Journal Article

Dynamic changes of angiopoietins and endothelial nitric oxide supply during fluid resuscitation for major gyn-oncological surgery: a prospective observation

Keyver-Paik, Mignon-Denise, Neumann, Claudia, Soehle, Martin, Mustea, Alexander, Hoeft, Andreas, Gehlen, Jennifer, Velten, Markus, Hilbert, Tobias, Klaschik, Sven, Frede, Stilla

2020

Overview

Background 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. Methods 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. Results 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). Conclusions 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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Abdomen / Angiopoietin / Angiopoietin-2 / Angiopoietins / Angiopoietins - blood / Bioavailability / Biomedical and Life Sciences / Biomedicine / Blood pressure / Blood proteins / Cancer / Catheters / Cell culture / Critical Care and Anesthesia / Endothelial Cells / Endothelial growth factors / Endothelium / eNOS / Female / Fluid intake / Fluid resuscitation / Fluids / Gynecologic Surgical Procedures / Health aspects / Humans / Infrared spectroscopy / Laparotomy / Measurement / Medicine/Public Health / Microvascular reactivity / Microvasculature / Nitric Oxide / Nitric Oxide Synthase Type III - blood / Nitric-oxide synthase / Nitrogen oxides / Occlusion / Ovarian cancer / Ovarian Neoplasms - surgery / Pain / Patient monitoring equipment / Patient outcomes / Patients / Phosphorylation / Prospective Studies / Proteins / Remifentanil / Resuscitation / Serum levels / Spectroscopy / Sufentanil / Surgery / Surgical oncology / Tumor removal / Tumors / Uterine cancer / Uterine Neoplasms - surgery / Vascular occlusion