Prospective Randomized Pilot Study Comparing Bivalirudin Versus Heparin in Neonatal and Pediatric Extracorporeal Membrane Oxygenation
Phase: PHASE4
Conditions: Extracorporeal Membrane Oxygenation Complication, Pediatric ALL, Anticoagulants
Sponsor: University of Texas Southwestern Medical Center

Official title: Prospective Randomized Pilot Study Comparing Bivalirudin 
Versus Heparin in Neonatal and Pediatric Extracorporeal Membrane 
Oxygenation 
 
NCT number: NCT03318393 
IRB approved date: 6/29/2018 

Version 1.3   13JUN2018 
1 | P a g e  
 
Title: Prospective randomized pilot study comparing bivalirudin versus heparin in neonatal and pediatric 
extracorporeal membrane oxygenation 
PI: Ali McMichael, M.D.  
Funding sponsor: Euro Extracorporeal Life Support Organization 
 
Version 1, June 27, 2017 
Version 1.1, August 17, 2017 
Version 1.2 05FEB2018 
Version 1.3 13JUN2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Version 1.3   13JUN2018 
2 | P a g e  
 
The University of Texas Southwestern Medical Center at Dallas 
Institutional Review Board 
Protocol for Investigator Initiated Studies 
 
Title: Prospective randomized pilot study comparing bivalirudin versus heparin in neonatal and pediatric 
extracorporeal membrane oxygenation 
 
1. Introduction and Purpose:  
Anticoagulation is essential during extracorporeal membrane oxygenation (ECMO) to prevent 
catastrophic circuit clotting. Use of unfractionated heparin (UFH) as the standard of care during ECMO 
was adapted from the knowledge gained from cardiopulmonary bypass. Unfortunately, UFH has several 
limitations during ECMO. Bivalirudin, a direct thrombin inhibitor, is an alternative and potentially 
superior anticoagulant for patients on ECMO. Previous studies of bivalirudin use during ECMO have 
shown that compared to UFH, bivalirudin is safe and may decrease bleeding, decrease blood product 
transfusion, and decrease ECMO cost [1-4]. Improving anticoagulation during ECMO is critically 
important as the most common complications during ECMO are secondary to bleeding and clotting [5].  
 
We hypothesize that neonatal and pediatric ECMO patients receiving bivalirudin will spend more time at 
goal anticoagulation and will experience less hemorrhagic and thrombotic complications when 
compared to patients receiving unfractionated heparin.   
 
Aim 1:  Compare the efficacy of bivalirudin versus UFH during neonatal and pediatric ECMO. 
Aim 2:  Define the incidence of hemorrhagic and thrombotic complications in patients receiving 
bivalirudin during ECMO. 
Aim 3:  Determine the optimal dosing for bivalirudin for effective anticoagulation on ECMO. 
 
The primary outcome of the study will be to compare the percentage of time spent at goal 
anticoagulation for patients receiving UFH versus patients receiving bivalirudin. Secondary outcomes will 
include incidence of major bleeding events as defined by the International Society of Thrombosis and 
Hemostasis including fatal bleeding, intracranial hemorrhage, retroperitoneal hemorrhage, extrasurgical 
or unexpected surgical site bleeding that causes a decrease of hemoglobin of > 2 g/dL or leads to 
transfusion of two or more red blood cell transfusions within a 24 hour period, and surgical site bleeding 
that requires surgical intervention [6, 7]. We will compare the need for blood product transfusion of 
packed red blood cells, platelets, fresh frozen plasma, cryoprecipitate, and antithrombin III (thrombate) 
between those who received UFH versus those who received bivalirudin. Lastly, we will describe the 
median dose needed for bivalirudin in all patients and for those with renal insufficiency and renal 
failure.   
 
2. Background:  
Extracorporeal membrane oxygenation (ECMO) is a lifesaving therapy for patients with respiratory 
and/or cardiac failure. Approximately 1500 to 2000 neonatal and pediatric patients are placed onto 
extracorporeal membrane oxygenation (ECMO) each year for respiratory failure [8]. At Children's 
Medical Center, we place approximately 40 neonatal and pediatric patients onto ECMO each year. 
Despite advancements in ECMO circuit technology such as heparin coated tubing, smaller oxygenators, 
and improved cannula, hemorrhage and thrombosis are the most common complications during ECMO 
[8, 9]. Approximately 4-11% of neonatal and pediatric ECMO patients suffer an intracranial hemorrhage 
and 30% have some form of thrombosis [10, 11]. Hemostatic complications during ECMO are associated 

Version 1.3   13JUN2018 
3 | P a g e  
 
with increased morbidity and mortality [5, 11]. In order to prevent catastrophic circuit clotting, 
anticoagulation is essential.  
 
As mentioned previously, UFH is currently the standard anticoagulant for ECMO but it has several 
important limitations. UFH requires antithrombin for maximum therapeutic effect but neonates and 
critically ill patients are known to be deficient in antithrombin. Besides binding to antithrombin, UFH 
binds to the ECMO circuit and other plasma proteins altering its pharmacokinetics. The tests used to 
monitor UFH’s clinical effectiveness such as aPTT, ACT and anti-factor Xa are all imperfect tests and have 
been shown to have variable correlation to themselves and to UFH during ECMO [12-16]. There are no 
randomized studies that have investigated superiority of UFH over other anticoagulants during ECMO. In 
addition, there is no universally accepted test or combination of tests to monitor the functional effect of 
UFH during ECMO.  
 
Bivalirudin is a specific and reversible direct thrombin inhibitor. Bivalirudin binds to both bound free and 
clot-bound thrombin and unlike UFH it does not require antithrombin. In addition, bivalirudin also has a 
short half-life of 25 minutes and has low to negligible immunogenic potential. Bivalirudin is currently 
FDA approved for patients with unstable angina undergoing percutaneous transluminal coronary 
angioplasty (PTCA), percutaneous coronary intervention (PCI) with use of glycoprotein IIb/IIA inhibitor, 
and patients with heparin induced thrombocytopenia undergoing PCI [17]. Bivalirudin is currently used 
off label for pediatrics.  
Bivalirudin has been used off label in children for deep venous thrombosis prophylaxis and treatment, 
cardiopulmonary bypass, cardiac catherization and ECMO [17]. An open label study conducted by the 
manufacture of 110 neonatal and pediatric patients identified the dosing regimen, plasma 
concentration, and safety profile of bivalirudin. Bleeding occurred in 2 of 110 patients (1.8%) and 
thrombosis occurred in 8 of 110 patients (7.5%) [18]. At our institution, 6 non-ECMO neonatal and 
pediatric patients have been initiated on bivalirudin for concern of or confirmed heparin induced 
thrombocytopenia. In the six patients there were no thrombotic or hemorrhagic complications.  
 
Pediatric ECMO studies using bivalirudin have thus far shown benefit and confirmed safety of bivalirudin 
but are limited to single case reports, one small case series, and one small retrospective study. Nagle et 
al described 12 neonatal and pediatric ECMO patients on bivalirudin and found no major bleeding 
events [1]. The study also defined the maintenance dose need to achieve goal aPTT. A combined 
pediatric and adult retrospective review compared 21 total patients using bivalirudin to UFH and found 
that patients receiving bivalirudin had decreased bleeding, decreased blood product transfusion, and 
decreased pediatric ECMO cost compared to patients receiving UFH [2]. An adult case-control study of 
10 patients receiving UFH compared to 10 patients receiving bivalirudin, found that patients receiving 
bivalirudin had less variation of aPTT and a trend towards decreased number of changes of bivalirudin 
dose compared to patients receiving UFH [3]. No difference was seen in bleeding or thrombotic 
complications between the two groups [3]. To our knowledge, there is no prospective study comparing 
bivalirudin to UFH for pediatric or adult ECMO.  
 
3. Concise Summary of Project: 
We will prospectively enroll 30 neonatal and pediatric ECMO patients in the Pediatric Intensive Care 
Unit and Pediatric Cardiovascular Intensive Care Unit at Children’s Medical Center, Dallas campus. The 
patients will be randomized into two arms; one arm will receive unfractionated heparin and the other 
arm will receive bivalirudin. There will be 15 patients in each arm for a total of 30 patients. We estimate 
that we will need to consent 50 patients to achieve our goal of 30 enrolled patients. Enrollment and 
completion of this study will require approximately two years.  

Version 1.3   13JUN2018 
4 | P a g e  
 
 
After consent is obtained, patients will be randomized into either the unfractionated heparin group or 
bivalirudin group. The UFH group will be given UFH as is currently standard of care at Children’s Medical 
Center. A bolus of UFH will be given on initiation and the UFH infusion will be titrated throughout the 
entire ECMO run based on combination testing of anti-factor Xa, aPTT, and thromboelastogram (TEG).  
 
The bivalirudin group will receive an UFH bolus during cannulation and UFH infusion until consent 
obtained (maximum time of 24 hours) and then transitioned immediately from UFH infusion to 
bivalirudin infusion. Once initiated, the bivalirudin infusion will be titrated based on aPTT.  
 
Bivalirudin’s trade name is ANGIOMAX® and is manufactured by The Medicines Company. Bivalirudin 
directly inhibits thrombin by binding to the free and clot-bound thrombin. It stored in a single-dose vial 
with 250 millograms of bivalirudin to be reconstituted with sterile water. After reconstitution it may be 
stored at 2-8°C for up to 24 hours. It is excreted predominantly through proteolysis with 20% cleared 
renally. Patients with renal insufficiency or failure required a decrease in infusion rate based on 
creatinine clearance.  
 
ECMO circuit tubing will be collected at time of circuit tubing change or at the end of ECMO.  
Normally, the used circuit tubing system is discarded in the appropriate biohazard waste container. For 
this study, will analyze the circuit tubing after it has been removed from the patient. After removal, the 
circuits will be drained and filled with normal saline (to prevent further clotting) by one of the ECMO 
team members or one of our study team members. The steps involved are detailed in the paragraphs 
bellow and will be covered by study finances and not billed to the patient in any way.  
 
The cannula with the circuit tubing system attached is cut away from the patient per standard of care 
and the circuit is drained of blood.  The A-V loop (arterial venous) is created using a T-connector (1/4 x 
3/8 inch size) and connected to the circuit.  A 1 liter bag of normal saline is run through the circuit until 
the fluid looks clear with the exception of clots, or fibrin strands, already adhering to the tubing. The 
bridge ports are then capped and the circuit is placed in a biohazard bag.  
 
After removal of the circuit from the patient, the blood will be appropriately drained into a biohazard 
bag. The circuit will be filled with normal saline and stored in a biohazard bag. The circuit and the 
biohazard bag will be labeled with the patient study ID and date. There will be no patient identifiers on 
the circuit, biohazard bag, or shipment label. The biohazard bag will then be stored in a dedicated 
storage area that is locked with badge-access entrance only.  The circuits will be shipped in the red 
biohazard bags, in a standard FedEx cardboard box (flushed circuits are non-infectious), with the 
appropriate shipping label for shipment to Biotechnology Building (IBB) at the Georgia Institute of 
Technology. The individual responsible for receiving the study circuits is Susan Hastings.  
 
For the primary outcome, all aPTT and anti-factor Xa values (for the UFH group only) will be recorded 
during the ECMO run.  Hemorrhagic complications will be defined using the International Society of 
Thrombosis and Hemostasis major bleeding criteria. Blood product transfusion will recorded in 
ml/kilogram/ECMO day. Thrombosis will be defined as need for circuit change and clot burden in the 
ECMO circuit. A clot burden score will be performed on each patient every 6 hours. ECMO cost will 
include cost of the circuit, cost of blood products including antithrombin, cost of circuit change, and cost 
of anticoagulant.  
 

Version 1.3   13JUN2018 
5 | P a g e  
 
Patients in the UFH arm may cross over into the bivalirudin arm if they develop heparin induced 
thrombocytopenia or heparin resistance defined as UFH dose of > 70 u/kg/hour with inability to obtain 
goal Xa or aPTT. Bivalirudin patients may cross over into the UFH arm if they are unable to achieve 
adequate anticoagulation and have continued development of thrombosis in the circuit or the patient or 
if the patient develops an intracardiac thrombus. The primary team or parent/guardian can withdraw 
the patient from the study for any reason at any time.  
 
4. Study Procedures: 
Unfractionated heparin group:  
Patients in this group will receive UFH anticoagulation as is current standard of care at Children’s. During 
cannulation a bolus dose of 50-100 units/kg of intravenous UFH will be given. A continuous UFH infusion 
based on age will be initiated once ACT is < 300 seconds. Infants less than one year will receive a starting 
dose of 28 units/kg/hour and children > 1 year will receive a starting dose of 20 units/kg/hour per 
current Children’s protocol.  
 
The UFH infusion will be titrated based on targeted anti-factor Xa, aPTT, and thromboelastogram. Labs 
will be drawn per current standard of care as noted below.  
 
aPTT and anti-factor Xa levels:  
From time of cannulation until goal anticoagulation achieved: every 4-6 hrs 
Once achieved goal: every 6 hours 
Heparin dose change: 4 hours after change 
 
Other labs:  
Daily TEG, PT/INR, d-dimer, fibrinogen, antithrombin, triglycerides, plasma free hemoglobin 
Every 12 hour complete blood count 
Every one hour ACT 
 
Bivalirudin group:  
Patients in the bivalirudin group will initially receive UFH to allow for time for consent and 
randomization. During cannulation, an intravenous UFH bolus of 50-100 units/kg will be given. A 
continuous UFH infusion based on age will be initiated once ACT is < 300 seconds. Infants less than one 
year will receive a starting dose of 28 units/kg/hour and children > 1 year will receive a starting dose of 
20 units/kg/hour. Once consent is obtained, the patients will be immediately transitioned from UFH to 
bivalirudin. The initial bivalirudin dose will be 0.15mg/kg/hr.  
 
The bivalirudin infusion will be titrated via the nomogram below based on aPTT. Goal aPTT will be 1.5-
2.5 times baseline. For patients with a normal aPTT prior to cannulation this translates to aPTT between 
60-80 seconds.   
 

Version 1.3   13JUN2018 
6 | P a g e  
 
 
 
 
 
 
 
 
 
 
 
 
 
For patients with renal insufficiency or failure, the initial bivalirudin dose will be adjusted based on 
creatinine clearance according to the nomogram below.   
 
 
 
 
 
 
 
aPTT labs:  
From time of cannulation until goal anticoagulation achieved: every 2 hours 
Once achieved goal: every 6 hours 
Bivalirudin dose change: 2 hours after change 
 
Other labs:  
Daily TEG, PT/INR, d-dimer, fibrinogen, antithrombin, triglycerides, plasma free hemoglobin 
Every 12 hour complete blood count 
Every hour ACT 
 
Blood product transfusion:  
For both arms of the study patients, transfusion parameters will include: 15 ml/kg (maximum of 1 unit) 
of platelets for platelet count < 100 x 109, 1 unit/kg of cryoprecipitate for fibrinogen < 100 mg/dL, and 
15 ml/kg (maximum of 1 unit) of packed red blood cells for hemoglobin < 8 -10 g/dL.  
 
Cross over:  
Patients in the UFH arm may cross over into the bivalirudin arm if they develop heparin induced 
thrombocytopenia or heparin resistance defined as UFH dose of > 70 u/kg/hour with inability to obtain 
goal Xa or aPTT. Bivalirudin patients may cross over into the UFH arm if they are unable to achieve 
adequate anticoagulation and have continued development of thrombosis in the circuit or the patient or 
if the patient develops an intracardiac thrombus.  
 
Randomization: 
Patients will be randomized 50/50 into the bivalirudin group or the heparin group. Each group will have 
15 patients for a total of 30 patients. Randomization will occur via a sealed envelope assignment.  
 
Research related costs:  
Measured aPTT 
Bivalirudin dose adjustment 
< 45 seconds or < 16 seconds 
below target aPTT 
Increase by 0.04 mg/kg/hr 
45-59 seconds or 1-15 seconds 
below target aPTT 
Increase by 0.02 mg/kg/hr 
60-80 seconds or 1.5-2.5 times 
baseline aPTT 
No change 
81-95 seconds or 1-15 seconds 
above target aPTT 
Decrease by 0.02 mg/kg/hr 
>95 seconds or > 16 seconds 
above target aPTT 
Decrease by 0.04 mg/kg/hr 
Creatinine Clearance (CrCl) 
Initial infusion rate 
> 60 ml/minute 
0.15 mg/kg/hr 
30-60 ml/minute 
0.08 mg/kg/hr 
< 30 ml/minute 
0.05 mg/kg/hr 
Dialysis dependent  
0.02mg/kg/hr 

Version 1.3   13JUN2018 
7 | P a g e  
 
Thrombin generation assay will be performed on day one and on day three for patients in both arms. 
The patients will not be responsible for the cost of the test. In addition, per current standard of care at 
Children’s echocardiograms will be performed at time of cannulation and as needed to evaluate cardiac 
function and/or cannula position. If an echocardiogram is performed on patients in the bivalirudin arm 
to evaluate for intracardiac thrombus, the patient will not be responsible for the charge.  
 
Patients will be responsible for all standard ECMO related costs including blood product transfusion and 
anticoagulant. The average wholesale price of bivalirudin for a 250mg vial is $609. On average one vial 
per day will be used per patient. The average wholesale price of unfractionated heparin for a 250ml bag 
is $20. The entire bag or portion of bag will be used per day per each patient. Therefore, the patients in 
the bivalirudin arm may incur a higher cost.  
 
Data will be collected on the patients from time of ECMO cannulation to time of hospital discharge.  
Blood draws for the both groups of patients will follow current CMC protocol for ECMO except that 
bivalirudin patients will not get anti-factor Xa testing. The only additional test will be a thrombin 
generation assays. Thrombin generation assays will require an extra 5.4 ml total of blood.  In addition, 
blood samples for dilute thrombin time, ecarin chromogenic assay, bivalirudin level and aPTT will be 
frozen and stored for future analysis after study completion. Samples will be drawn daily, and obtained 
from leftover SOC coagulation labs drawn per protocol so no additional blood sampling will be required.  
Patients will not be responsible for the cost of this analysis.  
 
5. Sub-Study Procedures: 
None 
 
6. Criteria for Inclusion of Subjects: 
All patients aged 0 days to less than 18 years that require venovenous or venoarterial ECMO in the 
Pediatric Intensive Care Unit and Pediatric Cardiovascular Intensive Care Unit at Children’s Medical 
Center, Dallas campus.   
 
7. Criteria for Exclusion of Subjects: 
Exclusion criteria will include:  
1) Patients with known or suspected heparin induced thrombocytopenia prior to consent 
2) Patients with aPTT > 2 times normal with AST and or ALT > 500 
3) Patients with plan to decannulate from ECMO within 48 hours 
4) Known or suspected pregnant women 
5) Previous enrollment in this study 
6) Primary language spoken that is not English or Spanish 
7) Patients with congenital diaphragmatic hernia since this small subgroup of patients are receiving 
surgical repair while on ECMO and if they were in the Bivalirudin group would need to have the 
Bivalirudin suspended during and after the surgical procedure. Since the study team is not 
aware of any published data to suggest how long to hold Bivalirudin for this particular 
operation, this population is excluded due to safety concerns. 
 
8. Sources of Research Material: 
The electronic medical records of each enrolled patient will be accessed to obtain demographic data, 
laboratory values, echocardiogram reports, imaging reports, blood product transfusion requirements, 
and disposition. All study documents containing patient information will remain password protected. 
Only study personnel will have access to the study records.  

Version 1.3   13JUN2018 
8 | P a g e  
 
 
9. Recruitment Methods and Consenting Process: 
Patients will be identified by the Children’s Medical Center ECMO team. It is possible that potential 
subjects will be patients of the investigators. In that case where possible another member of the study 
team will approach the parent or guardians for consent. Parents or guardians will be approached by the 
study team within 24 hours of the start of ECMO.  
 
If the patient is between 10 to 17 years old, we will obtain assent once sedation is removed and the 
patient is clinically able to give assent.  
 
10. Potential Risks: 
Bivalirudin is rapidly cleaved by proteotlytic enzymes creating a short half-life of 25 minutes. There is a 
theoretical increased risk of intracardiac thrombus development if the patient has stagnant blood flow 
due to poor cardiac output [19]. Daily echocardiograms will be performed to rule out intracardiac 
thrombus if there is clinical concern for stagnation of intracardiac blood flow including pulse pressure ≤ 
10mmHg on arterial line or non-palpable pulses. Echocardiograms on patients in the bivalirudin arm that 
are performed to evaluate for intracardiac thrombus will not be charged to the patient. If the patient 
develops an intracardiac thrombus the patient will be changed to heparin infusion.  
 
As noted previously, there is a potential risk of increased cost for the patient’s in the bivalirudin group as 
bivalirudin is more expensive than heparin. A retrospective study comparing bivalirudin versus heparin 
noted that pediatric patients who received bivalirudin actually had decreased overall ECMO cost due to 
decreased number of blood product transfusions as compared to patients receiving UFH [2]. Like all 
anticoagulants, bivalirudin may cause unintended bleeding.    
 
11. Subject Safety and Data Monitoring: 
Per current ECMO protocol all patients will be monitored closely for bleeding including intracranial 
hemorrhage. Neonates (patients aged 0 days to 28 days) will receive a head ultrasound every day for the 
first 3 days and thereafter per clinical discretion per current standard of care at CMC. All patients will 
receive a MRI after decannulation and prior to hospital discharge per current standard of care at CMC.  
 
See DSMP for further information regarding data safety and monitoring.  
 
12. Procedures to Maintain Confidentiality: 
Data will be stored in a password protected excel file with access granted only to study personnel.  
 
13. Potential Benefits: 
This study has the potential to have a tremendous impact on the anticoagulation practice for all future 
neonatal and pediatric ECMO patients. Pending the results of this pilot study, we plan to develop and 
implement a multicenter study randomized control trial to confirm the benefits of bivalirudin.  
Improving ECMO anticoagulation is essential as the most common complications on ECMO are due to 
hemorrhage or thrombosis. Besides potentially devastating intracranial hemorrhage, ECMO patients are 
at risk for stroke, surgical site bleeding, cannula site bleeding, and exposure to multiple blood products. 
Improving anticoagulation could decrease these complications and significantly improve the outcomes 
of these critically ill children. 
 
14. Biostatistics:  

Version 1.3   13JUN2018 
9 | P a g e  
 
Based on prior data from Ranucci et al in adult ECMO patients a sample size of approximately 10 in each 
arm (total 20 patients) will be sufficient to obtain statistical significance for the primary outcome. In this 
study we will use a variety of methods including tests of differences in means and medians, ANOVAS, 
correlations between changes of doses and changes in aPTT and multivariate ANOVAS and logistic 
regressions to analyze the impact of these treatments on a variety of patient outcomes such as time to 
goal aPTT, time in goal range of aPTT, ACT levels and changes , incidence of bleeding and clotting events, 
number of changes in dosage and other events, variations in aPTT level during treatment, time on 
ECMO, time in the ICU, ventilator days and mortality outcomes.  Duration models will be used where 
appropriate.  
 
 
 

Version 1.3   13JUN2018 
10 | P a g e  
 
References 
 
1. 
Nagle, E.L., et al., Bivalirudin in pediatric patients maintained on extracorporeal life 
support. Pediatr Crit Care Med, 2013. 14(4): p. e182-8. 
2. 
Ranucci, M., et al., Bivalirudin-based versus conventional heparin anticoagulation for 
postcardiotomy extracorporeal membrane oxygenation. Crit Care, 2011. 15(6): p. R275. 
3. 
Pieri, M., et al., Bivalirudin versus heparin as an anticoagulant during extracorporeal 
membrane oxygenation: a case-control study. J Cardiothorac Vasc Anesth, 2013. 27(1): 
p. 30-4. 
4. 
Sanfilippo, F., et al., Bivalirudin for Alternative Anticoagulation in Extracorporeal 
Membrane Oxygenation: A Systematic Review. J Intensive Care Med, 2016. 
5. 
Murphy, D.A., et al., Extracorporeal membrane oxygenation-hemostatic complications. 
Transfus Med Rev, 2015. 29(2): p. 90-101. 
6. 
Schulman, S., et al., Definition of major bleeding in clinical investigations of 
antihemostatic medicinal products in surgical patients. J Thromb Haemost, 2010. 8(1): p. 
202-4. 
7. 
Schulman, S. and C. Kearon, Definition of major bleeding in clinical investigations of 
antihemostatic medicinal products in non-surgical patients. J Thromb Haemost, 2005. 
3(4): p. 692-4. 
8. 
Paden, M.L., et al., Extracorporeal Life Support Organization Registry Report 2012. 
Asaio j, 2013. 59(3): p. 202-10. 
9. 
Rehder, K.J., et al., Technological advances in extracorporeal membrane oxygenation 
for respiratory failure. Expert Rev Respir Med, 2012. 6(4): p. 377-84. 
10. 
Paden, M.L., P.T. Rycus, and R.R. Thiagarajan, Update and outcomes in extracorporeal 
life support. Semin Perinatol, 2014. 38(2): p. 65-70. 
11. 
Dalton, H.J., et al., Association of bleeding and thrombosis with outcome in 
extracorporeal life support. Pediatr Crit Care Med, 2015. 16(2): p. 167-74. 
12. 
Baird, C.W., et al., Anticoagulation and pediatric extracorporeal membrane oxygenation: 
impact of activated clotting time and heparin dose on survival. Ann Thorac Surg, 2007. 
83(3): p. 912-9; discussion 919-20. 
13. 
Liveris, A., et al., Anti-factor Xa assay is a superior correlate of heparin dose than 
activated partial thromboplastin time or activated clotting time in pediatric extracorporeal 
membrane oxygenation*. Pediatr Crit Care Med, 2014. 15(2): p. e72-9. 
14. 
Khaja, W.A., et al., Evaluation of heparin assay for coagulation management in 
newborns undergoing ECMO. Am J Clin Pathol, 2010. 134(6): p. 950-4. 
15. 
Sulkowski, J.P., et al., Comparison of routine laboratory measures of heparin 
anticoagulation for neonates on extracorporeal membrane oxygenation. J Extra Corpor 
Technol, 2014. 46(1): p. 69-76. 
16. 
O'Meara, L.C., et al., Anti-xa directed protocol for anticoagulation management in 
children supported with extracorporeal membrane oxygenation. Asaio j, 2015. 61(3): p. 
339-44. 
17. 
Buck, M.L., Bivalirudin as an Alternative to Heparin for Anticoagulation in Infants and 
Children. J Pediatr Pharmacol Ther, 2015. 20(6): p. 408-17. 
18. 
O'Brien, S.H., et al., UNBLOCK: an open-label, dose-finding, pharmacokinetic and safety 
study of bivalirudin in children with deep vein thrombosis. J Thromb Haemost, 2015. 
13(9): p. 1615-22. 
19. 
Ranucci, M., Bivalirudin and post-cardiotomy ECMO: a word of caution. Crit Care, 2012. 
16(3): p. 427.