Friday, March 19, 2021

Protamine Reaction in a Patient Undergoing Vascular Surgery Case File

Posted By: Medical Group - 3/19/2021 Post Author : Medical Group Post Date : Friday, March 19, 2021 Post Time : 3/19/2021
Protamine Reaction in a Patient Undergoing Vascular Surgery Case File
Lydia Conlay, MD, PhD, MBA, Julia Pollock, MD, Mary Ann Vann, MD, Sheela Pai, MD, Eugene C. Toy, MD

Case 23
A 65-year-old man with severe claudication secondary to peripheral vascular disease is scheduled for a right femoral-popliteal artery bypass. He has type II diabetes treated with NPH insulin, and hypertension treated with metoprolol. He also has coronary artery disease treated by coronary artery bypass surgery several years ago, and has been asymptomatic from his heart disease since that time. The patient’s past surgical history includes a femoral popliteal bypass on the other side, and a vasectomy, without problems with anesthesia. He is allergic to iodine and seafood. The patient’s pertinent labs include a hematocrit of 35, a potassium of 3.8, and an ECG which showed an old inferior myocardial infarction. By echocardiogram, his ejection fraction is 25%.

Mindful of his coronary artery disease, anesthesia is induced with etomidate, and the patient is paralyzed with succinylcholine and intubated easily. The anesthetic is maintained with desflurane, fentanyl is added for analgesia. His vital signs remain stable throughout. As the arterial anastomosis is begun, the surgeons request that the patient be given 7,000 units of heparin. The heparin is administered, and the anastomosis is completed expeditiously and with minimal blood loss. At the end of the surgery, they request that protamine be administered to reverse the heparin.

Suddenly, the patient became severely hypotensive with blood pressure of 60/30 mm Hg, and a heart rate of 130 bpm. He is cold and clammy in appearance.

➤ What most likely triggered the events?

➤ How should this patient be treated?

➤ Are special monitors indicated?

Protamine Reaction in a Patient Undergoing Vascular Surgery

Summary: A 65-year-old man with a history of multiple vascular procedures, coronary artery bypass surgery, and vasectomy, undergoing femoral-popliteal artery bypass surgery, suddenly became severely hypotensive after protamine is administered.

Triggering events: The temporal correlation is highly suggestive of a protamine reaction.

Treatment: Volume, either crystalloid or colloids, should be infused, and vasopressors such as phenylephrine or norepinephrine should be administered. Inotropes such as epinephrine and/or milrinone should be added if needed.

Special monitors: If patient is not responding to the above interventions, a pulmonary artery catheter and/or transesophageal echocardiography probe may be placed.


1. Learn to recognize the protamine reaction.
2. Understand the risk factors for protamine reaction.
3. Become familiar with the different types of protamine reactions, and treatment of each.

The fact that the patient is severely hypotensive shortly following the administration of protamine strongly suggests a protamine reaction. Since the pressure measured by an arterial line can be artifactual, it is confirmed by another method such as a blood pressure cuff. However, the patient’s cold, clammy appearance is consistent with the hypotensive measurement being correct. Next, other potential causes of severe hypotension must be excluded. The differential diagnosis includes bleeding from the surgical site resulting in hypovolemia, excessive anesthetic agent, ongoing myocardial ischemia, pulmonary embolism, etc.

Protamine reactions are not uncommon, especially in patients who were exposed to protamine in the past such as during previous vascular surgeries and a coronary artery bypass surgery. This patient also has additional risk factors for a protamine reaction including an allergy to iodine and seafood, treatment with NPH insulin, and (although controversial) a history of vasectomy.

This patient’s pressure is 60/30. He is treated by stopping the protamine, calling for help, and notifying the surgeons so that they can assess the surgical site for bleeding and help in the resuscitation if needed. Vasopressors including phenylephrine and a fluid bolus are administered. If patient does not respond, epinephrine, and then milrinone are added. To aid in treatment decisions such as whether vasoconstriction, volume, or inotropy are needed, an invasive arterial pressure monitor and pulmonary catheter are inserted.

Protamine Reaction in a Patient Undergoing Vascular Surgery

PROTAMINE REACTION: An hemodynamic response to protamine, ranging from mild hypotension to cardiorespiratory arrest.

Heparin is a direct inhibitor of thrombin, and a potent anticoagulant used frequently in cardiovascular surgical procedures. For example, if a patient was cannulated and placed on cardiopulmonary bypass without heparin, the cannulae would clot and the patient would die. However, such potent anticoagulation also predisposes to significant surgical bleeding, so it is typically reversed at the end of the case. Protamine is the only drug currently approved by the FDA to reverse heparin. It is a strong base, which combines with heparin, a strong acid, to form a stable salt which does not have any anticoagulant effect.

Protamine can produce different hemodynamic reactions which can range from mild hypotension to severe hemodynamic instability including cardiorespiratory arrest. The mechanisms for these reactions can be quite different. Depending on the cause, the mechanisms of protamine reactions can be divided into four types:

TYPE 1: Systemic hypotension from rapid injection: A predictable side effect of the drug, prevented by diluting and injecting the protamine slowly. This most common protamine reaction, can be accompanied by severe hypotension from massive peripheral vasodilatation. The best way to prevent this kind of reaction is to anticipate the resultant hypotension, particularly in patients who are hypovolemic and vasoconstricted at the time protamine is administered. This type of protamine reaction is treated by stopping or slowing the protamine, while infusing fluids. Treatment with intravenous fluids, vasopressors like phenylephrine or norepinephrine may be necessary to help restore the blood pressure. Insertion of another large-bore i.v. may be warranted.

TYPE 2: Protamine reaction secondary to histamine release: Protamine can cause histamine release and thus produce hypotension. Histamine-induced hypotension is suggested by tachycardia, and flushing. Treatment is combination of H1 blocker like diphenhydramine and H2 blocker like ranitidine. The patient also might require additional fluids and vasopressors. Since it may be difficult to determine the signs of histamine release, it is recommended to administer diphenhydramine and ranitidine intravenously anyway.

TYPE 3: Anaphylactic or anaphylactoid reaction: The patient experiences severe hypotension, tachycardia, and possibly bronchospasm. The response may be immediate or delayed. It is most commonly an anaphylactic reaction associated with an IgE-mediated antibody response, although an anaphylactoid response without antibody involvement is also possible.

This reaction is more common in patients who have had multiple exposures to protamine, or diabetic patients who are on NPH insulin for prolonged period of time. Additional risk factors include allergies to seafood and iodine, and though controversial, having had a vasectomy.

Anaphylactic reactions usually present with severe hemodynamic instabilityincluding cardiovascular collapse, and possible bronchospasm. Like anyother anaphylactic reaction, treatment of choice is epinephrine and volume resuscitation. Vasopressors may also be needed along with volume resuscitation. Steroids such as hydrocortisone may also be given for anaphylaxis, even though benefit of this drug is controversial.

TYPE 4: Protamine reaction with severe pulmonary vasoconstriction and right ventricular failure: Probably the most severe reaction, it is fortunately very rare. This reaction may be difficult to distinguish from type 3 unless patient has pulmonary artery catheter or TEE probe in place. It is mediated by complement C5b. It is optimally treated with an inodilator like milrinone, which causes pulmonary vasodilatation and inotropy. In the event that it is uncertain whether a reaction is type 3 or type 4, therapy can be begun with epinephrine, and milrinone added if required.

The most important way to reduce the morbidity and mortality from a protamine reaction is to prevent and/or attenuate the reaction with anticipation and vigilance. In patients at high risk, such as those with a history of previous multiple exposures to protamine, NPH insulin, an allergy to seafood and iodine, and perhaps those who have had a vasectomy, the intensity of the reaction can be decreased significantly by the prophylactic administration of H1- and H2-receptor antagonists and steroids.

One of the most deadly medication errors involves the mistaken administration of protamine—either instead of heparin, in combination with heparin, or in place of another intended drug. Indeed, to prevent even the possibility of this complication, standard practice is not to even draw the protamine up into a syringe until it is to be used. Protamine in and of itself produces a DIC-like coagulopathy, due to the inactivation of factor 2 and platelets. Patients appear “oozy,” and bleed almost as though heparinized. However, in reality, this clinical picture is quite different from heparinization. Heparin and protamine induced bleeding can be distinguished by the activated clotting time, which is elevated by heparin. The ACT is unaffected by protamine, since protamine is not a direct thrombin inhibitor.

Comprehension Questions

23.1. Which of the following statements is most accurate regarding the treatment of protamine reactions?
A. To reduce bleeding, continue the protamine until the heparin is satisfactorily reversed.
B. Administer diuretics to reduce “third spacing.”
C. Steroids are contraindicated in this situation.
D. If inotropy is required in addition to vasoconstriction, then milrinone may be indicated in addition to the epinephrine.

23.2. A 72-year-old female patient is undergoing aortic valve surgery on cardiopulmonary bypass machine. After separation from bypass machine, surgeons asked the anesthesiologist for protamine. What is the best site for the injection of protamine?
A. Central line in the right internal jugular vein
B. Peripheral i.v.
C. Left atrial injection by surgeons
D. Pulmonary artery port of the pulmonary artery catheter

23.3. A 56-year-old man with history of unstable angina and diagnosed coronary artery disease comes to the operating room for coronary artery bypass surgery. The surgeons just finished triple vessel bypass on cardiopulmonary bypass, and just “came off pump.” The patient is allergic to protamine, and has a history of severe hypotension followed by cardiac arrest with protamine infusion during the previous vascular surgery. What should be used for reversal of heparin now to prevent bleeding from heparin-induced anticoagulation?
A. Try protamine again.
B. Hexadimethrine.
C. Transfuse blood products until ACT (activated clotting time) is normal and close the chest.
D. Bivalirudin as anticoagulant in the place of heparin.

23.1. D. The treatment for a protamine reaction is also the treatment for an allergic drug reaction. First, the administration of the drug is stopped. Epinephrine, vasopressors, fluids, and steroids are administered, although the later is controversial. If additional inotropy is required in addition to vasoconstriction, then milrinone may be indicated in addition to the epinephrine.

23.2. C. Injecting a high dose of protamine into the central line or the PA port of Swan-Ganz catheter can produce severe pulmonary hypertension and right ventricular failure due to the activation of the C5b complement pathway. Most commonly, protamine is administered slowly through the peripheral IV, giving ample time for dilution before it reaches pulmonary vasculature. Protamine can still elicit pulmonary hypertension and right ventricular failure if given rapidly and in large quantity through the peripheral IV, since despite dilution, the pulmonary vasculature can be exposed to a large quantity of the drug. For these reasons, protamine should ideally be administered distal to the pulmonary vasculature, which means through the left atrium. Occasionally the surgeons administer protamine from the operative (sterile) field in this manner.

23.3. C. No suitable alternative is currently available for protamine. When faced with this situation, the best course is to transfuse blood products like fresh frozen plasma and platelets, and ask the surgeons to observe for bleeding until activated clotting time returns to normal and bleeding has stopped. As this patient had a severe reaction from protamine during his previous surgery, the protamine should not be repeated.

Hexadimethrine is a variant of protamine currently under investigation but not approved by FDA, perhaps because it produces nephrotoxicity and pulmonary hypertension. There is no role for the heparin alternative, bivalirudin, in this case since the patient does not have heparin-induced thrombocytopenia and thrombosis.

Clinical Pearls
➤ A high degree of suspicion, vigilance, and anticipation helps to prevent and/or attenuate protamine reactions.
➤ It is important to recognize the risk factors for protamine reactions including: previous multiple exposures to protamine, an allergy to seafood and iodine, treatment with NPH insulin, and a history of vasectomy. Patients at high risk should be pretreated with H1 and H2 antagonists to prevent or at least decrease the intensity of the reaction.
➤ Understanding the different types of protamine reactions is important, since the type of reaction carries different implications for treatment. Distinguishing between types 3 and 4 may require the insertion of a pulmonary artery catheter or TEE probe.


Stoelting RK. Anticoagulants. In: Stoelting RK, ed. Pharmacology and Physiology in Anesthetic Practice. 2nd ed. Philadelphia, PA: J.B. Lippincott Company; 1991:466- 476. 

Yao FS, Skubas N. Ischemic heart disease and coronary artery bypass grafting. In: Yao FS, ed. Anesthesiology. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:131-197.


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