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The purpose of this study is to compare anti-inflammatory effects of two anti-fibrinolytic drugs (Tranexamic acid versus Epsilon-aminocaproic acid) in pediatric patients undergoing pediatric cardiac surgery.
Bleeding under cardiopulmonary bypass (CPB) is one of the most common complications in patients undergoing pediatric cardiac surgery. The inflammatory response produced during and after CPB is a factor that adds significantly to the morbidity after cardiac surgery. A number of factors have been shown to be involved inducing the inflammatory response. These include complement system activation and activation of inflammatory cytokines, especially Interleukin (IL)-1, IL-6, IL-8 and Tumor necrosis factor (TNF) alpha.
Tranexamic Acid (TXA) and Epsilon-Aminocaproic Acid (EACA) are lysine analogues frequently used as anti-fibrinolytic agents in patients undergoing CPB. Many authors have highlighted the role of TXA in reducing blood loss and blood transfusion during and after CPB. Role of EACA and aprotinin in decreasing pro-inflammatory response during and after CPB has been well documented in adult literature. Patients undergoing redo sternotomy have higher inflammatory response as compared to patients undergoing first cardiac surgery. It has also been shown that the TXA can reduce the inflammatory response after CPB by acting directly or indirectly on the inflammatory cytokines.
There are no studies directly comparing the anti-inflammatory properties of EACA and TXA in the pediatric population undergoing CPB. In our institution, EACA is used as the standard of practice to reduce the blood loss during pediatric cardiac surgeries, but the investigators have now started using TXA more recently.
The aim of this study is to compare the anti-inflammatory and anti-fibrinolytic properties of these two anti-fibrinolytic agents in pediatric patients undergoing CPB for cardiac surgery.
Hypothesis: Tranexamic acid (TXA) has better anti-inflammatory profile as compared to €-Amino Caproic Acid (EACA) which may help in reducing blood loss, renal injury, hepatic injury and blood transfusion during and after CPB
Specific Objectives: During redo sternotomy procedures there is significant anti-inflammatory response which occurs and plays a role in increasing amount chest tube output, blood loss, renal injury, hepatic injury and ultimately patient morbidity and/or mortality. The proposed study will help to know if antifibrinolytic agents are beneficial in reducing the anti-inflammatory response produced and which of the two drugs (EACA or TXA), has a better anti-inflammatory profile when used in a similar setting for patients undergoing pediatric cardiothoracic surgery.
Specific Aims:
Evaluate whether TXA or EACA can decrease inflammatory response produced during redo sternotomy procedures in pediatric patients and which drug decreases the injury and/or cardiac dysfunction more as reflected by fluid balances, inotropic support, diuretic requirement, length of ventilator support, length of ICU stay, and length of hospital stay.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Tranexamic Acid Arm | Active Comparator | TXA arm will include 10 subjects who will receive TXA for duration of surgery. |
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| Epsilon Aminocaproic Acid Arm | Active Comparator | EACA arm will include 10 subjects who will receive EACA for the duration of surgery. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Tranexamic acid | Drug | TXA Loading dose: 31 mg/kg diluted to 2 ml/kg Normal saline (NS) -in syringe |
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| Measure | Description | Time Frame |
|---|---|---|
| Inflammatory Markers/Cytokines | Consented patients had research-related blood draws (0.3 ml) at three time points: pre-CPB, post-CBP following protamine administration and 24 hours post-CPB. Average of the values run in duplicate was used for calculations. For samples with values reported as out of range (due to level being below detection), the lowest detectable value was assigned for analysis. | 24 hours post-surgery |
| Measure | Description | Time Frame |
|---|---|---|
| Chest Tube Output | Chest tube output in ml/kg for the first 48 hours | 48 hours post-surgery |
| Blood Replacement Volume | Compare the volume of blood product replacement needed in first 48 hours of surgery (including blood products used in OR) |
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Inclusion Criteria:
Exclusion Criteria:
Patients undergoing Fontan or Glenn procedures
Allergy to EACA or TXA
Baseline coagulation profile abnormality * (The coagulation profile will be used as an exclusion criteria, if results available. Occasionally the results of coagulation profile may be unavailable prior to surgery due to a clotted sample. For such patients, as per the current clinical practice, we would not be redrawing the lab solely for a research purpose)
Acute or chronic renal failure (creatinine > 2x high normal for age)
Chronic hepatopathy (any transaminase > 2x high normal for age)
Use of immunosuppressant drugs (within last 1 month)
History of seizures (currently on antiepileptic drugs for epilepsy or history of seizure within last 6 months)
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| Name | Affiliation | Role |
|---|---|---|
| Andrew VanBergen, M.D. | Director, Section of Pediatric Cardiac Critical Care | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Advocate Childrens Hospital | Oak Lawn | Illinois | 60453 | United States |
1 patient excluded after consent, prior to randomization, as exclusion criteria were present prior to surgery.
At mid-study analysis, 1 significant outlier was noted (met inclusion criteria but was inpatient at time of randomization with multiple comorbidities where all other subjects were admitted on day of surgery).
Dates of recruitment: From February 2016 to September 2016
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| ID | Title | Description |
|---|---|---|
| FG000 | Tranexamic Acid (TXA) Arm | TXA arm will include 10 subjects who will receive TXA for duration of surgery. Tranexamic acid: TXA Loading dose: 31 mg/kg diluted to 2 ml/kg NS |
| FG001 | Epsilon Aminocaproic Acid (EACA) Arm |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | May 1, 2017 |
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| Epsilon Aminocaproic Acid | Drug | Aminocaproic acid Loading dose: 75 mg/kg diluted to 2 ml/kg NS |
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| 48 hours post-surgery |
| Platelet Levels | Antifibrinolytic effect using platelets levels x 1000/mL | Immediately post-surgery and 24 hours post-surgery |
| Liver Enzymes | Tests were recorded and compared between the groups to analyze the effect of the antifibrinolytic agent used on the amount of blood loss as well as effect of inflammation on the liver and kidney. | Immediately post-surgery and 24 hours post-surgery |
| Hemoglobin | Tests were recorded and compared between the groups to analyze the effect of the antifibrinolytic agent used on the amount of blood loss as well as effect of inflammation on the liver and kidney. | Immediately post-surgery and 24 hours post-surgery |
| Creatinine | Tests were recorded and compared between the groups to analyze the effect of the antifibrinolytic agent used on the amount of blood loss as well as effect of inflammation on the liver and kidney. | Immediately post-surgery and 24 hours post-surgery |
| Length of Stay | Length of stay in the ICU and overall hospital stay. | 2 months |
EACA arm will include 10 subjects who will receive EACA for the duration of surgery.
Epsilon Aminocaproic Acid: Aminocaproic acid Loading dose: 75 mg/kg diluted to 2 ml/kg NS.
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | Tranexamic Acid Arm | TXA arm included 10 subjects who received TXA for duration of surgery. TXA dosing strategy used an initial 31 mg/kg load at start of surgery, followed by 14 mg/kg/hr continuous infusion, and weight-dependent bolus dose after heparinization. |
| BG001 | Epsilon Aminocaproic Acid Arm | EACA arm included 10 subjects who will received EACA for the duration of surgery. EACA dosing strategy used an initial 75 mg/kg load at start of surgery, followed by 75 mg/kg/hr continuous infusion, and 75 mg/kg bolus dose after heparinization. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
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| Sex/Gender, Customized | Number | participants |
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| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
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| Weight | Mean | Standard Deviation | Weight (kg) |
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| Height | Mean | Standard Deviation | centimeters |
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| STAT category | STAT Mortality Categories are a multi-institutional, validated complexity stratification tool for pediatric and congenital heart surgery. Operations were sorted by increasing risk and grouped into 5 categories (the STAT Mortality Categories). STAT Category 1 is associated with the lowest risk of mortality and STAT Category 5 is associated with the highest risk of mortality. The STAT Mortality Categories allow outcomes to be assessed in relation to the complexity of the operations being performed. | Mean | Standard Deviation | units on a scale |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Inflammatory Markers/Cytokines | Consented patients had research-related blood draws (0.3 ml) at three time points: pre-CPB, post-CBP following protamine administration and 24 hours post-CPB. Average of the values run in duplicate was used for calculations. For samples with values reported as out of range (due to level being below detection), the lowest detectable value was assigned for analysis. | Posted | Median | Inter-Quartile Range | pg/dl | 24 hours post-surgery |
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| Secondary | Chest Tube Output | Chest tube output in ml/kg for the first 48 hours | Posted | Median | Inter-Quartile Range | ml/kg | 48 hours post-surgery |
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| Secondary | Blood Replacement Volume | Compare the volume of blood product replacement needed in first 48 hours of surgery (including blood products used in OR) | Posted | Median | Inter-Quartile Range | ml/kg | 48 hours post-surgery |
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| Secondary | Platelet Levels | Antifibrinolytic effect using platelets levels x 1000/mL | Posted | Mean | Standard Deviation | Platelets x1000/mL | Immediately post-surgery and 24 hours post-surgery |
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| Secondary | Liver Enzymes | Tests were recorded and compared between the groups to analyze the effect of the antifibrinolytic agent used on the amount of blood loss as well as effect of inflammation on the liver and kidney. | Posted | Mean | Standard Deviation | U/L | Immediately post-surgery and 24 hours post-surgery |
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| Secondary | Hemoglobin | Tests were recorded and compared between the groups to analyze the effect of the antifibrinolytic agent used on the amount of blood loss as well as effect of inflammation on the liver and kidney. | Posted | Mean | Standard Deviation | g/dl | Immediately post-surgery and 24 hours post-surgery |
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| Secondary | Creatinine | Tests were recorded and compared between the groups to analyze the effect of the antifibrinolytic agent used on the amount of blood loss as well as effect of inflammation on the liver and kidney. | Posted | Mean | Standard Deviation | mg/dl | Immediately post-surgery and 24 hours post-surgery |
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| Secondary | Length of Stay | Length of stay in the ICU and overall hospital stay. | Posted | Median | Inter-Quartile Range | days | 2 months |
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9 months
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Tranexamic Acid Arm | TXA arm will include 10 subjects who will receive TXA for duration of surgery. Tranexamic acid: TXA Loading dose: 31 mg/kg diluted to 2 ml/kg NS. | 0 | 10 | 1 | 10 | 0 | 10 |
| EG001 | Epsilon Aminocaproic Acid Arm | EACA arm will include 10 subjects who will receive EACA for the duration of surgery. Epsilon Aminocaproic Acid: Aminocaproic acid Loading dose: 75 mg/kg diluted to 2 ml/kg NS. | 0 | 10 | 0 | 10 | 0 | 10 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Pulmonary hemorrage | Respiratory, thoracic and mediastinal disorders | Systematic Assessment | 1 patient had acute pulmonary hemorrhage noted 36 hours after surgery, requiring reintubation. The likely etiology was spontaneous rupture of tracheobronchial vessel and was felt to be unrelated to TXA use. |
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Small sample size and wide age range lead to substantial variation in values, making it difficult to draw conclusions. Biomarker levels were collected at three time points, not including a 4-hour post-CPB level, when most cytokines are known to peak.
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Andrew VanBergen | Advocate Children's Hospital | 7086848758 | andrew.vanbergen@advocatehealth.com |
| Sep 6, 2024 |
| Prot_SAP_000.pdf |
| ID | Term |
|---|---|
| D014148 | Tranexamic Acid |
| D015119 | Aminocaproic Acid |
| ID | Term |
|---|---|
| D003509 | Cyclohexanecarboxylic Acids |
| D000146 | Acids, Carbocyclic |
| D002264 | Carboxylic Acids |
| D009930 | Organic Chemicals |
| D000614 | Aminocaproates |
| D002208 | Caproates |
| D000144 | Acids, Acyclic |
| D000596 | Amino Acids |
| D000602 | Amino Acids, Peptides, and Proteins |
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| Pre-CPB-IL4 |
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| Pre-CPB-IL5 |
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| Pre-CPB-IL6 |
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| 24 hour post CPB IL-1 |
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