新生儿缺氧缺血性脑病促红细胞生成素治疗试验。
Trial of Erythropoietin for Hypoxic-Ischemic Encephalopathy in Newborns.
机构信息
From the Departments of Neurology (Y.W.W., A.M.G., H.C.G.), Pediatrics (Y.W.W., F.F.G., E.E.R., H.C.G.), and Epidemiology (H.C.G.), University of California, San Francisco, San Francisco, the Department of Pediatrics, Stanford University School of Medicine, Stanford (K.P.V.M., S. Bonifacio), and the Departments of Pediatrics (T.-W.W., J.L.W.) and Radiology (J.L.W., S. Bluml), Children's Hospital Los Angeles, and the Departments of Pediatrics (T.-W.W., J.L.W.) and Radiology (J.L.W., S. Bluml), University of Southern California Keck School of Medicine, Los Angeles - all in California; the Department of Biostatistics, University of Washington (B.A.C., P.J.H.), and the Department of Pediatrics, University of Washington School of Medicine (D.E.M., U.M., S.E.J.) - both in Seattle; the Department of Pediatrics, Children's Healthcare of Atlanta (N.L.M.), and the Department of Pediatrics, Emory University (N.L.M., B.B.P.) - both in Atlanta; the Division of Neurology, Children's National Hospital, and the Department of Neurology, George Washington School of Medicine and Health Sciences - both in Washington, D.C. (T.C.); the Department of Neonatology, Children's Minnesota, St. Paul (A.L.L.), and the Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester (E.B.-S.) - both in Minnesota; the Department of Pediatrics, Saint Louis University School of Medicine (A.M.M.), and the Departments of Radiology (R.C.M., C.D.S.), Pediatrics (R.R., C.D.S.), and Neurology (C.D.S.), Washington University in St. Louis School of Medicine - both in St. Louis; the Department of Pediatrics, Cook Children's Medical Center, the Department of Pediatrics, Texas Christian University, and the Department of Pediatrics, University of North Texas Health Science Center, Ft. Worth (D.R.), the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas (L.C.), and Pediatrix Medical Group of San Antonio, Children's Hospital of San Antonio, and Methodist Children's Hospital, San Antonio (K.A.A.) - all in Texas; the Department of Pediatrics, Indiana University School of Medicine, Indianapolis (U.M., G.M.S.); the Department of Pediatrics, Children's Hospital of Philadelphia, and the Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia (J.F.), and the Department of Pediatrics, University of Pittsburgh School of Medicine, the Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, and the Department of Pediatrics, UPMC Magee-Womens Hospital, Pittsburgh (T.D.Y.) - all in Pennsylvania; the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (J.-H.W.); the Department of Pediatrics, University of Utah, Salt Lake City (M.B.); the Department of Pediatrics, University of New Mexico School of Medicine, Albuquerque (J.R.L.); the Department of Pediatrics, Boston University Medical Center, Boston (K.C.K.K.); the Department of Pediatrics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill (T.M.O.); the Department of Pediatrics, Nationwide Children's Hospital, Columbus (K.L.B.), and the Department of Pediatrics, Cincinnati Children's Hospital Medical Center, and the Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati (S.M.) - all in Ohio; and the Department of Pediatrics, University of Chicago, Chicago (M.D.S.).
出版信息
N Engl J Med. 2022 Jul 14;387(2):148-159. doi: 10.1056/NEJMoa2119660.
BACKGROUND
Neonatal hypoxic-ischemic encephalopathy is an important cause of death as well as long-term disability in survivors. Erythropoietin has been hypothesized to have neuroprotective effects in infants with hypoxic-ischemic encephalopathy, but its effects on neurodevelopmental outcomes when given in conjunction with therapeutic hypothermia are unknown.
METHODS
In a multicenter, double-blind, randomized, placebo-controlled trial, we assigned 501 infants born at 36 weeks or more of gestation with moderate or severe hypoxic-ischemic encephalopathy to receive erythropoietin or placebo, in conjunction with standard therapeutic hypothermia. Erythropoietin (1000 U per kilogram of body weight) or saline placebo was administered intravenously within 26 hours after birth, as well as at 2, 3, 4, and 7 days of age. The primary outcome was death or neurodevelopmental impairment at 22 to 36 months of age. Neurodevelopmental impairment was defined as cerebral palsy, a Gross Motor Function Classification System level of at least 1 (on a scale of 0 [normal] to 5 [most impaired]), or a cognitive score of less than 90 (which corresponds to 0.67 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition.
RESULTS
Of 500 infants in the modified intention-to-treat analysis, 257 received erythropoietin and 243 received placebo. The incidence of death or neurodevelopmental impairment was 52.5% in the erythropoietin group and 49.5% in the placebo group (relative risk, 1.03; 95% confidence interval [CI], 0.86 to 1.24; P = 0.74). The mean number of serious adverse events per child was higher in the erythropoietin group than in the placebo group (0.86 vs. 0.67; relative risk, 1.26; 95% CI, 1.01 to 1.57).
CONCLUSIONS
The administration of erythropoietin to newborns undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy did not result in a lower risk of death or neurodevelopmental impairment than placebo and was associated with a higher rate of serious adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT02811263.).
背景
新生儿缺氧缺血性脑病是导致死亡和幸存者长期残疾的重要原因。促红细胞生成素被认为对患有缺氧缺血性脑病的婴儿具有神经保护作用，但当与治疗性低温联合使用时，其对神经发育结局的影响尚不清楚。
方法
在一项多中心、双盲、随机、安慰剂对照试验中，我们将 501 名胎龄 36 周或以上、患有中度或重度缺氧缺血性脑病的婴儿随机分为接受促红细胞生成素或安慰剂组，同时接受标准治疗性低温治疗。促红细胞生成素（1000 单位/千克体重）或生理盐水安慰剂在出生后 26 小时内静脉内给药，然后在 2、3、4 和 7 天龄时给药。主要结局是 22 至 36 个月时死亡或神经发育障碍。神经发育障碍定义为脑瘫、粗大运动功能分类系统至少 1 级（0 分为正常，5 分为最严重）或贝利婴幼儿发育量表第三版的认知评分低于 90 分（相当于低于平均水平 0.67 标准差，分数越高表示表现越好）。
结果
在改良意向治疗分析的 500 名婴儿中，257 名接受了促红细胞生成素治疗，243 名接受了安慰剂治疗。促红细胞生成素组的死亡率或神经发育障碍发生率为 52.5%，安慰剂组为 49.5%（相对风险，1.03；95%置信区间[CI]，0.86 至 1.24；P=0.74）。促红细胞生成素组每例患儿严重不良事件的平均数量高于安慰剂组（0.86 比 0.67；相对风险，1.26；95%CI，1.01 至 1.57）。
结论
与安慰剂相比，接受治疗性低温治疗缺氧缺血性脑病的新生儿使用促红细胞生成素并未降低死亡或神经发育障碍的风险，反而与更高的严重不良事件发生率相关。（由美国国立神经病学和中风研究所资助；ClinicalTrials.gov 编号，NCT02811263。）
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