A Pilot Study Comparing Anti-Inflammatory Effects Of TXA Versus EACA In Pediatric Congenital Heart Surgery

Study Overview
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Brief Summary
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The purpose of this study is to compare anti-inflammatory effects of two anti-fibrinolyntic drugs (Tranexamic acid versus Epsilon-aminocaproic acid) in pediatric patients undergoing pediatric cardiac surgery.

Detailed Description
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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 activation3 and activation of inflammatory cytokines, especially IL-1 IL-64, IL-8 and 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 CBP 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.

Official Title
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A Pilot Study Comparing Anti-Inflammatory Effects Of Tranexamic Acid Versus Epsilon Aminocaproic Acid In Pediatric Congenital Heart Surgery

Conditions
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Pediatric Cardiac Surgery, Complication of Extracorporeal Circulation

Intervention / Treatment
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* Drug: Tranexamic acid
* Drug: Epsilon Aminocaproic Acid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients undergoing pediatric cardiac surgery, with redo sternotomy needing cardiopulmonary bypass 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) Prothrombin time [PT] >50% of High Normal value Partial Thromboplastin Time [PTT] > 50% of High Normal value Platelets < 50,000/mm3 International normalized ratio (INR) >2 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)

Ages Eligible for Study
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Minimum Age: 3 Months
Maximum Age: 17 Years

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: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Tranexamic Acid Arm<br>TXA arm will include 10 subjects who will receive TXA for duration of surgery. | Drug: Tranexamic acid<br>* TXA Loading dose: 31 mg/kg diluted to 2 ml/kg NS (in syringe) 31 x _______kg = _______ mg TXA (max: 930mg) 2 x _______ kg = _______ ml NS (max: 60 ml) TXA infusion: 14 mg/kg hour = 1 ml/kg/hour (6 hour bag) (Max rate of infusion = 30ml/hr) 14 x ______ kg = _____mg x 6 = ______ mg TXA (max: 2,520mg) 1 x ______ kg = _______ml x 6 = ______ ml NS (max: 180ml) TXA second bolus in 1 ml/kg NS < 16 kg: TXA 45 mg in 1 ml/kg NS = _______ml NS 16-30 kg: TXA 90 mg in 1 ml/kg NS = _______ml NS > 30 kg: TXA 120 mg 1 ml/kg NS = _______ml NS (max 30ml)<br>* Other names: TXA;|
| Active Comparator: Epsilon Aminocaproic Acid Arm<br>EACA arm will include 10 subjects who will receive EACA for the duration of surgery. | Drug: Epsilon Aminocaproic Acid<br>* Aminocaproic acid Loading dose: 75 mg/kg diluted to 2 ml/kg NS 75 x _______kg = _______ mg EACA (max: 2,250mg) 2x _______ kg = _______ ml NS (max 60ml) Aminocaproic acid infusion: 75 mg/kg hour = 1 ml/kg/hour (6 hour bag) 75 x ______ kg = _____mg x 6 = ______ mg EACA (max: 13,500 mg) 1 x ______ kg = _______ml x 6 = ______ ml NS (max: 180ml) Aminocaproic acid second bolus: 75 mg/kg in 1ml/kg NS 75 x _______kg = _______ mg EACA (max: 2,250mg) 1 x _______ kg = _______ ml NS (max 30 ml)<br>* Other names: EACA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of pro inflammatory markers/cytokines by comparing Area under curve of cytokine production | Area under the curve (AUC) of cytokine production. Markers to be analyzed include (part of single cytokine multiplex assay) GM-CSF IFN gamma IL-1beta IL-2 IL-4 IL-6 IL-8 IL-10 IL-12(p70) MCP-1 TNF-alpha | upto 24 hours post surgery | 
| time to net negative fluid balance | Compare time taken for patient to have net negative fluid balance during first 2 weeks post surgery | assessed at 2 weeks | 
| time of chest tube removal | compare time of chest tube removal in hours in the two groups | time to chest tube removal or death whichever is earlier, assessed at 1 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Chest tube output in first 48 hours |  | assessed at 48 hours | 
| Compare the volume of blood product replacement needed in first 48 hours of surgery (including blood products used in OR), in each study arm | reported in milliliters (ml) for each patient | 48 hours after surgery | 
| Comparison of antifibrinolytic effect of TXA vs EACA using routine lab tests | TEG, Fibrinogen, D-Dimer, CBC, CMP | baseline and 24 hours | 
| ICU length of stay and Hospital length of stay | evaluated through study completion | compare length of stay in days of patients in each study arm, at an average of 2 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pediatric Cardiac surgery, Inflammatory response, Tranexamic acid, Epsilon Aminocaproic Acid