Understanding Restrictive Versus Liberal Fluid Therapy for Major Abdominal Surgery Trial Results: Did Liberal Fluids Associate With Increased Endothelial Injury Markers?

Abstract

Liberal fluid strategies in critically ill patients are associated with harm, thought to be due to endothelial and glycocalyx injury. As the restrictive versus liberal fluid therapy for major abdominal surgery trial not only failed to report survival benefit with restrictive fluids but was associated with a higher rate of acute kidney injury, we hypothesized that factors other than endothelial and glycocalyx injury were likely to account for these findings. Consequently, we measured injury biomarkers in a cohort of the restrictive versus liberal fluid therapy for major abdominal surgery trial.

Design: The restrictive versus liberal fluid therapy for major abdominal surgery trial was an international, randomized, assessor-blinded trial comparing restrictive with liberal IV fluid regimens that represented traditional care in patients undergoing major abdominal surgery.

Setting and patients: Cohort of restrictive versus liberal fluid therapy for major abdominal surgery bloods was collected at a single major site (161 patients) prior to, day 1 and day 3 after surgery.

Intervention: Bloods were blindly and randomly batch analyzed for plasma markers of endothelial/glycocalyx injury-angiopoietin-1, angiopoietin-2, soluble tyrosine-protein kinase-2 receptor, soluble intracellular adhesion molecule-1, syndecan, and tumor necrosis factor-α. Data were examined as restrictive versus liberal enrollment groups and high versus low (± 5,000 mL) fluid groups. Differences were examined by linear mixed modeling.

Measurement and main results: There were no significant differences in any biomarkers between the restrictive (n = 75) and liberal (n = 86) groups. When examined as low (n = 81) and high (n = 79) fluid groups, plasma angiopoietin-2 (p = 0.009) and soluble intracellular adhesion molecule-1 (p = 0.01) were elevated in the high fluid group. There were no differences in other biomarkers.

Conclusions: Although these results are consistent with previous findings of vascular injury following liberal fluid therapy, they suggest alternative mechanisms underlie the clinical outcomes from restrictive versus liberal fluid therapy for major abdominal surgery study.

Clinicaltrialsgov identifier: NCT01424150.

Keywords: abdominal surgery; biomarkers; endothelial injury; glycocalyx injury; inflammation; restrictive fluid strategy.

Figure 1.

Plasma biomarkers, normalized for change in plasma volume, by treatment groups during the first 3 d from surgery. Ang = angiopoietin, sICAM = soluble intracellular adhesion molecule.

Figure 2.

Plasma biomarkers, normalized for change in plasma volume, by total IV fluid administered, dichotomized into High greater than 5,000 mL and Low less than 5,000 mL groups, during the first 3 d from surgery. Ang = angiopoietin, sICAM = soluble intracellular adhesion molecule.

Figure 3.

Plasma biomarkers, normalized for change in plasma volume, by total IV fluid administered, analyzed as quartiles, during the first 3 d from surgery. ^*Significantly different from less than 3,500 mL group; p ≤ 0.011. Ang = angiopoietin, sICAM = soluble intracellular adhesion molecule.