A generalized skin erythema and severe hypotension developed following administration of protamine for the reversal of heparin anticoagulation after an unsuccessful attempt at percutaneous transluminal angioplasty in a patient who had never been exposed to protamines before. Evidence of classical pathway complement activation was present indicating that this reaction could have been triggered by a non-immunological mechanism. The patient could not adequately be resuscitated because of the presence of severe coronary artery diseas

MEIER, B.

MOREL, D. R.

NEIDHART, P. P.

POLLA, B. S.

SCHIFFERLI, J. A.

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European Heart Journal (1992) 13, 856-858Fatal anaphylactoid response to protamine after percutaneoustransluminal coronary angioplastyP. P. NEIDHART*, B. MmERf, B. S. POLLAJ, J. A. SCHIFFERLI§ AND D. R. MOREL*Departments of * Anaesthesia and Medicine (^Cardiology Center, XAllergy Unit and§Nephrology Division), UniversityHospital of Geneva, Geneva, SwitzerlandKEY WORDS: Protamine, adverse reactions, anaphylaxis, anticoagulation, heparin, coronary angioplasty.A generalized skin erythema and severe hypotension developed following administration of protamine for the reversal ofheparin anticoagulation after an unsuccessful attempt at percutaneous transluminal angioplasty in a patient who had neverbeen exposed to protamines before. Evidence of classical pathway complement activation was present indicating that thisreaction could have been triggered by a non-immunological mechanism. The patient could not adequately be resuscitatedbecause of the presence of severe coronary artery disease.IntroductionThe widespread use of protamine for the reversal ofheparin anticoagulation has attracted great attentionbecause of its potentially harmful side effects. However,most of the adverse reactions are reported in patientsundergoing heparin neutralization after cardiopulmon-ary bypass or in patients previously exposed to pro-tamines. Here we report a case of fatal protamine reactionin a patient with no history of prior protamine exposurewho underwent an unsuccessful attempt of percutaneoustransluminal coronary angioplasty.Case reportA 64-year-old man was admitted for unstable angina.He had never had surgery before, had no known allergiesand had none of the previously reported risk factors attri-buted to protamine allergy, such as the use of protamine-containing NPH insulins, a prior vasectomy or a historyoffish allergy1'21. The electrocardiogram showed normalsinus rhythm and flattening of the ST segment in V^ . Thestress test performed the evening before catheterizationwas clinically and electrically positive at 100 W with an STsegment depression of more than 1-5 mm in II, III andaVF and ST segment elevation in V,^ lasting for morethan lOmin.The coronary angiography showed a proximal totalocclusion of the left anterior descending coronary artery,its distal bed being collateralized by the dominant rightcoronary artery. The right coronary artery showed severalsignificant stenoses. A localized hypokinesia of theanterior wall was present, with normal global ventricularfunction. At the end of the diagnostic study, it was decidedto attempt recanalization of the occluded left anteriordescending coronary artery, by percutaneous translumi-nal coronary angioplasty. For anticoagulation 20 000units of heparin (LiquemineR, Hoffmann-LaRoche,Submitted for publication on 5 April 1991, and in revised form 2 August 1991Correspondence: Denis R Morel, M.D.. Department of Anaesthesiology,University Hospital of Geneva, 1211 Geneva 4. SwitzerlandBasel, Switzerland) and 250 mg of aspirin were adminis-tered intravenously. The occluded left anterior descend-ing coronary artery could not be passed and electivebypass surgery was recommended to the patient. He hadbeen asymptomatic during the entire intervention.Before removal of the catheter placed in the femoralartery, i.e. about 45 min after anticoagulation, heparinwas reversed with 200 mg protamine hydrochlorid (Pro-tamine 1000, Hoffmann-La Roche, Basel, Switzerland) asan intravenous bolus. Approximately 2 min later, thepatient developed a generalized skin erythema, becamerestless and complained about general itching, butwithout evidence of bronchospasm. The arterial bloodpressure (120/80 mmHg) and heart rate (84-94 beatmin~') remained unchanged. Diphenhydramine (50 mg),a histamine-receptor-blocking agent, and prednisone(100 mg) were given intravenously. However, 10 minlater, systolic blood pressure dropped (< 70 mmHg). Acrystalloid solution was rapidly administered togetherwith 10mg of adrenaline subcutaneously, without anyeffect on blood pressure. Therefore a second dose of1-0 mg of adrenaline was infused slowly into a peripheralvein. Systolic blood pressure transiently increased(>90 mmHg) but the patient complained about typicalchest pain. An ST elevation of more than 1-5 mm wasobserved in the infero-lateral leads, and the systolic bloodpressure dropped progressively (< 50 mmHg). Cardio-pulmonary resuscitation was started, the patient wasintubated and ventilated with 100% oxygen. Peak airwaypressure was above 35 cmH20, indicating the occurrenceof bronchospasm and/or acute pulmonary oedema.Several episodes of ventricular fibrillation occurrednecessitating defibrillation. However, although adequateblood pressure could be maintained initially by cardiacmassage and intravenous administration of inotropes,irreversible electro-mechanical dissociation developed,and the patient could not be resuscitated.To corroborate the diagnosis of protamine-inducedadverse reaction, different components of the comp-lement system were determined in plasma, left fromthe blood sample routinely taken before percutaneous0195-668X/92/060856 + 03 S03.00/0 © 1992 The European Society of CardiologyFatal anaphylactoid response to pro tamine 85 7Table 1 Total haemolylic complement (CHX) and the complementcomponents C3 and C4 before and after adverse protamine reactionBefore After Normal valuesCHW(%)C3(gl-')C4(gl-')1321590-56500-880-2675-1250-63-1-350-10-0-40C3 C3b.jjjj*Figure 1 Two-dimensioned immunoelectrophoresis showing acti-vation of C3. Without activation, no C3b is visible.transluminal angioplasty, and from a blood sample takenduring cardiopulmonary resuscitation.The results of complement fragments are given inTable 1 and Fig. 1. Histamine could be measured only inthe first blood sample and was, with 23-7 nmol I"1, wellabove the normal value of less than 10 nmol 1 ~'.At autopsy, there was a haemopericardium containing400 ml of fresh blood associated with a perforation ofthe right ventricle measuring 0-3 cm in diameter (mostprobably due to the temporary pacemaker during resusci-tation). The hypertrophic heart (535 g) showed extensivearteriosclerosis with an occlusion of the left anterior des-cending coronary artery, 1-8 cm after its origin and astenosis, occluded by a fresh thrombus, in the rightcoronary artery, 5 cm distally of its ostium. A recentantero-septal and postero-lateral infarct was present. Theaortic valve showed signs of inactive endocarditis withmultiple perforations of the leaflets. Both lungs showedcongestion and oedema. The thoraco-abdominal aortaand its branches showed severe arteriosclerosis.DiscussionThe patient probably died from acute occlusion of theright coronary artery supplying blood to the inferiorand, via collaterals, to the anterior myocardial wall.This occlusion was triggered by the adverse reaction toprotamine.It appears that protamine can induce more thanone type of adverse response in humans. Complementactivation through the classical pathway, timely relatedto protamine administration, can occur after cardiaccatheterization in patients with previous exposure toprotamine12'. The depletion of haemolytic complementactivity, C4 and C3 and the presence of circulating C3bsuggests that the classical complement pathway was acti-vated in our patient despite no history of prior exposureto protamine. This indicates that complement was mostprobably not activated by an immune complex131 butrather by an interaction between the polycation pro-tamine and the polyanion heparin'4-51. C-reactive proteinwhich is increased during myocardial ischaemia, enhancesthis reaction161. Split products of complement activationsuch as C3a and C5a or complement-induced release ofhistamine has been proposed as being one of the causesof protamine-induced hypotension178'. However, wecannot exclude that a non-specific, non-immunologicalprotamine-induced release of cellular mediators, e.g.histamine, caused the severe hypotension. As in anothercase reported'81, our patient had an increased plasmahistamine level prior to protamine exposure, whichsuggests that elevated circulating histamine concen-trations could favour adverse reactions to protamine.Some patients may poorly tolerate protamine-inducedhaemodynamic changes. Slow administration through afree-running intravenous catheter1'1 may reduce rapidrelease of vasoactive substances and allow spontaneouscompensatory mechanisms to become operative. Ifprotamine is suspected to have caused adverse sideeffects it calls for immediate therapeutic intervention.This includes cessation of protamine administration andrestoration of blood pressure with intravenous fluids, andcardio-circulatory support drugs. Maintenance of pul-monary gaseous exchange with supplemental oxygen and,if necessary, with assisted ventilation is mandatory. As inour patient, this aggressive therapy may interfere with anadequate myocardial oxygen supply-demand ratio'10',leading to ventricular arrythmia, fibrillation andeventually electro-mechanical dissociation.Cardiac catheterization can be safely performedwithout the use of protamine. We therefore advocate thatit should be administered only if it can significantly con-tribute to reduce bleeding in a heparinized patient. Theocclusion of the right coronary artery by a fresh thrombusin our patient may have been favoured by the reversal ofheparin activity, combined with low blood flow due tosystemic hypotension.References[1] Horrow JC. Protamine- a review of its toxicity. Anesth Analg1985; 64: 348-61.[2] Stewart WJ, McSweeney SM, Kelett MA, Faxon DP, Ryan TJ.Increased risk of severe protamine reactions in NPH insulin-dependent diabetics undergoing cardiac catheterization.Circulation 1984; 70: 788-92.[3] Weiss ME, Nyhan D, Peng Z, Horrow JC, Lowenstein E,Hirshman C, Adkinson NF. Association of protamine IgE andIgG antibodies with life-threatening reactions to intravenousprotamine. N Engl J Med 1989; 320: 886-92.[4] Fehr J, Rohr H. In vivo complement activation by polyanion-polycation complexes: evidence that C5a is generated intra-858 P. P. Neidhart et al.vascularly during heparin-protamine interaction. Clin ImmunImmunopathol 1983; 29: 7-14.[5] Rent R, Ertel N, Eisenstein R, Gewurz H. Complement acti-vation by interaction of polyanions and polycations. J Immunol1975; 114: 120-4.[6] Siegel F, Rent R, Gewurz H. Interactions of C-reactive proteinwith the complement system. J Exp Med 1974; 140: 631—47.[7] White JV. Complement activation during cardio pulmonarybypass. N Engl J Med 1981; 305: 51.[8] Morel DR, Zapol WM, Thomas SJ, KJtain EM, Robinson DR,Moss J, Chenoweth DE, Lowenstein E. C5a and thromboxanegeneration associated with pulmonary vaso- and broncho-constriction during protamine reversal of heparin. Anesthesiol1987; 66:597-604.[9] Casthely PA, Goodman K, Fyman PN, Abrams LM, Aaron D.Hemodynamic changes after the administration of protamine.Anesth Analg 1986; 65: 78-80.[10] Sethna D, Gray R, Bussel J, Raymond M, Matloff J. Furtherstudies on the myocardial metabolic effects of protamine sulfatefollowing cardiopulmonary bypass. Anesth Analg 1982; 61:476-7.

Fatal anaphylactoid response to protamine after percutaneous transluminal coronary angioplasty

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