Pharmacologic strategies for combating the inflammatory response.
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.
Landis
Clive
C
Edmund Cohen Laboratory for Vascular Research, Chronic Disease Research Centre, UWI Bridgetown, Barbados. clive.landis@uwichill.edu.bb
D007611:Aprotinin; D001777:Blood Coagulation; D002315:Cardiopulmonary Bypass / Q000009:adverse effects*; D003167:Complement Activation; D005342:Fibrinolysis; D006801:Humans; D007610:Kallikreins; D012307:Risk Factors; D015842:Serine Proteinase Inhibitors; D018746:Systemic Inflammatory Response Syndrome / Q000188:drug therapy* / Q000209:etiology
D015842:Serine Proteinase Inhibitors; D007611:Aprotinin; D007610:Kallikreins