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Protamine: Administration and management of adverse reactions during cardiovascular procedures

Protamine: Administration and management of adverse reactions during cardiovascular procedures
Literature review current through: Aug 2023.
This topic last updated: Feb 28, 2023.

INTRODUCTION — Protamine sulfate is routinely administered to reverse the systemic anticoagulation effects of unfractionated heparin (UFH) after cardiac surgery or surgical and percutaneous vascular procedures. There are no alternative agents to reverse UFH.

This topic will discuss protamine administration and dosing, as well as recognition, treatment, and prevention of adverse reactions to protamine.

Reversal of heparin anticoagulation with protamine in nonsurgical patients with heparin-associated bleeding is discussed separately. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Bleeding' and "Reversal of anticoagulation in intracranial hemorrhage", section on 'Protamine sulfate'.)

A separate topic discusses detailed management of a perioperative anaphylactic reaction to any agent. (See "Perioperative anaphylaxis: Clinical manifestations, etiology, and management".)

PROTAMINE REVERSAL OF HEPARIN ANTICOAGULATON: USES AND DOSING STRATEGIES — Intravenously administered protamine sulfate rapidly binds to unfractionated heparin (UFH) to reverse its effect, with a half-life of approximately five minutes after IV administration [1]. Protamine dosing strategies depend on the heparin dose administered and the specific setting (eg, cardiovascular surgery with cardiopulmonary bypass [CPB] or cardiovascular interventions without CPB).

Protamine administration after cardiopulmonary bypass

General considerations — General considerations for reversal of anticoagulation with protamine after CPB include the following:

Neutralizing heparin at the end of CPB High heparin concentrations are present immediately after weaning from CPB in patients undergoing cardiac surgery. Systemic anticoagulation with heparin is maintained at a higher level during CPB compared with other procedures or medical conditions in which heparin is used. The degree of heparin anticoagulation is monitored throughout CPB, using a point-of-care (POC) contact activation test of the effects of heparin, the activated clotting time (ACT). ACT values are measured approximately every 30 minutes, and additional heparin is administered as necessary to achieve and maintain a targeted value (typically >480 seconds). ACT values of 400 to 480 seconds correlate with blood levels of heparin of approximately 4 to 6 units/mL [2-4]. However, the relationship between ACT values and blood levels of UFH is not linear and is often inconsistent during CPB, after separation from CPB, and following protamine administration to reverse anticoagulation [4-6].

Details regarding heparin administration and maintenance of heparin anticoagulation throughout CPB are discussed in separate topics. (See "Blood management and anticoagulation for cardiopulmonary bypass", section on 'Heparin administration and monitoring' and "Management of cardiopulmonary bypass", section on 'Maintenance of anticoagulation'.)

Timing of protamine administration Administration of protamine to neutralize heparin is typically initiated after weaning from CPB and completed following successful aortic decannulation. Exact timing of administration (before or after aortic decannulation) varies according to institutional and surgical preferences. (See 'Timing of administration' below.)

Notably, use of cardiotomy suction (ie, the “pump sucker”) to suction blood from the surgical field into the CPB reservoir is discontinued either at the onset of protamine administration or when a small portion (typically less than one-third) of the total initial dose has been administered. Conceptually, this avoids neutralization of heparin and clot formation in the blood remaining in the CPB reservoir, which would prohibit emergency reinstitution of CPB.

Initial protamine dosing strategies — We agree with professional society recommendations noting that optimal reversal of systemic anticoagulation after CPB is based on stoichiometric measurements of currently circulating heparin levels, using a POC heparin-protamine titration assay, if available [7-12]. Such assays facilitate appropriate protamine dosing to neutralize residual heparin, while avoiding excess protamine administration.

Professional society recommendations also note that if empiric dosing of protamine is used (eg, because a POC heparin-protamine titration assay is not available), this should be based on a protamine-to-heparin ratio that does not exceed 1 mg of protamine for every 100 units of previously administered heparin [7-12].

Titration based on point-of-care heparin assays — Several POC heparin-protamine titration assay systems are commercially available and used in cardiac surgical patients to determine the residual circulating heparin level based on incremental dosing of protamine in the cartridge (eg, Hepcon/HMS®, Hemochron RxDx, or other protamine-dose assays). These devices measure the residual heparin concentration at the end of CPB to automatically calculate a precise dose of protamine [4]. At the completion of protamine administration, the presence of any residual heparin can be determined using such devices to calculate any additional dose of protamine that may be needed. (See 'Dosing for continued bleeding after initial protamine administration' below and 'Avoiding heparin rebound' below.)

A 2013 meta-analysis of four randomized trials in 507 cardiac surgical patients noted that use of a heparin-protamine titration assay resulted in significantly less postoperative blood loss (range 625 to 839 mL) compared with use of fixed empiric protamine dosing methods (range 765 to 995 mL) [13]. Furthermore, overall transfusion of red blood cells (RBCs) was less in the assay group (0.2 to 1.8 units) compared with the fixed dose group (0.3 to 2.7 units) [13].

However, heparin-protamine titration assay systems are expensive and are not available in every institution. Furthermore, institutions with only one or two systems may reserve their use for more complex high-risk cardiac surgical procedures.

Empiric dosing strategies — If a POC heparin-protamine titration assay is not available, most centers employ an empiric (fixed dose) strategy, basing a calculated protamine dose on the amount of heparin that had been administered. Although ACT values are measured in an attempt to determine adequacy of anticoagulation reversal, the correlation of ACT values and blood levels of UFH is neither linear nor consistent [4-6].

A classic empiric dosing strategy used a calculation of 1 mg of protamine for every 100 units of heparin administered (ie, a 1:1 ratio). In some centers, the calculated protamine dose included the heparin used to prime the extracorporeal circuit, as well as any additional doses of heparin that were administered during CPB [4]. Empiric dosing strategies do not take into account heparin metabolism or consumption by the extracorporeal circuit; thus, an excessive dose of protamine may be administered. This increases the risk for coagulopathy due to the adverse anticoagulant effects of protamine. Exacerbated coagulopathy due to excess protamine administration is particularly likely when the protamine-to-heparin dosing ratio exceeds 1.3:1 [14-16].

For these reasons, we suggest modifications of this classic empiric dosing strategy that may minimize risk of administering excess protamine. Examples include:

Using a lower dosing ratio of protamine-to-heparin that is less than 1:1 in calculations of the empiric dose.

This strategy may reduce transfusions. One randomized trial in 96 cardiac surgical patients compared use of a lower ratio of 0.8:1 with use of a higher ratio of 1.3:1 of protamine to heparin [15]. Post-reversal ACT values were similar in both protamine dosing groups. However, significantly less 24-hour postoperative chest tube drainage (470 versus 615 mL) and decreased incidences of transfusion of fresh frozen plasma (0 versus 11 percent) and platelet concentrates (6 versus 21 percent) were noted in the lower ratio group. In addition, higher values for thrombin generation (a measure of adequacy of clot formation) were noted in the lower ratio group (38 ± 40 versus 6 ± 9 percent).

Limiting the protamine dose calculation by using only the initial heparin dose administered with or without including the heparin dose used to prime the CPB circuit.

We do not use empiric dosing strategies that are based on the total amount of heparin administered throughout the duration of CPB. Also, we do not use older empiric dosing methods that were based on body weight.

Pharmacokinetic dosing to avoid excess protamine — Protamine dosing algorithms based on pharmacokinetics of heparin have been developed to consider all heparin doses and timing in calculating a protamine dose [16]. The goal is to improve reversal of anticoagulation, while avoiding excess protamine after CPB.

In one randomized trial conducted in 40 cardiac surgical patients, calculation of protamine doses using a pharmacokinetic-based algorithm was compared with use of the institution’s traditional heparin and protamine dosing strategy based on body weight [17]. Patients in the pharmacokinetic algorithm group received lower protamine doses (211 ± 56 versus 330 ± 61 mg) and had a lower protamine-to-heparin ratio (0.49 versus 0.81), as well as less postoperative bleeding (480 versus 694 mL). However, such pharmacokinetic dosing strategies are not pragmatic in the operating room setting.

Dosing for continued bleeding after initial protamine administration — After administration of the initial calculated protamine dose following CPB, residual coagulopathy may be present in some cardiac surgical patients. (See "Achieving hemostasis after cardiac surgery with cardiopulmonary bypass", section on 'Achieving hemostasis and management of bleeding'.)

When persistent microvascular bleeding is observed after CPB, a small additional dose of protamine, typically 50 to 100 mg of protamine is often administered. This is reasonable if residual heparin is documented using a POC heparin-protamine titration assay, or suspected due to ACT values that are higher than baseline. In some cases, small amounts of heparin may be present due to reinfusion of heparinized blood from the CPB pump and/or release of heparin from poorly perfused colder peripheral tissues as rewarming occurs. However, each additional dose of protamine should be carefully considered, and protamine doses higher than 50 to 100 mg are avoided for the following reasons:

Any residual heparin concentration is usually minimal after administration of the initial dose of protamine, as described above (see 'Initial protamine dosing strategies' above). In fact, complete reversal of anticoagulation is usually achieved with a relatively low protamine-to-heparin ratio of approximately 0.5 to 0.8 mg/kg of protamine, with absence of blood levels of circulating heparin [1].

Persistent bleeding after CPB is common and usually due to factors other than the presence of residual heparin. These factors include inadequate surgical hemostasis, loss of platelets and coagulation factors due to high volume cell saver use, and effects of CPB including coagulopathy due to platelet activation (and consumption), hyperfibrinolysis induced by the extracorporeal circuit, hemodilution, and hypothermia. (See "Achieving hemostasis after cardiac surgery with cardiopulmonary bypass", section on 'Achieving hemostasis and management of bleeding'.)

Owing to its intrinsic anticoagulant effects, administration of excess protamine may actually prolong rather than shorten the ACT and result in exacerbation of bleeding and coagulopathy [7,14-16,18]. One study in 487 cardiac surgical patients employed a dosing strategy with a protamine-to-heparin ratio of 0.8:1; however, additional 50 mg doses of protamine were administered empirically or if the ACT did not return to baseline levels [19]. These investigators noted that higher doses of protamine were associated with increased risk of postoperative bleeding and transfusions. (See 'Anticoagulant effects' below.)

Ideally, any additional doses of protamine are calculated using a heparin-protamine titration assay [20-23]. Other tests that may help confirm residual heparin effect include checking ACT values and obtaining laboratory measurements of activated partial thromboplastin time (aPTT). (See "Intraoperative transfusion and administration of clotting factors", section on 'Tests of hemostatic function'.)

Avoiding heparin rebound — To prevent heparin rebound after initial protamine dosing, we administer a protamine infusion at 25 mg/hour, beginning after initial reversal of heparin anticoagulation and normalization of the ACT, and extending into the postoperative period over approximately four hours [24-26].

Heparin rebound is defined as evidence of reappearance of heparin with evidence on heparin-protamine titration assay, heparinase ACT, or additional laboratory data such as elevation of aPTT after initial protamine administration and documented normalization of the ACT. Rebound can occur regardless of the protamine dose administered to reverse heparin. Typically, heparin rebound occurs two to three hours after initial protamine dosing. Causes of rebound may include release of heparin previously bound in heparin-protamine complexes and possibly from poorly perfused tissues, vascular endothelium, or other stores [4,24]. Rebound may also be more likely in patients who receive large doses of heparin to achieve initial anticoagulation for CPB due to altered heparin responsiveness (ie, “heparin resistance”) [1,7]. (See "Blood management and anticoagulation for cardiopulmonary bypass", section on 'Heparin resistance'.)

Although ACT values are routinely measured to document complete heparin reversal after protamine administration, this clot-based test is insensitive to low doses of heparin [4-6]. Measurements of aPTT are also insensitive for detecting heparin levels in the low range of 0.1 to 0.3 international units/mL [27,28]. Residual heparin effect in this range can potentially be measured using a POC heparin-protamine titration assay or heparinase ACT. However, even lower blood levels (ie, 0.05 up to 0.1 unit/mL) of heparin are not readily detectable with any of these tests but may still exert an anticoagulant effect.

One trial randomized 300 cardiac surgical patients to receive a six-hour infusion of protamine at 25 mg/hour or a placebo beginning in the early postoperative period [24]. Heparin rebound was noted in every patient in the placebo group between one and six hours after surgery, as reflected by increased thrombin clotting time and antifactor Xa activity, as well as by measurement of protein-bound heparin. However, rebound was not demonstrated in any patient in the protamine infusion group. Also, postoperative chest tube drainage was 13 percent less in patients receiving the protamine infusion [24]. However, there were no differences in allogeneic blood transfusion between the two groups.

Use of protamine during other open or percutaneous cardiovascular procedures — Lower heparin doses are employed for open and percutaneous vascular surgical cases that do not involve the need for systemic anticoagulation for CPB. Thus, lower protamine doses are administered for heparin reversal in such cases, as discussed in separate topics:

Open abdominal aortic surgery – (See "Anesthesia for open abdominal aortic surgery", section on 'Anticoagulation management'.)

Open thoracic aortic surgery – (See "Anesthesia for descending thoracic aortic surgery", section on 'Point-of-care laboratory testing'.)

Carotid endarterectomy – (See "Anesthesia for carotid endarterectomy and carotid stenting", section on 'Anticoagulation during CEA'.)

Percutaneous endovascular aortic procedures – (See "Anesthesia for endovascular aortic repair", section on 'Management of anticoagulation'.)

Percutaneous carotid artery stenting – (See "Anesthesia for carotid endarterectomy and carotid stenting", section on 'Anticoagulation during CAS or TCAR'.)

Electrophysiology suite – (See "Anesthetic considerations for electrophysiology procedures", section on 'Coagulation management'.)

ADVERSE EFFECTS OF PROTAMINE: RECOGNITION AND MANAGEMENT

Protamine reactions: General considerations — Protamine reactions may occur rapidly, and it may not be possible to immediately determine the mechanism in an individual patient. Initial management is similar for each type of reaction, as described below.

Adverse reactions may display a spectrum of signs and symptoms that include urticaria, bronchospasm, pulmonary hypertension with right ventricular (RV) failure, systemic hypotension, and/or shock [29,30]. Reactions may be either nonimmunologic (eg, direct pharmacologic effects, mast cell degranulation/activation) or immunologic (eg, direct degranulation of mast cells, complement activation due to protamine-heparin complexes, or anaphylaxis due to IgE and/or IgG mediated responses) [30].

Severe life-threatening reactions are immediate hypersensitivity reactions and are not dose-dependent. However, determining whether milder adverse reactions are due to an immunologic response or direct effect of protamine such as vasodilation or myocardial depression can be challenging. Furthermore, if protamine is administered during cardiac surgery with cardiopulmonary bypass (CPB) or during another interventional cardiovascular procedure, cardiovascular complications unrelated to protamine administration, such as left or right ventricular dysfunction and/or arrhythmias, may contribute to development of hypotension and/or shock. In addition, identifying protamine as the culprit antigen for a suspected anaphylactic reaction is difficult if allogeneic blood products such as red blood cells, fresh frozen plasma (FFP), platelets, or cryoprecipitate were transfused concomitantly or shortly after protamine administration [31].

Vasodilation

Clinical manifestations and mechanisms — The most common adverse reaction to protamine is vasodilation. Although hypotension may develop, this is usually transient, not severe, and easily treated.

Mechanisms for vasodilation may include complement activation due to protamine-heparin complexes. Following protamine administration, heparin binds to protamine as a simple acid-base interaction, forming a polyanionic-polycationic complex that binds and inactivates heparin. Furthermore, protamine has the potential for complement system activation by binding to C1 esterase and initiating classical complement pathway activation and the formation of C3a and C5a anaphylatoxins [32]. Degranulation of connective tissue mast cells resulting in histamine release has also been implicated as a potential mechanism [33].

Management — Although hypotension due to vasodilation is common (see 'Vasodilation' above), this is usually transient, not severe, and easily managed by administering vasopressors as necessary (table 1).

Anaphylaxis and hypersensitivity reactions

Clinical manifestations and mechanisms — Multiple mechanisms are implicated in producing acute anaphylaxis and other acute hypersensitivity reactions to protamine [34].

Overt reactions generally occur within five minutes of protamine administration but may occur up to 20 minutes later [30]. Signs range from local cutaneous responses such as urticaria, pulmonary responses including wheezing and bronchospasm, and cardiovascular responses including marked vasodilation with profound hypotension (also described as vasoplegia), and shock [35,36]. Immediate hypersensitivity is IgE-mediated, causing mast cell and basophil activation with subsequent mediator release. In classic IgE mediated anaphylaxis, typical findings noted with transesophageal echocardiography (TEE) imaging in cardiac surgical patients include hypovolemia and hyperdynamic left ventricular (LV) function [30]; however, some patients develop acute cardiopulmonary dysfunction and/or arrhythmias. (See "Perioperative anaphylaxis: Clinical manifestations, etiology, and management", section on 'Characteristic signs and symptoms'.)

Severe life-threatening anaphylactic reactions have been unpredictable [37], suggesting that most are immunologically-induced IgE- or IgG-mediated responses. IgE is identified as the cause in 60 percent of severe anaphylactic reactions [38,39], but other important pathophysiologic mechanisms include complement activation due to IgG formation [30,40]. In particular, patients sensitized to protamine after previous exposure may form both IgE and specific IgG antibodies [38]. Such IgG-mediated anaphylaxis has also been reported following reactions to proteins or volume expanders (dextrans) [30]. In one study of 86 patients who had an anaphylactic reaction, IgG antibodies were found, as well as neutrophil activation and platelet activating factor levels that correlated with the severity of anaphylaxis [41].

Protamine-specific IgG antibodies may also activate complement activation, causing acute pulmonary vasoconstriction in some patients [30]. (See 'Acute (catastrophic) pulmonary vasoconstriction' below.)

Management — First-line treatment for suspected acute anaphylaxis includes stopping protamine and administration of epinephrine bolus(es) and infusion, as noted in the table (table 2). Severe pulmonary responses may include wheezing and bronchospasm, while severe cardiovascular responses may include marked vasodilation with profound hypotension [35,36]. (See "Perioperative anaphylaxis: Clinical manifestations, etiology, and management", section on 'Initial management'.)

For patients with refractory vasodilatory hypotension that does not respond to infusion of epinephrine, norepinephrine or vasopressin should be initiated (table 1). Other agents such as methylene blue may also be administered for persistent severe vasodilation (table 3). (See "Intraoperative problems after cardiopulmonary bypass", section on 'Vasoplegia'.)

In some cardiac surgical cases, acute cardiovascular collapse may prompt readministering heparin to achieve systemic anticoagulation, reinserting arterial and venous cannulas (if these had been removed), and reinstituting CPB. Anti-inflammatory agents are administered after stabilizing the patient on CPB, if this was not done previously. Specifically, we treat for presumed anaphylaxis by administering a systemic steroid dose (eg, methylprednisolone 125 mg), together with the H1 antihistamine diphenhydramine 50 mg and an H2 receptor antagonist (eg, famotidine, cimetidine), as noted in the table (table 2).

Acute (catastrophic) pulmonary vasoconstriction

Clinical manifestations and mechanisms — Acute pulmonary vasoconstriction with severe RV failure (also termed catastrophic pulmonary vasoconstriction) is an uncommon idiosyncratic life-threatening reaction that has been reported after protamine administration to reverse anticoagulation after CPB [42]. Mean pulmonary artery pressure (PAP) may increase severalfold during acute pulmonary vasoconstriction. Since the RV is accustomed to ejecting against a relatively low mean PAP of approximately 15 mmHg, sudden increases in RV afterload cause acute RV dilatation, shifting the intraventricular septum into the LV cavity and further impeding ventricular loading. Shock develops rapidly.

Catastrophic pulmonary vasoconstriction with RV failure is a rare hypersensitivity reaction that is probably complement-mediated due to antiprotamine IgG antibody interaction and/or protamine-heparin complex development, with C5a-mediated thromboxane formation [30,43]. Pulmonary vasoconstriction occurs due to generation of the anaphylotoxin C5a, activation and aggregation of neutrophils that sequester in the pulmonary vasculature, microcirculatory occlusion, and thromboxane release [37].

Management — Similar to anaphylaxis, first-line treatment includes stopping protamine and administration of epinephrine bolus(es) and infusion, and other therapies as noted in the table (table 2). In addition, inhaled pulmonary vasodilator agents may be administered. Patients who develop severe pulmonary vasoconstriction with RV failure and shock may require reinstitution of CPB, necessitating readministration of heparin to achieve systemic anticoagulation, as described above for cardiovascular collapse during anaphylaxis. (See 'Management' above and 'Redosing protamine after a reaction' below.)

If acute pulmonary vasoconstriction with shock develops in an intensive care unit setting after protamine administration, then venoarterial (VA) extracorporeal membrane oxygenation (ECMO) is occasionally initiated as a life-saving strategy. (See "Extracorporeal life support in adults: Management of venoarterial extracorporeal membrane oxygenation (V-A ECMO)".)

Redosing protamine after a reaction — There are no clear guidelines regarding the safety of readministering protamine after a severe protamine reaction in patients who received additional heparin to achieve anticoagulation because of the need to reinstitute CPB. In most settings, readministration of the agent believed to cause anaphylaxis should be avoided. However, management of bleeding in a cardiac surgical patient who remains systemically anticoagulated is particularly challenging. Consultation among members of the anesthesiology, surgical, and perfusion teams is necessary to choose among the following options:

Some clinicians readminister protamine after weaning from CPB for the second time. There are reports of successful protamine administration in these settings [44]. Theoretical reasons to explain why it is usually possible to readminister protamine without triggering another severe reaction in this setting include:

Other causes of acute severe ventricular dysfunction are relatively common in cardiac surgical patients following weaning from CPB; thus, a hypersensitivity reaction to protamine may not have been the actual cause of cardiovascular collapse necessitating reinstitution of CPB.

The initial hypersensitivity reaction may lead to a refractory period with blunting of the response to a repeated exposure to the allergen, either due to inflammatory mediator depletion [30,44] or acute consumption of IgG antibodies [39,45].

Other clinicians avoid readministration of protamine, electing instead to reverse anticoagulation with use of blood products. In the absence of reversal, heparin has a half-life of approximately 60 to 90 minutes; thus, its anticoagulant effect may persist for four to six hours. Significant ongoing bleeding may occur during this period. Transfusion of large volumes of fresh frozen plasma (FFP), platelets, and fibrinogen, as well as red blood cells (RBCs) are typically necessary to control bleeding and coagulopathy until the anticoagulant effects of heparin are no longer clinically evident. Although large volume blood loss and replacement with blood products and/or volume expanders may result in dilution of the residual heparin concentration, massive blood transfusion has significant adverse clinical consequences [44,46]. (See "Massive blood transfusion", section on 'Complications'.)

Some patients remain unstable after redosing protamine after a second attempt to wean from CPB due to severe noncardiogenic pulmonary edema, acute lung injury, or cardiogenic shock. In such patients, temporary venoarterial (VA) or venovenous (VV) extracorporeal membrane oxygenation (ECMO) may rarely be employed after failed attempts to wean from CPB. (See "Intraoperative problems after cardiopulmonary bypass", section on 'Extracorporeal membrane oxygenation'.)

Additional testing — Notably, in any patient with a suspected anaphylactic reaction, a blood sample should be collected during or as soon as possible after the event for tryptase determination, which may be processed later. After postoperative recovery and hospital discharge, patients who had a severe reaction should be referred to an allergy specialist, as discussed in separate topics:

(See "Perioperative anaphylaxis: Clinical manifestations, etiology, and management", section on 'Laboratory tests at the time of the reaction'.)

(See "Perioperative anaphylaxis: Clinical manifestations, etiology, and management", section on 'Referral for allergy evaluation'.)

Anticoagulant effects — As noted above, direct adverse anticoagulant effects can occur if excess protamine is administered. These include inhibition of coagulation factors and platelet function. These effects may increase risk for bleeding, with increases in activated clotting time (ACT) values [3,4]. (See 'Dosing for continued bleeding after initial protamine administration' above.)

PREVENTION AND MITIGATION OF PROTAMINE REACTIONS

Anticipating risk for protamine reactions — The general incidence of reactions to protamine in cardiac surgical patients is approximately 0.06 percent [47]. Although there may be a slightly higher risk for a protamine reaction in the following groups of patients, screening for potential anti-protamine antibodies would not be clinically useful or practical and is not performed.

Patients taking protamine-containing insulin – Previous chronic use of protamine-containing insulin, particularly neutral protamine Hagedorn (NPH) insulin, is associated with increased risk for a protamine reaction. Repeated subcutaneous administration of NPH insulin induces anti-protamine IgE and/or anti-protamine IgG antibodies [38]. The incidence of anaphylaxis after protamine administration in cardiac surgical patients using NPH insulin is in the range of 0.6 to 2 percent, while the incidence of reactions in other cardiac surgical patients is approximately 0.06 percent [47,48].

Although patients receiving protamine-containing insulins may be at slightly increased risk, screening such patients for potential anti-protamine antibodies is not currently performed because:

Risk is relatively low even in those who have taken NPH insulin, and NPH insulin is used less commonly than in the past.

There are no clinically available tests for the IgE and IgG antibodies that are likely responsible for most hypersensitivity reactions to protamine.

There are no alternative heparin reversal agents.

Patients who have had a vasectomy Prior vasectomy is associated with increased risk for a protamine reaction because of development of autoantibodies to the patient’s own sperm [49]. Testes are immunologically isolated, but following vasectomy, the immune system develops antibodies to human sperm. Case reports postulate that the antisperm antibodies can also cross-react with protamine, potentially causing hypersensitivity reactions since protamine is derived from salmon testes [29,49]. However, in a prospective study that included 16 patients with a prior vasectomy before cardiac surgery, none developed an adverse reaction following protamine administration [47].

Patients with shellfish or other fish allergies Patients with a history of multiple drug or food allergies, particularly shellfish or fish allergies, may be at risk for hypersensitivity to various agents administered in a surgical setting. Limited evidence confined to case reports suggests that a history of fish allergy may be associated with increased risk for a protamine reaction [29,30]. However, this risk is low since humans consume fish muscle tissue, while protamine is produced from the milt (testes) of salmon. In one prospective study, six patients undergoing cardiac surgery had a history of fish allergy; none of these developed an adverse reaction following protamine administration [47].

Administering a test dose — We typically administer a test dose of protamine (ie, a small dose of 5 to 10 mg) initially, with a brief pause before administration of the remainder of the full therapeutic dose.

A test doses provides the first antigenic exposure of a patient to an agent. However, even a test dose may produce an anaphylactic reaction, or a reaction may still occur after a negative response to a test dose [30]. For these reasons, the clinician should always be prepared to treat any reaction before administering any protamine. (See 'Adverse effects of protamine: Recognition and management' above.)

Other efforts

Using a slow infusion rate — After administration of the test dose, the remainder of the full therapeutic protamine dose is administered while taking care to avoid rapid IV push to maintain hemodynamic stability [4,33]. (See 'Protamine reversal of heparin anticoagulaton: Uses and dosing strategies' above.)

Although prescribing information suggests that “protamine sulfate injection should be given by very slow intravenous (IV) injection over a 10-minute period in doses not to exceed 50 mg” [50], this very slow rate of administration is impractical in clinical settings like cardiac surgery that require large doses of protamine [4,51]. For example, expeditious reversal of systemic anticoagulation is necessary after weaning from CPB so that bleeding can be controlled. Since typical protamine doses are 200 to 300 mg in cardiac surgical settings (see 'Protamine administration after cardiopulmonary bypass' above), a suggested rate of administration of only 50 mg every 10 minutes would require approximately 60 minutes for full reversal of anticoagulation, resulting in adverse consequences that include significant bleeding and need for transfusion during the post-bypass period.

Timing of administration — Administration of protamine is accomplished shortly after weaning from cardiopulmonary bypass (CPB). Some surgeons avoid protamine prior to aortic decannulation to avoid risk of thrombus formation at the tip of the cannula, while others prefer to administer some of the initial protamine dose before removing the aortic cannula to facilitate an immediate return to CPB in the event of a severe reaction to protamine. (See 'Anaphylaxis and hypersensitivity reactions' above and 'Acute (catastrophic) pulmonary vasoconstriction' above.)

Choosing the site of administration — Protamine can be administered either via a peripheral IV catheter or a central venous catheter. Since severe reactions are due to immunologic responses to preexisting antibodies, using a peripheral IV route of administration is not an effective preventive measure [30]. We avoid other alternative routes of protamine injection such as left atrial or intra-aortic protamine infusion that have been suggested to bypass the lungs. Concerns regarding these alternative routes include increased likelihood of inducing hemodynamic instability, as well as risk for cerebral or coronary embolism of injected air or particles formed by protamine-heparin complexes [52,53].

SUMMARY AND RECOMMENDATIONS

Administration of protamine after cardiopulmonary bypass (CPB) – During cardiac surgical procedures, systemic anticoagulation with unfractionated heparin (UFH) is monitored throughout cardiopulmonary bypass (CPB) using a point-of-care (POC) contact activation test of the effects of heparin (the activated clotting time [ACT]). After weaning from CPB, protamine is administered intravenously (IV) for rapid reversal of heparin anticoagulation. There are no alternative agents to reverse UFH. (See 'General considerations' above.)

Initial intraoperative dosing – We suggest calculating the protamine dose based on a POC titration assay to existing heparin in the blood, if available (Grade 2C). A reasonable alternative is an empiric protamine dosing strategy with administration of 0.8 mg protamine per 100 units of the initial prebypass heparin dose with use of ACT monitoring. (See 'Titration based on point-of-care heparin assays' above and 'Empiric dosing strategies' above.)

Dosing for continued intraoperative bleeding – If residual heparin effect is suspected due to persistent microvascular bleeding and/or ACT values that are higher than baseline, we suggest administering an additional protamine dose according to POC assay measurements of residual heparin, or a dose of 25 to 50 mg if this assay is not available (Grade 2C). We avoid excess protamine to avoid its anticoagulant effects. (See 'Dosing for continued bleeding after initial protamine administration' above and 'Anticoagulant effects' above.)

Avoiding heparin rebound – We suggest also administering a protamine infusion at 25 to 50 mg/hour to avoid "heparin rebound,” beginning later in the intraoperative period and continuing for four to six postoperative hours (Grade 2C). (See 'Avoiding heparin rebound' above.)

Recognition and management of protamine reactions

Vasodilation – The most common adverse reaction to protamine is vasodilation. Although hypotension may develop, this is usually transient, not severe, and easily managed by administering vasopressors as necessary (table 1). (See 'Vasodilation' above.)

Anaphylaxis – A more severe anaphylactic is less common and unpredictable. Treatment includes stopping protamine administration, and administration of epinephrine and other therapies as described in the table (table 2). (See 'Anaphylaxis and hypersensitivity reactions' above and "Perioperative anaphylaxis: Clinical manifestations, etiology, and management".)

Acute pulmonary vasoconstriction – Acute pulmonary vasoconstriction leading to right ventricular failure is a rare and catastrophic reaction. First-line treatment is similar to that for anaphylaxis (table 2). In most cases, readministration of heparin to achieve systemic anticoagulation and reinstitution of CPB is necessary. (See 'Acute (catastrophic) pulmonary vasoconstriction' above.)

Redosing protamine after a reaction – For patients who received additional heparin to achieve systemic anticoagulation for reinstitution of CPB after a severe protamine reaction (see 'Redosing protamine after a reaction' above):

Some clinicians cautiously readminister protamine as usual, since a severe second reaction is rare.

Other clinicians avoid readministration of protamine, instead reversing anticoagulation by administering blood products.

Rarely, temporary extracorporeal membrane oxygenation (ECMO) is considered in a patient with severe noncardiogenic pulmonary edema, acute lung injury, or cardiogenic shock after failed attempts to wean from CPB.

Prevention and mitigation of protamine reactions and other adverse effects

Anticipating higher risk – Despite the possibility of very slightly higher risk for a protamine reaction in patients receiving neutral protamine Hagedorn (NPH) insulin, and in those with known fish allergies or prior vasectomy, screening for potential anti-protamine antibodies would not be clinically useful or practical and is not performed. (See 'Anticipating risk for protamine reactions' above.)

Administering a test dose – A "test dose" of protamine 5 to 10 mg is administered to possibly allow early detection of a severe protamine reaction; the remaining dose is administered after approximately five minutes later. (See 'Administering a test dose' above.)

Other efforts

-After the test dose, the remainder of the full therapeutic protamine dose is administered while taking care to avoid rapid IV push to maintain hemodynamic stability. (See 'Using a slow infusion rate' above.)

-Many surgeons avoid protamine prior to aortic decannulation to avoid risk of thrombus formation; however, some surgeons administer part of the dose before removing the aortic cannula to facilitate immediate return to CPB. (See 'Timing of administration' above.)

-Either a peripheral IV catheter or a central venous catheter may be used. (See 'Choosing the site of administration' above.)

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Topic 140293 Version 5.0

References

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