Successful heparin desensitization after heparin-induced anaphylactic shock

Thrombosis

Research,

Pergamon

Volume 79, Nos. 5/6, pp. X23-526, 1995 Copyright 8 1995 Ekevier Science Ltd F&ix-in the USA All rights reserved OC49-3848/95 $9.50 + .oO

0049-3848(95)00142-S

BRIEF SUCCESSFUL

HEPARIN

COMMUNICATION

DESENSITIZATION ANAPHYLACTIC

AFIXR SHOCK

HEPARIN-INDUCED

Adel Y. Al-Eryani*, Abdul-Kareem Al-Momen*, Desouky F. Fayed**, and Abdul-Kader Allam* *Department of Medicine and **Pharmacy, College of Medicine King Kbalid University Hospital, King Saud University, P.O. Box 2925, Riyadb 11461, Saudi Arabia

(Received 16 January 1995 by Editor J. Swedenbofg; revisedaccepted

&

4 July 1995)

Anaphylactic reactions to heparin are rare. The incidence of such reaction has further declined after the introduction of the highly purified heparin. We recently encountered a patient with unstable angina who developed anaphylactic reaction after intravenous injection of bovine mucous heparin sodium. The patient was successfully desensitized before coronary bypass surgery, a procedure that requires the administration of large doses of heparin.

CASE REPORT A 34-year-old male was admitted to the coronary care unit with one month history of exertional chest pain that has increased in severity few days prior to admission. After the further usual evaluation, the patient was diagnosed and treated as unstable angina. The treatment included the administration of intravenous bovine mucous heparin sodium (Multiparin) from CP Pharmaceutical (UK) which also contains 0.15 % chlorocresol as a preservative. A loading dose of 5000 IU/5 ml was administered intravenously to be followed by intravenous infusion of 1000 IU of heparin/lO ml of dextrose water per hour. Approximately 5 min after the loading dose, the patient developed generalized severe pruritic erythematous circumscribed skin rashes and severe burning sensation in the infusion site of heparin which was red, warm, and oedematous. This was accompanied by dyspnoea and clinical evidence of bronchospasm. The systolic blood pressure dropped from 120 mmHg to 85 mmHg over the following 5-10 min. Nitroglycerin infusion which was held because of the low blood pressure was restarted an hour later with no

Key words:

Heparin, anaphylaxis, desensitization 523

524

HEPARIN DESENSITIZATION

Vol. 79, Nos. 5/6

adverse reactions. The other medicines, namely, oral propranolol and aspirin which were given approximately 60 min before the above described reaction in doses of 10 mg and 300 mg, respectively, were continued as planned with no adverse reactions. The heparin infusion was immediately stopped and intravenous hydrocortisone 200 mg, promethazine HCl 50 mg, and nebulized salbutamol were given to treat the allergic reaction. We did not give adrenaline because of the patient’s underlying disease (unstable angina). Thrombocytopenia which is a well known adverse reaction to heparin therapy was not observed in this patient. After a coronary angiography the patient was put on the maximum tolerable antianginal treatment. However, he remained symptomatic and he had to go for coronary bypass grafting, a procedure which requires the administration of large doses of heparin. Since porcine heparin and other porcine-derived dctgs are not used in Saudi Arabia and other few Islamic states, only bovine heparin was available; for the procedure. A skin test done to find out the cause of the allergic reaction was positive (as manifested by redness, hotness and itching) 10 min after the intradermal injection of preservative-free heparin 500 IU in 0.2 ml of normal saline. Positive reactions were also observed after intradermal injection of 500 IU chlorbutol preserved heparin and 500 IU of chlorocresol preserved heparin given in two distant sites in the right and left forearms. No reaction developed after the intradermal injection of control preservative-free normal saline. It was concluded that heparin is the cause of the anaphylactic reaction. Immunoglobulin E level and heparin-associated antibodies were not done. Our patient underwent a desensitization procedure. The clinical condition, the procedure and the possible side effects were explained and discussed with the patient and informed consent was obtained. Bovine mucous heparin sodium 100 IU diluted in 1000 ml of normal saline was intravenously infused over the first 24 hr, followed by 1000 IU diluted in 1000 ml of normal saline in the second 24 hr, then 5000 IU diluted in 1000 ml of normal saline over the next 24 hr. The patient was then kept on subcutaneous heparin 5000 IU twice daily till the time of surgery. The intraoperative and postoperative course was uneventful with no allergic or other adverse reactions reported.

DISCUSSION Commercially available heparin is a highly acidic, anionic, sulphated, mucopolysaccharide (glycosoaminoglycans) derived from beef lung or pork intestinal mucosa (1). Since its first clinical use as anticoagulant in the late 193Os, hypersensitivity reactions in general, and anaphylactic reaction in particular, were very rarely reported (2-10). None of the 440 patients reported by Murray had anaphylaxis and only in one case out of 30,OOtl cases of heparin use was anaphylactic reaction reported in the analysis of Crafoord and Jorpes (11,12). The incidence of such reactions has become even more rare due to marked improvement of the manufacturing processes and the resultant production of highly purifid heparin (7). It is probable that most of the allergic reactions were caused by animal protein contaminants (7,13). Both local and systemic hypersensitivity reactions of the immediate and delayed types were described (2-10,1.2,!3). Most of these reactions are usually short-lasting and nonfatal. Nevertheless, fatal anaphylactic reactions have been reported (5). It is believed that these reactions are caused by heparin and/or its commonly used preservatives chlorocresol and chlorbutol (5,12-15,19). Occasionally, these reactions were avoided by switching from bovine to porcine heparin (6,13) or vice-versa. However, cross reactivity is not uncommon and this procedure should be pursued with utmost precautions. Due to religious considerations, porcine heparin is not available in Saudi Arabia. Most of the cases of heparin hypersensitivity were

525

HEPARIN DESENSITIZATION

Vol. 79, Nos. 516

treated by stopping the drug or by replacing it with an oral anticoagulant. However, this might not be feasible in haemodialysis patients and the bypass procedure used during open heart surgery particularly in situations where alternative anticoagulants like defibrinogenating agents or synthetic thrombin inhibitors are not available. Desensitization procedures which were successfully used in various types of allergens including drugs (but not heparin) can be, as shown in this report, of potential help in patients for whom the use of alternative anticoagulant is not feasible. In patients who are not going to receive heparin immediately after the desensitization procedure, it is recommended to keep them on a small dose of subcutaneous heparin or to repeat the skin test before further administration of intravenous heparin. The latter recommendation is also true for those who need readministration of heparin. In case the skin test is positive, it is likely that a tolerance state rather than true desensitization was induced and it is recommended to either use an alternative anticoagulant or repeat the above described procedure.

REFERENCES 1.

JAQUUES, L.B. 350-353, 1976.

Addendum: The discovery of heparin.

2.

O’DONNELL, Br J Dermatol.

3.

DROUET, M., LE-PABIC, F., LE-SELLIN, J., BONNEAU, J.C., SABBAH, A. Allergy to heparin. Special problems set by pregnant women. Allergol Zmmunopathol (Madr.), 20, 225-229, 1992.

4.

RIVERS, J.K. and GIANOUTSOS, M.P. Delayed hypersensitivity subcutaneous heparin. Aust N 2 J kg. 61, 865868, 1991.

5.

HANCOCK, B.W. and NAYSMITH, A. heparin. Br Med J. 3, 746-747, 1975.

6.

CURRY, N., BARDANA, E.J. and PIROFSKY, Med. 182, 744-745, 1973.

7.

TURCOlTE, J.G., and RICHARD, Arch Surg. 90, 375-379, 1965.

8.

BERNSTEN,

9.

CHERNOFF, A. Anaphylactic reaction following injection of heparin. 242, 315, 1950.

N EngZ J Med.

10.

BARY, J.G. Jr. Heparin allergy and cardiopulmonary Vast Anesth. 7, 505-506, 1993.

J Cardiothorac

B.F. and TANY, C.Y. 129, 634-636, 1993.

H.

Semin Thromb Hemost. 4,

Delayed hypersensitivity

O.K.

Hypersensitivity

reaction to heparin.

reaction

to

to chlorocresol-preserved

B. Heparin sensitivity.

Arch Intern

Heparin reactions with vascular disease.

Anaphylaxis to heparin sodium.

JAMA, 161, 1379, 1956.

bypass [Letter].

526

11.

HEPARIN DESENSITIZATION

MURRAY, 307-325,

G.D.W.

Vol. 79, Nos. 6/6

Heparin in surgical treatment of blood vessels. Arch Surg. 40,

1940;.

12.

CRAFOORD, C. and JORPES, E. Heparin as prophylactic against thrombosis. 116, 2831-2835, 1941.

13.

ZINN,

14.

AINLEY, E.J., MACKIE, I.G. and McARTHUR, D. Adverse reaction to chlorocresolpreserved heparin (Letter). Lancet, 1, 705, 1977.

15.

DUX, S., PITLIK, S., PERRY, G., ROSENFELD, J.B. Hypersensitivity chlorbutol-preserved heparin (Letter). Lancet, 1, 149, 1981.

16.

MISHLER, J.M. Adverse reactions associated with heparin therapy for ischemic heart disease and thrombophlebitis. Am J Hosp Pharm. 30, 1158-1161, 1973.

17.

JAMA,

W.J. Side reactions of heparin in clinical practice. Am J Curdiol. 14, 36, 1964;

RAJKA,

G. and SKOG, E. Question of heparin hypersensitivity.

Actu Derm Vemol.

42, 27, 1962.

18.

MARSH,

19.

O’LOOLE,

B.T. R.D.

Preservatives in heparin. “Chlorocresol”.

reaction to

Lance& 1, 860, 1977.

Ann Intern Med. 74, 749, 1976.