Frank Pigula's research has focused on decreasing the long-term neurologic effects of surgery to repair cogenital heart defects, which are the consequence of hypothermic cardiopulmonary bypass. Using non-invasive techniques, he and his colleagues have begun to describe some of the effects of bypass on cerebral blood flow, oxygenation, and metabolism.

One of the underlying hypotheses of their work is that a non-pulsed, cooled blood flow, as well as inflammation can damage the smallest vessels of the brain by leading to arteriovenous shunting--formation of abnormal connections between the arterial system and the venous system, in which blood flow and pressure are increased. They believe that identifying the factors that promote arteriovenous shunting will enable them to design improved processes, procedures, and instruments to reduce the incidence and severity of such injuries.