Abstract
目的
探索硬膜外阻滞对结直肠癌患者预后的影响。
方法
本研究为一项回顾性队列研究，纳入2011年8月至2012年12月在北京大学第一医院接受择期结直肠癌切除术的患者。根据患者接受的麻醉和术后镇痛方式将患者分为单纯全身麻醉(general anesthesia，GA)组和硬膜外阻滞复合全身麻醉(epidural-general anesthesia, EGA)组。主要观察终点为患者远期生存状态，次要观察终点为住院期间并发症发生率和术后住院时间。采用倾向性评分进行病例匹配。术后生存时间采用Kaplan-Meier生存分析，组间比较采用Log-rank test；采用多因素Cox风险回归模型分析麻醉方式及其他变量对患者远期生存状态的影响。
结果
对264例患者完成了术后随访，其中GA组166例，EGA组98例。患者平均年龄为(63.3±12.1)岁，平均生存时间为47.2(95%CI 45.7~48.7)个月。在倾向性评分前，EGA组患者死亡率为16.9%(28/166)，而GA组死亡率为9.2%(9/98)，组间差异无统计学意义(P=0.091)。经倾向性评分匹配后，GA和EGA组共有87对匹配病例。EGA组死亡率低于GA组死亡率(5.7% vs.16.1%，HR=0.34，95%CI 0.12~0.96，P=0.041)，平均生存时间长于GA组患者(50.3个月vs. 42.9个月，P=0.032)，术后整体并发症发生率低于GA组(8.0% vs.16.4%，P=0.044)。多因素Cox风险模型显示围术期使用硬膜外阻滞是降低患者远期死亡风险的独立因素之一(HR=0.33，95%CI 0.12~0.91，P=0.032)，而年龄(HR=1.04，95%CI 1.00~1.09，P=0.046)和术前淋巴结转移(HR=2.92，95%CI 1.16~7.36，P=0.023)分别是增加患者远期死亡风险的独立危险因素。
结论
与单纯全身麻醉组相比，硬膜外阻滞复合全身麻醉组患者的远期生存时间延长，但仍需要进一步开展高质量研究进行验证。
Keywords: 全身麻醉, 硬膜外阻滞, 结直肠癌, 远期, 生存状态
Abstract
Objective
To investigate the effect of epidural anesthesia on the long-term prognosis of patients after selective colorectal cancer resection surgery.
Methods
This was a retrospective cohort study and approved by local institution review board. Patients who underwent selective colorectal cancer resection surgery from August 2011 to December 2012 in Peking University First Hospital were enrolled. The patients were divided into general anesthesia (GA) group and combined epidural-general anesthesia (EGA) group according to anesthesia type. Primary outcome was patient's long-term survival status. Secondary outcome included the overall incidence of in-hospital complications and length of postoperative in-hospital stay. Propensity score was used to match cases between the two groups based on the probability of receiving EGA. Survival was analyzed by Kaplan-Meier analysis and compared by Log-rank test between the two groups. Multivariate Cox regression analysis was used to investigate the relationship between epidural anesthesia and other variables with long-term survival status.
Results
A total of 264 patients were entered into final analysis, including 166 cases in GA group and 98 cases in EGA group. Mean age of the patients was (63.3±12.1) years and mean survival time was 47.2 (95%CI 45.7-48.7) months. Before the propensity score match, the mortality in EGA group was 16.9% (28/166) and 9.2% (9/98) in GA group. But comparison between the two groups had no statistical significance (P=0.091). After the propensity score match, 87 paired cases were matched and analyzed. The risk of long-term mortality in EGA group was lower than that of GA group by Kaplan-Meier analysis (5.7% vs.16.1%, HR=0.344, 95%CI 0.124-0.955, P=0.041). Mean survival time of EGA group was longer than that of GA group (50.3 months vs. 42.9 months, P=0.032). Multivariate Cox regression ana-lysis showed that EGA, in comparison with GA, was related with lower risk of long-term mortality (HR=0.326, 95%CI 0.117-0.909, P=0.032). Age (HR=1.042, 95%CI 1.001-1.085, P=0.046) and preoperative lymph node metastasis (HR=2.924, 95%CI 1.162-7.356, P=0.023) were also related with increased risk of long-term mortality.
Conclusion
Present study found that perioperative use of epidural anesthesia and analgesia was associated with improvement of the patient's long-term survival. Well-designed studies are needed to verify this hypothesis.
Keywords: General anesthesia, Epidural anesthesia, Colorectal cancer, Long-term, Survival status
结直肠癌在中国人群中的发病率约为26/10万，而且占据因癌死亡率的第五位，对国家医疗卫生和社会经济造成了沉重的负担[1]。手术切除是结直肠癌的主要治疗方式[2]。一项研究对1 145例接受结直肠癌手术的患者进行了长期随访(中位随访时间为33.4个月)，结果显示肿瘤复发率约为24.3%[3]。多项随访研究显示，结直肠癌术后5年生存率约为70%，10年生存率约为40%[4-6]。
加速康复外科措施(enhanced recovery after surgery，ERAS)可以显著改善结直肠癌切除术患者的预后，例如降低围术期并发症发生率和缩短住院时间[7]。硬膜外阻滞(术中硬膜外麻醉和术后硬膜外镇痛)是ERAS的重要组成部分[7-8]。多项随机对照研究显示硬膜外阻滞可以有效降低术后30 d内并发症(如肺炎)发生率和缩短术后住院时间[9-10]。硬膜外阻滞对结直癌患者远期预后的影响也是当前研究的热点。一项荟萃分析显示，与单纯全身麻醉相比较，联合使用硬膜外阻滞和全身麻醉可以显著降低结直肠癌患者术后的肿瘤复发率和死亡率[11]。术后使用硬膜外镇痛可以使直肠癌患者术后5年时的死亡风险降低10%~48%[12-13]。一项meta分析显示硬膜外镇痛虽然不能降低结直肠癌术后肿瘤复发的风险，但是可以使术后全因死亡风险降低约28%[14]，而一项前瞻性队列研究纳入560例接受结直肠癌根治术的患者，比较了术后静脉镇痛和硬膜外镇痛对患者预后的影响，但是未发现两组间生存时间差异有统计学意义[15]。
麻醉和镇痛是结肠癌患者在围术期面临的重要变量，而且是可以进行干预的变量，但是现有研究的结论存在较大的异质性，尚无法明确硬膜外阻滞是否可以影响此类患者远期预后[14-15]。更为重要的是，上述研究多为国际性研究，而结直肠癌在中国人群中的病理类型分布特点和临床特征都存在自身特点，目前尚缺少关于中国人群中硬膜外阻滞对结直肠癌患者远期预后影响的数据[16-17]，因此，有必要探索在中国患者中硬膜外阻滞是否与结直肠癌患者远期预后相关。
1. 资料与方法
1.1. 研究人群
入选标准：(1)2011年8月至2012年12月在北京大学第一医院接受择期结直肠癌切除术的患者；(2)年龄及性别不限；(3)未同时合并其他器官肿瘤。排除标准：(1)术后病理为非恶性肿瘤；(2)复发病例；(3)转移瘤；(4)资料缺失导致无法随访。
1.2. 研究设计
本研究为一项回顾性队列研究，研究方案获北京大学第一医院临床研究伦理委员会批准(批准号：2014[074])。本研究采用电话随访，经伦理委员会同意免除患者签署书面知情同意，但征得所有患者或家属的口头知情同意，并由随访人员进行记录。
1.3. 麻醉与术后镇痛
根据患者接受的麻醉和术后镇痛方式将患者分为单纯全身麻醉(general anesthesia, GA)组和硬膜外阻滞复合全身麻醉(combined epidural-general anesthesia, EGA)组。
对于GA组，术中采用异丙酚或吸入麻醉剂(异氟醚或七氟醚)维持麻醉深度，使用阿片类药物维持镇痛，间断给予非去极化肌松药(罗库溴铵或阿曲库铵)维持肌松。患者术后使用自控静脉镇痛，镇痛配方为吗啡0.5 g/L或舒芬太尼1.25 mg/L，总剂量为100 mL，持续输注剂量为1 mL/h，单次追加剂量为2 mL，锁定间隔时间为6~8 min。
对于EGA组，患者入室后首先接受硬膜外穿刺置管，穿刺间隙为T12/L1或L1/L2。穿刺成功后，采用和GA组相同的全身麻醉维持方案，但是术中镇痛采用经硬膜外导管以2~8 mL/h的速度持续输注1%~2%(体积分数)利多卡因或0.5%(体积分数)罗哌卡因。患者在术后接受患者自控硬膜外镇痛，镇痛配方为0.12%(体积分数)罗哌卡因加芬太尼2 mg/L或0.12%罗哌卡因加舒芬太尼0.5 mg/L，总剂量为250 mL，背景输注剂量为4 mL/h，单次追加剂量为2 mL，锁定间隔时间为20 min。
1.4. 术后随访
我们根据电子病例系统收集患者的信息，随后根据患者联系方式进行电话随访，随访截止时间为2016年2月25日。
1.5. 资料收集
术前资料包括患者性别、年龄、体重指数(body mass index, BMI)、术前合并疾病及美国麻醉医师学会(American Society of Anesthesiology, ASA)分级等基线信息。术中资料包括麻醉方式(全身麻醉和硬膜外阻滞)及术后镇痛方案类型(患者自控静脉镇痛、患者自控硬膜外镇痛)、手术时长、麻醉时长、术中是否输异体血等。术后资料包括肿瘤直径、病理类型、分化程度分级、术后住院时间、并发症、是否放化疗及生存时间等。
1.6. 主要和次要观察终点
本研究的主要观察终点为患者远期生存状态，次要观察终点为住院期间并发症发生率和术后住院时间。
1.7. 质量控制
我们采取了如下措施以保证随访数据的客观和准确：(1)为避免随访偏倚，由一名研究人员负责收集围术期资料及患者联系方式，另外一名研究人员负责电话随访采集患者生存资料，其掌握的信息仅限于姓名、性别、年龄、手术日期、手术方式及联系方式等用于随访的变量；(2)死亡时间以医学死亡证明上的日期为准。
1.8. 统计学分析
根据术中麻醉及术后镇痛方式将患者分为GA组和EGA组。术后生存时间采用Kaplan-Meier生存分析，组间比较采用Log-rank test。本研究采用多因素Cox风险回归模型分析硬膜外阻滞及其他变量对患者远期生存状态的影响，首先使用单因素回归分析筛选相关因素，再将P < 0.10的相关变量采用多因素Cox回归模型进行分析。
采用倾向性评分将两组患者按照1 ∶1进行匹配。首先，使用年龄、BMI、术前合并疾病(冠心病、高血压、脑梗死、糖尿病、肾功能衰竭、慢性阻塞性肺病)、ASA分级、肿瘤直径、手术部位、术前有无淋巴结转移作为患者是否接受硬膜外阻滞的倾向性评分匹配因素，并计算相应赋值。然后，采用最邻近匹配方法和容差小于0.2的规则进行病例匹配，对匹配病例同样采用Kaplan-Meier分析和多因素Cox风险回归模型分析硬膜外阻滞对远期生存率的影响。
连续变量采用均数±标准差或中位数(四分位间距)表示；正态分布变量的组间比较采用t检验，非正态分布变量的组间比较采用秩和检验。分类变量采用例数(百分数)表示，组间比较采用卡方检验或Fisher精确检验。
统计分析采用SPSS 24.0软件，P < 0.05被认为差异有统计学意义。
2. 结果
2.1. 入组情况
2011年8月至2012年12月期间，共计420例患者在北京大学第一医院接受了择期结肠癌和直肠癌切除术。根据研究的入选标准及排除标准，本研究对264例患者完成了术后随访，其中GA组患者166例，EGA组患者98例。患者平均年龄为(63.3±12.1)岁，中位随访时间41.0 (39.0, 43.0)个月，见表 1。
表 1.
入选患者的基本资料
Baseline characteristic of all patients
| Variables | All patients (n=264) |
Before matching | After matching | |||||
| GA group(n=166) | EGA group(n=98) | P | GA group(n=87) | EGA group(n=87) | P | |||
| GA, general anesthesia with postoperative intravenous analgesia; EGA, combined epidural-general anesthesia with postoperative epidural analgesia; BMI, body mass index; CAD, coronary artery disease; CRF, chronic renal failure; COPD, chronic obstructive pulmonary disease; ASA, American Society of Anesthesiology. | ||||||||
| Age/year, x±s | 63.3±12.1 | 64.2±12.7 | 61.6±10.9 | 0.082 | 61.2±12.8 | 60.5±10.5 | 0.698 | |
| BMI, x±s | 23.8±3.3 | 23.8±3.6 | 23.7±2.8 | 0.749 | 24.2±3.7 | 23.7±2.8 | 0.360 | |
| Preoperative comorbidity, n (%) | ||||||||
| CAD | 37 (14.0) | 29 (17.5) | 8 (8.2) | 0.035 | 4 (4.6) | 5 (5.7) | 1.000 | |
| Hypertension | 117 (44.3) | 82 (49.4) | 35 (35.7) | 0.031 | 38 (43.7) | 29 (33.3) | 0.161 | |
| Stroke | 26 (9.8) | 21 (12.7) | 5 (5.1) | 0.047 | 6 (6.9) | 2 (2.3) | 0.148 | |
| Diabetics | 45 (17.0) | 33 (19.9%) | 12 (12.2) | 0.111 | 11 (12.6) | 8 (9.2) | 0.466 | |
| CRF | 6 (2.3) | 6 (3.6) | 0 (0) | 0.057 | 2 (2.3) | 0 (0) | 0.155 | |
| COPD | 6 (2.3) | 2 (1.2) | 4 (4.1) | 0.130 | 2 (2.3) | 3 (3.4) | 1.000 | |
| ASA grade, n (%) | 0.008 | 0.794 | ||||||
| 1 | 21 (8.0) | 10 (6.0) | 11 (11.2) | 9 (10.3) | 11 (12.6) | |||
| 2 | 188 (71.2) | 111 (66.9) | 77 (78.6) | 76 (87.4) | 73 (83.9) | |||
| 3 | 55 (20.9) | 44 (26.5) | 10 (10.2) | 2 (2.3) | 3 (3.4) | |||
| Surgery site, n (%) | 0.759 | 0.762 | ||||||
| Colon | 118 (44.7) | 73 (44.0) | 45 (45.9) | 45 (51.7) | 43 (49.4) | |||
| Rectal | 146 (55.3) | 93 (56.0) | 53 (54.1) | 42 (48.3) | 44 (50.6) | |||
| Anesthesia time/h, x±s | 5.5±1.7 | 5.4±1.8 | 5.5±1.7 | 0.877 | 5.7±1.6 | 5.5±1.6 | 0.595 | |
| Allogenic blood transfusion, n (%) | 14 (5.3) | 10 (6.0) | 4 (4.1) | 0.496 | 1 (1.1) | 3 (3.4) | 0.312 | |
| Tumor size, n (%) | (n=259) | (n=162) | (n=97) | 0.601 | 0.931 | |||
| < 2 cm | 13 (4.9) | 7 (4.2) | 6 (6.1) | 5 (5.7) | 5 (5.7) | |||
| 2- < 3 cm | 49 (18.6) | 29 (17.5) | 20 (20.4) | 18 (20.7) | 18 (20.7) | |||
| 3- < 5 cm | 117 (44.3) | 71 (42.8) | 46 (46.9) | 38 (43.7) | 42 (48.3)) | |||
| 5- < 7 cm | 50 (18.9) | 36 (21.7) | 14 (14.3) | 15 (17.2) | 11 (12.6) | |||
| ≥7 cm | 30 (11.4) | 19 (11.4) | 11 (11.2) | 11 (12.6) | 11 (12.6) | |||
| Pathological grade, n (%) | 0.158 | 0.346 | ||||||
| Undifferentiation | 1 (0.4) | 0 (0) | 1 (1.0) | 0 (0) | 1 (1.1) | |||
| Low differentiation | 29 (11.0) | 16 (9.6) | 13 (13.3) | 7 (8.0) | 12 (13.8) | |||
| Medium differentiation | 204 (77.3) | 125 (75.3) | 79 (80.6) | 67 (77.0) | 70 (80.5) | |||
| Well differentiation | 5 (1.9) | 1 (0.6) | 4 (4.1) | 1 (1.1) | 4 (4.6) | |||
| Not available | 25 (9.5) | 24 (14.5) | 1 (1.0) | 12 (13.8) | 0 (0) | |||
| Lymph node metastasis, n (%) | 123 (46.6) | 85 (51.2) | 38 (38.8) | 0.060 | 31 (35.6) | 34 (39.1) | 0.638 | |
| Postoperative radio-/chemotherapy, n (%) | 132 (50.4)(n=263) | 81 (48.8)(n=166) | 51 (53.1)(n=97) | 0.411 | 42 (48.3) | 49 (56.3) | 0.288 | |
2.2. 主要研究终点
EGA组患者死亡率为16.9%(28/166)，GA组死亡率为9.2%(9/98)，组间差异无统计学意义(P=0.091)，见表 2。所有患者的平均生存时间为47.2(95%CI 45.7~48.7)个月，GA组平均生存时间为42.1(95%CI 40.4~43.9)个月，而EGA组平均生存时间为48.9(95%CI 46.9~50.9)个月，两组间的差异无统计学意义(P=0.085)，见图 1A。
表 2.
主要研究终点和次要研究终点
Primary and secondary outcomes
| Variables | Before matching | After matching | ||||||
| GA group(n=166) | EGA group(n =98) | P | GA group(n =87) | EGA group(n =87) | HR, OR or difference (95%CI) | P | ||
| GA, general anesthesia; EGA, combined epidural-general anesthesia; CI, confidence interval; HR, hazard ratio; OR, odds ratio; LOS=length of in-hospital stay; IQR, interquartile range. | ||||||||
| Primary outcome | ||||||||
| Overall survival, death, n (%) | 28 (16.9) | 9 (9.2) | 0.091 | 14 (16.1) | 5 (5.7) | HR=0.34 (0.12, 0.96) | 0.041 | |
| Secondary outcome, n (%) | ||||||||
| Total incidence of complications | 32 (19.3) | 10 (10.2) | 0.052 | 16 (18.4) | 7 (8.0) | OR=0.39 (0.15, 1.00) | 0.044 | |
| Individualized complications | ||||||||
| Ischemic cardiac events | 2 (1.2) | 0 (0) | 0.531 | 1 (1.1) | 0 (0) | OR=0.99 (0.97, 1.01) | 1.000 | |
| Hypertension | 24 (14.5) | 5 (5.1) | 0.019 | 12 (13.8) | 4 (4.6) | OR=0.30 (0.09, 0.97) | 0.036 | |
| Heart failure | 3 (1.8) | 0 (0) | 0.297 | 2 (2.3) | 0 (0) | OR=0.98 (0.95, 1.10) | 0.497 | |
| Arrythmia | 4 (2.4) | 3 (3.1) | 0.713 | 0 (0) | 1 (1.1) | OR=1.01 (0.99, 1.04) | 1.000 | |
| Atelectasis | 1 (0.6) | 0 (0) | 1.000 | 1 (1.1) | 0 (0) | OR=0.99 (0.97, 1.01) | 1.000 | |
| Pneumonia | 2 (1.2) | 1 (1.0) | 1.000 | 1 (1.1) | 1 (1.1) | OR=1.00 (0.06, 16.25) | 0.751 | |
| Hydrothorax | 5 (3.0) | 0 (0) | 0.161 | 3 (3.4) | 0 (0) | OR=0.97 (0.93, 1.01) | 0.246 | |
| Deep venous thrombi | 0 (0) | 2 (2.0) | 0.137 | 0 (0) | 2 (2.3) | OR=1.02 (0.99, 1.06) | 0.497 | |
| Postoperative LOS/day, median (IQR) | 11 (9, 14) | 11 (9, 14) | 0.810 | 11 (9, 13) | 11 (9, 14) | Difference=0 (-1.0, 1.0) | 0.783 | |
图 1.
Kaplan-Meier分析
Kaplan-Meier analysis
A, Kaplan-Meier analysis before propensity score match. Mean survival time had no statistical difference between GA and EGA groups (42.1 months vs. 48.9 months, P=0.085); B, Kaplan-Meier analysis after propensity score match. Mean survival time in EGA group was longer than that of GA group (50.3 months vs. 42.9 months, P=0.032). GA, general anesthesia; EGA, combined epidural-general anesthesia.
2.3. 次要研究终点
GA组和EGA组术后并发症整体发生率分别为19.3% (32/166)和10.2% (10/98)，两组间的差异无统计学意义(P=0.052)，见表 2。EGA组术后高血压发生率低于GA组(5.1% vs.14.5%，P=0.019)，其余并发症和术后住院时间的组间比较差异无统计学意义(分别为P=0.052和P=0.810)，见表 2。
2.4. 倾向性评分分析
经倾向性评分匹配，GA和EGA组共有87对匹配病例(174例)。GA组死亡率约为16.1%(14/87)，EGA组死亡率约为5.7%(5/87)；EGA组死亡风险低于GA组(HR=0.34，95%CI 0.12~0.96，P=0.041)。EGA组患者平均生存时间长于GA组患者(50.3 vs. 42.9个月，P=0.032)，见图 1B。EGA组术后并发症整体发生率低于GA组(8.0% vs. 16.4%，P=0.044)，见表 2。EGA组术后高血压发生率也低于GA组(P=0.036)。
2.5. 多因素Cox风险模型分析
倾向性评分匹配前与匹配后的多因素Cox风险模型均显示，围术期使用硬膜外麻醉和镇痛是降低患者远期死亡风险的独立因素之一(匹配后，HR=0.33，95%CI 0.12~0.91，P=0.032)，而年龄和术前淋巴结转移分别是增加患者远期死亡的独立危险因素，见表 3。
表 3.
多因素Cox风险回归分析
Multivariate Cox regression analysis
| Variables | Before matching | After matching | |||||||||
| Univariate analysis | Multivariate analysis | Univariate analysis | Multivariate analysis | ||||||||
| HR (95%CI) | P | HR (95%CI) | P | HR (95%CI) | P | HR (95%CI) | P | ||||
| ASA, American Society of Anesthesiology; HR, hazard ratio; CI, confidence interval. a, indicates per year increase; b, indicates every one indices increase; c, indicates patients with diagnosed diseases; d, indicates per grade increase of ASA physical status, higher grade means increased risk of perioperative death; e, indicates patients who received intraoperative epidural anesthesia and postoperative epidural analgesia; f, indicates per grade increase, pathological grade was divided into undifferentiation, low differentiation, medium differentiation and well differentiation, higher grade means better differentiation; g, indicates per grade increase, tumor size was divided into 5 grades: < 2 cm, 2- < 3 cm, 3- < 5 cm, 5- < 7 cm and ≥7 cm, higher grade means larger tumor size. | |||||||||||
| Agea | 1.04 (1.01, 1.07) | 0.005 | 1.04 (1.02, 1.07) | 0.001 | 1.04 (1.00, 1.08) | 0.070 | 1.04 (1.00, 1.09) | 0.046 | |||
| Body mass indexb | 0.88 (0.79, 0.98) | 0.015 | |||||||||
| Coronary artery diseasec | 2.25 (1.06, 4.77) | 0.035 | |||||||||
| Diabeticsc | 1.86 (0.90, 3.84) | 0.095 | |||||||||
| Chronic renal failurec | 4.32 (1.32, 14.10) | 0.015 | 4.27 (1.49, 12.27) | 0.007 | |||||||
| ASA physical graded | 2.28 (1.29, 4.41) | 0.004 | |||||||||
| EGA groupe | 0.52 (0.25, 1.11) | 0.091 | 0.53 (0.28, 0.98) | 0.044 | 0.34 (0.12, 0.96) | 0.041 | 0.33 (0.12, 0.91) | 0.032 | |||
| Pathological gradef | 0.49 (0.24, 1.03) | 0.061 | 0.42 (0.24, 0.72) | 0.002 | |||||||
| Tumor sizeg | 1.02 (1.00, 1.04) | 0.076 | |||||||||
| Lymph node metastasisc | 2.23 (1.11, 4.49) | 0.024 | 2.81 (1.48, 5.34) | 0.02 | 2.44 (0.98, 6.06) | 0.056 | 2.92 (1.16, 7.36) | 0.023 | |||
3. 讨论
本研究在接受择期结直肠癌根治术的患者中发现，与单纯全身麻醉组相比较，硬膜外阻滞复合全身麻醉组患者的术后远期生存时间延长。
多项临床研究显示硬膜外阻滞可以改善不同类型肿瘤(例如卵巢癌、前列腺癌和食管癌等)患者远期生存时间[18-20]，但是硬膜外阻滞是否可以改善结直肠癌患者远期预后的研究结果存在较大差异。例如，一项回顾性研究显示硬膜外阻滞并不能降低结直肠癌患者的术后肿瘤复发风险[21]。针对一项随机对照研究的二次分析显示，硬膜外阻滞仅可以改善结直肠癌患者术后1.46年的生存率，但是对再长时期的生存率无影响[22]。
硬膜外阻滞可以改善结直肠癌患者预后的可能原因包括：(1)硬膜外麻醉可以抑制围术期炎症反应和减轻对免疫系统的抑制。一项随机对照研究显示，在维持适宜麻醉深度的情况下，硬膜外阻滞复合全身麻醉可以有效抑制炎症反应和应激反应[23]，在接受结肠癌手术的患者也观察到了同样的现象[24]。与单纯全身麻醉相比较，硬膜外阻滞复合全身麻醉可以有效减轻结肠癌术中的免疫抑制(表现为Th1细胞升高，Th2和调节T细胞降低)和保护肠道功能[25]。(2)硬膜外阻滞可以降低术后早期并发症发生率，例如肺炎和心肌梗死等[9-10]。多项临床研究显示减少术后早期并发症可以显著改善远期生存率[26]。(3)基础研究显示利多卡因和罗哌卡因可以抑制直肠癌细胞的增殖。
硬膜外阻滞也可能增加患者预后恶化的风险：(1)硬膜外阻滞可以增加围术期低血压的发生率，从而增加器官缺血性损伤的发生率(如心肌缺血和急性肾损伤等)[27-28]；(2)硬膜外阻滞可能导致硬膜外血肿或神经损伤等并发症[29]。
麻醉方式对肿瘤患者远期预后影响的结果尚存在较大的异质性，可能的影响因素包括：首先，硬膜外阻滞对不同病理类型肿瘤的影响可能是不同的[30]；其次，现有的研究结果多为回顾性研究，存在样本量较小和混杂因素造成的偏倚等缺陷；第三，在以往的研究中，尽管患者被区分为单纯全身麻醉组，但是并未区分全凭静脉麻醉和吸入麻醉，而静脉麻醉药物(如异丙酚)和吸入麻醉药物(如七氟醚)对肿瘤细胞的增殖、侵袭能力影响不同[31-32]。
本研究存在不足之处。第一，为回顾性研究，尽管采用了倾向性评分进行匹配，但是仍然存在样本量较小和数据缺失造成的分析偏倚。第二，未统计肿瘤远期复发率，这是由于患者死亡时间均有医疗记录，但是肿瘤复发时间缺少客观记录。第三，目前仍缺少关于麻醉方式对患者预后的高质量研究证据，亟需开展前瞻性随机对照研究进一步验证研究假设。
本研究在接受择期结直肠癌根治术的患者中发现，与单纯全身麻醉组相比较，硬膜外阻滞复合全身麻醉组患者的术后远期生存时间延长，但是仍需要进一步开展高质量研究进行验证。
References
- 1.杜 灵彬, 李 辉章, 王 悠清, et al. 2013年中国结直肠癌发病与死亡分析. 中华肿瘤杂志. 2017;39(9):701–706. doi: 10.3760/cma.j.issn.0253-3766.2017.09.012. [DOI] [Google Scholar]
- 2.Glynne-Jones R, Wyrwicz L, Tiret E, et al. Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl 4):22–40. doi: 10.1093/annonc/mdx224. [DOI] [PubMed] [Google Scholar]
- 3.Chang W, Wei Y, Ren L, et al. Short-term and long-term outcomes of robotic rectal surgery-from the real word data of 1145 consecutive cases in China. Surg Endosc. 2020;34(9):4079–4088. doi: 10.1007/s00464-019-07170-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.van Gijn W, Marijnen CA, Nagtegaal ID, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial. Lancet Oncol. 2011;12(6):575–582. doi: 10.1016/S1470-2045(11)70097-3. [DOI] [PubMed] [Google Scholar]
- 5.Tarantino I, Muller SA, Warschkow R, et al. Baseline mortality-adjusted survival in resected rectal cancer patients. J Gastrointest Surg. 2014;18(10):1837–1844. doi: 10.1007/s11605-014-2618-x. [DOI] [PubMed] [Google Scholar]
- 6.Bos A, Kortbeek D, van Erning FN, et al. Postoperative mortality in elderly patients with colorectal cancer: The impact of age, time-trends and competing risks of dying. Eur J Surg Oncol. 2019;45(9):1575–1583. doi: 10.1016/j.ejso.2019.04.020. [DOI] [PubMed] [Google Scholar]
- 7.ERAS Compliance Group The impact of enhanced recovery protocol compliance on elective colorectal cancer resection: Results from an international registry. Ann Surg. 2015;261(6):1153–1159. doi: 10.1097/SLA.0000000000001029. [DOI] [PubMed] [Google Scholar]
- 8.Helander EM, Webb MP, Bias M, et al. Use of regional anesthesia techniques: Analysis of institutional enhanced recovery after surgery protocols for colorectal surgery. J Laparoendosc Adv Surg Tech A. 2017;27(9):898–902. doi: 10.1089/lap.2017.0339. [DOI] [PubMed] [Google Scholar]
- 9.Popping DM, Elia N, Marret E, et al. Protective effects of epidural analgesia on pulmonary complications after abdominal and thoracic surgery: A meta-analysis. Arch Surg. 2008;143(10):990–999. doi: 10.1001/archsurg.143.10.990. [DOI] [PubMed] [Google Scholar]
- 10.Rigg JR, Jamrozik K, Myles PS, et al. Epidural anaesthesia and analgesia and outcome of major surgery: A randomised trial. Lancet. 2002;359(9314):1276–1282. doi: 10.1016/S0140-6736(02)08266-1. [DOI] [PubMed] [Google Scholar]
- 11.Chen WK, Miao CH. The effect of anesthetic technique on survi-val in human cancers: A meta-analysis of retrospective and prospective studies. PLoS One. 2013;8(2):e56540. doi: 10.1371/journal.pone.0056540. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Gupta A, Bjornsson A, Fredriksson M, et al. Reduction in mortality after epidural anaesthesia and analgesia in patients under-going rectal but not colonic cancer surgery: A retrospective analysis of data from 655 patients in central Sweden. Br J Anaesth. 2011;107(2):164–170. doi: 10.1093/bja/aer100. [DOI] [PubMed] [Google Scholar]
- 13.Cummings KC,3rd, Xu F, Cummings LC, et al. A comparison of epidural analgesia and traditional pain management effects on survival and cancer recurrence after colectomy: A population-based study. Anesthesiology. 2012;116(4):797–806. doi: 10.1097/ALN.0b013e31824674f6. [DOI] [PubMed] [Google Scholar]
- 14.Sun X, Yang C, Li K, et al. The impact of anesthetic techniques on survival for patients with colorectal cancer: Evidence based on six studies. Hepatogastroenterology. 2015;62(138):299–302. [PubMed] [Google Scholar]
- 15.Turi S, Gemma M, Braga M, et al. Epidural analgesia vs systemic opioids in patients undergoing laparoscopic colorectal surgery. Int J Colorectal Dis. 2019;34(5):915–921. doi: 10.1007/s00384-019-03284-4. [DOI] [PubMed] [Google Scholar]
- 16.Florea A, Sangare L, Lowe K. A multinational assessment of gastric, esophageal, and colorectal cancer burden: A report of disease incidence, prevalence, and fatality. J Gastrointest Cancer. 2020;51(3):965–971. doi: 10.1007/s12029-019-00328-4. [DOI] [PubMed] [Google Scholar]
- 17.Kokelaar RF, Jones H, Beynon J, et al. Meta-analysis of the prognostic value of CpG island methylator phenotype in rectal can-cer. Int J Colorectal Dis. 2018;33(8):995–1000. doi: 10.1007/s00384-018-3108-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Tseng JH, Cowan RA, Afonso AM, et al. Perioperative epidural use and survival outcomes in patients undergoing primary debul-king surgery for advanced ovarian cancer. Gynecol Oncol. 2018;151(2):287–293. doi: 10.1016/j.ygyno.2018.08.024. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Biki B, Mascha E, Moriarty DC, et al. Anesthetic technique for radical prostatectomy surgery affects cancer recurrence: A retrospective analysis. Anesthesiology. 2008;109(2):180–187. doi: 10.1097/ALN.0b013e31817f5b73. [DOI] [PubMed] [Google Scholar]
- 20.Perez-Gonzalez O, Cuellar-Guzman LF, Navarrete-Pacheco M, et al. Impact of regional anesthesia on gastroesophageal cancer surgery outcomes: A systematic review of the literature. Anesth Analg. 2018;127(3):753–758. doi: 10.1213/ANE.0000000000003602. [DOI] [PubMed] [Google Scholar]
- 21.Gottschalk A, Ford JG, Regelin CC, et al. Association between epidural analgesia and cancer recurrence after colorectal cancer surgery. Anesthesiology. 2010;113(1):27–34. doi: 10.1097/ALN.0b013e3181de6d0d. [DOI] [PubMed] [Google Scholar]
- 22.Christopherson R, James KE, Tableman M, et al. Long-term survival after colon cancer surgery: A variation associated with choice of anesthesia. Anesth Analg. 2008;107(1):325–332. doi: 10.1213/ane.0b013e3181770f55. [DOI] [PubMed] [Google Scholar]
- 23.Hou BJ, Du Y, Gu SX, et al. General anesthesia combined with epidural anesthesia maintaining appropriate anesthesia depth may protect excessive production of inflammatory cytokines and stress hormones in colon cancer patients during and after surgery. Medicine (Baltimore) 2019;98(30):e16610. doi: 10.1097/MD.0000000000016610. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Xu YJ, Chen WK, Zhu Y, et al. Effect of thoracic epidural anaesthesia on serum vascular endothelial growth factor C and cytokines in patients undergoing anaesthesia and surgery for colon cancer. Br J Anaesth. 2014;113(Suppl 1):49–55. doi: 10.1093/bja/aeu148. [DOI] [PubMed] [Google Scholar]
- 25.Chen WK, Ren L, Wei Y, et al. General anesthesia combined with epidural anesthesia ameliorates the effect of fast-track surgery by mitigating immunosuppression and facilitating intestinal functional recovery in colon cancer patients. Int J Colorectal Dis. 2015;30(4):475–481. doi: 10.1007/s00384-014-2098-1. [DOI] [PubMed] [Google Scholar]
- 26.O'Brien WJ, Gupta K, Itani KMF. Association of postoperative infection with risk of long-term infection and mortality. JAMA Surg. 2020;5(1):61–68. doi: 10.1001/jamasurg.2019.4539. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Sudfeld S, Brechnitz S, Wagner Y, et al. Post-induction hypotension and early intraoperative hypotension associated with general anaesthesia. Br J Anaesth. 2017;119(1):57–64. doi: 10.1093/bja/aex127. [DOI] [PubMed] [Google Scholar]
- 28.Leslie K, Myles P, Devereaux P, et al. Neuraxial block, death and serious cardiovascular morbidity in the POISE trial. Br J Anaesth. 2013;111(3):382–390. doi: 10.1093/bja/aet120. [DOI] [PubMed] [Google Scholar]
- 29.Liu H, Brown M, Sun L, et al. Complications and liability related to regional and neuraxial anesthesia. Best Pract Res Clin Anaesthesiol. 2019;33(4):487–497. doi: 10.1016/j.bpa.2019.07.007. [DOI] [PubMed] [Google Scholar]
- 30.Kim GH, Lee JJ, Lee SH, et al. Exposure of isoflurane-treated cells to hyperoxia decreases cell viability and activates the mitochondrial apoptotic pathway. Brain Res. 2016;1636:13–20. doi: 10.1016/j.brainres.2016.01.052. [DOI] [PubMed] [Google Scholar]
- 31.Bundscherer AC, Ullrich V, Malsy M, et al. Effects of volatile anesthetics on proliferation and viability of sw480 colon cancer cells in vitro. Anticancer Res. 2019;39(11):6049–6055. doi: 10.21873/anticanres.13811. [DOI] [PubMed] [Google Scholar]
- 32.Tat T, Jurj A, Selicean C, et al. Antiproliferative effects of propofol and lidocaine on the colon adenocarcinoma microenvironment. J Buon. 2019;24(1):106–115. [PubMed] [Google Scholar]