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Successful perioperative management of a patient with C1 esterase inhibitor deficiency with a novel bradykinin receptor B2 antagonist.

C1 esterase inhibitor deficiency is a hereditary condition where reduced activity of C1 inhibitor leads to episodic angioedema, often triggered by stress, trauma and surgery. Dental surgery carries one of the highest risks of precipitation of an attack with potential for airway oedema and asphyxiation (1,2). Management of such cases requires careful preoperative planning and often requires the use of a C1 esterase inhibitor concentrate as prophylaxis. Recent laboratory research into the pathophysiology of hereditary angioedema (HAE) has identified bradykinin as a crucial vasoactive compound in the pathophysiology of attacks (3). This has led to the development of icatibant (Firazyr, Shire, North Ryde, NSW), a selective bradykinin receptor 2 antagonist that has shown promising results in the clinical setting (4). Icatibant has current Australian Therapeutic Goods Administration approval for symptomatic treatment of acute attacks of HAE in adults, although it is currently unlicensed in Australia for prophylactic use. We present the successful short-term prophylactic use of this drug in the perioperative setting.


A 28-year-old female with previously diagnosed C1 esterase inhibitor deficiency was referred to our hospital for removal of wisdom teeth. The patient was seen preoperatively by an immunologist, maxillofacial surgeon and anaesthetist for pre-operative planning. The patient gave written informed consent to this report.

The patient described her first episode of angioedema at age two with recurrent episodes of angioedema causing abdominal pain and hand swelling since then. She was diagnosed at the age of 16 as having sporadic onset C1 esterase inhibitor deficiency by her immunologist. There was no immediate or extended family history of angioedema. The attacks occurred at a frequency of two to three per year and were triggered by stress and sustained pressure on the hands.

She described two episodes of facial oedema, with one of these episodes involving her airway at age 22. This manifested as hoarseness only and she had not presented to a hospital for treatment. She had only had one presentation needing hospitalisation, which was for severe abdominal pain.

She had no other medical co-morbidities and was otherwise fit and well. Her only medication was an Implanon (Merck Sharp and Dohme, North Ryde, NSW) implant (a synthetic progestogen) for contraception. She had no known allergies. Past surgical history included dental fillings, which had been carried out uneventfully with a six-week course of pre-procedure danazol.

Preoperative investigations were unremarkable except for a reduced C4 level of 0.041 g/l (0.1 to 0.3 g/l), a reduced C1 inhibitor level of 62 mg/l (195 to 440 mg/l) and a reduced C1 inhibitor activity level of 107 u/l at 37C (477 to 923 u/l), all of which confirmed the diagnosis of C1 esterase inhibitor deficiency.

On the day of surgery the patient was given subcutaneous 30 mg icatibant (a bradykinin antagonist) one hour prior to the procedure as per the treating immunologist. Informed consent was obtained from the patient for the use of the drug. Arrangements were also made to have C1 esterase concentrate readily available if needed. Administration of icatibant was uneventful with no local or systemic reaction.

Following premedication with midazolam 2 mg and fentanyl 100 [micro]g, anaesthesia was induced with propofol using target-controlled infusion (6 [micro]g/ml). Upon attainment of an adequate depth of anaesthesia, a size 3 reinforced laryngeal mask airway was gently inserted and secured in place. Anaesthesia was maintained with target-controlled infusion of propofol. She received morphine 10 mg and intravenous parecoxib 40 mg intraoperatively for analgesia. She also received dexamethasone 8 mg and granisetron 1 mg as anti-emesis.

Surgical removal of the wisdom teeth was uneventful. Cardiorespiratory observations were unremarkable during anaesthesia.

At the end of surgery anaesthetic agents were ceased and the supraglottic airway removed when consciousness was regained. She had an unremarkable stay in the post anaesthesia care unit with minimal pain and no evidence of swelling. She was then electively admitted to our intensive care unit for overnight observation. Progress was uneventful although the patient noted a slight degree of facial oedema which did not worsen. She was discharged home the next day with a sevenday prescription for amoxicillin/clavulanic acid and chlorhexidine mouthwash.

She was reviewed two weeks post surgery at the maxillofacial outpatient clinic where her progress was noted to be unremarkable with no episodes of angioedema at home.


C1 esterase inhibitor deficiency, also known as HAE, is an autosomal dominant condition caused by a functional or true deficiency of C1 esterase inhibitor complex. It affects approximately one in 50,000 individuals with no particular gender or racial predilection (5). The condition is associated with recurrent non-pitting swelling in the limbs, trunk, intestines and, of more concern, in the airway, particularly larynx and tongue. It is a life-threatening condition with estimates that about a quarter of patients with the condition die from it (predominantly due to airway complications) (6).

C1 esterase inhibitor is known to carry out several important biochemical reactions in plasma, including inhibition of complement (C1r, C1s) and coagulation (Factor 12) pathways. During normal contact activation (caused by tissue damage), activated factor 12 cleaves prekallikrein to kallikrein which then leads to bradykinin formation. Bradykinin (acting via bradykinin 2 receptor) is known to be a highly vasoactive compound leading to vasodilation and increased vascular permeability. C1 esterase inhibitor is a check in this pathway, inhibiting F12a synthesis of kallikrein and hence bradykinin. In this way it controls vascular permeability and oedema. The role of uncontrolled complement activation leading to oedema in C1 esterase inhibitor deficiency has probably been overstated in the past with new evidence suggesting a crucial and dominant role for bradykinin (7).

There are two major types of HAE, with a further third type recently being discovered. Type 1 hereditary angioedema results from a mutation in C1 esterase inhibitor gene leading to decreased secretion of the protein, thus leading to reduced plasma levels. In Type 2 HAE, on the other hand, a mutation in the gene leads to secretion of a non-functional peptide. It should be noted that although a majority of patients with type 1 and 2 may have a family history of HAE, sporadic mutations can account for about 30% of cases (as in our patient described above) (8). In type 3 HAE, levels and activity of C1 inhibitor levels are normal, but a mutation coding for factor 12 leads to over-production of kallikrein and hence bradykinin (9). Type 3 HAE is a relatively new entity awaiting further characterisation and guidelines on management.

The need for preoperative short-term pharmacological prophylaxis in patients with C1 esterase inhibitor deficiency requires a risk/benefit analysis in consultation with the patient's immunologist. Factors that may necessitate prophylaxis include:

* airway or dental surgery;

* surgery necessitating an airway device for anaesthesia;

* previous episodes of angioedema affecting the airway;

* surgery during pregnancy, particularly in the first trimester (10).

International consensus guidelines recommend preoperative infusion of C1 esterase inhibitor concentrate in patients considered at high risk for perioperative angioedema (5). Recommended regimens include intravenous administration of 500 to 1500 u (20 u/kg) up to 24 hours before the procedure (11). The formulation of C1 esterase inhibitor available in Australia is currently derived from human plasma (Berinert, CSL, Broadmeadows, Vic.) thus carrying a theoretical, but small risk of pathogen transmission. Other treatment options for prophylaxis include infusion of 2 units of FFP one to two hours prior to surgery (7). This may be particularly useful in situations where C1 esterase inhibitor is unavailable yet surgery needs to be undertaken urgently. The use of preoperative danazol (an attenuated androgen) and tranexamic acid for short-term prophylaxis has also been described (12).

Bradykinin modulators

The discovery of the important role of bradykinin in HAE has led to the development of icatibant, a synthetic peptide drug that selectively blocks the bradykinin receptor B2. Phase 3 studies involving icatibant have shown promising results for treatment of acute attacks of angioedema. In the For Angioedema Subcutaneous Treatment (FAST) 2 trial, of subcutaneous icatibant 30 mg was shown to be far superior in terms of time to symptom resolution and need for rescue C1 esterase inhibitor concentrate compared to tranexamic acid in acute angioedema attacks (4). In the FAST 1 trial, there was only a non-significant benefit of subcutaneous icatibant 30 mg compared to placebo (4). The authors believe this may have been due to the early use of rescue medication (C1 esterase concentrate) in the placebo group. A subsequent prospective randomised controlled study (FAST 3) carried out to further investigate the equivocal results of the FAST 1 trial showed that icatibant provided significantly faster time to initial symptom relief as well as time to almost complete symptom relief compared to placebo (from internet publication of preliminary results) (13). Serious side-effects with icatibant are rare although local skin reactions are common. There are currently no trials to our knowledge comparing C1 esterase inhibitor concentrate with icatibant.

Icatibant has several potential advantages over C1 esterase inhibitor concentrate in the treatment of acute attacks as well as short-term prophylaxis. The subcutaneous mode of administration may mean that it finds a role in prehospital management of angioedema. There may also be a role for icatibant in the management of patients with type 3 HAE where C1 inhibitor levels are normal (14). Additionally, it may also be of use in individuals who have developed resistance to C1 esterase concentrate through repeated use15. Being a synthetic peptide, it has no potential for disease transmission unlike FFP or plasma derived C1 esterase concentrate.

The use of icatibant in short-term prophylaxis preoperatively has been described in two previous case reports (15,16). In one case, icatibant was used prophylactically in a patient with diagnosed type 2 HAE (with suspected C1 inhibitor resistance) who needed head and neck surgery (15). There were no postoperative episodes of angioedema and the authors concluded that it was probable that angioedema was averted by icatibant use. In another case, icatibant was used successfully in preventing angioedema following fine needle aspiration of a thyroid mass (16). It is worthwhile noting, however, that in both these case reports there was a prior history of beneficial response to icatibant as it had been used in these patients for treatment of acute attacks.

The decision to use icatibant in our case was made due to cost (icatibant AUS$2750 for one subcutaneous treatment vs C1 inhibitor concentrate AU$4950 for a 70 kg adult at our institution), as well as ease of administration. The anaesthetic technique itself required only little modification with our patient. We were more alert to the need to provide effective anxiolysis with pharmacological and non-pharmacological methods as attacks can sometimes be triggered by emotional stress (7). We elected to use a reinforced laryngeal mask airway rather than an endotracheal tube as we felt this would be less likely to cause airway trauma and trigger angioedema. It could be argued that endotracheal intubation may have been safer as this would have ensured a secure airway had airway oedema occurred during the operation. Dexamethasone use was purely for antiemetic prophylaxis and there is no evidence that it is useful in preventing or treating episodes of angioedema (17).

In summary, while C1 esterase inhibitor deficiency is an uncommon condition in the community, it is likely that most anaesthetists will be involved in the perioperative management of such patients at least once in their career. Given the potential for serious adverse outcomes, careful planning and a multidisciplinary approach is crucial. All anaesthetists and medical personnel in acute medicine need to be aware of the condition as well as the treatment options. New insights into the pathophysiology of hereditary angioedema has led to the development of new treatment modalities that are promising in the treatment of acute attacks, although their role in short-term prophylaxis in the perioperative setting is yet to be defined. Our case describes the successful management of a patient who was at relatively high risk for postoperative airway oedema with the use of a novel bradykinin receptor 2 antagonist.


Published with the written consent of the patient.


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(15.) Clemens PC. Short-term prophylactic treatment of hereditary angioedema (HAE) type 2 with icatibant. Poster presentation at the 30th Congress of the European Academy of Allergy and Clinical Immunology, 11-15 June 2011, Istanbul, Turkey.

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K. T. SENARATNE *, A. M. COTTRELL ([dagger]), R. L. PRENTICE ([double dagger])

Department of Anaesthesia and Peioperative Medicine, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia

* BHB, MB ChB, Provisional Fellow in Anaesthesia

([dagger]) FANZCA, Consultant Anaesthetist

([double dagger]) FRACP, Director, Department of Clinical Immunology and Allergy

Address for correspondence: Dr K. Senaratne, Department of Anaesthesia and Perioperative Medicine, Royal Brisbane and Women's Hospital, Herston, Brisbane, Qld 4029. Email:

Accepted for publication on January 10, 2012.
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Article Details
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Title Annotation:Case Reports
Author:Senaratne, K.T.; Cottrell, A.M.; Prentice, R.L.
Publication:Anaesthesia and Intensive Care
Article Type:Clinical report
Geographic Code:8AUST
Date:May 1, 2012
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