Effects of Microplegia on Transfusion Rates After Cardiac Surgery: A Randomized Prospective Analysis
Phase: PHASE4
Conditions: Aortic Valve Disease, Mitral Valve Disease
Sponsor: Washington University School of Medicine

Microplegia Study 
 
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Title: Effects of microplegia on transfusion rates after cardiac surgery: A randomized prospective analysis 
 
 
 
 
NCT05076604 
 
 
 
 
 
03/25/2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Microplegia Study 
 
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Project Title 
Effects of microplegia on transfusion rates after cardiac surgery: A 
randomized prospective analysis 
 
Short Title 
 
 
Microplegia Study 
 
Protocol Number 
 
MICROPLEG-001 
 
Protocol Version, Date  
1.3, 25MAR2019 
 
Principal Investigator   
Spencer J. Melby, MD1 
 
Co-Investigators 
 
Ralph J. Damiano Jr., MD 1 
 
 
 
 
Thomas J. Graetz, MD2  
 
 
 
Marc R. Moon, MD1 
Richard B. Schuessler, PhD1 
 
Co-Authors 
 
 
Joshua L. Manghelli, MD1 
 
 
 
 
Ali J. Khiabani, MD1 
 
 
 
 
Daniel I. Carter, BS1 
 
 
Investigator Affiliations 
1. Washington University School of Medicine, Department of Surgery, 
Division of Cardiothoracic Surgery 
2. Washington University School of Medicine, Department of 
Anesthesiology  
 
 
 
 
Sites 
 
 
 
Barnes-Jewish Hospital 
St. Louis, MO 63110 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Protocol Amendment 1.1 
1. Section 6.0, Table 1: Added and removed variables 
 
Protocol Amendment 1.2 
1. Section 6.0, Table 1: Variables moved to Appendix 3 
2. Appendix 3: added variables 
 
Protocol Amendment 1.3 
1. Change inclusion/exclusion criteria and study design to be more flexible and accurately capture 
cardiac surgery patient population. 
 
 

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Table of Contents 
 
1.0 
INTRODUCTION AND BACKGROUND…………………………………………………………………………………… 3 
2.0 
OBJECTIVES AND HYPOTHESES……………………………………………………………………………………….…… 3  
3.0 
INCLUSION CRITERIA…………………………………………………………………………………………………………… 4 
4.0  
EXCLUSION CRITERIA…………………………………………………………………………………………………………… 4 
5.0 
STUDY DESIGN ………………………………………………….………………………………………………………………… 4  
6.0 
OUTCOME MEASURES (DATA) ……………………………………………………………………………………………..5 
7.0  
RISKS ……………………………………………………………………………………………………………………………………6 
8.0 
BENEFITS ……………………………………………………………………………………………………………………………..6 
9.0 
STATISTICAL ANALYSIS …………………………………………………………………………………………………………6 
10.0 
DATA AND SAFETY MONITORING …………………………………………………………………………………………7 
11.0  
REFERENCES………………………………………………………………………………………………………………………...7 
12.0 
ABBREVIATIONS AND ACRONYMS ……………………………………………………………………………………….7 
13.0  
APPENDIX 1 ………………………………………………………………………………………………………………………....9 
14.0 
APPENDIX 2…………………………………………………………………………………………………………………………..10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1.0 
INTRODUCTION AND BACKGROUND 
Cardioplegia was first introduced as a method to protect the heart during cardiac surgery in the 1950s 
(1).  Initially, it consisted of a crystalloid solution and in the 1970s Follette and colleagues proposed that 
blood was the best mode of delivery of cardioplegia as it is rich in nutrients and oxygen (2).  Blood has 
better osmotic, buffering, and antioxidant qualities that are needed by ischemic myocardium.  More 
recent studies comparing blood and crystalloid cardioplegias showed that there was less cardiac edema, 
and recovery of ventricular function was more rapid with blood based cardioplegia (3).  A meta-analysis 
of over 5000 patients corroborated these findings and showed that blood based cardioplegia reduced 
the incidence of postoperative low cardiac output syndrome and was associated with less myocardial 
damage (4).  
 
Standard diluted blood cardioplegia can also be modified to undiluted blood cardioplegia also known as 
microplegia.  To compare the cardioprotection of 4:1 blood:crystalloid cardioplegia to microplegia, 
McCann et al randomized 20 pigs to either group.  Cardiac edema was measured using histologic 
morphometrics and echocardiogram.  It was noted that both edema percentage and left ventricular 
mass were significantly more decreased in the microplegia group.  Furthermore, all animals receiving 
microplegia were successfully weaned off cardiopulmonary bypass, whereas only 40% of those receiving 
standard cardioplegia were successfully weaned (5). 
 
More recently, Algarni et al. showed decreased prevalence of low cardiac output syndrome in patients 
who received microplegia (n=2,630) (6).  Another study compared microplegia and standard cardioplegia 
in patients undergoing coronary artery bypass grafting and found that the microplegia group had lower 
troponin levels during the post-operative course.  Moreover, microplegia resulted in lower transfusion 
rates and decreased length of hospital stay (7). 
 
A high rate of patients undergoing cardiac surgery require red blood cell transfusions (RBC). Red blood 
cell transfusions are strongly associated with both infection and ischemic postoperative morbidity, 
length of stay, increased early and late mortality, and overall hospital costs (8).  Given that previous 
studies have shown that microplegia is associated with less transfusions, it would be reasonable to 
incorporate this into practice at Washington University.  
 
2.0  
HYPOTHESIS AND AIMS 
The hypothesis is that diluted 4:1 cardioplegia used in adult cardiac surgery at Washington University in 
St. Louis contributes to increased transfusion rates peri-operatively and incorporation of Quest, Inc. 
microplegia may decrease RBC transfusion rates, and thus, impact overall morbidity and mortality after 
cardiac surgery.  
 
Specific aims are: 
1. To determine if use of microplegia results in less peri-operative transfusions compared to diluted 4:1 
cardioplegia.  
 
2. To investigate the effects of microplegia on overall morbidity and mortality during the peri-operative 
period.  We will assess operative mortality and 30 day mortality.  We will examine intra-operative and 
post-operative complications. A complete list of variables to be examined can be found in table 1. We 
will determine if microplegia results in better myocardial protection than standard cardioplegia by 
assessing pre-operative, intra-operative and post-operative serum troponin levels.  
 
 

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3.0  
INCLUSION CRITERIA 
Patients must meet all of the following criteria to be considered eligible for study participation:  
 
1.  Are to undergo non-emergent cardiac surgery 
 
2.  ≥ 18 years of age.  
 
3.  Willing and able to provide informed consent. 
 
4.0  
EXCLUSION CRITERIA 
Patients must not meet any of the following criteria to be considered eligible for study participation:  
 
 
1. History of endocarditis. 
2. Dialysis-dependent renal failure. 
3. Currently on pre-operative mechanical circulatory support (i.e. ECMO, LVAD or intra-aortic 
balloon pump [IABP]). 
4. Contraindication to receiving a blood transfusion (i.e. Jehovah’s Witness).  
 
5. Emergent procedures. 
 
 
5.0  
STUDY DESIGN 
The hypothesis will be accomplished in a randomized, blinded, prospective institutional study conducted 
at two sites, Barnes Jewish Hospital and Christian Northeast Hospital.  314 patients will be randomized 
to either receive diluted 4:1 cardioplegia or nondiluted microplegia. This will be a blinded study to both 
the patient and surgeon.  The patient will be randomized during the preoperative period.  Quest Medical 
Inc. will supply us with the microplegia MPS-2 machines needed to conduct this study. Outcomes will be 
measured by a blinded clinician.  
 
Microplegia 
The microplegia machine to be used for all study subjects is the FDA approved MPS2 Microplegia 
delivery machine manufactured and distributed by Quest Medical, Inc.  
 
The microplegia solution that is standard of care for all cardiac surgery patients, and which all study 
subjects will receive is:  
Induction 
240 mL Baxter Cardioplegia Solution 
10. 5 mL Potassium Chloride 2 meq/ml (21 meq) 
250.5 mL total volume 
  
Maintenance 
747 mL Baxter Cardioplegia Solution 
3.4 mL Potassium Chloride 2 meq/ml (6.75 meq) 
750.4 mL total volume 
 
Subjects will be randomly assigned to 4:1 cardioplegia or nondiluted microplegia.  
4:1 cardioplegia consists of 4 parts crystalloid intravenous fluid to one part human blood.  
Nondiluted microplegia consists of all parts human blood.  
 

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Recruitment   
Potential participants will be identified as inpatients or in new patient clinics of the adult cardiac 
surgeons in the Division of Cardiothoracic Surgery, Department of Surgery, Washington University 
School of Medicine.  Patients will be introduced to the study at the preoperative consultation visit, at 
which point they will be invited to participate and provide informed consent if they agree to join the 
study. Potential subjects will have at least 48 hours, typically longer and up until the time of surgery to 
consider participation and may take the consent home to discuss with friends and family, if they so 
choose. They will have ample time to ask questions of the surgeon prior to agreeing to participate. Upon 
providing informed consent, the subject will be considered enrolled into the study.  
 
Peri-operative period 
Troponins will be drawn in the operating room prior to initiation of cardiac surgery and post-operatively 
upon arrival to the ICU, 12 hours, and 24 hours.  
 
Subjects will undergo their standard of care, planned cardiac surgery procedure as directed by their 
treating surgeon. 
 
Given that our primary endpoint is transfusion requirement, we will assess this need throughout the 
entire peri-operative period.  Standard blood draws after surgery to evaluate hematocrit will be used for 
analysis.  We will use the electronic medical records to obtain this information.  
 
Post-Operative Follow-Up 
There is no active participation for subjects beyond the 24 hour troponin and hematocrit collection time 
points.  Health information on post-operative complications, should they occur, will be collected until 
the patient is discharged from the hospital. Data on vital status will be collected from the subject’s 
medical record at the time of the standard of care 30-day post-operative visit with the surgeon.  
 
6.0 
OUTCOME MEASURES (DATA) 
Data will be obtained from the electronic medical record system at Washington University. Study staff 
from each participating site will review the subject’s medical record and obtain the study-specific data 
to include but is not limited to the following. For a complete list of all data variables to be collected 
please see table 1.  The study-specific data will be collected by the study staff and entered into a 
REDCap database that will be created specifically for this study. REDCap is a mature, secure web 
application for building and maintaining databases (https://redcap.wustl.edu).   
 
Electronic study data will be entered in a secure REDCap database.  Only investigators and the study 
team for this study will have access to the study data. They will each use a unique log-in ID and 
password that will be kept confidential. 
 
See Appendix 3: Data Collection for Table 1 
 
 
7.0 
RISKS 
All microplegia will be delivered using the MPS-2 Myocardial Protection System. This is an approved 
device currently used in many cardiac centers worldwide. There is no change in risk that can be 
associated with the use of microplegia versus standard cardioplegia currently used as standard of care. 
 

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Blood drawing poses the following risks: pain, bleeding, or bruising and rarely, infection. All peri-
operative blood draws can be performed while the subject has a standard of care intravenous line in 
place. There will be no needle sticks required.   
 
There is a rare risk of breach of confidentiality of study data.  
 
8.0 
BENEFITS 
There are no known direct benefits to subjects; however, there will be an improved understanding of 
cardioplegia techniques and possibly improved outcomes of cardiac surgery patients.  
 
9.0 
STATISTICAL ANALYSIS 
Continuous variables will be expressed as mean ± standard deviation or as median with range. 
Categorical variables will be expressed as frequencies and percentages with outcomes compared using 
the χ2 or the Fisher exact test. Continuous outcomes will be compared using the t test for means of 
normally distributed continuous variables and the Mann-Whitney U nonparametric test for skewed 
distributions. Significant covariates on univariate analysis (p ≤ 0.10) or covariates deemed clinically 
relevant based on experience will be entered into a multivariate binary logistic regression analysis. 
 
A sample size of 314 patients will be randomized to either receive standard 4:1 cardioplegia or 
microplegia. The sample size was calculated based on a one tailed test with alpha 0.05 and beta 0.2 
(80% power) to detect a 25% relative risk reduction in pRBC units transfused. An interim analysis will be 
completed following the enrollment of 150 patients.  
 
 
10.0 
DATA AND SAFETY MONITORING 
The PI and sub-I, Dr. Schuessler, will monitor the study for any serious adverse events (SAEs).  All serious 
adverse events will be reported to the Washington University Human Research Protection Office per 
their guidelines and policies by the research coordinator(s).  An investigation into the event will be 
conducted, and a findings reported.  
 
11.0 
REFERENCES 
1. W.G. Bigelow, W.K. Lindsay, W.F. Greenwood. Hypothermia; its possible role in cardiac surgery: an 
investigation of factors governing survival in dogs at low body temperatures Ann Surg, 1950; 132: 849-
866 
2. D.M. Follette, K. Fey, G.D. Buckberg, et al. Reducing postischemic damage by temporary modification 
of reperfusate calcium, potassium, pH, and osmolarity J Thorac Cardiovasc Surg, 1981; 82: 221-238 
3. S.E. Fremes, G.T. Christakis, R.D. Weisel, et al. A clinical trial of blood and crystalloid cardioplegia J 
Thorac Cardiovasc Surg, 1984; 88:726-41  
4. V. Guru, J. Omura, A.A. Al ghamdi, R. Weisel, S. Fremes. Is blood superior to crystalloid cardioplegia?: 
A meta-analysis of randomized clinical trials. Circ. 2006; 114:1331-38  

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5. U.G. McCann II, C.J. Lutz, A.L. Picone, et al. Whole blood cardioplegia (minicardioplegia) reduces 
myocardial edema after ischemic injury and cardiopulmonary bypass. J Extra Corpor Technol. 2008; 
38:14-21  
6. K.D. Algarni, R.D. Weisel, C.A. Caldarone, et al. Microplegia during coronary artery bypass grafting was 
associated with less low cardiac output syndrome: A propensity-matched comparison. Ann thorac surg 
2013; 95:1532-8 
7. F. Onorati, F. Santini, R. Dandale, et al. “Polarizing” microplegia improves cardiac cycle efficiency after 
CABG for unstable angina. Int J Card. 2013; 167:2739-46 
8.  G.J Murphy, B.C. Reeves, C.A. Rogers, et al. Increased mortality, postoperative morbidity, and cost 
after red blood cell transfusion in patients having cardiac surgery. Circulation. 2007; 116:2544-2552 
 
12.0 
ABBREVIATIONS AND ACRONYMS 
 
COPD 
Chronic obstructive pulmonary disease 
CPB 
Cardiopulmonary bypass 
FFP 
Fresh frozen plasma 
ICU 
Intensive Care Unit 
LVEF 
Left ventricular ejection fraction 
OR 
Operating room 
PCI 
Percutaneous coronary intervention 
pRBC 
Packed red blood cells 
WMSI 
Wall motion score index 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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13.0    APPENDIX 1: Protocol for transfusion of packed red blood cells (pRBC) 
 
• Please record blood transfusion on the peri-operative blood transfusion form.  
Deviations should be justified clearly on the peri-operative transfusion form. 
• Discussion with primary cardiac surgeon or fellow/resident should occur prior to 
transfusion whenever possible.  
 
Intraoperative: 
1. It is appropriate to transfuse if predicted hematocrit on cardiopulmonary bypass <20% or actual 
hematocrit on cardiopulmonary bypass falls below 20%. 
 
Postoperative: 
1. It is appropriate to transfuse if hemoglobin falls below 7 g/dL 
2. It is appropriate to transfuse if hemoglobin falls below 8 g/dL and any of the following are present: 
       -patient has borderline hemodynamics, or has become dependent upon pressors/inotropes 
       -patient is symptomatic (i.e. dizziness, lightheadedness, unable to ambulate) 
       -patient is in acute renal failure 
 3. It is appropriate to transfuse in any case of ongoing hemorrhage/acute blood loss  
 
 
 
 
 
 
 
 
 
 

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14.0 APPENDIX 2: TRANSFUSION FORMS 
 
INTRAOPERATIVE TRANSFUSION 
FORM 
 
Study number__________ 
 
 Date of Surgery ________________ 
 
 
 
1st Transfusion 
Date 
# of units 
Ordered by (name) Predicted/Actual 
Hematocrit (%) 
Justify if Hematocrit > 20% 
 
 
 
 
 
 
2nd Transfusion 
Date 
# of units 
Ordered by (name) Predicted/Actual 
Hematocrit (%) 
Justify if Hematocrit > 20% 
 
 
 
 
 
 
3rd Transfusion 
Date 
# of units 
Ordered by (name) Predicted/Actual 
Hematocrit (%) 
Justify if Hematocrit > 20% 
INSTRUCTIONS 
1. All blood (pRBC) transfusions will be recorded on the transfusion form.  
 
2. Deviations from the protocol must be justified clearly on the transfusion 
form.  
 
PROTOCOL 
It is appropriate to transfuse:  
• if predicted hematocrit on cardiopulmonary bypass <20%  
• or actual hematocrit on cardiopulmonary bypass falls below 20% 

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4th Transfusion 
Date 
# of units 
Ordered by (name) Predicted/Actual 
Hematocrit (%) 
Justify if Hematocrit > 20% 
 
 
 
 
 
 
Transfusion (example) 
Date 
# of units 
Ordered by (name) Predicted/Actual 
Hematocrit (%) 
Justify if Hematocrit > 20% 
Aug 8, 
2018 
2 
Dr. First Last 
25 
Active bleeding 
 
 
 

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POSTOPERATIVE TRANSFUSION FORM 
 
Study number__________ 
 
 Date of Surgery ________________ 
 
 
 
1st Transfusion 
Date 
# of units 
Ordered by (name) 
Hgb level (g/dL) Justify if Hgb ≥7.0 g/dL 
 
 
 
 
 
 
2nd Transfusion 
Date 
# of units 
Ordered by (name) 
Hgb level (g/dL) Justify if Hgb ≥7.0 g/dL 
 
 
 
 
 
 
More on other side if needed 
 
INSTRUCTIONS 
1. All blood (pRBC) transfusions will be recorded on the  transfusion form.  
 
2. Deviations from the protocol must be justified clearly on the transfusion 
form.  
 
PROTOCOL 
1. It is appropriate to transfuse if hemoglobin falls below 7 g/dL 
2. It is appropriate to transfuse if hemoglobin falls below 8 g/dL and any of the 
following are present: 
• patient has borderline hemodynamics, dependent upon pressors 
• patient is symptomatic (i.e. dizziness, lightheadedness, pallor, 
shortness of breath) 
• patient is in acute or chronic renal failure 
3. It is appropriate to transfuse in any case of ongoing hemorrhage 
 

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3rd Transfusion 
Date 
# of units 
Ordered by (name) 
Hgb level (g/dL) Justify if Hgb ≥7.0 g/dL 
 
 
 
 
 
 
4th Transfusion 
Date 
# of units 
Ordered by (name) 
Hgb level (g/dL) Justify if Hgb ≥7.0 g/dL 
 
 
 
 
 
 
Transfusion (example) 
Date 
# of units 
Ordered by (name) 
Hgb level (g/dL) Justify if Hgb ≥7.0 g/dL 
Aug 8, 
2018 
2 
Dr. First Last 
7.6 
Borderline 
hemodynamics, 
dependent upon 
pressors 
 
 

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15.0 Appendix 3: Data Collection 
 
Table 1: Baseline pre-operative, operative, and post-operative variables to be examined.  
Pre-operative variables 
Intra-Operative Variables 
Post-Operative Variables 
Age 
pRBC transfusion (see 
appendix 2, peri-operative 
transfusion form): date, 
number of units, name of staff 
ordering transfusion, 
actual/predicted hematocrit, 
justification if hematocrit 
>20% 
pRBC transfusion (see appendix 2, 
perioperative transfusion form): date, 
number of units, name of staff 
ordering transfusion, hemoglobin 
level, justification if hemoglobin ≥7.0 
g/dL. 
Weight 
Platelet transfusion: number 
of units 
Platelet transfusion: number of units 
Dyslipidemia 
FFP transfusion: number of 
units 
FFP transfusion: number of units 
Hypertension 
Mortality 
Hematocrit on arrival to ICU 
COPD 
Clamp time 
Hematocrit 24 hours post-operatively 
Coronary artery disease 
Amount of 
cardioplegia/microplegia 
delivered 
30 day mortality 
Liver disease 
Type of surgery 
Time on ventilator 
Cerebrovascular disease 
CPB time 
Hours in the intensive care unit 
Previous cardiac 
interventions 
Cross-clamp time 
Length of hospital stay 
History of arrhythmia 
Cardioplegia technique 
Renal failure 
Diabetes mellitus 
Number of grafts 
Pulmonary complications 
LVEF (%) 
Concomitant procedures 
Low output syndrome 
Congestive heart failure 
Pre-CPB hematocrit 
Myocardial infarction 
Peripheral vascular disease 
On-CPB hematocrit 
Serial troponins: arrival to ICU, 12 and 
24 hours post-op 
Hemoglobin, hematocrit 
Post-CPB hematocrit 
New onset post-op atrial fibrillation 
Creatinine  
Date of surgery 
Stroke 
Troponin 
Skin incision to skin close time 
Mortality 
Previous PCI +/- stents 
Cardioplegia Delivery 
Readmission  
Angina 
Additive Volume 
Readmission date 
BMI 
Arrest Agent Volume 
Readmission reason 
Height 
Total CDPG 
 
Ethnicity 
Crystalloid Amount 
 
Race 
Crystalloid Total  
 
Chronic Lung Disease 
Anesthesiologist 
 
Immunocompromise 
Perfusionist 
 
Mediastinal Radiation 
Starting glucose 
 

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Thoracic Aorta Disease 
Final glucose 
 
Sex 
TEE score 
 
Date of admission 
Time to arrest 
 
 
Volume to arrest 
 
 
Cryoprecipitate volume 
Cryoprecipitate volume