Table 3.

Three potential perioperative targets for reducing the stress response to major surgery.

Target	Stressor, crosstalk, and responder modulation
Tissue injury	Reduce the local tissue damage signals released from the first incision. Dampen pain signals to CNS via modulation of nerve afferents, pain receptors and mediators. Inhibit tissue activation of immune and inflammatory cells, including the production of IL-1, IL-6 and TnF-alpha cytokine and their post-translational pathways. Protect the endothelium and localize the coagulation effects in response to injury.
CNS control	Reduce the brain’s responsiveness to tissue damage signals. Protect the blood brain barrier from becoming leaky and proinflammatory. Reduce activation of the HPA axis and sympathoadrenal system (e.g., cortisol, catecholamines, and vasopressin). Reduce medullary NTS sympathetic discharge in favor of parasympathetic outflow including activation of the anti-inflammatory reflex. Place the body in a mild hibernating-like, hypotensive state. Improve baroreceptor sensitivity and heart rate variability. Optimize arterial resistance and tissue blood flow, including blunting catecholamine-induced changes to splanchnic blood reservoir and circulation to maintain venous return and cardiac output (CO). Reduce gut ischemia and prevent or reduce the gut “cytokine storm”.
Systemic manifestations	Promote cardiovascular-endothelial coupling and induce a high flow, hypotensive, vasodilatory state with maintained tissue O2 perfusion. Reduce systemic inflammation and coagulopathy. Protect the gut and liver from “overshooting” their immune functions. Maintain systemic cellular immunity Th1/Th2 cytokine balance and prevent immunosuppression. Reduce whole body energy demand.