Angiotensin-converting enzyme inhibitor-induced angioedema: a multicenter review and an algorithm for airway management.

Angioedema is a nonpitting edema of which the presentation ranges from benign facial swelling to airway obstruction managed by intubation or tracheotomy. The presentation of this disease is reviewed, and a treatment algorithm based on initial signs and symptoms is proposed for proper airway management. We performed a retrospective review of 108 patients treated in 2 tertiary care centers in the Washington, DC, area over a 5-year period. Ninety-eight patients (90.7%) were African-American, and 81 (75%) were female. Seventy-four patients (68.5%) were taking angiotensin-converting enzyme inhibitors (ACEIs). A classification system was developed based on the location of the edema at initial presentation: 1) isolated facial swelling and oral cavity edema, excluding the floor of the mouth; 2) floor of mouth and/or oropharyngeal edema, and 3) oropharyngeal edema with glottic and/or supraglottic involvement. Fourteen patients (13%) needed airway intervention, 2 of whom underwent a cricothyrotomy after a failed intubation attempt. Eleven (78.6%) were taking ACEIs. The indication for each intubation was massive tongue and floor of mouth edema. The patients were extubated 48 to 72 hours later. No patient demonstrated symptom progression after medical treatment was initiated. Therapy included discontinuation of the ACEI or other inciting agent, a high-humidity face tent, an initial dose of intravenous antihistamines, and a continued course of intravenous steroids. Within 48 hours, most patients had a resolution of their edema. Only cases of significant tongue and oropharyngeal edema took longer than 48 hours to resolve. The ACEIs are a common cause of angioedema. Left untreated, angioedema may progress to involve the oropharynx and supraglottis, resulting in a life-threatening airway compromise. Marked floor of mouth and tongue edema are the indications for airway intervention. An algorithm based on the initial presentation is essential for proper airway and patient management. Once treatment has begun, angioedema is nonprogressive and often resolves within 24 to 48 hours.

Angioedema associated with angiotensin II receptor antagonists: challenging our knowledge of angioedema and its etiology.

INTRODUCTION: Use of angiotensin converting enzyme inhibitors has long been associated with angioedema. Increased levels of bradykinin caused by the inhibition of angiotensin converting enzyme have been thought to be responsible for this side effect. Angiotensin II receptor antagonists (AT2 blockers), such as losartan potassium (Cozaar; Merck & Co., West Point, PA), are a new class of antihypertensives developed in part to eliminate cough and angioedema associated with ACE inhibitors. These agents act by selectively binding to angiotensin II receptor sites, thereby eliminating the hypertensive effects of angiotensin without affecting local and systemic bradykinin levels. We present three cases of AT2 receptor antagonist-induced angioedema, and examine its significance in the treatment of angioedema and its proposed etiology. METHODS: A retrospective chart review and review of the literature. RESULTS: Three patients taking the AT2 blocker losartan presented with mucosal swelling in the head and neck clinically consistent with angioedema. All three patients had prior episodes of angioedema while on losartan. Two patients presented with involvement of the anterior tongue and face that resolved within 12 hours of discontinuation of the losartan and a course of intravenous steroids. The third patient experienced recurring episodes of angioedema that eventually required a tracheotomy for airway compromise. After discontinuing the losartan and receiving a course of intravenous steroids, the angioedema resolved in 5 days. The patient was decannulated 10 days after onset of symptoms. CONCLUSION: Angioedema is a potentially life-threatening condition commonly associated with ACE inhibitor use. AT2 blockers bind to angiotensin II receptor sites and have no demonstrable effect on local or systemic bradykinin levels. We present three cases that demonstrate AT2 blocker-induced angioedema. They were all complicated by the fact that the inciting agent, losartan, was not discontinued after the initial episode and resulted in recurrent episodes of angioedema, one of which required surgical airway intervention. The incidence of AT2 blocker-induced angioedema brings into question prior theories on the etiology of angioedema and bradykinin's role in its pathogenesis.

Lung peptidases, including carboxypeptidase, modulate airway reactivity to intravenous bradykinin.

We investigated the effect of inhibition of carboxypeptidase, neutral endopeptidase, or angiotensin converting enzyme on airway reactivity to intravenous bradykinin in guinea pigs. Bradykinin reactivity in intact, unanesthetized, spontaneously breathing animals was determined by measuring specific airway resistance in response to increasing doses of intravenous bradykinin or acetylcholine. We found that phosphoramidon and/or captopril (specific antagonists of neutral endopeptidase and angiotensin converting enzyme, respectively) increased airway reactivity to bradykinin, but the combination had no effect on muscarinic reactivity. Although 2-mercaptomethyl-3-guanidinoethylthiopropanoic acid (MGTA, a carboxypeptidase inhibitor) alone did not alter bradykinin reactivity, MGTA in the presence of both phosphoramidon and captopril significantly potentiated bradykinin-induced airway reactivity. In comparison, this did not affect reactivity to acetylcholine. Having found that carboxypeptidase inhibition could augment kinin-induced airway reactivity, we subsequently assayed for and identified carboxypeptidase M activity in guinea pig lung. We found considerable carboxypeptidase M activity in guinea pig lung subcellular fractions, the 100,000 x g membrane pellet having the highest specific activity. Our data indicate that airway reactivity to intravenous bradykinin is modulated by the activity of endogenous neutral endopeptidase, angiotensin converting enzyme, and carboxypeptidase, all of which are present in lung cell membranes. This study also suggests that the influence of carboxypeptidase per se may be substantially enhanced if endogenous pulmonary neutral endopeptidase and angiotensin converting enzyme activities are reduced.