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Abstract
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.
- paediatric cardiothoracic surgery
- clinical trial
- paediatric intensive & critical care
- immunology
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STRENGTHS AND LIMITATIONS OF THIS STUDY
The ULTrafiltration to enhance Recovery After paediatric cardiac surgery (ULTRA) trial will directly assess the anti-inflammatory effect of continuous ultrafiltration exchange rate in a randomised and double-blinded fashion with broad inclusion criteria.
ULTRA will collect and analyse clinical outcomes, clinical score times series and comprehensive inflammatory mediator biomarker data through the perioperative course of children undergoing congenital heart surgery.
The high-exchange subzero balance ultrafiltration intervention aims to reduce morbidity and critical care requirements following paediatric cardiac surgery, which is important to patients, their families and healthcare institutions.
Relative limitations of the study are power, patient population heterogeneity and generalisability due to single-centre design. Notwithstanding, the trial is powered to detect a significant difference in the validated clinical score primary outcome as a surrogate to other important clinical results.
Background
Congenital heart disease occurs in 1% of all live births, and approximately one-quarter of these individuals will require surgical intervention in the first year of life.1 Although there has been a marked reduction in operative mortality over the last three decades—due to significant advances in surgical technique, myocardial protection, intensive care management and mechanical circulatory support—cardiopulmonary bypass (CPB)-associated inflammation continues to negatively impact recovery. Exposure to the non-endothelialised circuit instantly triggers the complement system, contact activation, coagulation cascade and acute-phase reactants.2–6 The sterile innate response features circulating proinflammatory mediators, including complement anaphylatoxins (C3a and C5a), cytokines (tumour necrosis factor (TNF), IL-1α, IL-1β and IL-6) and chemokines (CXCL-8), which stimulate endothelial leak, neutrophil recruitment, translocation and ultimately tissue injury.2–5 7 Clinically, CPB-associated inflammation manifests as a systemic inflammatory response syndrome with cardiac, pulmonary, and vasomotor dysfunction yielding hours or days of intensive care requirements in the postoperative period and potentially secondary organ dysfunction.2–5 7 8 Unfortunately, there are no proven treatments to manage this syndrome, which negatively affects these vulnerable patients, their families and have substantial healthcare costs.1 8
Ultrafiltration has been used during paediatric cardiac surgery since the 1990s, primarily to remove excess volume and prevent tissue oedema.9 Shortly after its implementation, due to observations of improved haemodynamic parameters and cardiopulmonary function, the therapy was hypothesized to extract proinflammatory substances and myocardial depressants from the patient’s circulation.10–12 Currently, 22 inflammatory mediators are known to be extracted by this modality throughout CPB, including C3a, C5a, TNF, IL-1β, IL-6, CXCL-8 and others.8 13 C3a and C5a appear to be the most relevant to clinical inflammation and, importantly, ultrafiltration effectively extracts these factors with sieving coefficients of 1019% and 46%, respectively.13 To maximise the extraction of proinflammatory mediators during CPB, we have designed an ultrafiltration protocol—subzero balance ultrafiltration (SBUF)—that facilitates continuous therapy throughout the entire CPB time.14 In theory, a high-exchange rate of SBUF (H-SBUF) will extract more proinflammatory mediators from the circulation and dampen the systemic inflammatory response relative to a low-exchange SBUF (L-SBUF), thereby ameliorating the clinical sequelae of CPB-associated inflammation. Ultrafiltration during paediatric cardiac surgery is universal, with 97% of global centres using the therapy during CPB, however, protocols can vary widely.8 15 Particularly, there is no standard rate of effluent removal, and both the low and high-exchange therapies in this trial are within the range of accepted practices in the published literature.8
A validated clinical score, peak postoperative vasoactive-ventilation-renal score (VVR), is the primary outcome of this trial.16 The score directly represents the cardiopulmonary, vasomotor, renal and medical stability of the patient in the early postoperative period and is a robust predictor of ventilation time and intensive care unit length of stay.16 Therefore, peak VVR, along with key secondary clinical outcomes of acute renal injury, low cardiac output syndrome, inotrope-free days, ventilator-free days, along with perioperative inflammation mediator biomarkers, will directly assess the anti-inflammatory efficacy of H-SBUF.17 18
ULTrafiltration to enhance Recovery After paediatric cardiac surgery (ULTRA) is a 1:1 allocation parallel-group, double-blinded, superiority trial designed to test the hypothesis that, in paediatric patients less than 15 kg undergoing cardiac surgery for congenital heart disease utilising CPB, H-SBUF will reduce peak postoperative VVR relative to L-SBUF.
Methods
Study design
The high-exchange ULTRA trial is a 96-patient, single-centre, double-blinded, randomised controlled trial conducted at the academic IWK Health Centre, Nova Scotia, Canada. ULTRA is registered on clinicaltrial.gov and follows a prespecified protocol reported here. This protocol is reported following Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines (online supplemental file 1), and the trial will be reported following Consolidated Standards of Reporting Trials (CONSORT) guidelines.19 20 Patient enrolment began in September 2021 and is expected to complete in June 2025.
Supplemental material
Patient population
The study population will consist of neonatal, infant and child patients with weight between 2.5 and 15.0 kg undergoing cardiac surgery with CPB. Patients undergoing Fontan operation will be enrolled up to 18.0 kg. Exclusion from participation is by absence of informed written consent, isolated secundum atrial septal defect, severe hepatic disease, severe chronic renal disease, severe hematologic abnormality, genetic syndrome with severe multiorgan abnormalities, severe immunodeficiency syndrome and preoperative mechanical circulatory support.
Randomisation
Patients are randomised 1:1 to either H-SBUF or L-SBUF using permuted block randomisation, consisting of randomly permuted block sizes 2 and 4 and stratified by two risk groups defined by the updated 2020 Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery (STS-EACTS STAT) score.21 The first is a low-risk group defined as STAT=1, and the high-risk group defined as STAT=2–5. This stratification is important as our pilot study revealed these two groups to have significantly different values of peak VVR (the primary outcome of ULTRA), and increasing STAT score is known to have significant implications on morbidity and mortality following children’s heart surgery.21 22 The randomisation sequence was uploaded to Research Electronic Data Capture (REDCap) for administration.23 Randomisation occurs at the preoperative surgical team briefing on the day of operation.
Blinding
ULTRA is a double-blinded trial. Patients, their families, surgeon, anaesthetist, critical care physician, cardiologist, nursing, outcome assessor, research coordinator and statistician are blinded to the assigned treatment group. Only the perfusionists, who execute the randomisation order on REDCap and administer the ultrafiltration treatments, are privy to the treatment allocation. The perfusionist has no other role in the ULTRA study and does not participate in outcome assessment or statistical analysis. Additionally, the infusion pumps and ultrafiltration effluent reservoir are masked from the operating room team using a physical barrier to prevent inadvertent unblinding of the surgical team. Perfusion and ultrafiltration data are recorded by perfusionists and stored in a locked datasheet within the database.
Study treatment
SBUF-simple modified ultrafiltration (SMUF) technique during paediatric CPB has been previously published.14 Infusion pumps allow for the precise management of ultrafiltration effluent removal and physiologic replacement during SBUF, which facilitates both high and low-exchange treatments within the same CPB circuit. The treatment arm of the trial consists of H-SBUF administered throughout the entire CPB time, with effluent extraction of 60 mL/kg/hour and physiologic crystalloid volume replacement of 55 mL/kg/hour, yielding a net negative 5 mL/kg/hour. The control arm of the trail is L-SBUF administered throughout the entire CPB time, with effluent extraction of 6 mL/kg/hour and physiologic crystalloid volume replacement of 1 mL/kg/hour yielding net negative 5 mL/kg/hour. Both groups receive standard-of-care perfusion and ultrafiltration techniques, including buffered preparation of sanguineous prime, conventional ultrafiltration used to immediately remove cardioplegia or surgical field irrigation and simple modified ultrafiltration (SMUF) after the cessation of CPB.14 24 Importantly, this trial is designed to test the impact of continuous ultrafiltration rate while controlling for differences in volume balances between groups. Postoperative care is administered to meet best practices by the institution’s blinded multidisciplinary team.
Study outcomes
The primary outcome is peak VVR in the postoperative period. Along with VVR, vasoactive inotrope score, ventilation index and oxygenation index are defined in table 1 and will be collected in a prespecified time series depicted in figure 1.16 25–27 The peak clinical score is the single highest measurement for each score collected in the standardised time series. Secondary clinical outcomes—including cardiac, pulmonary, renal morbidities and critical care requirements—as well as inflammatory mediator biomarker data are outlined in table 2. Outcomes collected represent a range of validated clinical and biomarker outcomes to evaluate the efficacy of H-SBUF.
Trial longitudinal data collection. CPB, cardiopulmonary bypass; ICU, intensive care unit; OI, oxygenation index; VI, ventilation index; VIS, vasoactive inotrope score; VVR, ventilation-vasoactive-renal score.
Clinical score calculations
Study outcomes
Sample size
The primary outcome of ULTRA is the peak postoperative VVR score. The sample size calculation was based on a minimal clinically important relative reduction in the primary outcome of 25%. This threshold was identified by consultation with clinical experts and represents a significant improvement in cardiopulmonary and vasomotor function. A two-way analysis of variance (ANOVA)which considered the stratification by STAT score (STAT 1 and STAT 2–5) with alpha=0.05 and beta=0.2. The decision to stratify by surgical risk STAT score was crucial to ensure this variable is balanced for comparison between treatment groups, as STAT score is strongly correlated with morbidity and mortality after paediatric cardiac surgery.21 The sample size calculation used peak VVR data from the pilot study for patients that matched ULTRA’s inclusion criteria. According to these parameters, 48 patients in each group are required, yielding a total of 96 patients.
Data collection and management
JB, blinded to randomised treatment allocation, prospectively collects prespecified clinical outcomes on a primary hard copy template and biologic samples for biomarker analysis. Follow-up is until hospital discharge or death. The data are transferred and managed on REDCap electronic data capture tools hosted at the IWK Health Centre.23 Data records are deidentified, participating patients will be assigned an anonymising code with the key stored separately and securely.
Inflammatory mediator analysis
Arterial blood samples will be collected at baseline (after anaesthesia induction and sternotomy but before CPB-initiation), post-CPB-0 hours (after weaning of CPB and conclusion of SMUF) and post-CPB-24 hours. Samples are collected in EDTA tubes, processed to platelet-free plasma and flash-frozen to be stored at −80°C. Complement factors (C3, C3a, C3b, C5, C5a, among other), cytokines (IL-1, IL1-Ra, IL-6, IL-10, TNF, and others), chemokines (CXCL-8) and other relevant mediators will be quantified by multiplex immunoassay. All samples will be analysed simultaneously after patient enrolment is completed by JB.
Statistical analyses
There will be no interim analyses. The final analysis will follow the intention-to-treat principle and be completed in a blinded fashion by PA who does not participate in data collection or outcome assessment. If there are deviations from the assigned treatment, an as-treated analysis will be considered to supplement the intention-to-treat results. Descriptive statistics will describe the characteristics of both treatment arms. Clinical and biomarker outcomes will be assessed for normalcy by quantile-quantile plots and Shapiro-Wilk test. Normally distributed outcomes will be compared using an independent t-test, and non-normally disturbed outcomes will be compared using the Mann-Whitney U test. Dichotomous outcomes will be compared by either Pearson’s χ2 test or Fisher’s exact test. Time-to-event analyses forlow cardiac output syndrome (LCOS), vasoplegic shock and clinical composite endpoint will be conducted by Kaplan-Meier or proportional hazard regression. Longitudinal time series analyses (clinical score and inflammatory mediator) will compare the two treatment groups at each time point individually and together through generalised linear mixed models. Statistical significance is α=0.05.
There will be a subgroup analysis based on the STS-EACTS STAT score 1 and 2–5 in accordance with the stratification method. There will be exploratory subgroup analyses based on sex (male and female) and CPB prime (sanguineous and asanguineous). The CPB prime subgroups, which also equates to those below (sanguineous) and above 10 kg (asanguineous) at our institution, are of particular interest as this approach eliminates significant sources of patient heterogeneity due to age, weight, corresponding congenital heart disease and operations as well as CPB prime exposures.
Data Safety Monitoring Board
The Data Safety Monitoring Board (DSMB) consists of a Paediatric Cardiologist, an Intensivist and a Perfusionist at the IWK Health Centre, none of whom is study investigators. The DSMB will meet to review blinded results at 25%, 50%, 75% and 100% enrolment. Each report will feature enrolment progression, perfusion complication, acute kidney injury, mechanical circulatory support and operative mortality. The DSMB can request an unblinding of the results if there is a substantial differential in safety outcomes between the two groups. The DSMB will recommend to the steering committee that the trial continue, be modified, or terminated following each analysis. The recommendation letter will be submitted to the Research Ethics Board (REB) as part of the study protocol. The purpose of the DSMB is to monitor the safety and proceedings for the ULTRA trial, independent of the investigators.
Serious adverse event reporting
Paediatric cardiac surgery carries substantial risk as many patients can experience morbidities, organ failure and even mortality despite optimal care. Complications or events that are part of the congenital heart disease natural history or convalescence following cardiac surgery will not be reported as serious adverse events. All adverse events which are potentially or causally related to the study SBUF intervention will be reported to the REB. Specific events primarily revolve around perfusion complications such as air embolism, pump thrombosis, and severe haemolysis; these are extraordinarily rare in modern practice.
Study organisation
The study leadership consists of a steering committee and an independent DSMB. The steering committee comprises the principal investigator and investigators with expertise in all aspects of the translational randomised trial, including paediatric cardiac surgery, paediatric clinical perfusion, paediatric critical care, immunology, statistics, and randomised trial methods. The steering committee was responsible for the design and maintenance of the trial.
Ethics
The study will be conducted with protocol and standard operating procedures approved by the REB at the IWK Health Centre (#1024932). Annual renewal of the approval and submission of all four DSMB reports are required. Informed written consent is required by the patient’s substitute decision-maker before enrolment. The consent form and standard operating procedures are part of the IWK Health Centre’s REB approved protocol #1 024 932 dated August 31, 2021. An example of the consent form is seen in online supplemental file 2. Research personnel discuss participation with the substitute decision-maker during preoperative surgical assessment in the outpatient clinic or inpatient ward. Protocol deviations are submitted to the principal investigator and recorded in the patient’s study record. Participant confidentiality is maintained through de-identification methods and secured records.
Supplemental material
Dissemination policy
The results of this trial will be disseminated to congenital cardiac care clinicians and researchers through peer-reviewed publication and conference presentations. Authorship will be assessed using criteria from the publisher. In general, the dataset will not be publicly available. Data requests will be considered on a case-by-case basis and in line with the trial’s Research Ethics Board approval.
Patient and public involvement
There was no patient or public involvement in the design of this trial.
Ethics statements
Patient consent for publication
Acknowledgments
The authors would like to thank the children and families for participating in this research as well as the IWK Health Centre Cardiac Surgery, Clinical Perfusion, Anesthesia, Cardiology, Critical Care, and Peri-operative care for facilitating data collection and study procedures.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
X @jbierer
Contributors JB, RS, MH, KK, PA, JSM, JS and DH designed the study. JB wrote this manuscript, which was reviewed by RS, MH, KK, PA, JSM, JS and DH, and revisions were incorporated. JB is the guarantor.
Funding This study received funding from the Canadian Institutes of Health Research (#181479), Dalhousie University Department of Surgery, Dalhousie Medical Research Foundation and Research Nova Scotia. JB receives salary support from the Nova Scotia Ministry of Health through the Dalhousie University Clinician Investigator Program.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer-reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.