Pharmacologic strategies for combating the inflammatory response

Abstract

The "systemic inflammatory response" is a multifaceted defensive reaction of the body to surgical trauma and cardiopulmonary bypass (CPB), characterized by systemic activation of fibrinolysis, coagulation, complement, immune cells, platelets, and oxidative pathways, all overlaid onto localized trauma to the grafted vessel or vascular beds susceptible to ischemia/reperfusion. There is going to be no single magic bullet to diminish such a broad host defense response to surgery. The best chance lies with combinatorial--or promiscuous--pharmacotherapy. Combinations of anti-fibrinolytics, anti-coagulants targeted higher up the coagulation cascade, anti-thrombin receptor therapy, improved coated circuits, anti-complement, anti-leukocyte, and antioxidant therapies may blunt sufficient arms of the systemic inflammatory response to be clinically effective. The alternative is a promiscuous drug like aprotinin, which targets plasmin in the fibrinolytic pathway, kallikrein in the coagulation pathway, thrombin receptors on platelets and endothelium, and leukocytes at the extravasation step. Because of the overriding safety concerns relating to the use of anti-fibrinolytics in cardiothoracic surgery, any future combinatorial or promiscuous pharmacotherapy involving anti-fibrinolytics will require solid underpinning with a known mechanism of action and clinical safety data powered to detect well-defined adverse events (stroke, myocardial injury, renal failure requiring dialysis), preferably in isolation and not as a composite endpoint.

Figure 1.

Potential molecular targets in the host response to CPB. Two multi-targeting interventions are shown: aprotinin, a broad acting serine protease inhibitor, and “improved” coated circuits (“improved” because present coating strategies do not efficiently abrogate contact activation). An exciting area for future research is to examine novel pharmacologic agents targeted against the endothelial-leukocyte adhesion cascade; some 30+ such agents, mostly at preclinical-phase II stage, have been developed for use in a host of unrelated inflammatory conditions but may exhibit efficacy in the setting of CPB, possibly in synergy with other mono-targeting drugs such as the complement C5 inhibitor pexelizumab, leukofiltration, or antioxidants.