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Supplemental material is available online. Cardiopulmonary bypass (CPB) can be used during cardiac surgery to oxygenate and subsequently recirculate blood that has been diverted from the heart and lungs. The practice of CPB has changed-and continues to change-dramatically since its advent in the 1950s. Although structured reviews of the evidence supporting the practice of cardiac surgery have been in the literature for more than a decade and continue to be refined in the wake of new and emerging evidence, E1,E2 additional targeted reviews, focusing on issues such as minimizing the effect of the inflammatory response or minimizing neurologic injury, are warranted. E3-E5 Previous attempts, by Edwards and colleagues E6 and Bartels and associates, E7 at synthesizing the evidence base to support the principles of CPB have selectively reviewed the cardiac surgery literature or focused on unique patient populations. Additionally, the development of these reviews has not involved all members of the clinical team, most notably the individuals tasked with operating the CPB circuit. This gap in knowledge is in stark contrast with the shared goal of the cardiac team, namely to improve the conduct of CPB to reduce the patient's risk of adverse outcomes caused by cardiac surgery.Despite a preponderance of evidence supporting key principles of managing safe and effective CPB practice, wide variation in the use of technology and techniques for conducting CPB persists regionally and nationally. E8,E9 Variations in practice have previously been shown to be associated with increased costs, lengths of stay, neurologic injury, and mortality. 1-3,E5,E10,E11 This variation might be attributed to clinical uncertainty or institutional or local practice standards. To reduce this unwanted practice variation, we must provide our clinical colleagues with critically evaluated and evidence-based review for conducting CPB.What follows is an evidence-based review for conducting safe, patient-centered, and effective CPB practice. The authors have graded the level of evidence and classified the findings listed below by using the criteria promulgated by the American Heart Association and the American College of Cardiology Task Force on Practice Guidelines (Table 1). The development of these findings evolved from a structured MEDLINE search coupled with critical review of the peer-review literature and debates stemming from presentations at regional and national conferences, including the