Does Clear Priming of the Cardiopulmonary Bypass Circuit Reduce Bypass Associated Inflammation in Ventricular Septal Defect Patients?

Cardiopulmonary bypass (CPB) is required for surgical correction/palliation of congenital heart defects. Exposure to CPB results in a robust activation of inflammatory responses. It is now well established that exposure to the CPB circuit is associated with an overwhelming, detrimental systemic inflammatory response. The factors associated with this response may be related to the circuit and exposure to the circuit surface, or may be associated with the body's response to surgical trauma, changes in temperature, etc. Multiple pathways have been shown to be mediating this response, including complement activation, leukocyte activation, endotoxin release, release of oxygen-free radicals, nitric oxide, cytokines, platelet-activation factor, arachidonic acid metabolites and endothelins. Activation of these inflammatory pathways has been implicated in the development of some of the major postoperative complications, such as bleeding tendencies, respiratory insufficiency, renal dysfunction, abnormalities in liver function, and, most seriously, multi-organ failure. Multiple pharmacological therapies have been investigated, with a single aim, to modulate this systemic inflammation. The most widely investigated ones have been corticosteroid administration, use of heparin-coated circuits, leukocyte depletion and ultrafiltration. Despite these efforts, the activation of inflammatory pathways in response to CPB remains a significant clinical problem especially in neonates undergoing CPB.

Over the last several years, several centers including Seattle Children's have been pursuing efforts to restrict the administration of blood products during CPB. In some of the recent publications on the topic, the justifications for moving towards "bloodless CPB" include reducing potential infection risks, consideration that blood products are valuable limited resource, and the concerns of certain religious communities. A limitation of these studies is that they do not examine a patient's clinical course or markers of inflammation in depth. CPB patients experience significant post-CPB inflammation - including increased cytokine levels, inflammatory cell infiltration, vascular leak, and multi-organ dysfunction. In children recovering from complicated cardiac surgeries, increased cytokine levels are associated with high mortality and extended intensive care stays. Typically, a blood-containing prime has been used as a method to preserve high hematocrit levels and maintain oxygen delivery. There are several mechanisms by which exposure to blood products can activate inflammation-which include allergic reactions, cytokines in the blood products, or release of proinflammatory proteins from red blood cells. These mechanisms serve as the basis for the hypothesis that "clear prime" CPB patients will have reduced inflammation as compared to standard of care CPB patients.

Since 5/2021, 174 CPB patients have been operated on at Seattle Children's Hospital (SCH) using restrictive blood management. In 90 of these patients, "bloodless" surgery was attempted. These patients received CPB priming with crystalloid fluids only and without any addition of blood products. These crystalloid fluids are same ones used in current standard of care treatment for pediatric cardiac surgery cases. All other aspects of the patients' treatment were the same including the same bypass machines and tubing. 47 of these patients did not receive blood products during the surgery. 35 patients did not receive any blood products during the hospitalization. There were no statistical differences between the median ventilation time and Intensive Care Unit (ICU) length of stay between the patients operated on with such restrictive blood management as compared to patient controls from our center in which blood products were added to CPB prime.

Dr. Bohuta's recent observational study of 99 SCH neonatal cardiac cases using historical controls identified no statistical difference in postoperative seizures, bleeding events, and lactate levels during CPB between patients who received clear prime versus those who received a blood prime. In this same study, both length of stay and postoperative mechanical ventilation time was shorter in the clear prime group. Hematocrit was consistently lower post-operatively for patients in the crystalloid only group, otherwise, there were no unintended consequences/ adverse events identified in the crystalloid only cohort.