Methylene Blue as a Treatment for Refractory Anaphylaxis

Abstract

INTRODUCTION: Protamine is a polycationic protein added to insulin and used to reverse heparin-induced anticoagulation. We describe the case of a 71-year-old man who had anaphylaxis to protamine intraoperatively, which was refractory to conventional therapy.CASE REPORT: A 71-year-old diabetic man previously on insulin NPH was undergoing cardiac surgery. He was weaned off cardiopulmonary bypass and then received a slow infusion of 100 mg protamine for heparin reversal. He immediately developed systemic hypotension, pulmonary hypertension and diffuse urticaria. Resuscitative efforts with standard therapy for anaphylaxis were unsuccessful. Cardiopulmonary bypass was reinstituted and an intraaortic balloon pump was inserted. Based on a few published cases by a single group describing methylene blue as an effective treatment for protamine-induced and anaphylactoid reactions, the patient received 100 mg intravenous methylene blue. Within minutes, the patient's systemic blood pressure and pulmonary artery pressure normalized, and he was weaned off pressors and bypass without using protamine. Thirty days later, skin testing to protamine and protamine-containing insulin preparations was positive.CONCLUSIONS: The mechanism of protamine-induced reactions is uncertain. In addition to being IgE-mediated, it is speculated that protamine directly leads to severe vasodilation by causing release of endothelium-derived relaxing factor and nitric oxide, which is inhibited by methylene blue.Our case supports methylene blue as an adjunctive treatment for refractory anaphylaxis and suggests that it may be prudent to skin test diabetics with previous protamine exposure to exclude protamine allergy. Increased awareness of this diagnosis and potential therapy among allergists, anesthesiologists, and surgeons may prevent perioperative fatalities from refractory anaphylaxis. INTRODUCTION: Protamine is a polycationic protein added to insulin and used to reverse heparin-induced anticoagulation. We describe the case of a 71-year-old man who had anaphylaxis to protamine intraoperatively, which was refractory to conventional therapy. CASE REPORT: A 71-year-old diabetic man previously on insulin NPH was undergoing cardiac surgery. He was weaned off cardiopulmonary bypass and then received a slow infusion of 100 mg protamine for heparin reversal. He immediately developed systemic hypotension, pulmonary hypertension and diffuse urticaria. Resuscitative efforts with standard therapy for anaphylaxis were unsuccessful. Cardiopulmonary bypass was reinstituted and an intraaortic balloon pump was inserted. Based on a few published cases by a single group describing methylene blue as an effective treatment for protamine-induced and anaphylactoid reactions, the patient received 100 mg intravenous methylene blue. Within minutes, the patient's systemic blood pressure and pulmonary artery pressure normalized, and he was weaned off pressors and bypass without using protamine. Thirty days later, skin testing to protamine and protamine-containing insulin preparations was positive. CONCLUSIONS: The mechanism of protamine-induced reactions is uncertain. In addition to being IgE-mediated, it is speculated that protamine directly leads to severe vasodilation by causing release of endothelium-derived relaxing factor and nitric oxide, which is inhibited by methylene blue. Our case supports methylene blue as an adjunctive treatment for refractory anaphylaxis and suggests that it may be prudent to skin test diabetics with previous protamine exposure to exclude protamine allergy. Increased awareness of this diagnosis and potential therapy among allergists, anesthesiologists, and surgeons may prevent perioperative fatalities from refractory anaphylaxis.