Erythropoietin Does Not Alter Serum Profiles of Neuronal and Axonal Biomarkers After Traumatic Brain Injury: Findings From the Australian EPO-TBI Clinical Trial
Erythropoietin Does Not Alter Serum Profiles of Neuronal and Axonal Biomarkers After Traumatic Brain Injury: Findings From the Australian EPO-TBI Clinical Trial
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DOI：
10.1097/ccm.0000000000002938
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发表时间：
2018-04-01
影响因子：
8.8
通讯作者：
Morganti-Kossmann, Maria C.
中科院分区：
文献类型：
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作者：
Hellewell, Sarah C.;Mondello, Stefania;Morganti-Kossmann, Maria C.
目的：确定血清泛素羧基末端水解酶 L1 和磷酸化神经丝重链的概况，检查促红细胞生成素给药是否会降低其浓度，以及生物标志物是否区分促红细胞生成素治疗组和安慰剂治疗组。设计：单中心、前瞻性观察性研究。背景：在墨尔本阿尔弗雷德医院进行的促红细胞生成素创伤性脑损伤临床试验的子研究，澳大利亚。患者：44 例中重度脑外伤患者。干预措施：脑外伤后 24 小时内皮下注射阿法依泊汀 40,000 IU 或 1 mL 氯化钠 0.9。测量和主要结果：通过酶联免疫吸附剂测量血清中泛素羧基末端水解酶 L1、磷酸化神经丝重链和促红细胞生成素浓度。从 D0（损伤后 24 小时内，在促红细胞生成素/载体施用之前）到 D5 进行测定。比较损伤严重程度、弥漫性与局灶性创伤性脑损伤以及促红细胞生成素或安慰剂治疗组之间的生物标志物浓度。泛素羧基末端水解酶 L1 在 D0 时达到峰值 146.0 ng/mL，在 D1 时显着下降至 84.30 ng/mL，此后下降。磷酸化神经丝重链水平在 D0 时最低，在 D5 时达到峰值，为 157.9 ng/mL。弥漫性创伤性脑损伤中 D0 泛素羧基末端水解酶 L1 浓度较高。 D3 和 D4 上的磷酸化神经丝重链峰值水平与格拉斯哥结果评分扩展相关，预测不良结果。促红细胞生成素不会降低泛素羧基末端水解酶 L1 或磷酸化神经丝重链的浓度。结论：创伤性脑损伤后血清泛素羧基末端水解酶 L1 和磷酸化神经丝重链增加，反映早期神经元和进行性轴突损伤。与使用促红细胞生成素治疗的创伤性脑损伤患者的结果缺乏改善一致，生物标志物浓度和分布不受促红细胞生成素的影响。促红细胞生成素的药代动力学表明，所给予的剂量可能太低而无法发挥神经保护作用。
Objective: To determine profiles of serum ubiquitin carboxy-terminal hydrolase L1 and phosphorylated neurofilament heavy-chain, examine whether erythropoietin administration reduce their concentrations, and whether biomarkers discriminate between erythropoietin and placebo treatment groups.Design: Single-center, prospective observational study.Setting: A sub-study of the erythropoietin-traumatic brain injury clinical trial, conducted at the Alfred Hospital, Melbourne, Australia.Patients: Forty-four patients with moderate-to-severe traumatic brain injury.Interventions: Epoetin alfa 40,000 IU or 1 mL sodium chloride 0.9 as subcutaneous injection within 24 hours of traumatic brain injury.Measurements and Main Results: Ubiquitin carboxy-terminal hydrolase L1, phosphorylated neurofilament heavy-chain, and erythropoietin concentrations were measured in serum by enzyme-linked immunosorbent assay from D0 (within 24 hr of injury, prior to erythropoietin/vehicle administration) to D5. Biomarker concentrations were compared between injury severities, diffuse versus focal traumatic brain injury and erythropoietin or placebo treatment groups. Ubiquitin carboxy-terminal hydrolase L1 peaked at 146.0 ng/mL on D0, significantly decreased to 84.30 ng/mL on D1, and declined thereafter. Phosphorylated neurofilament heavy-chain levels were lowest at D0 and peaked on D5 at 157.9 ng/mL. D0 ubiquitin carboxy-terminal hydrolase L1 concentrations were higher in diffuse traumatic brain injury. Peak phosphorylated neurofilament heavy-chain levels on D3 and D4 correlated with Glasgow Outcome Score-Extended, predicting poor outcome. Erythropoietin did not reduce concentrations of ubiquitin carboxy-terminal hydrolase L1 or phosphorylated neurofilament heavy-chain.Conclusions: Serum ubiquitin carboxy-terminal hydrolase L1 and phosphorylated neurofilament heavy-chain increase after traumatic brain injury reflecting early neuronal and progressive axonal injury. Consistent with lack of improved outcome in traumatic brain injury patients treated with erythropoietin, biomarker concentrations and profiles were not affected by erythropoietin. Pharmacokinetics of erythropoietin suggest that the dose given was possibly too low to exert neuroprotection.