Evidence-Based Diagnosis and Management of ENT Emergencies

Michael Winters, MD

Disclosures

February 15, 2007

Angioedema

Angioedema is characterized by the abrupt onset of nonpitting, nonpruritic edema involving the reticular dermis, subcutaneous, and submucosal layers.[20,21,22] Lesions are well defined, asymmetric, and located in nondependent areas. Common locations include the lips, periorbital area, extremities, abdominal viscera, and genitalia. The duration of individual lesions typically ranges from 24 to 96 hours. Most patients present with the combination of urticaria and angioedema. In fact, up to 25% of the US population will have an episode of urticaria and/or angioedema during their lifetime.[23,24] Of these patients, up to 10% will have isolated angioedema.

Angioedema is caused by either mast cell-mediated or nonmast cell-mediated mechanisms. Mast cell-mediated mechanisms typically present with the combination of urticaria and angioedema. Regardless of the exact mechanism, there is degranulation of mast cells and the release of vasoactive substances. Patients with isolated angioedema usually have symptoms as a result of a nonmast cell-mediated mechanism. The two most common nonmast cell-mediated mechanisms include alterations in the bradykinin pathway, ie, angiotensin-converting enzyme (ACE) inhibitor-induced angioedema and abnormalities in the complement system -- hereditary angioedema.

The evaluation of patients with angioedema centers on the history, and one of the most important aspects of the history is to determine symptom duration. Acute angioedema is arbitrarily defined as symptom duration of less than 6 weeks. The most common causes of acute angioedema include medications, foods, infections, insect venom, contact allergens (latex), and radiocontrast material.[22,24,25] Of these, medications, foods, and viral infections account for the majority of cases. Patients with angioedema must be questioned about medications, new foods, and infectious symptoms. Less common etiologies of acute angioedema include physical stimuli, environmental triggers, and endocrine disorders. Patients with symptoms longer than 6 weeks are classified as having chronic angioedema. The evaluation of chronic angioedema and/or urticaria can be challenging. In the majority of cases, no etiology is ever found.

Unless suggested by findings from the history and/or physical examination, there is no role for "routine" labs (complete blood count, basic metabolic panel, liver function tests, erythrocyte sedimentation rate, and urinalysis) in the evaluation of acute angioedema. Laboratory testing, in an attempt to detect occult disease, is typically deferred until at least 6 weeks of persistent symptoms. Even in patients with protracted symptoms, laboratory testing yields little additional information. In a recent study of over 6400 patients with angioedema and/or urticaria with at least 6 weeks of symptoms, laboratory testing detected occult disease in just 1.6% of patients.[26]

In addition to a good history and physical examination, fiber-optic NPL is often used. It is well known that angioedema of the larynx is a marker of severe disease and can result in rapid airway obstruction. Fiber-optic NPL provides the physician the ability to determine the presence of laryngeal edema. On the basis of recent studies, patients with angioedema who complain of dyspnea, hoarseness, voice changes, odynophagia, or have stridor on physical exam are likely to have laryngeal involvement.[27,28] Patients with angioedema and these symptoms should undergo fiber-optic NPL. All patients with laryngeal edema require admission to the ICU.

For patients with the combination of angioedema and urticaria, treatment may consist of epinephrine, antihistamines, and corticosteroids. Patients presenting in severe respiratory distress or with marked laryngeal edema on NPL should be given epinephrine subcutaneously at a dose of 0.3 mg (0.3 mL of 1:1000 solution). For the majority of these patients, H1-antihistamines are the cornerstone of therapy. In addition to relieving pruritus, these medications reduce the number, size, and duration of lesions.[29] Although effective, the first-generation H1-antihistamines (diphenhydramine, hydroxyzine) are limited by the side effect of profound sedation. As a result, second-generation H1-antihistamines (loratadine, cetirizine, desloratadine, and fexofenadine) have become the agents of choice.[30] These medications have less central nervous system penetration, thereby producing less sedation. There are currently no controlled trials that demonstrate the superiority of any second-generation H1-antihistamine.[31] For patients whose symptoms are not controlled with an H1-antagonist, an H2-antagonist may be added to the medical regimen. Up to 15% of histamine receptors in the skin are of the H2 subtype. The combination of an H1- and H2-antagonist has been shown to be beneficial in some patients.[24] Corticosteroids are indicated for patients with anaphylaxis, laryngeal edema, and severe symptoms unresponsive to antihistamines.[32] Recommended corticosteroid doses for patients with severe angioedema and urticaria range from 0.5 to 1.0 mg/kg/day.[32]

Management of the patient with isolated angioedema is controversial. As discussed, these patients typically have nonmast cell-mediated mechanisms of angioedema. The majority of patients have isolated angioedema secondary to an ACE inhibitor. In fact, up to 68% of cases of isolated angioedema are due to an ACE inhibitor.[33,34,35,36] Treatment of ACE inhibitor angioedema focuses on discontinuation of the drug, airway management, and supportive care. In addition to severe laryngeal edema on NPL, indications for intubation of the patient with ACE inhibitor angioedema include tongue edema and edema of the floor of the mouth.[33,34,37] Although epinephrine, antihistamines, and corticosteroids can be given to these patients, there are no controlled trials that demonstrate their efficacy in ACE inhibitor angioedema.[22,38,39] All intubated patients, patients with laryngeal edema, and those with severe symptoms require admission to the ICU.

Finally, it is important to recognize and avoid medications that can exacerbate angioedema and/or urticaria. Medications that have been shown to exacerbate symptoms are aspirin, nonsteroidal anti-inflammatory drugs, opiates, and estrogen-containing compounds in any patient with angioedema..[22,25] In addition, any patient with ACE inhibitor angioedema should not be switched to an angiotensin receptor blocker (ARB). Although the incidence is less than that with ACE inhibitors, ARBs have been shown to also cause angioedema. A recent study illustrated that 32% of patients with angioedema due to an ARB had a prior episode of ACE inhibitor angioedema.[40] ARBs should not be considered a safe alternative in patients with ACE inhibitor angioedema.

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