单肺通气时间对肺损伤的影响
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摘要
自电视辅助胸腔镜手术(Video-assisted thoracoscopic surgery, VATS)在九十年代报道后,VATS由于微创和低死亡率而成为最广泛和经常使用的手术方式。在胸科手术,特别是在电视辅助胸腔镜手术中,单肺通气(One-lung ventilation, OLV)是辅助手术可视的最经常使用的技术。由于VATS的手术视野小,需用手术器具替代手工操作,胸内手术操作时间比传统的胸廓切开术长。而单肺通气对通气侧肺和萎陷侧肺有不同程度的损伤。
OLV对通气肺的影响主要是机械牵张性肺损伤。机械牵张包括：机械正压通气、OLV时不断重复肺组织萎陷和复张的过程、胸科手术操作对肺组织的牵拉。而OLV对萎陷肺影响较通气侧肺影响大。在OLV时由于缺氧性肺血管收缩的作用,萎陷侧肺血流量降低为心输出量的20%-25%,而萎陷肺的肺泡内无氧气,所以当萎陷肺经历了由萎陷到复张的过程时,也是肺泡组织经历缺氧到复氧、缺血-再灌注损伤的过程。众多研究认为肺复张可以激活严重的氧化应激反应,氧自由基产生与OLV的时间相关。长时间单肺通气增加术后肺并发症。但长时间OLV对肺损伤的影响如何,多久才是长时间单肺通气?是3小时、4小时、还是更长?
研究发现OLV和双肺通气(Two-lung ventilation,TLV)均可导致血白介素-6(Interleukin-6, IL-6)和白介素-8(Interleukin-8, IL-8)升高,但OLV更显著；OLV患者在术后48h,无论是IL-6还是IL-8的浓度可降到与TLV组相似,OLV2小时后再TLV,动脉血氧分压也可以恢复到术前水平。这说明只要很好的控制OLV的时间,临床上应用OLV麻醉还是安全的。但这一研究只观察了OLV2h后再TLV,肺损伤有减轻的结果,对长时间OLV后再TLV的情况如何就暂无文献报道?
目前,对OLV的时间限制尚无明确的数据说明。因此,本研究拟尝试从临床和动物实验来观察不同单肺通气时间对肺损伤的影响,从而寻找单肺通气的时间限制；我们还从动物实验来观察单肺通气结束后24小时内肺损伤修复的情况,为日后探讨单肺通气后肺损伤修复的机制而做准备。
目的
回顾性分析电视辅助胸腔镜手术后肺部并发症的相关因素；研究不同单肺通气时间对兔支气管肺泡灌洗液(Bronchoalveolar lavage fluid, BALF)肿瘤坏死因子-alpha (Tumor necrosis factor-alpha, TNF-a)、IL-8及肺组织表面活性蛋白A(Surfactant protein A, SPA)的影响；研究不同单肺通气时间对胸科手术患者BALF中TNF-a, IL-8的影响。
方法
1、电视辅助胸腔镜手术后肺部并发症的相关因素分析
1.1一般资料
选取2010年1月1日到2011年3月31日在广州呼吸疾病研究所行VATS患者330例,男212例,女118例,年龄18-77岁,体重42-80kg。排除标准：术前已存在肺感染或其他感染性疾病；术前经验性应用抗感染治疗者；行气管切开等创伤性操作及长期机械通气等易继发感染者；纵隔胸腺瘤伴重症肌无力者；术中出现心肺复苏等抢救情况；中转开胸手术者；术中不能耐受单肺通气者；有术前放化疗史；术前停止吸烟未足2周者。
1.2麻醉方法
所有患者麻醉前30min均肌肉注射咪达唑仑0.05mg/kg和阿托品0.01mg/kg。根据患者术前的后前位胸片胸骨锁骨端气管横径,选择双腔支气管导管(Double-lumen tubes, DLT)的型号,并根据患者身高计算插管深度。患者入手术室后完善生命体征监测,设定丙泊酚血浆靶控浓度3gg/ml,面罩吸氧去氮5min后行丙泊酚靶控输注静脉诱导,同时缓慢静脉注射舒芬太尼0.4μg/kg和顺阿曲库铵0.2mg/kg。经口明视下按计算的深度插入DLT,并以纤维支气管镜(Fiberoptic bronchoscopy, FOB)调整管端位置。插管完成后行右颈内静脉和桡动脉穿刺置管。
所选病例通气模式均相同,潮气量、呼吸频率及吸呼比等各项参数设置也基本一致,麻醉方法、用药及术后镇痛方式和镇痛药物也大致相仿。根据患者病变部位及大小选择合适的手术方式,手术均由同一组医师完成。患者术中生命体征平稳,手术结束均鼓肺,待患者清醒拔管后送入ICU监护。
1.3对病例采用回顾性分析与肺部并发症发生可能相关的影响因素
包括年龄、性别、体重指数(Body mass index,BMI)、术前肺功能评级及测量指标：包括肺功能正常、轻度、中度、中重度、重度和极重度通气功能障碍；第一秒用力呼气量(Forced expiratory volume in first second, FEV1)、用力肺活量(Forced vital capacity, FVC)、FEV1/FVC比值、最大随意通气量(Maximal voluntary ventilation, MVV);及心彩超检查结果,单肺通气时间及麻醉时间、术中失血量及补液量、手术侧及手术切除范围(胸腔镜探查、肺楔形切除、单个或多个肺叶切除、全肺切除)、ICU入住时间、术后引流管留置时间、术后住院时间、手术前后血白蛋白值,以及术前是否合并糖尿病、慢性呼吸道疾病、心血管疾病、胸科手术史等,搜集、整理以上相关资料。
胸科手术后肺部并发症诊断标准：观察术后三天内肺部影像学变化是否出现肺渗出增加、肺炎、肺不张或肺压缩、肺栓塞、胸壁皮下气肿增多、胸腔积液等,以及呼吸衰竭、需要纤维支气管镜吸痰、重新气管插管等。
麻醉时间是指：麻醉诱导开始到拔除气管导管；单肺通气时间是指：手术开始前10分钟开始单肺通气到恢复双肺通气。本研究将麻醉时间按小于2小时、2-3小时、3-4小时、大于4小时分为四个阶段来分析；将单肺通气时间按小于1小时、1-2小时、2-3小时、大于3小时分为四个阶段来分析。
1.4统计分析
采用SPSS13.0统计分析软件包进行分析。计量资料采用均数±标准差表示。有肺并发症组与无肺并发症组比较,视资料情况采用两独立样本t检验或卡方检验；所有变量与术后是否有肺并发症关系用多因素逐步Logistic回归分析,P<0.05有统计学意义。
2.不同单肺通气时间对兔支气管肺泡灌洗液TNF-α、IL-8及肺组织SPA的影响
2.1动物准备和分组
健康新西兰大白兔68只,雄性,实验前一天禁食禁水。随机分为C组和01组、02组、03组、04组、05组。C组为对照组(假单肺通气组,n=10),只进行穿刺操作并保持自主呼吸；O1—05组建立右肺单肺通气,01和02组10只兔,03组11只兔,04组12只兔,05组15只兔。每组分别给予单肺通气1、2、3、4、5小时。各组兔子完成单肺通气后恢复双肺通气30分钟,其中每组一半兔立即处死,另一半兔待恢复自主呼吸后拔除各种管道,缝合胸廓和气管切口后饲养24小时再处死。
2.2实验操作
经耳缘静脉注射戊巴比妥钠30mg/kg后取仰卧位固定。2%利多卡因局麻下游离颈动脉或股动脉穿刺置管,通过动脉压力转换器测心率(Heart rate, HR)和平均动脉压(Mean arterial blood pressure, MAP)。颈静脉或股静脉穿刺置管予生理盐水10mL·kg-1·h-1输注。予2%利多卡因局部喷洒后在甲状软骨下3个气管环处行气管切开,并插入带气囊的3.0号改良单腔气管导管,深度约3cm左右。插管即刻予维库溴胺0.1mg/kg静脉注射,间断予戊巴比妥钠10mg/h和维库溴胺0.1mg/kg静注麻醉。连接HX-300S小动物呼吸机行机械通气,呼吸机参数：潮气量10mL/kg,呼吸频率35次/分,吸呼比1：1,吸入氧浓度(Fi02)1.0；实验开始时将导管插入右侧,建立右肺OLV动物模型,经左第6肋间开一小口(1cmxlcm)观察肺萎陷情况,以左肺通气膨胀到萎陷为单肺通气模型建立成功。单肺通气期间呼吸参数改为潮气量8mL/kg,呼吸频率40次/分,吸呼比1：1。在单肺通气时,若检测动脉血气SA02≤80%则恢复双肺通气15分钟后再继续单肺通气,记录每只兔子恢复双肺通气次数。整个实验过程中维持室温26-28℃,予台灯照射保暖,维持动物肛温(37-38℃)。实验结束后,实验兔通过静脉注射20ml空气处死。
2.3实验动物排除标准：
实验操作失误或意外死亡,包括未达到预定观察时间点死亡者；支气管肺泡灌洗液回收率低于40%者；实验中恢复双肺通气>5次等。实验动物被排除后,再进行动物实验直至每组有10只动物完成实验。
2.4观察时间点及标本采集
2.4.1观察时间点
T0气管插管前；
T1单肺通气开始前；
T2单肺通气结束恢复双肺通气30min；
T3养活24小时后。
2.4.2心率(HR)、平均动脉压(MAP)和呼吸力学指标监测
记录01-05组在T1和T2时的HR、MAP、呼末二氧化碳分压(PETCO2)。观察中若SBP下降至60mmHg时予以血管活性药维持血压。分析在T2时HR、 MAP、PETCO2与OLV时间相关性。
HX-300S动物呼吸机记录01-05组在T1及T2时的的潮气量(VT)、呼吸频率、吸气峰压(Ppeak)。根据公式计算分钟通气量(Minute volume, MV)和肺顺应性。
分钟通气量(MV)=潮气量(VT)×呼吸频率
肺顺应性=VT-(Ppeak-PEEP)(PEEP=0)
2.4.3血气分析指标
01-05组动物在T1和T2时经颈动脉或股动脉采动脉血0.5mL经iSTAT'快速血气分析机行血气分析,测定pH、PaCO2、PaO2、碳酸氢根、BE、SaO2。分析在T2时血气分析值与OLV时间相关性。
插管前,每组随机取两个动物血气值作为T0值。C组和01-05组动物在T3时经中耳动脉或颈动脉采血0.5mL经iSTAT快速血气分析机行血气分析,测定pH、PaCO2、PaO2、碳酸氢根、BE、SaO2。比较T0和T3时点的血气值。
2.4.4肺组织病理学检查
实验结束后开胸分离左右肺,在支气管肺泡灌洗前,各取左右下肺叶相同部位约1.0cm3肺组织,浸泡于10%福尔马林溶液中固定,常规石蜡包埋、切片,染色,用普通光学显微镜在一张玻片上看10个高倍(400倍)视野进行肺损伤评分。肺组织损伤评分内容为肺萎陷、肺泡壁透明膜形成、中性粒细胞浸润或聚集,肺泡内充血或出血,分别依其严重程度评0-4级(0,无病变或非常轻微；1,轻度损伤,<25%；2,中度损伤,25%-50%；3,重度损伤,50%-75%；4,极重度损伤,>75%),并计算四项指标的总分为肺损伤评分。
2.4.5Western Blot半定量检测肺组织中SPA的含量
实验结束后开胸分离左右肺,取左右肺下叶相同部位1.0cm3肺组织置-70℃待测SPA。按标准步骤采用Western Blot法检测SPA。使用ChemiDocXRS (BIO-RAD)成像仪获得图像,在PVDF膜相对应的分子量的位置标记上目的蛋白,采用image J软件计算目的条带灰度×面积值来评判蛋白含量。每个样本重复三次实验。
2.4.6检测支气管肺泡灌洗液中TNF-a和IL-8浓度值
实验结束后开胸分离取出左右肺,用止血钳夹闭右主支气管,将气管导管插入左肺,经气管导管注入4℃磷酸盐缓冲液(Phosphate buffered solution, PBS)5ml/次,轻度反复灌洗,停留1min后抽出,共灌洗3次后获得总的BALF量。左肺灌洗结束后再用同样方法灌洗右肺。灌洗液取上清,用ELISA方法检测TNF-a、IL-8.分析在T2时TNF-a、IL-8值与OLV时间相关性。
2.4.7支气管肺泡灌洗液的细胞计数
灌洗液经离心后的沉淀部分经处理后取1ml的PBS细胞液用16×25规格的血细胞计数板行细胞计数。
2.5统计学方法
采用SPSS13.0统计软件(SPSS Inc.; Chicago)对数据进行分析。各组数据以均数±标准差(x±s)表示。比较T1和T2时点的血循环、呼吸力学指标和血气分析值、以及左右肺BALF中TNF-α、IL-8值和细胞数、左右肺SPA灰度值、左右肺损伤评分采用配对t检验；比较对TO和T3时点的血气分析值采用单方向方差分析(one-way analysis of variance);比较T2和T3时点的肺损伤评分、BALF中TNF-α、IL-8值和细胞数、SPA灰度值采用两独立样本t检验。比较不同时间点不同组间的各观察值采用单个重复测量因素方差分析(analysis of variance of repeated measures data),多重比较采用最小显著差值法(Least-significant difference)。计数资料比较采用卡方检验。血循环、血气分析值、TNF-α、IL-8值与OLV时间相关性采用等级相关(Spearman)分析,P<0.05示有统计学意义。
3.临床研究：不同单肺通气时间对胸科手术患者BALF中TNF-α、IL-8的影响
3.1病例分组及入选研究标准
选择年龄25-64岁、ASA Ⅰ或Ⅱ级患者。术前心肝肾功能正常。实验分组：(1)选择胸腔镜辅助下行左侧开胸食管癌或肺癌根治术患者36例为单肺通气组(OLV组),按单肺通气时间分为3个亚组：O1组(<1.5hOLV)；02组(2.0-2.5hOLV);03组(3.0-3.5hOLV),每组12例患者。2)双肺通气组：选取行双肺通气的非胸科手术患者12例,设为T组(3.0-3.5hTLV)。
入选病例标准：术前无化疗、放疗、机械通气史；非小细胞肺癌患者；肿瘤分级T1N1M0(肿瘤直径<3cm,肿瘤侵犯未达食管外膜；邻近肺门淋巴结组有1或2枚淋巴结转移,无远处脏器和淋巴结转移)；一周内无感染病史,无皮质激素和抗生素使用史；肺功能正常或仅有轻度通气功能障碍；无肝肾功能障碍。支气管肺泡灌洗液回收率>40%。术中鼓肺<5次。对术中出血量超过体重15%或输血者排除研究。麻醉后体温<35.5℃或>37.5℃排除研究。若患者在OLV后出现SP02<90%,需要提高吸入Fi02>70%超过1小时者排除研究。T组入选患者肺功能正常且肺部无恶性肿瘤或内分泌性肿瘤患者。
3.2麻醉方法
麻醉前30min肌肉注射咪达唑仑0.05mg/kg和阿托品0.01mg/kg。OLV组患者根据术前后前位胸片胸骨锁骨端气管横径,选择右双腔支气管导管(DLT)的型号。患者入室后开放外周静脉,滴注乳酸林格注射液,速率10m1.kg-1.h-1。患者入室后监测II导联心电图、心率(HR)、右上臂无创血压、脉搏氧饱和度(SpO2)。围术期麻醉处理及手术操作均由同一位麻醉医师和同一胸科小组完成。
面罩吸氧去氮5min后,予丙泊酚血浆靶控浓度3.0ug/ml、舒芬太尼0.4gg/kg和顺阿曲库胺0.2mg/kg静脉诱导,经口插入右双腔支气管导管,纤维支气管镜确定导管位置。行右颈内静脉穿刺置管及右桡动脉穿刺置管。麻醉维持：丙泊酚2.3～3.5μg/ml靶控输注；瑞芬太尼0.05-0.3ug/kg/min泵注镇痛；间歇追加顺阿曲库铵。根据失血量、尿量和中心静脉压(CVP)调整静脉输液速度和羟乙基淀粉130/0.4氯化钠注射液用量。
患者均以Datex-Ohmeda S型麻醉机行机械间歇正压通气,Datex-Ohmeda S5型气体监测仪连续监测吸气峰压(Ppeak)、平台压(Pplateau)、VT、分钟通气量(MV)和呼末二氧化碳分压(PETCO2),维持PETCO2于35～45mm Hg。OLV组患者在双肺通气20min后摆放侧卧位,FOB观察并调整DLBT管端位置。双肺通气时VT8～10ml/kg, I:E=1:2,呼吸频率12次/min,吸入氧分数(Fi02)60%；在手术开始前10分钟开始行单肺通气,单肺通气时VT7-8ml/kg,I：E=1：2,呼吸频率12-16次/min。患者在手术结束置放胸腔引流管时恢复TLV。而双肺通气组(T组)则保持通气参数设置不变。患者均送入麻醉恢复室,术后给予充分静脉镇痛,剂量按公斤体重计算。待自主呼吸恢复、VT满意后拔出气管导管,术后予鼻导管吸氧2L/min。
3.3观测时点
T1：麻醉前
T2：气管插管平卧位双肺通气后20min；
T3：手术结束前(OLV组恢复双肺通气30min后)；
T4：术后24h,鼻导管吸氧2L/min。
3.4血流动力学及呼吸力学指标
观察O1-03组和T组患者在T2-T3时点的Sp02、平均动脉血压(MAP)、心率(HR)、CVP, Ppeak、Pplateau、MV、VT和PETCO2;并记录T1和T4时点的SpO2、MAP、HR。
3.5血气分析值
01-03组和T组患者在T1-T4时点抽取动脉血,予Stat Profile(?) Critical Care Xpress Analyzer进行血气分析,观察pH、动脉血二氧化碳分压(PaCO2)、PaO2、Sa02、氧合指数(由动脉氧分压PaO2/FiO2得出)、碳酸氢根变化。
3.6支气管肺泡灌洗中TNF-α、IL-8浓度
01-03组和T组患者在T2和T3时点行支气管肺泡灌洗。将纤支镜顶端紧密楔入段或亚段支气管开口处,经活检孔通过硅胶管快速注入灭菌生理盐水30m1,用负压吸引回收灌洗液至痰液收集器中,记录回收液总量。将回收液体离心,取上清用ELISA法检测上清液TNF-α、IL-8。OLV组灌洗左右两侧肺,首选灌洗左下叶及右中下叶肺段,当该肺段有病变时则灌洗左上叶及右上叶肺段；T组只灌洗右中下叶肺段作为对照。
3.7其余观察项目
(1)单肺通气时间；(2)麻醉时间；(3)失血量和尿量；(4)术中液体静脉输入量；(5)PACU停留时间；(6)麻醉药物用量；(7)记录OLV组术后3天内的胸片结果异常者；(8)记录OLV组术后3天内并发症出现情况(如低氧血症、肺炎、二次手术发生率、肺不张等)。
3.8统计学方法：
所有数据均以均数±标准差(x+s)表示,采用SPSS13.0软件包进行统计学分析。不同组间患者一般情况及其余计量资料比较采用单向方差分析(one-way analysis of variance),多重比较采用最小显著差值法(Least-significant difference)。计数资料比较采用卡方检验；组内不同时间点的血流动力学指标和血气分析值比较采用单向方差分析,呼吸力学指标和TNF-α、IL-8值比较采用配对t检验；不同时间点不同组间的血流动力学指标、呼吸力学指标、血气分析值以及TNF-α、IL-8值比较采用单个重复测量因素方差分析(analysis of variance of repeated measures data); P<0.05有统计学意义。
结果
1.电视辅助胸腔镜手术后肺部并发症的相关因素分析
1.1术后肺并发症
330例VATS胸科手术后三天内,诊断为肺并发症有72例,占21.82%,其中肺渗出增加24例(占7.27%),肺炎23例(占6.97%),肺不张18例(占5.45%),胸腔积液4例(占1.21%),纤支镜吸痰2例(占0.61%),重新气管插管1例(占0.3%),无一例死亡
1.2与无肺并发症组比较,有肺并发症组的术前白蛋白较低(P<0.05),单肺通气时间和术后ICU入住时间(P<0.01)较长。有肺并发症组的男：女比例高于无肺并发症组(P<0.05)。
1.3多因素逻辑回归(Forward LR)分析表明：术前白蛋白水平、单肺通气时间和ICU入住时间是独立危险因素,OR值分别是0.922、1.379、1.362(P<0.05)。
2.不同单肺通气时间对兔支气管肺泡灌洗液TNF-α、IL-8及肺组织SPA的影响
2.105组OLV时有一只兔恢复双肺通气次数7次；03组、04组和05组分别有1、2、4只兔按实验动物排除标准被排除,动物实验实际数量为60只。C组和01-05组实验兔在体重、潮气量、分钟通气量上无差异(P>0.05)。
2.2单肺通气前后不同组间HR.MAP比较
经重复测量方差分析,结果显示组间的HR.MAP差异无显著性(HRF:1.142,P=0.349；MAP F=2.363,P=0.067)；不同时点间HR.MAP差异有显著性(HR F=69.699,P=0.000；MAP F=23.546,P=0.000)；各组的HR同时间之间无交互作用(F=1.996,P=0.111),而各组MAP与时间之间有交互作用(F=6.612,P=0.000),提示各组随时间的增加,HR变化趋势相同,MAP变化趋势不同。
进一步分析MAP的单独效应,结果显示01-02组、04-05组内两时间点比较有显著性(P均<0.05),各组MAP在T1时点间差异无显著性(P=0.867),各组MAP在T2时点间差异有显著性(P=0.001)。
2.3单肺通气前后不同组间PETCO2、Peak、肺顺应性比较
经重复测量方差分析,结果显示组间的PETCO2、Ppeak、肺顺应性差异无显著性(PETCO2F=0.119, P=0.975; Ppeak F=0.258, P=0.903;肺顺应性F=0.435,P=0.782)；不同时点间PETCO2、Ppeak、肺顺应性差异有显著性(PETCO2F=22.575, P=0.000; Ppeak F=56.687, P=0.000;肺顺应性F=58.345,P=0.000)。各组的PETCO2、Ppeak、肺顺应性和时间之间有交互作用(P均<0.037),提示各组随时间的增加,PETCO2、Ppeak、肺顺应性变化趋势不同。
进一步分析单独效应,结果显示04-05组内PETCO2两时间点比较有显著性(P均<0.05),03-05组内Ppeak、肺顺应性两时间点比较有显著性(P均<0.05)；PETCO2、Ppeak、肺顺应性分别在T1和T2时间点各组间差异无显著性(P均>0.172)。
2.4单肺通气前后不同各组血气值比较
经重复测量方差分析,结果显示组间的pH、PaCO2、碳酸氢根差异有显著性(pH F=2.770,P=0.038;PaCO2F=3.098,P=0.025;碳酸氢根F=2.609,P=0.048),PaO2、BE、SaO2差异无显著性(PaO2F=0.592,P=0.670; BEF=1.450, P=0.233; SaO2F=1.568, P=0.199);不同时点间pH、PaCO2、PaO2、碳酸氢根、SaO2差异有显著性(P均=0.000)。各组的pH、PaO2、碳酸氢根、SaO2同时间之间无交互作用(P均>0.124),各组的PaCO2同时间之间有交互作用(P=0.004),提示各组随时间的增加,pH、PaO2、碳酸氢根、Sa02变化趋势相同,而PaCO2变化趋势不同。
进一步分析单独效应,结果显示04-05组内PaCO2两时间点比较有显著性(P均<0.001)；PaCO2在T1时点各组间比较差异无显著性(P=0.740),PaCO2在T2时点各组间比较差异有显著性(P=0.001)。
2.5单肺通气24小时后与插管前血气值比较
在T3时点,04和05组的pH、PaCO2、O1-05组的Pa02和SaO2、05组的碳酸氢根和BE值与T0、C组比较均有统计学意义(P<0.05)。
与TO比较,C组的碳酸氢根有统计学差异(P<0.01)；C组其余观测指标与TO时各值比较无统计学意义(P>0.05)。
2.6在T2时点各组血循环、血气分析值与单肺通气时间相关性
HR与单肺通气时间正相关性(HR r=0.396,P<0.01)；MAP与单肺通气时间负相关性(MAPr=-0.537, P<0.01)。PETCO2、Ppeak、Cdyn与单肺通气时间无相关性(P>0.05)。
pH、PaO2、BE、SaO2与单肺通气时间呈负相关性(pH r=-0.451, PaO2r=-0.373, BE r=-0.502, SaO2r=-0.421, P<0.01)、碳酸氢根与单肺通气时间显著正相关(PaC02r=0.466,碳酸氢根r=0.412,P<0.01)。
2.7病理学改变及肺损伤评分
2.7.1大体标本所见
C组和01组左右侧肺无明显改变。03、04和05组,左萎陷肺颜色暗淡,表面充血淤血明显；右通气肺部分肺叶也出现充血淤血。与单肺通气时比较,单肺通气24小时后的对照组、01组无明显差异；02-05组左右肺仍有不同程度淤血,以OLV时间超过3小时明显。
2.7.2光镜下检查
单肺通气时：C组及01组左右侧肺泡完整,肺泡腔内无渗出,无炎症细胞。03、04和05组左侧萎陷肺间质增厚不明显,肺间质和肺泡腔有炎性细胞和血细胞浸润,肺泡壁破坏或肺泡不张,以05组最明显；03、04和05组右侧肺间质明显增厚。
单肺通气结束后24小时：对照组和01组肺泡腔内无明显渗出,01组左肺可见部分肺萎陷,右肺部分肺泡壁破坏。02组左肺部分肺泡萎陷,肺间质稍增厚；右肺间质稍增厚,部分肺泡壁破坏。03组左右肺部分肺泡萎陷,肺泡壁破坏,肺间隔增厚不明显,肺间质有红细胞浸润。04-05组左侧肺泡萎陷和肺泡壁破坏明显,肺间质可见较多红细胞和中性粒细胞浸润；右侧肺间隔增厚,肺间质有较多红细胞浸润。
2.7.3肺组织损伤病理评分
经重复测量方差分析,结果显示在T2和T3时间点各组间的肺损伤评分差异均有显著性(P均=0.000)；在T2和T3时间点左右肺的肺损伤评分差异均有显著性(T2F=6.748,P=0.012；T3F=7.779,P=0.007)。在T2时间点,各组的肺损伤评分同时间之间有交互作用(F=5.121,P=0.001),在T3时间点,各组的肺损伤评分同时间之间无交互作用(F=0.262,P=0.932),提示在T2时间点,各组肺损伤评分随时间的增加变化趋势不同,而在T3时点,肺损伤评分随时间增加变化趋势相同。
进一步分析单独效应,结果显示在T2时点,05组内左右肺间的肺损伤评分比较有显著性(F=4.944,P=0.001)；左右肺损伤评分在各组间比较差异有显著性(左肺F=69.303,P=0.000；右肺F=19.909,P=0.000)。
05组左肺在T2时点的肺损伤评分比T3时高(P>0.05)。
2.8Western Blot测定肺组织中SPA的表达
2.8.1经重复测量方差分析,结果显示在T2和T3时点左肺SPA灰度值组间差异有显著性(F=9.540,P=0.001)；不同时点间差异有显著性(F=21.884,P=0.001)；各组同时间之间有交互作用(F=14.652,P=0.000),提示不同组随时间的增加,左肺SPA变化趋势不同。进一步分析单独效应,结果显示04-05组内两时间点比较有显著性(P均<0.001),各时间点不同组间差异均有显著性(P均<0.05)。
2.8.2经重复测量方差分析,结果显示在T2和T3时点右肺SPA灰度值组间差异有显著性(F=10.990,P=0.000)；不同时点间差异有显著性(F=359.691,P=0.000)；各组同时间之间有交互作用(F=14.171,P=0.000),提示不同组随时间的增加,右肺SPA变化趋势不同。进一步分析单独效应,结果显示01-05组内两时间点比较有显著性(P均<0.05),在同一时间点不同组间差异均有显著性(P均<0.01)。
2.8.3经重复测量方差分析,结果显示在T2时点左右肺SPA灰度值组间差异有显著性(F=10.876,P=0.000)；左右肺间差异有显著性(F=36.394,P=0.000)；各组左右肺之间有交互作用(F=11.577,P=0.000),提示不同组间左右肺的SPA变化趋势不同。进一步分析单独效应,结果显示01-03组内左右肺间SPA灰度值比较有显著性(P均<0.05),左右肺不同组间差异均有显著性(P均<0.01)。
2.8.4经重复测量方差分析,结果显示在T3时点左右肺SPA灰度值组间差异有显著性(F=19.860,P=0.000)；左右肺间差异无显著性(F=0.083,P=0.778)：各组左右肺之间无交互作用(F=1.946,P=0.160),提示不同组间左右肺的SPA变化趋势相同。
2.9BALF中TNF-α、IL-8浓度值比较
2.9.1经重复测量方差分析,结果显示在T2和T3时点左右肺间TNF-α值差异有显著性(T2F=56.146,P=0.002；T3F=14.619,P=0.001)；在T2时点,不同组间差异有显著性(F=29.336,P=0.000),在T3时点,不同组间差异无显著性(F=1.054,P=0.410)；在T2时点各组左右肺间有交互作用(F=4.792,P=0.005),而在T3时点各组左右肺间无交互作用(F=0.333,P=0.888),提示在T2时点各组左右肺间TNF-α值变化趋势不同；在T3时点各组左右肺间TNF-α值变化趋势相同。
进一步分析单独效应,结果显示在T2时点O3-O5组左右肺间比较有显著性(P均<0.05),左右肺各组间差异有显著性(P=0.000)。
与T3时点各组比较,T2时点左肺的O3-O5组TNF-α值较高(P<0.05)。
2.9.2经重复测量方差分析,结果显示在T2和T3时点左右肺间IL-8值差异有显著性(T2F=9.460,P=0.005；T3F=11.784,P=0.002)；在T2时点,不同组间差异有显著性(F=20.703,P=0.000),在T3时点,不同组间差异无显著性(F=5.824,P=0.001)；在T2时点各组左右肺间有交互作用(F=2.882,P=0.035),而在T3时点各组左右肺间无交互作用(F=2.452,P=0.063),提示在T2时点各组左右肺间IL-8值变化趋势不同；在T3时点各组左右肺间IL-8值变化趋势相同。
进一步分析单独效应,结果显示在T2时点O4组左右肺间比较有显著性(P=0.043),左右肺各组间差异有显著性(P均<0.01)。
与T3时点比较,T2时点O4-O5组左肺IL-8值较高(P<0.01),右肺O5组IL-8值较高(P<0.05)。
2.10BALF由TNF-α、IL-8浓度值与单肺通气时间相关性
在T2时点,左肺和右肺的TNF-α、IL-8值与OLV时间成正相关(左肺TNF-αr=0.901,右肺TNF-αr=0.748;左肺IL-8r=0.840,右肺IL-8r=0.660,P<0.01)。在T3时点,左肺TNF-α、左右肺IL-8值与OLV时间成正相关(左肺TNF-αr=0.430,P<0.05；左肺IL-8r=0.697,右肺IL-8r=0.592,P<0.01)。
2.11BALF中炎症细胞数比较
经重复测量方差分析,结果显示在T2和T3时点左右肺间细胞数差异有显著性(T2F=13.606,P=0.001；T3F=47.137,P=0.000)；在T2时点,不同组间差异有显著性(F=10.181,P=0.000),在T3时点,不同组间差异无显著性(F=16.161,P=0.000)；在T2时点各组左右肺间有交互作用(F=2.834,P=0.038),而在T3时点各组左右肺间有交互作用(F=2.644,P=0.048),提示在T2和T3时点各组左右肺间IL-8值变化趋势不同。进一步分析单独效应,结果显示在T2时点05组左右肺间比较有显著性(P=0.006),左右肺各组间差异有显著性(P均<0.05)。
与T3时点比较,05组左肺在T2时点的细胞数增加(P<0.05)。
3.临床研究：不同单肺通气时间对胸科手术患者血流动力学、呼吸力学及支气管肺泡灌洗液中TNF-α、IL-8的影响
3.1一般情况
01-03组单肺通气时间分别为1.36±0.22h、2.21±0.26h、3.17±0.25h。两组患者的性别、年龄、ASA分级、BMI比较无统计学意义(P>0.05)。各组患者术中失血量均不超过450ml,无输血病例。
3.2血液动力学指标和Sp02
经重复测量方差分析,结果显示HR、MAP、SPO2、CVP组间差异无显著性(P均>0.186)；HR、MAP、CVP不同时点间差异有显著性(P均<0.05)；各组同时间之间无交互作用(P均>0.05),提示不同组随时间的增加,HR、MAP、 SPO2、CVP变化趋势相同。
3.3两组患者呼吸力学比较
经重复测量方差分析,结果显示PETCO2、Ppeak、Pplateau、MV、VT组间差异无显著性(P均>0.065)；Ppeak、Pplateau、VT在不同时点间差异有显著性(P均<0.05)；PETCO2、MV、VT各组同时间之间无交互作用(P均>0.05),Ppeak、Pplateau各组同时间之间有交互作用(P均=0.000),提示不同组随时间的增加,PETCO2、MV、VT变化趋势相同,Ppeak、Pplateau变化趋势不同。
进一步分析单独效应,结果显示各组内不同时点间的Ppeak、Pplateau、VT比较有显著性(P均<0.048),各时点不同组间差异无显著性(P均>0.805)。
3.4术中血气分析指标
经重复测量方差分析,结果显示PaCO2、SaO2在不同时点差异无显著性(P均>0.05),pH、PaO2、碳酸氢根、氧合指数在不同时点差异有显著性(P均<0.011); pH、PaCO2、PaO2、SaO2、碳酸氢根、氧合指数在不同组间差异无显著性(P均>0.216)；各组同时间之间无交互作用(P均>0.05),提示不同组随时间的增加,pH、PaCO2、PaO2、碳酸氢根、氧合指数变化趋势相同。
3.5手术前后OLV组不同观察时点患者的胸片结果变化比较
术后03组患者胸片提示肺部炎症发生率高于O1和02组患者。
3.6支气管肺泡灌洗中TNF-α、IL-8浓度
3.6.1不同时点及不同组间比较
经重复测量方差分析,结果显示左右肺TNF-α、右肺IL-8值在不同时点差异有显著性(P均=0.000)；左右肺TNF-α和右肺IL-8值在不同组间差异有显著性(P均=0.000)；各组左右肺TNF-α、右肺IL-8值同时间之间有交互作用(P均<0.001),提示不同组随时间的增加,左右肺TNF-α和右肺IL-8变化趋势不相同。
进一步分析单独效应,结果显示各组左右肺TNF-α和IL-8值在两时点间比较均有显著性(P均<0.008)；在T2时点,左右肺TNF-α和IL-8值各组间比较均无显著性(P均>0.221),在T3时点,左右肺TNF-α和IL-8值各组间比较均有显著性(P均=0.000)。
3.6.2左右肺BALF的TNF-α、IL-8值比较
在T2时点,01-03组及T组的左右肺间BALF中TNF-α、IL-8值比较无统计学差异(P>0.05)。在T3时点,01组左BALF中IL-8值、02组左BALF中TNF-α和IL-8值、03组左BALF中IL-8值均比右BALF高(P<0.01)。
结论
1.回顾性分析表明：术前白蛋白水平、单肺通气时间和ICU入住时间是VATS术后肺并发症的主要影响因素。有术后肺并发症组患者OLV时间平均超过3.3小时。
2.单肺通气大于3小时造成萎陷肺的组织病理损伤、肺炎症反应增加,SPA合成减少,肺损伤明显；术后24小时,萎陷肺损伤的修复比通气肺及短时间单肺通气的肺损伤修复缓慢。而不同时间单肺通气对通气肺的肺损伤在单肺通气结束时组间差异无萎陷侧肺明显；术后24小时通气肺的肺损伤可修复。
3.不同单肺通气时间对患者术中、术后24小时的血流动力学、血气分析值无显著影响；但支气管肺泡灌洗液TNF-α、IL-8浓度随着单肺通气时间延长而增加,萎陷肺比通气肺明显,以单肺通气超过3小时后最显著。
Since the first video-assisted thoracoscopic surgery (VATS) was reported in the nineties, the use of VATS has become widespread. VATS is now more generally used than the open thoracotomy owing to its minimal invasiveness and the low morbidity. However, due to small view of surgery, VATS requires surgical instruments to complete the operation, thus operation time maybe is longer than the traditional thoracotomy. One-lung ventilation (OLV) is a commonly used technique that facilitates surgical visualization during thoracic surgical procedure. In particular, during VATS, OLV may play a vital role in the successful completion of the surgery. Degrees of damage of OLV on ventilated lung and non-ventilated lung was different.
The major impact of OLV on ventilated lung is mechanical stretch-induced lung injury. Mechanical stretch includes:mechanical positive pressure ventilation, lung tissue repeated collapse and reexpansion during OLV, lung tissue stretch by surgical operators. But the impact of OLV on non-ventilated lung is larger than that of ventilated lung. The non-ventilated lung is known to be hypoperfused owing to hypoxic vasoconstriction, pulmonary blood flow decreases by20-25%and the collapsed lung alveoli have no oxygen. So that collapsed lung experiences the process of collapse to re-expansion, just is the same as the process of hypoxia and reoxygenation. It is an ischemia-reperfusion injury. A lot of clinical researches have proved that lung re-expansion can evoke severe oxidative stress, oxygen free radicals was associated with OLV time. The long time of OLV increases postoperative complications. How is the impact of duration of OLV on lung injury, and how long is the long time OLV? Is it3hours,4hours, or longer?
Data haved showed that plasma IL-6and IL-8increased both in OLV and two-lung ventilation (TLV), but OLV may increase higher. The concentration of IL-6and IL-8increased in OLV can resume to the similar level as those in TLV after48hours. This demonstrates that once we have a good control of OLV duration, the clinical application of OLV anesthesia is safe. But this study only observed that lung injury was relieved when OLV was only two hour, there is no literature about the impact of longterm OLV on lung injury.
Currently, there is no clear data description the time limitation of OLV. Therefore, this study attempts to observe the effect of different duration of OLV on lung injury from clinical and animal experiments, and to find out the time limitation of OLV. We still observe the repair of lung injury in24hours after OLV through animal experiments, and expect to find out the mechanism of lung injury and repair in the future.
Objective
1. Retrospective analysis of pulmonary complications correlative factors after video-assisted thoracic surgery.
2. To search the effect of different duration of OLV on rabbit Tumor necrosis factor-alpha(TNF-α) and Interleukin-8(IL-8) in bronchoalveolar lavage fluid and Surfactant protein A(SPA) expression in lung tissue.
3. To search the effect of different duration of OLV on clinical patients'TNF-a and IL-8in bronchoalveolar lavage fluid (BALF).
Methods
1. The correlative factor analysis of pulmonary complications after video-assisted thoracoscopic surgery
1.1Patients
330patients (ASA physical status I or II,212male patients,118female patients, age range18-77years, body weight42-80kg) undergoing elective video-assisted thoracic surgery at Guangzhou Institute of Respiratory Disease from2010.1.1to2011.3.31were enrolled in the study. Exclusion criteria included:lung infection or other infectious diseases before surgery; empirical application of anti-infective therapy before surgery; tracheotomy and other traumatic operation and long-term mechanical ventilation; mediastinal thymoma with myasthenia gravis; intraoperative cardiopulmonary resuscitation and emergency treatment; transfer to open-thoracic surgery; a long time to restore two-lung ventilation during operation; preoperative chemotherapy and radiotherapy; stop smoking for less than2weeks before surgery.
1.2General anaesthesia
Midazolam0.05mg/kg and atropine0.01mg/kg were intramuscular injected30mins before anesthesia. The size of Broncho-Cath(?) double-lumen tube (DLT) was determined by the tracheal inner diameter at the level of sternoclavicular articulation measured in the chest x-ray. The intubation depth of DLT was determined based on the regressive equation.
Patients had the vital signs monitor after getting into the operation room. After inhalation of oxygen for5min, Anaesthesia was induced with target controlled infusing propofol (target blood concentration3ug/ml), sufentanyl0.4μg/kg and cisatracurium0.2mg/kg. A flexible styletted DLT was accomplished via direct laryngoscopy according to a standardized protocol, and a fiberoptic bronchoscope (FOB) was then employed to confirm correct positioning of the tube. After intubation, Radial artery and internal jugular vein were catheterized.
All the selected patients had the same ventilation mode. The ventilation parameters setting, including tidal volume, the ratio of inspiratory and expiratory, and respiratory rate were basically the same. The anesthesia method and medication, postoperative analgesia and analgesic drugs were also the same. The operations were performed by the same group of surgeons. All patients were sent to ICU for further care after extubation.
1.3Logistic regression analysis for possible factors about postoperative pulmonary complications in VATS
Possible factors of postoperative pulmonary complications in VATS included: Age, sex, body mass index(BMI), preoperative pulmonary function rating, the forced expiratory volume in first second(FEV1), forced vital capacity(FVC), FEV1/FVC, maximal voluntary ventilation(MVV), echocardiography, duration of OLV, duration of anesthesia, intraoperative blood loss, intraoperative fluids, laterality of surgery, extent of pulmonary resection(inspection without resection, wedge resection, lobectomy, multi-lobectomy, pneumonectomy), length of ICU stay, duration of chest tube drainage, length of postoperative hospitalization, preoperative and postoperative albumin values, the comorbidities of diabetes mellitus, angiocardiopathy, chronic respiratory disease, and history of thoracic surgery. The above data were collected and collated.
In the first3days after VATS, pulmonary exudation increasing, pneumonia, atelectasis or lung compression, pulmonary embolism, pneumoderma of chest wall increasing, pleural effusion, respiratory failure, suction with FOB, and reintubation were considered to be postoperative pulmonary complications in VATS.
Length of anaesthesia was defined as the period between induction and extubation. Length of OLV was defined as the period between starting OLV10min before operation and resuming two-lung ventilation. According to the Gerald's definition of long-term operation, the anaesthesia time was divided into4stages(2h<,2-3h,3-4h,≥4h), and the OLV time was divided into4stages(lh≤,1-2h,2-3h,>3h).
1.4Statistical analyses
SPSS13.0statistical software package was used for all analyses. Descriptive statistics (x±s) were used to summarize the measurement data, medians were used in categorical data. The independent t-test or Chi-square test was used to compare continuous data or categorical data between no complication group and complication group. Binary logistic regression (Forward LR method) was applied to determine the relationship between variables and postoperative pulmonary complications. P values <0.05were considered to be statistically significant.
2. The effect of different duration of one-lung ventilation on rabbit TNF-α and IL-8in BALF and SPA in lung tissue
2.1Animals and Experimental Design
Sixty-eight New Zealand White rabbits (both males, body weight2.5±0.2kg) were forbidden food and water for one day before experiment. All rabbits were randomised divided into6experimental groups:controlled group (group C) and group O1,O2,O3,O4,O5. Group C (n=10) just received endotracheal intubation and vascular puncture but the spontaneous breath was ramained. Groups01-05respectively received right-lung ventilation for1,2,3,4,5hours (group01and02n=10; group O3n=11, group O4n=12, group O5n=15). Each rabbit resumed two-lung ventilation for30minutes after OLV. Half of rabbits in each group were executed at the end of experiment, the other half rabbits were feed for24hours after resuming spontaneous breath, and then were executed.
2.2Experimental operation
Rabbits were anesthetized with sodium pentobarbital (30mg/kg) intravenously administered through the ear vein and maintained at doses of10mg/h. Each rabbit had a cervical tracheotomy with an inserted endotracheal tube (a diameter of3.0mm self-made cuffed endotracheal tube). After intubation, animals were given vecuronim (0.1mg/kg) per hour and ventilated with a tidal volume of10ml/kg, a rate of35breaths/min, inspiration-expiration (I:E) ratio of1:1, an inspired oxygen concentration (FiO2)100%by use of the animal ventilator. Each rabbit had a carotid or femoral artery puncture to measure heart rate (HR) and median arterial pressure (MAP) by a safedraw transducer blood sampling set. Tracheal tube was put forward into the right-main stem bronchus to build OLV model. The sixth of left intercostal space was opened a small incision (1cm×1cm) to observe the lung collapse. The OLV model was successfully established according to the left lung from expansion to collapse. After OLV model established, right OLV was given a tidal volume of8ml/kg, a rate of40breaths/min, I:E ratio1:1, and a FiO2100%. The effectiveness of left lung collapse was checked by continuous inspection. If the oxygen can't be maintained during experiments, animals were checked endotracheal tube position and resumed two-lung ventilation for15minutes, then continued OLV. Rabbit's body temperature was kept at37℃by use of a warm blanket and measured with a mercury thermometer in the anus. Physiologic saline solution was given intravenously10mL·kg-1·h-1. At the end of experiment, half of rabbits in each group were executed by injection of20ml of air; the other half of rabbits were sutured trachea and intercostal space after resuming spontaneous breathing, and were executed after feeding for24hours.
2.3Exclusion criteria
Accidental death in the experiment, including death before the scheduled observation time; the recovery rate of BALF less than40%; resuming two-lung ventilation more than five times, et al. The data of exclusion rabbit was removed. Animal experiments were continued until there were10rabbits to complete experiments in each group.
2.4Times for variables recording and specimen collection
2.4.1Times for variables recording
TO:Before the tracheal intubation;
T1:Before the beginning of OLV;
T2:Resuming two-lung ventilation for30min after the end of OLV;
T3:Feeding for24hours.
2.4.2The recorded data of heart rate (HR), mean arterial pressure (MAP) and respiratory mechanics
HR, MAP, PETCO2, VT, breath rate, peak inspiratory airway pressure (Ppeak) of group01-05were recorded at T1and T2. If SBP drops to60mmHg, rabbits were given vasoactive drugs to maintain blood pressure stable. MV and lung compliance were calculated by formula. Analyzed the correlation between HR, MAP, PETCO2with duration of OLV at T2.
2.4.3Blood Gas Analysis
Blood samples were obtained by taking0.5ml heparinized blood from the carotid or femoral artery. Blood gas analysis of group01-05was performed at T1and T2by an i-STAT blood gas analyzer. Analyzed the correlation between blood gas values with duration of OLV at T2
Before intubation, two animal blood gas values were randomly selected from each group and taken as TO values. Blood gas analysis of group C and group01-05were performed at T3. The blood gas analysis was compared between at TO and T3.
2.2.4Pulonary histopathological examination
Left and right lung were taken out at the end of the experiment.1.0cm3lung tissues were taken at the same parts of lower lobes in left and right lung. Lung tissue was soaked in10%buffered formalin and fixed, then embedded in paraffin, slice, row, hematoxylin-eosin stainng. Lung injury score was viewed10high-power (400times) under an ordinary optical microscope. The contents of lung injury score were atelectais, hyaline membrane formation, infiltration or aggregation of neutorphils in airspaces and alveolar congestion or hemorrhage. The injury score was used a damage scale of0to4(0, minimal or no damage;1, mild damage, less than25%of the field;2, moderate damage,25%to50%of the field;3, severe damage,50%to75%of the field;4, maximal damage, more than75%of the field). The total score of the four conetents was calculated as lung injury score.
2.4.5Western Blot Analysis for SPA in lung tissue
1.0cm3lung tissues were taken at the same parts of lower lobes in left and right lung and were stored in-70℃refrigerator. Western blot was used to determination of SPA expression in lung tissue. The protein was formed image by ChemiDocXRS (BIO-RAD) and the immunoreactive bands were scanned and normalized by GAPDH bands of the same membrane. The band density was analyzed by Image J software. Each sample was repeated3times.
2.4.6The concentration of TNF-a and IL-8in BALF
The right lung was inserted a diameter of3.0mm endo-tracheal tube into the right main bronchus and infused5ml of ice-cold sterile PBS. Lavages were repeated three times and the recovery fluid was combined. The left main airway was clamped during right lung lavaged. The left lung was also taken the same method to get BALF after finishing right lung lavage. Supernatant aliquots was used to test the concentrations of TNF-a and IL-8by enzyme-linked immunosorbent assay (ELISA). The correlation between TNF-a, IL-8and duration of OLV were analyzed at T2.
2.4.7BALF Cell Counts
The cell pellets of BAL were washed by PBS and added10%acetic acid to remove red blood cells,1ml PBS were taken out and counted under light microscopy.
2.5Statistical analysis
The Statistical Package for the Social Sciences13.0(SPSS Inc.; Chicago) was used for results analysis. The results are presented as means±standard error of the mean. The paired-samples t test was used to compare hemodynamics, respiratory mechanism and blood gas values at T1and T2, and compare the concentration of TNF-a, IL-8, cell number, SPA gray-value, lung injury scorce in left and right lung. One-way analysis of variance was used to compare blood gas values at TO and T3. The independent samples t test was used to compare lung injury score, the concentration of TNF-a and IL-8, cell number, SPA gray-value at T2and T3. Analysis of variance of repeated measures data was used to compare different group variables at different time point. Least-significant difference was used for multiple comparisons. The count data was compared by Chi-square test. The correlation between circulation, blood gas values, the concentrations of TNF-a and IL-8with duration of OLV was analyzed by Spearman analysis. P values<0.05were considered to be statistically significant.
3. Clinical research:the effect of different duration of one-lung ventilation on patient's TNF-a and IL-8in BALF
3.1Patients groups and selected standards
Patient's age was range between25-64year; ASA physical status I or II. Patients were assigned into two groups:1) one-lung ventilation group (OLV group, n=36): patients who undergone elective esophageal and lung cancer surgery via left VATS were enrolled in the study. According to OLV time, patients were divided into three subgroups:group01(<1.5hOLV); group02(2.5-3hOLV); group O3(3.0-3.5hOLV),12patients in each group.2) Two-lung ventilation group (T group,3.0-3.5hTLV, n=12):patients who undergone non-thoracoscopic surgery were enrolled in the study.
Selected case criteria:no dysfunction of heart, liver and kidney; No preoperative chemotherapy and radiotherapy; no history of mechanical ventilation; Non-small cell lung cancer; the tumor grade T1N1M0(tumor size<3cm, no distant metastasis); no infection history within a week; no history of using corticosteroids and antibiotic; normal lung function or mild pulmonary dysfunction; the recovery rate of BALF was more than40%; re-expand lung less than5times during operation; patients whose blood loss more than15%of weight or transfusion were exclude from study. The patients enrolled in group T had normal pulmonary function and had no lung cancer or endocrine cancer. The case was excluded when the patients need to inhale FiO2>70%more than1hours. The enrolled patients of group T had normal pulmonary function and had no lung cancer or endocrine cancer.
3.2General anaesthesia and ventilation method
Anaesthesia was induced and maintained with target controlled infusing propofol. In the OLV group, a flexible styletted DLT was accomplished via direct laryngoscopy according to a standardized protocol, and a fiberoptic bronchoscope (FOB) was then employed to confirm correct positioning of the tube. All patients were placed central venous catheter and radial arterial catheter. Intravenous infusion speed and fluid dosage were decided according to blood loss, urine output and central venous pressure (CVP).
The patients were ventilated with a FiO2of0.6through out. Ventilator settings were adjusted from VT of8-10ml/kg, rate of12-min-1(TLV) to VT of7-8ml/kg, rate of12-16-min-1(OLV); I:E ratio was1:2. Ventilator settings were kept constant during the study. Patients were sent to the PACU. All patients'post-operative analgesia and analgesic drugs were the same, analgesic dose was calculated by body weight. Patients were pulled out the endotracheal tube after recovery of spontaneous breathing.
3.3Observations time points
T1:before anesthesia;
T2:20minutes after two-lung ventilation in supine position
T3:at the end of surgery (resuming two-lung ventilation for30min in group OLV)
T4:in the first postoperative day while the patients were receiving oxygen via nasal catheter (2L/min)
3.4Hemodynamics and respiratory mechanics
SpO2, MAP, HR, CVP, Ppeak, Pplateau, MV, VT, PETCO2of group01-03and group T were recorded at T2and T3. SpO2, MAP, HR were recorded at T1and T4.3.5The blood gas analysis values
Arterial blood gas analysis was performed at T1to T4respectedly. PH, PaCO2, PaO2, SaO2, oxygenation index (PaO2/FiO2), and bicarbonate were measured by Stat Profile(?) Critical Care Xpress Analyzer.
3.6The concentration of TNF-α and IL-8in BALF
BALF was performed at T2and T3. Put the top of bronchoscopy to the opening of segment or sub-segmental bronchi, and used silicone tube rapidly injecting sterile normal saline30ml through the biopsyhole (10ml/time, total30ml). Lavage fluid was stored at a clean sputum collection through a vacuum suction and recorded the recovery volume. The supernatant was taken to measure the concentrations of TNF-a and IL-8by ELISA. In group OLV, lavage bilateral pulmonary, first preferred lavage lung segment in the left lower lobe and right lower lobe, second preferred lavage lung segment in the left upper lobe and right upper lobe. In group T, we only lavage the right middle lobe segment and taken as controlled value.
3.7Other observation items
(1) duration of OLV;(2) duration of anesthesia;(3) the amount of blood loss and urine;(4) intraoperative intravenous input;(5) the residence time in the PACU;(6) the amount of narcotic drugs;(7) record the abnormal chest X-ray results in3days after surgery in OLV group;(8) record complication occurrence in3days after surgery in group OLV, such as hypoxemia, pneumonia, reoperation incidence, pulmonary atelectasis, etc.
3.8Statistical analyses
Descriptive statistics (x±s) were used to summarize the continuous data, medians were used in categorical data. SPSS13.0statistical software package was used for all analyses. One-way analysis of variance was used to compare patients' general situation and measurement data. Least-significant difference was used for multiple comparisons. Chi-square was used to compare count data. One-way analysis of variance was used to compare the hemodynamic values and blood gas values at different time point in the same group, and the paired-samples t test was used to compare mechanics values and TNF-α, IL-8values at different time point in same group. Analysis of variance of repeated measures data was used to compare hemodynamics, respiratory mechanics, blood gas values and the concentrations of TNF-α, IL-8at same time point in defferent groups. P values<0.05were considered to be statistically significant.
Results
1. The correlative factor analysis of pulmonary complications after video-assisted thoracoscopic surgery
1.1Postoperative Pulmonary Complications (PPC)
72of300patients (21.88%) suffered PPC in the first3days after VATS.24pulmonary exudation increasing (7.27%), pneumonia in23(6.97%),18atelectasis (5.45%),4pleural effusion (1.21%),2suction with FOB (0.61%),1reintubation (0.3%). No mortality occurred.
1.2Compared with non-PPC group, Preoperative albumin was lower(P<0.05), length of OLV and ICU stay were longer than in PPC group (P<0.01).
1.3Binary Logistic Regression (Forward LR)
Preoperative serum albumin level, length of OLV, length of ICU stay were independent risk factors, the values of OR were0.922,1.379and1.362(P<0.05).
2. The effect of different duration of one-lung ventilation on TNF-a, IL-8in BALF and SPA in lung tissue
2.1One rabbit restored two-lung ventilation for7times in group05; there had1,2and4rabbit respectively in group03,04and05were excluded during experiment. There had no difference in body weight, Vt and MV in each group (P>0.05)
2.2The comparison of HR and MAP before and after OLV
The repeated measures ANOVA analysis showed that HR and MAP had no significant difference between groups (HR F=1.142, P=0.349; MAP F=2.363, P=0.067). HR and MAP at different time point had significant difference (HR F=69.699, P=0.000; MAP F=23.546, P=0.000); HR of each group had no interaction with time (F=1.996, P=0.111), but MAP of each group had interaction with time (F=6.612, P=0.000), these suggested that HR had the same trend but MAP has not.
Further analysis of MAP, the results showed that the comparison of group01 and02, group04and05had significant difference (P<0.05), MAP of each group had no difference at T1(P=0.867).
2.3The comparison of PETCO2, Peak, lung compliance before and after OLV
The repeated measures ANOVA analysis showed that PETCO2, Peak, lung compliance had no significant difference between groups (PETCO2F=0.119, P=0.975; Ppeak F=0.258, P=0.903; Cdyn F=0.435, P=0.782). The comparison of PETCO2, Peak, lung compliance had significant difference at different time point (PETCO2F=22.575, P=0.000; Ppeak F=56.687, P=0.000; Cdyn F=58.345, P=0.000). PETCO2, Peak, and lung compliance of each group had interaction with time (P<0.037), these suggested that the trend of PETCO2, Peak, Cdyn is different with time.
Further analysis, the results showed that the comparison of PETCO2in group04and05had significant difference (P<0.05), Peak, and lung compliance in group03to05had significant difference (P<0.05); PETCO2, Peak, and lung compliance had no significant difference at T1and T2in each group(P>0.172).
2.4Blood gas analysis in each group
The repeated measures ANOVA analysis showed that pH, PaCO2and bicarbonate had significant difference between groups (pH F=2.770, P=0.038; PaCO2F=3.098, P=0.025; bicarbonate F=2.609, P=0.048), PaO2、BE、SaO2had no significant difference (PaO2F=0.592, P=0.670; BE F=1.450, P=0.233; SaO2F=1.568, P=0.199); pH, PaCO2,PaO2, bicarbonate and SaO2had significant difference (P=0.000). PH, PaO2, bicarbonate and SaO2had no interaction with time (P>0.124), PaCO2of each group had interaction with time (P=0.004), these suggested that the trend of pH, PaO2, bicarbonate and SaO2is same with time, but the trend of PaC02is different with time.
Further analysis, the results showed that the comparison of PaCO2in group04and05had significant difference between T1and T2(P<0.01); PaCO2of each group had no significant difference at T1(P=0.740), PaCO2of each group had no significant difference at T2(P=0.001).
2.5The comparison of blood gas values between24h after OLV and before anesthesia
At T3, ph and PaCO2of group04-05, PaO2and SaO2of group01-05, Bicarbonate and BE of group05had difference with those at TO and in group C (P<0.05)
Bicarbonate of group C had difference with that in TO (P<0.01), the other observations had no statistical difference (P>0.05)
2.6The correlation of blood circulation, blood gas analysis with OLV time at T2
HR was positively correlated with OLV time (HR r=0.396, P<0.01); MAP was negatively correlated with OLV time (MAPr=-0.537, P<0.01). PETCO2, Ppeak and Cdyn had no correlation with OLV time (P>0.05)
pH, PaO2, BE and SaO2were negatively correlated with OLV time (pH r=-0.451, PaO2r=-0.373, BE r=-0.502, SaO2r=-0.421, P<0.01), PaCO2and bicarbonate were positively correlated with OLV time (PaCO2r=0.466, bicarbonate r=0.412,P<0.01).
2.7Pathological changes and lung injury score
2.7.1Specimens
There had no significant changes in left and right lung in group C and01. But in group O3-O5, the colour of left lung was dim and the surface was congestion, the right lung also had surface congestion in some part of the lobes. The group C and group01at24h later had no difference with those at OLV; different degrees of congestion were still in group02-05in24hours later, especially when OLV time was longer than3h.
2.7.2Light microscope examination
During OLV: In group C and group01, alveolar was integrity, alveolar spaces had no exudation and less inflammatory cells. But in group03-05left lung, pulmonary interstitial was obvious thicken, pulmonary interstitial and alveolar space had inflammatory cells and blood cell infiltration, alveolar wall was destructed and alveolar atelectasis, especially in group05. In the right lung of group03-05, pulmonary interstitial was obvious thichening and alveolar space was less exudation than in left lung.
24h after OLV: there had no obvious exudation in group C and O1, and a little atelectasis was seen in group O1. In group O2, there had alveolar collapse, intertitial congestion thichen, and red blood cells in left lung; there also had neutrophil in right lung alveolar. In group O3, alveolar collapsed, interstitial thichening and red blood cells in alveolar spaces. In group O4, alveolar was obvious collapsed and exudation, many red blood cells and neutrophils were seen. In group O5, lung collapsed obviously and a large number of red blood cells and macrophage infiltration were seen.
2.7.3Lung tissue injury score
The repeated measures ANOVA analysis showed that lung injury score had significant difference at T2and T3(P=0.000); lung injury score also had significant difference between left and right lung(T2F=6.748, P=0.012; T3F=7.779, P=0.007). lung injury score of each group had interaction with time at T2(F=5.121, P=0.001), but it had no interaction with time at T3(F=0.262, P=0.932), these suggested that the trend of the lung injury score is different with time at T2, but the trend is same with time at T3.
Further analysis, the results showed that the comparison of lung injury score in group05had significant difference at T2(F=6.748, P=0.012); lung injury score of each group had significant difference between left and right lung (left lung F=69.303, P=0.000; right lung F=19.909, P=0.000)
Left lung injury score of group O5was higher at T2than at T3(P>0.05).
2.8Western blot for SPA expression in lung tissue
2.8.1The repeated measures ANOVA analysis showed that SPA of left lung had significant difference at T2and T3(F=9.540, P=0.001); SPA had significant difference in different time point (F=21.884, P=0.001); SPA of each group had interaction with time (F=14.652, P=0.000), these suggested that the trend of SPA is different with time. Further analysis, the results showed that the comparison of SPA in group O4and O5had significant difference between T2and T3(P<0.001), there had significant difference between groups at different time point (P<0.05)
2.8.2The repeated measures ANOVA analysis showed that SPA of right lung had significant difference at T2and T3(F=10.990, P=0.000); SPA had significant difference in different time point (F=359.691,P=0.000); SPA of each group had interaction with time (F=14.171, P=0.000), these suggested that the trend of right lung SPA is different with time. Further analysis, the results showed that the comparison of SPA in group01to05had significant difference between T2and T3(P<0.05), there also had significant difference between groups at different time point (P<0.01)
2.8.3The repeated measures ANOVA analysis showed that SPA of left and right lung had significant difference at T2(F=10.876, P=0.000); SPA had significant difference between left and right lung (F=36.394, P=0.000); SPA of each group had interaction with left and right lung (F=11.577, P=0.000), these suggested that the trend of each group is different with left and right lung. Further analysis, the results showed that the comparison of SPA in group01to O3had significant difference between left and right lung (P<0.05), there also had significant difference between left and right lung in different groups (P<0.01)
2.8.4The repeated measures ANOVA analysis showed that SPA of left and right lung had significant difference at T3(F=19.860, P=0.000); SPA had significant difference between left and right lung (F=0.083, P=0.778); SPA of left and right lung had no interaction with groups(F=1.946, P=0.1600), these suggested that the trend of left and right lung is same with different groups.
2.9The comparison of TNF-α、IL-8in BALF
2.9.1The repeated measures ANOVA analysis showed that TNF-a of left and right lung had significant difference at T2and T3(T2F=56.146, P=0.002; T3F=14.619, P=0.001); TNF-a had significant difference between groups at T2(F=29.336, P=0.000), but TNF-a had no significant difference between groups at T3(F=1.054, P=0.410). TNF-a of each group had interaction with left and right lung at T2(F=4.792, P=0.005), but TNF-a of each group had no interaction with left and right lung at T3(F=0.333, P=0.888), these suggested that the trend of TNF-a in each group is different with left and right lung at T2, but the trend of TNF-a in each group is same with left and right lung at T3.
Further analysis, the results showed that the comparison of TNF-a in group03to05had significant difference between left and right lung at T2(P<0.05), there also had significant difference between left and right lung in different groups (P=0.000).
TNF-a of left BALF in group03-05was higher at T2than at T3(P<0.05).2.9.2The repeated measures ANOVA analysis showed that IL-8of left and right lung had significant difference at T2and T3(T2F=9.460, P=0.005; T3F=11.784, P=0.002); IL-8had significant difference between groups at T2(F=20.703, P=0.000), but IL-8had no significant difference between groups at T3(F=5.824, P=0.001) IL-8of each group had interaction with left and right lung at T2(F=2.882, P=0.035), but IL-8of each group had no interaction with left and right lung at T3(F=2.452, P=0.063), these suggested that the trend of IL-8in each group is different with left and right lung at T2, but the trend of IL-8in each group is same with left and right lung at T3.
Further analysis, the results showed that the comparison of IL-8in group04had significant difference between left and right lung at T2(P=0.043), there also had significant difference between left and right lung in different groups (P<0.01)
IL-8of left BALF in group04-05was higher at T2than at T3(P<0.01) IL-8of right BALF in group05was higher(P<0.05).2.10The correlation of TNF-a and IL-8values and duration of OLV
At T2, TNF-a and IL-8of left and right lung were positively correlated with duration of OLV (left lung TNF-a r=0.901, right lung TNF-a r=0.748, left lung IL-8r=0.840, right lung IL-8r=0.660, P<0.01). At T3, TNF-a in left BALF and IL-8in left and right BALF were positively correlated with duration of OLV(left lung TNF-a r=0.430, P<0.05; left lung IL-8r=0.697, right lung IL-8r=0.592, P<0.01).
2.11BALF cell counts
The repeated measures ANOVA analysis showed that cell counts of left and right lung had sig
OLV对通气肺的影响主要是机械牵张性肺损伤。机械牵张包括：机械正压通气、OLV时不断重复肺组织萎陷和复张的过程、胸科手术操作对肺组织的牵拉。而OLV对萎陷肺影响较通气侧肺影响大。在OLV时由于缺氧性肺血管收缩的作用,萎陷侧肺血流量降低为心输出量的20%-25%,而萎陷肺的肺泡内无氧气,所以当萎陷肺经历了由萎陷到复张的过程时,也是肺泡组织经历缺氧到复氧、缺血-再灌注损伤的过程。众多研究认为肺复张可以激活严重的氧化应激反应,氧自由基产生与OLV的时间相关。长时间单肺通气增加术后肺并发症。但长时间OLV对肺损伤的影响如何,多久才是长时间单肺通气?是3小时、4小时、还是更长?
研究发现OLV和双肺通气(Two-lung ventilation,TLV)均可导致血白介素-6(Interleukin-6, IL-6)和白介素-8(Interleukin-8, IL-8)升高,但OLV更显著；OLV患者在术后48h,无论是IL-6还是IL-8的浓度可降到与TLV组相似,OLV2小时后再TLV,动脉血氧分压也可以恢复到术前水平。这说明只要很好的控制OLV的时间,临床上应用OLV麻醉还是安全的。但这一研究只观察了OLV2h后再TLV,肺损伤有减轻的结果,对长时间OLV后再TLV的情况如何就暂无文献报道?
目前,对OLV的时间限制尚无明确的数据说明。因此,本研究拟尝试从临床和动物实验来观察不同单肺通气时间对肺损伤的影响,从而寻找单肺通气的时间限制；我们还从动物实验来观察单肺通气结束后24小时内肺损伤修复的情况,为日后探讨单肺通气后肺损伤修复的机制而做准备。
目的
回顾性分析电视辅助胸腔镜手术后肺部并发症的相关因素；研究不同单肺通气时间对兔支气管肺泡灌洗液(Bronchoalveolar lavage fluid, BALF)肿瘤坏死因子-alpha (Tumor necrosis factor-alpha, TNF-a)、IL-8及肺组织表面活性蛋白A(Surfactant protein A, SPA)的影响；研究不同单肺通气时间对胸科手术患者BALF中TNF-a, IL-8的影响。
方法
1、电视辅助胸腔镜手术后肺部并发症的相关因素分析
1.1一般资料
选取2010年1月1日到2011年3月31日在广州呼吸疾病研究所行VATS患者330例,男212例,女118例,年龄18-77岁,体重42-80kg。排除标准：术前已存在肺感染或其他感染性疾病；术前经验性应用抗感染治疗者；行气管切开等创伤性操作及长期机械通气等易继发感染者；纵隔胸腺瘤伴重症肌无力者；术中出现心肺复苏等抢救情况；中转开胸手术者；术中不能耐受单肺通气者；有术前放化疗史；术前停止吸烟未足2周者。
1.2麻醉方法
所有患者麻醉前30min均肌肉注射咪达唑仑0.05mg/kg和阿托品0.01mg/kg。根据患者术前的后前位胸片胸骨锁骨端气管横径,选择双腔支气管导管(Double-lumen tubes, DLT)的型号,并根据患者身高计算插管深度。患者入手术室后完善生命体征监测,设定丙泊酚血浆靶控浓度3gg/ml,面罩吸氧去氮5min后行丙泊酚靶控输注静脉诱导,同时缓慢静脉注射舒芬太尼0.4μg/kg和顺阿曲库铵0.2mg/kg。经口明视下按计算的深度插入DLT,并以纤维支气管镜(Fiberoptic bronchoscopy, FOB)调整管端位置。插管完成后行右颈内静脉和桡动脉穿刺置管。
所选病例通气模式均相同,潮气量、呼吸频率及吸呼比等各项参数设置也基本一致,麻醉方法、用药及术后镇痛方式和镇痛药物也大致相仿。根据患者病变部位及大小选择合适的手术方式,手术均由同一组医师完成。患者术中生命体征平稳,手术结束均鼓肺,待患者清醒拔管后送入ICU监护。
1.3对病例采用回顾性分析与肺部并发症发生可能相关的影响因素
包括年龄、性别、体重指数(Body mass index,BMI)、术前肺功能评级及测量指标：包括肺功能正常、轻度、中度、中重度、重度和极重度通气功能障碍；第一秒用力呼气量(Forced expiratory volume in first second, FEV1)、用力肺活量(Forced vital capacity, FVC)、FEV1/FVC比值、最大随意通气量(Maximal voluntary ventilation, MVV);及心彩超检查结果,单肺通气时间及麻醉时间、术中失血量及补液量、手术侧及手术切除范围(胸腔镜探查、肺楔形切除、单个或多个肺叶切除、全肺切除)、ICU入住时间、术后引流管留置时间、术后住院时间、手术前后血白蛋白值,以及术前是否合并糖尿病、慢性呼吸道疾病、心血管疾病、胸科手术史等,搜集、整理以上相关资料。
胸科手术后肺部并发症诊断标准：观察术后三天内肺部影像学变化是否出现肺渗出增加、肺炎、肺不张或肺压缩、肺栓塞、胸壁皮下气肿增多、胸腔积液等,以及呼吸衰竭、需要纤维支气管镜吸痰、重新气管插管等。
麻醉时间是指：麻醉诱导开始到拔除气管导管；单肺通气时间是指：手术开始前10分钟开始单肺通气到恢复双肺通气。本研究将麻醉时间按小于2小时、2-3小时、3-4小时、大于4小时分为四个阶段来分析；将单肺通气时间按小于1小时、1-2小时、2-3小时、大于3小时分为四个阶段来分析。
1.4统计分析
采用SPSS13.0统计分析软件包进行分析。计量资料采用均数±标准差表示。有肺并发症组与无肺并发症组比较,视资料情况采用两独立样本t检验或卡方检验；所有变量与术后是否有肺并发症关系用多因素逐步Logistic回归分析,P<0.05有统计学意义。
2.不同单肺通气时间对兔支气管肺泡灌洗液TNF-α、IL-8及肺组织SPA的影响
2.1动物准备和分组
健康新西兰大白兔68只,雄性,实验前一天禁食禁水。随机分为C组和01组、02组、03组、04组、05组。C组为对照组(假单肺通气组,n=10),只进行穿刺操作并保持自主呼吸；O1—05组建立右肺单肺通气,01和02组10只兔,03组11只兔,04组12只兔,05组15只兔。每组分别给予单肺通气1、2、3、4、5小时。各组兔子完成单肺通气后恢复双肺通气30分钟,其中每组一半兔立即处死,另一半兔待恢复自主呼吸后拔除各种管道,缝合胸廓和气管切口后饲养24小时再处死。
2.2实验操作
经耳缘静脉注射戊巴比妥钠30mg/kg后取仰卧位固定。2%利多卡因局麻下游离颈动脉或股动脉穿刺置管,通过动脉压力转换器测心率(Heart rate, HR)和平均动脉压(Mean arterial blood pressure, MAP)。颈静脉或股静脉穿刺置管予生理盐水10mL·kg-1·h-1输注。予2%利多卡因局部喷洒后在甲状软骨下3个气管环处行气管切开,并插入带气囊的3.0号改良单腔气管导管,深度约3cm左右。插管即刻予维库溴胺0.1mg/kg静脉注射,间断予戊巴比妥钠10mg/h和维库溴胺0.1mg/kg静注麻醉。连接HX-300S小动物呼吸机行机械通气,呼吸机参数：潮气量10mL/kg,呼吸频率35次/分,吸呼比1：1,吸入氧浓度(Fi02)1.0；实验开始时将导管插入右侧,建立右肺OLV动物模型,经左第6肋间开一小口(1cmxlcm)观察肺萎陷情况,以左肺通气膨胀到萎陷为单肺通气模型建立成功。单肺通气期间呼吸参数改为潮气量8mL/kg,呼吸频率40次/分,吸呼比1：1。在单肺通气时,若检测动脉血气SA02≤80%则恢复双肺通气15分钟后再继续单肺通气,记录每只兔子恢复双肺通气次数。整个实验过程中维持室温26-28℃,予台灯照射保暖,维持动物肛温(37-38℃)。实验结束后,实验兔通过静脉注射20ml空气处死。
2.3实验动物排除标准：
实验操作失误或意外死亡,包括未达到预定观察时间点死亡者；支气管肺泡灌洗液回收率低于40%者；实验中恢复双肺通气>5次等。实验动物被排除后,再进行动物实验直至每组有10只动物完成实验。
2.4观察时间点及标本采集
2.4.1观察时间点
T0气管插管前；
T1单肺通气开始前；
T2单肺通气结束恢复双肺通气30min；
T3养活24小时后。
2.4.2心率(HR)、平均动脉压(MAP)和呼吸力学指标监测
记录01-05组在T1和T2时的HR、MAP、呼末二氧化碳分压(PETCO2)。观察中若SBP下降至60mmHg时予以血管活性药维持血压。分析在T2时HR、 MAP、PETCO2与OLV时间相关性。
HX-300S动物呼吸机记录01-05组在T1及T2时的的潮气量(VT)、呼吸频率、吸气峰压(Ppeak)。根据公式计算分钟通气量(Minute volume, MV)和肺顺应性。
分钟通气量(MV)=潮气量(VT)×呼吸频率
肺顺应性=VT-(Ppeak-PEEP)(PEEP=0)
2.4.3血气分析指标
01-05组动物在T1和T2时经颈动脉或股动脉采动脉血0.5mL经iSTAT'快速血气分析机行血气分析,测定pH、PaCO2、PaO2、碳酸氢根、BE、SaO2。分析在T2时血气分析值与OLV时间相关性。
插管前,每组随机取两个动物血气值作为T0值。C组和01-05组动物在T3时经中耳动脉或颈动脉采血0.5mL经iSTAT快速血气分析机行血气分析,测定pH、PaCO2、PaO2、碳酸氢根、BE、SaO2。比较T0和T3时点的血气值。
2.4.4肺组织病理学检查
实验结束后开胸分离左右肺,在支气管肺泡灌洗前,各取左右下肺叶相同部位约1.0cm3肺组织,浸泡于10%福尔马林溶液中固定,常规石蜡包埋、切片,染色,用普通光学显微镜在一张玻片上看10个高倍(400倍)视野进行肺损伤评分。肺组织损伤评分内容为肺萎陷、肺泡壁透明膜形成、中性粒细胞浸润或聚集,肺泡内充血或出血,分别依其严重程度评0-4级(0,无病变或非常轻微；1,轻度损伤,<25%；2,中度损伤,25%-50%；3,重度损伤,50%-75%；4,极重度损伤,>75%),并计算四项指标的总分为肺损伤评分。
2.4.5Western Blot半定量检测肺组织中SPA的含量
实验结束后开胸分离左右肺,取左右肺下叶相同部位1.0cm3肺组织置-70℃待测SPA。按标准步骤采用Western Blot法检测SPA。使用ChemiDocXRS (BIO-RAD)成像仪获得图像,在PVDF膜相对应的分子量的位置标记上目的蛋白,采用image J软件计算目的条带灰度×面积值来评判蛋白含量。每个样本重复三次实验。
2.4.6检测支气管肺泡灌洗液中TNF-a和IL-8浓度值
实验结束后开胸分离取出左右肺,用止血钳夹闭右主支气管,将气管导管插入左肺,经气管导管注入4℃磷酸盐缓冲液(Phosphate buffered solution, PBS)5ml/次,轻度反复灌洗,停留1min后抽出,共灌洗3次后获得总的BALF量。左肺灌洗结束后再用同样方法灌洗右肺。灌洗液取上清,用ELISA方法检测TNF-a、IL-8.分析在T2时TNF-a、IL-8值与OLV时间相关性。
2.4.7支气管肺泡灌洗液的细胞计数
灌洗液经离心后的沉淀部分经处理后取1ml的PBS细胞液用16×25规格的血细胞计数板行细胞计数。
2.5统计学方法
采用SPSS13.0统计软件(SPSS Inc.; Chicago)对数据进行分析。各组数据以均数±标准差(x±s)表示。比较T1和T2时点的血循环、呼吸力学指标和血气分析值、以及左右肺BALF中TNF-α、IL-8值和细胞数、左右肺SPA灰度值、左右肺损伤评分采用配对t检验；比较对TO和T3时点的血气分析值采用单方向方差分析(one-way analysis of variance);比较T2和T3时点的肺损伤评分、BALF中TNF-α、IL-8值和细胞数、SPA灰度值采用两独立样本t检验。比较不同时间点不同组间的各观察值采用单个重复测量因素方差分析(analysis of variance of repeated measures data),多重比较采用最小显著差值法(Least-significant difference)。计数资料比较采用卡方检验。血循环、血气分析值、TNF-α、IL-8值与OLV时间相关性采用等级相关(Spearman)分析,P<0.05示有统计学意义。
3.临床研究：不同单肺通气时间对胸科手术患者BALF中TNF-α、IL-8的影响
3.1病例分组及入选研究标准
选择年龄25-64岁、ASA Ⅰ或Ⅱ级患者。术前心肝肾功能正常。实验分组：(1)选择胸腔镜辅助下行左侧开胸食管癌或肺癌根治术患者36例为单肺通气组(OLV组),按单肺通气时间分为3个亚组：O1组(<1.5hOLV)；02组(2.0-2.5hOLV);03组(3.0-3.5hOLV),每组12例患者。2)双肺通气组：选取行双肺通气的非胸科手术患者12例,设为T组(3.0-3.5hTLV)。
入选病例标准：术前无化疗、放疗、机械通气史；非小细胞肺癌患者；肿瘤分级T1N1M0(肿瘤直径<3cm,肿瘤侵犯未达食管外膜；邻近肺门淋巴结组有1或2枚淋巴结转移,无远处脏器和淋巴结转移)；一周内无感染病史,无皮质激素和抗生素使用史；肺功能正常或仅有轻度通气功能障碍；无肝肾功能障碍。支气管肺泡灌洗液回收率>40%。术中鼓肺<5次。对术中出血量超过体重15%或输血者排除研究。麻醉后体温<35.5℃或>37.5℃排除研究。若患者在OLV后出现SP02<90%,需要提高吸入Fi02>70%超过1小时者排除研究。T组入选患者肺功能正常且肺部无恶性肿瘤或内分泌性肿瘤患者。
3.2麻醉方法
麻醉前30min肌肉注射咪达唑仑0.05mg/kg和阿托品0.01mg/kg。OLV组患者根据术前后前位胸片胸骨锁骨端气管横径,选择右双腔支气管导管(DLT)的型号。患者入室后开放外周静脉,滴注乳酸林格注射液,速率10m1.kg-1.h-1。患者入室后监测II导联心电图、心率(HR)、右上臂无创血压、脉搏氧饱和度(SpO2)。围术期麻醉处理及手术操作均由同一位麻醉医师和同一胸科小组完成。
面罩吸氧去氮5min后,予丙泊酚血浆靶控浓度3.0ug/ml、舒芬太尼0.4gg/kg和顺阿曲库胺0.2mg/kg静脉诱导,经口插入右双腔支气管导管,纤维支气管镜确定导管位置。行右颈内静脉穿刺置管及右桡动脉穿刺置管。麻醉维持：丙泊酚2.3～3.5μg/ml靶控输注；瑞芬太尼0.05-0.3ug/kg/min泵注镇痛；间歇追加顺阿曲库铵。根据失血量、尿量和中心静脉压(CVP)调整静脉输液速度和羟乙基淀粉130/0.4氯化钠注射液用量。
患者均以Datex-Ohmeda S型麻醉机行机械间歇正压通气,Datex-Ohmeda S5型气体监测仪连续监测吸气峰压(Ppeak)、平台压(Pplateau)、VT、分钟通气量(MV)和呼末二氧化碳分压(PETCO2),维持PETCO2于35～45mm Hg。OLV组患者在双肺通气20min后摆放侧卧位,FOB观察并调整DLBT管端位置。双肺通气时VT8～10ml/kg, I:E=1:2,呼吸频率12次/min,吸入氧分数(Fi02)60%；在手术开始前10分钟开始行单肺通气,单肺通气时VT7-8ml/kg,I：E=1：2,呼吸频率12-16次/min。患者在手术结束置放胸腔引流管时恢复TLV。而双肺通气组(T组)则保持通气参数设置不变。患者均送入麻醉恢复室,术后给予充分静脉镇痛,剂量按公斤体重计算。待自主呼吸恢复、VT满意后拔出气管导管,术后予鼻导管吸氧2L/min。
3.3观测时点
T1：麻醉前
T2：气管插管平卧位双肺通气后20min；
T3：手术结束前(OLV组恢复双肺通气30min后)；
T4：术后24h,鼻导管吸氧2L/min。
3.4血流动力学及呼吸力学指标
观察O1-03组和T组患者在T2-T3时点的Sp02、平均动脉血压(MAP)、心率(HR)、CVP, Ppeak、Pplateau、MV、VT和PETCO2;并记录T1和T4时点的SpO2、MAP、HR。
3.5血气分析值
01-03组和T组患者在T1-T4时点抽取动脉血,予Stat Profile(?) Critical Care Xpress Analyzer进行血气分析,观察pH、动脉血二氧化碳分压(PaCO2)、PaO2、Sa02、氧合指数(由动脉氧分压PaO2/FiO2得出)、碳酸氢根变化。
3.6支气管肺泡灌洗中TNF-α、IL-8浓度
01-03组和T组患者在T2和T3时点行支气管肺泡灌洗。将纤支镜顶端紧密楔入段或亚段支气管开口处,经活检孔通过硅胶管快速注入灭菌生理盐水30m1,用负压吸引回收灌洗液至痰液收集器中,记录回收液总量。将回收液体离心,取上清用ELISA法检测上清液TNF-α、IL-8。OLV组灌洗左右两侧肺,首选灌洗左下叶及右中下叶肺段,当该肺段有病变时则灌洗左上叶及右上叶肺段；T组只灌洗右中下叶肺段作为对照。
3.7其余观察项目
(1)单肺通气时间；(2)麻醉时间；(3)失血量和尿量；(4)术中液体静脉输入量；(5)PACU停留时间；(6)麻醉药物用量；(7)记录OLV组术后3天内的胸片结果异常者；(8)记录OLV组术后3天内并发症出现情况(如低氧血症、肺炎、二次手术发生率、肺不张等)。
3.8统计学方法：
所有数据均以均数±标准差(x+s)表示,采用SPSS13.0软件包进行统计学分析。不同组间患者一般情况及其余计量资料比较采用单向方差分析(one-way analysis of variance),多重比较采用最小显著差值法(Least-significant difference)。计数资料比较采用卡方检验；组内不同时间点的血流动力学指标和血气分析值比较采用单向方差分析,呼吸力学指标和TNF-α、IL-8值比较采用配对t检验；不同时间点不同组间的血流动力学指标、呼吸力学指标、血气分析值以及TNF-α、IL-8值比较采用单个重复测量因素方差分析(analysis of variance of repeated measures data); P<0.05有统计学意义。
结果
1.电视辅助胸腔镜手术后肺部并发症的相关因素分析
1.1术后肺并发症
330例VATS胸科手术后三天内,诊断为肺并发症有72例,占21.82%,其中肺渗出增加24例(占7.27%),肺炎23例(占6.97%),肺不张18例(占5.45%),胸腔积液4例(占1.21%),纤支镜吸痰2例(占0.61%),重新气管插管1例(占0.3%),无一例死亡
1.2与无肺并发症组比较,有肺并发症组的术前白蛋白较低(P<0.05),单肺通气时间和术后ICU入住时间(P<0.01)较长。有肺并发症组的男：女比例高于无肺并发症组(P<0.05)。
1.3多因素逻辑回归(Forward LR)分析表明：术前白蛋白水平、单肺通气时间和ICU入住时间是独立危险因素,OR值分别是0.922、1.379、1.362(P<0.05)。
2.不同单肺通气时间对兔支气管肺泡灌洗液TNF-α、IL-8及肺组织SPA的影响
2.105组OLV时有一只兔恢复双肺通气次数7次；03组、04组和05组分别有1、2、4只兔按实验动物排除标准被排除,动物实验实际数量为60只。C组和01-05组实验兔在体重、潮气量、分钟通气量上无差异(P>0.05)。
2.2单肺通气前后不同组间HR.MAP比较
经重复测量方差分析,结果显示组间的HR.MAP差异无显著性(HRF:1.142,P=0.349；MAP F=2.363,P=0.067)；不同时点间HR.MAP差异有显著性(HR F=69.699,P=0.000；MAP F=23.546,P=0.000)；各组的HR同时间之间无交互作用(F=1.996,P=0.111),而各组MAP与时间之间有交互作用(F=6.612,P=0.000),提示各组随时间的增加,HR变化趋势相同,MAP变化趋势不同。
进一步分析MAP的单独效应,结果显示01-02组、04-05组内两时间点比较有显著性(P均<0.05),各组MAP在T1时点间差异无显著性(P=0.867),各组MAP在T2时点间差异有显著性(P=0.001)。
2.3单肺通气前后不同组间PETCO2、Peak、肺顺应性比较
经重复测量方差分析,结果显示组间的PETCO2、Ppeak、肺顺应性差异无显著性(PETCO2F=0.119, P=0.975; Ppeak F=0.258, P=0.903;肺顺应性F=0.435,P=0.782)；不同时点间PETCO2、Ppeak、肺顺应性差异有显著性(PETCO2F=22.575, P=0.000; Ppeak F=56.687, P=0.000;肺顺应性F=58.345,P=0.000)。各组的PETCO2、Ppeak、肺顺应性和时间之间有交互作用(P均<0.037),提示各组随时间的增加,PETCO2、Ppeak、肺顺应性变化趋势不同。
进一步分析单独效应,结果显示04-05组内PETCO2两时间点比较有显著性(P均<0.05),03-05组内Ppeak、肺顺应性两时间点比较有显著性(P均<0.05)；PETCO2、Ppeak、肺顺应性分别在T1和T2时间点各组间差异无显著性(P均>0.172)。
2.4单肺通气前后不同各组血气值比较
经重复测量方差分析,结果显示组间的pH、PaCO2、碳酸氢根差异有显著性(pH F=2.770,P=0.038;PaCO2F=3.098,P=0.025;碳酸氢根F=2.609,P=0.048),PaO2、BE、SaO2差异无显著性(PaO2F=0.592,P=0.670; BEF=1.450, P=0.233; SaO2F=1.568, P=0.199);不同时点间pH、PaCO2、PaO2、碳酸氢根、SaO2差异有显著性(P均=0.000)。各组的pH、PaO2、碳酸氢根、SaO2同时间之间无交互作用(P均>0.124),各组的PaCO2同时间之间有交互作用(P=0.004),提示各组随时间的增加,pH、PaO2、碳酸氢根、Sa02变化趋势相同,而PaCO2变化趋势不同。
进一步分析单独效应,结果显示04-05组内PaCO2两时间点比较有显著性(P均<0.001)；PaCO2在T1时点各组间比较差异无显著性(P=0.740),PaCO2在T2时点各组间比较差异有显著性(P=0.001)。
2.5单肺通气24小时后与插管前血气值比较
在T3时点,04和05组的pH、PaCO2、O1-05组的Pa02和SaO2、05组的碳酸氢根和BE值与T0、C组比较均有统计学意义(P<0.05)。
与TO比较,C组的碳酸氢根有统计学差异(P<0.01)；C组其余观测指标与TO时各值比较无统计学意义(P>0.05)。
2.6在T2时点各组血循环、血气分析值与单肺通气时间相关性
HR与单肺通气时间正相关性(HR r=0.396,P<0.01)；MAP与单肺通气时间负相关性(MAPr=-0.537, P<0.01)。PETCO2、Ppeak、Cdyn与单肺通气时间无相关性(P>0.05)。
pH、PaO2、BE、SaO2与单肺通气时间呈负相关性(pH r=-0.451, PaO2r=-0.373, BE r=-0.502, SaO2r=-0.421, P<0.01)、碳酸氢根与单肺通气时间显著正相关(PaC02r=0.466,碳酸氢根r=0.412,P<0.01)。
2.7病理学改变及肺损伤评分
2.7.1大体标本所见
C组和01组左右侧肺无明显改变。03、04和05组,左萎陷肺颜色暗淡,表面充血淤血明显；右通气肺部分肺叶也出现充血淤血。与单肺通气时比较,单肺通气24小时后的对照组、01组无明显差异；02-05组左右肺仍有不同程度淤血,以OLV时间超过3小时明显。
2.7.2光镜下检查
单肺通气时：C组及01组左右侧肺泡完整,肺泡腔内无渗出,无炎症细胞。03、04和05组左侧萎陷肺间质增厚不明显,肺间质和肺泡腔有炎性细胞和血细胞浸润,肺泡壁破坏或肺泡不张,以05组最明显；03、04和05组右侧肺间质明显增厚。
单肺通气结束后24小时：对照组和01组肺泡腔内无明显渗出,01组左肺可见部分肺萎陷,右肺部分肺泡壁破坏。02组左肺部分肺泡萎陷,肺间质稍增厚；右肺间质稍增厚,部分肺泡壁破坏。03组左右肺部分肺泡萎陷,肺泡壁破坏,肺间隔增厚不明显,肺间质有红细胞浸润。04-05组左侧肺泡萎陷和肺泡壁破坏明显,肺间质可见较多红细胞和中性粒细胞浸润；右侧肺间隔增厚,肺间质有较多红细胞浸润。
2.7.3肺组织损伤病理评分
经重复测量方差分析,结果显示在T2和T3时间点各组间的肺损伤评分差异均有显著性(P均=0.000)；在T2和T3时间点左右肺的肺损伤评分差异均有显著性(T2F=6.748,P=0.012；T3F=7.779,P=0.007)。在T2时间点,各组的肺损伤评分同时间之间有交互作用(F=5.121,P=0.001),在T3时间点,各组的肺损伤评分同时间之间无交互作用(F=0.262,P=0.932),提示在T2时间点,各组肺损伤评分随时间的增加变化趋势不同,而在T3时点,肺损伤评分随时间增加变化趋势相同。
进一步分析单独效应,结果显示在T2时点,05组内左右肺间的肺损伤评分比较有显著性(F=4.944,P=0.001)；左右肺损伤评分在各组间比较差异有显著性(左肺F=69.303,P=0.000；右肺F=19.909,P=0.000)。
05组左肺在T2时点的肺损伤评分比T3时高(P>0.05)。
2.8Western Blot测定肺组织中SPA的表达
2.8.1经重复测量方差分析,结果显示在T2和T3时点左肺SPA灰度值组间差异有显著性(F=9.540,P=0.001)；不同时点间差异有显著性(F=21.884,P=0.001)；各组同时间之间有交互作用(F=14.652,P=0.000),提示不同组随时间的增加,左肺SPA变化趋势不同。进一步分析单独效应,结果显示04-05组内两时间点比较有显著性(P均<0.001),各时间点不同组间差异均有显著性(P均<0.05)。
2.8.2经重复测量方差分析,结果显示在T2和T3时点右肺SPA灰度值组间差异有显著性(F=10.990,P=0.000)；不同时点间差异有显著性(F=359.691,P=0.000)；各组同时间之间有交互作用(F=14.171,P=0.000),提示不同组随时间的增加,右肺SPA变化趋势不同。进一步分析单独效应,结果显示01-05组内两时间点比较有显著性(P均<0.05),在同一时间点不同组间差异均有显著性(P均<0.01)。
2.8.3经重复测量方差分析,结果显示在T2时点左右肺SPA灰度值组间差异有显著性(F=10.876,P=0.000)；左右肺间差异有显著性(F=36.394,P=0.000)；各组左右肺之间有交互作用(F=11.577,P=0.000),提示不同组间左右肺的SPA变化趋势不同。进一步分析单独效应,结果显示01-03组内左右肺间SPA灰度值比较有显著性(P均<0.05),左右肺不同组间差异均有显著性(P均<0.01)。
2.8.4经重复测量方差分析,结果显示在T3时点左右肺SPA灰度值组间差异有显著性(F=19.860,P=0.000)；左右肺间差异无显著性(F=0.083,P=0.778)：各组左右肺之间无交互作用(F=1.946,P=0.160),提示不同组间左右肺的SPA变化趋势相同。
2.9BALF中TNF-α、IL-8浓度值比较
2.9.1经重复测量方差分析,结果显示在T2和T3时点左右肺间TNF-α值差异有显著性(T2F=56.146,P=0.002；T3F=14.619,P=0.001)；在T2时点,不同组间差异有显著性(F=29.336,P=0.000),在T3时点,不同组间差异无显著性(F=1.054,P=0.410)；在T2时点各组左右肺间有交互作用(F=4.792,P=0.005),而在T3时点各组左右肺间无交互作用(F=0.333,P=0.888),提示在T2时点各组左右肺间TNF-α值变化趋势不同；在T3时点各组左右肺间TNF-α值变化趋势相同。
进一步分析单独效应,结果显示在T2时点O3-O5组左右肺间比较有显著性(P均<0.05),左右肺各组间差异有显著性(P=0.000)。
与T3时点各组比较,T2时点左肺的O3-O5组TNF-α值较高(P<0.05)。
2.9.2经重复测量方差分析,结果显示在T2和T3时点左右肺间IL-8值差异有显著性(T2F=9.460,P=0.005；T3F=11.784,P=0.002)；在T2时点,不同组间差异有显著性(F=20.703,P=0.000),在T3时点,不同组间差异无显著性(F=5.824,P=0.001)；在T2时点各组左右肺间有交互作用(F=2.882,P=0.035),而在T3时点各组左右肺间无交互作用(F=2.452,P=0.063),提示在T2时点各组左右肺间IL-8值变化趋势不同；在T3时点各组左右肺间IL-8值变化趋势相同。
进一步分析单独效应,结果显示在T2时点O4组左右肺间比较有显著性(P=0.043),左右肺各组间差异有显著性(P均<0.01)。
与T3时点比较,T2时点O4-O5组左肺IL-8值较高(P<0.01),右肺O5组IL-8值较高(P<0.05)。
2.10BALF由TNF-α、IL-8浓度值与单肺通气时间相关性
在T2时点,左肺和右肺的TNF-α、IL-8值与OLV时间成正相关(左肺TNF-αr=0.901,右肺TNF-αr=0.748;左肺IL-8r=0.840,右肺IL-8r=0.660,P<0.01)。在T3时点,左肺TNF-α、左右肺IL-8值与OLV时间成正相关(左肺TNF-αr=0.430,P<0.05；左肺IL-8r=0.697,右肺IL-8r=0.592,P<0.01)。
2.11BALF中炎症细胞数比较
经重复测量方差分析,结果显示在T2和T3时点左右肺间细胞数差异有显著性(T2F=13.606,P=0.001；T3F=47.137,P=0.000)；在T2时点,不同组间差异有显著性(F=10.181,P=0.000),在T3时点,不同组间差异无显著性(F=16.161,P=0.000)；在T2时点各组左右肺间有交互作用(F=2.834,P=0.038),而在T3时点各组左右肺间有交互作用(F=2.644,P=0.048),提示在T2和T3时点各组左右肺间IL-8值变化趋势不同。进一步分析单独效应,结果显示在T2时点05组左右肺间比较有显著性(P=0.006),左右肺各组间差异有显著性(P均<0.05)。
与T3时点比较,05组左肺在T2时点的细胞数增加(P<0.05)。
3.临床研究：不同单肺通气时间对胸科手术患者血流动力学、呼吸力学及支气管肺泡灌洗液中TNF-α、IL-8的影响
3.1一般情况
01-03组单肺通气时间分别为1.36±0.22h、2.21±0.26h、3.17±0.25h。两组患者的性别、年龄、ASA分级、BMI比较无统计学意义(P>0.05)。各组患者术中失血量均不超过450ml,无输血病例。
3.2血液动力学指标和Sp02
经重复测量方差分析,结果显示HR、MAP、SPO2、CVP组间差异无显著性(P均>0.186)；HR、MAP、CVP不同时点间差异有显著性(P均<0.05)；各组同时间之间无交互作用(P均>0.05),提示不同组随时间的增加,HR、MAP、 SPO2、CVP变化趋势相同。
3.3两组患者呼吸力学比较
经重复测量方差分析,结果显示PETCO2、Ppeak、Pplateau、MV、VT组间差异无显著性(P均>0.065)；Ppeak、Pplateau、VT在不同时点间差异有显著性(P均<0.05)；PETCO2、MV、VT各组同时间之间无交互作用(P均>0.05),Ppeak、Pplateau各组同时间之间有交互作用(P均=0.000),提示不同组随时间的增加,PETCO2、MV、VT变化趋势相同,Ppeak、Pplateau变化趋势不同。
进一步分析单独效应,结果显示各组内不同时点间的Ppeak、Pplateau、VT比较有显著性(P均<0.048),各时点不同组间差异无显著性(P均>0.805)。
3.4术中血气分析指标
经重复测量方差分析,结果显示PaCO2、SaO2在不同时点差异无显著性(P均>0.05),pH、PaO2、碳酸氢根、氧合指数在不同时点差异有显著性(P均<0.011); pH、PaCO2、PaO2、SaO2、碳酸氢根、氧合指数在不同组间差异无显著性(P均>0.216)；各组同时间之间无交互作用(P均>0.05),提示不同组随时间的增加,pH、PaCO2、PaO2、碳酸氢根、氧合指数变化趋势相同。
3.5手术前后OLV组不同观察时点患者的胸片结果变化比较
术后03组患者胸片提示肺部炎症发生率高于O1和02组患者。
3.6支气管肺泡灌洗中TNF-α、IL-8浓度
3.6.1不同时点及不同组间比较
经重复测量方差分析,结果显示左右肺TNF-α、右肺IL-8值在不同时点差异有显著性(P均=0.000)；左右肺TNF-α和右肺IL-8值在不同组间差异有显著性(P均=0.000)；各组左右肺TNF-α、右肺IL-8值同时间之间有交互作用(P均<0.001),提示不同组随时间的增加,左右肺TNF-α和右肺IL-8变化趋势不相同。
进一步分析单独效应,结果显示各组左右肺TNF-α和IL-8值在两时点间比较均有显著性(P均<0.008)；在T2时点,左右肺TNF-α和IL-8值各组间比较均无显著性(P均>0.221),在T3时点,左右肺TNF-α和IL-8值各组间比较均有显著性(P均=0.000)。
3.6.2左右肺BALF的TNF-α、IL-8值比较
在T2时点,01-03组及T组的左右肺间BALF中TNF-α、IL-8值比较无统计学差异(P>0.05)。在T3时点,01组左BALF中IL-8值、02组左BALF中TNF-α和IL-8值、03组左BALF中IL-8值均比右BALF高(P<0.01)。
结论
1.回顾性分析表明：术前白蛋白水平、单肺通气时间和ICU入住时间是VATS术后肺并发症的主要影响因素。有术后肺并发症组患者OLV时间平均超过3.3小时。
2.单肺通气大于3小时造成萎陷肺的组织病理损伤、肺炎症反应增加,SPA合成减少,肺损伤明显；术后24小时,萎陷肺损伤的修复比通气肺及短时间单肺通气的肺损伤修复缓慢。而不同时间单肺通气对通气肺的肺损伤在单肺通气结束时组间差异无萎陷侧肺明显；术后24小时通气肺的肺损伤可修复。
3.不同单肺通气时间对患者术中、术后24小时的血流动力学、血气分析值无显著影响；但支气管肺泡灌洗液TNF-α、IL-8浓度随着单肺通气时间延长而增加,萎陷肺比通气肺明显,以单肺通气超过3小时后最显著。
Since the first video-assisted thoracoscopic surgery (VATS) was reported in the nineties, the use of VATS has become widespread. VATS is now more generally used than the open thoracotomy owing to its minimal invasiveness and the low morbidity. However, due to small view of surgery, VATS requires surgical instruments to complete the operation, thus operation time maybe is longer than the traditional thoracotomy. One-lung ventilation (OLV) is a commonly used technique that facilitates surgical visualization during thoracic surgical procedure. In particular, during VATS, OLV may play a vital role in the successful completion of the surgery. Degrees of damage of OLV on ventilated lung and non-ventilated lung was different.
The major impact of OLV on ventilated lung is mechanical stretch-induced lung injury. Mechanical stretch includes:mechanical positive pressure ventilation, lung tissue repeated collapse and reexpansion during OLV, lung tissue stretch by surgical operators. But the impact of OLV on non-ventilated lung is larger than that of ventilated lung. The non-ventilated lung is known to be hypoperfused owing to hypoxic vasoconstriction, pulmonary blood flow decreases by20-25%and the collapsed lung alveoli have no oxygen. So that collapsed lung experiences the process of collapse to re-expansion, just is the same as the process of hypoxia and reoxygenation. It is an ischemia-reperfusion injury. A lot of clinical researches have proved that lung re-expansion can evoke severe oxidative stress, oxygen free radicals was associated with OLV time. The long time of OLV increases postoperative complications. How is the impact of duration of OLV on lung injury, and how long is the long time OLV? Is it3hours,4hours, or longer?
Data haved showed that plasma IL-6and IL-8increased both in OLV and two-lung ventilation (TLV), but OLV may increase higher. The concentration of IL-6and IL-8increased in OLV can resume to the similar level as those in TLV after48hours. This demonstrates that once we have a good control of OLV duration, the clinical application of OLV anesthesia is safe. But this study only observed that lung injury was relieved when OLV was only two hour, there is no literature about the impact of longterm OLV on lung injury.
Currently, there is no clear data description the time limitation of OLV. Therefore, this study attempts to observe the effect of different duration of OLV on lung injury from clinical and animal experiments, and to find out the time limitation of OLV. We still observe the repair of lung injury in24hours after OLV through animal experiments, and expect to find out the mechanism of lung injury and repair in the future.
Objective
1. Retrospective analysis of pulmonary complications correlative factors after video-assisted thoracic surgery.
2. To search the effect of different duration of OLV on rabbit Tumor necrosis factor-alpha(TNF-α) and Interleukin-8(IL-8) in bronchoalveolar lavage fluid and Surfactant protein A(SPA) expression in lung tissue.
3. To search the effect of different duration of OLV on clinical patients'TNF-a and IL-8in bronchoalveolar lavage fluid (BALF).
Methods
1. The correlative factor analysis of pulmonary complications after video-assisted thoracoscopic surgery
1.1Patients
330patients (ASA physical status I or II,212male patients,118female patients, age range18-77years, body weight42-80kg) undergoing elective video-assisted thoracic surgery at Guangzhou Institute of Respiratory Disease from2010.1.1to2011.3.31were enrolled in the study. Exclusion criteria included:lung infection or other infectious diseases before surgery; empirical application of anti-infective therapy before surgery; tracheotomy and other traumatic operation and long-term mechanical ventilation; mediastinal thymoma with myasthenia gravis; intraoperative cardiopulmonary resuscitation and emergency treatment; transfer to open-thoracic surgery; a long time to restore two-lung ventilation during operation; preoperative chemotherapy and radiotherapy; stop smoking for less than2weeks before surgery.
1.2General anaesthesia
Midazolam0.05mg/kg and atropine0.01mg/kg were intramuscular injected30mins before anesthesia. The size of Broncho-Cath(?) double-lumen tube (DLT) was determined by the tracheal inner diameter at the level of sternoclavicular articulation measured in the chest x-ray. The intubation depth of DLT was determined based on the regressive equation.
Patients had the vital signs monitor after getting into the operation room. After inhalation of oxygen for5min, Anaesthesia was induced with target controlled infusing propofol (target blood concentration3ug/ml), sufentanyl0.4μg/kg and cisatracurium0.2mg/kg. A flexible styletted DLT was accomplished via direct laryngoscopy according to a standardized protocol, and a fiberoptic bronchoscope (FOB) was then employed to confirm correct positioning of the tube. After intubation, Radial artery and internal jugular vein were catheterized.
All the selected patients had the same ventilation mode. The ventilation parameters setting, including tidal volume, the ratio of inspiratory and expiratory, and respiratory rate were basically the same. The anesthesia method and medication, postoperative analgesia and analgesic drugs were also the same. The operations were performed by the same group of surgeons. All patients were sent to ICU for further care after extubation.
1.3Logistic regression analysis for possible factors about postoperative pulmonary complications in VATS
Possible factors of postoperative pulmonary complications in VATS included: Age, sex, body mass index(BMI), preoperative pulmonary function rating, the forced expiratory volume in first second(FEV1), forced vital capacity(FVC), FEV1/FVC, maximal voluntary ventilation(MVV), echocardiography, duration of OLV, duration of anesthesia, intraoperative blood loss, intraoperative fluids, laterality of surgery, extent of pulmonary resection(inspection without resection, wedge resection, lobectomy, multi-lobectomy, pneumonectomy), length of ICU stay, duration of chest tube drainage, length of postoperative hospitalization, preoperative and postoperative albumin values, the comorbidities of diabetes mellitus, angiocardiopathy, chronic respiratory disease, and history of thoracic surgery. The above data were collected and collated.
In the first3days after VATS, pulmonary exudation increasing, pneumonia, atelectasis or lung compression, pulmonary embolism, pneumoderma of chest wall increasing, pleural effusion, respiratory failure, suction with FOB, and reintubation were considered to be postoperative pulmonary complications in VATS.
Length of anaesthesia was defined as the period between induction and extubation. Length of OLV was defined as the period between starting OLV10min before operation and resuming two-lung ventilation. According to the Gerald's definition of long-term operation, the anaesthesia time was divided into4stages(2h<,2-3h,3-4h,≥4h), and the OLV time was divided into4stages(lh≤,1-2h,2-3h,>3h).
1.4Statistical analyses
SPSS13.0statistical software package was used for all analyses. Descriptive statistics (x±s) were used to summarize the measurement data, medians were used in categorical data. The independent t-test or Chi-square test was used to compare continuous data or categorical data between no complication group and complication group. Binary logistic regression (Forward LR method) was applied to determine the relationship between variables and postoperative pulmonary complications. P values <0.05were considered to be statistically significant.
2. The effect of different duration of one-lung ventilation on rabbit TNF-α and IL-8in BALF and SPA in lung tissue
2.1Animals and Experimental Design
Sixty-eight New Zealand White rabbits (both males, body weight2.5±0.2kg) were forbidden food and water for one day before experiment. All rabbits were randomised divided into6experimental groups:controlled group (group C) and group O1,O2,O3,O4,O5. Group C (n=10) just received endotracheal intubation and vascular puncture but the spontaneous breath was ramained. Groups01-05respectively received right-lung ventilation for1,2,3,4,5hours (group01and02n=10; group O3n=11, group O4n=12, group O5n=15). Each rabbit resumed two-lung ventilation for30minutes after OLV. Half of rabbits in each group were executed at the end of experiment, the other half rabbits were feed for24hours after resuming spontaneous breath, and then were executed.
2.2Experimental operation
Rabbits were anesthetized with sodium pentobarbital (30mg/kg) intravenously administered through the ear vein and maintained at doses of10mg/h. Each rabbit had a cervical tracheotomy with an inserted endotracheal tube (a diameter of3.0mm self-made cuffed endotracheal tube). After intubation, animals were given vecuronim (0.1mg/kg) per hour and ventilated with a tidal volume of10ml/kg, a rate of35breaths/min, inspiration-expiration (I:E) ratio of1:1, an inspired oxygen concentration (FiO2)100%by use of the animal ventilator. Each rabbit had a carotid or femoral artery puncture to measure heart rate (HR) and median arterial pressure (MAP) by a safedraw transducer blood sampling set. Tracheal tube was put forward into the right-main stem bronchus to build OLV model. The sixth of left intercostal space was opened a small incision (1cm×1cm) to observe the lung collapse. The OLV model was successfully established according to the left lung from expansion to collapse. After OLV model established, right OLV was given a tidal volume of8ml/kg, a rate of40breaths/min, I:E ratio1:1, and a FiO2100%. The effectiveness of left lung collapse was checked by continuous inspection. If the oxygen can't be maintained during experiments, animals were checked endotracheal tube position and resumed two-lung ventilation for15minutes, then continued OLV. Rabbit's body temperature was kept at37℃by use of a warm blanket and measured with a mercury thermometer in the anus. Physiologic saline solution was given intravenously10mL·kg-1·h-1. At the end of experiment, half of rabbits in each group were executed by injection of20ml of air; the other half of rabbits were sutured trachea and intercostal space after resuming spontaneous breathing, and were executed after feeding for24hours.
2.3Exclusion criteria
Accidental death in the experiment, including death before the scheduled observation time; the recovery rate of BALF less than40%; resuming two-lung ventilation more than five times, et al. The data of exclusion rabbit was removed. Animal experiments were continued until there were10rabbits to complete experiments in each group.
2.4Times for variables recording and specimen collection
2.4.1Times for variables recording
TO:Before the tracheal intubation;
T1:Before the beginning of OLV;
T2:Resuming two-lung ventilation for30min after the end of OLV;
T3:Feeding for24hours.
2.4.2The recorded data of heart rate (HR), mean arterial pressure (MAP) and respiratory mechanics
HR, MAP, PETCO2, VT, breath rate, peak inspiratory airway pressure (Ppeak) of group01-05were recorded at T1and T2. If SBP drops to60mmHg, rabbits were given vasoactive drugs to maintain blood pressure stable. MV and lung compliance were calculated by formula. Analyzed the correlation between HR, MAP, PETCO2with duration of OLV at T2.
2.4.3Blood Gas Analysis
Blood samples were obtained by taking0.5ml heparinized blood from the carotid or femoral artery. Blood gas analysis of group01-05was performed at T1and T2by an i-STAT blood gas analyzer. Analyzed the correlation between blood gas values with duration of OLV at T2
Before intubation, two animal blood gas values were randomly selected from each group and taken as TO values. Blood gas analysis of group C and group01-05were performed at T3. The blood gas analysis was compared between at TO and T3.
2.2.4Pulonary histopathological examination
Left and right lung were taken out at the end of the experiment.1.0cm3lung tissues were taken at the same parts of lower lobes in left and right lung. Lung tissue was soaked in10%buffered formalin and fixed, then embedded in paraffin, slice, row, hematoxylin-eosin stainng. Lung injury score was viewed10high-power (400times) under an ordinary optical microscope. The contents of lung injury score were atelectais, hyaline membrane formation, infiltration or aggregation of neutorphils in airspaces and alveolar congestion or hemorrhage. The injury score was used a damage scale of0to4(0, minimal or no damage;1, mild damage, less than25%of the field;2, moderate damage,25%to50%of the field;3, severe damage,50%to75%of the field;4, maximal damage, more than75%of the field). The total score of the four conetents was calculated as lung injury score.
2.4.5Western Blot Analysis for SPA in lung tissue
1.0cm3lung tissues were taken at the same parts of lower lobes in left and right lung and were stored in-70℃refrigerator. Western blot was used to determination of SPA expression in lung tissue. The protein was formed image by ChemiDocXRS (BIO-RAD) and the immunoreactive bands were scanned and normalized by GAPDH bands of the same membrane. The band density was analyzed by Image J software. Each sample was repeated3times.
2.4.6The concentration of TNF-a and IL-8in BALF
The right lung was inserted a diameter of3.0mm endo-tracheal tube into the right main bronchus and infused5ml of ice-cold sterile PBS. Lavages were repeated three times and the recovery fluid was combined. The left main airway was clamped during right lung lavaged. The left lung was also taken the same method to get BALF after finishing right lung lavage. Supernatant aliquots was used to test the concentrations of TNF-a and IL-8by enzyme-linked immunosorbent assay (ELISA). The correlation between TNF-a, IL-8and duration of OLV were analyzed at T2.
2.4.7BALF Cell Counts
The cell pellets of BAL were washed by PBS and added10%acetic acid to remove red blood cells,1ml PBS were taken out and counted under light microscopy.
2.5Statistical analysis
The Statistical Package for the Social Sciences13.0(SPSS Inc.; Chicago) was used for results analysis. The results are presented as means±standard error of the mean. The paired-samples t test was used to compare hemodynamics, respiratory mechanism and blood gas values at T1and T2, and compare the concentration of TNF-a, IL-8, cell number, SPA gray-value, lung injury scorce in left and right lung. One-way analysis of variance was used to compare blood gas values at TO and T3. The independent samples t test was used to compare lung injury score, the concentration of TNF-a and IL-8, cell number, SPA gray-value at T2and T3. Analysis of variance of repeated measures data was used to compare different group variables at different time point. Least-significant difference was used for multiple comparisons. The count data was compared by Chi-square test. The correlation between circulation, blood gas values, the concentrations of TNF-a and IL-8with duration of OLV was analyzed by Spearman analysis. P values<0.05were considered to be statistically significant.
3. Clinical research:the effect of different duration of one-lung ventilation on patient's TNF-a and IL-8in BALF
3.1Patients groups and selected standards
Patient's age was range between25-64year; ASA physical status I or II. Patients were assigned into two groups:1) one-lung ventilation group (OLV group, n=36): patients who undergone elective esophageal and lung cancer surgery via left VATS were enrolled in the study. According to OLV time, patients were divided into three subgroups:group01(<1.5hOLV); group02(2.5-3hOLV); group O3(3.0-3.5hOLV),12patients in each group.2) Two-lung ventilation group (T group,3.0-3.5hTLV, n=12):patients who undergone non-thoracoscopic surgery were enrolled in the study.
Selected case criteria:no dysfunction of heart, liver and kidney; No preoperative chemotherapy and radiotherapy; no history of mechanical ventilation; Non-small cell lung cancer; the tumor grade T1N1M0(tumor size<3cm, no distant metastasis); no infection history within a week; no history of using corticosteroids and antibiotic; normal lung function or mild pulmonary dysfunction; the recovery rate of BALF was more than40%; re-expand lung less than5times during operation; patients whose blood loss more than15%of weight or transfusion were exclude from study. The patients enrolled in group T had normal pulmonary function and had no lung cancer or endocrine cancer. The case was excluded when the patients need to inhale FiO2>70%more than1hours. The enrolled patients of group T had normal pulmonary function and had no lung cancer or endocrine cancer.
3.2General anaesthesia and ventilation method
Anaesthesia was induced and maintained with target controlled infusing propofol. In the OLV group, a flexible styletted DLT was accomplished via direct laryngoscopy according to a standardized protocol, and a fiberoptic bronchoscope (FOB) was then employed to confirm correct positioning of the tube. All patients were placed central venous catheter and radial arterial catheter. Intravenous infusion speed and fluid dosage were decided according to blood loss, urine output and central venous pressure (CVP).
The patients were ventilated with a FiO2of0.6through out. Ventilator settings were adjusted from VT of8-10ml/kg, rate of12-min-1(TLV) to VT of7-8ml/kg, rate of12-16-min-1(OLV); I:E ratio was1:2. Ventilator settings were kept constant during the study. Patients were sent to the PACU. All patients'post-operative analgesia and analgesic drugs were the same, analgesic dose was calculated by body weight. Patients were pulled out the endotracheal tube after recovery of spontaneous breathing.
3.3Observations time points
T1:before anesthesia;
T2:20minutes after two-lung ventilation in supine position
T3:at the end of surgery (resuming two-lung ventilation for30min in group OLV)
T4:in the first postoperative day while the patients were receiving oxygen via nasal catheter (2L/min)
3.4Hemodynamics and respiratory mechanics
SpO2, MAP, HR, CVP, Ppeak, Pplateau, MV, VT, PETCO2of group01-03and group T were recorded at T2and T3. SpO2, MAP, HR were recorded at T1and T4.3.5The blood gas analysis values
Arterial blood gas analysis was performed at T1to T4respectedly. PH, PaCO2, PaO2, SaO2, oxygenation index (PaO2/FiO2), and bicarbonate were measured by Stat Profile(?) Critical Care Xpress Analyzer.
3.6The concentration of TNF-α and IL-8in BALF
BALF was performed at T2and T3. Put the top of bronchoscopy to the opening of segment or sub-segmental bronchi, and used silicone tube rapidly injecting sterile normal saline30ml through the biopsyhole (10ml/time, total30ml). Lavage fluid was stored at a clean sputum collection through a vacuum suction and recorded the recovery volume. The supernatant was taken to measure the concentrations of TNF-a and IL-8by ELISA. In group OLV, lavage bilateral pulmonary, first preferred lavage lung segment in the left lower lobe and right lower lobe, second preferred lavage lung segment in the left upper lobe and right upper lobe. In group T, we only lavage the right middle lobe segment and taken as controlled value.
3.7Other observation items
(1) duration of OLV;(2) duration of anesthesia;(3) the amount of blood loss and urine;(4) intraoperative intravenous input;(5) the residence time in the PACU;(6) the amount of narcotic drugs;(7) record the abnormal chest X-ray results in3days after surgery in OLV group;(8) record complication occurrence in3days after surgery in group OLV, such as hypoxemia, pneumonia, reoperation incidence, pulmonary atelectasis, etc.
3.8Statistical analyses
Descriptive statistics (x±s) were used to summarize the continuous data, medians were used in categorical data. SPSS13.0statistical software package was used for all analyses. One-way analysis of variance was used to compare patients' general situation and measurement data. Least-significant difference was used for multiple comparisons. Chi-square was used to compare count data. One-way analysis of variance was used to compare the hemodynamic values and blood gas values at different time point in the same group, and the paired-samples t test was used to compare mechanics values and TNF-α, IL-8values at different time point in same group. Analysis of variance of repeated measures data was used to compare hemodynamics, respiratory mechanics, blood gas values and the concentrations of TNF-α, IL-8at same time point in defferent groups. P values<0.05were considered to be statistically significant.
Results
1. The correlative factor analysis of pulmonary complications after video-assisted thoracoscopic surgery
1.1Postoperative Pulmonary Complications (PPC)
72of300patients (21.88%) suffered PPC in the first3days after VATS.24pulmonary exudation increasing (7.27%), pneumonia in23(6.97%),18atelectasis (5.45%),4pleural effusion (1.21%),2suction with FOB (0.61%),1reintubation (0.3%). No mortality occurred.
1.2Compared with non-PPC group, Preoperative albumin was lower(P<0.05), length of OLV and ICU stay were longer than in PPC group (P<0.01).
1.3Binary Logistic Regression (Forward LR)
Preoperative serum albumin level, length of OLV, length of ICU stay were independent risk factors, the values of OR were0.922,1.379and1.362(P<0.05).
2. The effect of different duration of one-lung ventilation on TNF-a, IL-8in BALF and SPA in lung tissue
2.1One rabbit restored two-lung ventilation for7times in group05; there had1,2and4rabbit respectively in group03,04and05were excluded during experiment. There had no difference in body weight, Vt and MV in each group (P>0.05)
2.2The comparison of HR and MAP before and after OLV
The repeated measures ANOVA analysis showed that HR and MAP had no significant difference between groups (HR F=1.142, P=0.349; MAP F=2.363, P=0.067). HR and MAP at different time point had significant difference (HR F=69.699, P=0.000; MAP F=23.546, P=0.000); HR of each group had no interaction with time (F=1.996, P=0.111), but MAP of each group had interaction with time (F=6.612, P=0.000), these suggested that HR had the same trend but MAP has not.
Further analysis of MAP, the results showed that the comparison of group01 and02, group04and05had significant difference (P<0.05), MAP of each group had no difference at T1(P=0.867).
2.3The comparison of PETCO2, Peak, lung compliance before and after OLV
The repeated measures ANOVA analysis showed that PETCO2, Peak, lung compliance had no significant difference between groups (PETCO2F=0.119, P=0.975; Ppeak F=0.258, P=0.903; Cdyn F=0.435, P=0.782). The comparison of PETCO2, Peak, lung compliance had significant difference at different time point (PETCO2F=22.575, P=0.000; Ppeak F=56.687, P=0.000; Cdyn F=58.345, P=0.000). PETCO2, Peak, and lung compliance of each group had interaction with time (P<0.037), these suggested that the trend of PETCO2, Peak, Cdyn is different with time.
Further analysis, the results showed that the comparison of PETCO2in group04and05had significant difference (P<0.05), Peak, and lung compliance in group03to05had significant difference (P<0.05); PETCO2, Peak, and lung compliance had no significant difference at T1and T2in each group(P>0.172).
2.4Blood gas analysis in each group
The repeated measures ANOVA analysis showed that pH, PaCO2and bicarbonate had significant difference between groups (pH F=2.770, P=0.038; PaCO2F=3.098, P=0.025; bicarbonate F=2.609, P=0.048), PaO2、BE、SaO2had no significant difference (PaO2F=0.592, P=0.670; BE F=1.450, P=0.233; SaO2F=1.568, P=0.199); pH, PaCO2,PaO2, bicarbonate and SaO2had significant difference (P=0.000). PH, PaO2, bicarbonate and SaO2had no interaction with time (P>0.124), PaCO2of each group had interaction with time (P=0.004), these suggested that the trend of pH, PaO2, bicarbonate and SaO2is same with time, but the trend of PaC02is different with time.
Further analysis, the results showed that the comparison of PaCO2in group04and05had significant difference between T1and T2(P<0.01); PaCO2of each group had no significant difference at T1(P=0.740), PaCO2of each group had no significant difference at T2(P=0.001).
2.5The comparison of blood gas values between24h after OLV and before anesthesia
At T3, ph and PaCO2of group04-05, PaO2and SaO2of group01-05, Bicarbonate and BE of group05had difference with those at TO and in group C (P<0.05)
Bicarbonate of group C had difference with that in TO (P<0.01), the other observations had no statistical difference (P>0.05)
2.6The correlation of blood circulation, blood gas analysis with OLV time at T2
HR was positively correlated with OLV time (HR r=0.396, P<0.01); MAP was negatively correlated with OLV time (MAPr=-0.537, P<0.01). PETCO2, Ppeak and Cdyn had no correlation with OLV time (P>0.05)
pH, PaO2, BE and SaO2were negatively correlated with OLV time (pH r=-0.451, PaO2r=-0.373, BE r=-0.502, SaO2r=-0.421, P<0.01), PaCO2and bicarbonate were positively correlated with OLV time (PaCO2r=0.466, bicarbonate r=0.412,P<0.01).
2.7Pathological changes and lung injury score
2.7.1Specimens
There had no significant changes in left and right lung in group C and01. But in group O3-O5, the colour of left lung was dim and the surface was congestion, the right lung also had surface congestion in some part of the lobes. The group C and group01at24h later had no difference with those at OLV; different degrees of congestion were still in group02-05in24hours later, especially when OLV time was longer than3h.
2.7.2Light microscope examination
During OLV: In group C and group01, alveolar was integrity, alveolar spaces had no exudation and less inflammatory cells. But in group03-05left lung, pulmonary interstitial was obvious thicken, pulmonary interstitial and alveolar space had inflammatory cells and blood cell infiltration, alveolar wall was destructed and alveolar atelectasis, especially in group05. In the right lung of group03-05, pulmonary interstitial was obvious thichening and alveolar space was less exudation than in left lung.
24h after OLV: there had no obvious exudation in group C and O1, and a little atelectasis was seen in group O1. In group O2, there had alveolar collapse, intertitial congestion thichen, and red blood cells in left lung; there also had neutrophil in right lung alveolar. In group O3, alveolar collapsed, interstitial thichening and red blood cells in alveolar spaces. In group O4, alveolar was obvious collapsed and exudation, many red blood cells and neutrophils were seen. In group O5, lung collapsed obviously and a large number of red blood cells and macrophage infiltration were seen.
2.7.3Lung tissue injury score
The repeated measures ANOVA analysis showed that lung injury score had significant difference at T2and T3(P=0.000); lung injury score also had significant difference between left and right lung(T2F=6.748, P=0.012; T3F=7.779, P=0.007). lung injury score of each group had interaction with time at T2(F=5.121, P=0.001), but it had no interaction with time at T3(F=0.262, P=0.932), these suggested that the trend of the lung injury score is different with time at T2, but the trend is same with time at T3.
Further analysis, the results showed that the comparison of lung injury score in group05had significant difference at T2(F=6.748, P=0.012); lung injury score of each group had significant difference between left and right lung (left lung F=69.303, P=0.000; right lung F=19.909, P=0.000)
Left lung injury score of group O5was higher at T2than at T3(P>0.05).
2.8Western blot for SPA expression in lung tissue
2.8.1The repeated measures ANOVA analysis showed that SPA of left lung had significant difference at T2and T3(F=9.540, P=0.001); SPA had significant difference in different time point (F=21.884, P=0.001); SPA of each group had interaction with time (F=14.652, P=0.000), these suggested that the trend of SPA is different with time. Further analysis, the results showed that the comparison of SPA in group O4and O5had significant difference between T2and T3(P<0.001), there had significant difference between groups at different time point (P<0.05)
2.8.2The repeated measures ANOVA analysis showed that SPA of right lung had significant difference at T2and T3(F=10.990, P=0.000); SPA had significant difference in different time point (F=359.691,P=0.000); SPA of each group had interaction with time (F=14.171, P=0.000), these suggested that the trend of right lung SPA is different with time. Further analysis, the results showed that the comparison of SPA in group01to05had significant difference between T2and T3(P<0.05), there also had significant difference between groups at different time point (P<0.01)
2.8.3The repeated measures ANOVA analysis showed that SPA of left and right lung had significant difference at T2(F=10.876, P=0.000); SPA had significant difference between left and right lung (F=36.394, P=0.000); SPA of each group had interaction with left and right lung (F=11.577, P=0.000), these suggested that the trend of each group is different with left and right lung. Further analysis, the results showed that the comparison of SPA in group01to O3had significant difference between left and right lung (P<0.05), there also had significant difference between left and right lung in different groups (P<0.01)
2.8.4The repeated measures ANOVA analysis showed that SPA of left and right lung had significant difference at T3(F=19.860, P=0.000); SPA had significant difference between left and right lung (F=0.083, P=0.778); SPA of left and right lung had no interaction with groups(F=1.946, P=0.1600), these suggested that the trend of left and right lung is same with different groups.
2.9The comparison of TNF-α、IL-8in BALF
2.9.1The repeated measures ANOVA analysis showed that TNF-a of left and right lung had significant difference at T2and T3(T2F=56.146, P=0.002; T3F=14.619, P=0.001); TNF-a had significant difference between groups at T2(F=29.336, P=0.000), but TNF-a had no significant difference between groups at T3(F=1.054, P=0.410). TNF-a of each group had interaction with left and right lung at T2(F=4.792, P=0.005), but TNF-a of each group had no interaction with left and right lung at T3(F=0.333, P=0.888), these suggested that the trend of TNF-a in each group is different with left and right lung at T2, but the trend of TNF-a in each group is same with left and right lung at T3.
Further analysis, the results showed that the comparison of TNF-a in group03to05had significant difference between left and right lung at T2(P<0.05), there also had significant difference between left and right lung in different groups (P=0.000).
TNF-a of left BALF in group03-05was higher at T2than at T3(P<0.05).2.9.2The repeated measures ANOVA analysis showed that IL-8of left and right lung had significant difference at T2and T3(T2F=9.460, P=0.005; T3F=11.784, P=0.002); IL-8had significant difference between groups at T2(F=20.703, P=0.000), but IL-8had no significant difference between groups at T3(F=5.824, P=0.001) IL-8of each group had interaction with left and right lung at T2(F=2.882, P=0.035), but IL-8of each group had no interaction with left and right lung at T3(F=2.452, P=0.063), these suggested that the trend of IL-8in each group is different with left and right lung at T2, but the trend of IL-8in each group is same with left and right lung at T3.
Further analysis, the results showed that the comparison of IL-8in group04had significant difference between left and right lung at T2(P=0.043), there also had significant difference between left and right lung in different groups (P<0.01)
IL-8of left BALF in group04-05was higher at T2than at T3(P<0.01) IL-8of right BALF in group05was higher(P<0.05).2.10The correlation of TNF-a and IL-8values and duration of OLV
At T2, TNF-a and IL-8of left and right lung were positively correlated with duration of OLV (left lung TNF-a r=0.901, right lung TNF-a r=0.748, left lung IL-8r=0.840, right lung IL-8r=0.660, P<0.01). At T3, TNF-a in left BALF and IL-8in left and right BALF were positively correlated with duration of OLV(left lung TNF-a r=0.430, P<0.05; left lung IL-8r=0.697, right lung IL-8r=0.592, P<0.01).
2.11BALF cell counts
The repeated measures ANOVA analysis showed that cell counts of left and right lung had sig
引文
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