Endothelial Homeostasis and Post-Cardiac Surgery Inflammatory Organ Injury

This thesis evaluates three most important etiological factors for organ injury namely, intravenous fluid, cardiopulmonary bypass (CPB) and blood transfusion, and considers their effects on endothelial dysfunction. This thesis evaluates 1. The safety of current fluid therapy, 2. The effects of novel versus established volume expanders on endothelial function and Acute Kidney Injury (AKI), 3. The effect of Sildenafil on renal glycocalyx in post-CPB AKI and 4. The effect of standard and modified red cell transfusions on lung and kidney injury. Using a systematic assessment of randomised controlled trials comparing colloids and crystalloids, we found that Hydroxyethylstarches are associated with increased risk of mortality and AKI. On the contrary, there was no evidence that Gelatins, Dextrans and Crystalloids were associated with increased harm. We evaluated the supremacy of novel AQIX RS-1® for intravenous resuscitation in a swine model of general anesthesia but failed to show its superiority as an endothelial and organ protective agent compared to Hartmann’s solution. We characterized that CPB mediated AKI is associated with modifications of Glycosaminoglycans and core protein components of Glycocalyx, but also that CPB induces detrimental changes in endothelial surface markers; vWF, Thrombomodulin, VE-Cadherin. These structural modifications caused direct reduction in Nitric Oxide bioavailability, renal artery vasomotor function and invoked AKI in swine. Post CPB-AKI was prevented by restoration of depleted NO bioavailability using Sildenafil Citrate without restoration of glomerular endothelial membrane (GEM) constituents. We explored the pathogenesis of Transfusion Related Acute Lung Injury (TRALI) and implicate alterations in red cell metabolomics; endothelial dysfunction, inflammation, microparticles and labile Iron and use a translational porcine model of TRALI to test red cell Rejuvenation coupled with red cell washing as a promising therapy. The work in this thesis has supported or generated ideas of novel pragmatic randomised clinical trials that seek to make direct difference in outcomes after cardiac surgery.