The ULTRA Randomized Controlled Trial investigated whether increasing the intensity of continuous ultrafiltration during pediatric cardiac surgery could meaningfully reduce systemic inflammation and improve postoperative recovery. Published in The Annals of Thoracic Surgery (2026), this single-center, double-blind randomized controlled trial enrolled 104 pediatric patients weighing less than 15 kilograms who underwent cardiac surgery with cardiopulmonary bypass (CPB).
Cardiopulmonary bypass is well known to trigger a systemic inflammatory response in children. Exposure to artificial surfaces in the CPB circuit activates complement pathways and promotes the release of proinflammatory cytokines, including interleukins, chemokines, and tumor necrosis factor. This inflammatory cascade may contribute to vasodilation, capillary leak, organ dysfunction, prolonged mechanical ventilation, and low cardiac output syndrome (LCOS). Despite decades of research, effective therapies to blunt CPB-associated inflammation remain limited.
Ultrafiltration has long been used in pediatric cardiac surgery to remove excess fluid, concentrate blood components, and reduce edema. It also extracts certain inflammatory mediators. The ULTRA trial specifically examined whether high-exchange subzero-balance ultrafiltration (H-SBUF)—performed continuously throughout CPB at 60 mL/kg per hour—could offer superior immunomodulatory and clinical benefits compared with low-exchange SBUF (L-SBUF) at 6 mL/kg per hour.
Patients were randomized in a 1:1 ratio. Both groups received standard ultrafiltration practices, including conventional ultrafiltration (CUF) and simple modified ultrafiltration (SMUF), in addition to their assigned SBUF strategy. The primary outcome was peak postoperative vasoactive-ventilation-renal (VVR) score, a validated composite metric reflecting cardiovascular, respiratory, and renal support requirements. Secondary outcomes included acute kidney injury, ventilation duration, inotropic support time, ICU length of stay, hospital length of stay, and inflammatory mediator fold changes.
Baseline characteristics were well balanced between groups. The cohort included neonates, infants, and children with a range of congenital heart lesions, including single-ventricle physiology and Fontan procedures. Operative variables such as CPB duration, myocardial ischemia time, transfusion requirements, and perfusion balance were similar between groups.
The results were clear: high-exchange ultrafiltration did not reduce peak VVR scores. Median peak VVR was 26.9 in the H-SBUF group and 27.8 in the L-SBUF group, with no statistically significant difference (P = .67). Secondary endpoints also demonstrated no meaningful differences. Rates of acute kidney injury, low cardiac output syndrome, mechanical circulatory support, prolonged intubation, and vasoplegic shock were comparable.
Inflammatory mediator analysis provided further insight. Although high-exchange ultrafiltration extracted larger volumes of effluent, the overall inflammatory burden at the end of CPB was not significantly reduced compared with low-exchange ultrafiltration. Interestingly, the H-SBUF group showed slightly higher fold increases in IL-1α, P-selectin, and vascular cell adhesion molecule-1. However, 36 other measured mediators—including complement factors and key cytokines—did not differ between groups. This suggests that simply increasing ultrafiltration exchange rates may not meaningfully alter systemic inflammatory biology.
The investigators noted that while SBUF extraction rates differed tenfold between groups, total ultrafiltration exposure was more similar than expected due to concurrent use of conventional and modified ultrafiltration. This overlap may have reduced the biological contrast between treatment arms. Additionally, prior mechanistic studies have shown that only a modest fraction of inflammatory mediators are removed by ultrafiltration relative to total circulating volume, limiting potential clinical impact.
Importantly, there were no operative deaths in the study, and overall outcomes were favorable in both groups. Most patients demonstrated clinical stabilization within 12 to 24 hours postoperatively and continued improvement by 48 hours.
The ULTRA trial contributes high-quality randomized evidence to the field of pediatric cardiac surgery. Previous smaller studies had suggested possible benefits of continuous ultrafiltration in reducing inflammatory markers or shortening ventilation time. However, ULTRA—larger and rigorously blinded—did not replicate those findings. The results align with other recent large trials evaluating anti-inflammatory strategies during pediatric CPB, including nitric oxide administration and corticosteroid therapy, which have also shown neutral results for primary clinical outcomes.
The study does have limitations. It was conducted at a single center, which may limit generalizability. The relatively small sample size and heterogeneity of congenital heart diagnoses may have increased variability. Additionally, despite protocol differences, total ultrafiltration volumes overlapped more than anticipated.
In conclusion, the ULTRA randomized controlled trial demonstrates that high-exchange continuous ultrafiltration during pediatric cardiopulmonary bypass does not improve postoperative clinical recovery or reduce systemic inflammation compared with low-exchange ultrafiltration. While ultrafiltration remains valuable for fluid management and hemoconcentration, its role as a primary immunomodulatory therapy appears limited. Future innovation will likely require novel biologic or device-based approaches to meaningfully mitigate CPB-associated inflammation and enhance recovery after pediatric heart surgery.
