Despite the widespread safe application of cardiopulmonary bypass (CPB) for cardiac surgery, it is inherently a pathologic state. CPB produces a generalized inflammatory reaction involving at least the complement, coagulation, kallikrein, and fibrinolytic cascades. Marked alterations in organ perfusion and metabolism occur during CPB which are further affected by the perfusion flow rate. During hypothermic CPB at 20 degrees C, there is a progressive decrease in perfusion of the microcirculation at flow rates less than 1.2 liters/min/m2. Experimental studies suggest that brain oxygen consumption and resistance remain relatively constant as flow rates are reduced during hypothermia, and the brain becomes the passive recipient of proportionally more blood flow. Recent ultrafiltration studies have demonstrated a specific increase in microvascular permeability to proteins after 2 h of normothermic CPB. This provides experimental support to the well-known clinical observation of increased interstitial fluid following CPB. The development of uniformly safe CPB depends upon prevention of the abnormalities of the microcirculation and upon neutralization of the deleterious effects of inflammatory mediators.