Gehlen Jennifer, Klaschik Sven, Neumann Claudia, Keyver-Paik Mignon-Denise, Mustea Alexander, Soehle Martin, Frede Stilla, Velten Markus, Hoeft Andreas, Hilbert Tobias
Department of Anesthesiology and Intensive Care Medicine, University Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany.
Department of Gynecology and Obstetrics, University Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany.
J Transl Med. 2020 Jan 31;18(1):48. doi: 10.1186/s12967-020-02236-9.
Despite goal-directed hemodynamic therapy, vascular function may deteriorate during surgery for advanced abdominal tumor masses. Fluid administration has been shown to be associated with distinct changes in serum levels of functional proteins. We sought to determine how serum total protein and angiopoietin (ANG) levels change during major abdominal tumor surgery. In addition, ex vivo endothelial nitric oxide synthase (eNOS) activation as well as NO bioavailability in vivo were assessed.
30 patients scheduled for laparotomy for late-stage ovarian or uterine cancer were prospectively included. Advanced hemodynamic monitoring as well as protocol-driven goal-directed fluid optimization were performed. Total serum protein, ANG-1, -2, and soluble TIE2 were determined pre-, intra-, and postoperatively. Phosphorylation of eNOS was assessed in microvascular endothelial cells after incubation with patient serum, and microvascular reactivity was determined in vivo by near-infrared spectroscopy and arterial vascular occlusion.
Cardiac output as well as preload gradually decreased during surgery and were associated with a median total fluid intake of 12.8 (9.7-15.4) mL/kg*h and a postoperative fluid balance of 6710 (4113-9271) mL. Total serum protein decreased significantly from baseline (66.5 (56.4-73.3) mg/mL) by almost half intraoperatively (42.7 (36.8-51.5) mg/mL, p < 0.0001) and remained at low level. While ANG-1 showed no significant dilutional change (baseline: 12.7 (11.9-13.9) ng/mL, postop.: 11.6 (10.8 -13.5) ng/mL, p = 0.06), serum levels of ANG-2 were even increased postoperatively (baseline: 2.2 (1.6-2.6) ng/mL vs. postop.: 3.4 (2.3-3.8) ng/mL, p < 0.0001), resulting in a significant shift in ANG-2 to ANG-1 ratio. Ex vivo phosphorylation of eNOS was decreased depending on increased ANG-2 levels and ANG-2/1 ratio (Spearman r = - 0.37, p = 0.007). In vivo, increased ANG-2 levels were associated with impaired capillary recruitment and NO bioavailability (Spearman r = - 0.83, p = 0.01).
Fluid resuscitation-associated changes in serum vascular mediator profile during abdominal tumor surgery were accompanied by impaired eNOS activity ex vivo as well as reduced NO bioavailability in vivo. Our results may explain disturbed microvascular function in major surgery despite goal-directed hemodynamic optimization.
尽管采用了目标导向的血流动力学治疗，但在晚期腹部肿瘤手术过程中，血管功能仍可能恶化。已表明液体输注与功能性蛋白质血清水平的明显变化有关。我们试图确定在腹部大肿瘤手术期间血清总蛋白和血管生成素（ANG）水平如何变化。此外，还评估了体外内皮型一氧化氮合酶（eNOS）的激活以及体内的一氧化氮生物利用度。
前瞻性纳入30例计划行剖腹手术治疗晚期卵巢癌或子宫癌的患者。进行了高级血流动力学监测以及基于方案的目标导向液体优化。在术前、术中和术后测定血清总蛋白、ANG-1、-2和可溶性TIE2。在与患者血清孵育后，评估微血管内皮细胞中eNOS的磷酸化，并通过近红外光谱和动脉血管闭塞在体内测定微血管反应性。
手术期间心输出量和前负荷逐渐下降，与平均总液体摄入量12.8（9.7-15.4）mL/kg·h和术后液体平衡6710（4113-9271）mL相关。血清总蛋白从基线水平（66.5（56.4-73.3）mg/mL）在术中显著下降近一半（42.7（36.8-51.5）mg/mL，p<0.0001），并维持在低水平。虽然ANG-1没有显著的稀释变化（基线：12.7（11.9-13.9）ng/mL，术后：11.6（10.8-13.5）ng/mL，p=0.06），但ANG-2的血清水平在术后甚至升高（基线：2.2（1.6-2.6）ng/mL对术后：3.4（2.3-3.8）ng/mL，p<0.0001），导致ANG-2与ANG-1比值发生显著变化。eNOS的体外磷酸化根据ANG-2水平和ANG-2/1比值的增加而降低（Spearman r=-0.37，p=0.007）。在体内，ANG-2水平升高与毛细血管募集受损和一氧化氮生物利用度降低相关（Spearman r=-0.83，p=0.01）。
腹部肿瘤手术期间液体复苏相关的血清血管介质谱变化伴随着体外eNOS活性受损以及体内一氧化氮生物利用度降低。我们的结果可能解释了尽管进行了目标导向的血流动力学优化，但大手术中微血管功能仍受到干扰的原因。
