Clinical trial NCT02656472
Conditions: Pediatric Cardiac Surgery Complication of Extracorporeal Circulation
Keywords: Pediatric Cardiac surgery Inflammatory response Tranexamic acid Epsilon Aminocaproic Acid
Sponsor: Wake Forest University Health Sciences
Start date: 2016-02-01; Completion date: 2017-04-01
Enrollment: 22 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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.

Detailed description:
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.

Arms: arm 1: TXA arm will include 10 subjects who will receive TXA for duration of surgery. arm 2: EACA arm will include 10 subjects who will receive EACA for the duration of surgery.
Interventions: intervention 1: Tranexamic acid intervention 2: Epsilon Aminocaproic Acid
Intervention descriptions: intervention 1: TXA Loading dose: 31 mg/kg diluted to 2 ml/kg Normal saline (NS) -in syringe intervention 2: Aminocaproic acid Loading dose: 75 mg/kg diluted to 2 ml/kg NS

Protocol documents:
Prot_SAP_000.pdf: 
Study Title: A Pilot Study Comparing Anti-Inflammatory Effects Of TXA Versus EACA In 
Pediatric Congenital Heart Surgery (TXAEACA). 
 
NCT#: NCT02656472 
 
Date: 5/1/2017 
 
 
Patient Selection 
 
This pilot study was conducted with a prospective, double blind, randomized control parallel block 
design. The study was conducted at a single, tertiary care center, Advocate Children’s Hospital 
in Oak Lawn, Illinois. The United States Food and Drug Administration currently approve neither 
TXA nor EACA for use in children, thus investigational new drug approvals were obtained for both 
drugs (number 127517). The study was approved by the hospital Institutional Review Board. 
Informed consent/assent was obtained from all patients prior to enrollment. Patients were enrolled 
from February 2016 to October 2016. 
Inclusion criteria included children age 3 months to 17 years undergoing heart surgery 
requiring CPB and redo sternotomy. Patients were excluded if they were undergoing Fontan or 
Glenn procedures, had coagulation profile abnormality, renal insufficiency, chronic hepatopathy, 
immunosuppressant drug use within last 1 month, history of seizures within last 6 months or 
current antiepileptic medication use, or had a known allergy to EACA or TXA. Patients were 
randomly assigned to TXA or EACA group in a 1:1 ratio. Patient allocation was performed by 
study pharmacist using a computer-generated list. Patient, family, surgical team, and 
cardiovascular intensive care unit (CVICU) team were blinded to treatment group. All data were 
managed using REDCap electronic data capture tool (16). 
Parents of all patients eligible for study were informed about the research and sent a study 
packet including a copy of the consent and assent form (if applicable) for review. An investigator 
subsequently called the parents to explain the research study and answer questions. 
Documentation of informed consent/assent was obtained prior to surgery during the preoperative 
visit or on the day of surgery. Assent was obtained on all patients >7 years of age. 


Perioperative Management of Patients 
 
Medications were prepared by the pharmacy. TXA (Mylan Institutional LLC) 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, pre-CPB (< 16kg: 45 mg; 16-30 kg: 
90mg; > 30kg: 120mg) (13). EACA (Hospira, Inc.) 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, pre-CPB (14). To ensure study blinding, loading doses for both medications were 
prepared in normal saline 2 ml/kg (0.9 % normal saline, Baxter). Continuous infusions were 
prepared in normal saline such that 1 ml/kg/hr delivered desired dosage. Second bolus was 
prepared in normal saline 1 ml/kg. The drugs were made similar in appearance and volume. 
Operating room nurse administered the study drugs. Infusion was discontinued prior to leaving 
operating room or immediately upon CVICU arrival. 
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. Blood samples were 
centrifuged and separated plasma stored at -70°C. At mid study, 30 samples (3/patient) were sent 
to Eve Technology Lab (Calgary, Canada) where multiplex human cytokine assays were run in 
duplicate. 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. Biomarkers in the single 13 multiplex cytokine assay included 
granulocyte macrophage colony-stimulating factor (GM-CSF), monocyte chemoattractant protein- 
1 (MCP-1), TNFα, interferonγ (IFN), IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10β, IL-12, and IL-13. 
Same procedures were followed for remainder of the samples at the conclusion of the study. 
 
Standard Intra-Operative Protocol 
 
Patients received general anesthesia using sevoflurane, fentanyl and rocuronium. Once under 
anesthesia, arterial and central venous access was obtained. All patients received 
methylprednisolone (30 mg/kg; maximum dose 500 mg) after induction of anesthesia. Intra- 


operative monitoring included arterial blood pressure, central venous pressure, systemic oxygen 
saturation, and cerebral and somatic (kidney) near-infrared spectroscopy. Surgical team and 
procedures remained constant during enrollment period, consisting of 3 surgeons (2 present in 
each surgery). 
Median sternotomy incision was performed on all patients. Heparin loading dose, 
maintenance and reversal were guided by Medtronic HMS Plus system. Post-heparinization, 
kaolin activated clotting time and heparin blood concentrations were measured at routine 
intervals. Standard, non-pulsatile, roller pump CPB, utilizing mild to moderate hypothermia (28- 
32°C) with pH stat acid-base management was used. CPB circuit consisted of Terumo hard shell 
reservoirs, polypropylene membrane oxygenators, Medtronic tubing with Trillium coating and 
Medtronic Affinity arterial filters. Under full heparinization (activated clotting time >300 seconds), 
CPB was initiated. The CPB circuit was primed with Plasmalyte A, 3000 U/L heparin and 15 mEq/L 
sodium bicarbonate. Mannitol (0.5 gm/kg) was added after initiation of CPB and during rewarming. 
Packed red blood cells were added as needed to maintain a hematocrit >22%, in 25 ml 
increments, paired with additional Plasmalyte A chasers and hemofiltration. Fresh frozen plasma 
(FFP) was given to patients <7 kg (50 ml post-CPB initiation and 50 ml during rewarming). 
Myocardial protection was obtained using cold blood cardioplegia, intermittent or continuous 
infusion, per surgeon’s request. A terminal warm reperfusion was used for all patients prior to 
aortic cross clamp removal. Hemoconcentration and modified ultrafiltration were used routinely. 
Protamine was given at conclusion of case. 
Standard Postoperative Protocol 
 
Patients were taken to a dedicated CVICU, staffed at all times by in-house pediatric 
cardiovascular attending physicians. Decision for transfusion was made clinically at the discretion 
of attending physicians. 


Duration of CPB, aortic cross clamp time, Society of Thoracic Surgeons - European 
Association for Cardiothoracic Surgery mortality category (STAT category) and inotropic score for 
first 48 hours after surgery were used to compare surgical complexity between groups. Blood 
product utilization during and after surgery, and chest tube output for first 72 hours was 
documented. 
Statistical Analysis 
 
As this was a pilot study, sample size calculation was not performed. We recruited 20 patients, 
10 per study group. An interim analysis was performed for safety evaluation, after which no 
adjustments were made to study protocol. 
Between group comparisons were examined using independent groups Student’s t-test or 
Mann-Whitney U tests when data were not normally distributed. Dichotomous variables were 
examined using Chi-square or Fisher exact test. Within group comparisons for change over time 
(pre-CPB, post-CPB and 24 hour post-CPB) were tested using Friedman test. A p value of <0.05 
was considered statistically significant. Adjustments for multiple comparisons were not made 
because of the explanatory nature of this study.