The systemic inflammatory response syndrome (SIRS) is a well-recognized phenomenon attending cardiopulmonary bypass (CPB) surgery. SIRS leads to costly complications and several strategies intended to ameliorate the symptoms have been studied, including leukocyte reduction using filtration. Although the body of work suggests that leukoreduction attenuates SIRS, discrepancies remain within the literature. The recent literature is reviewed, highlighting the areas where concordance is lacking. Investigations into many promising device-related technologies are often deterred by the high costs of clinical trials. Adding to costs is the fact that clinical end points generally require large sample sizes. An understanding, however, of the pathogenesis of reperfusion injury can guide the investigator to choose physiologic response measures that correlate well with clinical outcome, but feature low inherent variability, allowing for clinical trials with smaller sample sizes. With this goal in mind, a model for the pathogenesis of reperfusion injury is described. Using a model of reperfusion injury as underpinnings for the design of prospective pilot studies, we show that salvaged blood reinfused following CPB elicits time-dependent effects on pulmonary function as predicted by the model. Data are illustrative of principles that could expand the scope of clinical investigations designed to validate the use of physiologic response measures as correlates of clinical outcome. Such investigations would target surrogate markers of clinical outcome, measured at clinically relevant times. Once validated, these surrogate markers would, thereafter, become economical screening tools for clinical studies of device-related or pharmacological anti- inflammatory interventions.