Pre Bypass Ultrafiltration (PBUF) in Children Requiring Cardiopulmonary Bypass

Study Overview
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Brief Summary
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Newborn babies and children with congenital heart defects who need heart surgery need to be placed on the heart-lung machine for heart surgery. In order to use the heart-lung machine, the investigators have to use blood and other fluids to fill the tubing. During the operation, ultrafiltration is carried out as standard of care to remove extra fluid. Modified ultrafiltration is also performed after surgery. In this study, the investigators are looking to use the filter additionally before surgery. Using the pre bypass filtration before the subject is placed on the heart-lung machine will allow the investigators to better normalize electrolytes in the blood/fluid mixture used in the heart lung machine. This technique is called pre-bypass ultrafiltration, or PBUF (pronounced P Buff). The investigators are conducting a study to see if using PBUF to better normalize electrolytes in the blood will make a difference. The investigators have been adding fluids to prime the heart-lung machine in two different ways. The investigators believe both methods are safe and acceptable but hypothesize that there may be subtle differences in electrolytes and fluid status when one technique is used as opposed to the other. The investigators believe that neither technique introduces risk since both are currently used in practice. The standard method adds blood to the heart-lung machine. The alternate method adds blood to the heart-lung machine and then additional fluid is added and removed to more normalize the electrolytes. The investigators plan to randomized subjects undergoing heart surgery to receive the standard priming method versus PBUF to determine if there is any difference in outcomes. Laboratory and clinical data collected as part of clinical care will be used to determine difference sin outcomes. There will be no additional blood taken for this study. There are no known risks to PBUF. The benefits include helping investigators determine if PBUF does or does not make a difference to how subjects recover after surgery. The investigators believe that providing more normal blood values will either improve the subjects' outcome or have no benefit. The investigators do not anticipate increased risks. Given COVID -19 restrictions, the study is on hold.

Detailed Description
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Research question: Can PBUF provide more physiologic values for glucose, sodium, potassium and lactate throughout the cardiopulmonary bypass period without an increased incidence of adverse events? Background: The values for glucose, sodium, potassium and lactate in blood primes for subjects weighing less than 8 kg are known to be non-physiologic. The process of priming the cardiopulmonary bypass circuit is not standardized across institutions and there are several methods used to correct for known prime value issues. The investigators documented the prime values for 20 subjects weighing less than 8 kg and then performed pre-bypass ultrafiltration (PBUF) on the prime for those same circuits to achieve more physiologic prime values. The investigators were cautious not to implement too significant of a change as the investigators assessed the technique and documented that plasma-free hemoglobin importantly did not rise and that measured osmolality was still slightly above the normal range. Study type: Prospective randomized controlled study. Hypothesis: The investigators hypothesize that pre cardiopulmonary bypass ultrafiltration (PBUF) can provide more physiologic prime values for glucose, sodium, potassium and lactate. Plasma-free hemoglobin will not increase with the technique. Osmolality will be maintained slightly above the normal range. PBUF will not negatively impact clinical outcome measures and may improve them. Specific Aim 1 To determine if use of PBUF will result in more physiologic values for glucose, sodium, potassium and lactate during and immediately after cardiopulmonary bypass. Specific Aim 2 To determine if PBUF can be achieved with no increase in plasma free hemoglobin while maintaining plasma osmolality within acceptable range during and immediately after cardiopulmonary bypass. Specific Aim 3 To determine if use of PBUF will result in improved clinical outcomes after surgery on cardiopulmonary bypass. Randomization: Prior to surgery, subjects will be randomized to one of the two study groups using a randomly permuted blocks design. Statistical analysis: Analyses will be performed on an intention to treat basis. Comparisons of subject characteristics and outcomes will be made using the two-sample t test or Wilcoxon rank sum test for continuous variables, and Fisher's exact test for categorical variables. If imbalances in patient factors exist between the two groups, linear and logistic regression will be used to compare outcomes for the groups adjusting for these potential confounders. Sample size calculation: Sample size is calculated for comparisons of subjects in the normal range of values for the PBUF and standard care groups. This will be done separately for glucose, sodium, potassium, and lactate; each comparison will be performed at the 0.0125 level of significance. If 70% of standard care subjects are in the normal range versus 90% of PBUF subjects, a total of 176 subjects (88 per group) would be required to achieve 80% power. With 350 eligible subjects that meet inclusion criteria based on 2017 numbers and 75% consent rate the investigators will be able to enroll 260 subjects in 1 year. Given COVID-19 restrictions, the study is on hold.

Official Title
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Pre Bypass Ultrafiltration (PBUF) Improves Intraoperative Glucose, Sodium, Potassium and Lactate Levels in Children Requiring Cardiopulmonary Bypass

Conditions
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Congenital Heart Disease

Intervention / Treatment
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* Other: Use of prebypass ultrafiltration (PBUF)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All patients < 8 kilograms and < 1 year (to ensure that all patients receive steroids at initiation of CPB) undergoing an index cardiac operation for that hospitalization (using a single PBUF protocol) Exclusion Criteria: Patients undergoing repeat cardiac surgery within the same admission Patients undergoing transplants as their index surgery Patients undergoing Ventricular assist device implantation as their index surgery

Ages Eligible for Study
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Minimum Age: 1 Day
Maximum Age: 1 Year

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized Control Trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Control<br>Standard of care | |
| Active Comparator: Study<br>PBUF used prior to Cardiopulmonary bypass | Other: Use of prebypass ultrafiltration (PBUF)<br>* In addition to standard of care for cardiopulmonary bypass, in the study arm prebypass ultrafiltration will be performed.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glucose in milligrams per deciliter (mg/dL). Normal range 61 to 199 mg/dL | Differences in glucose (mg/dl) at the following time points, and also differences in the percentage of values within the normal range for each time point, for PBUF versus standard care. Final prime value (in the PBUF group after completion of PBUF and prior to cardio pulmonary bypass (CPB), in the control group prior to CPB) First measured levels on bypass - typically 10 minutes post initiation of bypass Last value on CPB Last value in OR First arrival to ICU | 12 hours | 
| Sodium in milliequivalents per liter (mEq/L). Normal range 135 to 148 mEq/L | Differences in sodium (mEq/L) at the following time points, and also differences in the percentage of values within the normal range for each time point, for PBUF versus standard care. Final prime value (in the PBUF group after completion of PBUF and prior to cardio pulmonary bypass (CPB), in the control group prior to CPB) First measured levels on bypass - typically 10 minutes post initiation of bypass Last value on CPB Last value in OR First arrival to ICU | 12 hours | 
| Potassium in milliequivalents per liter (mEq/L). Normal range 3.2 to 4.5 mEg/L | Differences in potassium (mEq/L) at the following time points, and also differences in the percentage of values within the normal range for each time point, for PBUF versus standard care. Final prime value (in the PBUF group after completion of PBUF and prior to cardio pulmonary bypass (CPB), in the control group prior to CPB) First measured levels on bypass - typically 10 minutes post initiation of bypass Last value on CPB Last value in OR First arrival to ICU | 12 hours | 
| Lactate in milliequivalents per liter (mEq/L). Normal range 0.5 to 2.2 mEq/L | Differences in lactate (mEq/L) at the following time points, and also differences in the percentage of values within the normal range for each time point, for PBUF versus standard care. Final prime value (in the PBUF group after completion of PBUF and prior to cardio pulmonary bypass (CPB), in the control group prior to CPB) First measured levels on bypass - typically 10 minutes post initiation of bypass Last value on CPB Last value in OR First arrival to ICU | 12 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Osmolality in milli osmoles per kilogram (mOsm/Kg). Normal Range 276- 295 mOsm/kg | Differences in osmolality in mOsm/Kg in final prime, first blood draw after CPB and on arrival to cardiac intensive care unit (CICU) for PBUF versus standard care. | 12 hours | 
| Plasma free hemoglobin in milligrams per deciliter (mg/dL). Normal < 5 mg/dL. | Differences in plasma free hemoglobin in mg/dL in final prime, first blood draw after CPB and on arrival to cardiac intensive care unit (CICU) for PBUF versus standard care. | 12 hours | 
| Inotrope use | Differences in vasoactive inotrope score between the PBUF and standard care groups at the following time points: i. Between cessation of CPB and admission to CICU as measured by vasoactive inotrope score (VIS) ii. In CICU as measure by VIS/ 24 hours for first 72 hours | 72 hours | 
| Body wall edema as measured daily weights in kilograms (Kg) | Differences in body wall edema as measure by daily weights in Kg between the PBUF and standard care groups. | Through study completion (until hospital discharge), an average of 15 days. | 
| Body wall edema as measured daily weights in kilograms (Kg) | Differences in body wall edema as measure by daily weights in Kg between the PBUF and standard care groups. | Through study completion (until hospital discharge) , an average of 15 days. | 
| Initial ventilation duration in days and hours | Differences in ventilation duration, Initial (days, hours) until first extubation between the PBUF and standard care groups. | Through study completion (until hospital discharge), an average of 15 days. | 
| Reintubation as a proportion subjects needing reintubation in each group Reintubation | Difference in proportion of subjects requiring unplanned reintubation for respiratory failure between the PBUF and standard care groups. | Through study completion (until hospital discharge), an average of 15 days. | 
| Total ventilation duration (days, hours) | Difference in total ventilation duration (includes all periods on the ventilator including period following unplanned reintubation for respiratory failure between the PBUF and standard care groups. | Through study completion (until hospital discharge), an average of 15 days. | 
| Postoperative Cardiac intensive care unit (CICU) length of stay (LOS) in days, | Difference in postoperative CICU LOS in days between the PBUF and standard care groups. | Through study completion (until hospital discharge), an average of 15 days. | 
| Postoperative hospital LOS | Difference in postoperative hospital LOS in days between the PBUF and standard care groups. | Through study completion (until hospital discharge), an average of 15 days. | 
| Composite of major adverse events (Postoperative extra corporeal membrane oxygenation (ECMO), reoperation for bleeding, reoperation for low cardiac output state, circuit clotting events) and mortality. Yes or No | Difference in proportion subjects who have a composite event between the PBUF and standard care groups. | Through study completion (until hospital discharge), an average of 15 days. |