Randomized Clinical Trial of Intraoperative Extracorporeal Membrane Oxygenation (ECMO) Versus Cardiopulmonary Bypass (CPB) in Lung Transplantation
Conditions: Lung Transplant; Complications
Sponsor: The Cleveland Clinic

 
 
Protocol 
    
Randomized Clinical Trial of Intraoperative ECMO versus 
Cardiopulmonary Bypass in Lung Transplantation 
  
Amendment 1. September 27, 2017 
  
  
  
  
 
  
  
  
 
 
  
  
  
  
  

 
 
TABLE OF CONTENTS 
 
DEFINITIONS, ACRONYMS, AND ABBREVIATIONS. 
ABSTRACT. 
BACKGROUND AND SIGNIFICANCE   
ENDPOINTS. 
STUDY DESIGN. 
STUDY POPULATION. 
DEFINITIONS AND MEASUREMENT OF ENDPOINTS. 
CLINICAL CENTERS. 
DATA COLLECTION. 
DATA MANAGEMENT 
ANALYTIC PLAN. 
REFERENCES. 
 
 
DEFINITIONS, ACRONYMS, AND ABBREVIATIONS 
CPB  Cardiopulmonary bypass 
ECMO  Extracorporeal membrane oxygenation 
PGD  Primary Graft Dysfunction 
  
  
  
  
STUDY INVESTIGATOR 
PI: Michael Tong 
 
Co-Authors 
Stefana Rafiroiu 
Usman Ahmad 
Kenneth McCurry 
Douglas Johnston 
Eugene Blackstone 
Valerie Slusarz 
Anand Mehta 
Shiva Sale 
  
  
  
  
  
  
  
  
  
 

 
 
 
 
ABSTRACT 
 
Title 
Randomized Clinical Trial of 
Intraoperative ECMO vs. 
Cardiopulmonary Bypass in 
Lung Transplantation 
  
Background 
Cardiopulmonary bypass (CPB) is the current 
standard of care for intraoperative 
cardiorespiratory support during lung 
transplantation. However, the blood-air interface 
and the need for full systemic anticoagulation 
may lead to systemic inflammatory response 
and coagulopathy. Some reports have suggested 
that intraoperative support with extracorporeal 
membrane oxygenation (ECMO) in lieu of CPB 
may be a better alternative with decreased 
bleeding, blood requirements and rates of 
primary graft dysfunction (PGD).   
  
  
Hypothesis 
patients on ECMO will have 
• 
decreased transfusion requirements,  
• 
decreased intubation time,  
• 
lesser PGD grade at 72 hours  
• 
No increase in major adverse events 
• 
Pump duration may be longer.  
 
Study Design 
A prospective randomized trial comparing 
intraoperative support with ECMO and CPB. 
This will be a superiority trial for efficacy and 
non-inferiority for safety. The allocation ratio 
will be 1:1.  
  
Number of Participants 
40 in each arm 
Study Objectives 
Determine if ECMO compared to CPB during 
lung transplantation has a beneficial effect on 

 
 
short term outcomes after lung transplantation. 
Interventions 
When patient need intraoperative 
cardiopulmonary support, patient would be 
randomized to ECMO or CPB 
Inclusion Criteria 
All patients undergoing lung transplantation. 
Not all patients randomized will need 
intraoperative support 
  
Exclusion Criteria 
Patients undergoing concomitant cardiac 
operations with indication for obligate use of 
cardiopulmonary bypass 
Patient with specific anatomy that require full 
cardiac decompression such as severe 
pulmonary hypertension or large heart that are 
shifted severely into the left chest (relative) 
Patients with high likelihood of significant 
pleural bleeding that will require returning the 
blood back into the cardiotomy reservoir 
(relative) 
Patients bridged to transplant with ECMO 
Patients who the surgeon feels would be better 
served with CPB rather than ECMO 
 
These patients will be entered into a 
registry and followed.  
 
1 ° Endpoint 
1 
Bleeding: total PRBC transfusion 
requirements at 72hours 
 
2 ° Endpoint 
Superiority 
1. Ventilation time (days) 
2. Intraoperative PRBC transfusion rates  
3. Duration of support 
4. Primary graft dysfunction (PGD) grade 
at 72 hours.  
5. Transfusion requirement of FFP, 
platelets, cryoprecipitate at 72 hours. 
 
Non-inferiority:  
6. Composite outcome of: 30-day or 
discharge date (if earlier than 30 days) 
mortality, bleeding requiring 

 
 
reoperation, new ECMO, new renal 
failure requiring dialysis 
 
Baseline and Clinical Outcomes Data 
From:  EDIT database, EPIC Medical records 
review 
  
 
 

 
 
BACKGROUND AND SIGNIFICANCE 
  
The Problem 
In lung transplantation where cardiopulmonary support is needed intraoperatively, the usage of 
CPB is historically and still currently the standard of care at most centers worldwide. 
While cardiopulmonary bypass allows for versatility and the conditions necessary to complete many 
transplant operations, there are disadvantages, such as the need for full dose heparinization with the 
associated risk of bleeding, and the activation of inflammatory mediators which have to potential to lead 
to higher degrees of postoperative primary graft dysfunction (PGD). To counter some of these 
complications, ECMO in a veno-arterial (VA ECMO) configuration has been proposed and studied as an 
alternative method of cardiopulmonary support. Prior reports have suggested that intraoperative support 
with extracorporeal membrane oxygenation (ECMO) in lieu of CPB may be a better alternative with 
decreased bleeding, blood requirements and rates of primary graft dysfunction (PGD).   
  
Currently, many centers would use one technique or the other and both are considered current standard of 
care and best practice. At Cleveland Clinic, we have used both methods. The method of support is 
currently not discussed with patients as both are considered acceptable.  
 
  
HYPOTHESIS 
Our hypothesis is that patients on ECMO will have a decreased transfusion requirements, decreased 
intubation time, lesser PGD grade at 72 hours without increase in adverse risk. Pump duration may be 
longer.  
 
 
ENDPOINTS 
 
Primary 
1 
Bleeding: total PRBC transfusion requirements at 72hours 
 
Secondary 
Superiority 
1. Ventilation time (days) 
2. Intraoperative PRBC transfusion rates  
3. Duration of support 
4. Primary graft dysfunction (PGD) grade at 72 hours.  
5. Transfusion requirement of FFP, platelets, cryoprecipitate at 72 hours. 
 
Non-inferiority:  
1. Composite outcome of: 30-day or discharge date (if earlier than 30 days) mortality, bleeding 
requiring reoperation, new ECMO, new renal failure requiring dialysis 
 
 
 
STUDY DESIGN 
 
Randomized clinical trial with an allocation ratio of 1:1, comparing CBP versus ECMO for intraoperative 
cardiopulmonary support. Study will have a superiority design for efficacy and a non-inferiority design 
for safety.  
  
 

 
 
Randomization:  
All lung transplant patients will be consented preoperatively. Patients will be randomized at the beginning 
of the case and the configuration of the cardiopulmonary bypass machine will be set accordingly. Not all 
patients randomized will require intraoperative cardiopulmonary support.  
  
Circuit design:  
separate tubing that connects the venous return line directly to the pump head bypassing the venous 
reservoir. The venous reservoir is still connected and but clamped. 
  
Incision and cannulation: 
The type of incision will be at the discretion of the surgeon but can be sternotomy, thoracotomy or 
clamshell. If patient has a sternotomy and randomized to ECMO, venous cannula should be placed 
through a percutaneous femoral venous cannula to avoid the potential of air embolus.  
 
Anticoagulation:  
ACT target 200-250. Repeat every 30 min. Bolus 5000U, give supplemental doses as needed. 
  
Conversion to full cardiopulmonary bypass:  
Give full dose heparin; release the clamp on the venous reservoir after act is above 480. 
  
Reasons to convert from ECMO to CPB intraoperatively: 
         
Significant bleeding to allow blood to return back to circuit 
         
Heart remain too distended to allow mobilization  
         
Air in the circuit 
         
The need to fibrillate or arrest the heart 
         
Hemodynamic instability from positioning 
  
Other safety mechanisms:     
 
 
Consider system for rapid transfusion 
 
Double lumen intubation: the heart does not decompress and there’s ejection requiring the need 
 
for ventilation. 
 
Use an urchin or heartnet for heart positioning if necessary 
 
Once the patient is decannulated, the blood from the circuit can be re-transfused back into the 
 
patient 
 
Transfusion triggers: 
Transfusion triggers will be hematocrit of .24 and at the discretion of the staff surgeon, anesthesiologist or 
intensivist. Coagulopathy will be corrected based on Cleveland clinic post cardiotomy bypass protocol 
(appendix 2) and at the discretion of surgeon, anesthesiologist or intensivist.  
 
Patients will be extubated at the discretion of the staff surgeon and intensivist.  
 
Patients who are consented but not included in the study and patients who are felt to be better candidates 
for cpb will be followed in a separate registry 
         
 
NUMBER OF PARTICIPANTS 
40 Patients in each arm 
 
Power calculation (based on 2015 CCF outcomes) 
 
Safety 
 
 
30 day mortality: 6.2% 

 
 
 
 
Bleeding requiring reoperation: 10.3% 
 
 
New ECMO: 1.3% 
 
 
New renal failure requiring dialysis: 10.3% 
 
 
Composite outcome 18.6%.  
 
 
 
 
 
Sample size calculation 
Non-inferior margin: 5% 
 
 
90%: 283, 80%:205, 70%: 155 
 
 
Non-inferior margin: 10% 
 
 
90%: 77, 80%:56, 70%: 42 
 
 
 
Efficacy 
 
 
PGD grade at 72 h:  
0: 
24.4% 
1: 
47.4%  
2: 
14.1%  
3: 
14.1% 
 
 
 
 
 
RBC transfusion 
 
 
 
CPB: 14.7(8.4) vs ECMO 9.3(6.9) 
 
 
 
90%: 51, 80%:39, 70%: 30 
 
 
Ventilation time 
 
 
 
CPB: 16.5days (27.3) vs ECMO 8.25 (16.4) 
 
 
 
90%: 83, 80%:62, 70%: 49 
 
 
For literature outcomes, see appendix 1.  
 
STUDY POPULATION 
 
The study population will be all patients undergoing lung transplantation at our institution. These patients 
will be randomized using the block method and allocated to either the CPB or ECMO group. Not all 
patients randomized will require intraoperative support.  
  
Inclusion Criteria 
All consented patients undergoing lung transplantation. 
  
Exclusion Criteria 
Patients undergoing concomitant cardiac operations with indication for obligate use of cardiopulmonary 
bypass 
Patient with specific anatomy that require full cardiac decompression such as severe pulmonary 
hypertension or large heart that are shifted severely into the left chest (relative) 
Patients with high likelihood of significant pleural bleeding that will require returning the blood back into 
the cardiotomy reservoir (relative) 
Patients bridged to transplant with ECMO 
Cystic fibrosis/bronchiectasis/resistant infection patients where surgeon will need to remove both lungs 
prior to implantation 

 
 
Patients who the surgeon feels would be better served with CPB rather than ECMO 
 
These patients will be entered into a registry and followed.  
 
 
CLINICAL CENTERS 
Patient Confidentiality 
All patient records will be kept confidential according to HIPAA guidelines. Study investigators and site 
Institutional Review Boards (IRBs) may review source documentation as necessary, but will then transmit 
this information to Clinical Investigations at Cleveland Clinic according to the patient’s unique study 
number. Linkage of that study number to the actual patient will reside only at the individual institutions. 
Aggregate data from this study may be published as per publication policy documented in the trial 
agreements; no data with patient identifiers will be published. 
  
Consent 
Patients will be consented for surgery ahead of time at time of listing 
DATA COLLECTION 
Data will be collected from Epic Systems chart review and supplemental data collection. All necessary 
data are currently already collected. Study terminates at patient discharge. No additional testing or 
followup is needed beyond what is already done for this patient population.  
  
DATA MANAGEMENT 
The data will be stored in Red Cap Sheets strictly secured and managed by the lead and other co-
investigators. No identifiable information will be shared with outside parties, ensuring that all data will 
remain safely stored on Cleveland Clinic Main Campus user hard drives and will only be shared amongst 
our study team. 
ANALYTIC PLAN 
Basic statistical analysis will be required to compare the outcomes in the groups. Patients who are 
excluded will be included in a separate registry.  
Analysis will be based on intention to treat.  
A statistical significant difference is defined as a two-sided P value less than 0.05.  
 
 

 
 
REFERENCES 
  
1. Machuca (2015) Outcomes of intraoperative extracorporeal membrane oxygenation versus 
cardiopulmonary bypass for lung transplantation. 
  
2. Bermudez (2014) Outcomes of Intraoperative Venoarterial Extracorporeal Membrane Oxygenation 
Versus Cardiopulmonary Bypass During Lung Transplantation. 
  
3.Ius (2012) Lung transplantation on cardiopulmonary support: Venoarterial extracorporeal membrane 
oxygenation outperformed cardiopulmonary bypass. 
 
4. Hoechter (2015) The Munich Lung Transplant Group: Intraoperative Extracorporeal Circulation in 
Lung Transplantation.           
 
  
 
 

 
 
Appendix 1 
Outcomes from Literature on CPB vs. CPB  
 
CPB 
ECMO 
Surgical time (min) 
444 
425 
Heparin intraop (IU/kg) 
490.1 
54.6 
ECC time (min) 
203.5 
216 
Crystalloid (mL) 
2484 
3466 
Colloid (mL) 
1500 
1300 
Cell saver (mL)  
690 
500 
Intraop Transfusion (units) 
PRC  9 units 
FFP 8.5 units 
Platelets 3.5 units 
FibGen 5 (g) 
PPSB 3 (IU) 
 
TXA 2.5 (mg) 
PRC 6  
FFP 9  
Platelets 2  
FibGen 0 (g) 
PPSB (prothrombin complex 
concentrate) 0 (IU) 
TXA 2 (mg) 
Overall Transfusion (units) 
PRC 16  
FFP 13  
Plts 4  
FIbGen 4 
PPSB 2.5 (IU) 
TXA 2.5 (mg) 
PRC 8  
FFP 15  
Plts 2  
FIbGen 0 
PPSB 0 (IU) 
TXA 2 (mg) 
ECMO prolonged into postop 
(n) 
6 
15 
→Duration of prolonged ECMO 
(days) 
4 
3 
→Graft failure/reperfusion 
injury (n) (indication for 
prolonged ECMO) 
2 
9 
→pHT /hemodynamic (n) 
(indication for prolonged 
ECMO) 
4 
6 
Redo-surgery (n) 
15 
13 
Ventilator support (days) 
21 
4.5 
ICU LOS (days) 
36 
14.5 
ICU free survival (days)  
54 
72 
Hospital LOS (days) 
47 
42.5 
Hospital free survival (days)   
14 
36.5 
30 day mortality (n) 
1 
3 
One year mortality (n) 
4 
5 
 
Hoechter (2015): ECMO perioperative advantages (CPB higher transfusion, ventilator support, 
ICU stay), long-term not affected (same 30 day and 1 year mortality); excluded bridge to ECMO; 
* 2 analyses (1) CPB and ECMO   (2) full-dose and low-dose heparinization during ECC; (better 
outcomes in ECMO related to heparin use not the ECC device; yet independent of heparin the 
ECMO still better at reducing PGD/hemodynamic instability  (retrospective, N=188) 
 
 
CPB 
ECMO 

 
 
Intraop ischemic time (min) 
363  
375 
ECC support (min) mean 
232.5 
366.6 
Intraop transfusion (units) 
RBC 5.9 
FFP 3.1  
Platelets 8 
RBC 7.7 
 FFP 3 
Platelets 4  
Periop transfusion ( 72 hrs) 
(units) 
RBC 14.9 
FFP 9.3 
Platelets 11 
RBC 13 
FFP 8.4 
Platelets 10.7  
Postop initial ventilation (hrs) 
226 
184.7 
Reintubation (n) 
80 (36%) 
10 (20%) 
Postop total ventilation (hrs) 
380 
250 
ICU LOS  
21.9 
15 
Hospital LOS (days)  
43 
41 
Reoperation for bleeding (n) 
39 (17%) 
4 (8.2%) 
Postop renal failure requiring 
dialysis (n) 
49 (22%) 
4 (8%) 
Postop ECMO (severe PGD) 
(n) 
34 (15%) 
9 (18%) 
30 day mortality (n) 
11 (5%) 
2 (4%) 
1 year mortality (n)  
42 (19%) 
9 (19%) 
 
Bermudez (2014): ECMO decreased pulmonary (reintubation)/renal complications, (same 
severe PGD, perioperative rbc transfusion, mortality long term 30d 6m), longer time on support / 
more RBC intraop transfusion for ECMO(included cardiac procedures) (CPB n= 222, ECMO 
n=49)  
 
 
 
 
 
 
 
 
 
 
 
 
CPB 
ECMO 
Ischemic time (min)  
518 L, 432 R, 495 
single lung  
581 L, 450 R, 400 
single lung 
ECC time 
162 min  
Not given 
Intraop transfusion (units) 
PRBS 12  
2.5 platelet 
concentrate 
7.2 FFP 
2 fibrinogen 
PRBS 7.1  
1.5 platelet 
concentrate 
7.1 FFP 
1.6 fibrinogen 

 
 
4 prothrombin 
complex 
concentrate  
3.7 prothrombin 
complex 
concentrate 
Postop transfusion (units) 
PRBC 17.9   
PC 4.8  
17.6 FFP  
Fibrinogen 0.6 (g) 
prothrombin 
complex 
concentrate 1.3  
PRBC 12.7  
PC 3.3 
11.1 FFP 
Fibrinogen 0.5 (g) 
prothrombin 
complex 
concentrate 2.7  
New postop ECMO support  
26% 
4% 
Postop VA ECMO (n)  
1 (2%) 
19 (41%) 
Rethoracotomy for bleeding 
(n) 
16 (35%) 
9 (19) 
New requirement for dialysis 
(n) 
22 (48%) 
6 (13%) 
Ventilation time (days) 
21.4 
14 
ICU LOS (days) 
29 
19 
In-hospital mortality  
39% 
13% 
Survivors at discharge (n) 
28 (61%) 
40 (87%)  
Survival rate at 3 months (%) 
70% 
87% 
Survival rate at 12 months 
(%) 
56% 
81% 
 
Ius (2012): 2 groups; significant in hospital mortality reduction with ECMO , lower rates of PGD 
and renal failure. ECMO better periprocedural management, less postop complications; 
increased survival despite greater preoperative morbidity, transfusion req, postop complications 
(hemodyalisys) (did not exclude cardiac procedure) (N=46 CPB and ECMO groups) 
 
 
 
 
 
 
 
CPB 
ECMO 
Intraop pump time (min) 
199 
210 
Warm ischemic time (min) 
69 L, 64 R, 74 single  
73 L, 70 R, 74 single  
Intraop Transfusion (units)  
6 pRBC  
1 Platelets  
4 FFP  
3 pRBC  
0 Platelets  
0 FFP  
Postop Transfusion up to 72 
hrs  
2 pRBC   
1 pRBC   
Length of mechanical 
ventilation (days ) 
7.5 
3 
ICU LOS (days) 
9.5 
5 
Hospital LOS (days) 
27 
19 

 
 
Extracorporeal life support 
postop requirement (n) 
5 
0 
Dialysis req (n) 
12 (18%) 
3 (9%) 
Reoperation for bleeding (n) 
18 (27%) 
3 (9%) 
90 day mortality (n) 
10 (15%) 
2 (6%) 
 
Machuca (2015): ECMO may be considered as first choice cardiorespiratory support during LT 
a. Excluded: patients bridged w extracorporal life support, required emergency cannulation for 
cardiopulmonary support, concomitant cardiac procedure/transplant, B cenocepacia; b.Matched: 
age, lung transplantation indication, procedure type (bil/single), Recipient factors similar ( BMI, 
gender, donor info)  c. Outcomes i.Perioperative: blood product transfusion  ii.Early outcomes: 
mechanical ventilation requirement, ICU stay, hospital stay iii. 90day mortality (33 ECMO 
matched with 66 CPB) 
 
 
 
 

 
 
Appendix 2: 
 
Post Cardiopulmonary Bypass Coagulopathy Protocol 
 
CCF TEG Normal Values: 
R time: 2-8 mins 
K time: 1-3 mins 
Angle: 55-78 degrees 
MA: 51-69 
EPL 0-15% 
LY30 0-8 
 
Once the bladder temperature reaches 36.5⁰ C during rewarming on cardiopulmonary bypass, obtain 
the following labs: TEG with heparinase, PT, INR, fibrinogen and platelet count. 
 
1. If the R time and INR is elevated, consider transfusing FFP as below. If the R time is normal, but the 
INR is elevated and there is microvascular bleeding once the temperature has normalized, transfusion of 
FFP can still be considered. 
a. 8 < R < 11 (mins) → 1 U FFP 
b. 11 < R < 14 (mins) → 2 U FFP 
c. 14 ≤ R (mins) → 4 U FFP 
 
2. If the α angle and fibrinogen is decreased, consider transfusing cryoprecipitate as below. If 
the α angle is normal, but the fibrinogen is still decreased and there is microvascular bleeding 
once the temperature has normalized, transfusion of cryoprecipitate can still be considered. 
a. Angle < 45⁰ → 10 U cryoprecipitate 
 
3. If the Max Amplitude (MA) and platelet count is decreased, consider transfusing platelets as below. If 
the MA is normal, but the platelet count is decreased and there is microvascular bleeding once the 
temperature has normalized, transfusion of platelets can still be considered. 
a. 46 ≤ MA < 51 (mm) → 1 U Platelets 
b. 40 ≤ MA < 46 (mm) → 2 U Platelets 
c. MA < 40 (mm) → 2-3 U Platelets 
 
4. If the LY30 is elevated at greater than 8%, consider the addition of antifibrinolytic therapy with 
aminocaproic acid infusion