中华流行病学杂志  2019, Vol. 40 Issue (11): 1445-1449   PDF    
http://dx.doi.org/10.3760/cma.j.issn.0254-6450.2019.11.019
中华医学会主办。
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文章信息

陈琰姝, 连立飞, 许奕华, 李绪辉, 张莹, 黄佳瑜, 李檬妤, 杨洁, 王芙蓉.
Chen Yanshu, Lian Lifei, Xu Yihua, Li Xuhui, Zhang Ying, Huang Jiayu, Li Mengyu, Yang Jie, Wang Furong.
入院时糖化血红蛋白A1与脑出血患者预后的关系
Association of glycosylated hemoglobin level at admission with outcomes of intracerebral hemorrhage patients
中华流行病学杂志, 2019, 40(11): 1445-1449
Chinese Journal of Epidemiology, 2019, 40(11): 1445-1449
http://dx.doi.org/10.3760/cma.j.issn.0254-6450.2019.11.019

文章历史

收稿日期: 2019-04-05
入院时糖化血红蛋白A1与脑出血患者预后的关系
陈琰姝1 , 连立飞2 , 许奕华1 , 李绪辉1 , 张莹1 , 黄佳瑜1 , 李檬妤1 , 杨洁1 , 王芙蓉2     
1. 华中科技大学同济医学院公共卫生学院流行病与卫生统计学系, 环境与健康教育部重点实验室, 武汉 430030;
2. 华中科技大学同济医学院附属同济医院神经内科, 武汉 430030
摘要: 目的 探究自发性脑出血(ICH)患者入院时糖化血红蛋白A1(HbA1c)水平与脑出血后90 d预后之间的关系。方法 前瞻性连续纳入2017年1-12月同济医院神经内科住院ICH患者,收集患者入院时相关临床资料,在患者出血后90 d使用改良的RANKIN量表评估其功能结局。构建单变量及多变量条件logistic回归模型,根据HbA1c测量值的四分位数将患者分为4组,以每组患者HbA1c的M为替代值纳入模型,计算趋势检验P值。应用限制性立方样条法拟合logistic回归模型,评估入院时HbA1c水平与ICH预后的关系。结果 共纳入ICH患者345例,其中预后良好214例,预后不良131例(严重残疾99例,死亡32例)。多因素logistic回归分析结果显示,随着入院时HbA1c升高,ICH后90 d发生预后不良的风险升高,趋势检验P < 0.001(与HbA1c低水平组相比,中、高及极高水平组90 d预后不良的风险分别为OR=2.33,95%CI:1.07~5.07;OR=2.52,95%CI:1.12~5.64;OR=6.80,95%CI:3.01~15.34)。限制性样条结果显示,入院时HbA1c水平与ICH患者出血后90 d预后不良之间具有相关性(χ2=14.81,P < 0.001),且为线性关系(非线性检验:P=0.118)。入院时HbA1c < 6.5%的患者与HbA1c=6.5%的患者相比,随着HbA1c含量的降低,预后不良的风险呈线性降低趋势;HbA1c>6.5%的患者与HbA1c=6.5%的患者相比,预后不良的风险更大,但差异无统计学意义。结论 入院时HbA1c水平升高与出血后90 d时预后不良风险有联系,HbA1c升高是脑出血预后不良的独立预测因子。
关键词: 脑出血     糖化血红蛋白     预后    
Association of glycosylated hemoglobin level at admission with outcomes of intracerebral hemorrhage patients
Chen Yanshu1 , Lian Lifei2 , Xu Yihua1 , Li Xuhui1 , Zhang Ying1 , Huang Jiayu1 , Li Mengyu1 , Yang Jie1 , Wang Furong2     
1. Department of Epidemiology and Biostatistics, Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China;
2. Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
Corresponding author: Xu Yihua, Email: xuyihua_6@hotmail.com; Wang Furong, Email: wangfurong.china@163.com
Fund program: National Key Research and Development Plan of China (2017YFC1310000)
Abstract: Objective To explore the association of the glycosylated hemoglobin (HbA1c) level at admission with 90 days functional outcome in patients with spontaneous intracerebral hemorrhage (ICH). Methods Patients admitted to the Department of Neurology, Tongji Hospital from January to December 2017 were prospectively and continuously enrolled in this study. Clinical data were collected at admission and functional outcomes 90 days after ICH were assessed by using the modified RANKIN scale. Univariate and multivariate conditional logistic regression models were constructed. Patients were divided into four groups according to the quartile of HbA1c values. The median value of HbA1c in each group was taken as the substitute value and P for trend was calculated. The logistic regression model was fitted by restricted cubic splines to investigate the association between HbA1c level and outcome of ICH. Results A total of 345 patients with ICH were enrolled, including 214 with favorable outcomes and 131 with poor outcomes (99 severe disability cases and 32 deaths). The risk of poor 90 days outcomes was significantly associated with HbA1c level at admission indicated by multivariate logistic regression analysis, and the P for trend test was < 0.001 (middle-level group vs. low-level group:OR=2.33, 95%CI:1.07-5.07; high-level group vs. low-level group:OR=2.52, 95%CI:1.12-5.64; extremely high-level group vs. low-level group:OR=6.80, 95%CI:3.01-15.34). Results from the restricted cubic spline showed that there was a linear correlation between HbA1c level at admission and poor 90 days outcomes of ICH (χ2=14.81, P < 0.001; non-linear test:P=0.118). Compared with patients with HbA1c level of 6.5%, the risk of poor outcomes in patients with HbA1c level of < 6.5% decreased linearly with the decrease in HbA1c level at admission, and the risk in patients with HbA1c level>6.5% was higher but not significantly. Conclusion There was correlation between high HbA1c level at admission and 90 days poor outcome of ICH. High HbA1c level is an independent prediction indicator for ICH.
Key words: Intracerebral hemorrhage     HbA1c     Outcome    

自发性脑出血(intracerebral hemorrhage,ICH)指原发性非外伤性脑实质内出血,约占全部脑卒中亚型的10%~20%[1],死亡率比其他亚型更高[2],功能结局更差[3-5],是我国居民残疾和死亡的主要原因[6]。高血糖是缺血性脑卒中[7-8]及蛛网膜下腔出血[9]的预后影响因素,然而与ICH预后间的相关性尚存在争议。有研究发现,高血糖水平导致了ICH患者更高的病死率[10]及更差的功能结局[11-13],但高血糖对糖尿病ICH患者的预后预测价值较低[12],胰岛素强化降糖治疗也未能显著改善ICH的神经功能预后[14]。此外,不同的血糖测量指标也显示出不同的预后预测价值。糖化血红蛋白A1(HbA1c)能够反映患者最近6~8周内的平均血糖水平,比随机血糖或FPG更加准确和稳定,并且高HbA1c已经被证实与缺血性脑卒中的严重程度和不良预后有关[15]。因此,本研究建立了ICH前瞻性队列,收集患者入院时相关临床资料,并对其进行随访,探讨患者入院时HbA1c水平与ICH预后之间的关系,以期为ICH患者的血糖控制及结局预测提供参考。

对象与方法

1.调查对象:前瞻性连续纳入2017年1-12月同济医院神经内科住院ICH患者。纳入标准:①符合WHO制定的ICH诊断标准[16];②经头部CT或MRI证实。排除标准:①继发性脑出血,包括颅内肿瘤、外伤、颅内动脉瘤、颅内动/静脉畸形、恶性肿瘤等引起的出血以及脑梗死后出血性转化等;②原发性蛛网膜下腔出血,硬膜下、硬膜外出血或脑室出血;③严重心、肝、肾功能不全,凝血功能障碍等;④严重认知功能障碍;⑤临床资料不完整。本研究经华中科技大学同济医学院医学伦理委员会审核批准,所有研究对象均签署书面知情同意书。

2.基线调查:所有基线资料收集均在患者入院24 h内进行。收集的资料包括①一般人口学特征:年龄、性别、文化程度等;②既往疾病史:高血压、高脂血症、糖尿病、心脏病、心房颤动、脑卒中病史;③个人史:吸烟、饮酒等;④一般检查:体温、心率、呼吸、SBP、DBP等;⑤神经系统检查;⑥影像学检查:CT-头颅平扫、核磁共振等;⑦实验室检查:包括糖代谢相关检测、生化常规检测、血细胞检测以及血栓与止血检测等项目。使用美国国立卫生研究院脑卒中量表(NIHSS)评估入院时脑卒中严重程度。由2位神经内科专家根据CT检查结果,判断出血位置及是否存在破入脑室。

3.随访调查:在患者出院后90 d进行门诊或电话随访。使用改良的RANKIN量表(mRS)评估神经功能恢复情况,同时收集患者的死亡信息,包括是否死亡及死亡日期。

4.指标定义及标准:

(1)吸烟:平均吸烟≥1支/d,且连续≥1年;饮酒:包括白酒、啤酒、葡萄酒或黄酒,每周饮酒≥2次,每次摄入量≥50 g,连续饮用时间≥1年;心脏病史:任何心脏病的病史,包括冠状动脉疾病、瓣膜病、异常节律或心肌病。出血位置及是否破入脑室的判断均使用最初的CT检查结果,出血位置分为脑叶和非脑叶,破入脑室分为存在或不存在。

(2)使用mRS评估患者出血后90 d神经功能恢复情况。预后良好:mRS评分0~2分;预后不良:mRS评分3~6分。预后不良分为严重残疾(mRS评分3~5分)和死亡(mRS评分6分)。

5.统计学分析:应用SAS 9.4软件进行统计学分析。将研究对象按入院时HbA1c测量值的四分位数分为4组。进行基线特征描述时,正态分布计量资料以x±s表示,非正态分布计量资料以MP25~P75)表示,计数资料以频数(%)表示。根据资料的类型,选用单因素方差分析、Kruskal-Wallis秩和检验或χ2检验进行组间基线特征比较。构建单变量及多变量条件logistic回归模型,其中多变量logistic回归模型对基线比较有差异的因素及ICH预后常见影响因素进行调整。以每组患者HbA1c的M为替代值纳入模型,计算趋势检验P值。应用限制性立方样条法拟合logistic回归模型,评估入院HbA1c水平与ICH预后的关系,节点个数为3,调整的变量与多变量logistic回归模型保持一致。在R 3.5.1软件中绘制限制性立方样条图。所有检验采取双侧检验,以P<0.05为差异有统计学意义。

结果

1.基本情况:共纳入ICH患者345例,其中男性231例,女性114例;年龄(55±12)岁;入院时NIHSS得分M为7分。出院后90 d预后良好214例,预后不良131例,其中严重残疾99例,死亡32例。

根据入院HbA1c检测值的四分位数将研究对象分为低、中、高和极高4个HbA1c水平组,其HbA1c范围分别为4.0%~5.2%、5.3%~5.6%、5.7%~6.2%和6.3%~11.2%。对4组间基线特征进行差异性比较,结果显示不同年龄、高血压、高脂血症、糖尿病、入院NIHSS评分、出血位置、是否破入脑室组中,ICH患者入院时HbA1c水平之间的差异有统计学意义(P<0.05)。见表 1

表 1 不同基线糖化血红蛋白水平的脑出血患者特征比较

2. HbA1c水平与ICH预后的logistic回归分析:多因素logistic回归分析显示,与低水平组相比,中、高、极高水平组患者,ICH后90 d发生预后不良(死亡或严重残疾)的风险更高(OR=2.33,95%CI:1.07~5.07;OR=2.52,95%CI:1.12~5.64;OR=6.80,95%CI:3.01~15.34),趋势检验P<0.001。与低水平组相比,中和极高水平组患者,ICH后90 d发生严重残疾的的风险也更高(OR=2.45,95%CI:1.21~4.94;OR=4.45,95%CI:2.19~9.05),趋势检验P<0.001。见表 2

表 2 入院糖化血红蛋白与脑出血预后之间的关系

3.非糖尿病患者HbA1c与ICH预后关系的限制性立方样条分析:应用限制性立方样条结合logistic回归模型,对年龄、出血位置、是否破入脑室、高脂血症、高血压和入院NIHSS评分几项变量进行调整后,分析入院时HbA1c水平与ICH预后不良之间的关系。通过比较不同节点个数所对应模型的AIC值,确定节点个数为3,此时对应的AIC值最小(AIC=319.36)。以HbA1c=6.5%为参比值(HbA1c为6.5%的患者4例)。结果显示,入院时HbA1c水平与ICH预后不良之间具有相关性(χ2=14.81,P<0.001),且为线性关系(非线性检验χ2=2.44,P=0.118)。当HbA1c<6.5%时,与HbA1c=6.5%相比发生预后不良的风险更小,且随着HbA1c水平的降低,风险呈线性降低趋势;当HbA1c>6.5%时,发生预后不良的风险随HbA1c水平升高有增加趋势,但趋势无统计学意义。见图 1

图 1 基于限制性立方样条模型分析糖化血红蛋白与脑出血预后的关系
讨论

本研究中logistic回归分析结果显示,入院时HbA1c水平是ICH后90 d发生预后不良或严重残疾的危险因素,不是仅发生死亡的危险因素。此外,限制性立方样条拟合logistic回归分析结果显示,当入院时HbA1c<6.5%时,ICH后90 d发生预后不良的风险随入院时HbA1c水平的降低而降低。

传统ICH预后预测因素多为代谢性因素,如高血脂,高血压等,ICH患者多为老年人,衰老导致机体代谢紊乱,传统预后因素似乎并不适用于ICH患者[17-18]。急性期血糖升高已经被广泛证明与脑出血疾病的预后密切相关,然而研究显示,血糖水平波动较大,且易受测量时间等多种因素的影响,此外,以往的研究主要探讨某特定时点的血糖水平与ICH预后的关系,而未关注一段时间内的平均血糖水平对ICH预后的影响。相较于急性期血糖值,入院时HbA1c水平真实反映了脑卒中前较长时间段的血糖状态,是更理想的葡萄糖测量指标,因此本研究探讨入院时HbA1c水平与ICH预后之间的关系。

有研究发现,入院血糖能独立预测ICH后血肿量,但不能预测ICH后结局,而高HbA1c水平与ICH患者大血肿体积、深部出血和不良结局均独立相关[19]。早在2010年,美国糖尿病协会就建议将HbA1c检测值≥6.5%(48 mmol/mol)作为糖尿病的诊断标准[20]。因此,本研究以HbA1c=6.5%为参比,所得结果与Sun等[12]的研究结果一致,他们发现当HbA1c<6.5%时,HbA1c水平与心脑血管疾病的发生率和死亡率之间存在显著性关联,本研究结果进一步证明了这种相关性。值得注意的是,尽管ICH的发生具有年轻化趋势,但主要患者仍为老年人群,而老年人群HbA1c水平与预后间的关联性尚不清楚[21-23],本研究患者的年龄为(55±12)岁,因此,本研究结果进一步证实了老年人群中,正常范围内的HbA1c与ICH不良预后之间的显著相关性。

本研究未观察到HbA1c≥6.5%时入院HbA1c水平与不良结局之间的相关性。可能的一种解释是HbA1c=6.5%的患者数量较少,增大了Ⅱ型错误概率;另一种可能是关联性真实不存在。然而,多个研究发现,当按糖尿病史对患者进行分层后,在糖尿病患者中观察到了HbA1c对结局的预测作用[19, 24]。同时研究显示,尽管HbA1c与不良预后间关系的机制尚不清楚,但它可能涉及增强的代谢危险因素[25]、严重的脑水肿[26-27]、增加的血肿周围神经元死亡[27]、更高的动脉斑块易损性[28]和胰岛素抵抗[29],这些都可能诱发血管并发症,从而导致ICH后更差的结局。因此,高于正常范围的HbA1c水平与ICH预后之间的相关性仍需要更多的研究进行探讨。值得注意的是,有研究发现,在HbA1c≥8%的患者亚组中,治疗的依从性差与HbA1c升高显著相关,这可能进一步掩盖了HbA1c与ICH预后不良之间的相关性[30]

本研究存在局限性。首先,本研究为单中心队列研究,样本量较小,后续将逐步纳入更多病例,扩大样本量。其次,未对HbA1c≥6.5%的ICH患者进行进一步糖尿病确诊,而研究表明,使用糖尿病诊断新标准,有超过1/3的无糖尿病病史的ICH患者被诊断为糖尿病[24];也未对糖尿病史进行分层分析,而糖尿病与非糖尿病患者群体中相同水平HbA1c对ICH预后的影响是不同的[19, 24]。此外,部分影响因素也未被评估,例如出血体积、药物摄取情况等,都可能影响ICH后90 d的预后情况。总体来看,本研究仅观察到了正常范围内的低HbA1c水平对ICH患者预后的保护作用,尚需更多大样本研究,探究不同糖尿病疾病状态下入院HbA1c水平与ICH预后之间的关联。

利益冲突 所有作者均声明不存在利益冲突

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