The Effect of Intravenous EACA on Blood Loss and Transfusion Requirements After Bilateral VRO

Study Overview
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Brief Summary
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E-Aminocaproic acid (EACA) is an anti-fibrinolytic agent that is used to decrease blood loss and transfusion requirements after several orthopedic procedures. The aim of this prospective double-blind placebo-controlled randomized trial is to determine whether IV EACA reduces intra-operative calculated total blood loss in patients undergoing bilateral varus rotational osteotomy (VRO). This study will also investigate intraoperative cell saver utilization, transfusion of allogeneic blood, hospital length-of-stay (LOS), short term complications, and long-term outcomes.This study will provide Level I evidence and has the potential to improve outcomes in children undergoing this procedure.

Detailed Description
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The participating anesthesiologists will not be blinded to study arms and hypotheses. Dr. Christopher Edmonds will be the head anesthesiologist for this study and will administer anesthetics to participants in this trial whenever his schedule makes it possible. Anesthesia will be conducted in a standardized fashion, with IV sedation using Versed and IV propofol, +/- Fentanyl and Ketamine . A Combined Spinal-Epidural (CSE) will be placed using 12.5-20 mg of bupivacaine. If a CSE is unsuccessful and an epidural and/or spinal are successfully obtained, the patient may still be included in the study. Patients not receiving neuraxial anesthesia will be excluded. If a patient requires general anesthesia, it will be induced at this time, but the patient will be excluded from the study. An arterial line and additional venous access will be obtained in standardized sterile practice. Sedation will be maintained with IV propofol. IV Valium, Toradol and IV acetaminophen will be given towards the end of the case, per anesthesiologist's discretion. The blood pressure target will be 20-25% below baseline, which will be achieved primarily with the neuraxial anesthesia. For blood pressure above this range, the epidural will be dosed with a short-acting local anesthetic, and/or IV sedation will be titrated as per the anesthesiologist's judgment. For hypotension below this range, pressors or intravenous pressors will be given. An IV fluid bolus may also be given in the amount of 10-20cc/kg. Additional maintenance IV fluids will be given to maintain urine output of at least 0.5-1ml/kg/hr. The criteria for transfusion of blood products will be a hemoglobin level of < 7.0 g/dL or a hemoglobin level of < 10.0 g/dL with clinical signs of symptomatic anemia (e.g., unexplained tachycardia, hypotension unresponsive to fluids or vasopressors, change in mental status, low urine output, and shortness of breath). Blood will be administered 1 unit at a time, and the presence of symptoms or signs will be reassessed after each unit. This algorithm may be altered by the treating physician (e.g., PACU attending, surgeon, or the OR anesthesiologist), however all decisions will be supported by reasonable documentation. Drains will be removed on POD 2 unless specified by the attending surgeon. Of note, the chart of the patient will clearly indicate him/her as a study patient; a sticker will be place on the front of each participating patient's chart. Their enrollment will also be communicated in the clinician rounding notes for each patient. Drains will be labeled for each study participant as well, and nurses will record the drain outputs per their floor protocol. Attending surgeons, orthopedic surgery residents, physician assistants and research assistants involved with this study will assist in data collection. For each patient, we will collect demographic data, pre-operative CBC data, intra-operative cell saver auto-transfusion volumes, post-operative number of packed red blood cell units transfused, post-operative CBC data, post-operative drain outputs, and post-operative complications. This information will be gathered from the peri-operative medical records and electronic medical records. Surgeons and clinical and research personnel will review medical chart and progress notes for evidence of clinically significant VTE, reoperation, hematoma, seroma, and infection.

Official Title
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The Effect of Intravenous E-Aminocaproic Acid (EACA) on Blood Loss and Transfusion Requirements After Bilateral Varus Rotational Osteotomy (VRO)

Conditions
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E-Aminocaproic Acid, Bilateral Varus Rotational Osteotomy

Intervention / Treatment
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* Drug: E-Aminocaproic acid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Scheduled for bilateral varus rotational osteotomy (VRO) with or without associated soft tissue and osseous procedures Exclusion Criteria: Preoperative use of an anticoagulant (Plavix, warfarin, lovenox, etc.) History of hypersensitivity to EACA History of thromboembolic event (e.g., PE or DVT) History of renal insufficiency or failure Congenital or acquired coagulopathy as evidence by INR >1.4 or PTT > 1.4 times normal, or Platelets <150,000/mm3 on preoperative laboratory testing Use of hormone replacement therapy or hormonal contraceptive agents within days prior to surgery Use of acetylsalicylic acid (ASA), antiplatelet agents within 7 days prior to surgery Pregnant Breastfeeding Not received neuraxial anesthesia

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 18 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: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: E-Aminocaproic acid (EACA)<br>An EACA loading dose of 100 mg/kg with a max of 4-5 grams will be given up to 1 hour prior to incision. During the case, an EACA infusion of 33 mg/kg/hr (max of 1 gram/hr) will be maintained. The use of EACA will be terminated at the end of the case. | Drug: E-Aminocaproic acid<br>* E-Aminocaproic acid (EACA) is a synthetic lysine analog that competitively inhibits the activation of plasminogen to plasmin and subsequently decreases the degree of fibrinolysis (Faraoni,2014} and is currently being used to decrease blood loss and transfusion requirements after orthopaedic procedures.(Eubanks,2010} Multiple meta analyses and retrospective and prospective studies have shown that EACA decreases blood loss and transfusion requirements after orthopaedic surgery{ McLeod,2013; Thompson, 2005; Thompson,2008; Gill,2008; Florentino-Pineda,2001}.Results from these studies also suggest that EACA will decreased post-operative morbidity, length of hospital stay, hospital costs, and complications.{Chimento,2013; Thompson,2005; Florentino-Pineda,2001}<br>* Other names: EACA;|
| Placebo Comparator: Placebo<br>Equivalent volume of normal saline prepared by the pharmacy. | Drug: E-Aminocaproic acid<br>* E-Aminocaproic acid (EACA) is a synthetic lysine analog that competitively inhibits the activation of plasminogen to plasmin and subsequently decreases the degree of fibrinolysis (Faraoni,2014} and is currently being used to decrease blood loss and transfusion requirements after orthopaedic procedures.(Eubanks,2010} Multiple meta analyses and retrospective and prospective studies have shown that EACA decreases blood loss and transfusion requirements after orthopaedic surgery{ McLeod,2013; Thompson, 2005; Thompson,2008; Gill,2008; Florentino-Pineda,2001}.Results from these studies also suggest that EACA will decreased post-operative morbidity, length of hospital stay, hospital costs, and complications.{Chimento,2013; Thompson,2005; Florentino-Pineda,2001}<br>* Other names: EACA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intraoperative Calculated Total Blood Loss | Determined by estimated blood volume, calculated using difference in preoperative and postoperative hemoglobin and applied to the Nadler equation for estimating blood volume while adjusting for transfused hemoglobin to produce a single metric of calculated intraoperative blood loss. | Intraoperative (3-6 hours) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intraoperative Cell Saver Utilization | Number of participants requiring 1 unit of intraoperative cell saver transfusion. Patients either received or did not receive intraoperative cell saver transfusion. The maximum number of intraoperative units transfused in this study was 1 unit. The count of participants in the data table refers to the number of patients who received this transfusion. | Intraoperative, 1 day | 
| Postoperative Allogeneic Blood Transfusion | The number of participants that required 1 unit of blood transfused post-operatively. Patients received blood if necessary post operatively, and the maximum number of units a patient received was 1. The count of participants refers to the number of patients who received this transfusion unit. | Post-Surgery, an expected average of 1 week | 
| Post Operative Blood Loss | 24 hour drain output (mL) | Post-Surgery, 24 hours | 
| Length of Hospital Stay | postoperative day of discharge after surgery- day of intake. | Post-Surgery, an expected average of 1 week | 
| Complications [VTE (Symptomatic of DVT or PE), Infection (Superficial, Deep), Hematoma, Seroma, Reoperation, and Death] | Incidence of VTE (symptomatic of DVT or PE), infection (superficial, deep), hematoma, seroma, reoperation, and death, measured in person-years ( x cases per 100,000 person years) | an expected average of 1 week (post-surgery), Follow-up at 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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E-Aminocaproic Acid, Bilateral Varus Rotational Osteotomy, Blood Loss and Transfusion, Complications, Safety