279~7.174,P=0.012)。

表 4 HIE新生儿喂养困难高危因素Logistic回归分析结果 Tab 4 Logistic regression analysis results of high risk factors for FD in neonates with HIE
Factors β P OR 95% CI
Neonatal convulsions 0.447 0.434 1.564 0.510-4.797
Neonatal sepsis 0.772 0.118 2.165 0.822-5.699
Neonatal pneumonia 0.828 0.090 2.289 0.878-5.969
Neonatal respiratory failure -0.010 0.985 0.990 0.357-2.749
Therapeutic hypothermia -1.237 0.007 0.290 0.118-0.715
Day of mechanical ventilation 0.325 < 0.001 1.384 1.184-1.618
Clinical grade of HIE 1.108 0.012 3.029 1.279-7.174
Constant -1.761

HIE新生儿喂养困难组临床特征回归分析  将亚低温治疗、机械通气天数、HIE分度、MRI总评分、脑电图分级,纳入Logistic回归分析(条件法,向后逐步回归),计算OR及回归系数,建立相应的回归方程(表 5)。HIE患儿喂养困难组主要具有长机械通气天数、高临床分度、高MRI总评分的特征。

表 5 HIE新生儿喂养困难临床特征Logistic回归分析结果 Tab 5 Logistic regression analysis results for clinical characteristic of FD in neonates with HIE
Clinical characteristics β P OR 95%CI
Day of mechanical ventilation 0.207 0.019 1.230 1.034-1.461
Therapeutic hypothermia -0.862 0.082 0.422 0.160-1.115
Clinical grade of HIE 1.265 0.012 3.545 1.320-9.523
MRI total score 0.079 0.037 1.082 1.005-1.165
Constant -1.752
讨论

新生儿独立经口喂养需要出生后的自主吮吸、吞咽、呼吸、消化等一系列神经肌肉的精密协调,是早期神经发育的重要组成部分。吮吸时口腔形成真空腔,同时保持呼吸顺畅,吞咽动作需要喉部、食管及胃肌肉的有序舒缩。在婴儿早期,这一系列动作主要通过脑干中央模式发生器(brainstem central pattern generators,CPG)快速产生,随着发育逐渐整合入皮层感觉与运动[7]。新生儿缺氧缺血性脑病导致的分水岭损伤和深部灰质损伤涉及到独立口服喂养的感觉运动复合功能损害,包括运动皮层、脑干运动核、基底神经节、丘脑等,这种脑损伤的模式和程度可以被MRI反映[8-9]。本研究结果表明,有40.9%的HIE患儿会出现喂养困难,延长住院时间。

在本研究中,长机械通气天数是喂养困难的危险因素。HIE患儿接受机械通气天数越长,发生喂养困难的风险越高。随着婴儿发育成熟,他们的吞咽模式会从“呼吸暂停-吞咽-呼吸暂停”,逐渐发育为“吸气-吞咽-呼气”模式。新生儿接受机械通气导致呼吸模式发生改变;另一方面,部分HIE患儿表现出口咽惰性、分泌物积聚、食物清除延迟和气道保护不足。这可能是由于核或核上病变导致的迷走胆碱能功能障碍;以及第Ⅸ和Ⅹ颅神经运动感觉障碍导致的上消化道运动反应不协调和近端食管骨骼肌收缩幅度减小,肌肉收缩率降低[10]。健康新生儿会在咽部受刺激时出现口唇、舌的吸吮蠕动,并以吞咽的方式清除刺激物,在2~4周时间窗内逐步建立起咽食管保护性反射。但是机械通气使得这一发育过程遭到阻碍,从而影响呼吸与吞咽的协调。此外,插管干预措施也会使患儿暴露于厌恶的口腔刺激下并延迟口腔喂养过程[11-12]

半个世纪以来,HIE治疗方式从复苏成功后实施对症支持治疗进一步演变为标准的亚低温治疗。在出生6 h内,以全身冷却或选择性头部冷却的方式将中重度HIE患儿肛温维持在33.5 ℃ 72 h,显著减少大脑损伤程度,成功将死亡和严重神经发育障碍综合相对危险度降低了25%[13]。本研究结果显示接受亚低温治疗能降低重度HIE患儿喂养困难发生率,与Gupta等[14]的研究结果相一致。

新生儿独立经口喂养所需神经肌肉的成熟和整合功能发生在妊娠中晚期,这一获得口腔喂养技能的关键发育过程会被早产破坏。Crapnell等[15]的研究显示了早产与2岁时的喂养困难相关。本研究显示出生胎龄与新生儿期的喂养困难无关,可能与当前研究只观察到出生后早期,远期结局并未统计相关。另一个影响因素可能是我们纳入了HIE患儿,将出生胎龄 < 35周的新生儿排除在外,只有出生胎龄≥35周的晚期早产儿。

我们研究的局限性在于因放弃治疗出院导致资料不全患儿有45例,占总HIE患儿的16.7%,我们将这部分患儿排除在外。原始资料分析这部分患儿大部分为重度HIE,其中7例(15.6%)在放弃治疗后立即死亡,24例(53.3%)放弃时仍未开奶,9例(20%)仍需鼻饲喂养。这使得我们纳入分析的患儿存在不同程度的偏倚。此外,纳入的样本量不大,属于单中心回顾性研究,多中心高危因素分析只是初步的内部建立,需要收集更多病例进行外部验证。

本研究明确了HIE患儿发生喂养困难的一些暴露因素:机械通气天数,亚低温治疗,HIE临床分度。在后续的研究中,我们将新生儿期喂养困难与远期神经发育结局之间建立联系,探究在新生儿期非常容易辨别的喂养困难是否可成为远期神经发育结局的良好预测因子,以期减少新生儿期不必要的侵入性检查,并尽早进行干预,以获得更好的神经发育结局。

作者贡献声明  钱天阳  论文构思、撰写和修订,数据采集和分析。高婷,邱寒  论文构思,数据分析指导。张鹏  论文构思。程国强  论文构思和修订。王来栓  论文构思和修订,数据分析。

利益冲突声明  所有作者均声明不存在利益冲突。

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表 1 喂养困难与无喂养困难组一般情况对比 Tab 1 Comparison of baseline between the FD group and NFD group
Parameters n FD (n=72) NFD (n=104) P
Male 113 48 (66.7%) 65 (62.5%) 0.633
Premature infant/Postterm infant 10 5 (7.0%) 5 (4.8%) 0.529
Birth weight (g)a 175 3186±581 3192±443 0.972
Apgar-1 min 171 70 (97.2%) 101 (97.1%) 0.135
  0-3 113 50 (71.4%) 63 (62.4%)
  4-7 57 19 (27.1%) 38 (37.6%)
  8-10 1 1 (1.4%) 0 (0)
Apgar-5 min 165 68 (94.4%) 97 (93.3%) 0.071
  0-3 32 19 (27.9%) 13 (13.4%)
  4-7 93 35 (51.5%) 58 (59.8%)
  8-10 40 14 (20.6%) 26 (26.8%)
NICU death 4 4 (5%) 0 (0) 0.027
Hospital stay(d)b 175 19 (15,29.75) 12 (10,15) < 0.001
Caesarean delivery 78 34 (47.2%) 44 (42.3%) 0.540
Abnormal amniotic fluid 77 31 (43.1%) 46 (48.4) 0.540
Fetal distress 71 29 (40.3%) 42 (40.4%) 0.870
Premature rupture of membranes 32 9 (12.5%) 23 (22.1%) 0.116
Abnormal umbilical cord 17 3 (5.0%) 14 (14.9%) 0.275
Abnormal placenta 26 11 (19.6%) 15 (17.9%) 0.827
Mother had fever before/during delivery 17 3 (4.2%) 14 (13.5%) 0.066
Preeclampsia 3 2 (2.8%) 10 (0.1%) 0.702
Gestational hypertension 5 2 (2.8%) 3 (2.9%) 1.000
Gestational diabetes 19 5 (6.9%) 14 (13.5%) 0.220
a:Data is represented by mean±SD;b:Data is represented by M (P25,P75);Counting data is represented by n (%).
表 2 喂养困难与无喂养困难组临床疾病暴露与治疗措施暴露对比 Tab 2 Comparison of clinical disease exposure and treatment exposure between the FD group and NFD group  
[M(P25, P75)or n(%)]
Parameters n FD (n=72) NFD (n=104) P
Clinical grade of HIE 176 72 (100) 104 (100) < 0.001
  Mild HIE 5 0 (0) 5 (4.8)
  Moderate HIE 78 19 (26.4) 59 (56.7)
  Sever HIE 88 48 (66.7) 40 (38.5)
  Unknown 5 5 (6.9) 0 (0)
Fetal intracranial nontraumatic hemorrhage 52 20 (27.8) 32 (30.8) 0.738
Neonatal convulsions 31 18 (25) 13 (12.5) 0.044
Neonatal sepsis 42 24 (33.3) 18 (17.3) 0.019
Neonatal pneumonia 40 22 (30.6) 18 (17.3) 0.045
Neonatal respiratory failure 41 23 (31.9) 18 (17.3) 0.030
Pneumothorax 17 7 (9.7) 10 (9.6) 1.000
Electrolyte disorder 40 19 (12.5) 21 (20.2) 0.364
Hypoglycemia 21 7 (9.7) 14 (13.5) 0.489
Stress hyperglycemia 29 13 (4.2) 16 (15.4) 0.682
Metabolic acidosis 74 24 (33.3) 50 (48.1) 0.063
Atrial septal defect 117 45 (6.9) 72 (69.2) 0.417
Patent ductus arteriosus 86 30 (41.7) 56 (53.8) 0.127
Pulmonary arterial hypertension 37 16 (22.2) 21 (20.2) 0.851
Myocardial damage 37 15 (20.8) 22 (21.2) 1.000
Neonatal shock 7 4 (5.6) 3 (2.9) 0.446
Multiple organ dysfunction syndrome 17 9 (12.5) 8 (7.69) 0.310
Abnormal renal function 9 4 (5.6) 5 (4.8) 1.000
Abnormal liver function 13 7 (9.7) 6 (5.8) 0.385
Endotracheal intubation 137 59 (81) 78 (75) 0.081
Mechanical ventilation 101 58 (80.6) 43 (41.39) < 0.001
Day of mechanical ventilation(d) 158 4.5 (1,9) 0 (0,2) < 0.001
Nasal oxygen catheter 106 43 (59.7) 63 (60.6) 1.000
therapeutic hypothermia 103 28 (38.9) 75 (72.1) < 0.001
Postnatal hours of therapeutic hypothermia(h) 96 4 h (2.5,4.5) 3.5 h (2.5,4) 0.275
表 3 喂养困难与无喂养困难组头颅MRI和脑电图比较 Tab 3 Comparison of MRI and aEEG between the FD group and NFD group  
[M(P25, P75) or n(%)]
Parameters n FD (n =72) NFD (n =104) P
MRI total score 163 12 (3,17) 2 (1,5) < 0.001
  Deep grey matter 163 8 (0,12) 0 (0,0)
  Cerebral white matter/cortex 163 3 (0,6) 0 (0,4)
  Cerebellum 163 0 (0,0) 0 (0,0)
  Presence of intraventricular or subdural hemorrhages 163 0 (0,1) 0 (0,1)
aEEG 140 60 (83.3) 80 (76.9) < 0.001
  Normal 17 3 (5.0) 14 (17.5)
  Mild abnormal 39 13 (21.6) 26 (32.5)
  Moderate abnormal 46 18 (30.0) 28 (35.0)
  Sever abnormal 38 26 (43.3) 12 (15.0)
表 4 HIE新生儿喂养困难高危因素Logistic回归分析结果 Tab 4 Logistic regression analysis results of high risk factors for FD in neonates with HIE
Factors β P OR 95% CI
Neonatal convulsions 0.447 0.434 1.564 0.510-4.797
Neonatal sepsis 0.772 0.118 2.165 0.822-5.699
Neonatal pneumonia 0.828 0.090 2.289 0.878-5.969
Neonatal respiratory failure -0.010 0.985 0.990 0.357-2.749
Therapeutic hypothermia -1.237 0.007 0.290 0.118-0.715
Day of mechanical ventilation 0.325 < 0.001 1.384 1.184-1.618
Clinical grade of HIE 1.108 0.012 3.029 1.279-7.174
Constant -1.761
表 5 HIE新生儿喂养困难临床特征Logistic回归分析结果 Tab 5 Logistic regression analysis results for clinical characteristic of FD in neonates with HIE
Clinical characteristics β P OR 95%CI
Day of mechanical ventilation 0.207 0.019 1.230 1.034-1.461
Therapeutic hypothermia -0.862 0.082 0.422 0.160-1.115
Clinical grade of HIE 1.265 0.012 3.545 1.320-9.523
MRI total score 0.079 0.037 1.082 1.005-1.165
Constant -1.752

文章信息

钱天阳, 高婷, 邱寒, 张鹏, 程国强, 王来栓
QIAN Tian-yang, GAO Ting, QIU Han, ZHANG Peng, CHENG Guo-qiang, WANG Lai-shuan
新生儿缺氧缺血性脑病中喂养困难的临床特征和高危因素分析
Clinical characteristic and risk factors for feeding difficulties in neonates with hypoxic-ischemic encephalopathy
复旦学报医学版, 2023, 50(3): 405-411.
Fudan University Journal of Medical Sciences, 2023, 50(3): 405-411.
Corresponding author
WANG Lai-shuan, E-mail: laishuanwang@fudan.edu.cn.

工作空间

新生儿缺氧缺血性脑病中喂养困难的临床特征和高危因素分析
钱天阳 , 高婷 , 邱寒 , 张鹏 , 程国强 , 王来栓