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“The Science Behind the Art” 
Volume 10 - No.3 2022 

Anesthesia eJournal - Online 
ISSN 2333-2611

Page 3

Protamine Reaction in Cardiovascular Surgery
Gage Walker, BSN, RN, CCRN

Affiliation:
Texas Christian University 

Grant/Financial Support: 
None 

KEYWORDS:  Protamine reaction, Cardiovascular surgery, Coronary artery bypass

Abstract
Coronary artery bypass grafting is the most performed cardiac surgery throughout the world today. The United States 
alone performs over 200,000 of these procedures every year. Protamine sulfate is administered to neutralize heparin 
given during these cases. Known hemodynamic effects are associated with protamine and on rare occasions, true 
anaphylaxis. A 10.7% chance exists of a protamine reaction occurring after its administration and five different risk 
factors that increase that chance is an allergy to fish, use of NPH insulins, previous vasectomy, previous exposure to 
protamine, and rapid administration of protamine. Treatment includes fluid resuscitation, administration of vasopressors, 
intra-aortic balloon pump, and methylene blue but this has not been studied. A heparin removal device as an alternative 
to protamine shows promise.

AEJ
Volume 10- No. 3 2022

About the Author: Gage Walker is a registered nurse pursuing his doctorate in nurse anesthesia at Texas Christian 
University, Fort Worth, Texas. His primary clinical site is in Wichita Falls, TX 



Texas Christian University 
“The Science Behind the Art” 
Volume 10 - No.3 2022 

Anesthesia eJournal - Online
ISSN 2333-2611 

Page 4

PowerPoint Template ©2009 Texas Christian University, Center for Instructional Services. For Educational Use Only. Content is the property of the presenter and their resources.

Introduction
• Cardiopulmonary bypass grafting (CABG) is the most performed cardiac 

procedure done throughout the world today1

• 10.7% of patients receiving protamine experience a protamine reaction2,3,4

• Protamine is administered to neutralize the anticoagulant effects of heparin4 

Evidence shows that when a reaction does occur, there is an increased 
mortality risk4

• Reactions to protamine can be respiratory in nature such as wheezing, 
cardiovascular such as hypotension, impaired cardiac output, arrhythmias, 
pulmonary hypertension, or cardiac arrest, skin such as urticaria, flushing and 
angioedema, or hematologic such as bleeding3

• Protamine is administered routinely in many vascular procedures therefore 
anesthesia providers should know the risks associated with it and what to do 
if a reaction occurs

• Purpose: to discuss known risk factors that precipitate a reaction to 
protamine, how often a reaction may occur, appropriate treatment for when a 
reaction does occur, and if there are any alternatives to the administration of 
protamine available

Discussion
• Studies show that suggested treatment is supportive. Examples 

are diphenhydramine 50 mg IV to treat cutaneous manifestations, 
large volumes of fluid to replace intravascular loss, epinephrine up
to 4 mcg/min, dopamine 5 mcg/kg/min, and isoproterenol 2 to 20 
mg/min to support cardiac function. Intra-aortic balloon pump has
also been utilized to support cardiac function2

• Methylene blue (500 mg) has successfully treated sustained
hypotension after traditional supportive measures were 
unsuccessful5

• A fixed protamine: heparin ratio dose may be overdosing or
underdosing the protamine leading to adverse outcomes6

• A heparin removal device which is an extracorporeal 
plasmapheresis filter that contains a resin which binds and 
immobilizes heparin from circulating heparinized blood, was 
utilized after patient suffered a reaction from protamine and was 
still bleeding after wound closure. Patient was brought back to OR
and HRD was able to bring ACT to 160 seconds which was below 
the baseline of 192 seconds after a 25-minute run time7

• A bovine study demonstrated HRD was able to reverse heparin 
equal to protamine in an average of 31 minutes compared to a
standard 15-minute infusion8

Case Critique
• Utilizing a fixed protamine: heparin ratio overdosing the

protamine could have led to the reaction6

• The use of methylene blue was a positive, but it could have
possibly been administered sooner

• A heparin removal device could have been utilized to reverse the
heparin lowering the amount of time the patient required 
cardiopulmonary bypass but as of now it has not received FDA 
approval7

• Appropriate utilization of vasopressors and intra-aortic balloon 
pump to support cardiac function2

• Protamine was administered via micro drip over 15 minutes which
aligns with research2

Protamine Reaction in Cardiovascular Surgery
Gage Walker, BSN, RN, Texas Christian University

Figure 1. Demonstration of Protamine Pathophysiology Causing Hypotension9

Case Summary
• 80-year-old female, 165 cm, 77 kg, scheduled for elective CABG
Anesthetic evaluation
• PMH: CAD, HTN, MI with stent, PPM due to heart block, GERD, Hypothyroid, 

DDD, Parkinson’s disease
• Labs: Na-139, K-4.6, Cl-105, CO2-28, Gap-11, BUN-30, Crea-0.93, EGFR-58, 

Glucose-132, Calcium-9.8, Alk Phos-78, Albumin-3.8, WBC-4.7, RBC-4.03, 
Hgb-11.1, Hct-35.3, Plt-267

• Echo: EF 45%, moderate mitral regurgitation, moderate pulmonary 
hypertension

• Angiography: Left main 70-80% stenosis, RCA 80% stenosis, LAD 80-90% 
stenosis

• Medications: aspirin, omeprazole, potassium chloride, levetiracetam, 
escitalopram, levothyroxine, metoprolol, calcium carbonate,
carbidopa/levodopa, acetaminophen, atorvastatin

• PSH: Cardiac stent placement, hysterectomy
• Premedication: None
• Anesthetic plan: GETA, A-line and CVL post-induction
Intraoperative course
• Monitors applied, preoxygenation
• Induction: 60 mg propofol, 5 mcg sufentanil, 50 mg lidocaine, 30 mg 

rocuronium for muscle relaxation
• Intubation: DL x 1, Grade I view, ETT 8.0
• Maintenance: Sevoflurane titrated to effect, IVP sufentanil, vecuronium for 

muscle relaxation
• Emergence: Postoperative ventilatory support, dexmedetomidine infusion @ 

0.5 mcg/kg/hr
• Severe reaction after administration of protamine with BP dropping as low as 

32/17 mmHg
• Treated with norepinephrine, epinephrine, vasopressin and calcium chloride
• Methylene blue was administered, and the patient was placed on an IABP
• Decision: to heparinize again and place the patient back on CPB 
• Once ACT was 175 seconds, patient was closed and taken to the ICU on IABP
Postoperative course
• IABP was discontinued on POD 2. Extubated POD 3. Oxygen requirements 

began increasing on POD 8 which required BIPAP. Reintubated and eventually 
suffered cardiac arrest with CPR initiated and ROSC on POD 9. Comfort 
measures were later initiated, and patient passed on POD 9. 

References
1. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics--2012 update: a report from the

American Heart Association [published correction appears in Circulation. 2012 Jun 5;125(22):e1002]. Circulation. 
2012;125(1):e2-e220. doi:10.1161/CIR.0b013e31823ac046

2. Porsche R, Brenner ZR. Allergy to protamine sulfate. Heart & Lung. 1999;28(6):418-428
3. Weiler JM, Gellhaus MA, Carter JG, et al. A prospective study of the risk of an immediate adverse reaction to

protamine sulfate during cardiopulmonary bypass surgery. J Allergy Clin Immunol. 1990;85(4):713-719.
doi:10.1016/0091-6749(90)90189-b

4. Nybo M, Madsen JS. Serious anaphylactic reactions due to protamine sulfate: a systematic literature review. Basic 
Clin Pharmacol Toxicol. 2008;103(2):192-196. doi:10.1111/j.1742-7843.2008.00274.x

5. Lutjen DL, Arndt KL. Methylene blue to treat vasoplegia due to a severe protamine reaction: a case report. AANA J. 
2012;80(3):170-173

6. Hecht P, Besser M, Falter F. 2020. Are We Able to Dose Protamine Accurately Yet? A Review of the Protamine
Conundrum. J Extra Corpor Technol. 52(1):63-70. doi:10.1182/ject-1900038

7. Conti, V.R., Vertrees, R.A., Zwischenberger, J.B., Kurusz, M., 1995. First clinical use of a heparin removal device: An
alternative to protamine. J Thorac Cardiovasc Surg. 109, 1015–1017.. doi:10.1016/s0022-5223(95)70332-2

8. Tao W, Deyo DJ, Brunston RL Jr, Vertrees RA, Grochoske TL, Zwischenberger JB. Efficacy of a heparin removal device
in comparison with protamine after hypothermic cardiopulmonary bypass. ASAIO J. 1997;43(5):M825-M830

9. Pearson P, Evora P, Schaff H, et al. Protamine Releases Endothelium‐Derived Relaxing Factor From Systemic Arteries:
A Possible Mechanism of Hypotension During Heparin Neutralization. Circulation. 1992;86:289-294.

Recommendations for Practice
• Set guidelines to run protamine over at least a 5–15-

minute time frame2

• Screen all patients who will be given protamine for risk
factors of allergy to fish, use of NPH insulins, previous 
vasectomy, and previous exposure to protamine

Recommendations for Future Research
• Further studies on the use of methylene blue to treat

hypotension after protamine administration
• Further studies on the use of a heparin removal device to

determine efficacy and appropriateness of its use with 
known protamine allergies

• Further studies to assess appropriate dosing of protamine

Risk Factors for a Protamine Reaction
q Allergy to fish2

q Use of NPH insulins2

q Previous vasectomy2

q Previous exposure to protamine sulfate2

q Rapid administration of protamine sulfate2

f

Supportive Evidence
• A retrospective analysis by Porsche et al assessed incidence and symptoms associated with protamine.2 A reaction occurred between 

0.06% and 10.7%.2 Different reactions ranged from hypotension, increases in pulmonary artery pressure, bronchospasm, flushing,
angioedema, erythema, and pruritus, chills, chest pain, or nausea and vomiting2 

• A prospective study by Weiler et al examined incidence of protamine reaction.3 248 patients were given protamine, 26 experienced a
reaction (10.7%).3 A reaction was considered mild (20-29 mmHg decrease in SBP), moderate (30-49 mmHg decrease in SBP), or severe
(50 mmHg decrease in SBP).3 Eleven of the reactions were mild, 9 were moderate, and 4 were severe.3 Patient risk factors and statistical 
significance were also significant for T2DM and received protamine-containing insulin3

• A SR by Nybo M et al examined incidence of anaphylactic reactions after the administration of protamine sulfate.4 Nine retrospective
studies found (0.19%) anaphylaxis, 16 prospective studies found anaphylaxis (0.69%).4 Prior treatment with NPH insulin was the most
common predisposing factor to suffer an anaphylactic reaction4

• Hecht P et al examined optimal protamine dosing.6 Fixed-protamine: heparin ratio dose is one of the most common strategies utilizing 1
mg of protamine for every 100 units of heparin.6 The ACT-based model is discussed incorporating a mathematical relationship to help 
determine the appropriate protamine dose based on ACT levels measured at baseline, before CPB, and pre-protamine as well as initial 
heparin dose and patient’s weight.6 The ACT-based model found on average a 40 mg reduction in protamine dose required6

• A randomized controlled trial assessed 12 Yorkshire female swine for heparin removal device efficacy compared to protamine 
administration.8 Six were randomly allocated to a protamine group, which were given 1 mg of protamine for every 100 units of heparin
and the other 6 were allocated to the heparin removal device group, that had a target of 90% heparin removal.8 No statistically significant
changes in hemodynamics were associated with use of the heparin removal device.8 The study found that the heparin removal device was
able to reverse systemic heparin anticoagulation by returning PT, APTT, ACT and heparin concentration to near baseline levels after an 
average run time of 31.5 minutes8 

• A case study by Conti et al examined of the first use of a heparin removal device.7 A 44-year-old woman with a history of diabetes that
was on NPH insulin underwent a CABG.7 A test dose of protamine was given, which resulted in a rapid decrease in SBP from 130 to below
40 mmHg, and an increase in the PAP to 52 mmHg, along with right heart failure.7 Open cardiac massage and an epinephrine infusion
were initiated, and hemodynamics were stabilized after 5 minutes.7 The chest was closed and the patient was taken to the ICU with an
ACT of 459 seconds.7 Extensive bleeding occurred and the patient was taken back to the OR where the decision was made to use a
heparin removal device.7 After a run time of 25 minutes the ACT was 160 seconds, which was below the baseline of 192 seconds7

• A case study by Lutjen and Arndt examined a 57-year-old woman undergoing a CABG that suffered a protamine reaction. After 80% of the
infusion, SBP dropped rapidly from 120 to 62 mmHg, and eventually to as low as 50 mmHg.5 The PAP rose from 17/8 mmHg to 28/16 
mmHg.5 Aggressive treatment with vasopressors, fluids, blood products, and IV steroids maintained SBP between 50 and 60 mmHg.5
Methylene blue, 500 mg IV yielded an immediate increase in the SBP to 100 mmHg.5 The operation was completed, and the patient was
transferred to the ICU in stable condition and discharged 5 days later5


