Anaesthesia, 1977,Volume 32, pages 265-267 CASE R E P O R T
Laryngeal oedema due to hereditary angioedema
A . G. H A M I L T O N , A . R. J. B O S L E Y
Hereditary angioedema (HAE) is a rare but well-described condition first recognised by Osler' in the last century. The disorder is inherited as an autosomal dominant and is due to abnormally low levels of the plasma inhibitor for the activated first component of complement (CT-inhibitor).z The exact pathogenesis of the oedema is not fully understood, but attacks are probably precipitated by local exhaustion of this inhibitor as a result of consumption by any of the plasma enzymes with which the inhibitor can react. The absence locally of all inhibitor permits spontaneous activation of the initial stages of the complement system and leads to the production of a kinin-like peptide which causes oedema by increasing vascular ~ermeability.~ A full description of HAE has recently been the subject of an excellent re vie^.^ Unlike other forms of angioedema, there is no known allergic basis to HAE and not only antihistamines, but also adrenaline and adrenal cortico~teroids,~are ineffective in treating this disorder. However, epsilon aminocaproic acid (EACA)3*6- tranexamic acidg* O and fresh frozen plasma (FFP)4* I * I have been reported to be effective in prophylaxis and therapy. There is, as yet, n o complete understanding of what initiates the attack of oedema, but the most frequent precipitants are trauma and
D. J . BOWEN
emotional stress. There is often no obvious precipitating factor for what may bealife-threatening attack of oedema and this is illustrated by the following case history. Case report
The patient, a 29-year-old man, was admitted with severe oedema of the face and eyelids, dysphagia and hoarseness. The swelling had started 8 hours earlier and had awoken him from sleep. No obvious cause could be elicited for the oedema but his past history revealed similar recurrent attacks of facial swelling, though less severe, since the age of 14 years. These attacks had been diagnosed as angioneurotic oedema and had apparently always responded within a few hours to treatment with chlorpheniramine maleate (Piriton), adrenaline and hydrocortisone. This admission was the first occasion on which he had developed hoarseness. From the age of 7 years he had also suffered recurrent attacks of abdominal pain and vomiting which had been diagnosed as the periodic syndrome. On admission, treatment was started with chlorpheniramine, adrenaline and hydrocortisone, but despite this the oedema progressively worsened and 5 hours after admission he was semicomatose with severe respiratory distress
A. G. Hamilton,* FFARCS, Senior Registrar, A. R. J. Bosley,? MRCP, Registrar and D. J. Bowen, FFARCS, Consultant, Department of Anaesthesia, Royal Hants. County Hospital, Winchester. Present addresses: *Anaesthetic Department, Southampton General Hospital, Southampton. TDepartment of Child Health, Llandough Hospital, Cardiff.
A . G.Hamilton, A . R.J . Bosley and D . J . Bowen
due to upper airway obstruction. Laryngoscopy at this stage revealed gross pharyngeal and laryngeal oedema and it was only with great difficulty that intubation was performed with a 6 mm tracheal tube. This temporarily relieved the obstruction but within 5 minutes the tube became blocked and the patient was deeply cyanosed. The patient rapidly regained consciousness after emergency tracheostomy and, during the next 48 hours, the oedema subsided. The tracheostomy tube was removed 7 days after admission. During this time the patient revealed that his father had died from acute laryngeal oedema at the age of 42 years. The diagnosis of HAE was confirmed in our patient when his serum CT-inhibitor level was shown to be only 27% of normal, and prophylactictherapy was started at once with EACA 3 g every 4 hours. Three days later clinical signs of deep vein thrombosis developed in the left calf. The patient was treated with anticoagulants and, although 3 weeks later a phlebogram showed no evidence of deep vein thrombosis, anticoagulation was maintained for a further 2 months. Treatment with EACA was continued during this period but after 3 months this was changed to tranexamic acid 0.5 g qds which has been continued up to the present time. The patient was discharged from hospital 4 weeks after admission but since then he has been admitted with facial swelling on 6 more occasions, once after a dental injection. On each occasion he has received 2 units of FFP and, during one admission, 2 extra units were required. The swelling has settled each time without the development of respiratory d f i culty. He has also been admitted once for dental extractions under general anaesthesia. Immediately pre-operatively he received 2 units of FFP. Oral intubation was performed with an 8.5 mm cuffed tracheal tube and no throat pack was used. He was observed postoperatively in the intensive care unit but no facial or laryngeal oedema developed. The patient’s family has been investigated recently. His mother and two sisters are unaffected as are three of his four children. However, his youngest child, a boy aged 8 months, has a serum CT-inhibitor level of only 25% but so far has shown no symptoms of
Discussion HAE is characterised by recurrent, acute, circumscribed oedema of the skin, subcutaneous tissue or mucous membranes and most conimonly affects the skin of the face or the limbs. Involvement of the mucous membranes of the larynx causing laryngeal oedema is much less common but far more serious. Oedema of the gastro-intestinal tract with abdominal colic, diarrhoea and vomiting often leads to laparotomy to exclude intestinal obstruction. Symptoms of HAE usually begin in childhood and the acute attacks may last from a few hours up to 4 days, with periods of remission ranging from days to years. Although many attacks of swelling are not clearly related to a precipitating event, oedema is produced in about half of the patients following direct blunt trauma, although major surgical procedures have often been performed without complications.’ Because of the potential risk of oedema causing obstruction of the airway, the dangers of dental trauma and tonsillectomy have been repeatedly emphasised. Acute laryngeal oedema is the cause of the inordinately high mortality associated with HAE. In a review of the literature, Landermans found 414 patients described as having HAE, and 100 of these had died from laryngeal obstruction, generally in the third decade of life. Reports of individual families afflicted with the disorder have revealed a mortality as high as 54% (15 of 28 affected)12 due to laryngeal oedema. Greater understanding of the pathogenesis of HAE has led to two different approaches to the management of the condition. The first is by use of the antifibrinolytic agent EACA and its analogue tranexamic acid. These agents inhibit activation of the first component of complement but in addition they inhibit the activation of the plasma proteases with which Ci-inhibitor reacts, thus producing an ‘inhibitor-sparing’ e f f e ~ t .EACA ~ has been reported to be successful in the treatment of an acute attack of oedema’ and has been shown to reduce the frequency and severity of attacks when used pr~phylactically.~~~ It has also been used successfully to prevent oedema during oral surgery.* Tranexamic acid has been shown to reduce the frequency and severity of acute attacksg*’O with fewer side effects
Laryngeal oedema due to hereditary angioedema than EACA. The risk of thrombosis must be considered with these drugs, and our patient, whilst receiving EACA developed all the classical clinical signs of a deep vein thrombosis although a phlebogram later revealed a normal venous system. The frequency and severity of his attacks of oedema have not changed significantly since starting treatment with EACA and tranexamic acid. The second approach to the management of HAE is by the intravenous administration of FFP which has been reported to terminate acute attacks of edema,^^'^ and also prevent oedema during dental surgery.” FFP acts by restoring satisfactory levels of the missing inhibitor, although this technique is theoretically dangerous because substrates are supplied which might lead to production of the kinin which causes increased vascular permeability. l 4 In our case, no oedema followed dental trauma when FFP was given before and during surgery, but when plasma was not used a dental injection was followed by an attack of facial swelling. It is also the patient’s opinion that the acute attacks of oedema subside more rapidly when he is treated with FFP. This evidence, although from only one subject, appears to support the use of FFP both prophylactically and in the termination of an acute attack. The authors would confirm that its use should be considered in these patients, either prophylactically for any surgery of the head and neck, or therapeutically in an acute attack of HAE which does not improve rapidly and spontaneously. Summary
A case is reported in which a young man suffering from hereditary angioedema was admitted with severe airway obstruction due to gross pharyngeal and laryngeal oedema. Tracheostomy was necessary. The rationale of treatment with epsilon aminocaproic acid, tranexamic acid and fresh frozen plasma is discussed. The patient subsequently underwent dental extractions under general anaesthesia with tracheal intubation without complications. Key words INTENSIVE CARE; hereditary angioedema. LARYNX; oedema.
Acknowledgment The authors wish to acknowledge the courtesy shown by Dr D. A. F. McGill, FRCP, under whose care this patient was admitted. References 1. OSLER, W. (1888) Hereditary angioneurotic edema.
American Journal of the Medical Sciences, 95, 362. V.H. & EVANS,R.R. (1963) A bio2. DONALDSON, chemical abnormality in hereditary angioneurotic edema. Absence of serum inhibitor of C’I-esterase. American Journal of Medicine, 35, 37. P.J. (1971) K. & LACHMANN, 3. HADJIYANNAKI, Hereditary angio-oedema: a review with particular reference to pathogenesis and treatment. Clinical Allergy, 1, 221. 4. BECK,P., WILLS,D., DAVIES,G.T., LACHMANN, P.J. & SUSSMAN,M . (1973) A family study of hereditary angioneurotic oedema. Quarterly Journal of Medicine, 42, 3 17. N.S. (1962) Hereditary angioneurotic 5. LANDERMAN, edema. Journal of Allergy, 33,316. 6. FRANK, M.M., SERGENT,J.S., KANE, M.A. & ALLING.D.W. (1972) Epsilon aminocaproic acid therapy of hereditary angioneurotic edema. A double-blind study. New England Journal of Medicine, 286, 808. 7. NILSSON,I.M., ANDERSON.L., BJORKMAN, S.E. (1966) Epsilon aminocaproic acid (E-ACA) as a therapeutic agent based on 5 years’ clinical experience. Acta Medica Scandinauica, Suppl. 448. 8. PENCE, H.L., EVANS, R., GUERNSEY, L.H. & GERHARD, R.C. (1974) Prophylactic use of epsilon aminocaproic acid for oral surgery in a patient with hereditary angioneurotic edema. Journal of Allergy and Clinical Immunology, 53, 298. H., 9. LUNDH, B., LAURELL,A.-B., WETTERQVIST, WHITE,T. & GRANERUS, G. (1968) A case of hereditary angioneurotic oedema, successfully treated with e-aminocaproic acid. Studies on C’1 esterase inhibitor, C’1 activation, plasminogen level and histamine metabolism. Clinical and Experimental Immunology, 3, 733. 10. SHEFFER, A.L., AUSTEN,K.F. & ROSEN,F.S. (1 972) Tranexamic acid therapy in hereditary angioneurotic edema. New England Journal of Medicine, 287, 452. I I . JAFFE, C.J., ATKINSON, J.P., GELFAND,J.A. & FRANK,M.M. (1975) Hereditary angioedema: The use of fresh frozen plasma for prophylaxis in patients undergoing oral surgery. Journal of Allergy and Clinical Immunology, 55, 386. J.R. 8c CROWDER, T.R. (1917) Five 12. CROWDER, generations of angioneurotic edema. Archiues of Internal Medicine, 20, 840. R.J., KELLY, J.R., GOOD, R.A. & 13. PICKERING, GEWURZ,H. (1969) Replacement therapy in hereditary angioedema. Successful treatment of 2 patients with fresh frozen plasma. Lancet, E, 326. V.H. (1972) Therapy of ‘The Neurotic 14. DONALDSON, Edema’. New England Journal of Medicine, 286,835.