ANGIOEDEMA is a rare disease caused by a deficiency of C1 esterase inhibitor. Deficiency, either absolute or functional, of this moderator of the complement cascade can result in unregulated complement activation during periods of infection, trauma, or stress. The clinical presentation can include edema of the head and neck, mucous membranes, and gastrointestinal tract. The most alarming cases include the potential for severe airway edema. 1
Cardiopulmonary bypass (CPB) is a particularly stressful perioperative event and is known to significantly increase complement activation, further increasing the risk of angioedema in C1 esterase inhibitor–deficient patients. 2,3Few reports exist of the management of this rare but significant disease during cardiac surgery. We present a successful case of coronary artery bypass grafting (CABG) in a C1 esterase inhibitor–deficient patient using an off-pump technique.
A 45-yr-old man was admitted to the hospital for monitoring and investigation of unstable angina. He had a history significant for coronary artery disease, including an inferior myocardial infarction 2 yr previously. Also significant was a history of C1 esterase deficiency (with several previous episodes of angioedema) being treated with stanozolol (6 mg daily by mouth). He was also receiving an oral β blocker and calcium channel but not an angiotensin converting enzyme inhibitor. Coronary angiography revealed a 100% stenosis of the left anterior descending artery and a 75% stenosis of the right coronary artery, with a 50% left ventricular ejection fraction. Given these results, it was elected to perform CABG surgery.
Considering the risk associated with the activation of complement caused by the extracorporeal circulation, it was opted to perform off-pump CABG (OPCAB). The patient was brought to the operating room, and during placement of invasive monitors, 2 units fresh frozen plasma, aprotinin (1 × 106kIU intravenously), and hydrocortisone (100 mg intravenously) were administered. Anesthesia was induced with thiopental, fentanyl, and succinylcholine and maintained with isoflurane, pancuronium, and intermittent boluses of fentanyl. Heparin (20,000 U) was administered before vascular grafting, with two additional boluses (each 5,000 U) administered to maintain an activated clotting time greater than 300 s (a level consistent with our institutional OPCAB standards). Protamine (150 mg intravenously) was administered after completion of all three bypass grafts. The patient remained hemodynamically stable throughout the 232-min procedure and was subsequently transferred to the intensive care unit. In the absence of angioedema, he was extubated 3 h after arrival, and after an unremarkable hospital stay, he was discharged to his home 3 days later.
Blood samples for C1 esterase inhibitor concentration determinants were drawn from the arterial line and immediately spun with the supernatant frozen at −80°C until analysis. The analysis was performed using radioimmunodiffusion with the results reported as a percent of normal C1 esterase inhibitor function. The levels were 17, 63, 69, and 50% of normal in the preinduction, postheparin, final anastomosis, and postprotamine periods, respectively.
Angioedema, also known as angioneurotic edema caused by the psychologic stress that may precipitate attacks, is a rare condition (most commonly hereditary, but occasionally acquired) with potentially life-threatening complications. C1 esterase inhibitor, deficient in angioedema patients, regulates the classic complement pathway, and its absence leads to unregulated complement activation. This can cause increased endothelial and bronchial permeability with resultant angioedema and bronchial edema.
There are four principle reasons why cardiac surgery is particularly problematic in patients with angioedema. Cardiopulmonary bypass leads to an increase in activated complement factors. 2Complement activation is also observed secondary to the surgical trauma itself. 4,5Dilution associated with the additional fluid in the CPB prime may further decrease C1 esterase inhibitor concentrations. Finally, it has been demonstrated that heparin–protamine complexes activate the classic complement pathway. 3,6
This case shows the successful use of an alternative surgical technique for performing CABG in a patient with C1 esterase inhibitor deficiency. The advantages of this technique are several-fold. Firstly, it minimizes direct complement activation by avoiding the foreign surfaces of the CPB apparatus. 5In a study of 62 patients, Gu et al. 7demonstrated lower complement levels in patients undergoing CABG without CPB compared with those undergoing conventional CABG. Secondly, OPCAB avoids the obligatory dilution of C1 esterase inhibitor resulting from the hemodilution caused by the pump prime. Finally, OPCAB can generally be performed with lower doses of heparin, with the potential for less complement activation from fewer circulating heparin–protamine complexes after heparin reversal. The potential disadvantage of using an OPCAB technique may be an increased propensity toward hemodynamic instability because of the manipulation of the beating heart. Whether this increases the stress response, and with it the potential for angioedema, is not known.
There are several other potential modalities available to treat angioedema patients requiring CABG. In addition to modifying the surgical technique, fresh frozen plasma was preoperatively administered to this patient. Fresh frozen plasma contains a range of complement proteins, including C1 esterase inhibitor. The effect of the fresh frozen plasma can be seen in the increase in C1 esterase inhibitor functional activity from 17% to 63% after administration. The patient was already receiving stanozolol, which may increase C1 esterase inhibitor concentrations through increased hepatic production. However, it may take from 5 to 12 days to be effective. Aprotinin was administered for its generalized antiinflammatory effect, which may decrease complement activation. The rationale for administering steroids was based on its complement production–modifying effects (not on any specific effect in C1 inhibitor deficient patients); however, it may also attenuate the activation of complement caused by heparin–protamine complexes. 8
There have been several reports about the use of CPB in patients with angioedema. In particular, a patient with angioedema who underwent conventional CABG died after the development of progressively increasing airway pressures, coagulopathy, and pulmonary edema. 9Successful CPB in patients with C1 esterase inhibitor deficiency has also been reported in cases in which C1 inhibitor concentrate was infused preoperatively, thereby preventing an acute attack of angioedema. 10Haering and Comunale 11reported successful use of chronic stanozolol therapy for angioedema with stanozolol increasing C1 esterase inhibitor concentrations to 68% of normal. In comparison, the current patient had activity that was only 17% of normal, despite androgen use.
The patient with C1 esterase inhibitor deficiency requiring CABG presents the anesthesiologist with unique challenges. There are several management options to consider, and we report the use of successful OPCAB.