Clinical trial NCT05426031
Conditions: Coagulation; Intravascular
Sponsor: University of Miami
Start date: 2022-06-28; Completion date: 2023-06-01
Enrollment: 130 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to compare two different dosing strategies of a drug named protamine.

Detailed description:

Arms: arm 1: Participants in the group will receive a one time dose of 250 mg Protamine to reverse heparin during the standard cardiopulmonary bypass management during cardiac surgery. arm 2: Participants in the group will receive a ratio dose of Protamine in a 1mg per 100 units of heparin ratio to reverse heparin during the standard cardiopulmonary bypass management during cardiac surgery.
Interventions: intervention 1: Protamine fixed dose intervention 2: Protamine ratio dose
Intervention descriptions: intervention 1: 250 mg of protamine intravenously (IV), one time use intervention 2: 1mg of protamine per 100 units of heparin given intravenously (IV), one time use

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
OPTIMAL PROTAMINE DOSING FOR HEPARIN REVERSAL FOLLOWING 
CARDIOPULMONARY BYPASS: A BLINDED RANDOMIZED CONTROL TRIAL 
COMPARING TWO STRATEGIES 
 
 
IRB: 20220234 
 
 
PROTOCOL VERSION 1 
 
MAY 5, 2022 
 
PRINCIPAL INVESTIGATOR: DR. MICHAEL FABBRO 
 
 
NCT: NCT05426031 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Objectives: 
 
The primary objective is to compare two protamine dosing strategies in cardiac surgical patients. A fixed 
dosing strategy, using 250 mg of intravenous (IV) protamine, will be compared to a standard dosing strategy of 
1mg IV protamine for every 100 IU of heparin given before the initiation of cardiopulmonary bypass (CPB). Only 
patients with calculated protamine doses over 250 mg will be included. The primary outcome is mean difference 
in activated clotting time between baseline and reversal of heparin. Secondary outcomes will include additional 
protamine dosing, chest tube output and units of packed red blood cells transfused.  
Additionally, a retrospective review of protamine and heparin dosing will be performed using existing 
data. This will be done to compare prospective randomized results to our historical practices. 
 
 
Background: 
 
Currently, protamine dosing for heparin reversal following cardiopulmonary bypass varies highly among 
centers, and even among practitioners in a given center. Reversal practices include heparin ratio-based dosing, 
heparin concentration based dosing, and formulaic dosing based on calculations utilizing values like activated 
clotting time (ACT).1  These variations in practice seek to address two primary concerns. The first concern is 
inadequate reversal of heparin following cardiac surgery, leading to bleeding in a patient group at high risk for 
bleeding and transfusion.2 The second concern these variations seek to address is overdosing of protamine, which 
has also been shown to increase measures of clinical bleeding.3 In the COVID era a third concern has arisen which 
is drug shortages.  
 
 
Each of these strategies has advantages and disadvantages. Protamine dosing based on heparin ratios are 
simple and the most widely employed. There is variation even within this practice since ratios can be based on 
initial heparin dose or total dose, and heparin dosing itself can be based on ideal or total body weight. The most 
common form of ratio-based dosing is 1mg protamine to every 100 IU of heparin given before initiation of 
cardiopulmonary bypass (CPB). Evidence suggests that lower ratios may be just as effective at reversal with no 
increase in bleeding measures.4 While heparin concentration-based dosing objectively determines protamine 
doses, point-of-care devices for this purpose remain expensive and unavailable in many institutions including 
ours. Furthermore, the benefit of this strategy remains controversial.1 Some guidelines support this method with 
low quality evidence behind the recommendation.  
 
 
Current guideline recommendations for heparin dosing incorporate low quality evidence to support 
weight-based dosing.5 A commonly cited dose is 300 units/kg of actual body weight. A previous analysis of 
heparin and protamine dosing strategies have identified an average patient weight of 78 kg, and 91-105 units of 
heparin per 1 mg of protamine (heparin: protamine ratio), depending on the protamine dosing strategy.6 With 300 
units/kg and average body weight these ratios would result in an 230-260 mg of protamine doses. Current practices 
which often employ higher heparin dosing strategies, up to 400 units/kg actual body weight, and 1 mg protamine 
per 100 units of heparin, often result in much higher protamine doses than this. Some studies supporting low 
 
1 Hecht, P., Besser, M., & Falter, F. (2020). Are We Able to Dose Protamine Accurately Yet? A Review of the Protamine Conundrum. The journal of 
extra-corporeal technology, 52(1), 63. 
2 Hajjar L a, Vincent J-L, Galas FRBG, et al. Transfusion requirements after cardiac surgery: the TRACS randomized controlled trial. JAMA. 2010;304(14):1559-1567. 
doi:10.1001/jama.2010.1446. 
3 Boer, C., Meesters, M. I., Veerhoek, D., & Vonk, A. B. A. (2018). Anticoagulant and side-effects of protamine in cardiac surgery: a narrative 
review. British journal of anaesthesia, 120(5), 914-927. 
4 Meesters, M. I., Veerhoek, D., de Lange, F., de Vries, J. W., de Jong, J. R., Romijn, J. W., ... & Boer, C. (2016). Effect of high or low protamine dosing 
on postoperative bleeding following heparin anticoagulation in cardiac surgery. Thrombosis and haemostasis, 116(08), 251-261. 
5 Shore-Lesserson, L., Baker, R. A., Ferraris, V., Greilich, P. E., Fitzgerald, D., Roman, P., & Hammon, J. (2018). STS/SCA/AmSECT clinical practice 
guidelines: Anticoagulation during cardiopulmonary bypass. The journal of extra-corporeal technology, 50(1), 5. 
6 Shore-Lesserson, L., Reich, D. L., & DePerio, M. (1998). Heparin and protamine titration do not improve haemostasis in cardiac surgical 
patients. Canadian journal of anaesthesia, 45(1), 10-18. 


protamine ratios, 0.8 mg per 100 units of heparin, have average protamine doses as high as 329 mg, again 
demonstrating variation in heparin practices.7 
 
In addition to variation, another concerning feature of protamine ratio dosing based on initial heparin dose 
is heparin pharmacology. The effective half life of heparin is 60-90 minutes.8 This can be further increased for 
larger heparin doses used in the context of  CPB. In a study of over 4000 patients, average CPB times exceeded 
100 minutes.9 With this considered, the pharmacokinetics of heparin do not support the use of initial heparin 
doses to calculate protamine dosing. Indeed, in a recent randomized controlled trial, patients randomized to 
receive post CPB protamine doses based on a mathematical model of heparin clearance were administered 
significantly lower doses of protamine without any difference in viscoelastic testing or bleeding end points.10 
Lastly, protamine is available in two vial configurations, 250 mg and 50 mg. In times of critical medication 
shortages, as seen in pandemics, doses exceeding 250 mg require the use of additional protamine vials.   
 
The intent of this investigation is to address the following concerns: the expense of heparin concentration 
monitoring and controversial evidence supporting its use, variation in practice with ratio dosing strategies, lack 
of pharmacological support for use of heparin initiation doses for protamine dosing, and lastly, medication 
shortages. Our hypothesis is that standard heparin dosing, 350 units/kg actual body weight with fixed protamine 
dosing, 250 mg, will be non-inferior to a conventional ratio-based protamine dosing strategy of 1 mg protamine 
per 100 units of heparin in patients with calculated protamine doses over 250 mg. We also hypothesize that the 
fixed dosing group will receive less protamine overall. The outcomes of interest are primarily the pre CPB to post 
CPB ACT ratio, and secondarily, additional protamine administration and chest tube output.  
 
Inclusion Criteria: 
 
• Patients greater than or equal to 18 years of age undergoing elective cardiac surgery with cardiopulmonary 
bypass. 
• Patients must have a calculated protamine dose greater than 250 mg based on standard 1:1 initial heparin 
to protamine dosing calculation. 
 
Exclusion Criteria: 
 
• Patients who are under 18 years of age or pregnant.  
• Patients undergoing emergency surgery (ASA class E) 
• Patients with known coagulation disorders.  
• Patients requiring circulatory arrest or deep hypothermia.  
• Patients who have not had the appropriate interruption in coumadin, direct oral anticoagulants or non-
aspirin antiplatelet agents.  
• Patients on pre-operative intravenous unfractionated heparin infusions.  
• Patients ineligible for heparin administration due to known adverse reactions including allergy or heparin 
induced thrombocytopenia or known heparin resistance.  
• Patients who are unable to provide informed consent in the form of a signature. 
• History of adverse reaction to protamine. 
• Have any condition that, in the opinion of the investigator, will compromise the well-being of the patient 
or the study, or prevent the patient from meeting or performing study requirements.  
 
 
7 Meesters, M. I., Veerhoek, D., de Lange, F., de Vries, J. W., de Jong, J. R., Romijn, J. W., ... & Boer, C. (2016). Effect of high or low protamine dosing 
on postoperative bleeding following heparin anticoagulation in cardiac surgery. Thrombosis and haemostasis, 116(08), 251-261. 
8 Tahir R. A review of unfractionated heparin and its monitoring. US pharm. 2007;32(7):26-36. 
9 ElBardissi, A. W., Duclos, A., Rawn, J. D., Orgill, D. P., & Carty, M. J. (2013). Cumulative team experience matters more than individual surgeon 
experience in cardiac surgery. The Journal of thoracic and cardiovascular surgery, 145(2), 328-333. 
10 Miles LF, Burt C, Arrowsmith J, McKie MA, Villar SS, Govender P, Shaylor R, Tan Z, De Silva R, Falter F. Optimal protamine dosing after 
cardiopulmonary bypass: The PRODOSE adaptive randomised controlled trial. PLoS medicine. 2021 Jun 7;18(6):e1003658. 


Procedures involved: 
 
Following written informed consent, a predicted protamine dose will be calculated based on a 1mg of protamine 
to each 100 units of heparin (heparin dosing will follow 350 u/kg). Any patient with a calculated dose over 250mg 
will be randomized to one of two groups; standard protamine dosing of 1mg per 100 units of pre-CPB heparin 
dose or fixed dosing of 250 mg. The cardiac surgery procedure will commence, with 350 units/kg of heparin used 
for initiation of cardiopulmonary bypass. This is based on our centers anecdotal experience of 300 units/kg being 
inadequate. Additional heparin (in aliquots of 50 units/kg) will be administered prior to CPB initiation if the target 
Activated Clotting Time (ACT) of 450 seconds is not achieved. Pharmacy will prepare blinded protamine dose 
based on the group each patient is assigned to. Following discontinuation of bypass protamine will be 
administered centrally and slowly based on standard clinical practice. ACT will be measured after protamine 
administration in standard fashion. Additional protamine administration will be at the surgeon and 
anesthesiologists’ discretion based on post bypass ACT and bleeding. Transfusion practices will follow current 
protocol. 
 
 
Data Banking: 
The study team intends to store only data from this study, for future research and retrospective analysis of it.  
All data for each patient will be recorded on an individual study sheet by the assigned anesthesia personnel caring 
for the patient. Once each enrollment is completed data sheets will be collected by study investigators and placed 
in in individual study folders and locked in a Department of Anesthesia faculty office. Data will subsequently be 
transferred and stored on a University of Miami network computer in compliance with the Electronic Data Quality 
Policy for Clinical Research.  
Data Stored: 
• Patient age 
• Surgery type 
• ASA status 
• Preoperative INR 
• Pre-cardiopulmonary bypass ACT 
• Post-cardiopulmonary bypass ACT  
• Patient’s weight 
• Initial heparin dose 
• Total heparin dose 
• Initial protamine dose 
• Additional protamine dose 
• Total Protamine dose 
• Time each sample is collected and reported will be recorded 
• Packed blood cells units transfused intraoperatively 
• Fresh frozen plasma units transfused intraoperatively 
• Platelets units transfused intraoperatively 
• Cryoprecipitate units transfused intraoperatively 
• 4 hour and 24-hour chest tube output 
Data collection and release: 


Anesthesiologists will administer heparin and protamine in standard fashion. Activated clotting times will be 
measured by perfusionists in standard fashion. Protamine dose preparation will occur in the UHealth Tower 
pharmacy for the purposes of blinding and standardization. 
Data access will be limited to the listed study investigators only. All investigators will complete required CITI 
training. Data will be stored on study sheets in individual patient folders locked in anesthesia office with access 
available to principal investigator only.  Original consent forms will be kept in subject study charts, with a copy 
given to all subjects and a second copy placed in the medical charts. All study charts, regulatory binders will be 
stored at the Research office located at University of Miami Hospital, 1400 NW 12th Avenue, Room 3075J. 
Miami, FL 33136.The data will be transferred to a password protected University of Miami computer in the 
department of anesthesia. The excel sheet data will be made available to investigators through password protected 
excel document.  
All study records and documents, will be retained for studies that are subject to both FDA and HIPAA 
regulations: According to HIPAA regulations will be retained for a minimum of six (6) years following 
study closure. Our research department will retain all research data until the later of any of these possible 
dates listed above. 
Data Management: 
Total number of subjects: 130 
Using retrospective sample data and STATA v 17.0 and considering a power = 0.80 and alpha = 0.05 and equal 
randomization to control and experimental groups, and 1 pre and 1 post intervention (protamine) measurement 
the sample sizes required to be able to detect a 2-sided difference between groups of 5, 10, or 15 were as follows11: 
  
DD power calc:  n= 230   mde= 5   power=.8   p=.5   pre=1   post=1   depvar=act 
DD power calc:  n=  59   mde=10   power=.8   p=.5   pre=1   post=1   depvar=act 
DD power calc:  n=  27   mde=15   power=.8   p=.5   pre=1   post=1   depvar=act 
 
Previous studies comparing ACT devices have used a difference of 10 seconds as clinically meaningful.12 To 
detect a difference of 10, we would need to be powered to 118 subjects. We have chosen 130 subjects to account 
for any patients with incomplete data or that need excluded after enrolment for any reason. 
Risks to subjects: 
This study poses minimal risk to patients. Additional heparin will be administered to ensure an ACT > 450 
seconds prior to initiation of CPB. Additional protamine will be administered after the initial post CPB dose if 
the ACT values are greater than 20% of baseline, or if there is concern for clinical bleeding.  
Potential Benefits 
Direct potential benefits cannot be guaranteed to the patients. This is a study that seeks to compare a type of 
protamine dosing strategy and increase the knowledge of heparin reversal in cardiac bypass surgery.  
 
11 Burlig F, Preonas L, Woerman M. Panel data and experimental design. Journal of Development Economics. 2020 May 
1;144:102458. 
12 Li H, Serrick C, Rao V, Yip PM. A comparative analysis of four activated clotting time measurement devices in cardiac 
surgery with cardiopulmonary bypass. Perfusion. 2021 Sep;36(6):610-9. 
 


Vulnerable Populations: 
This study will not include any vulnerable patient population. Pregnant women, prisoners and patients unable to 
provide consent in the form of a signature will be excluded 
Setting: 
Research consents will be obtained in the operating room holding area of University of Miami Hospital for 
patients admitted the day of surgery. In hospital patients will be consented the night prior to surgery in their 
admitted locations. Heparin and protamine administration, and ACT measurements will take place within the 
Operating Room, as is standard. Post-surgical care and monitoring including blood product administration and 
chest tube output recording will be conducted in the intensive care unit 
Resources available: 
Dr. Michael Fabbro Assistant Professor of Anesthesiology. He is a board certified cardiac anesthesiologist who 
has conducted previous research as the principal investigator in the area of coagulation. Namely he has previously 
written IRB’s and provided oversight for research comparing viscoelastic testing measures to routine laboratory 
tests similar to the proposed study design. Dr. Fabbro will be responsible for the recruitment and consent of all 
test subjects. He will oversee the collection and testing of all samples. Lastly he will be collecting, storing and 
dissimilating data to other investigators. He will be responsible for constructing the manuscript. 
Dr. Pankaj Jain is an Associate Professor of Anesthesiology and is a board certified cardiac  
anesthesiologist. Dr. Jain has participated in and published on coagulation issues in cardiac  
surgery patients. He will be assisting in the recruitment and consent of all test subjects. He  
will also assist in the collection and testing of all samples. and provide substantial  
contribution to the manuscript. 
 
Dr. Richard Epstein is Professor of Anesthesiology and a board certified anesthesiologist. Dr. Epstein has prolific 
publications on statistical methods and analyses and will be providing the statistical analysis. 
 
Kabir Bedi is a medical student at the University of Miami. He will be assisting in consenting, data collection and 
manuscript editing.  
 
Dr. Alejandra Silva is an International Medical Graduate currently working as Research Coordinator for the 
Anesthesia Department. She will be assisting with IRB submission, consenting, data collection, and manuscript 
editing.  
Patient Recruitment Methods: 
Potential subjects will be identified using the daily released operating room schedule. Patients on the 
schedule will be pre-screened using available medical data for exclusion criteria. If patients do not meet 
any of the exclusion criteria they will be visited by the Principal Investigator, Sub-investigator and/or 
Study coordinators on the morning of surgery or the night before depending on their admission status. If 
the subject is currently an inpatient at the hospital, the medical team taking care of the patient will be 
approached by the study team to get permission to approach the subject. Study details, risks, benefits and 
alternatives will be discussed with each potential subject. If the patient shows interest into the study, the 
PI will notify research personnel of potential participant to start the process of consent. Study information 
and informed consent document (attached) will be provided to each subject. If the patient agrees to the 
study a copy of the signed consent will be provided to the patient and one placed in the patient medical 
chart. The original document will be placed in the study specific subject folder.  


Study End Point: 
Primary Outcome: Mean difference in activated clotting time 
Primary Outcome Measure Description:  Activated clotting time is going to be measured with the Hemocron 
Elite device (point of care).   
Primary Outcome Measure Timeframe: two time points: once before incision and five minutes after protamine 
administration.  
Secondary outcome: additional protamine dosing 
Secondary outcome Measure Description: measured in mg.  
Secondary outcome Measure Timeframe: the additional amount of protamine used on the patient will be 
added and recorded at the end of surgery.  
Secondary outcome: chest tube output 
Secondary outcome Measure Description: measured in mL 
Secondary outcome Measure Timeframe:  measured since the beginning of surgery for 24 hours 
Secondary outcome: units of red blood cells transfused 
Secondary outcome Measure Description: measured in units 
Secondary outcome Measure Timeframe:  measured only during the time of surgery.  
 
Confidentiality: 
Data will be recorded on study sheets locked in the Department of Anesthesia in a locked filing cabinet 
for the period of one year. Additionally, data will be stored on a password protected University of Miami 
computer in the Department of Anesthesia. Data will remain in a password protected excel sheet with 
access provided only to investigators listed on the IRB protocol. All study records and documents, will be 
retained for studies that are subject to both FDA and HIPAA regulations: According to HIPAA regulations 
will be retained for a minimum of six (6) years following study closure. Our research department will 
retain all research data until the later of any of these possible dates listed above. 
 
(a).   ☒  Data will be collected from the EMR or subjects at UHealth or JHS.   
   ☒ Research Subjects will sign a HIPAA Authorization before the research will collect this data.  
   ☐ Research Subjects will not sign a HIPAA Authorization for this data collection and the 
research is requesting a waiver of HIPAA authorization from the IRB.  (Complete Section 17 
below) 
   (b).  Data collected: 
 Will not include Protected Health information or Personally Identifiable Information 
 Will include Protected Health information or Personally Identifiable Information 
    (c).  How will the research store the data?                 
☒  On a University of Miami electronic device (e.g. encrypted, password-protected computer) 


☐  On a cloud-based storage system that is approved by the University of Miami  
☒  Other, specify: Data will be recorded on study sheets locked in the Department of Anesthesia in a 
locked filing cabinet for the period of one year. 
 
Select one of the following:  
☐  The Principal Investigator (and/or Study Team members) will record (e.g. write down, abstract) data 
acquired in a manner that does not include any indirect or direct identifiers (listed in the instructions 
for Section 15 of this protocol), and the recorded data will not be linked to the individual’s’ identity.   
   OR 
☒  The Principal investigator (and/or Study Team members) will record (e.g. write down, abstract) the 
data collected in a manner that does not include any direct identifiers (see list in the instructions for 
Section 15 of this protocol) of any subject. Instead, the Principal Investigator and/or Study Team 
members shall will assign a code (that is not derived in whole or in part from any direct or indirect 
identifiers of the individual) to each study subject and link the code to the study subject’s identity. 
The link to each subject’s identity and/ or other identifiable information will be maintained on 
a document separate from the research data.  
Biospecimens 
☒  Not applicable.  No biospecimens will be collected  
 
  Bio-Specimens obtained for this research will be stored without any direct or indirect 
identifiers.   
 
 
 Bio-Specimens obtained for this research will be stored in a de-identified coded manner.   
  When required to transport data or bio-specimens for this research, the research team will 
transport the data and bio-specimens in a de-identified (or anonymous) manner with a link to 
the individual subject’s identity maintain separately from the data and/or bio-specimen. 
Authorization for Use and Disclosure of Protected Health Information (HIPAA)  
 
Type of Request: 
 Waiver of Authorization for access to medical record for subject identification/recruitment. 
 Waiver of Authorization for access to medical record to obtain data for the research. 
 
Confirm that you will destroy or de-identify the information you collect at the earliest opportunity.  
  I confirm 
 
Confirm that the information you collect will not be reused or disclosed to any other person or entity, 
except as required by law, for authorized oversight of the research study or for other research for which 
the use or disclosure of PHI is permissible. 
 
   I confirm          
 
Provision to Protect Privacy Interests of Subjects: 


Study information packets and consent forms (attached) provided to each patient will list all investigators and 
will provide immediate contact information for the principal investigator. Subjects will be advised that the can 
withdrawal from the study at any time point. If subjects withdrawal all information regarding that subjected will 
be deleted and subject files will be placed in approved medical record disposal bins. 
Consent Process: 
Written informed consent will be obtained for each subject. Consents will be obtained in English; the consenting 
process can also be given in Spanish by the Study Coordinators, who speak Spanish and can perform the process 
in Spanish. For Spanish-speaking subjects, a Spanish consent form will be provided. As detailed, research 
consents will be obtained in the operating room holding area of University of Miami Hospital for patients admitted 
the day of surgery. In hospital patients will be consented the night prior to surgery in their admitted locations. 
Patient's identity and age must be verified prior to obtaining informed consent, as well as his understanding 
of Risks and benefits and possible alternatives available explained before any informed consent signature 
from those patients willing to participate. The PI(s) with each study participant will:  
• Ensure each patient is given full and adequate oral and written information about the nature, purpose, 
possible 
risk, 
and 
benefit 
of 
the 
study. 
• Ensure each patient is notified that they are free to discontinue from the study at any time. 
• Ensure that each patient is given the opportunity to ask questions and allowed time to consider the 
information 
provided. 
• Ensure each patient provides signed and dated ICF before conducting any procedure specifically for the 
study. 
• 
Ensure 
the 
original, 
signed 
ICF(s) 
is/are 
stored 
in 
the 
investigator’s 
Study 
File. 
• Ensure a copy of the signed and dated ICF is given to the patient for future reference of the study. 
• Ensure that any incentives for patients who participate in the study as well as any provisions for patients 
harmed as a consequence of study participation are described in the ICF that is approved by an IEC/IRB. 
All potential subjects will be given ample time to review the consent form and discuss any questions and 
concerns with research personnel or study doctor as well as they will be provided with a copy of the signed 
ICF. Consent must be documented with a dated signature on the consent form from both the patient and 
the study personnel conducting the consent discussion.