【作者】 鲁宁；

【导师】 胡侦明；

【作者基本信息】 昆明医科大学 ， 外科学， 2012， 博士

【副题名】基于危险因素多元回归分析、多重血栓预防方案运用和血清炎性因子在血栓与非血栓病人中的测定

【摘要】 目的：1：通过分析本院髋关节置换病人血栓的发生率。重点关注使用抗凝方案和未使用抗凝方案之间发生率的对比。根据血栓发生病人通过多元回归分析来确定髋关节置换病人血栓发生的危险因素。2：分析HSS医院多重血栓预防方案在全髋关节置换病人中的应用,确定该方案的有效性和安全性。3：根据第一部分的危险因素分析、HSS医院的多重预防方案及本院的实际情况制定本院的多重血栓预防方案运用于髋关节置换的病人,并与国内标准的血栓预防方案进行对比。确定该预防方案的有效性和安全性。4：通过髋关节置换术后发生血栓与未发生血栓病人之间血清炎性因子(C反应蛋白,肿瘤坏死因子,巨噬细胞炎性蛋白1α)对比,确定血清炎性因子与髋关节置换术后发生血栓之间的关系。方法：第一部分：髋关节置换术后的血栓发生率及髋关节置换术后引起血栓性疾病相关因素多元回归分析髋关节置换术后的血栓性疾病的发生率骨科行全髋或人工股骨头关节置换的病人共298例,从2007年1月到2010年1月。其中男性142例占病人总数47.7%,女性为156例,占病人总数的52.3%。此组病人平均年龄68(28-93),术前诊断：股骨颈骨折(Gardon三型或四型)占36.9%,骨性骨性关节炎(OA)占28.4%,股骨头坏死26.5%,内风湿性关节炎5%,髋关节发育不良3.5%,其他诊断占1.7%。术后使用下肢气压泵和低分子肝素作为血栓预防方案。当临床上怀疑有DVT时,使用彩色Doppler或静脉造影进行检查。怀疑有PE时,使用肺血管造影检查。如果确诊为深静脉血栓,给予低分子肝素治疗。远端的DVT治疗六周,近端的DVT治疗3个月。确诊为PE采用肝素治疗3-6个月。所有的病人随访至少3个月,没有一个病人失随访。髋关节置换术后引起血栓性疾病相关因素多元回归分析临床资料选取我院骨科行全髋或人工股骨头关节置换的病人共874例,从2004年1月到2010年1月。其中男性365例占病人总数41.7%,女性为509例,占病人总数的58.3%。此组病人平均年龄66(30-94),排除骨科手术原因以外引起的静脉血栓形成。其中诊断为血栓性疾病的304例。其中所有病例中采用血栓预防的为298例,占总病例数34%,发生血栓的病例数为18例,发生率为6.7%；未使用血栓预防的为576例,占总病例数的66%,发生血栓病例为286例,发生率为32.7%。统计学方法应用非条件Logistic回归模型进行单因素和多因素分析非条件Logistic回归分析。治疗所得资料运用SPSS17.0软件进行分析,计量资料采用均数±标准差(x±S)表示采用t检验。第二部分HSS医院髋关节置换病人危险因素多元回归分析及多重预防方案的应用HSS医院多重预防组病人：在纽约特种外科医院的病人共993例,其中男性473例,女性529例,从2006年1月到2010年8月在HSS行全髋关节置换手术。排除了患有血小板减少症、有出血体质以及不能行硬膜外麻醉的病人。此组病人平均年龄64Y(20从96),47.2%为男性,52.8%为女性。术前诊断：91.9%为骨性关节炎(OA),2.3%为股骨头坏死,2.1%为髋关节发育不良,1.9%为内风湿性关节炎,1.7%为其它诊断。同时对术前存在的疾病进行统计,并根据美国麻醉医师协会评分(ASA)对病人进行分级。手术由两位医生完成(EAS,TPS),采用硬膜外低压麻醉(平均动脉压维持在45-55mmHg).手术采用后外侧切口,尽量减少股静脉扭曲的时间,反复的冲洗和吸引出股骨髓腔内容物。当处理髋臼侧的时候,下肢处于中立位置。处理股骨侧髓腔之前2-3分钟,静脉给予肝素(10-15U/kg)。此组病人平均手术时间(35min-268min),平均失血量183ml(50ml-1400ml).术后病人一到复苏室就给与周期性加压装置,穿戴超膝的弹力袜,立即进行主动的背伸和跖屈踝关节活动,术后早期下床活动,一般为术后1-2天。术后当晚根据术前患血栓性疾病风险评估给予抗凝药物。对于风险较低的给予阿司匹林；对于术前评估患VTE风险高的病人和不能耐受阿司匹林的给予华法林,同时定期监测凝血功能,保持1NR在1.8-2.0之间。抗凝药物使用4-6周。当病人在临床上怀疑有DVT时,使用彩色Doppler或磁共振造影进行检查；临床上怀疑PE时,使用肺血管造影扫描或螺旋CT检查。深静脉血栓根据所发生的部位分为近端(血栓在骨盆、股骨和胭血管内),远端(血栓在小腿的血管内)。有症状的PE使用肺扫描。如果确诊为深静脉血栓,给予华法林治疗。远端的DVT治疗六周,近端的DVT治疗3个月。确诊为PE采用肝素治疗3-6个月。所有的病人随访至少3个月,没有一个病人失随访。HSS医院髋关节置换病人危险因素多元回归分析收集从2006年1月年到2010年8月在HSS医院行全髋关节置换术病人993例,.其中男469例,女524例。排除标准、有出血体质以及不能行硬膜外麻醉的病人。此组病人平均年龄64(20-96)),,91.3%为骨性关节炎(OA),2.3%为股骨头坏死,2.1%为髋关节发育不良,1.9%为内风湿性关节炎,1.7%为其它诊断.根据上面的分析结果进行血栓危险因素多元回归分析。2.1统计学方法应用非条件Logistic回归模型进行单因素和多因素分析非条件Logistic回归分析。治疗所得资料运用SPSS17.0软件进行分析,计量资料采用均数±标准差(x±S)表示采用t检验。在SPSS17.0软件中以血栓发生(DVT和PE)为因变量；性别、年龄、体重指数、既往史、麻醉、手术时间、术前献血、血栓药物为自变量,进行Logistic多因素回归分析。P值以0.05为界,P>0.05表示差异无显著性意义,P<0.05表示差异有显著性意义。第三部分多重血栓预防方案在我院的应用本院多重干预组：参考HSS的多重预防方案、AAOS的预防方案以及2009年《骨科大手术静脉血栓栓塞症预防指南》与本地区所研究的血栓性发病因素特点以及本院的实际情况进行多重干预措施的制定。术前：术前及教育病人主动背伸和跖屈踝关节,锻炼股四头肌。术中：硬膜外麻醉；股骨侧处理和下肢位置选择,尽量降低髋关节处于屈曲位的时间；术后：周期性充气加压装置应用；术后早期活动强有力的背伸和跖屈踝关节；术后抗凝药物采用阿司匹林。使用6-8周。周期性充气加压装置应用：手术结束返回病房后即刻开始,间隔6h使用1次,每次使用时间1h,连续使用7d。标准组：根据2009年《骨科大手术静脉血栓栓塞症预防指南》制定。术中：麻醉方式由麻醉师制定；术后：周期性加压装置的运用和踝关节主动运动；术后使用抗凝血药物：低分子肝素；2010年10月-2012年8月在我科行髋关节置换病人共120例病人,其中男性50例,女性70例.随机分为两组。第一组为多重方案预防组,此组病人共58例,其中男性20例,女性38例,平均年龄69.06±11.42岁。第二组为标准组,此组病人共62例,其中男性30例,女性32例,平均年龄72.80±6.45岁。采用的两组病例年龄、性别,原发病及治疗术式均无显著性。统计学方法。采用SPSS17.0统计软件,率的比较采用检验,P<0.05为差异有统计学意义。第四部分髋关节置换后血清炎性因子表达与深静脉血栓形成的相关性研究一般资料：本院2010年10月-2012年8月住院髋关节置换术后病例12例。均经彩色超声多普勒确立诊断为下肢深静脉栓塞。其中,男性4例,女性8例,年龄36-80岁,平均年龄64.6岁。对照组髋关节置换术后无血栓形成20例,其中男8例,女12例,年龄24-74岁,平均48.87岁。2组患者一般资料差异无统计学意义。对下肢DVT对照组,采集晨起空腹肘静脉血5ml以109mmo1/L枸橼酸钠抗凝,迅速转移到中心实验室(时间不超过40分钟,以避免蛋白质的变性和降解)。在中心实验室内采用高速离心机进行离心,以去除细胞和杂质。剩余的存入-80℃的深低温冰箱内保存,等待酶联免疫分析检测,此过程必须在一小时内完成,避免蛋白变性和降解.C反应蛋白,肿瘤坏死因子及巨噬细胞炎性蛋白-1α酶联免疫分析采用SPSS17.0分析软件进行统计处理,实验数据以x±s表示,行t检验分析,P<0.05为差异有显著性意义,P<0.01为差异有非常显著性意义。结果第一部分：髋关节置换术后的血栓发生率及髋关节置换术后引起血栓性疾病相关因素多元回归分析髋关节置换术后血栓的发生率病例共有298例,其中发生了血栓性疾病18例。占病人总数的6.7%、、其中16例为DVT,占病例总数的5.3%,其中2例为PE,占病例总数的0.67%。髋关节置换术后引起血栓性疾病相关因素多远回归分析危险因素多元回归分析：结果显示：高血压、高血脂,PE史,DVT史,恶性肿瘤放或化疗以及手术时间与THA术后VTE的发生有相关性。第二部分HSS多重方案预防方案的应用术前的平均HCT为38.6%,出院时平均为32.0%。术前的平均HB为13.2mg/dl,出院的平均血红蛋白为10.9mg/dl。输血统计：共210个患者没有输血,占总数的21.1%。共783个病人接受了输血,占病人总数的78.9%；其中只输了自体血的690个,占病人总数的69.4%,占输血总人数的88.1%；,只输异体血44个,占病人总数的4.4%,占输血总人数的5.6%,两者都输的49个,占病人总数的4.9%,占输血总人数的6.2%。自体血的平均输血量为单位1.09(1-3；SD,0.3),异体血平均输血量为1.25单位(1-4；SD,0.53),。接受异体血病人中,34个接受1个单位,8个接受了2个单位,2个接受了3个单位。本组病人共有13人发生血栓性疾病,占病人总数的1.3%。所有血栓病人中确诊为DVT的有8例,发生率为0.8%。其中彩超诊断的个6,磁共振造影诊断2个。DVT位于近端的有4个,其中0个在髂静脉,2个在股静脉,2个在胭静脉,0个髂静脉和股静脉都有,0个股静脉和胭静脉都有。DVT位于远端4个。在这些DVT病人中同侧6个,对侧2个,双侧0个。所有血栓病人中有症状并且诊断为PE的有5个,发生率为0.5%。其中肺扫描诊断4个,螺旋CT诊断1个。没有一个为致命性的PE。8个病人在术后一周确诊(术后1-7天),5个在术后第二周,0个在术后6周。在所有13个诊断为血栓性疾病的病人中,10个术前评估有临床易感因素。接受阿司匹林的病人中7例发生VTE,占接受阿司匹林治疗患者的0.9%,其中下肢深静脉血栓4例,有症状的肺栓塞3例；接受华法林的病人中6个发生VTE,占接受华法林治疗患者的2%,其中下肢深静脉血栓5,有症状肺栓塞1例。两组病人VTE发生率比较多重预防方案组VTE发生率与本院298例髋关节置换术后使用抗凝方案的VTE发生率相比之间有显著性差异(1.3%对6.7%,P=0.008)危险因素多元回归分析：结果显示：高血压,PE史,DVT史,手术时间,恶性肿瘤或化疗于THA术后VTE的发生有相关性。第三部分多重血栓预防方案在我院的应用多重预防组：平均手术时间92.73±10.47min,平均手术出血量280.48±74.17,有5例发生了下肢深静脉血栓,发生率为4.16%,无一例肺栓塞。标准组：：平均手术时间87.85±15.59min,平均手术出血量320.00±56.65ml,有7例发生了下肢深静脉血栓,发生率为5.83%,无一例肺栓塞。多重预防组于标准组比较出血量和手术时间之间有无差异性,P>0.05,血栓的发生率没有差异性,P=0.207。抗凝费用多重预防组明显低于标准组(P<0.001)第四部分髋关节置换后血清炎性因子表达与深静脉血栓形成的相关性研究结果：本院2010年10月-2012年8月髋关节置换病人病例12例,均经彩色多普勒确立诊断为下肢深静脉栓塞。其中,男性4例,女性8例,年龄36-80岁,平均年龄64.6岁。没有发生血栓的髋关节置换病人18例,其中男8例,女10例,年龄24-74岁,平均48.87岁。髋关节置换均由同一组骨科医师进行。30例患者中,采用气管插管全身麻醉20例,硬膜外麻醉下10例,均经髋关节外侧入路,置换方法及置换后处理均相同；5例采用骨水泥骨定,25例采用非骨水泥固定。酶联免疫结果显示两组病人血清C-反应蛋白、肿瘤坏死因子-α、巨噬细胞炎性蛋白-1α表达水平之间有明显的差异。结论高血脂、高血压,PE史,DVT史,手术时间,恶性肿瘤或化疗与THA术后VTE的发生有相关性。HSS医院人工髋关节置换病人采用多重血栓预防方案,血栓(包括深静脉血栓和肺栓塞)的发生率很低。术中的出血量很少和手术时间短,需要输血的病人和输血量都很低。而且安全可靠,与此相关的并发症也很低。本院根据HSS的多种预防方案及本院THA术后血栓性疾病的危险因素相关性分析及本院的实际情况建立的多重预防方案。临床上运用该多重预防方案并与标准方案进行对比。血栓发生率两组没有差别,但抗凝费用上两组之间有明显的差异。进一步的研究需要大样本进行分析对比。酶联免疫结果显示两组病人血清C-反应蛋白、肿瘤坏死因子-α、巨噬细胞炎性蛋白-1α表达水平之间有明显的差异。说明髋关节置换后及时检测、观察上述指标,如指标明显升高可能对判断髋关节置换术后是否会发生DVT具有一定实际意义。但具体的危险数值就一定会有血栓的发生还需要进一步的研究.关键词血栓性疾病人工髋关节置换多重预防方案多远回归分析血清炎性因子更多还原

【Abstract】 Part1Investigate the incidence of clinical symtomatic VTES after THA at our hospital and analysis the main factors of VTE after THA at our hospital1:Investigate the incidence of clinical symtomatic VTES after THA at our hospital Method:we retrospectively the298patients which performed THA at our hospital between jan,2007to Jan2010.We investigate the incidence of clinical symtomatic VTES after THA. We compare the incidence of clinical symtomatic VTES after THA between HSS and Our hospital.2:Analysis the main factors of VTE after THA at our hospital using Multivariate statistical analysis of Discrimint analysis and Logistic regression analysis.Part2Multimodal Prophylaxis for Venous Thromboembolism Disease after Total Hip Arthroplasty at HSSMethodWe observed993consecutive patients who had THAs performed between Jan,2006and August,2010.We excluded patients with thrombocytopenia or preexising bleeding diathesis and patients for whom epidural analgesia was not possible.The median age of the patients was64years (range,20-96years);52.8%were women (529of933));47.2%were men(473Of933);and91.9%had osteoarthritis(913of933),2.3%had osteonerrosis(23of933),2.1%had dysplasia(21of933),1.9%had rheumatoid arthritis (19of933),and1.7%had other diagnoses(17of933). Preexiting comrbidities were identified and patients were classified according to the ASA classification.Surgery was performed by one of two surgeons (EAS, TPS). The mean operative time was83minutes.The surgeries were performed under hypotensive epidural anestheisa (mean arterial pressure between45-55mm Hg) through a posterolateral approach,minimizing the duration of femoral vein obstruction and reducing the load of intramedullary content to the venous system by repeated pulsatile lavage and aspiration of the femoral canal.The lower extremity was in the neutral position while working on the acetabulum and flexed and internally rotated while working on the femur. Whenever possible, the lower extremity was extended to a neutral position to restore femoral venous flow.Patients received one bolus of unfractionated intravenous heparin (10-15U/kg),1to2minutes before femoral canal preparation.Postoeratively,all patients recived intermittent pneumatic compression as soon as the patient arrived to the recovery room,knee-high elastic stockings.immediate active ankle flexion and extension exercises, and early ambulation beginning on postoperative Day1.In addition,71.1%(707of933) of patients received an antiplatelet agent (325mg aspirin twice a day) and28.9%(286of933) received warfarin because of intolerance to aspirin, previous cardiac comorbidities,or a high clinical risk for thromboembolic disease.The pharmacologic prophylaxis started the night of surgery and continued for4to6weeks. Warfarin was monitored to maintain prothrombin time levels at1.8to2times control.If there was clinical suspicion of DVT, the patients were evaluated with Doppler ultrasound and with magnetic resonance venography.DVT were classified as proximal (pelvic, femoral, popliteal) or distal (calf). Symptomatic PEs were evaluated with ventilation perfusion scans or Spiral CT. Patients had spiral comtuted tomography.All patients with a positive DVT were treated with warfarin (patients with distal DVTs for6weeks;Patients with proximal DVTs for3months).Patients with clinically symptomatic Pes,confirmed by ventilation and perfusion scans were treated with heparin followed by warfarin for3-to6months。All patients followed up at least3months postoperatively.No patient was lost to followup.The comparaed groups were divided into two two goups.The first one is the patients were performed THA in the second hospital afficiated with kunming medical university. We observed298consecutive patients who had THAs performed between Jan,2007and May,2011..The median age of the patients was68years (range,28-93years);52.4%were women;47.6%were men;and36.9%were femoral neck fracture;28.4%were OA,26.5%had osteonerrosis;3.5%had dysplasia(21of933),5%had rheumatoid arthritis (19of933),and1.7%had other diagnoses(17of933)2:Multivariate statistical analysis of Discrimint analysis and Logistic regression analysis for the main factors of VTE after THAMethod:We retrospectively993consecutive patients who had THAs performed between Jan,2006and August,2010.We excluded patients with thrombocytopenia or preexising bleeding diathesis and patients for whom epidural analgesia was not possible.The median age of the patients was64years (range,20-96years);52.8%were women (529of933));47.2%were men(473Of933);and91.9%had osteoarthritis(913of933),2.3%had osteonerrosis(23of933),2.1%had dysplasia(21of933),1.9%had rheumatoid arthritis (19of933),and1.7%had other diagnoses(17of933). Preexiting comrbidities were identified and patients were classified according to the ASA classification.We analyze the main factors associated with VTE after THA using Multivariate statistical analysis of Discrimint analysis and Logistic regression analysis.Part3Multimodal Prophylaxis for Venous Thromboembolism Disease after Total Hip Arthroplasty at our hospitalMethod:We randomly divided the patients who performed THA into two groups.Group one choose mutimodal prophylaxis for VTE after THA.Group two choose standard prophylaxis for VTE after THA.Part4Changes of the expressions of plasma inflammatory cytokine in patients with deep vein thrombosis after total hip replacementTo evaluate the changes of the expressions of tumor necrosis factor alpha (TNF-α), C-Creative Protein, macrophageinn-matoryprotein-la in patients with deep vein thrombosis (DVT) after total hip replacement (THR),30inpatients treated with THR were selected between October2010and August2012. All the patients accepted ultrasound imaging examination and various laboratory serum sampling collections voluntarily. Blood flow of deepvein in lower limbs was examined with color Doppler ultrasound in all the patients after THR. The concentrations of TNF-α,C-Creative Protein, macrophageinn-matoryprotein-la were determined with enzyme linked immunosorbent assay.ResultsPart11:The incidence of clinical symoptomatic VTE is6.7%(18Of298) The incidence of Deep vein thrombosis was5.3%. with prophylaxis after hip arthroplasty.2:2:The factors including more thanHTN,,the history of DVT and PE,,duration of surgery were associated with VTEs after THA.Part21:The multimodal prophylaxis protocol at HSS was associated with a low requirement of homologous blood transfusion.Comp lete information on blood loss was avaible for patients.It showed a mean preoperative hematocrit of38.6%.The mean hematocrit decrease at discharge was32%.21.1%Of patients required no blood transfusion.69.4%of the remaining patients received autologous blood,4.4%received homologous blood, and4.9%received both.The mean number of autologous units transfusion was1.09and the amount of homologous blood transfused was1.25units per patient. Among the patients receiving homologous blood,34patients received one unit,8patients received two units, and2patients received three units.The incidence of clinical symoptomatic VTE is0.03%(13Of933) The incidence of Deep vein thrombosis was0.8%,which diagnosed with ultrasound in6patients and magnetic resonance venography in2patients.There were8proximal and distal clots.4Of the proximal clots,0were iliac,2were femoral,2were popliteal and femoral, and0was femoral and iliac. Among the DVTs dianosed in this study,6were ipsilateral,2were contralateral, and0were bilateral.5Of patients had a symptomatic PE. These were documented by ventilation and perfusion scans in4patients and bi spiral computed tomography in1patient. There was no fatal Pes.8Of these patients were diagnosed during the first postoperative week (postoperative Day 1to postoperative Day7);5VTEs developed during the second postoperative week.Among13patients who had VTEs develop,10had clinical predisposing factors.The prevalence of synptpmatic VTEs in patients who received aspirin was0.9%(7of707) and Coumadin prophylaxis was2%(6Of286).2:The factors including HTN,the history of DVT and PE,,duration of surgery and cheo and radio tumor with were associated with VTEs after THA.Part3The incidence of clinical symoptomatic VTE between Multi group and control group is no signicant diffrience (p=0.207).There is no significant difference of bood loss and duration of surgery between the multi group and control group (P>0.05)).There is significant difference of expence of anticoagulants between two groups (P<0.001).Part4The expressionsof inflammatory cytokines of TNF-α, TNF-α,C-Creative Protein, macrophageinn-matoryprotein-la postoperatively in the thrombus group were obviously higher than those in the control group (P<0.01-0.05). The expressions of related plasma inflammatory cytokines areenhanced in patients with DVT early after THR.ConclusionThe prevalence of venous thrombolism (DVT AND PE) after Total Hip Arthroplasty is very low using Multimodal prophylaxis. The amount of blood loss in the surgery and duration time of the surgery is also low.Less patients who need transfusin and the amount of transfusion is very low.We implemented mutlmodal prophylaxis for VTEafter THA according to the HSS protoclo and the factors which analyzed at our hospital.We compared two groups at pur hospital.The result shows The incidence of clinical symoptomatic VTE between Multi group and control group is no signicant diffrience (p=0.207) and there is no significant difference of bood loss and duration of surgery between the multi group and control group (P>0.05). There is significant difference of expence of anticoagulants between two groups (P<0.001).So we need more cases or multi center to evaluate the multi protoclo in advance.更多还原