Figure 4.

A broad schematic of the Central-CardioVascular-Endothelium (CCVE) “uncoupling” hypothesis that may be responsible for the high mortality and morbidity after major surgery. Loss of whole body homeostatic control during surgical trauma may be leveled at: (1) the CNS, (2) the heart, (3) the vascular tree, and (4) the endothelium. There is an urgent need to develop a pharmacological therapy that supports a high flow (maintained cardiac output), hypotensive, vasodilatory state with endothelial protection and tissue oxygenation (287). If central and local control of cardiac output and ventricular-arterial coupling are improved, endothelial and micro-vascular function will be improved and tissue O₂ delivery will be maintained. An uncoupling is reflected in increased stress hormones, sympathetic discharge, loss of baroreceptor sensitivity, and loss of heart rate variability (229, 230). Impaired sympathetic control and a loss of heart rate variability are two of the strongest predictors of death in critically ill patients (188), and promote a pro-inflammatory state with higher IL-1, IL-6, TnF-alpha, and CRP levels, and coagulopathy. A new whole body therapy is required to bolster the patient’s defense against the trauma of surgery and prevent “secondary hit” complications from ischemic and inflammatory cascades, coagulopathy, multiple organ failure, and immunosuppression.