BRIEF REPORT

SEVERE BRONCHIAL REACTION AND CARDIO-PULMONARY ARREST FOLLOWING INTRAVENOUS INJECTION OF HYDROCORTISONE IN A NON-ATOPIC, NON-ASPIRIN

SENSITIVE ASTHMATIC

Kevin Ward and John S. Prichard

Department of Medicine, Trinity College Medical School, St. James's Hospital, Dublin 8.

Summary A 56 year old woman who was a non-atopic,

non-aspirin sensitive asthmatic developed a sev- ere bronchial and cardiovascular reaction follow- ing intravenous injection of hydrocortisone. The reaction resulted in respiratory and cardiac arrest.

Introduction The intravenous injection of hydrocort isone is

an important component of the treatment of severe asthmatic attacks (Beeson and McDermott, 1975; Editorial, 1975). Fortunately, severe reactions to parenteral steroids after such use are extremely rare but recently reports have appeared. In 1974, Mendelson et al described an anaphylaxis-l ike reaction fol lowing the administration of intraven- ous steroid to an atopic asthmatic patient. Sub- sequently, 2 similar cases were reported by Kounis (1976) but the exact nature of the pat- ients' asthma was not defined. Most recently Partridge and Gibson (1978) described acute bronchial obstruction induced by intravenous steroids in 2 aspirin sensitive asthmatics.

Case Hislory The patient was a 56 year old woman who had

a 25 year history of bronchial asthma and who had undergone a nasal polypectomy at age 22. She had not suffered from asthmatic symptoms or diseases of the chest during childhood. Also, she had never shown evidence of eczema, aller- gic rhinitis, migraine or hereditary angioedema. She had taken a variety of drugs, including aspirin, on many occasions without any untoward results. Treatment of her asthma consisted of regular use of Medihaler-lso Inhaler ( isoprenaline sulphate, 0.08 mg/dose : Riker LH) and a self administered injection of 20 i.u. of ACTH (Acthar Gel : Armour Limited) on alternate days. She did not use her inhaler to excess even during asth- matic attacks and had received intravenous hydro- cortisone previously on one occasion only. This was prior to anaesthesia for a bronchoscopy to investigate haemoptysis. No reaction to the hydro- cortisone had occurred and no cause had been

found for the haemoptysis which had not re- curred.

On the day on which the severe reaction to hydrocortisone occurred, the patient attended hospital for treatment of an asthmatic attack She had been relatively asymptomatic until 24 hours previously, but one hour prior to admission her symptoms had worsened considerably. Her inhaler had given her no relief, although she had not taken more than 4 puffs (0.32 mg isoprenaline in total) in the 3 4 hours preceding admission. At the hospital she was seen to be in some distress. She was able to converse, but there were fre- quent pauses in her speech. She was afebrile, her pulse was 100/minute and regular, the blood pressure was 120/80 and the respiratory rate 25/minute. There was an audible wheeze and ausculation revealed diffuse inspiratory and ex- piratory rhonchi. The chest x-ray showed no evidence of pneumonia. PaO~ was 59 tort and PaCO= was 49 torr.

The patient was given 100 mg of Efcortelan Soluble (hydrocort isone sodium succinate ester: Glaxo Limited) intravenously. Within 2 minutes, her breathing had become laboured and bron- chial obstruction increased. She became cyan- osed and pulseless. She was treated promptly for cardiac and respiratory arrest and required artificial venti lation for 40 minutes with a slow intravenous drip of salbutamol (1-2 mcg/minute) . Subsequently, a normal pulse, blood pressure and spontaneous ventilation were established, but the cardio-pulmonary arrest was not recog- nised as being a consequence of the hydrocor- tisone injection and it was decided to continue steroid therapy. A second intravenous injection of 500 mg of Efcortelan Soluble was given 8 hours after. Again, she promptly developed severe bronchial obstruction, hypotension, tachy- cardia and cyanosJs. She was treated immediately with aminoph'ylline 250 mg i.v. and chlorpheniram- ine 10 mg i.v. and recovered rapidly.

Over the fol lowing 2 weeks, the patient made an uneventful recovery and was discharged from hospital. At no time during her convalescence

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SEVERE BRONCHIAL REACTION IN ASTHMA 125

has she been treated with steroids, either intra- venously or orally, but she has continued to take ACTH without untoward effect.

Investigations on numerous occasions showed that there was no sputum or blood eosinophilia. Prick tests to a number of common allergens produced no positive reaction and plasma IgE was 27 i.u. Patch tests with hydrocortisone sod- ium succinate from the same batch as that used in the patient were carried out and read after 24, 48 and 72 hours (Hjorth, 1963). All were negative. Aspergillus precipitins were not present in the serum. An assessment was made of the comple- ment pathway. C, esterase inhibitor was 46 mg/ 100 ml. Other results were also normal (C~ 136 mg/dl, C, 33 mg/dl, C~ 22 rag/all). After 3 weeks, aspirin sensitivity was assessed by a provocation test. The patient was given a dose of soluble aspirin each morning after an overnight fast. Pulmonary function was assessed during the subsequent hours by spirometry. No evidence of an asthmatic attack occurred after aspirin doses which were increased progressively from 10 to 600 mg.

The batch of Efcortelan Soluble sodium suc- cinate and water for injection from which the injections had been taken were returned to the manufacturer for chemical analysis, assessment of pyrogen content and bacteriological investiga- tions. No abnormality of either component was found.

Discussion The case of a severe reaction to intravenous

steroids which we report occurred in an asthmatic patient who was neither aspirin-sensitive nor atopic, Thus it differs from the previously re- ported episodes and widens the spectrum of disease wherein this dangerous reaction may occur, The reaction is particularly dangerous both because of its rarity and because it mimics the very condition which is being treated.

The reports in the literature and the case de- scribed here raise questions which cannot yet be answered. The most important of these are whether the reaction is due to the steroid com- ponent of the injection and whether the reaction is allergic in nature ?

In each of the cases described (Mendelson et al, 1974; Kounis, 1976; Partridge and Gibson, 1978) there has been some doubt as to whether the reaction was due to the steroid component of the injection. Efcortelan (used in our patient) is supplied as pure hydrocortisone sodium suc- cinate ester powder and contains no preservative or other substance. It is reconstituted in Water for Injection B.P. Careful analysis revealed that both the batch of the drug and of the water were normal and uncontaminated. Therefore, there is no reason to doubt that the steroid was the

causal agent. It might seem surprising that a hormone normally present in the circulation could cause such a reaction. However, immediately after intravenous injection combination with nor- mal carriers proteins in the serum has not yet taken place.

Reactions which are al lergic in nature can certainly take place fol lowing parenteral use of steroids (Hollander, 1953; Kendall, 1958; King, 1960; O'Garra, 1962; Comaish, 1969) and, in this case, the possible sensitising effect of the patient's previous ACTH therapy might be of importance. However, the reactions described always occur more than 40 minutes after adminis- tration and are quite unlike the effects we are discussing. Kendall (1958) reported one case of bronchial obstruction in a series of 6,700 injec- tions which had produced 73 reactions in all. O'Garra (1962) had 3 cases of bronchial obstruc- tion in 4,000 injections and King (1960) one case in 2,000.

There is now no consistent pattern of allergic abnormality in the cases of immediate reaction to intravenous steroids which have been de- scribed in the literature (Mendelson et al, 1974; Kounis, 1976; Partridge and Gibson, 1978). Atopic, non-atopic and aspirin-sensitive asthmatics are all included and even when patch tests are posi- tive these may show marked inconsistency with the results of intravenous challenge (Partridge and Gibson, 1978). In the case we have de- scribed, the clinical presentation was highly suggestive of an anaphylactic reaction, but no abnormal allergic features could be detected and the patient did not have hereditary angioedema (Brasher et al, 1975). The possibil ity arises, therefore, that the reaction is pharmacological or pathological and that a component of the injection might itself be causing histamine re- lease or acting directly upon the smooth muscle of the vascular beds and bronchi. A variety of such non-allergic reactions may occur following high doses of steroids and the possibility of such mechanisms have been discussed by Kounis (1976) and by O'Garra (1962).

References

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Brasher, G. W., Starr, J. C., Hall, F. F. and Spiek- erman, M. 1975. Complement component analy- sis in angioedema. Arch. Dermatol. 111, 1140.

Comaish, S. 1969. A case of hypersensitivity to Corticosteroids. Br. J. Derm. 81, 919.

Editorial. 1975. Management of acute asthma. Br. Med. J. iv, 65.

126 IRISH JOURNAL OF MEDICAL SCIENCE

Hjorth, N. 1963. Routine patch tests. Transactions of the St. Johns Hospital Dermatology Society (London). 49, 99.

Hollander, J. L. 1953. Proceedings of the 8th International Congress of Rheumatic Diseases. Geneva. Medicine et Hygiene. pp. 143-145.

Kendall, P. M. 1958. Untoward effects following local hydrocortisone injection. Ann. Physical Med. 4, 170.

King, R. A. 1960. A severe anaphylactoid reaction to hydrocortisone. Lancet ii, 1093.

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Mendelson, L. M., Meltzer, E. D. and Hamburger, R. N. 1974. Analphylaxis-like reactions to cor- ticosteroid therapy. J. Allergy Clin. tmmunol. 54, 125.

O'Garra, J. A. 1962. Anaphylactic reactions to hydrocortisone injections. Br. Med. J. i, 615.

Partridge, M. R. and Gibson, G. J. 1978. Adverse bronchial reaction to intravenous hydrocorti- sone in two aspirin-sensitive asthmatic patients. Br. Med. J. i, 1521.