The Inflammatory Response during Pediatric Cardiac Surgery with Cardiopulmonary Bypass and Continuous Ultrafiltration

Abstract

Congenital heart disease (CHD) is the most common birth defect, and surgical correction is often the gold standard treatment. Cardiopulmonary bypass (CPB) is essential to effective cardiac operations, but it triggers a complex systemic inflammatory response, contributing to post-operative morbidity and prolonged recovery, and effective solutions to this problem have been elusive for decades. This thesis, comprising results from two prospective translational studies (Pilot and ULTRA), investigates the immunologic mechanisms underlying CPB-associated inflammation during pediatric cardiac surgery and evaluates the efficacy of continuous ultrafiltration as an immunomodulatory therapy.

The Pilot study (n=40) described distinct inflammatory profiles induced by sternotomy and CPB, with sternotomy associated with systemic cytokine and chemokine activity, while CPB primarily featured complement system activation and select cytokines. Furthermore, it appeared that the complement system, and particularly the complement anaphylatoxins C3a and C5a, rather than traditional pro-inflammatory cytokines and chemokines, was most closely associated with morbid and prolonged post-operative recoveries. Sanguineous CPB prime, used as standard of care for neonates and infants, was found to contain supraphysiologic concentrations of complement factors, primarily derived from fresh-frozen plasma. Exposure to sanguineous prime accelerated the complement reaction upon CPB initiation, which was sustained throughout the CPB exposure. Continuous ultrafiltration, while shown to extract a range of inflammatory mediators, demonstrated only modest immunomodulatory effects, with no significant clinical benefit. The ULTRA trial (n=104) compared high-exchange continuous ultrafiltration to a low-exchange protocol in a double-blinded and randomized fashion. There was no difference in post-operative ventilation-vasoactive-renal scores, ventilation time, intensive care unit requirements, and the inflammatory profiles of patients in both groups were largely similar.

Systemic inflammation during children’s heart surgery remains an unresolved challenge, despite modern-day perfusion technology and techniques, with significant impacts on the patient, their family and the health care system. High-exchange continuous ultrafiltration appears to have only a modest immunomodulatory and clinical impact, while new alternatives to sanguineous prime could yield important benefits for neonates and infants. This work establishes a scientific foundation for future research aimed at mitigating CPB-associated inflammation and enhancing recovery for children with CHD.