Angioedema Treatment & Management

Inpatient care for angioedema is usually not necessary; however, moderate to severe angioedema is often seen in the emergency department. Epinephrine should be used when laryngeal angioedema is suspected. Supportive care should also be provided, regardless of the etiology.

Airway protection is the most important consideration in patients with angioedema. In cases of possible airway compromise, early intervention with intubation may be preferred. Intubation may be exceedingly difficult, and advanced techniques (eg, fiberoptic intubation) may be necessary. When intubation is required, admission to an intensive care unit (ICU) is often needed. Anesthesiologists, critical care specialists or pulmonologists, otolaryngologists, and respiratory therapists are helpful for the management team.

In severe cases of laryngeal edema, a surgical airway must be created via cricothyrotomy or tracheotomy. A surgeon should be consulted in this regard.

Depending on the etiology of angioedema, management can be dramatically different. To guide therapeutic approaches, angioedema can be regarded as either histamine-mediated or bradykinin-mediated. Understanding this distinction helps to direct proper patient care.

Diet and activity

Dietary modification is only necessary if food allergy or food additive hypersensitivity has been established.

Most patients do not need activity restriction. However, physical trauma may trigger certain types of angioedema; therefore, caution should be taken when engaging in contact sports.

Consultations and monitoring

When symptoms are moderate or severe and the offending factors are not easily identifiable, referral to allergy and immunology specialists should be considered. In cases of laryngeal attacks, consultations with ear, nose, and throat (ENT) and intensive care specialists is advisable. Allergy and immunology specialists should be consulted (eg, to identify potential allergies, medication reactions, changes in certain body enzymes).

Most patients require regular office visits to monitor their response to treatment and to assess ongoing or new episodes of angioedema.

Histamine-mediated angioedema is either IgE-dependent (eg, allergic reaction due to food or drug) or IgE-independent (eg, radiocontrast media). NSAID-related and most idiopathic angioedema are treated with the same measures.

Most cases can be managed well with outpatient treatment alone. Antihistamines are often used as the first-line treatment for angioedema. Leukotriene antagonists may be helpful in theory; however, clinical observation has not confirmed their benefits in urticaria or angioedema.

For moderate to severe cases, close monitoring is often necessary. Diphenhydramine (50) mg intramuscular (IM)/intravenous (IV) is helpful. Hydrocortisone (200 mg) or Solu-Medrol (40-60 mg) IV may reduce the possibility of relapse.

For laryngeal swelling and airway obstruction, close monitoring of the airway is mandatory. Epinephrine (1:1000) should be administrated intramuscularly at 0.01 mg/kg or 0.3 mg repeated every 10-15 min, if necessary. Occasionally, intubation, or even tracheostomy, may be necessary. These patients should be admitted for at least 24 hours of observation.

Prophylactic second-generation antihistamines, often at doses up to 4 times the standard dose, with or without H2 blockers, are often used to help reduce the severity or frequency of attacks.

Cyclosporin A and various other immunomodulatory drugs, including omalizumab, have shown to be effective for many recalcitrant cases of chronic idiopathic urticaria and angioedema.^{[37, 38]} Corticosteroid use in histamine-mediated angioedema should be limited to severe cases. (Outpatient treatment should avoid long-term corticosteroid use.)

ACE inhibitor–induced angioedema is a classic example of this type of angioedema. Hereditary angioedema (HAE), acquired angioedema (AAE), estrogen-dependent angioedema, and certain idiopathic angioedemas are bradykinin-mediated. Antihistamines do not work for these patients, and cortical steroids have limited or no value. In AAE, treatment of the underlying disorder usually results in correction of the abnormality.

In recalcitrant cases of angioedema, consider possible misdiagnosis and other concurrent medical problems.

Acute angioedema

Monitor and support the airway, as in histamine-mediated angioedema. Epinephrine does not work as well in bradykinin-mediated angioedema as it does in histamine-mediated angioedema. Its value for treating acute HAE attacks is limited.

Severe abdominal pain may sometimes be the only presenting symptom for these patients when seeking emergency medical care. Supportive care includes pain control and relief of nausea.

Fresh frozen plasma (2 units) has been shown to be helpful in certain patients. However, fresh frozen plasma worsening an acute attack of laryngoedema has also been reported. If this treatment is used, be ready to intubate or perform a tracheostomy, if necessary. Antifibrinolytics (eg, Amicar or tranexamic acid) may be helpful in acute angioedema.

C1-INH infusion (Berinert, 20 U/kg) can be used for acute HAE attacks. It is reportedly used in other types of angioedema as well, although its clinical efficacy in nonhereditary forms of the disease has not been fully studied.^[39]

Ecallantide (Kalbitor, a kallikrein inhibitor that suppresses bradykinin generation) received FDA approval for treatment of acute HAE attacks in December 2009. During attacks, unregulated plasma kallikrein activity results in excessive bradykinin generation, resulting in swelling, inflammation, and pain. Ecallantide is a potent, selective, reversible inhibitor of plasma kallikrein, thereby reducing the conversion of kininogen to bradykinin.

Cicardi et al observed significantly better outcome scores in patients treated for acute attacks of angioedema with ecallantide than in those treated with placebo.^[40]

Icatibant (Firazyr) 30 mg (a B2 bradykinin receptor antagonist) SC may be used for moderate to severe acute HAE attacks. Icatibant was approved by the FDA for the treatment of acute attacks of HAE in adults in August 2011. Approval was based on 3 double-blind, randomized, controlled clinical trials known as For Angioedema Subcutaneous Treatment (FAST) 1, 2, and 3.^{[41, 42]}

In FAST 3, the median time to 50% reduction in symptoms for patients with cutaneous or abdominal attacks treated with icatibant (n=43) compared with placebo (n=45) was 2 hours versus 19.8 hours, respectively, and the median times to almost complete symptom relief were 8 versus 36 hours for icatibant and placebo, respectively. FAST 3 was a placebo-controlled study of 98 adult patients with a median age of 36 years. The primary endpoint was assessed using a 3-item composite visual analog score (VAS), composed of averaged assessments of skin swelling, skin pain, and abdominal pain. Additional rescue medications were used by 3 patients (7%) treated with icatibant and 18 patients (40%) treated with placebo.

Two randomized trials by Zuraw et al evaluating the use of nanofiltered C1-INH concentrate (Cinryze) for the management of hereditary angioedema found that nanofiltered C1-INH concentrate shortened the duration of acute attacks and, when used for prophylaxis, reduced the frequency of acute attacks.^[43]

Prevention of attacks (short-term and long-term prophylaxis)

Remove ACE inhibitors from the patient's regimen. Most patients with angioedema induced by ACE inhibitors can tolerate an angiotensin II receptor blocker (ARB). In rare patients, even an ARB must be avoided.

Avoid estrogen-based oral contraceptives. The administration of androgen derivatives or antifibrinolytics may be considered. C1-INH infusion may also be considered. Purified C1-INH (Cinryze) is currently FDA-approved only for prophylactic treatment. The use of fresh frozen plasma for short-term prophylaxis may be considered as well.^[39]

For idiopathic angioedema, the response to treatment varies tremendously among individuals. Many patients may need multiple attempts to find the right combination of medicine to control their symptoms. Antihistamines and H2 antagonists are still most commonly prescribed for this condition. Leukotriene antagonists (montelukast and zafirlukast), 5-lipoxygenase inhibitor (zileuton), and immunomodulators (eg, cyclosporine) have been used in these patients.

Corticosteroid is reserved for very recalcitrant cases. (Outpatient treatment should avoid long-term corticosteroid use.) Antifibrinolytics have been tried in some patients with success. Androgen derivatives and progesterone-only oral contraceptives may also be considered for these patients.