Ann Thorac Surg 2008;85:1079-1081. doi:10.1016/j.athoracsur.2007.09.031
© 2008 The Society of Thoracic Surgeons
Case Reports
Management of Hereditary Angioedema During Off-Pump Coronary Arterial Surgery
Sharon A. Pecsi, RN, MSNa,
G. Hossein Almassi, MDa,b,*,
Renee B. Bojrab, MDb,
Paul S. Pagel, MD, PhDa,b
a Department of Cardiothoracic Surgery, Clement J. Zablocki Veterans Affairs Medical Center, Medical College of Wisconsin, Milwaukee, Wisconsin
b Department of Anesthesiology, Clement J. Zablocki Veterans Affairs Medical Center, Medical College of Wisconsin, Milwaukee, Wisconsin
Accepted for publication September 17, 2007.
* Address correspondence to Dr Almassi, 9200 W Wisconsin Ave, Milwaukee, WI 53226 (Email: halmassi{at}mcw.edu).
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Abstract
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A 62-year-old man presented with coronary artery disease complicated by a history of hereditary angioedema. In preparation, extensive consultation and literature review were completed. Close cooperation between immunology, anesthesiology, and cardiac surgery teams, as well as an off-pump technique led to a favorable outcome.
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Introduction
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Hereditary angioedema (HAE) is a genetically transmitted disorder caused by deficiency or reduced activity of C1 esterase inhibitor (C1INH), precipitating activation of the complement cascade and causing potentially life-threatening swelling of the face, mouth, and airway as a result of increased endothelial and bronchial capillary permeability [1, 2]. Surgery and cardiopulmonary bypass (CPB) are known to activate the complement cascade, increasing the risk of angioedema [3]. In the current report, we describe the perioperative considerations of HAE during off-pump coronary artery bypass graft surgery (OP-CABG) and review the pathophysiology and management of this rare disorder.
A 62-year-old man with a history of HAE chronically treated with a synthetic androgen (danazol) underwent cardiac catheterization for chest pain evaluation, which revealed 75% stenoses of the left main and right coronary arteries. The patient was referred to cardiothoracic surgery. An immunology consultation was obtained to optimize HAE treatment and minimize the risk of perioperative angioedema. The activity of C1INH was initially determined to be normal (84%), but the plasma C1INH concentration was markedly reduced (5 mg/dL; normal range, 11 to 26 mg/dL). These laboratory results put the patient at risk of angioedema developing during surgery. Incremental danazol maintenance doses (as much as 400 mg orally twice daily) were administered over several weeks to normalize C1INH activity and enhance plasma C1INH concentration. These interventions further increased C1INH activity, but the plasma C1INH concentration remained depressed (8 mg/dL), and the decision was made to proceed with surgery concomitant with exogenous C1INH supplementation using fresh frozen plasma. Three units of fresh frozen plasma were administered the day before surgery, and an OP-CABG technique was chosen for surgery to reduce the risk of complement cascade activation known to trigger angioedema.
After induction of general anesthesia and intubation, two additional units of fresh frozen plasma were administered. A full loading dose of intravenous heparin was administered to maintain an activated clotting time greater than 480. This heparin dose was used to facilitate emergent use of CPB if necessary. The left anterior descending and right coronary arteries were grafted using the left internal thoracic artery and a saphenous vein graft, respectively. The proximal vein graft–aortic anastomosis was completed using a Heartstring device (Guidant, St. Paul, Minnesota). Two additional units of fresh frozen plasma were administered during the operation to maintain plasma C1INH concentration. Plasma C1INH activity, C1INH concentration, and C4 concentration (a marker of complement cascade activation) were measured after administration of heparin, after infusion of fresh frozen plasma, and after graft completion. The C1INH activity (84% to 94%) remained within the normal range (>68%) during surgery. The plasma C1INH concentration was initially depressed (8 mg/dL), but increased to 12 mg/dL after graft completion. The plasma C4 concentration remained between 11 and 12 mg/dL throughout the operation (normal range, 11 to 26 mg/dL). The anticoagulation was reversed with intravenous protamine after completion of the grafts, with documented normalization of the activated clotting time. The patient was transported to the intensive care unit in stable condition. Emergency airway equipment was located at the bedside in the event of acute HAE-induced airway compromise. The patient was extubated the next morning without complications. Maintenance danazol therapy was reinitiated. No episodes of angioedema occurred, and the patient was discharged on the seventh postoperative day.
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Comment
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The C1 esterase inhibitor inhibits the classical complement cascade as well as the clotting and antifibrinolytic systems [1, 2]. Production of C2 kinin and bradykinin occurs owing to uninhibited activation of the complement and contact systems, and these proteins may be responsible for HAE-induced edema by causing endothelial cell retraction in post-capillary venules forming gaps and allowing leakage of plasma [3]. Hereditary angioedema produces substantial morbidity by causing edema of any part of the body; most often the extremities [1]. Patients may experience concurrent visceral involvement manifested by abdominal pain accompanied by diarrhea, usually occurring late during an attack. The mortality associated with HAE approaches 25% when oropharyngeal edema develops [1]. Airway obstruction may be manifested by alterations in voice quality and dysphagia that progresses to complete airway obstruction. Most patients with HAE experience their first attack during early childhood [1]. In a National Institutes of Health study, angioedema of the extremities, face, or oropharynx developed in 79% of HAE patients during attacks, but only 21% of patients had symptoms limited to the gastrointestinal tract [1, 2]. Hereditary angioedema-induced edema usually lasts between 24 and 72 hours, but may be limited to less than 4 hours or persist for as long as 1 week [1]. Patients with HAE identify a number of common precipitating factors, including dental manipulation, acute illness, tonsillectomy, and trauma [1, 2]. Establishing the clinical diagnosis of HAE is not difficult in a patient with a family history or a medical history of swelling, but is difficult in those with a negative family history or atypical symptoms [1]. Specific protein assays of components of the complement system are evaluated to diagnose HAE. Plasma C4 concentrations are reduced during an attack in patients with HAE, but do not predict severity of the episode [4]. Declines in plasma C1INH concentrations are observed in 80% to 85% of cases [5].
Patients with a history of HAE-induced face, neck, or oropharyngeal edema with or without airway obstruction require chronic treatment with synthetic androgens, antifibrinolytic drugs, or C1INH concentrates [2]. Synthetic androgens (danazol, stanozolol) produce dose-related increases in plasma C1INH concentrations [2], reducing the incidence and severity of attacks. Antifibrinolytic agents control angioedema by inhibiting plasminogen and C1 activation, but these drugs do not affect plasma C1INH concentrations, and chronic use causes adverse side effects [2]. In contrast to the report of Bainbridge and coworkers [5], we chose not to administer the antifibrinolytic drug aprotinin. We believed that chronic anabolic steroid therapy had been optimized, and the administration of exogenous C1INH using fresh frozen plasma minimized the risk of angioedema independent of the use of aprotinin. Long-term therapy with purified C1INH concentrates is an effective alternative for HAE patients experiencing side effects with other therapeutic approaches [2]. The C1INH not only regulates the initiation of the classical complement pathway, but also modulates factor XI and XII activities, thereby potentially contributing to thrombosis [6]. However, such an enhanced coagulation state may be balanced by plasma antithrombin III and endogenous endothelial anticoagulant mechanisms [6].
Treatment of acute HAE attacks emphasizes airway management [2]. However, patients with HAE often do not respond to epinephrine, antihistamines, or corticosteroids [1, 2]. Thus, definitive treatment for oropharyngeal angioedema may be limited to intubation or tracheostomy during a crisis. Administration of fresh frozen plasma during an attack is beneficial, but this intervention may also exacerbate the attack by providing additional complement cascade substrates [2]. Replacement therapy using a purified C1INH concentrate is the treatment of choice in Europe [2]. Hereditary angioedema-induced angioedema usually resolves within 2 hours after purified C1INH concentrate injection, with complete remission occurring within 24 hours, but the concentrate has yet to be approved for clinical use in the United States [2].
The presence of HAE complicates the surgical management of coronary artery disease, and OP-CABG may be the preferred operative technique in patients with HAE. Cardiopulmonary bypass stimulates a generalized inflammatory response, including the complement cascade, potentially triggering an attack [4], and produces a dilutional reduction in plasma C1INH concentration that occurs as a result of pump prime [5]. Reversal of heparin with protamine creates circulating complexes of these molecules that activate the classic complement pathway [3]. Lower doses of heparin may be used during OP-CABG, reducing the potential for heparin-protamine complex-induced complement activation. In the current case, we administered a full dose of heparin to facilitate rapid initiation of CPB if hemodynamic instability arose during OP-CABG, but we were able to reverse this anticoagulation using a reduced dose of protamine, thereby reducing the heparin-protamine complex load. The surgical stress response also activates complement [7], but such a stress response is known to occur during both on- and off-pump CABG surgery.
Three previous reports of the use of CPB in patients with HAE undergoing CABG surgery are documented. Progressive increases in airway pressure, acute pulmonary edema, and severe coagulopathy contributed to the intraoperative death of 1 patient [4], but 2 other patients were successfully managed using preoperative administration of C1INH concentrate or chronic stanozolol therapy to increase plasma C1INH concentration [7]. Bainbridge and associates [5] published the only other report of OP-CABG in a patient with HAE. The preoperative plasma C1INH concentration of the patient in this report [5] was substantially lower than observed in our patient despite chronic anabolic steroid treatment, but the authors were unable to intervene with additional stanozolol before the operation because the surgery was emergent. In our case, we were able to increase the dose of danazol over several weeks to enhance C1INH activity and reduce the potential for perioperative angioedema. Safe conduct of surgical procedures mandates close cooperation among immunology, anesthesiology, and surgical teams.
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References
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- Frank MM, Gelfand JA, Atkinson JP. Hereditary angioedema: the clinical syndrome and its management Ann Intern Med 1976;84:580-593.[Abstract/Free Full Text]
- Sim TC, Grant A. Hereditary angioedema: its diagnostic and management perspectives Am J Med 1990;88:656-664.[Medline]
- Shastri K, Logue GL, Stern MP, Rehman S, Raza A. Complement activation by heparin-protamine complexes during cardiopulmonary bypass: effect of C4 null allele J Thorac Cardiovasc Surg 1997;114:482-488.[Abstract/Free Full Text]
- Bosner RS, Dave J, Morgan J, et al. Complement activation during bypass in acquired C1 esterase inhibitor deficiency Ann Thorac Surg 1991;52:541-543.[Abstract]
- Bainbridge DT, Mackensen GB, Newman MF, Landolfo KP, Grocott HP. Off-pump coronary bypass surgery in a patient with C1 esterase inhibitor deficiency Anesthesiology 2001;95:795-796.[Medline]
- Frank MM. Complement in the pathophysiology of human disease N Engl J Med 1987;316:1525-1530.[Medline]
- Alvarez JM. Successful use of C1 esterase inhibitor protein in a patient with hereditary angioneurotic edema requiring coronary artery bypass surgery J Thorac Cardiovasc Surg 2000;119:168-171.[Free Full Text]
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Abstract
Introduction
