Introduction Surgical repair is the standard of care for most infants and children with congenital heart disease. Cardiopulmonary bypass (CPB) is required to facilitate these operations but elicits a systemic inflammatory response, leading to postoperative organ dysfunction, morbidity and prolonged recovery after the surgery. Subzero-balance ultrafiltration (SBUF) has been shown to extract proinflammatory cytokines continuously throughout the CPB exposure. We hypothesize that a high-exchange SBUF (H-SBUF) will have a clinically relevant anti-inflammatory effect compared with a low-exchange SBUF (L-SBUF). Methods and analysis The ULTrafiltration to enhance Recovery After paediatric cardiac surgery (ULTRA) trial is a randomised, double-blind, parallel-group randomised trial conducted in a single paediatric cardiac surgery centre. Ninety-six patients less than 15 kg undergoing cardiac surgery with CPB will be randomly assigned to H-SBUF during CPB or L-SBUF during CPB in a 1:1 ratio with stratification by The Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery (STAT) score 1 and STAT score 2-5. The primary outcome is peak postoperative vasoactive-ventilation-renal score. Time series and peak values of vasoactive-ventilation renal score, vasoactive-inotrope score, ventilation index and oxygenation index will be collected. Secondary clinical outcomes include acute kidney injury, ventilator-free days, inotrope-free days, low cardiac output syndrome, mechanical circulatory support, intensive care unit length of stay and operative mortality. Secondary biomarker data include cytokine, chemokine and complement factor concentrations at baseline before CPB, at the end of CPB exposure and 24 hours following CPB. Analyses will be conducted on an intention-to-treat principle. Ethics and dissemination The study has ethics approval (#1024932 dated August 31, 2021) and enrolment commenced in September 2021. The primary manuscript and any subsequent analyses will be submitted for peer-reviewed publication. Trial registration number NCT04920643.

BackgroundThe inflammatory response to cardiopulmonary bypass (CPB) in pediatric patients remains an unresolved challenge. Sanguineous CPB prime, composed of allogenic blood products, is one potentially important stimulus. This study aims to identify specific inflammatory mediators active in sanguineous CPB prime and their impact on the inflammatory response at CPB initiation.MethodsIn a post-hoc analysis of a prospective observational cohort study (NCT05154864), where pediatric patients undergoing cardiac surgery with CPB were enrolled after informed consent, patients were grouped by CPB prime type (sanguineous vs crystalloid). Arterial samples were collected post-sternotomy as a baseline and again at CPB initiation from all patients. In the sanguineous group, CPB prime samples were also collected after buffered ultrafiltration but before CPB initiation. Luminex® measured concentrations of 24 inflammatory mediators for comparison between groups. Statistical analyses were by Mann-Whitney test and Wilcoxon signed-rank test. Data are presented as median [IQR].ResultsForty consecutive pediatric patients participated. The sanguineous group (n = 26) was younger (4.0 [0.2 - 6.0] vs 48.5 [39.0 - 69.5] months; p = 2.6 × 10-7) and smaller (4.9 [34 - 6.6] vs 17.2 [14.9 - 19.6] kg; p = 2.6 × 10-7) than the crystalloid group (n = 14). Despite this, baseline concentrations of 20 complement and cytokine concentrations were comparable between groups (p > 0.05) while four showed differences between groups (p < 0.05). The sanguineous prime contained supraphysiologic concentrations of complement mediators: C2, C3, C3a, C3b, and C5a. Correspondingly, upon CPB initiation, patients receiving sanguineous prime exhibited a significantly larger burden of C2, C3, C3b, C5, and C5a (p < 0.001) relative to the crystalloid group. Cytokine and chemokine mediators were present at trace levels in the sanguineous prime.ConclusionsSanguineous prime contains activated complement that accelerates the inflammatory response at CPB initiation in neonates and infants. Immunomodulatory interventions targeting complement during CPB prime preparation could offer substantial benefits for these vulnerable patients.

Abstract Background Cardiopulmonary bypass (CPB) causes systemic inflammation during pediatric cardiac surgery, which can contribute to post-operative organ dysfunction and prolonged recovery. This study aims to identify key inflammatory mediators related to this clinically significant immunologic response. Methods Pediatric patients were enrolled in a single-arm prospective clinical study (NCT05154864) and received standard cardiac operation, CPB and subzero-balance ultrafiltration. Arterial samples were taken before CPB initiation and immediately after weaning, and concentrations of 33 inflammatory mediators were assayed. A principal component analysis with hierarchical clustering (PCA-HCPC) included inflammatory mediator concentrations measured at the end of CPB, validated peak post-operative clinical scores, ventilation time and intensive care length of stay. Mahalanobis distance assessed statistical differences between clusters. Spearman’s correlation described the linear relationship between mediator concentrations at the end of CPB and intensive care length of stay. Results are median (IQR). Results Forty consecutive patients were enrolled; the majority were male (58%), age of 7.3 (1.7–39.0) months and weight of 6.7 (4.6–14.9) kg. The PCA-HCPC revealed activated complement factors along with all peak clinical scores and prolonged intensive care requirements in the same cluster. Cytokine, chemokine, and leukocyte adhesion molecule concentrations were found in two other distinct clusters (Mahalanobis distance = 16.5; p = 0.004 and Mahalanobis distance = 17.4; p = 5.8 × 10–4). Mediator concentrations of C2 (Rho = 0.50; p = 0.001), C3 (Rho = 0.58; p = 1.1 × 10–4), C3b (Rho = 0.47; p = 0.002), C5 (Rho = 0.48; p = 0.002) and C5a (Rho = 0.63; 1.7 × 10–5) showed linear correlations with intensive care unit length of stay. Conclusions Activated complement factors, but not pro-inflammatory cytokines or chemokines, were most related to cardiopulmonary dysfunction and prolonged recovery in this novel analysis. Investigation of therapies that inhibit complement to dampen CPB-associated inflammation and enhance recovery after pediatric cardiac surgery is warranted. Trial Registration ClinicalTrials.gov, NCT05154864

Background Cardiopulmonary bypass (CPB) is associated with systemic inflammation, featuring increased levels of circulating pro-inflammatory cytokines. Intra-operative ultrafiltration extracts fluid and inflammatory factors potentially dampening inflammation-related organ dysfunction and enhancing post-operative recovery. This study aimed to define the impact of continuous subzero-balance ultrafiltration (SBUF) on circulating levels of major inflammatory mediators. Methods Twenty pediatric patients undergoing cardiac surgery, CPB and SBUF were prospectively enrolled. Blood samples were collected prior to CPB initiation (Pre-CPB Plasma) and immediately before weaning off CPB (End-CPB Plasma). Ultrafiltrate effluent samples were also collected at the End-CPB time-point (End-CPB Effluent). The concentrations of thirty-nine inflammatory factors were assessed and sieving coefficients were calculated. Results A profound increase in inflammatory cytokines and activated complement products were noted in plasma following CBP. Twenty-two inflammatory mediators were detected in the ultrafiltrate effluent. Novel mediators removed by ultrafiltration included cytokines IL1-Ra, IL-2, IL-12, IL-17A, IL-33, TRAIL, GM-CSF, ET-1, and the chemokines CCL2, CCL3, CCL4, CXCL1, CXCL2 and CXCL10. Mediator extraction by SBUF was significantly associated with molecular mass < 66 kDa (Chi 2 statistic = 18.8, Chi 2 with Yates’ correction = 16.0, p < 0.0001). There was a moderate negative linear correlation between molecular mass and sieving coefficient (Spearman R = − 0.45 and p = 0.02). Notably, the anti-inflammatory cytokine IL-10 was not efficiently extracted by SBUF. Conclusions CPB is associated with a burden of circulating inflammatory mediators, and SBUF selectively extracts twenty of these pro-inflammatory factors while preserving the key anti-inflammatory regulator IL-10. Ultrafiltration could potentially function as an immunomodulatory therapy during pediatric cardiac surgery. Trial registration ClinicalTrials.gov, NCT05154864. Registered retrospectively on December 13, 2021. https://clinicaltrials.gov/ct2/show/record/NCT05154864 .

The use of cardiopulmonary bypass (CPB) can be associated with significant hemodilution, coagulopathy and a systemic inflammatory response for infants and children undergoing cardiac surgery. Intra-operative ultrafiltration has been used for decades to ameliorate these harmful effects. The novel combination of a continuous and non-continuous form of ultrafiltration, Subzero Balance Simple Modified Ultrafiltration (SBUF-SMUF) here described, seeks to enhance recovery from pediatric cardiac surgery and CPB.

Background Cardiac surgery with cardiopulmonary bypass (CPB) is associated with a systemic inflammatory syndrome that adversely impacts cardiopulmonary function and can contribute to prolonged postoperative recovery. Intra-operative ultrafiltration during CPB is a strategy developed by pediatric cardiac specialists, aiming to dampen the inflammatory syndrome by removing circulating cytokines and improving coagulation profiles during the cardiac operation. Although ultrafiltration is commonly used in the pediatric population, it is not routinely used in the adult population. This study aims to evaluate if randomized evidence supports the use of continuous intra-operative ultrafiltration to enhance recovery for adults undergoing cardiac surgery with CPB. Methods This systematic review and meta-analysis will include randomized controlled trials (RCT) that feature continuous forms of ultrafiltration during adult cardiac surgery with CPB, specifically assessing for benefit in mortality rates, invasive ventilation time and intensive care unit length of stay (ICU LOS). Relevant RCTs will be retrieved from databases, including MEDLINE, Embase, CENTRAL and Scopus, by a pre-defined search strategy. Search results will be screened for inclusion and exclusion criteria by two independent persons with consensus. Selected RCTs will have study demographics and outcome data extracted by two independent persons and transferred into RevMan. Risk of bias will be independently assessed by the Revised Cochrane Risk-of-Bias (RoB2) tool and studies rated as low-, some-, or high- risk of bias. Meta-analyses will compare the intervention of continuous ultrafiltration against comparators in terms of mortality, ventilation time, ICU LOS, and renal failure. Heterogeneity will be measured by the χ 2 test and described by the I 2 statistic. A sensitivity analysis will be completed by excluding included studies judged to have a high risk of bias. Summary of findings and certainty of the evidence, determined by the GRADE approach, will display the analysis findings. Discussion The findings of this systematic review and meta-analysis will summarize the evidence to date of continuous forms of ultrafiltration in adult cardiac surgery with CPB, to both inform adult cardiac specialists about this technique and identify critical questions for future research in this subject area. Systematic review registration This systematic review and meta-analysis is registered in PROSPERO CRD42020219309 ( https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020219309 ).

INTRODUCTION:The use of cardiopulmonary bypass in pediatric cardiac surgery is associated with significant inflammation, fluid overload, and end-organ dysfunction yielding morbidity and mortality. For decades, various intraoperative ultrafiltration techniques such as conventional ultrafiltration, modified ultrafiltration (MUF), zero-balance ultrafiltration (ZBUF), and combination techniques (ZBUF-MUF) have been used to mitigate these toxicities and promote improved postoperative outcomes. However, there is currently no consensus on the ultrafiltration technique or strategy that yields the most benefit for infants and children undergoing open heart surgery.METHODS:A librarian-conducted PubMed literature search from 1990 to 2018 yielded 90 clinical studies or publications on the various forms of ultrafiltration and the impact on physiologic markers and clinical outcomes. All publications were reviewed, summarized, and conclusions synthesized. The data sets were not combined for systematic or meta-analysis due to significant heterogeneity in study protocols and patient populations.RESULTS:Modified ultrafiltration significantly promotes improved myocardial function, reduction in fluid overload, and reduced bleeding and transfusion complications. Furthermore, ZBUF has shown a consistent reduction in inflammatory cytokines and improved pulmonary function and compliance. There is conflicting evidence that MUF, ZBUF, and ZBUF-MUF culminate in reduced ventilation time and intensive care unit stay.CONCLUSION:Various modes of ultrafiltration have been shown to be associated with improved physiologic function or clinical outcomes in pediatric cardiac surgery. There are some inconsistent trial results that can be explained by heterogeneity in ultrafiltration, clinical staff preferences, and institution protocols. Ultrafiltration has some essential benefit as it is ubiquitously used at pediatric heart centers; however, the optimal protocol could be yet identified.

There have been many advances in the perfusion equipment used for cardiopulmonary bypass (CPB) surgery. A key component, the membrane oxygenator, has had a number of modifications in recent years and a recent clinical evaluation demonstrated disparity in various aspects of device performance. One difference among oxygenators, which to-date has received little attention, was the impact on the patient's immune cells, with some oxygenators producing a significantly greater increase in immune cell numbers after cross clamp. Such increases in immune cell proliferation may contribute to the development of a systemic inflammatory response (SIR), which has been demonstrated to have a negative impact on patient outcomes. Although factors contributing to immune cell proliferation during CPB are recognized to be multi-factorial, the goal of the current communication was to perform an ad hoc analysis of these raw data for evidence that pressure gradients through an oxygenator contributes to this outcome. Despite the observation that higher-pressure gradient oxygenators appeared to associate with increased immune cell proliferation, no correlation was detected in this analysis. This finding, however, provides further evidence for the complex nature of inflammation during CPB, which deserves ongoing discussion and investigation.