Ann Thorac Surg 2009;87:640-642. doi:10.1016/j.athoracsur.2008.07.017
© 2009 The Society of Thoracic Surgeons
Case Reports
Use of Methylene Blue for Catecholamine-Refractory Vasoplegia from Protamine and Aprotinin
Danny Del Duca, MDa,
Shashank S. Sheth, MDb,
Ann E. Clarke, MDb,
Kevin J. Lachapelle, MDa,
Patrick L. Ergina, MDa,*
a Division of Cardiovascular Surgery, McGill University Health Centre, Montreal, Quebec, Canada
b Division of Allergy and Clinical Immunology, McGill University Health Centre, Montreal, Quebec, Canada
Accepted for publication July 9, 2008.
* Address correspondence to Dr Ergina, Division of Cardiovascular Surgery, Royal Victoria Hospital, 687 Pine Ave W, Room S8.76B, Montreal, Quebec, H3A 1A1, Canada (Email: patrick.ergina{at}muhc.mcgill.ca).
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Abstract
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We present two cases of catecholamine-refractory and vasopressin-refractory vasoplegic syndrome associated with intraoperative anaphylaxis during cardiac surgery. One case was related to the administration of protamine and the other case to the administration of aprotinin. Both cases were successfully managed using intravenous methylene blue. The use of methylene blue blocks accumulation of cyclic guanosine monophosphate by competitively inhibiting the enzyme guanylate cyclase. This results in reduced responsiveness of the vasculature to cyclic guanosine monophosphate–mediated vasodilators, such as nitric oxide. This report provides a description of severe anaphylaxis induced by different agents, in which the use of methylene blue was associated with a significant clinical response.
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Introduction
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Severe anaphylactic reactions in patients treated with either protamine or aprotinin during cardiac surgery are among the most significant complications associated with the use of these agents. These reactions may be refractory to aggressive resuscitation using conventional therapy, including catecholamines, vasopressin, antihistamines, corticosteroids, and volume expansion. Methylene blue (methylthionine chloride) is an indicator dye that has been traditionally used in a number of clinical settings and more recently in the management of anaphylactic shock [1]. Although the use of methylene blue in anaphylaxis specifically associated with protamine has been described in one report [2], its use in the context of intraoperative aprotinin reactions has not been previously presented. We describe two cases in which methylene blue was successfully used in the treatment of severe anaphylactic reactions related to protamine (patient 1) and aprotinin (patient 2).
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Case Reports
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Patient 1
A 72-year-old man was referred for elective coronary artery bypass grafting. The patient's history included hypertension and diabetes mellitus type 2 for which he had been using neutral protamine Hagedorn insulin. During surgery, four coronary bypass grafts were performed using cardiopulmonary bypass. The patient was weaned from cardiopulmonary bypass and a protamine infusion was started. After the administration of approximately 100 mg of protamine, the blood pressure decreased from 90/50 to 50/25 mm Hg, and generalized urticaria appeared. The hypotension remained refractory to resuscitation using epinephrine, norepinephrine, vasopressin, diphenhydramine, hydrocortisone, calcium chloride, and crystalloid boluses. On examination, the heart continued to beat vigorously, with a rate between 100 and 110 beats per minute. The patient was placed back on cardiopulmonary bypass and an intra-aortic balloon pump was inserted, with minimal improvement in blood pressure. Methylene blue (100 mg) was administered intravenously. After 15 minutes, the blood pressure stabilized, allowing cardiopulmonary bypass to be discontinued. The cannulae were removed without the reversal of systemic anticoagulation. There were no postoperative neurologic deficits or any evidence of further anaphylaxis. Four weeks later, outpatient cutaneous allergy testing confirmed the presence of immunoglobulin E (IgE) specific to neutral protamine Hagedorn insulin and protamine sulfate.
Patient 2
A 72-year-old woman was referred for elective replacement of a stenotic aortic valve bioprosthesis. Her past medical history included hypertension, recurrent urticaria, and aortic valve replacement for aortic stenosis 5 years earlier. The patient had received aprotinin at the primary operation without any adverse reaction. Aprotinin was used for the reoperation due to the increased risk of bleeding. While preparing for cardiopulmonary bypass, a 20,000 KIU test dose of aprotinin was administered. This was followed by a sudden drop in blood pressure from 115/60 to 39/20 mm Hg. The hypotension remained refractory to treatment with epinephrine, norepinephrine, vasopressin, diphenhydramine, and dexamethasone. The heart rate varied between 100 and 120 beats per minute and on examination, the cardiac contractility appeared depressed, but the heart was not distended. Cardiopulmonary bypass was instituted 9 minutes later. The aortic valve was replaced uneventfully, and this was followed by reperfusion on cardiopulmonary bypass for 35 minutes. Weaning from bypass remained difficult, despite the use of epinephrine and norepinephrine infusions. An intra-aortic balloon pump was inserted, and 100 mg of methylene blue was administered intravenously. After 10 minutes, cardiopulmonary bypass was discontinued, and the patient's blood pressure remained stable. The patient recovered without neurologic deficit and was discharged from the hospital 8 days later. Outpatient skin testing confirmed the presence of aprotinin-specific IgE.
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Comment
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Protamine, which is a fish-derived arginine-rich peptide, was discovered in 1868 and is used for the reversal of heparin-induced anticoagulation in more than 2 million patients annually. The adverse reactions associated with protamine were classified by Horrow [3] as systemic hypotension related to rapid protamine administration, antibody-mediated anaphylactic and complement-mediated anaphylactoid responses, and catastrophic pulmonary vasoconstriction. In our patient, the presence of protamine-specific IgE suggests that the adverse reaction was anaphylactic. The general incidence of significant adverse reactions to protamine has been reported as 0.9%. Among patients having previous exposure to neutral protamine Hagedorn-based insulin regimens, the incidence may be as high as 2.8% [4]. The mechanism by which protamine causes a systemic vasodilatory response, as seen in our patient, likely involves the cross-linking of protamine-specific IgE on mast cell surfaces resulting in the release of several mediators, some of which lead to increased nitric oxide (NO) production by upregulating nitric oxide synthase. Another possible mechanism is that protamine may directly stimulate endothelial cell-mediated conversion of the amino acid L-arginine to NO [5]. The release of NO leads to activation of the enzyme guanylate cyclase, thereby resulting in increased synthesis of cGMP, a mediator of vascular smooth muscle relaxation.
Aprotinin, a serine protease inhibitor derived from bovine lung, is a member of the class of anti-fibrinolytic agents that include the lysine analogues aminocaproic acid and tranexamic acid. The incidence of adverse clinical reactions on primary exposure to aprotinin is 0.09%. Among patients having re-exposure to aprotinin, the incidence increases to 1.5%. However, the frequency and severity of these reactions may be reduced as the time interval since primary exposure is increased [6]. The presence of aprotinin-specific IgE in our patient suggests that the adverse reaction was anaphylactic. The use of aprotinin during cardiac surgery has recently been associated with an increased risk of perioperative renal failure, myocardial infarction, heart failure, stroke, and encephalopathy, which was not observed in patients receiving aminocaproic acid or tranexamic acid [7]. For these reasons, tranexamic acid has replaced aprotinin as the first-line anti-fibrinolytic agent used in high-risk cardiac surgical cases at our institution.
The indicator dye, methylene blue, is currently used in a number of clinical settings. It has a role in the management of methemoglobinemia, and may be used in the treatment of chronic urolithiasis. More recently, methylene blue has been used in the context of refractory vasoplegia and anaphylaxis [1], and it has been associated with improved hemodynamics in septic shock [8]. Dose-related toxicities include hemolytic anemia, cardiac arrhythmias, skin desquamation, abdominal pain, bluish skin and urine discoloration, and hyperbilirubinemia in neonates. Methylene blue is a competitive inhibitor of the enzyme guanylate cyclase, and thereby interferes with nitric oxide-mediated vascular smooth muscle relaxation by indirectly decreasing cGMP production. The dose used in our experience has been 1.5 mg/kg, which is administered intravenously.
The use of protamine and aprotinin during cardiac surgery may cause anaphylaxis with significant vasoplegia in which the endothelial synthesis and release of nitric oxide play a central role. The two cases presented here suggest that methylene blue, through its effect on the nitric oxide pathway, may have an important role in the treatment of refractory anaphylactic reactions associated with either of these two agents. Due to its inhibitory role in a pathway common to allergic reactions, methylene blue may be effective in the management of refractory anaphylaxis induced by different triggering agents.
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References
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- Horrow JC. Protamine: a review of its toxicity Anesth Analg 1985;64:348-361.[Free Full Text]
- Gupta SK, Veith FJ, Ascer E, et al. Anaphylactoid reactions to protamine: an often lethal complication in insulin-dependant diabetic patients undergoing vascular surgery J Vasc Surg 1989;9:342-350.[Medline]
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Abstract
Introduction
