脑梗死患者白细胞计数及与其他因素交互作用对预后的影响
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摘要
背景与目的
炎症反应是脑梗死重要的病理生理过程，白细胞（WBC）是炎症反应的主要参与者，是脑梗死发生的危险因素。然而，脑梗死急性期WBC计数水平与预后的关系尚未定论，WBC与其他因素间交互作用与脑梗死患者预后是否存在关联鲜见研究报道。本研究的目的是探讨急性脑梗死患者入院时WBC计数水平及与其他因素交互作用对预后的影响，为急性脑梗死入院时WBC计数升高是否进行干预提供理论依据。
方法
一、回顾性队列研究
以2003年1月-2009年12月期间在河北联合大学附属医院就诊并住院的2,808例急性脑梗死患者作为研究对象，采用统一设计的病例调查表，通过查阅病历档案，收集患者的人口统计学信息、生活方式因素、入院时WBC计数及其他实验室检查资料、病史相关资料以及临床结局[死亡或残疾（MRs≥3）]相关资料。研究结局定义为住院期间死亡和出院时残疾（MRs≥3）。采用SPSS16.0软件进行统计分析。比较具有不同临床结局的急性脑梗死患者之间基线特征的差异。采用单因素和多因素logistic回归方法，分析入院时外周血WBC计数水平与急性脑梗死患者住院期间死亡和残疾危险性的关联，计算相对危险度（Relative Risk, RR）和95%可信区间（95%confident interval,95%CI）。分析WBC升高与其他脑梗死危险因素的交互作用对不同临床结局的影响。
二、前瞻性队列研究
本阶段研究以中美合作“急性缺血性脑卒中降血压随机对照试验”研究的入选患者为研究对象，自2009年8月1日至2011年9月31日，“急性缺血性脑卒中降血压随机对照试验”研究共纳入2009例急性脑梗死患者。本阶段研究以这2009例急性脑梗死患者作为研究对象，探讨入院时WBC计数水平与急性脑梗死患者住院期间和3个月预后的关系。采用统一设计的基线调查表，收集患者的人口统计学信息、生活方式因素、入院时实验室检查资料以及病史相关资料，检测入院后24小时内WBC计数水平，收集出院时临床结局（死亡、残疾）、NIHSS评分和MRs评分的资料。发病后3个月时，对所有研究对象进行随访，收集期间临床结局资料，并进行神经功能（NIHSS评分）和生活自理程度的评价（MRs评分）。以死亡或残疾（MRs≥3）作为研究结局。采用SAS9.1和SPSS16.0软件进行统计分析。比较不同临床结局和不同WBC计数水平的急性脑梗死患者基线特征的差异。采用单因素和多因素Cox比例风险模型，分析入院时WBC计数水平与急性脑梗死患者住院期间和3个月时临床结局的关联，计算相对危险度（Relative Risk, RR）和95%CI。分析WBC升高与其他脑梗死危险因素的交互作用对不同临床结局的影响。
结果
一、回顾性队列研究
急性脑梗死患者住院期间的病死率为4.2%，残疾率为25.4%。男性患者的病死率为4.1%，残疾率为22.4%，女性患者的病死率为4.2%，残疾率为29.1%，男性患者的病死率与女性患者的病死率无统计学差异（p＞0.05），而女性患者的残疾率显著高于男性患者（p<0.05）。
死亡组和残疾组的年龄，吸烟率、饮酒率、糖尿病史率、冠心病史率、卒中史率、心率、脉搏、收缩压、NIHSS评分、意识障碍人数均显著高于无结局组。死亡组的年龄、吸烟率、饮酒率、高血压病史率、糖尿病史率、冠心病史率、卒中史率，脉搏、心率、NIHSS评分、意识障碍人数也显著高于残疾组。
死亡组血糖异常率、血脂异常率、肝功能异常率、肾功能异常率、尿酸水平、血小板计数和WBC计数均显著高于残疾组和无结局组。残疾组血糖异常率、血脂异常率、肾功能异常率、尿酸水平、血小板计数和WBC计数显著高于无结局组。
WBC＞10.0×10~9/L组年龄、吸烟、饮酒、高血压、糖尿病病史、血糖异常、血脂异常率均显著高于WBC≤10.0×10~9/L组。WBC＞10.0×10~9/L组的病死率为12.9%，残疾率43.6%，WBC≤10.0×10~9/L组的病死率1.7%，残疾率20.3%，WBC＞10.0×10~9/L组的病死率和残疾率明显高于WBC≤10.0×10~9/L组。
急性脑梗死患者入院时WBC计数水平与住院期间死亡、残疾及复合结局（死亡+残疾）的危险性均呈显著关联关系。与WBC≤10.0×10~9/L者相比，WBC计数水平11.0~11.9×10~9/L和≥12.0×10~9/L者，多因素调整的死亡RR值分别是5.60(2.14,13.08)和12.42(3.12,49.44)；多因素调整的残疾RR值分别是4.92(2.16,11.20)和8.93(4.03,19.81)；多因素调整的复合结局RR值分别是2.05(1.03,9.02)和6.08(3.09,11.71)；均P<0.05。
WBC升高与糖尿病、高尿酸血症、冠心病对脑梗死患者住院死亡、残疾及复合结局均无显著的相乘模型交互作用（P>0.05）；WBC升高与糖尿病对脑梗死患者住院死亡、残疾及复合结局均无显著的相加模型交互作用（P>0.05）；WBC升高与高尿酸血症对脑梗死患者住院死亡及复合结局均有显著的正相加模型交互作用，交互效应超额相对危险度分别为11.371和4.972；归因交互效应百分比分别为62.2%和41.6%。WBC升高与冠心病对脑梗死患者住院期间残疾、复合结局均有显著的正相加模型交互作用（P＜0.05），交互效应超额相对危险度分别为5.746和6.391，归因交互效应百分比分别为48.9%和49.0%。
二、前瞻性队列研究
本阶段研究共纳入急性脑梗死患者2009例，完成发病后3个月随访1737例。住院期间（14天内）和3个月内病死率分别为1.19%和2.94%。住院期间和3个月内残疾率分别为54.90%和40.87%。
住院期间死亡者的入院时WBC计数水平高于残疾者和无结局者，差异有统计学意义；而残疾者入院时WBC计数水平虽高于无结局者，但差异无统计学意义。
3个月内死亡者入院时WBC计数水平高于残疾者和无结局者，差异有统计学意义；而残疾者入院时WBC计数水平虽高于无结局者，但差异无统计意义。
将研究对象按入院时WBC计数水平分为WBC<7.02×10~9/L组和WBC≥7.02×10~9/L组，WBC≥7.02×10~9/L组住院期间、3个月时病死率和残疾率都明显高于WBC<7.02×10~9/L组，差异有统计学意义。
将研究对象按入院时WBC计数水平分为四组（第1组：WBC≤5.78×10~9/L；第2组：5.79×10~9/L≤WBC≤7.01×10~9/L;第3组7.02×10~9/L≤WBC≤8.70×10~9/L;第4组：WBC≥8.71×109/L），以第1组为参比，调整多因素后，第3组患者住院期间发生残疾相对危险度具有统计学意义，其住院期间发生残疾的RR值为1.20(1.01,1.43)；第4组患者住院期间和3个月内发生死亡、残疾、复合结局的相对危险度均具有统计学意义，其住院期间发生死亡、残疾和复合结局的RR值分别为4.75(1.49,15.15)，1.29(1.10,1.53)和1.32（1.25,1.56）；其3个月内发生死亡、残疾和复合结局的RR值分别为6.37(2.64,15.41)、1.45(1.17,1.78)和1.54（1.26,1.88）。
WBC升高与冠心病的相乘模型交互作用对住院期间死亡的RR值为2.31(P=0.051);对3个月内死亡的RR值为2.04(P=0.061)。
WBC升高与高尿酸血症的相乘模型交互作用对发病3个月内死亡的RR值为4.99(P=0.058)。
WBC升高与糖尿病、高尿酸血症、冠心病对脑梗死患者住院期间、3个月内死亡、残疾及复合结局均无显著的相加模型交互作用（P>0.05）。
结论
1、急性脑梗死患者入院时WBC计数水平与住院期间和3个月内死亡或残疾的危险性相关联，WBC计数水平升高可增加急性脑梗死患者住院期间和3个月死亡或残疾的危险性。
2、WBC升高与高尿酸血症、冠心病的交互作用可能增加脑梗死患者短期不良结局发生的危险性。
3、本研究建议进一步深入研究WBC计数及与其他因素的交互作用对预后的影响，有必要开展控制WBC计数水平与急性脑梗死预后关系的临床随机对照试验研究，以最终阐明WBC计数水平与急性脑梗死预后的关系。
Background and purpose：
Inflammatory reaction is one of pathological process of the acute cerebralinfarction. White blood cell (WBC), which plays an important part in the inflammatoryreaction, is the major risk factor for the incidence of acute cerebral infarction. However,the relationship between the level of WBC in the acute phase after onset of acutecerebral infarction and clinical outcome is inconclusive. Besides, few researches oninteraction between WBC and other factors have been conducted in the past years. Weexamine the influence of WBC count and its interactions with other factors on prognosisamong patients with acute cerebral infarction in order to provide scientific evidence forthe effective controlling of the increased WBC in the acute phase of cerebral infarction.
Method:
1. Retrospective cohort study
A total of2,808acute cerebral infarction patients in the affiliated hospital ofHebei United University from January,2003to December,2009，were included in thepresent study. Demographic characteristics, lifestyle factors, WBC count and otherlaboratory examinations at admission, medical history, and clinical outcome werecollected by referring to the medical records. Study outcome was defined as in-hospitaldeath or dependency [Modified Rankin’s scale (MRs)≥3] at discharge. Statistic analysiswas conducted using SPSS16.0software. Differences of the baseline characteristicswere compared among acute cerebral infarction patients with different outcome (death,dependency, and non-dependency). Unadjusted and multiple adjusted logistic regressionmodels were used to analyze the relationship between WBC count at admission andin-hospital death or dependency among acute cerebral infarction patients. Relative Risk(RR) and95%confident interval (95%CI) were evaluated. The influence of the interaction between the increased WBC and other risk factors on study outcomes wasanalyzed among acute cerebral infarction patients.
2. Prospective cohort study
Subjects of the China stroke project (A randomized controlled trial of reducing BPamong acute ischemic stroke patients) which was conducted by China and Americacooperation were served as subjects in the present study. A total of2009patients wereobtained from August1st,2009to September31th,2011in the project. The2009patients were served as study subject999in the present study to explore relationshipbetween WBC count at admission and in-hospital outcome and3rd month outcomeamong acute cerebral infarction patients. Demographic characteristics, lifestyle factors,laboratory examinations at admission and medical history were collected, and the WBCcount in the first24hours was examined. We collected clinical outcomes（death ordependency）, NIHSS score and MRs scores on discharge. Follow-up study wasconducted in the3rd month after stroke onset among all of the participants, clinicaloutcome during this period and NIHSS scores, MRs scores were collected. Studyoutcome was defined as death or dependency (MRs≥3). Statistic analysis was conductedusing SAS9.1and SPSS16.0software. Differences of the baseline characteristics werecompared among the patients with various clinical outcomes, and the different levels ofWBC count. Unadjusted and multiple adjusted Cox proportional hazard models wereused to analyze the relationship between WBC count in the acute phase and studyoutcome in-hospital and in the3rd month after stroke onset among acute cerebralinfarction patients, which were evaluated by the relative risk (RR) and95%CI. Theinfluence of the interaction between the increased WBC and other risk factors on studyoutcomes was analyzed among cerebral infarction patients.
Results:
1. Retrospective cohort study
The case-fatality rate and disability rate were4.2%and25.4%, respectively, inacute cerebral infarction patients. The case-fatality rate and disability rate were4.1%and22.4%respectively, for men,4.2%and29.1%respectively, for women. There wasno statistic difference in the case-fatality rate between men and women(p＞0.05). Thedisability rate of women patients was significantly higher than men patients (p <0.05).
The patients with study outcomes (death and dependency) were older than those without study outcomes. The rates of smoking, drinking, diabetes,coronary heart diseases, and stroke history, the heart rate, the pulse, the systolic pressure,the NIHSS scores, and the number of consciousness disturbance were significantlyhigher in patients with study outcomes than those without study outcomes. The deathgroups were older than the dependency group. The medical history rates of smoking,drinking, hypertention, diabetes, coronary heart disease and stroke, the levels of thepulse and heart rate, the NIHSS scores, and the number of disturbance of consciousnesswere significantly higher in death patients than in dependency patients.
The rates of hyperglycemia, dyslipidemia, liver dysfunction, and renal dysfunction,the level of uric acid, platelet and WBC counts were significantly higher in deathpatients than those with dependency and patient without study outcome. The rates ofhyperglycemia, dyslipidemia, liver dysfunction, and renal dysfunction, the levels ofuric acid, platelet and WBC counts were significantly higher in dependency patientsthan those without study outcome.
The age, the history rates of smoking, drinking, hypertension and diabetes, therates of hyperglycemia and dyslipidemia were significantly higher in patients with WBC＞10.0×10~9/L than those in patients with WBC≤10.0×10~9/L. The case-fatality rate anddisability rate were12.9%and43.6%,respectively, in patients with WBC＞10.0×10~9/L,and the case-fatality rate and disability rate were1.7%and20.3%, respectively, inpatients with WBC≤10.0×10~9/L. The disability rate was significantly higher in patientswith WBC＞10×10~9/L than in those with WBC≤10.0×10~9/L (P <0.05).
The levels of WBC count at admission were also significantly associated with therisk of death, dependency and combined outcome in-hospital in acute cerebral infarctionpatients. Compared with patients with WBC≤10.0×10~9/L, the multiple adjusted RRs ofdeath for patients with WBC11.0~11.9×10~9/L and≥12.0×10~9/L were5.60(2.14,13.08)and12.42(3.12,49.44), respectively. The multiple adjusted RRs of dependency forpatients with WBC11.0~11.9×10~9/L and≥12.0×10~9/L were4.92(2.16,11.20) and8.93(4.03,19.81), respectively. The multiple adjusted RRs of combined outcomes forpatients with WBC11.0~11.9×10~9/L and≥12.0×10~9/L were2.05(1.03,9.02) and6.08(3.09,11.71), respectively,(P <0.05).
There were no significantly interactions between the increased WBC count anddiabetes, hyperuricaemia or coronary heart disease on the study outcomes (death, dependency or combined outcomes) among acute cerebral infarction patients inmultiplicative model (P>0.05). There were no significantly interactions between theincreased WBC count and diabetes on the outcomes (death, dependency or combinedoutcomes) among acute cerebral infarction patients in additive model (P>0.05). Therewere significantly interactions between the increased WBC count and hyperuricaemiaon the study outcomes (death and combined outcomes) among acute cerebral infarctionpatients in additive model. The RERIs of death and combined outcome were11.371and4.972, respectively. The APs of death and combined outcome were62.2%and41.6%,respectively. There were significantly interactions between the increased WBC countand coronary heart disease on the study outcomes (dependency and combined outcome)of acute cerebral infarction patients in additive model. The RERIs of dependency andcombined outcome were5.746and6.391, respectively, and the APs of dependency andcombined outcome were48.9%and49.0%, respectively.
2. Prospective cohort study
A total of2009acute cerebral infarction patients were recruited in the study,1737patients completed the3rd month follow-up study. The case-fatality rates in hospital (infirst14days after stroke onset)and in the first3months were1.19%and2.94%,respectively. The disability rates in hospital and in the first3months54.90%and,40.87%, respectively.
Patients died in hospital had a higher level of WBC count at admission than thosewith dependency or without study outcome (P <0.05).
Patients died within first3months had a higher level of WBC count at admissionthan those with dependency or without study outcome (P <0.05).
Subjects were divided into two groups by admission WBC count (group one：WBC<7.02×10~9/L, group two: WBC≥7.02×10~9/L). The case-fatality and disablity rate inhospital and in the first3months were significantly higher in group one than those ingroup two, respectively(P <0.05).
Subjects were divided into four groups by admission WBC count (group one:WBC≤5.78×10~9/L, group two:5.79×10~9/L≤WBC≤7.01×10~9/L, group three:7.02×10~9/L≤WBC≤8.70×10~9/L, group four: WBC≥8.71×10~9/L). Compared with groupone, the multiple adjusted RRs of dependency in hospital in the group three werestatistically significant [RRs were1.20(1.01,1.43)], the multiple adjusted RRs for death, dependency and combined outcomes in hospital and in the first3months in the groupfour were statistically significant [RRs were4.75(1.49,15.15),1.29(1.10,1.53) and1.32(1.25,1.56) in hospital, respectively. RRs were6.37(2.64,15.41),1.45(1.17,1.78)and1.54(1.26,1.88) in the first3months, respectively.].
RR of death in hospital associated with the interactions between the increasedWBC count at admission and coronary heart disease was2.31(P=0.051)in multiplicativemodel; RR of death in the first3months associated with the interactions between theincreased WBC count at admission and coronary heart disease was2.04(P=0.061) inmultiplicative model.
RR of death in the first3months associated with the interactions between theincreased WBC count at admission and hyperuricaemia was4.99(P=0.058).
There were no significantly interactions between the increased WBC count anddiabetes, hyperuricaemia or coronary heart disease on the study outcomes (death,dependency or combined outcomes) in hospital and in the first3months among acutecerebral infarction patients in additive model (P>0.05).
Conclusion:
1. Increased level of WBC count at admission was positively and significantlyassociated with risks of death and dependency in hospital and in the first3months afteronset among patients with acute cerebral infarction.
2. Interactions between increased WBC and hyperuricaemia and coronary heartdisease probably increased the risk of short-term poor outcomes.
3. This study suggests that further research of interaction between the increasedWBC count and other risk factors on the prognosis should be conducted among acutecerebral infarction patients, and randomized controlled trials should be conducted to testthe potential beneficial effects of controlling WBC levels in acute cerebral infarctionpatients.
炎症反应是脑梗死重要的病理生理过程，白细胞（WBC）是炎症反应的主要参与者，是脑梗死发生的危险因素。然而，脑梗死急性期WBC计数水平与预后的关系尚未定论，WBC与其他因素间交互作用与脑梗死患者预后是否存在关联鲜见研究报道。本研究的目的是探讨急性脑梗死患者入院时WBC计数水平及与其他因素交互作用对预后的影响，为急性脑梗死入院时WBC计数升高是否进行干预提供理论依据。
方法
一、回顾性队列研究
以2003年1月-2009年12月期间在河北联合大学附属医院就诊并住院的2,808例急性脑梗死患者作为研究对象，采用统一设计的病例调查表，通过查阅病历档案，收集患者的人口统计学信息、生活方式因素、入院时WBC计数及其他实验室检查资料、病史相关资料以及临床结局[死亡或残疾（MRs≥3）]相关资料。研究结局定义为住院期间死亡和出院时残疾（MRs≥3）。采用SPSS16.0软件进行统计分析。比较具有不同临床结局的急性脑梗死患者之间基线特征的差异。采用单因素和多因素logistic回归方法，分析入院时外周血WBC计数水平与急性脑梗死患者住院期间死亡和残疾危险性的关联，计算相对危险度（Relative Risk, RR）和95%可信区间（95%confident interval,95%CI）。分析WBC升高与其他脑梗死危险因素的交互作用对不同临床结局的影响。
二、前瞻性队列研究
本阶段研究以中美合作“急性缺血性脑卒中降血压随机对照试验”研究的入选患者为研究对象，自2009年8月1日至2011年9月31日，“急性缺血性脑卒中降血压随机对照试验”研究共纳入2009例急性脑梗死患者。本阶段研究以这2009例急性脑梗死患者作为研究对象，探讨入院时WBC计数水平与急性脑梗死患者住院期间和3个月预后的关系。采用统一设计的基线调查表，收集患者的人口统计学信息、生活方式因素、入院时实验室检查资料以及病史相关资料，检测入院后24小时内WBC计数水平，收集出院时临床结局（死亡、残疾）、NIHSS评分和MRs评分的资料。发病后3个月时，对所有研究对象进行随访，收集期间临床结局资料，并进行神经功能（NIHSS评分）和生活自理程度的评价（MRs评分）。以死亡或残疾（MRs≥3）作为研究结局。采用SAS9.1和SPSS16.0软件进行统计分析。比较不同临床结局和不同WBC计数水平的急性脑梗死患者基线特征的差异。采用单因素和多因素Cox比例风险模型，分析入院时WBC计数水平与急性脑梗死患者住院期间和3个月时临床结局的关联，计算相对危险度（Relative Risk, RR）和95%CI。分析WBC升高与其他脑梗死危险因素的交互作用对不同临床结局的影响。
结果
一、回顾性队列研究
急性脑梗死患者住院期间的病死率为4.2%，残疾率为25.4%。男性患者的病死率为4.1%，残疾率为22.4%，女性患者的病死率为4.2%，残疾率为29.1%，男性患者的病死率与女性患者的病死率无统计学差异（p＞0.05），而女性患者的残疾率显著高于男性患者（p<0.05）。
死亡组和残疾组的年龄，吸烟率、饮酒率、糖尿病史率、冠心病史率、卒中史率、心率、脉搏、收缩压、NIHSS评分、意识障碍人数均显著高于无结局组。死亡组的年龄、吸烟率、饮酒率、高血压病史率、糖尿病史率、冠心病史率、卒中史率，脉搏、心率、NIHSS评分、意识障碍人数也显著高于残疾组。
死亡组血糖异常率、血脂异常率、肝功能异常率、肾功能异常率、尿酸水平、血小板计数和WBC计数均显著高于残疾组和无结局组。残疾组血糖异常率、血脂异常率、肾功能异常率、尿酸水平、血小板计数和WBC计数显著高于无结局组。
WBC＞10.0×10~9/L组年龄、吸烟、饮酒、高血压、糖尿病病史、血糖异常、血脂异常率均显著高于WBC≤10.0×10~9/L组。WBC＞10.0×10~9/L组的病死率为12.9%，残疾率43.6%，WBC≤10.0×10~9/L组的病死率1.7%，残疾率20.3%，WBC＞10.0×10~9/L组的病死率和残疾率明显高于WBC≤10.0×10~9/L组。
急性脑梗死患者入院时WBC计数水平与住院期间死亡、残疾及复合结局（死亡+残疾）的危险性均呈显著关联关系。与WBC≤10.0×10~9/L者相比，WBC计数水平11.0~11.9×10~9/L和≥12.0×10~9/L者，多因素调整的死亡RR值分别是5.60(2.14,13.08)和12.42(3.12,49.44)；多因素调整的残疾RR值分别是4.92(2.16,11.20)和8.93(4.03,19.81)；多因素调整的复合结局RR值分别是2.05(1.03,9.02)和6.08(3.09,11.71)；均P<0.05。
WBC升高与糖尿病、高尿酸血症、冠心病对脑梗死患者住院死亡、残疾及复合结局均无显著的相乘模型交互作用（P>0.05）；WBC升高与糖尿病对脑梗死患者住院死亡、残疾及复合结局均无显著的相加模型交互作用（P>0.05）；WBC升高与高尿酸血症对脑梗死患者住院死亡及复合结局均有显著的正相加模型交互作用，交互效应超额相对危险度分别为11.371和4.972；归因交互效应百分比分别为62.2%和41.6%。WBC升高与冠心病对脑梗死患者住院期间残疾、复合结局均有显著的正相加模型交互作用（P＜0.05），交互效应超额相对危险度分别为5.746和6.391，归因交互效应百分比分别为48.9%和49.0%。
二、前瞻性队列研究
本阶段研究共纳入急性脑梗死患者2009例，完成发病后3个月随访1737例。住院期间（14天内）和3个月内病死率分别为1.19%和2.94%。住院期间和3个月内残疾率分别为54.90%和40.87%。
住院期间死亡者的入院时WBC计数水平高于残疾者和无结局者，差异有统计学意义；而残疾者入院时WBC计数水平虽高于无结局者，但差异无统计学意义。
3个月内死亡者入院时WBC计数水平高于残疾者和无结局者，差异有统计学意义；而残疾者入院时WBC计数水平虽高于无结局者，但差异无统计意义。
将研究对象按入院时WBC计数水平分为WBC<7.02×10~9/L组和WBC≥7.02×10~9/L组，WBC≥7.02×10~9/L组住院期间、3个月时病死率和残疾率都明显高于WBC<7.02×10~9/L组，差异有统计学意义。
将研究对象按入院时WBC计数水平分为四组（第1组：WBC≤5.78×10~9/L；第2组：5.79×10~9/L≤WBC≤7.01×10~9/L;第3组7.02×10~9/L≤WBC≤8.70×10~9/L;第4组：WBC≥8.71×109/L），以第1组为参比，调整多因素后，第3组患者住院期间发生残疾相对危险度具有统计学意义，其住院期间发生残疾的RR值为1.20(1.01,1.43)；第4组患者住院期间和3个月内发生死亡、残疾、复合结局的相对危险度均具有统计学意义，其住院期间发生死亡、残疾和复合结局的RR值分别为4.75(1.49,15.15)，1.29(1.10,1.53)和1.32（1.25,1.56）；其3个月内发生死亡、残疾和复合结局的RR值分别为6.37(2.64,15.41)、1.45(1.17,1.78)和1.54（1.26,1.88）。
WBC升高与冠心病的相乘模型交互作用对住院期间死亡的RR值为2.31(P=0.051);对3个月内死亡的RR值为2.04(P=0.061)。
WBC升高与高尿酸血症的相乘模型交互作用对发病3个月内死亡的RR值为4.99(P=0.058)。
WBC升高与糖尿病、高尿酸血症、冠心病对脑梗死患者住院期间、3个月内死亡、残疾及复合结局均无显著的相加模型交互作用（P>0.05）。
结论
1、急性脑梗死患者入院时WBC计数水平与住院期间和3个月内死亡或残疾的危险性相关联，WBC计数水平升高可增加急性脑梗死患者住院期间和3个月死亡或残疾的危险性。
2、WBC升高与高尿酸血症、冠心病的交互作用可能增加脑梗死患者短期不良结局发生的危险性。
3、本研究建议进一步深入研究WBC计数及与其他因素的交互作用对预后的影响，有必要开展控制WBC计数水平与急性脑梗死预后关系的临床随机对照试验研究，以最终阐明WBC计数水平与急性脑梗死预后的关系。
Background and purpose：
Inflammatory reaction is one of pathological process of the acute cerebralinfarction. White blood cell (WBC), which plays an important part in the inflammatoryreaction, is the major risk factor for the incidence of acute cerebral infarction. However,the relationship between the level of WBC in the acute phase after onset of acutecerebral infarction and clinical outcome is inconclusive. Besides, few researches oninteraction between WBC and other factors have been conducted in the past years. Weexamine the influence of WBC count and its interactions with other factors on prognosisamong patients with acute cerebral infarction in order to provide scientific evidence forthe effective controlling of the increased WBC in the acute phase of cerebral infarction.
Method:
1. Retrospective cohort study
A total of2,808acute cerebral infarction patients in the affiliated hospital ofHebei United University from January,2003to December,2009，were included in thepresent study. Demographic characteristics, lifestyle factors, WBC count and otherlaboratory examinations at admission, medical history, and clinical outcome werecollected by referring to the medical records. Study outcome was defined as in-hospitaldeath or dependency [Modified Rankin’s scale (MRs)≥3] at discharge. Statistic analysiswas conducted using SPSS16.0software. Differences of the baseline characteristicswere compared among acute cerebral infarction patients with different outcome (death,dependency, and non-dependency). Unadjusted and multiple adjusted logistic regressionmodels were used to analyze the relationship between WBC count at admission andin-hospital death or dependency among acute cerebral infarction patients. Relative Risk(RR) and95%confident interval (95%CI) were evaluated. The influence of the interaction between the increased WBC and other risk factors on study outcomes wasanalyzed among acute cerebral infarction patients.
2. Prospective cohort study
Subjects of the China stroke project (A randomized controlled trial of reducing BPamong acute ischemic stroke patients) which was conducted by China and Americacooperation were served as subjects in the present study. A total of2009patients wereobtained from August1st,2009to September31th,2011in the project. The2009patients were served as study subject999in the present study to explore relationshipbetween WBC count at admission and in-hospital outcome and3rd month outcomeamong acute cerebral infarction patients. Demographic characteristics, lifestyle factors,laboratory examinations at admission and medical history were collected, and the WBCcount in the first24hours was examined. We collected clinical outcomes（death ordependency）, NIHSS score and MRs scores on discharge. Follow-up study wasconducted in the3rd month after stroke onset among all of the participants, clinicaloutcome during this period and NIHSS scores, MRs scores were collected. Studyoutcome was defined as death or dependency (MRs≥3). Statistic analysis was conductedusing SAS9.1and SPSS16.0software. Differences of the baseline characteristics werecompared among the patients with various clinical outcomes, and the different levels ofWBC count. Unadjusted and multiple adjusted Cox proportional hazard models wereused to analyze the relationship between WBC count in the acute phase and studyoutcome in-hospital and in the3rd month after stroke onset among acute cerebralinfarction patients, which were evaluated by the relative risk (RR) and95%CI. Theinfluence of the interaction between the increased WBC and other risk factors on studyoutcomes was analyzed among cerebral infarction patients.
Results:
1. Retrospective cohort study
The case-fatality rate and disability rate were4.2%and25.4%, respectively, inacute cerebral infarction patients. The case-fatality rate and disability rate were4.1%and22.4%respectively, for men,4.2%and29.1%respectively, for women. There wasno statistic difference in the case-fatality rate between men and women(p＞0.05). Thedisability rate of women patients was significantly higher than men patients (p <0.05).
The patients with study outcomes (death and dependency) were older than those without study outcomes. The rates of smoking, drinking, diabetes,coronary heart diseases, and stroke history, the heart rate, the pulse, the systolic pressure,the NIHSS scores, and the number of consciousness disturbance were significantlyhigher in patients with study outcomes than those without study outcomes. The deathgroups were older than the dependency group. The medical history rates of smoking,drinking, hypertention, diabetes, coronary heart disease and stroke, the levels of thepulse and heart rate, the NIHSS scores, and the number of disturbance of consciousnesswere significantly higher in death patients than in dependency patients.
The rates of hyperglycemia, dyslipidemia, liver dysfunction, and renal dysfunction,the level of uric acid, platelet and WBC counts were significantly higher in deathpatients than those with dependency and patient without study outcome. The rates ofhyperglycemia, dyslipidemia, liver dysfunction, and renal dysfunction, the levels ofuric acid, platelet and WBC counts were significantly higher in dependency patientsthan those without study outcome.
The age, the history rates of smoking, drinking, hypertension and diabetes, therates of hyperglycemia and dyslipidemia were significantly higher in patients with WBC＞10.0×10~9/L than those in patients with WBC≤10.0×10~9/L. The case-fatality rate anddisability rate were12.9%and43.6%,respectively, in patients with WBC＞10.0×10~9/L,and the case-fatality rate and disability rate were1.7%and20.3%, respectively, inpatients with WBC≤10.0×10~9/L. The disability rate was significantly higher in patientswith WBC＞10×10~9/L than in those with WBC≤10.0×10~9/L (P <0.05).
The levels of WBC count at admission were also significantly associated with therisk of death, dependency and combined outcome in-hospital in acute cerebral infarctionpatients. Compared with patients with WBC≤10.0×10~9/L, the multiple adjusted RRs ofdeath for patients with WBC11.0~11.9×10~9/L and≥12.0×10~9/L were5.60(2.14,13.08)and12.42(3.12,49.44), respectively. The multiple adjusted RRs of dependency forpatients with WBC11.0~11.9×10~9/L and≥12.0×10~9/L were4.92(2.16,11.20) and8.93(4.03,19.81), respectively. The multiple adjusted RRs of combined outcomes forpatients with WBC11.0~11.9×10~9/L and≥12.0×10~9/L were2.05(1.03,9.02) and6.08(3.09,11.71), respectively,(P <0.05).
There were no significantly interactions between the increased WBC count anddiabetes, hyperuricaemia or coronary heart disease on the study outcomes (death, dependency or combined outcomes) among acute cerebral infarction patients inmultiplicative model (P>0.05). There were no significantly interactions between theincreased WBC count and diabetes on the outcomes (death, dependency or combinedoutcomes) among acute cerebral infarction patients in additive model (P>0.05). Therewere significantly interactions between the increased WBC count and hyperuricaemiaon the study outcomes (death and combined outcomes) among acute cerebral infarctionpatients in additive model. The RERIs of death and combined outcome were11.371and4.972, respectively. The APs of death and combined outcome were62.2%and41.6%,respectively. There were significantly interactions between the increased WBC countand coronary heart disease on the study outcomes (dependency and combined outcome)of acute cerebral infarction patients in additive model. The RERIs of dependency andcombined outcome were5.746and6.391, respectively, and the APs of dependency andcombined outcome were48.9%and49.0%, respectively.
2. Prospective cohort study
A total of2009acute cerebral infarction patients were recruited in the study,1737patients completed the3rd month follow-up study. The case-fatality rates in hospital (infirst14days after stroke onset)and in the first3months were1.19%and2.94%,respectively. The disability rates in hospital and in the first3months54.90%and,40.87%, respectively.
Patients died in hospital had a higher level of WBC count at admission than thosewith dependency or without study outcome (P <0.05).
Patients died within first3months had a higher level of WBC count at admissionthan those with dependency or without study outcome (P <0.05).
Subjects were divided into two groups by admission WBC count (group one：WBC<7.02×10~9/L, group two: WBC≥7.02×10~9/L). The case-fatality and disablity rate inhospital and in the first3months were significantly higher in group one than those ingroup two, respectively(P <0.05).
Subjects were divided into four groups by admission WBC count (group one:WBC≤5.78×10~9/L, group two:5.79×10~9/L≤WBC≤7.01×10~9/L, group three:7.02×10~9/L≤WBC≤8.70×10~9/L, group four: WBC≥8.71×10~9/L). Compared with groupone, the multiple adjusted RRs of dependency in hospital in the group three werestatistically significant [RRs were1.20(1.01,1.43)], the multiple adjusted RRs for death, dependency and combined outcomes in hospital and in the first3months in the groupfour were statistically significant [RRs were4.75(1.49,15.15),1.29(1.10,1.53) and1.32(1.25,1.56) in hospital, respectively. RRs were6.37(2.64,15.41),1.45(1.17,1.78)and1.54(1.26,1.88) in the first3months, respectively.].
RR of death in hospital associated with the interactions between the increasedWBC count at admission and coronary heart disease was2.31(P=0.051)in multiplicativemodel; RR of death in the first3months associated with the interactions between theincreased WBC count at admission and coronary heart disease was2.04(P=0.061) inmultiplicative model.
RR of death in the first3months associated with the interactions between theincreased WBC count at admission and hyperuricaemia was4.99(P=0.058).
There were no significantly interactions between the increased WBC count anddiabetes, hyperuricaemia or coronary heart disease on the study outcomes (death,dependency or combined outcomes) in hospital and in the first3months among acutecerebral infarction patients in additive model (P>0.05).
Conclusion:
1. Increased level of WBC count at admission was positively and significantlyassociated with risks of death and dependency in hospital and in the first3months afteronset among patients with acute cerebral infarction.
2. Interactions between increased WBC and hyperuricaemia and coronary heartdisease probably increased the risk of short-term poor outcomes.
3. This study suggests that further research of interaction between the increasedWBC count and other risk factors on the prognosis should be conducted among acutecerebral infarction patients, and randomized controlled trials should be conducted to testthe potential beneficial effects of controlling WBC levels in acute cerebral infarctionpatients.
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