【作者】 王丽珺；

【导师】 薛张纲； 仓静；

【作者基本信息】 复旦大学 ， 麻醉学， 2009， 博士

【摘要】 第一部分胸段硬膜外阻滞复合七氟醚麻醉对兔缺氧性急性肺损伤的影响及可能机制研究目的:探讨胸段硬膜外阻滞复合七氟醚麻醉对缺氧引起的急性肺损伤的影响及可能机制。方法:28只健康新西兰大白兔随机分为4组,每组7只:对照组（C组）、缺氧组（H组）、七氟醚组（S组）和硬膜外复合七氟醚组（ES组）。ES组先行硬膜外置管后,首剂注射入1%利多卡因3mg/kg,此后每1h追加该剂量。各组动物麻醉后气管插管,机械通气,吸入21%的氧气。30 min后,H组、S组和ES组吸入14%的氮氧混合气体,S组和ES组同时吸入七氟醚1MAC,直至PaO₂/FiO₂＜300,急性肺损伤（ALI）模型建立。C组始终吸入21%的氧气。3h后各组动物恢复自主呼吸,吸入21%的氧气。H组、S组和ES组于自主呼吸（T₀）,ALI模型建立后15 min、30 min、1h、2h、3h和恢复自主呼吸后(T_1-6)分别测PaO₂,C组于机械通气相应时点测PaO₂。记录各组动物T₀和T₆时的心率（HR）、平均动脉压（MBP）、呼吸频率（RR）和潮气量（VT）。于T₀和T₅时抽右颈动脉血5mL,离心后测血清IL-6、IL-8和IL-10浓度。实验结束后立即处死动物,开胸取肺。进行支气管肺泡灌洗,取肺泡灌洗液离心后上清夜-70℃保存,以测总磷脂（TPL）、饱和卵磷脂（DSPC）及总蛋白（TP）含量。肺组织称湿干重,并分别送光镜和电镜检测。取小块肺组织,液氮保存以测IL-6、IL-8和IL-10mRNA表达结果:1.4组动物一般情况无显著差异。2.自主呼吸时,4组间心率（HR）、平均动脉压（MBP）、分钟通气量（MV）的差异均无统计学意义（P＞0.05）;H组、S组和ES组均于缺氧15min后建立ALI模型,急性缺氧导致HR和MBP降低。恢复自主呼吸后,H组、S组和ES组的MBP显著低于C组（P＜0.05）。ES组在T₁时的PaO₂和T₆时的MV分别为（33.3±6.7）mmHg和（928.2±27.3）mL/min,S组分别为（25±3.3）mmHg和（339.5±27.3） mL/min,ES组显著高于S组（P＜0.05）。3.H组T₅时的IL-6和IL-8分别为（94.1±15.1）和（59.5±14.9）pg/mL,S组此时的IL-6和IL-8分别为（90.2±17.3）和（53.9±8.7）pg/mL,均较T₀时显著升高（P＜0.05）。两组T₅时的IL-10分别为（24.9±7.6）和（25.2±4.9）pg/mL,较T₀时显著降低（P＜0.05）。ES组T₅时的IL-6为（56.2±19.9）pg/mL,显著低于H组和S组（P＜0.05）,较C组无显著差异（P＞0.05）,H组和S组该时点的IL-6浓度显著高于C组（P＜0.05）。4.H组、S组和ES组的SatPC/TPL及SatPC/TP显著降低（P＜0.05）。S组的SatPC/TP低于H组及ES组、SatPC/TPL低于ES组（P＜0.05）。3组的肺干/湿比均低于C组,但仅H组的差别具有统计学意义（P＜0.05）。5.C组、H组、S组和ES组的动物肺组织标本中IL-6 mRNA的表达量分别为1.000（0.671,1.671）、6.063（1.848,7.911）、3.605（1.589,5.203）和1.258（0.11,1.368）。H组显著高于其余3组（P＜0.05）,S组高于C组和ES组（P＜0.05）;IL-8 mRNA的表达量分别为1.000（0.370,1.370）、4.925（0.764,5.689）、5.401（2.328,7.730）和1.217（0.361,1.577）。H组和S组较其余2组显著升高（P＜0.05）,而前者之间没有统计学差异（P＞0.05）;IL-10 mRNA的表达量分别为1.000（0.263,1.263）、0.253（0.075,0.328）、0.287（0.092,0.379）和1.080（0.452,1.532）。ES组显著高于H组和S组（P＜0.05）,和C组相比,差别无统计学意义（P＞0.05）。H组和S组显著低于C组（P＜0.05）,两组之间无统计学差异（P＞0.05）。6.组织形态学观察提示:H组和S组肺泡壁血管明显扩张、充血,肺间质水肿伴大量中性粒细胞浸润;肺泡间隔增宽、部分肺泡萎陷,肺泡Ⅱ型上皮细胞肿胀,微绒毛破坏程度严重;板层体减少,并成大量空泡化。ES组肺泡结构尚可,未见肺泡萎陷,中性粒细胞浸润较前两组少,板层小体减少不明显。结论:急性缺氧可引起兔肺损伤,硬膜外阻滞复合七氟醚麻醉通过改善呼吸功能、抑制全身及局部炎症反应等多个环节,从而起到减轻肺组织损伤的作用。第二部分胸段硬膜外阻滞复合七氟醚麻醉对开胸手术患者的卫生经济学分析目的:针对胸科手术病人胸段硬膜外阻滞复合七氟醚麻醉技术进行费用与效果分析,为优化麻醉方式及合理配置医疗资源提供一定的依据。方法:40名年龄18-65岁,ASAⅠ～Ⅱ级的择期经胸食道癌根治术患者,随机分为2组,硬膜外复合全麻组（试验组）和单纯全麻组（对照组）,每组20人。入手术室后,试验组病人先于T_7-8椎间隙行硬膜外穿刺,头端置管4cm,硬膜外腔注入2%利多卡因3mL,以针刺法确定硬膜外平面。监测心率（HR）、持续动脉血压（ABP）、中心静脉压（CVP）、脉搏血氧饱和度（SpO₂）和脑电双频指数（BIS）。两组病人纯氧（氧流量5L/min）吸入下,静脉注射芬太尼2～3μg/kg,异丙酚1.5～2mg/kg,琥珀胆碱1～2mg/kg,肌松完善后插入左侧双腔气管导管,以维库溴铵0.08～0.1mg/kg维持肌松。连接呼吸机,IPPV模式,设定潮气量为8mL/kg,呼吸频率10次/分,吸呼比1:2,维持PeCO₂30～40mmHg。调整气体流量为1L/min,空氧混合（50%:50%）,七氟醚维持,监测MAC值在0.7～1.1MAC。试验组每隔5min硬膜外腔内注入0.25%布比卡因+1:20万肾上腺素混合液5mL,共15mL,此后,每小时追加硬膜外剂量0.25%布比+1:20万肾上腺素5mL。两组均维持BIS值在40～60之间,HR和ABP波动在术前基础值的20%以内,按需追加芬太尼和维库溴铵。根据CVP进行补液。单肺通气后改为纯氧1L/min,维持SpO₂ 90%以上。术后符合拔管条件时拔除气管导管。试验组患者采用0.125%布比卡因+20μg/mL吗啡硬膜外自控镇痛,对照组患者采用0.6～1mg/h吗啡静脉自控镇痛。术后患者送PACU,Aldrete评分大于或等于9分时出PACU回病房。采用调查问卷情式,记录患者一般情况、术中各时间指标、麻醉药物用量、失血量、尿量、术中补液量和输血量、PACU中情况、术后4h、术后5天平静及活动时的VAS评分、疼痛需要干预的情况、镇痛泵使用情况、镇痛总体评价、术后下肢运动阻滞情况、活动能力、麻醉相关并发症、术后住院天数、各费用指标及患者满意程度。结果:1.两组病人一般资料无显著性差异（P＞0.05）。2.两组病人的诱导插管时间、手术时间、术中的晶体补液量、胶体补液量、失血量和尿量均无明显差异（P＞0.05）,硬膜外复合全麻组的拔管时间以及术中芬太尼、异丙酚、维库溴铵和七氟醚的用量较单纯全麻组显著降低（P＜0.05）。3.硬膜外复合全麻组患者PACU停留时间和术后首次能够进行VAS评分时间分别为（36.7±18.9）min和（14.9±11.8）min,明显低于对照组（P＜0.05）。试验组中1名患者发生恶心呕吐,3名出现嗜睡,首次VAS评分为（1.4±1.1）,仅有1名患者需要疼痛干预,其VAS评分、需要疼痛干预以及发生嗜睡的人数均明显低于对照组（P＜0.05）,两组发生PONV的人数无显著差异（P＞0.05）。4.两组患者术后均未出现下肢运动阻滞。两组病人术后五天内活动时VAS评分均高于平静时。硬膜外复合全麻组患者平静时术后4h、术后1d、2d的VAS评分分别为1.2±0.5、1.7±1.1和1.8±1.2,显著低于单纯全麻组（P＜0.05）;活动时术后4h、术后1d、2d和3d的VAS评分分别为3.8±1.0、3.9±1.3、3.5±1.2和3.2±1.2,也较单纯全麻组显著降低（P＜0.05）。出现嗜睡或需要疼痛干预的人数,拔除导尿管时间和术后住院天数,试验组明显少于对照组（P＜0.05）,而出现皮肤瘙痒的患者却显著多于后者（P＜0.01）。发生头晕、恶心呕吐的人数,拔除胃管时间、进食时间、排气时间及下地时间两组没有明显差异（p＞0.05）。对照组患者术后镇痛泵使用时间和数量均明显高于试验组（P＜0.05）,但后者的镇痛效果评价却显著优于前者（P＜0.05）。两组的麻醉满意度评分分别为7.2±1.3和8.7±1.2,硬膜外复合全麻组患者的满意度明显高于对照组（p＜0.01）。5.对照组和试验组术中的麻醉费用分别占两组直接费用的11.3%和12.8%,两组的费用构成比类似。单纯全麻组术中的麻醉费用明显低于试验组（P＜0.01）,但术后镇痛泵使用费用、追加的镇痛药物费用、镇痛泵中止吐药物的费用、住院费、治疗费以及间接费用均高于试验组（P＜0.05）。两组的成本无显著性差异（p＞0.05）。结论:从社会的角度分析,胸段硬膜外阻滞复合七氟醚麻醉是对胸科手术患者的一种经济、有效的麻醉方式。更多还原

【Abstract】 PartⅠEffects of combined sevoflurane- thoracic epidural anesthesia on hypoxia-induced lung injuryObjective The acute hypoxic is one of the potential complications during thocacic surgery anesthesia which may lead to acute lung injury.Our objective was to assess the potential modifying effects of thoracic epidural anaesthesia on hypoxia-induced lung injury in the animals.Methods Twenty eight rabbits anaesthetised with pentobarbital(30 mg·kg^-1 iv) were randomly assigned to four groups:control group（Group C）,hypoxia group（Group G）, sevoflurane group（Group S） and combined sevoflurane-epidural anesthesia group （Group ES）（n=7）.in Group ES,the catheter was inserted at T_5-6 interspace and advanced 1 cm into the epidural space cephalad.3 mg·kg^-1 lidocaine 1%was injected after the epidural block was confirmed by epidurography,followed by injecting the same dose every one hour.After tracheotomized and intubated,the animals were mechanically ventilated（FiO₂=21%,VT=10～12 mL/kg,RR=25bpm,I:E=1:2）. 30 minutes later,animals in Group H,S and ES inhaled gas mixed with N₂ and O₂（FIO₂=14%）.The FiO₂ in Group C remained 21%.1 MAC of sevoflurane was also used in Group S and ES.The acute lung injury（ALI）models were considered to have been induced successfully after PaO₂/FiO₂＜300.3 hours after reaching the ALI standard,all animals recovered spontaneous breathing（FiO₂=21%）.Arterial bloodgases were measured during spontaneous breathing（T₀）（baseline）,at 15 min,30 rain,1 h,2 h,3 h after ALI induced and recovering spontaneous breathing(T_1-6) in Group H,S and ES and at the corresponding mechanically ventilation time in Group C.HR,MBP,RR and VT were recorded in all groups at T₀ and T₆.Arterial blood 5 mL were get in all groups at T₀ and T₅ in order to measure serum IL-6,IL-8 and IL-10. Bronchoalveolar lavage Fluid（BALF） were harvested for total phosholipid（TPL）, saturated phosphatidylcholine（SatPC） and total protein（TP） measurement.The Dry/Wet weight ratio（D/W）,light microscope and transmission electron microscope were also examined.The expression of IL-6,IL-8 and IL-10 mRNA in lung were assessed by realtime-PCR.Results1.There was no difference in general data among the four groups.2.There was no significant difference among the four groups during spontaneous breathing.Hypoxia leaded to the decrease of HR,MBP and PaO₂.ALI models were induced at 15 minites after hypoxia.MBP in Group H,S and ES were less than those in Group C at T₆（P＜0.05）.PaO₂ at T₁ and MV at T₆ in Group ES were （33.3±6.7） mmHg and（928.2±27.3） mL/min,which were higher than those in Group S（P＜0.05）.3.Serum IL-6 and IL-8 at T₅ in Group H were（94.1±15.1） and（59.5±14.9） pg/mL while they in Group S were（90.2±17.3） and（53.9±8.7） pg/mL.They were all significantly higher than those at T₀（P＜0.05）.IL-10 in the two groups were（24.9±7.6） and（25.2±4.9） pg/mL at T₅,which were lower than those at T₀（P＜0.05）. IL-6 at T₅ in Group ES were（56.2±19.9） pg/mL and they were lower than those in Group H and S（P＜0.05）.Besides,IL-6 in Group H and S at T₅ were significantly higher than control group（P＜0.05）. 4.Compared with control group,SatPC/TPL and SatPC/TP were decreased in Group H,S and ES（P＜0.05）.SatPC/TP in Group S was significantly less than those in Group H and ES（P＜0.05） while SatPC/TPL in Group S was less than in Group ES（P＜0.05）.Only in Group H,the Dry/Wet weight ratio was significantly less than in control group（P＜0.05）.5.Among the four groups,the expression of IL-6 mRNA in Group H was higher than that in other groups（P＜0.05） and it in Group S was higher than that in control group and Group ES（P＜0.05）.The expression of IL-8 mRNA in Group H and S were significantly higher than the other two groups（P＜0.05） while the expression of IL-10 mRNA were lower（P＜0.05）.6.Pathologic examination showed that the control group had no swelling or disruption of the alveolar epithelium while the other groups had some denuded basement membranes of it.The alveolar typeⅡcells in all groups contained several lamellar bodies（surfactant）.In Group H and S,the alveolar was congestion,edema and PMN adhering to epithelium,the alveolar typeⅡcells were swelling and the lamellar bodies were less than other groups no matter in numbers or the alveolar surfactant within them.There was less PMN in Group ES and the alveolar structure was better than Group H and S.Conclusions Acute hypoxia can cause lung injury in rabbit model.Combined sevoflurane-thoracic epidural anesthesia can lighten this injury by improving the respiratory function and inhibitting both systemic and local inflammation.PartⅡThe medical economics analysis of combined thoracic epidural-sevoflurane anesthsia for patients undergoing thoracic surgeryBackground Thoracotomy may induce severe postoperative pain and other serious complications.Combined epidural-general anesthesia and general anesthesia were both commonly used in thoracic surgery nowadays.However,in a pharmacoeconomic approach of anesthesia,the economic evaluation of the two methods were uncertain. Our objective was to analyze the cost and effectiveness for the comparison of combined thoracic epidural-sevoflurane anesthsia and general anesthesia for patients undergoing thoracic surgery.Methods In this prospective observational study,40 patients aged 18-65,ASAⅠ-Ⅱ, scheduled for esophagectomy were randomly divided into 2 groups:combined epidural-sevoflurane group（Group E） and general group（Group G）,with 20 patients in each group.Patients in Group G were induced with fentanyl 2-3μg/kg,propofol 1.5-2 mg/kg and succinylcholine 1-2mg/kg.oxygen（5 L/min） was administered via face mask throughout induction.Vecuroniun 0.08-0.1 mg/kg were used for muscle relaxation.Anesthesia was maintained with inhalation of sevoflurane（MAC 0.7-1.1） and intermittent fentanyl and vecuronium（ⅳ）.Patients in Group E underwent epidural blockade before induction.Epidural block was performed at T_7-8 with an epidural catheter inserted cranially for 4cm.A test dose of 2%lidocaine 3mL was given via the catheter.When epidurai blockade was confirmed,the patients were induced with the same agents as those in Group G.Before the operation,0.25% bupivacaine containing epinephrine 10μg/ml 15mL was infused via epidural catheter. The anesthesia was maintained with the same concentration of bupivacaine 5mL/h combined with inhalation of sevoflurane and intermittent fentanyl and vecuronium （ⅳ）.All the patients were mechanically ventilated（IPPV,FiO₂=50%,VT=8mL/kg, RR=10bpm,I:E=1:2）.HR,ABP,SpO₂,CVP and BIS were measured.BIS was maintained bewteen 40 and 60.The changes of HR and ABP were kept within 20% compared to the baseline.SpO₂ was retained above 90%during one-lung ventilation （FiO₂=100%,1L/min）.Fluid replacement was given according to CVP.Patients in Group E were received postoperative continuous epidural analgesia with 0.125% bupivacaine plus 20μg/ml morphine plus 6 mg tropistron.Patients in Group G received postoperative continuous intravenous analgesia with 0.6-1 mg/h morphine plus 6 mg tropistron.All patients were sent to PACU after surgery and were allowed to wards when their Aldrete scores were above 9.The information recorded included the patients’ epidemiologic characteristics,time indicatrix during operation,the use of anesthetics,the volume of blood loss,urinary,fluid replacement and blood transfusion, the information in PACU,the pain distribution,side effects,VAS scores and additional drugs to treat pain at postoperative several time points（4 h,1 d,2 d,3 d, 4 d and 5 d）.Locomotor activity,motion blockage of lower limbs,the hospital day （HOD） after operation,all costs and patients’ satisfaction scores were also recorded.Results1.There was no difference in general data between the two groups（P＞0.05）. 2.There were no differences in induction time,operation time,intraoperative fluid replacement,the volume of blood loss and urinary between the two groups（P＞0.05）,but the extubation time and the intraoperative use of fentanly, propofol,vecuronuim and sevoflurane were significantly lower in Group E（P＜0.05）.3.Length of stay in PACU and the first time to make VAS scores in Group E were （36.7±18.9） min and（14.9±11.8） min,respectively.They were both lower than those in control group（P＜0.05）.In Group E,3 patients occurred drowsiness.The first VAS score was 1.4±1.1.Only 1 patient needed additional pain intervention. They were all less than Group G（P＜0.05）.There was no difference in PONV incidence between the two groups（P＞0.05）.4.No motion blockage was observed in the patients.A better VAS score was showed in Group E than in Group G when the patients were quiet at 4 h,1 d and 2 d after surgery（P＜0.05）.Until 3 d after the operation,the VAS scores were still lower in Group E when the patients were at activity（P＜0.05）.There were less patients who had drowsiness or needed pain invention in Group E（P＜0.05）.The HOD after surgeries and the time of urethral catheterization were also shorter in Group E（P＜0.05）.But itch of skin occurred more frequently in Group E than in Group G（P＜0.01）.There were no differences in dizziness and PONV incidence between two groups（P＞0.05）.The average bed rest time,evacuation time and eating time were also the same（P＞0.05）.Group E was siginificantly better than Group G in postoperative analgesia（P＞0.05）.Overall satisfaction scores were significantly higher in Group E（8.7±1.2） than in Group G（7.2±1.3）（P＜0.01）.5.Direct costs of anesthesia costs accounted for 11.3%in control group while the ratio in Group E was 12.8%.The cost constituent ratio of the two groups was similar（P＞0.05）.Although the intraoperative anesthesia cost in control group was much lower than in Group E（P＜0.01）,the costs of postoperative analgesia, antiemetics,hospitalization,treatment and indirect costs were higher in Group G（P＜0.05）.There was no difference in costs between two groups（P＞0.05）.Conclusions From the social point of view,combined thoracic epidural-sevoflurane anesthsia is an economical and effective method for patients undergoing thoracic surgery.更多还原