The Effect of Intravenous E-Aminocaproic Acid (EACA) on Blood Loss and Transfusion Requirements After Bilateral Varus Rotational Osteotomy (VRO)
Phase: PHASE4
Conditions: E-Aminocaproic Acid, Bilateral Varus Rotational Osteotomy
Sponsor: Hospital for Special Surgery, New York

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The Effect of Intravenous EACA on Blood Loss and Transfusion Requirements After 
Bilateral VRO 
 
Protocol and Analysis Plan 
 
NCT # NCT02257580 
 
Approved 12/10/2014 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

1. What is the Study Design  
  
Experimental:  
  
Randomized controlled clinical trial (RCT) 
  
  
2. Who will be recruited and enrolled? 
  
Inclusion Criteria: 
  
Patients will be recruited from the practices of Dr. Scher and Dr. Dodwell.  Inclusion 
criteria will include the following:  
• 
Age less than or equal to 18  
• 
Scheduled for elective bilateral VRO with or without associated soft tissue and 
osseous procedures  
  
Exclusion Criteria:   
  
All patients will be asked to discontinue acetylsalicylic acid (ASA), antiplatelet agents, and 
hormone replacement and hormonal contraceptive agents at least 7 days prior to surgery. 
Other than ASA, these agents will be held 6 weeks postoperatively.   
  
• 
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 agent within 7 days prior 
to surgery  
• 
Pregnant  
• 
Breastfeeding  
• 
Older than 18 years of age  
• 
Patients not receiving neuraxial anesthesia  
  
  
This trial will be registered on ClinicalTrials.gov.  All patients undergoing bilateral VRO 
by the study surgeons (DS and ED) will be identified in their office and screened for 
eligibility as potential patients for participation in the study. A research assistant will 
review the office and operative calendars of the study surgeons each week to identify and 
recruit potential patients.  The assistant will record on the CONSORT diagram any 
reasons for ineligibility/exclusion.  
   

The surgeon, a co-investigator or research assistant will obtain consent prior to 
surgery, at the patient’s preadmission screening visit.  All authors on the protocol, in addition 
to their research assistants, will be designated to obtain consent.  
   
We will power the study to detect a 250mL difference in calculated intra-operative blood loss 
between groups.  This effect size has been used in the total hip literature, and it is considered to 
be a clinically significant difference in blood loss15. Our analysis shows that 12 patients are 
required in each arm of the study (24 patients total) to achieve 81% power with an independent-
sample t-test and statistical significance set to alpha equal to 0.05.  Expecting that 10-25% of 
patients will be excluded, we will aim to enroll a total of 30 patients in this study.  
  
  
Patients aged 18 or younger will be screened for study eligibility  
  
3. Interventions or Observations – what data are going to be collected and from what 
source?   
  
Only anesthesiologists agreeing to participate in the study will be paired with the study 
surgeons. Anesthesia will be conducted in a standardized fashion. The 
anesthesiologist will perform a neuraxial block (epidural, spinal, combined-spinal 
epidural) as well as administer general anesthesia. A neuraxial block will be placed 
using bupivicaine.  A balanced general anesthetic utilizing a combination of either 
isoflurane, sevoflurane with or without nitrous oxide, vecuronium, midazalam and 
either fentanyl, morphine or dilaudid as the narcotic will be used at the discretion of 
the anesthesiologist.  If a combined-spinal epidural is unsuccessful and an epidural 
and/or spinal are successfully obtained, the patient will still be included in the study.  
Patients not receiving neuraxial anesthesia will be excluded from the study.  Arterial 
and venous access will be obtained in the usual sterile manner for monitoring.  
   
      The blood pressure target will be 20-25% below baseline, which will be achieved 
primarily with the combination of the general anesthesia and the neuraxial 
anesthesia.  For blood pressure above this range, the epidural will be dosed with a 
short-acting local anesthetic, and/or the depth of the general anesthetic and will be 
titrated as per the anesthesiologist’s judgment.  For hypotension below this range, 
intravenous pressors, crystalloid, colloid or blood will be given. The technique of 
induced hypotension will not be utilized during these cases.  Additional maintenance 
IV fluids or colloid will be given to maintain urine output of at least 0.5-1ml/kg/hr.  
Toradol and IV acetaminophen may be given towards the end of the case per the 
anesthesiologist’s discretion.   
  
 Bilateral VRO will be performed as per the surgeon’s routine practice.  In general, the 
operative extremity will be prepped and draped in the usual sterile fashion. Prior to 
incision, the anesthesiologist will administer a loading dose of 100 mg/kg of EACA 
with a max of 4-5 grams up to 1 hour prior to incision.   During the case, an 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.  Patients randomized to the placebo arm will be 

infused with a comparable volume of normal saline prepared by the pharmacy. All 
participating anesthesiologists will not be blinded in this study.  A direct lateral 
approach to the femur will be used, and standard surgical techniques for intra-
operative hemostasis will be utilized. The surgeon will perform bilateral femoral 
osteotomies and associated soft tissue surgery and pelvic osteotomy.  After all 
hardware is placed, the wound will be thoroughly irrigated and suctioned.  A deep 
drain will be placed on each operative side, and the wound will be closed in 
layers.  Intra-operatively, a cell saver will be used, and the volume (mL) of auto-
transfusion will be recorded.   
  
Hematocrit levels will be monitored regularly in the post-operative period.  As per protocol, a 
post-op hematocrit will be drawn in the PACU, and subsequently, daily labs will be obtained 
unless specified by the medicine or surgical attending.  Routine, daily inpatient CBC data and 
drain output will be reviewed.  Inpatient and office records will be accessed to help identify 
postoperative complications. 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, pediatrician, 
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, and 
the 24-hour clock will begin once the patient is in the PACU. All drains, patient charts, and 
patient rooms will be clearly labeled in order to identify study patients.    
 
  
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.   
  
A sticker will be place on the front of each participating patient’s chart identifying him or her 
as a study patient.  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.  
  
Data recorded from the electronic medical record will include:  
• 
Date of surgery  
• 
Patient age at the time of surgery  
• 
Patient sex  
• 
Patient height (cm) and weight (kg) at time of admission   
• 
Preoperative CBC data and coagulation study data  

• 
Postoperative hemoglobin on all inpatient days postoperatively (g/dL)  
• 
Transfusion requirement during inpatient stay (units required)   
• 
Transfusion reaction  
• 
Total 24-hour drain output  
• 
Postoperative day and time of discharge  
• 
Chart review of progress notes for evidence of clinically significant VTE   
• 
Chart review of progress notes for evidence of reoperation, hematoma, seroma, or 
postoperative infection   
  
Data recorded from the operating room record will include:  
• 
Anesthetic used (e.g., spinal/epidural, general, etc.)  
• 
Operative times (minutes)  
• 
Intra-operative transfusion requirements (units of blood)  
• 
Use of cell saver intraoperatively (auto-transfusion volume, mL)  
• 
Intra-operative complications  
  
Data recorded from outpatient postoperative office records will include:  
• 
Chart review of progress notes for evidence of clinically significant VTE through 
six weeks post-operatively  
• 
Chart review of progress notes for evidence of re-operation, hematoma, seroma, 
or postoperative infection through six weeks post-operatively  
  
  
Patients will be randomized to either the intervention or control group, as per 
randomization protocol described elsewhere in the proposal. For patients who are 
randomized to the control group, study data will be collected in the same manner as 
for the intervention group.  
  
  
All tests and imaging used in this study are considered standard of care.  
  
Randomization Process:  
 The patients will be randomized into one of 2 groups: (1) Loading dose and infusion of EACA 
(2) Equivalent volume of normal saline prepared by the pharmacy.  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.  Assignment of patients will be made based on a 
sequential treatment assignment or minimization strategy in order to ensure an even distribution 
of patients in each treatment arm.  More specifically, each patient will be randomized to the 
treatment arm that would minimize differences between groups.  Randomization will be 
stratified by sex and surgery type (bilateral VRO, bilateral VRO with associated soft tissue or 
osseous procedure) so that the number of male/female patients and VRO/associated procedure 
patients will be balanced in each study group between trial arms.   
  

The Biostatistics Core of the HSS Healthcare Research Institute will randomize each patient 
based on the minimization strategy.  It will be a double-blind experiment with all parties, except 
the pharmacy, anesthesiologist, and designated research assistant, being blinded to the 
randomization schedule (surgeon, medical staff, and patient). Patient recruitment will continue 
until a total of 30 patients are enrolled. 
  
Treatment Groups:  
Bilateral VROs will be performed as per the study surgeon’s routine practice.  In general, the 
operative extremity will be prepped and draped in the usual sterile fashion. Prior to incision, the 
anesthesiologist, will administer a loading dose of 100 mg/kg of EACA with (max of 4-5 grams) 
or an equivalent volume of normal saline prepared by the pharmacy. The loading dose may be 
give 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.  Only anesthesiologists agreeing to participate in the study will be 
paired with the study surgeons, and all anesthesiologists will be aware of a patient’s 
randomization to the treatment or placebo group.   
 
Outcome Measures  
Primary outcome: Calculated total blood loss.  
Secondary outcomes of interest: Postoperative transfusion requirements (allogeneic blood 
transfusion and intraoperative cell saver utilization), post-operative blood loss, length of stay, 
and post-operative complications.   
  
Calculated total blood loss will be determined from the difference between the preoperative 
hemoglobin and the postoperative hemoglobin (or the lowest postoperative hemoglobin during 
the hospital stay prior to transfusion).  Based on hemoglobin balance, the estimated blood loss 
will be calculated according to the formula by Nadler et al.17:  
Estimated Blood Volume (EBV) = (k1 x Height3 (m)) + (k2 x Weight (kg)) + k3  
For men, k1 = 0.3669, k2 = 0.03219, and k3 = 0.6041  
For women, k1 = 0.3561, k2 = 0.03308, and k3 = 0.1833  
  
Multiplying the EBV by the hematocrit (Hct) gives the red blood cell (RBC) volume.  As such, a 
change in the RBC volume can be calculated from a change in the Hct level23,24:  
Total RBC volume loss = EBV x (Hct Preop – Hct Postop)  
  
Transfusions (mean volume per unit at HSS, 250 mL) can be taken into account by calculating 
the total blood loss16:  
  
Total blood loss (L) = Total RBC volume loss + (No. of Units Transfused x 0.25) / (Hct Preop – 
Hct Postop) / 2)  
  
The rate of perioperative blood transfusions, both intraoperative and postoperative, will be 
documented for analysis.  
  
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 ouput, 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.  
  
VTE prophylaxis is not commonly used for pediatric patients at our institution. However, all 
patients will also receive a comprehensive approach to postoperative care comprised  of 
mechanical (sequential compressive device) prophylaxis in-house, early mobilization with 
physical therapy, medical optimization, and regional anesthesia (if appropriate).  
  
  
4. What is the long-term significance?   
  
There are certain risks associated with blood loss and blood transfusion after elective orthopaedic 
procedures in young patients.  Blood loss and transfusion requirements can be reduced with 
several blood conservation measures, including the use of pharmacological agents such as 
EACA.  If the use of IV EACA is shown to decrease blood loss and transfusion requirements 
after bilateral VROs, it will provide an efficacious and inexpensive method to reduce post-
operative morbidity and improve patient outcomes after bilateral VROs.  
  
D. SAMPLE SIZE AND DATA ANALYSIS   
    
Sample Size – 
   
1. Proposed analysis (e.g., student’s t-test, ANOVA, chi-square, regression, etc.):  
Independent samples t-test will be utilized if the data is normally distributed (or non-
parametric Mann-Whitney U test if assumption of normality is not met).  
  
2. Alpha level:  0.05  
  
3. Beta or power level:  0.81  
  
4. Primary outcome variable estimate (mean +/- s.d. for continuous outcome, 
frequency/percentage for categorical variable):    
The primary outcome of interest in total intra-operative blood loss, which will be 
summarized as mean +/- standard deviation.  Based on an analysis of the twenty-four 
consecutive cases of bilateral VROs, the mean calculated intra-operative blood loss was 
671.24mL (SD: 233.69).  
  
5. Number of groups being compared (use 1 for paired analysis within the same subjects):    
Two groups are being compared: Treatment Group (Loading Dose + Infusion) vs. Placebo Group 
(NS)  
  
6. Effect size or change expected between groups:  250cc   
  

7. Resulting number per group:  12  
  
8. Total sample size required: 24  
  
Data Analysis  
  
The primary outcome of interest (calculated total blood loss) will be presented as a mean +/- 
standard deviation and compared between the EACA and placebo groups with a two-sample t-
test. Multivariable linear regression models will also be used to adjust for any potential 
confounding due to total blood loss volume between arms after adjustment for age, sex, BMI, 
and anesthesia type. To adjust for any patients lost due to early withdrawal, we will increase our 
sample size by 3 patients in each group for a total sample size of 30 patients.  
  
Calculated total blood loss will be determined from the difference between the preoperative 
hemoglobin and the postoperative hemoglobin (or the lowest postoperative hemoglobin during 
the hospital stay prior to transfusion).  Based on hemoglobin balance, the estimated blood loss 
will be calculated according to the formula by Nadler et al.17:  
Estimated Blood Volume (EBV) = (k1 x Height3 (m)) + (k2 x Weight (kg)) + k3  
For men, k1 = 0.3669, k2 = 0.03219, and k3 = 0.6041  
For women, k1 = 0.3561, k2 = 0.03308, and k3 = 0.1833  
  
Multiplying the EBV by the hematocrit (Hct) gives the red blood cell (RBC) volume.  As such, a 
change in the RBC volume can be calculated from a change in the Hct level23,24:  
Total RBC volume loss = EBV x (Hct Preop – Hct Postop)  
  
Transfusions (mean volume per unit at HSS, 250 mL) can be taken into account by calculating 
the total blood loss16:  
  
Total blood loss (L) = Total RBC volume loss + (No. of Units Transfused x 0.25) / (Hct Preop – 
Hct Postop) / 2)  
  
All continuous secondary outcomes such as postoperative allogeneic blood transfusion 
requirement, intraoperative cell saver utilization, and length of hospital stay, will be analyzed in 
the same manner as the primary outcome.  
  
Complications will be reported as incidence rates with 95% confidence intervals.  
  
All hypotheses will be evaluated with two-sided tests with statistical significance set at α = 0.05.  
 
 
 
 
 

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