CASE REPORT

Protamine-Induced Allergic Reaction Following Cardiopulmonary Bypass

Robert K. Stoelting, John W. Brown, Brad A. Winn, and Munier S. Jallad Indiana University School of Medicine Indianapolis, IN

Abstract ______ponents using a cell separator may be at an in­ creased risk for developing an allergic reaction A 59 year-old male with a 37-year history of 1 2 during a subsequent exposure to protamine. · diabetes mellitus treated with protamine zinc in­ Another group of patients who may form anti­ sulin (26 units daily) experienced cardiovascular bodies to protamine are those individuals receiving collapse shortly after infusion of protamine (250 protamine zinc insulin to treat diabetes mellitus. 3 mg) at the conclusion of cardiopulmonary bypass This report describes profound cardiovascular for elective coronary artery bypass graft surgery. collapse following the intravenous administration Generalized erythema of the face and arms and of protamine at the conclusion of cardiopulmonary massive facial edema accompanied the hypo­ bypass in a patient with diabetes mellitus who had tension suggesting an allergic reaction to pro­ been taking protamine zinc insulin for 37 years. tamine. Presumably, the patient's prior chronic This patient had not previously undergone surgery exposure to low doses of protamine in the insulin requiring reversal of heparin anticoagulation with preparation (25 units contains 0. 7 mg of protamine) protamine. The presumed mechanism for the car­ caused the formation of antibodies to protamine. diovascular collapse in this patient was an allergic The massive dose of intravenous protamine used to reaction to protamine secondary to the presence of reverse heparin anticoagulation relative to that drug-specific antibodies, the production of which present in the insulin preparation resulted in an was due to the chronic low dose exposure to pro­ antigen-antibody interaction manifesting as cardio­ tamine contained in the insulin preparation. vascular collapse.

Introduction______Case Report ______Prior exposure to protamine may stimulate the A 59 year-old 79 kg male was scheduled for an production of drug-specific antibodies such that a elective coronary artery bypass graft operation. subsequent administration of protamine results in 1 3 Pertinent past medical history included diabetes an allergic reaction. - For example, patients who mellitus for 37 years and a documented myocardial have received protamine uneventfully to reverse infarction 12 years earlier. Medications at the time heparin-induced anticoagulation as during certain of admission to the hospital included protamine operative procedures or donation of blood com- zinc insulin 26 units subcutaneously every morn­ ing, triamterene 50 mg daily, digoxin 0.25 mg Direct communications to: Robert K. Stoelting, M.D .. Department of Anesthesia. Fesler Hall Room 204. 1120 South Drive, Indianapolis, daily and isosorbide 20 mg every 4 hours. There IN 46223 was no pre-operative history of infertility, drug or Submitted 1/84. Accepted 2/84. food sensitivities.

Volume 16, Number 1, Spring 1984 The Journal of Extra-Corporeal Technology 37 Four proximal and five distal aortocoronary by­ left femoral artery. One hour later, the patient was pass grafts were placed during cardiopulmonary again weaned from cardiopulmonary bypass with bypass requiring 150 minutes. The patient was the aid of intra-aortic balloon counterpulsation. subsequently weaned from cardiopulmonary by­ The heparin effect was allowed to wane spon­ pass and was able to maintain an adequate blood taneously requiring about 4 hours for the activated pressure (124/70 mm/Hg), pulmonary artery end­ clotting time to return to less than 250 seconds diastolic pressure (I 0 mmHg) and cardiac output (control 105 seconds), despite the administration of (5 .6 Llmin) without pharmacologic support. In 2 units of fresh frozen plasma. The post-operative view of the apparent stable cardiovascular function course was complicated by a mediastinal hema­ as well as documentation of adequate vein graft toma requiring surgical evacuation 7 hours fol­ flow, it was elected to begin reversal of heparin lowing arrival in the Intensive Care Unit. The anticoagulation with protamine, 250 mg. At the activated clotting time was 140 seconds at this conclusion of infusion of 125 mg of protamine time. administered continuously over 3 minutes, the Blood for analysis for immunoglobin E (IgE) venous and aortic cannulae were removed and the and G (lgG) antibody concentrations was obtained remaining 125 mg of protamine was administered 30 minutes, 18 hours and 72 hours following the over a similar time frame. At the conclusion of administration of protamine (Table I). Subsequent protamine infusion, the blood pressure remained questioning of the patient elicited a history of skin at 116/64 mmHg and the pulmonary artery end­ erythema at the insulin injection site early in the use diastolic pressure was 10 mmHg. Approximately I of protamine zinc insulin. This reaction had been minute later, there was a rapid decline of the blood attributed to ''allergy.'' Nevertheless, the patient pressure to 36/16 mmHg in association with a continued to use protamine zinc insulin daily for reduction in pulmonary artery end-diastolic pres­ the subsequent 37 years. sure to 5 mmHg. At this time, the heart was The patient was discharged on the eleventh day contracting vigorously and the cardiac output was post-operatively and instructed that he was allergic 6.2 Llmin. No anesthetic drugs had been admin­ to protamine and should not receive this drug in the istered since the cessation of cardiopulmonary by­ future. His insulin preparation had been changed in pass and the lungs were being ventilated with pure the immediate post-operative period to lente oxygen. Generalized erythema of the face and arms insulin. anci massive facial and periorbital edema were present. Bronchospasm was not detectable. Des­ Discussion______pite administration of phenylephrine, 4.5 mg in divided doses, ephedrine 25 mg, epinephrine 100 The clinical manifestations following infusion of ug, calcium gluconate 1000 mg, diphenhydramine protamine plus the likelihood of prior stimulation 100 mg, cortisol 200 mg and the infusion of fluids of antibody production due to chronic treatment (approximately 1000 ml whole blood in 5 to 7 with low dose protamine support the occurrence of minutes) the systolic blood pressure remained less an allergic reaction in this patient. The intravenous than 40 mmHg in the presence of sinus tachycardia. administration of 250 mg of protamine over 6 Evidence of myocardial ischemia was not apparent minutes represented a dose about 300 times that during continuous recording of a precordial lead contained in the daily protamine zinc insulin in­

(V 5) of the electrocardiogram. One of the pre­ jection of 26 units (25 units of protamine zinc viously removed venous cannulae was replaced in insulin contains 0.7 mg protamine) administered the right atrium and 5 liters of fluid infused via the subcutaneously. Presumably, the massive dose of cardiopulmonary bypass machine. Despite this intravenous protamine relative to that present in the fluid infusion, the systolic blood pressure remained insulin injection resulted in an antigen-antibody below 60 mmHg. It was elected, therefore, to again interaction manifesting as cardiovascular collapse. administer heparin (24,000 units) and institute car­ The speculated presence of drug-specific anti­ diopulmonary bypass. In view of the unknown bodies to protamine is attributed to the chronic adverse effects of the prior hypotension, it was antigenic stimulation provided by the insulin elected to place an intra-aortic balloon through the therapy.

38 The Journal of Extra-Corporeal Technology Volume 16, Number I, Spring 1984 TABLE 1 era! vascular depressant actions. 7 Therefore, data obtained in dogs is not likely to reflect the cardio­ Immunoglobin Antibody Concentrations vascular effects of protamine administered to patients. Indeed, infusion of 3 mg/kg of protamine Time following administration Plasma concentration of protamine IgE IgG over 5 minutes to 15 patients at the conclusion of (units/ml) (mg/ml) cardiopulmonary bypass did not produce any cause

30 minutes 66 2.1 and effect reductions in blood pressure, central 7 18 hours 230 5 venous pressure or cardiac output. It should be 24 hours 230 l(l.5 noted that the infusion rate of protamine in this normal values for laboratory less than 250 9.8 ± 3 study (5 minutes) was similar to that in our patient Measurements of plasma IgE antibody con­ (6 minutes). Clearly, the infusion of 50 mg/10 min centrations suggested the occurrence of an antigen­ recommended in the package insert for protamine antibody interaction as depicted by the early con­ is both unrealistic and unsupported by controlled sumption of antibody (30 minute sample) followed measurements in patients. by an increase 18 and 72 hours later (Table I). 4 The exact mechanism responsible for the allergic Conceivably, the initial decrease in the plasma reaction elicited by protamine in our patient cannot concentration of IgE antibody reflected com­ be stated with certainty. The initial decrease in the plexing with the recently injected protamine. Fol­ plasma concentrations of lgE and IgG antibody lowing this initial decrease, there is typically an could be interpreted as evidence for an antigen­ increased production of antibodies manifesting as antibody interaction but the more likely ex­ an increased plasma concentration several hours planation is hemodilution due to the massive fluid following the allergic reaction. 4 Plasma IgE anti­ replacement required for treatment of the reaction. body concentrations did increase in our patient but Measurements of the plasma concentrations of never exceeded the upper limit of normal. In ad­ complement proteins C3 and C4, which would help dition to the acute reduction in plasma IgE antibody identify an allergic reaction due to activation of the concentration, the simultaneous reduction of IgG complement pathway were not obtained. Docu­ antibody concentration also suggested con­ mentation of specific antibodies for protamine in sumption of this protein. Although IgE antibody is our patient could be provided by the radio­ usually responsible for an allergic reaction there is allergosorbent test (RAST). x Unfortunately, pro­ a report of an anaphylactic reaction to protamine tamine is not available as an antigen for the per­ mediated by complement-dependent IgG formance of this test. All factors considered, it antibody. 2 However, the occurrence of an allergic seems most likely that our patient experienced an reaction characterized by simultaneous con­ allergic reaction due to the pre-existing presence of sumption of IgE and IgG antibody is unlikely and drug-specific IgE antibodies secondary to stimu­ lends support to our speculation that the plasma lation provided by chronic low dose exposure to concentrations of antibody measured at 30 minutes protamine in the insulin preparation. following the administration of protamine were A patient known to be allergic to protamine or influenced (hemodiluted) by the massive fluid in­ considered to be an increased risk (Table 2) for fusion and reinstitution of cardiopulmonary bypass allergy and undergoing an operative procedure that was occurring at this time. requiring heparin anticoagulation represents ather­ An alternative explanation to an allergic reaction apeutic dilemma. When allergy is suspected but for the cardiovascular collapse observed in our undocumented the recommendation is to admin­ patient would be direct toxic effects of protamine ister an initial 5 to I 0 mg test dose of protamine on the heart and peripheral vasculature. For exam­ over 5 to I 0 minutes with epinephrine and intra­ ple, previous reports using the dog as the experi­ venous fluid solutions readily available. 1 This mental model have suggested the occurrence of small dose of protamine should be associated with cardiovascular depression in association with the attenuated manifestations should an allergic reac­ 5 6 intravenous administration of protamine. _ How­ tion occur. When protamine cannot be admin­ ever, the cardiovascular system of the dog is istered, the only alternative drug for reversal of 1 9 uniquely vulnerable to the myocardial and periph- heparin is hexadimethrine (Polybrene). • This

Volume 16, Number 1, Spring 1984 The Journal of Extra-Corporeal Technology 39 TABLE 2 need to make hexadimethrine available on a limited Patients at increased risk for allergy to basis. protamine I. Previous exposure during surgical procedures References ______requiring antagonism of heparin anticoagulation I. Doolan. L.. McKenzie. 1.. Krafcheck. 1.. Parsom. B .. Buxton. B . Pro· tamine Sulfate Hype"ensitivity. Anaesth. Intms. Care. 9:147-149. 1981 2. Chronic treatment with protamine zinc insulin 2. Lakin. J.D .. Blocker. T. 1.. Strong. D. M .. Yocum. M. W .. Anaphylaxis 3. History of allergy to fish to Protamine Sulfate Mediated by a Complement-dependent lgG Antibody. J. Allergr Clin. lmmunol. 61:102-107. 1978. *4. Males with autoantibodies to sperm- history 3. Moorthy. S. S .. Pond. W .. Roland R. G.: Severe Circulatory Shock of infertility or following a vasectomy Following Protamine (an anaphylactic reaction). Anesth. Ana/g. 59:77-n. 1980. *theoretically possible but not yet supported by 4. Etter. M.S., Helrich, M .. MacKenzie. C. F .. lmmunoglobin E Fluctuation scientific data or clinical experience. in Thiopental Anaphylaxis. Ane.vthesiologr. 52:181-183. 1980. 5. Hurt. R .. Perkins. H.A .. Osborg. 1. 1.. Gerbode. F .. The Neutralization of Heparin by Protamine in Extracorporeal Circulation. J. Tlwrac. Surx. drug is effective but its sales market is limited and, 32:612-619. 1956. more importantly, an agglutinating effect on eryth­ 6. Gourin. A .. Streisand. R. L .. Greincder. 1. K .. Stuckey. J. H .. Protamine rocytes has been observed. 10 As a result, hex­ Sulfate Administration and the Cardiovascular Sy~tem. J. Tlwrac. Cardio­ v·a.vc. Sur/i. t\2:193-204. 1971 adimethrine is not currently available for use in the 7. Conahan, T. 1 .. Andrews. R. W. Mac Vaugh. H .. Cardiovascular Effects United States. Therefore, the only approach to of Protamine Sulfate in Man. Anesth Analg 60:33-36. 1981 patients who cannot receive protamine is admin­ 8. Gleich, G. 1 .. Yunginger. 1. W.: The Radioallergosorbent test: A Method to istration of fresh frozen plasma and reliance on in Measure lgE Antibodies. lgG Blocking Antibodies. and the Potency of Allergy Extracts. Bull. N.Y. A cad. Med. 57:559-567. 1981. vivo biodegradation of heparin. This may take 9. Weiss. W. A .. Gilman. 1. S .. Catenacci. A. 1.. Osterberg. A. E. Heparin several hours and be associated with post-operative Neutralitation with Polybrene Administered Intravenously. lAMA. hematoma formation as illustrated by our patient. 166:603-607. 1958. Perhaps, the occasional need for an alternative to 10. Grann. Y. R .. Homewood. K .. Golden. W.: Polybrenc Neutralization as a Rapid Means of Monitoring Blood Heparin Levels. Am. J. C/in. ?athol. protamine should prompt a reconsideration of the 58:26-32. 1972.

40 The Journal of Extra-Corporeal Technology Volume 16, Number I, Spring 1984