Controversy and significance of vascular mimicry in malignant tumors
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摘要: 血管拟态(VM)指实体肿瘤内部由肿瘤细胞独立形成的, 具有供氧及血液循环功能的管状结构。自1999年由美国俄亥俄州州立大学Hendrix教授提出后，其功能、结构及所提示的临床意义均备受争议。尽管如此，学术界众多研究还是倾向于这种管状结构符合血管的形态及功能特征。由于VM是模拟血管内皮细胞形成血管的过程，众多参与内皮细胞依赖性血管生成的信号在VM形成中的作用也相应被关注及研究。本文对近年来VM研究过程中的相关争议问题进行综述。Abstract: Vascular mimicry (VM) refers to a tubular structure with oxygen supply and blood circulation functions, which is independently formed by tumor cells in solid tumors. Since it was proposed by Professor Hendrix of Ohio State University in 1999, its function, structure and clinical significance have been controversial. Nevertheless, many academic studies still tend to believe that this tubular structure conforms to the morphological and functional characteristics of blood vessels. Because VM simulates the process of vascular endothelial cells forming blood vessels, the role of many signals involved in endothelial cell-dependent angiogenesis in VM formation has also been concerned and studied. This paper summarized the relevant controversial issues in the recent VM researches.
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术后患者的血容量不足、毛细血管渗漏易导致循环血量降低[1]。液体复苏不充分、不能及时纠正术后早期发生的组织灌注不足及缺血、缺氧持续时间延长最终会导致休克、器官衰竭甚至死亡。过度的液体复苏会加重组织水肿，增加心脏负担，稀释血液，最后造成凝血功能障碍等并发症[2-3]。被动抬腿试验是根据实验前后每搏输出量(SV)变异程度来评估容量反应性的一种方法，操作简单，参考依据可靠[4]。测量SV、心输出量(CO)等血流动力学指标有无创和有创2种方法，有创方法中的漂浮导管是监测血流动力学的金标准，但因其易导致气胸、血栓等严重并发症[5]，在临床工作中未广泛普及。无创血流动力学监测具有无创、动态、实时、准确等优点，更加符合临床治疗需要。本研究比较被动抬腿试验联合无创血流动力学监测补液治疗和术后常规补液治疗的效果，以评估2种方法的准确性和有效性。
1. 资料与方法
1.1 一般资料
选取2019年11月—2020年11月锦州医科大学附属第三医院重症医学科收治的胸腹部手术术后患者80例为研究对象，男44例，女36例，年龄54~85岁，平均(69.7±8.4)岁，开胸手术40例，开腹手术40例。将以上患者随机分为观察组和对照组，每组40例。观察组男22例，女18例，年龄55~85岁，开胸手术20例，开腹手术20例; 对照组男22例，女18例，年龄54~84岁，开胸手术20例，开腹手术20例。2组患者年龄、性别及手术方式比较，差异无统计学意义(P>0.05)。
1.2 方法
对照组接受常规液体管理方法，并根据患者心率(HR)、中心静脉压(CVP)、血压(BP)、24 h尿量等一般指标评估患者的液体需求。观察组采用无创血流监测系统合并被动抬腿试验指导液体管理，具体方法: 利用NICaS无创血流动力学监测系统对患者进行监测。患者取平卧位，采用75%酒精擦拭患者左手腕和右脚踝，待擦拭部位充分干燥后，左手腕连接2条红色导线，右脚踝连接2条蓝色导线，被动抬腿试验遵循5项黄金法则。测量并记录半卧位和半卧位被动抬腿45 °时CO、SV、心脏指数(CI)等指标。半卧位被动抬腿45 °后SV较平卧位增加的量称为每搏变异度(SVV)。SVV≥15%为有容量反应性; SVV < 15%为无容量反应性。对有容量反应性的患者静脉补液，无容量反应的患者停止补液。
1.3 观察指标
疗效指标: 记录患者治疗前、治疗3 d后HR、CVP、血肌酐(Scr)、平均动脉压(MAP)水平，测量并记录治疗前及治疗后6、24、48、72 h Lac水平。
1.4 统计学分析
采用统计学软件SPSS 26.0分析数据，计量资料采用(x±s)表示，组间比较行t检验; 计数资料采用χ2检验。P < 0.05表示差异有统计学意义。
2. 结果
观察组治疗后6、24 h乳酸水平显著低于对照组，差异有统计学意义(P < 0.05); 2组治疗前、治疗后48 h、72 h Lac水平比较，差异无统计学意义(P>0.05)。见表 1。治疗72 h后，观察组HR、CVP和Scr水平低于对照组，差异有统计学意义(P < 0.05); 观察组MAP大于对照组，差异有统计学意义(P < 0.05)。见表 2。
表 1 2组治疗前及治疗后6、24、48、72 h乳酸水平比较mmol/L 时点 观察组(n=40) 对照组(n=40) 治疗前 2.85±0.60 2.91±0.60 6 h 1.86±0.50* 2.15±0.50 24 h 1.66±0.50* 1.96±0.50 48 h 1.44±0.50 1.45±0.50 72 h 1.34±0.50 1.35±0.50 与对照组比较, *P < 0.05。 表 2 2组治疗前、治疗72 h后HR、MAP、CVP、Scr水平比较指标 时点 观察组(n=40) 对照组(n=40) HR/(次/min) 治疗前 120.30±16.50 129.90±16.50 治疗72 h后 85.50±12.60* 101.80±12.50* CVP/cmH2O 治疗前 9.20±3.80 9.90±3.50 治疗72 h后 7.80±2.30* 9.10±2.10* Scr/(μmol/L) 治疗前 176.61±18.22 176.15±18.37 治疗72 h后 136.12±16.10* 166.94±16.03* MAP/mmHg 治疗前 54.40±6.40 55.10±6.50 治疗72 h后 79.10±7.50* 72.90±7.70* HR: 心率; CVP: 中心静脉压; Scr: 血肌酐; MAP: 平均动脉压。与对照组比较, *P < 0.05。 3. 讨论
术后患者病理状态下炎症反应导致血管内皮细胞受损，血管完整性破坏，体液分布异常，机体代偿能力下降，最终导致有效循环血量不足，机体缺血、缺氧情况加重，液体复苏是重要治疗手段[6-7]。传统液体需求量评估指标包括HR、血压、CVP、尿量等，因这类指标缺乏敏感性和特异性，临床医师很难对患者血流动力学做出及时正确判断，不能精确指导术后患者液体复苏[8]。
根据机体容量状态进行液体复苏，可以增加回心血量和心脏前负荷，从而使心输出量增加，改善缺血、缺氧状态及组织灌注情况[9]。被动抬腿试验模拟补液试验，通过被动抬高下肢45 °, 使下肢静脉血回流[10], 回心血量增加150~200 mL[11]。根据患者SV、CO等血流动力学参数变化来评估液体容量反应性是一种简单、安全、可重复的评估方法，实验结果干扰因素少，具有较高的参考价值[12-13]。
与金标准漂浮导管比较，无创血流动力学监测能够随时且同步了解血流动力学变化，减少出血、气胸、血栓等并发症的发生[14-15]。SQUARA P等[16]证实，无创血流动力学监测数值准确性高。本研究采用无创血流动力学监测合并被动抬腿试验指导对照组患者补液，结果显示观察组治疗3 d后MAP显著高于对照组, HR、CVP、Scr显著低于对照组; 实验组治疗后6、24 h Lac水平显著低于对照组，表明NICAS系统合并被动抬腿试验能够真实有效地反应患者组织灌注情况，并依据监测参数变化及时调整补液量及补液速度，及时有效地改善组织低灌注情况，降低肾前性急性肾损伤发生率，缩短高乳酸血症持续时间，比常规液体治疗更具优势，但主动脉瓣或二尖瓣狭窄、关闭不全，重度心包积液等严重心脏病患者应限制使用，主要原因为回心血量增加可使病情恶化。近期下肢创伤、骨盆、股骨手术者禁忌被动抬腿，严重心率失常、胸腔积液、体型肥胖等患者SV的准确性[17]及实验结果也会存在偏差，需要更大样本量进行进一步研究。
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