Anaesthesia, 1979, Volume 34, pages 183-186 CASE R E P O R T

Hereditary angioneurotic oedema

R.B. H O P K I N S O N

AND

This rare disease was first described by Quincke in 1882 and its hereditary nature was recognised by Sir William Osler in 1888. It is characterised by episodic swelling of the extremities, face and airway and recurrent abdominal pain. The non-inflammatory oedema may be accompanied by an erythematous, serpiginous rash and is usually well circumscribed. When it affects the intestine it can produce severe attacks of abdominal pain and may result in acute obstruction. Oedema of the pharynx and larynx is of special concern to the anaesthetist and has, in some series, resulted in a 30% mortality,’ though more recent papers suggest a mortality of approximately IS%.’ This form of angioneurotic oedema must be distinguished from hereditary angioneurotic oedema of allergic origin and from non-hereditary types. Lack of prodromal symptoms prior to the onset of oedema, rapid evolution of the oedema, a good clinical response to adrenaline and antihistamines, and an excellent prognosis are characteristic of these latter types. The disease is inherited as an autosomal dominant and affected patients are heterozygotes. It is thought to be caused by an abnormality of the serum inhibitor of the activated first component of complement (CI esterase inhibitor (C1 INH)). Two forms have been described: the common and the variant forms. About 85% of patients have the common form with both immunochemical and functional concentrations of C1 INH less than 5004 of

A N N E J. S U T C L I F F E

normal, and more often less than 30%.’s3 The remaining 15%, the variant form, have normal or increased levels of an antigenically identical but functionally deficient protein. The first component of complement is normally in the inactivate state in serum. But subjected to precipitating factors, such as trauma, strenuous exercise, or even anxiety it may be activated and trigger the complement c a s ~ a d e Abnormality .~ of C1 INH may result in excessive activation. Diagnosis is confirmed by the demonstration of low levels of C1 INH either immunologically or using an esterolytic technique. However, the levels of C1 INH correlate poorly with the severity of the disease. A pregnant patient is presented suffering from hereditary angioedema (HAE) who required emergency anaesthesia for Caesarean section. Case report

A 21-year-old primiparous women was admitted to Birmingham Maternity Hospital in early labour. Six months previously she had been admitted to another hospital for treatment o f an attack of HAE involving one arm. Venepuncture of the other arm resulted in extension of the complaint to that arm. Plasma C1 INH levels were found to be 0.05 gilitre (normal 0.180.26 gllitre). Of her family, two of four siblings had low C1 INH levels. The father was severely affected and undergoing prophylactic therapy. The only episode of airway obstruction that had

R.B. Hopkinson,* M B BS, FFARCS, Senior Registrar in Anaesthesia, and Anne J. Sutcliffe. MB ChB, BSc. Registrar in Anaesthesia, Birmingham Maternity Hospital. * Present address: Consultant Anaesthetist, East Birmingham Hospital, Bordesley Green East, Birmingham 9. 0003-2409/79/0200-0183 $02.00 0 1 9 7 9 Blackwell Scientific Publications

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184 R.B. Hopkinson and Anne J. Sutcliye

occurred in the family was in one sibling who had developed dyspnoea following a blow to the throat. This was said to have resolved uneventfully following treatment (unknown) by a general practitioner. At the age of 13 years the patient had an acutely inflamed appendix removed under general anaesthesia and confirmed histologically. There is no record or recollection of any anaesthetic difficulty. Upon admission continuous lumbar epidural analgesia was provided using bupivacaine. However, fetal distress and a compound presentation necessitated urgent delivery by Caesarean section for which the epidural analgesia was inadequate at that time. The patient was given a further 30 ml of magnesium trisilicate mixture BPC, and following preoxygenation anaesthesia was induced with hyoscine 0.6 mg, thiopentone 250 mg and suxamethonium 100 mg intravenously and intubated whilst cricoid pressure was applied. The patient was ventilated with oxygen 8 litresl min, nitrous oxide 4 litreslmin and 0.2% trichloroethylene. An infusion of 0.1% suxamethonium was used to maintain relaxation. Following the delivery of a healthy infant (Apgar score 9 at 1 min and 10 at 5 min) syntocinon 10 iu and chlorpheniramine 10 mg were administered intravenously. During the final stages of surgery the surgeon commented upon excessive blood loss. A bleeding time and clotting screen were performed and subsequently found to be normal. At this point administration of fresh frozen plasma was commenced. At the end of surgery, following resumption of spontaneous respiration, and there being no visible oedema of limbs, face or larynx, the patient was extubated and returned to the intensive care unit. Postoperatively she was transfused with three units of whole blood and (a total of) two units of fresh frozen plasma (FFP). Other than some mild oedema around her intravenous cannula, her recovery was uneventful and she was discharged from the unit 16 hours postoperatively.

Discussion HAE is a disease which affects not only the complement system but also the kinin-generating and fibrinolytic systems. C1 INH is an inhibitor in blood of these systems. It derives its name from its ability to inhibit the esterase activity of

the first compound of complement (Cl), which is normally present in serum in the inactive state. Many patients suffering from HAE can identify a traumatic event as precipitating an attack.’ Dental manipulation is particularly n o t o r i o u ~It . ~is postulated that trauma exposes collagen, which in turn activates the Hageman factor (XII). This in turn will trigger clotting, kinin-generation, and fibrinolysis. Plasmin, the final product of fibrinolysis will activate C1. Hence, lacking the regulation of C1 INH, the complement cascade will produce excessive amounts of vasoactive fragments of complement. It is suggested that a polypeptide fragment with kinin-like activity (C2-Kinin) is released, which increases capillary permeability, thereby causing oedema. ’ Numerous treatments have been proposed for the disease, most of which have been, at best, partially successful. These include antihistamines, ACTH, vitamins, ultraviolet light, thyroid extract, aspirin, opiates and calcium salts.’ Therapy is intended to provide prophylaxis, both long and short term, and treatment of the occasional life-threatening attack of laryngeal or intestinal oedema. Long-term prophylaxis

Inactivation of the plasma proteases such as plasmin with epsilon amino-caproic acid (EACA), which also has a C1 INH sparing effect, has been advocated but is not without risk.4, Thrombotic phenomena, muscle necrosis, slowly resolving haematoma, fatigue, muscle and abdominal pain are some of the problem^.^ Also a teratogenic effect has been demonstrated in rats,’ which reinforces the opinions of some authors that its use in pregnancy is contraindicated.’ Nor does the drug guarantee prevention of oedema. Tranexamic acid, a cyclised derivative of EACA, is more potent and convenient to use, with far fewer side-effects.8 A recent report describes the use of this drug in doses of 8 g per day from the twenty-sixth week of pregnancy, initially intravenously but then orally, for the management of abruptio p l a ~ e n t a e Its . ~ use in the management of HAE during pregnancy would not seem to be contra-indicated. Some patients with HAE show agood response to chronic androgen therapy. However, methyltestosterone causes cholestatic jaundice and

Hereditary angioneurotic oedema even the less potent hormones can cause masculinization. Danazol, an ‘impeded’ androgen has been effective in preventing these attacks in men and women using dosages of 200 mg thrice daily. l o It is, however, suggested that androgens in any form are hazardous in children and pregnant women. The question of prophylaxis in pregnancy is debatable. It is said that the disease is exacerbated in women who take the contraceptive pill. It may flare up in early pregnancy and be markedly suppressed in late pregnancy to recrudesce after delivery. Patients appear not to have severe attacks during or immediately after delivery. However, Landeman’ describes a patient whose attacks became worse towards term. Ideally purified concentrates of C1 INH should be used. This is impractical at present as its purification is expensive and its duration of survival in the circulation brief, with a half-life of only 4 days.’

Short-term prophylusis Elective surgery, especially dental extraction, is a problem for patients who have occasional attacks of HAE. Introduction of EACA or tranexamic acid, 2-3 days before surgery, is one approach. However, FFP will restore deficient C1 I N H levels and has been shown to produce an improvement within 40 min during acute attacks of HAE.” After plasma infusion C1 INH levels take from 1 to 4 days to return to their previously sub-normal levels. It appears that the relatively small incremental increase supplied by transfusion is sufficient to prevent attacks of oedema. Administration of two units of FFP 24 hr before surgery has been shown to provide safe and effective prophylaxis in these patients. It has been suggested that the increased availability of coniplement might result in an exacerbation of an attack.” There is little evidence to suggest that this theoretical possibility has posed any practical problem.

Treatment of acute attacks Neither antifibrinolytic nor hormonal agents have been shown to be of great benefit during acute attacks. Response to adrenaline, steroids, and antihistamines is mixed, though during life threatening attacks these agents are often used. *

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Indeed, it has been suggested that adrenaline in large doses (1 mg subcutaneously each hour to a total of 11 mg) may be effective when F F P is not.’ Such therapy produced subjective and objective improvement within 6 h. The use of such high doses of catecholamine in the presence of airway obstruction with associated hypoxia and carbon dioxide retention could be hazardous. As suggested above F F P has been shown to be effective in the treatment of acute attacks.1Z*14 The abdominal pain in acute attacks of HAE is caused by oedema of the bowel wall and can result in colicky abdominal pain, nausea, vomiting, toxic megacolon and unnecessary laparotomy.L4It is important that HAE be not omitted as a diagnostic consideration in the causation of abdominal pain and the acute abdomen. The patient described has not had any severe attacks of HAE, though one brother had an episode of airway obstruction following trauma to the neck. Her father has required prophylactic treatment with tranexamic acid or, more recently, danazol. As in two recent it would have been preferable to use local or regional analgesia for surgery. The urgency of the situation necessitated general anaesthesia, and tracheal intubation was deemed essential. Despite its theoretical risks, F F P would appear to be the mainstay of therapy and transfusion was commenced as soon as possible, and an antihistamine given. Fortunately no oedema developed. Had it done so further therapy might have been necessary. Neither EACA nor tranexamic acid administration is without risk and it is suggested that haematological advice should be sought before its use. It is vital that should obstruction develop the airway be secured, as soon as possible, preferably by tracheal intubation but if not by tracheostomy. As obstruction develops, patients notice dysphagia and then a change in tone of their voice due to swelling of the larynx. If possible this should be evaluated, using indirect laryngoscopy, by an experienced ear, nose and throat surgeon. Intubation may be requited for 24 to 12 h. The conclusion of some authors16 that ‘a partial airway obstruction of only 3-4 h duration is best managed by careful observation, institution of EACA therapy and the traditional lherapy of oedema (epinephrine, etc.)’, should

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be questioned. The assessment of such cases requires an extremely high standard of vigilance on the part of nursing and medical staff. It would seem preferable to secure the airway before obstruction becomes severe-as it might very quickly-and then to institute therapy. HAE is a relatively rare disease. Landeman in his review of the world literature documented 414 cases in fifty-five families. In consequence the gravity of the disease is often not appreciated by the attendant clinician, as in this case when the significance of the patient’s history was not recognised until emergency anaesthesia was required. It is important that junior anaesthetists who may be invited to treat such cases presented as surgical emergencies be well versed in the potential complications and their therapy. This will normally consist of avoiding tracheal and laryngeal trauma if at all possible and prophylaxis with FFP.

Summary Hereditary angioedema (HAE) is characterised by episodic swelling of the extremities, face, larynx and recurrent abdominal pain, which can mimic the acute abdomen. Trauma of the larynx may result in acute airway obstruction. The management of emergency anaesthesia for Caesarean section of a patient with documented HAE is described and the special problems presented discussed. The methods of prophylaxis available are considered and the use of fresh frozen plasma advocated.

Key words AIRWAY; obstruction, hereditary angioneurotic oedema. ANAESTHESIA ; obstetric. COhlPLICATIONS; hereditary angioneurotic oedema. GENETIC FACTORS; hereditary angioneurotic oedema.

Acknowledgment The authors thank Mr Henry Roberts for permission to present his patient.

References I . LANDEMAN, N.S. (1962) Hereditary angioneuretic edema. I. Case reports and review of the literature. Journal of Allergy, 33, 316. J.A. & ATKINSON,J.P. 2. FRANK,M.M., GELFAND, (1976) Hereditary angioedema: the clinical syndrome and its management. Annals of Internal Medicine, 84, 580. L. & CULTER,R. (1975) 3. ROTH, M., SCHREIER, Adrenalin treatment for hereditary angioneurotic edema. Annals of Allergy, 35, 175. 4. GWYNN, C.M. (1974) Therapy in hereditary angioneurotic oedema. Archives of Disease in Childhood, 49, 636. 5 . 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. 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. J., KLEMPERER, 7. ROSEN,F.S., ALPER,C.A., PENSKY, M.R. & DONALDSON, V.H. (1971) Genetically determined heterogeneity of the C1 esterase inhibitor in patients with hereditary angioneurotic edema. Journal of Clinical Investigation, 50,2143. A.L., AUSTEN,F.K. & ROSEN,F.S. (1972) 8. SHEFFER, Tranexamic acid therapy in hereditary angioneurotic edema. New England Journal of Medicine, 281, 452. 9. ASTEDT, B. & NILSSON,I.M. (1978) Recurrent

abruptio placentae treated with the fibrinolytic inhibitor tranexamic acid. British Medical Journal, 1, 756. 10. GELFAND, J.A., SHERINS,R.J., ALLING,D.W. & FRANK,M.M. (1976) Treatment of hereditary

angioedema with danazol. New England Journal of Medicine, 295, 1444. 11. ROSEN, F.S. & AUSTEN,K.F. (1976) Androgen therapy in hereditary angioneurotic edema. New England Journal of Medicine, 295, 1476. 12. PICKERING, R.J., KELLY, J.R., GOOD, R.A. & GEWURTZ,H. (1969) Replacement therapy in hereditary angioedema. Successful treatment of two patients with fresh frozen plasma. Lancet, 1, 326. V.H.(1972) Therapy of ‘the neurotic 13. DONALDSON, edema’. New England Journal of Medicine, 286,835. 14. BECK,P., WILLIS,D., DAVIS,G.T., LACHMANN, P.J. & SUSSMAN, M. (1973) A family study of hereditary

angioneurotic edema. Quarterly Journalof Medicine, 42, 317. 15. ABADA,R.P. & OWENS,W.D. (1977) Hereditary

angioneurotic edema, an anesthetic dilemma. Anesthesiology, 46,428. 16. Grnns, P.S., LOSASSO,A.M., MOORTHY,S.S. & HUTTON,C.E. (1977) The anesthetic and perioperative management of a patient with documented hereditary angioneurotic edema. Anesthesia and Analgesia: Current Researches, 56. 571.

Hereditary angioneurotic oedema.

Anaesthesia, 1979, Volume 34, pages 183-186 CASE R E P O R T Hereditary angioneurotic oedema R.B. H O P K I N S O N AND This rare disease was firs...
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