Immunologic reactions to protamine sulfate during cardiac surgery are very rare. The frequency and outcome of such adverse reactions is unclear. We report a case of lethal anaphylactic reaction to protamine that occurred in a non-diabetic patient following the uneventful replacement of the ascending aorta. We also briefly review the mechanisms of this adverse reaction and emit some considerations on the management of this situatio

Chevalley, C.

Kalangos, A.

Orrit, X.

Panos, A.

RERO DOC Digital Library

Case reportDramatic post-cardiotomy outcome, due to severeanaphylactic reaction to protamineA. Panos*, X. Orrit, C. Chevalley, A. KalangosClinic for cardio-vascular surgery, Department of Surgery, University Hospital of Geneva, 24, rue Micheli-du-Crest, 1211 Geneva 14, SwitzerlandReceived 17 December 2002; received in revised form 28 March 2003; accepted 1 April 2003AbstractImmunologic reactions to protamine sulfate during cardiac surgery are very rare. The frequency and outcome of such adverse reactions isunclear. We report a case of lethal anaphylactic reaction to protamine that occurred in a non-diabetic patient following the uneventfulreplacement of the ascending aorta. We also briefly review the mechanisms of this adverse reaction and emit some considerations on themanagement of this situation.q 2003 Elsevier Science B.V. All rights reserved.Keywords: Cardiac surgery; Protamine; Allergy1. IntroductionProtamine is a polycationic peptide that is mainly usedto reverse the anticoagulant effects of heparin. Althoughprotamine is a relatively safe drug, it is occasionallyassociated with a severe systemic reaction and significantmorbidity and mortality [1].A 64-year-old male, with a history of smoking andarterial hypertension, but no diabetes mellitus, was admittedfor a symptomatic aneurysm of the ascending aorta diag-nosed by computed tomography (CT)-scanner. Echocardio-graphy showed severe aortic valve insufficiency, but nosigns of aortic wall rupture. Coronary angiography revealednormal coronary arteries. The patient was transferred to theoperating room. Femoro-femoral cardiopulmonary bypass(CPB) was initiated, the patient was cooled to 308C andantegrade blood cardioplegia was administered in thecoronary ostia. The aortic aneurysm was resected andreplaced by a 26 mm Dacron tube (Sulzer Medica)according to Tirone David’s technique. Total aortic cross-clamping time was 61 min. The patient was successfullyweaned from CPB with no inotropic support. Heparin wasreversed by a slow intravenous injection of 40,000 IUprotamine sulfate. Ten minutes after the complete admin-istration of protamine, rapid right ventricular dilatation wasobserved. Mean systemic and pulmonary arterial pressurewere 38 and 60 mmHg, respectively, without any electro-cardiographic alterations. CPB was restarted. Following20 min of CPB assistance and a complete hemodynamicrecovery, the CPB was weaned. A transesophageal echo-cardiography did not show any cardiac anomalies. At thattime, an isolated pulmonary vascular reaction to protaminewas suspected and only half-dose of the necessary prot-amine was infused very slowly via the arterial cannula,40 min after having stopped the second CPB. However,once again, the patient responded with a marked bloodpressure drop, with the mean index of systemic vascularresistance of 860 dyne s cm25 and pulmonary hypertensionsimultaneously with global cardiac failure, 5 min aftercompletion of the protamine administration. We stronglysuspected an anaphylactic reaction to protamine. No cutane-ous manifestations were present at any moment. CPB wasre-started, but this time without any myocardial recoverydespite the administration of inotrope drugs, steroids, andanti-histamines. A Berlin Heart assist device (FehlingMedical, D-13355 Berlin, Germany) was implanted andthe CPB could be stopped without administration of anyprotamine. Suddenly, ventricular fibrillation occurred andafter prolonged unsuccessful reanimation associated toventilation difficulties with increased airway resistanceand resultant fall in PaO2, the patient succumbed in theoperating room. The autopsy failed to demonstrate any1010-7940/03/$ - see front matter q 2003 Elsevier Science B.V. All rights reserved.doi:10.1016/S1010-7940(03)00252-5European Journal of Cardio-thoracic Surgery 24 (2003) 325–327www.elsevier.com/locate/ejcts* Corresponding author. Tel.: þ41-223727624; fax: þ41-223727634.E-mail address: aristotepanos@yahoo.com (A. Panos).cardiac or pulmonary anomalies but showed a generalisedvascular eosinophilia, suggesting a severe anaphylacticshock in response to the administration of protamine.2. DiscussionProtamine is a polycationic polypeptide belonging to agroup of low molecular proteins contained in fish sperm. Itis used extensively to neutralize heparin following cardiacand vascular surgical procedures, but it is also used indialysis and leucopheresis. Another major use of protamineoccurs in the complexing of insulin to delay absorption andprolong duration of action. When injected intravenously, thebasic reacting protamine combines with the acidic heparinto form a neutral salt, thus eliminating the anticoagulatingproperties of heparin.Adverse responses to protamine have been identified formany years. The incidence of such adverse reactions hasbeen reported as varying from 0.06 to 10.6% [2]. They havebeen reported in patients with fish allergy, in those pre-viously exposed to protamine, principally diabetics whohave received protamine zinc insulin. In addition, bothvasectomised and infertile men have a theoretical risk ofsensitivity via antibodies raised to protamine, contained insperm released into the blood stream. The incidence ofcatastrophic reactions to protamine during cardiovascularsurgery is reported to be 0.13% [3]. Although the exactmechanisms by which protamine produces anaphylaxis arenot completely understood, some possible mechanisms aredescribed. Protamine may act as an antigen and bind to theIgE antibodies. This process may lead to cross-linking withthe antibody surfaces, which then initiates a process of celldegranulation. Adverse reactions may also be associatedwith the interaction between protamine and complement-fixing antiprotamine IgG antibodies. Protamine binds to acell. Circulating IgG antibodies recognize the drug as anantigen and bind with the protamine. The cell-bound IgGactivates the complement system. Moreover, adverseresponses to protamine seem to be related to the formationof protamine–heparin complexes, which appear to activatethe classical complement cascade with subsequent gener-ation of anaphylatoxins [4]. Protamine adverse reactions fallinto three different categories: transient systemic hypo-tension related to rapid drug administration, anaphylactoidreactions, and catastrophic pulmonary vasoconstriction [5].Anaphylactoid responses to protamine are characterized byedema of the skin, mucosa, and viscera, decreased systemicvascular resistance, bronchospasm, and occasionally flush-ing. Catastrophic pulmonary vasoconstriction is accom-panied by right ventricular dilation, pulmonary arterialhypertension, decreased left ventricular filling pressure, andsystemic hypotension. This type of reaction appear to occurin patients with abnormal pulmonary hemodynamics [5].A well-controlled study [6] with constant monitoring ofcardiac output, systemic blood pressure, and ventricularpressures of patients during protamine infusion after CPBestablished that protamine causes significant reduction inperipheral vascular resistance. Hypotension occurred whenthe increase in cardiac output was insufficient to offset thedecreased peripheral resistance. A small reduction in leftventricle contractile activity is present only in patients witha decrease .10 mmHg in systemic blood pressure.However the precise mechanism that explains protamine-mediated systemic hypotension is unknown. Evora et al. [7]reported that pulmonary circulation is extensively involvedin protamine-mediated effects on endothelial function.In vitro organ chambers and canine pulmonary arterystudies indicate that protamine induces endothelium-dependent vasodilation, instead of a vasoconstriction, aspreviously documented [5]. Heparin, in contrast to thesystemic circulation, inhibits the endothelium-dependentvasodilation to protamine [7]. However, this inhibitoryeffect can be overcome by higher doses of protamine,concluding that protamine complexed with heparin does notinduce vasodilation. As in the systemic circulation, theprecise mechanism is still unknown. Since the direct effectof protamine is vasodilation due to EDRF/NO release, itappears that this vasoconstriction may be secondary. It ispossible that the protamine use for anticoagulation reversioncauses release of thromboxane, which induces catastrophicpulmonary vasoconstriction [8]. Horrow [5], who reportedmultiple animal studies, demonstrated a depressed ventri-cular contractility and thrombocytopenia. In our case, weobserved similar reaction with a pulmonary hypertension, adramatic decrease of the systemic blood pressure accom-panied by major depression of ventricular contractility.Multiple studies demonstrated increased cardiovasculareffects with rapid injection of protamine [5]. The AmericanHospital Formulary Service recommendation for dosing is“no more than 50 mg of the drug is administered in any10-min-period” [9]. We think that a major step in thesurgical outcome of our patient was the decision to againadminister protamine after the weaning of the second CPBperiod. This decision was initially taken because we didnot think that we were dealing with a protamine-relatedanaphylactic reaction, as there was no drop in peripheralresistances and the patient completely recovered under CPBassistance. After the second administration of protamine,cardiac failure was global and unfortunately irreversibledespite the prolonged CPB assistance and implantation ofan external ventricular assist device (Berlin Heart). Themechanism of this irreversible cardiac failure remainsunexplained and supports the hypothesis of a direct effectof the heparin–protamine complexes on cardiac contrac-tility [5]. At the present time, no alternatives to the use ofprotamine are available. Hexadimethrine bromide (poly-brene) and some heparinases are agents that have been usedoccasionally as reversal agents for heparin. Both havesignificant side effects.In the absence of a safe and efficient agent for thereversal of heparin, when the risks of adverse reaction toA. Panos et al. / European Journal of Cardio-thoracic Surgery 24 (2003) 325–327326protamine outweigh the risks of extensive bleeding,spontaneous reversal of heparin is allowed. We estimatethat this strategy should have been used in our patient afterthe first major hemodynamic alteration. Treatment ofadverse responses to protamine is based on supporting theaffected organs and reducing the effects of histamine.Aggressive resuscitative efforts must be initiated immedi-ately including restoration of CPB, when still available.Viaro et al. [10] suggest methylene blue as a novel experi-mental approach to prevent and treat hemodynamiccomplications caused by the use of protamine after CPB.According to them, six patients presented an anaphylactoidtype adverse reaction to protamine and were treatedsuccessfully with methylene blue ‘bolus’ infusion of1.5 mg/kg (120 mg), followed by continuous infusion ofanother 120 mg diluted in 5% of glucose in water. Theanaphylactic manifestation reversion was complete in10–15 min. Immunologic reactions to protamine havereceived little attention among clinicians. In view of ourexperience, we should like to suggest that anaphylacticreactions to protamine are uncommon but potentially deva-stating. Patients, who have had previous protamine injec-tions during cardiovascular surgery, diabetics on protaminecontaining insulin, as well as patients with allergy to fishand vasectomised patients should perhaps be routinelytested for such sensitivity and be appropriately premedi-cated. Finally, when suspecting a severe adverse reaction toprotamine, we estimate that heparin should not be reversedeven with a greater risk of bleeding and subsequentre-exploration. It is hoped that the future will also provideincreased knowledge to prevent and improve patientoutcomes related to adverse response to protamine.References[1] Kimmel S, Sekeres M, Berlin J, Ellison N. Mortality and adverseevents after protamine administration in patients undergoing cardio-pulmonary bypass. Anesth Analg 2002;94:1402–8.[2] Weiler JM, Gelhaus M, Carter J, Meng R, Benson P, Hottel R, SchilligRN, Vegh A, Clarke W. A prospective study of the risk of animmediate adverse reaction to protamine sulfate during cardio-pulmonary bypass surgery. J Allergy Clin Immunol 1990;85:713–9.[3] Levy J, Zaidan J, Faraj B. Prospective evaluation of risk of protaminereactions in patients with NPH insulin-dependent diabetes. AnesthAnalg 1986;65:739–42.[4] Porsche R, Brenner Z. Allergy to protamine sulfate. Heart Lung 1999;28(6):418–28.[5] Horrow JC. Protamine:a review of its toxicity. Anesth Analg 1985;64:358–61.[6] Shapira N, Schaff HV, Piehler JM, White RD, Still JC, Pluth JR.Cardiovascular effects of protamine sulfate in man. Thorac Cardio-vasc Surg 1982;84:505–14.[7] Evora PR, Pearson PJ, Schaff HV. Protamine induces endothelium-dependent vasodilation of the pulmonary artery. Ann Thorac Surg1995;60:405–10.[8] Schumacher WA, Heran CL, Ogletree ML. Effect of thromboxanereceptor antagonism on pulmonary hypertension caused byprotamine–heparin interactions in pigs. Circulation 1988;78(suppl):II-207.[9] McEvoy G, editor. American hospital formulary service. Bethesda,MD: American Society of Health-system Pharmacists; 1998.[10] Viaro F, Dalio MB, Evora PR. Catastrophic cardiovascular adversereactions to protamine are nitric oxide/cyclic guanosine monophos-phate dependent and endothelium mediated: should methylene blue bethe treatment of choice? Chest 2002;122(3):1061–6.A. Panos et al. / European Journal of Cardio-thoracic Surgery 24 (2003) 325–327 327

Dramatic post-cardiotomy outcome, due to severe anaphylactic reaction to protamine

Abstract

Similar works

Full text

Available Versions

RERO DOC Digital Library