Anesth Prog 38:99-100 1991
An Anaphylactic Reaction to Protamine
Sulfate
James A. Roelofse, MBChB, MMED, PhD, and Pieter Van Der Bijl, BSc (Hons), BChD, PhD Departments of Maxillo-Facial Surgery and Oral Medicine and Periodontics, University of Stellenbosch, Tygerberg, South Africa.
types of reactions are relatively rare.2'3 However, when they do occur, patients require urgent and aggressive therapy with a-adrenergic agents, corticosteroids, and plasma volume expansion, as illustrated by the following case report.
Presented is a case in which protamine sulfate administration caused an immediate allergic-like reaction. The patient, a 50-year-old woman, had received protamine previously to reverse the anticoagulant effect of heparin after open heart surgery. In a similar operation 7 years later, protamine was used again for the same reason. Immediately following intravenous infusion of 3 mg/kg protamine sulfate, a sudden drop of the mean arterial blood pressure to 40 mm Hg occurred, and the heart rate increased from 100 to 130 beats/min. Severe angioneurotic edema of the face and trunk also developed. The reaction was successfully treated with vasopressors, steroids, and volume expansion. Subsequent skin testing revealed a positive reaction to protamine sulfate.
CASE REPORT A 50-year-old woman had an aortic valve replacement for aortic stenosis in 1983. During cardiopulmonary bypass she received intravenous heparin (3 mg/kg) for anticoagulation therapy, which was reversed uneventfully with protamine sulfate at the end of the bypass. She was later discharged from the hospital without any problems. The patient was admitted to the hospital 7 years later for a second operation due to a malfunctioning valve. General anesthesia was induced with intravenous fentanyl (50 ag/kg) and diazepam (7.5 mg) and maintained with morphine (0.5 mg/kg) and oxygen. Pancuronium (0.15 mg/kg) was administered for muscle relaxation. During extracorporeal circulation (ECC) enflurane and pancuronium were administered as needed. The patient received intravenously 3 mg/kg heparin before the aortic and vena cava cannulas were inserted, after which the activated clotting time (ACT) was maintained at levels above 450 sec. The patient tolerated surgery and anesthesia well and was weaned from ECC without any problems. After the aortic and vena cava cannulas were removed 3 mg/kg protamine sulfate was slowly administered intravenously, via a peripheral route, to reverse the anticoagulation effect
rotamine is a low molecular weight polypeptide isolated from the sperm or mature testes of fish belonging to the family Clupeidae or Balmonidae. The purified compound has basic properties, due to its high content of arginine residues, and combines readily with heparin to form a stable complex that is devoid of anticoagulant activity. For this reason protamine sulfate has been extensively used to neutralize the effects of heparin following cardiac and vascular surgery. Rapid intravenous infusion of a protamine sulfate solution may cause hypotension, flushing, dyspnea, and bradycardia, perhaps due to the release of histamine.1 Two other types of adverse reactions to protamine sulfate may also occur.2 The first is of the immediate anaphylactic type, with all the characteristics of an antibody-mediated reaction, while the second type has a delayed (> 30 min) onset. In the latter type of reaction, antibodies do not seem to be involved, and skin tests are negative. Both
of heparin. Protamine infusion resulted in a sudden drop of mean arterial blood pressure to 40 mm Hg, and the heart rate increased from 100 to 130 beats per min. At this point extensive and severe angioneurotic edema of the face and trunk was noticed. Despite prompt intravenous injection of phenylephrine and calcium chloride the patient remained severely hypotensive, the mean blood pressure remaining in the range between 40 and 50 mm Hg. Not until 500 ,g epinephrine and 500 mg methylprednisolone Na-succinate had been given did the blood pressure rise and the angioneurotic edema begin to subside. Initial volume expansion was achieved by a rapid infusion of
Received March 19, 1991; accepted for publication May 28, 1991. Address correspondence to Dr. James A. Roelofse, Faculty of Dentistry, Private Bag Xl, Tygerberg 7505, Republic of South Africa. ©C) 1991 by the American Dental Society of Anesthesiology
ISSN 0003-3006/91/$3.50
99
Anesth Prog 38:99-100 1991
100 Anaphylaxis to Protamine Sulfate
fresh frozen plasma. A postoperative X-ray of the chest showed no evidence of pulmonary edema. During this period of resuscitation, which lasted approximately 30 min, the patient received only oxygen. The patient was taken to the intensive care unit in a satisfactory condition. She received vasopressor support, was extubated after 12 hr, and had an uneventful recovery. Skin testing was done 6 wk later with several anesthetic agents and protamine sulfate. A positive skin test was found only for the protamine sulfate.
DISCUSSION Studies on the cardiovascular effects of protamine sulfate differ with respect to the dose of protamine, rate and route of injection, condition of the patient, and the anesthetic conditions. When given slowly, investigators have shown that the systemic blood pressure decreases minimally, if at all.4 The cardiac index remains unchanged, although there are varying results in studies of patients with poor ventricular function. It also seems that the pulmonary artery pressures remain unaffected. When given rapidly, the systemic vascular resistance and arterial blood pressure may decrease. Little evidence exists to conclude that protamine directly depresses myocardial contractility. Protamine sulfate administration, however, has been associated with a variety of adverse hemodynamic responses. These reactions include hypotension, pulmonary vasoconstriction, and acute anaphylactoid reactions. 1 Some of these hemodynamic effects have been ascribed to histamine release from mast cells following the administration of protamine.5 Neither blood loss nor malfunction of the replaced aortic valve was thought to be the cause of the acute cardiovascular collapse seen in our patient at the end of the operation. We believe that we were dealing with acute anaphylactic shock in a patient previously sensitized by intravenous protamine sulfate for reversal of heparin anticoagulation. This assessment is supported by the positive skin test for protamine sulfate performed 6 wk after the operation. Caution must be exercised when protamine sulfate is administered to patients who may have been previously sensitized, and perhaps patients should be routinely tested for such sensitivity. This can be done either preoperatively or by giving an initial small test dose, such as 5 mg of protamine sulfate immediately prior to heparin neutralization.
Preoperative administration of drugs to decrease the incidence or severity of an intraoperative drug-induced allergic reaction has been recommended for patients with a history of allergies.6 These agents may include an H1receptor antagonist (0.5 to 1 mg/kg diphenhydramine)
and an H2-receptor antagonist (4 to 6 mg/kg cimetidine), both of which act by occupying peripheral receptor sites of histamine. Kambam et a17 reported the successful use of cimetidine in two cases of anaphylactoid reactions to protamine, and this form of treatment may be useful in reversing these types of reactions after conventional treatment with epinephrine and steroids has been given. Preoperative prophylactic administration of histaminereceptor antagonists would be particularly appropriate for the patient who has previously experienced an allergic type of reaction to a drug that is to be administered during a subsequent procedure, as in our case. The drug to which the reaction has occurred should be administered slowly and, if possible, in a reduced dose so as to minimize the likelihood of high plasma concentrations that would facilitate degranulation of mast cells and basophils. In this respect a drug such as aprotinin (10,000 u/kg) could be used before administering protamine sulfate to reduce the dose of protamine needed for heparin neutralization.8 An effective prophylactic regimen could also include oral prednisone (50 mg in the adult patient every 6 hr) for 1 day with the last dose given 1 hr before the operation. It has also been recommended that hexadimethrine (Polybrene) can be used to neutralize heparin4; however, this drug is not widely available. In conclusion, the nature of the adverse reactions to protamine sulfate requires that patients sensitive to the drug be identified by careful history and skin testing, and that, when necessary, appropriate precautions be taken before administration.
REFERENCES 1. Moorthy SS, Pond W, Rowland RG: Severe circulatory shock following protamine (an anaphylactoid reaction) Anesth Analg 1980;59:77-78. 2. Holland CL, Singh AK, McMaster PRB, Fang W: Adverse reactions to protamine sulfate following cardiac surgery. Clin Cardiol 1984;7:157-162. 3. Doolan L, McKenzie I, Krafchek J, Parsons B, Buxton B: Protamine sulfate hypersensitivity. Anesth Intens Care 1981;9:147-149. 4. Horrow JC: Protamine: a review of its toxicity. Anesth Analg 1985;64:348-361. 5. Lakin JD, Blocker TJ, Strong DM, Yocum MW: Anaphylaxis to protamine sulfate mediated by a complement-dependent IgG antibody. J Allergy Clin Immunol 1978;61:102-107. 6. Beaven MA: Anaphylactoid reactions to anesthetic drugs. Anesthesiology 1981;55:3-5. 7. Kambam JR, Merrill WH, Smith BE: Histamine2 receptor blocker in the treatment of protamine related anaphylactoid reactions: two case reports. Can J Anaesth 1989;36:463-465. 8. Roelofse JA: Die gebruik van aprotinien tydens en na kardiopulmonale omleiding. Geneeskunde 1983;25:456-458.
An Anaphylactic Reaction to Protamine
Sulfate
James A. Roelofse, MBChB, MMED, PhD, and Pieter Van Der Bijl, BSc (Hons), BChD, PhD Departments of Maxillo-Facial Surgery and Oral Medicine and Periodontics, University of Stellenbosch, Tygerberg, South Africa.
types of reactions are relatively rare.2'3 However, when they do occur, patients require urgent and aggressive therapy with a-adrenergic agents, corticosteroids, and plasma volume expansion, as illustrated by the following case report.
Presented is a case in which protamine sulfate administration caused an immediate allergic-like reaction. The patient, a 50-year-old woman, had received protamine previously to reverse the anticoagulant effect of heparin after open heart surgery. In a similar operation 7 years later, protamine was used again for the same reason. Immediately following intravenous infusion of 3 mg/kg protamine sulfate, a sudden drop of the mean arterial blood pressure to 40 mm Hg occurred, and the heart rate increased from 100 to 130 beats/min. Severe angioneurotic edema of the face and trunk also developed. The reaction was successfully treated with vasopressors, steroids, and volume expansion. Subsequent skin testing revealed a positive reaction to protamine sulfate.
CASE REPORT A 50-year-old woman had an aortic valve replacement for aortic stenosis in 1983. During cardiopulmonary bypass she received intravenous heparin (3 mg/kg) for anticoagulation therapy, which was reversed uneventfully with protamine sulfate at the end of the bypass. She was later discharged from the hospital without any problems. The patient was admitted to the hospital 7 years later for a second operation due to a malfunctioning valve. General anesthesia was induced with intravenous fentanyl (50 ag/kg) and diazepam (7.5 mg) and maintained with morphine (0.5 mg/kg) and oxygen. Pancuronium (0.15 mg/kg) was administered for muscle relaxation. During extracorporeal circulation (ECC) enflurane and pancuronium were administered as needed. The patient received intravenously 3 mg/kg heparin before the aortic and vena cava cannulas were inserted, after which the activated clotting time (ACT) was maintained at levels above 450 sec. The patient tolerated surgery and anesthesia well and was weaned from ECC without any problems. After the aortic and vena cava cannulas were removed 3 mg/kg protamine sulfate was slowly administered intravenously, via a peripheral route, to reverse the anticoagulation effect
rotamine is a low molecular weight polypeptide isolated from the sperm or mature testes of fish belonging to the family Clupeidae or Balmonidae. The purified compound has basic properties, due to its high content of arginine residues, and combines readily with heparin to form a stable complex that is devoid of anticoagulant activity. For this reason protamine sulfate has been extensively used to neutralize the effects of heparin following cardiac and vascular surgery. Rapid intravenous infusion of a protamine sulfate solution may cause hypotension, flushing, dyspnea, and bradycardia, perhaps due to the release of histamine.1 Two other types of adverse reactions to protamine sulfate may also occur.2 The first is of the immediate anaphylactic type, with all the characteristics of an antibody-mediated reaction, while the second type has a delayed (> 30 min) onset. In the latter type of reaction, antibodies do not seem to be involved, and skin tests are negative. Both
of heparin. Protamine infusion resulted in a sudden drop of mean arterial blood pressure to 40 mm Hg, and the heart rate increased from 100 to 130 beats per min. At this point extensive and severe angioneurotic edema of the face and trunk was noticed. Despite prompt intravenous injection of phenylephrine and calcium chloride the patient remained severely hypotensive, the mean blood pressure remaining in the range between 40 and 50 mm Hg. Not until 500 ,g epinephrine and 500 mg methylprednisolone Na-succinate had been given did the blood pressure rise and the angioneurotic edema begin to subside. Initial volume expansion was achieved by a rapid infusion of
Received March 19, 1991; accepted for publication May 28, 1991. Address correspondence to Dr. James A. Roelofse, Faculty of Dentistry, Private Bag Xl, Tygerberg 7505, Republic of South Africa. ©C) 1991 by the American Dental Society of Anesthesiology
ISSN 0003-3006/91/$3.50
99
Anesth Prog 38:99-100 1991
100 Anaphylaxis to Protamine Sulfate
fresh frozen plasma. A postoperative X-ray of the chest showed no evidence of pulmonary edema. During this period of resuscitation, which lasted approximately 30 min, the patient received only oxygen. The patient was taken to the intensive care unit in a satisfactory condition. She received vasopressor support, was extubated after 12 hr, and had an uneventful recovery. Skin testing was done 6 wk later with several anesthetic agents and protamine sulfate. A positive skin test was found only for the protamine sulfate.
DISCUSSION Studies on the cardiovascular effects of protamine sulfate differ with respect to the dose of protamine, rate and route of injection, condition of the patient, and the anesthetic conditions. When given slowly, investigators have shown that the systemic blood pressure decreases minimally, if at all.4 The cardiac index remains unchanged, although there are varying results in studies of patients with poor ventricular function. It also seems that the pulmonary artery pressures remain unaffected. When given rapidly, the systemic vascular resistance and arterial blood pressure may decrease. Little evidence exists to conclude that protamine directly depresses myocardial contractility. Protamine sulfate administration, however, has been associated with a variety of adverse hemodynamic responses. These reactions include hypotension, pulmonary vasoconstriction, and acute anaphylactoid reactions. 1 Some of these hemodynamic effects have been ascribed to histamine release from mast cells following the administration of protamine.5 Neither blood loss nor malfunction of the replaced aortic valve was thought to be the cause of the acute cardiovascular collapse seen in our patient at the end of the operation. We believe that we were dealing with acute anaphylactic shock in a patient previously sensitized by intravenous protamine sulfate for reversal of heparin anticoagulation. This assessment is supported by the positive skin test for protamine sulfate performed 6 wk after the operation. Caution must be exercised when protamine sulfate is administered to patients who may have been previously sensitized, and perhaps patients should be routinely tested for such sensitivity. This can be done either preoperatively or by giving an initial small test dose, such as 5 mg of protamine sulfate immediately prior to heparin neutralization.
Preoperative administration of drugs to decrease the incidence or severity of an intraoperative drug-induced allergic reaction has been recommended for patients with a history of allergies.6 These agents may include an H1receptor antagonist (0.5 to 1 mg/kg diphenhydramine)
and an H2-receptor antagonist (4 to 6 mg/kg cimetidine), both of which act by occupying peripheral receptor sites of histamine. Kambam et a17 reported the successful use of cimetidine in two cases of anaphylactoid reactions to protamine, and this form of treatment may be useful in reversing these types of reactions after conventional treatment with epinephrine and steroids has been given. Preoperative prophylactic administration of histaminereceptor antagonists would be particularly appropriate for the patient who has previously experienced an allergic type of reaction to a drug that is to be administered during a subsequent procedure, as in our case. The drug to which the reaction has occurred should be administered slowly and, if possible, in a reduced dose so as to minimize the likelihood of high plasma concentrations that would facilitate degranulation of mast cells and basophils. In this respect a drug such as aprotinin (10,000 u/kg) could be used before administering protamine sulfate to reduce the dose of protamine needed for heparin neutralization.8 An effective prophylactic regimen could also include oral prednisone (50 mg in the adult patient every 6 hr) for 1 day with the last dose given 1 hr before the operation. It has also been recommended that hexadimethrine (Polybrene) can be used to neutralize heparin4; however, this drug is not widely available. In conclusion, the nature of the adverse reactions to protamine sulfate requires that patients sensitive to the drug be identified by careful history and skin testing, and that, when necessary, appropriate precautions be taken before administration.
REFERENCES 1. Moorthy SS, Pond W, Rowland RG: Severe circulatory shock following protamine (an anaphylactoid reaction) Anesth Analg 1980;59:77-78. 2. Holland CL, Singh AK, McMaster PRB, Fang W: Adverse reactions to protamine sulfate following cardiac surgery. Clin Cardiol 1984;7:157-162. 3. Doolan L, McKenzie I, Krafchek J, Parsons B, Buxton B: Protamine sulfate hypersensitivity. Anesth Intens Care 1981;9:147-149. 4. Horrow JC: Protamine: a review of its toxicity. Anesth Analg 1985;64:348-361. 5. Lakin JD, Blocker TJ, Strong DM, Yocum MW: Anaphylaxis to protamine sulfate mediated by a complement-dependent IgG antibody. J Allergy Clin Immunol 1978;61:102-107. 6. Beaven MA: Anaphylactoid reactions to anesthetic drugs. Anesthesiology 1981;55:3-5. 7. Kambam JR, Merrill WH, Smith BE: Histamine2 receptor blocker in the treatment of protamine related anaphylactoid reactions: two case reports. Can J Anaesth 1989;36:463-465. 8. Roelofse JA: Die gebruik van aprotinien tydens en na kardiopulmonale omleiding. Geneeskunde 1983;25:456-458.
