Angioedema Treatment & Management

Updated: Sep 04, 2018
  • Author: Huamin Henry Li, MD, PhD, CPI; Chief Editor: Michael A Kaliner, MD  more...
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Approach Considerations

Patients with moderate to severe angioedema often present to the emergency department (ED). Epinephrine should be used when laryngeal angioedema is suspected. Supportive care (eg, pain control) should also be provided, regardless of the etiology.

Inpatient care for angioedema is usually not necessary when timely treatment is administered. For patients with a known history of hereditary angioedema (HAE), a treatment option approved by the US Food and Drug Administration (FDA) (eg, C1 esterase inhibitor [C1-INH] concentrate, ecallantide, or icatibant) should be administered as soon as an angioedema attack is recognized. [53]

Airway protection is the most important consideration with laryngeal angioedema. It is helpful to include anesthesiologists, critical care specialists or pulmonologists, otolaryngologists, and respiratory therapists in the management team. In cases of possible airway compromise, early intubation may be preferred.

When intubation is required, admission to an intensive care unit (ICU) is often needed; the procedure may be exceedingly difficult, and advanced techniques (eg, fiberoptic intubation) may be necessary. In severe cases of laryngeal edema, a surgeon should be consulted, because a surgical airway will have to be created via cricothyrotomy or tracheotomy.

Clinicians should attempt to identify and patients should attempt to avoid triggers such as the following:

  • Food allergies

  • Drugs

  • Physical factors (eg, vibrations, cold or heat, or pressure)

  • Nonsteroidal anti-inflammatory drugs (NSAIDs)

  • Angiotensin-converting enzyme (ACE) inhibitors

For patients who have angioedema without urticaria, clinicians must rule out HAE, acquired C1-INH deficiency (C1-INH-AAE), and ACE inhibitor−induced angioedema (ACEI-AAE).

Depending on the etiology of the angioedema, management can vary dramatically. To guide therapy, angioedema with unidentifiable causes can be regarded as histaminergic or nonhistaminergic.


The 2015 guidelines from the Standards of Care Committee of the British Society for Allergy and Clinical Immunology (BSACI) provide guidance for the management of patients with chronic urticaria/angioedema. [54]

For adult patients with weals

  • Check that symptomatic episodes have not followed ingestion of a nonsteroidal anti-inflammatory drug such as aspirin or ibuprofen.

  • Give a once-daily dose of a long-acting, nonsedating antihistamine (prn if symptoms are infrequent).

  • If necessary, double the dose of antihistamine (usually given at night), and/or add a second antihistamine.

  • Consider further increase in dose of antihistamine up to 4 times the recommended dose.

  • Consider adding one or more second-line drugs.

  • Consider short-term oral corticosteroid rescue treatment.

For adult patients with angioedema with weals

In addition to the instructions above for adult patients with weals, the following steps should be considered:

  • If the patient is taking an ACE inhibitor, this drug should be stopped.

  • Even if the patient is not taking an ACE inhibitor, these drugs should be avoided in the future.

  • Consider addition of tranexamic acid for higher-dose antihistamine-resistant angioedema.

  • An adrenaline autoinjector is rarely required and should only be considered if there is a history of significant angioedema affecting the upper airway (rare in angioedema with urticaria). The patient should then be shown how to use the device and provided with a written self-management protocol.

  • Consider short-term oral corticosteroid rescue treatment.

For adult patients with angioedema without weals

  • Exclude C1 inhibitor deficiency; a normal plasma C4 during an attack—or normal C4, C1 inhibitor, and C1 inhibitor function between attacks—will typically exclude this.

  • If the patient is taking an ACE inhibitor, this drug should be stopped.

  • Even if the patient is not taking an ACE inhibitor, such drugs should be avoided in the future.

  • Give a once-daily dose of a long-acting, nonsedating antihistamine (prn if symptoms are infrequent) and consider higher doses of antihistamines.

  • Consider tranexamic acid in antihistamine-resistant angioedema.

  • An adrenaline autoinjector and short-term oral corticosteroids are unlikely to be beneficial unless an underlying histaminergic mechanism is considered to be responsible for the angioedema.

In 2013, the World Allergy Organization (WAO) issued the following recommendations for the management of HAE types 1 and 2 [14] :

  • Assess all patients suspected of having HAE-1/2 for blood levels of C4, C1 esterase inhibitor (C1-INH) protein, and C1-INH function

  • Consider on-demand treatment for all HAE attacks that (1) result in debilitation or dysfunction or (2) involve the face, the neck, or the abdomen; attacks affecting the upper airways must be treated

  • Treat all HAE attacks as early as possible with C1-INH, ecallantide, or icatibant; do not use oral antifibrinolytics as on-demand treatment

  • Consider intubation or tracheotomy early in progressive upper airway edema

  • Administer adjuvant therapy in HAE attacks when indicated, but use specific therapies without delay when indicated

  • All HAE-1/2 patients should (1) have on-demand treatment for 2 attacks and (2) carry their on-demand treatment at all times

  • Plasma-derived (pd) C1-INH is the preferred on-demand therapy for HAE-1/2 attacks in children and in pregnant or breast-feeding women

  • All patients should have an action plan, product available to treat HAE attacks, and an HAE identification card

  • Instruct all patients given on-demand treatment licensed for self-administration on how to self-administer

  • All patients should have at least 1 annual assessment by an HAE specialist

The WAO’s 2013 recommendations regarding prophylaxis and screening in HAE are as follows [55] :

  • Consider administering short-term preprocedural prophylaxis, particularly in cases involving dental or intraoral surgery and bronchoscopy or endoscopy; endotracheal intubation; and manipulation of the upper airway or pharynx

  • Before beginning long-term prophylaxis with androgens, obtain a complete blood count (CBC), urinalysis, liver function tests (LFTs), lipid profile, and liver ultrasonography, as well as assess the patient for cardiac risk factors; during use of androgens for long-term prophylaxis and for 6 months after cessation of therapy, monitor the patient’s CBC, urinalysis, lipid profile, LFTs, and blood pressure every 6 months; perform annual ultrasonography of the liver

  • Defer screening children for HAE-1/2 until the age of 12 months; test all offspring of an affected parent

  • Family members of HAE-1/2 patients should be screened so that appropriate therapy can be available for treatment

  • Administer HAV and HBV vaccinations to HAE-1/2 patients receiving blood products, including pdC1-INH; administer influenza vaccine to all HAE-1/2 patients


Histaminergic Angioedema (IH-AAE)

Histaminergic angioedema (IH-AAE) is either immunoglobulin E (IgE)-dependent (eg, an allergic reaction to a food or drug) or IgE-independent (eg, a reaction to radiocontrast medium). NSAID-related angioedema and most cases of idiopathic angioedema are treated with the same measures.

Most cases of angioedema can be managed well with outpatient treatment alone. Antihistamines, usually second-generation agents (eg, cetirizine, desloratadine, fexofenadine, levocetirizine, and loratadine), are often used as first-line treatment. These agents are also given to help reduce the severity or frequency of attacks, in dosages often as high as 4 times the standard dosage. [56]

Current urticaria and angioedema treatment guidelines support the use of higher dosages of second-generation antihistamines as a treatment of choice in preference to the use of corticosteroids or other immune modulators. [38] However, this recommendation for updosing is primarily based on expert opinion, [57] and there is only limited clinical evidence to support it. [56]

Although the relative efficacy and safety of the various second-generation antihistamines have not been adequately studied, some data indicate that cetirizine 10 mg is more effective than fexofenadine 180 mg [58] and that levocetirizine 5 mg is more effective than desloratadine. [59] However, although some studies found the sedative effects of cetirizine to be greater than those of fexofenadine or loratadine, [60] another study found no such differences among cetirizine, levocetirizine, and loratadine. [61]

For moderate-to-severe cases of angioedema, close monitoring is often necessary. Diphenhydramine 50 mg intramuscularly (IM) or intravenously (IV) is helpful. Hydrocortisone 200 mg IV or methylprednisolone 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 administered IM at a dose of 0.01 mg/kg or 0.3 mg, repeated every 10-15 minutes if necessary. Occasionally, intubation, or even tracheostomy, may be necessary. These patients should be admitted for at least 24 hours of observation.

Other pharmacologic options

Theoretical considerations suggest that leukotriene antagonists might be helpful; however, clinical observation has not confirmed the benefits of these agents in either urticaria or angioedema.

Because of their sedative side effects, first-generation antihistamines are usually recommended as add-on therapy when a second-generation antihistamine fails to relieve symptoms adequately. Thus, H1 antihistamines may be given in combination with H2 antihistamines. Most often, the initial dose is given at bedtime or late in the evening. Many patients may become more tolerant to the sedative effects of the first-generation antihistamine after a few days of treatment. The dosage can be gradually titrated toward better symptom control as tolerated.

Doxepin is a tricyclic antidepressant (TCA) that has potent H1-blocking activity. For this reason, it has been used off label to treat so-called recalcitrant angioedema—that is, angioedema that does not respond adequately to antihistamine treatment.

A number of well-controlled studies have shown cyclosporine and various other immunomodulatory drugs, including omalizumab, [62, 63] to be effective for many recalcitrant cases of chronic idiopathic urticaria and angioedema. [64, 47] However, a major limitation of omalizumab treatment is high cost. The beneift of these immunomodulators has not been well studied in angioedema without urticaria. [65]

Corticosteroid use in histamine-mediated angioedema should be limited to severe cases. Outpatient treatment should avoid long-term corticosteroid use.


Nonhistaminergic Angioedema (InH-AAE)

Angioedema caused by ACE inhibitors is a classic example of bradykinin-mediated angioedema. HAE, AAE, estrogen-dependent angioedema, and certain forms of idiopathic angioedema are also bradykinin-mediated. Antihistamines do not work for these patients, and corticosteroids have limited or no value. In C1-INH-AAE, treatment of the underlying disorder usually results in correction of the abnormality.

Administration of 2 units of fresh frozen plasma (FFP), which contains C1-INH, has been shown to be helpful in certain patients. However, FFP also contains substrates that may worsen angioedema attacks. If this treatment is used, be ready to intubate or perform a tracheostomy, if necessary.

Antifibrinolytic agents (eg, aminocaproic acid or tranexamic acid) may be helpful in treating HAE, C1-INH-AAE, and certain cases of InH-IAE. However, they are not indicated in the treatment of IH-AAE. The exact mechanism by which these agents act against angioedema is uncertain, but it is probably related to inhibition of plasmin and a subsequent effect on bradykinin metabolism.

Acute HAE attacks can be treated with infusion of C1-INH 20 U/kg. This agent is also reportedly used to treat other types of angioedema attacks, though its clinical efficacy against those other types has not been fully studied.

Administration of nanofiltered C1-INH concentrate can shorten the duration of acute HAE attacks. In randomized trials by Zuraw et al, the median time to onset of unequivocal relief was 2 hours with nanofiltered C1-INH concentrate versus more than 4 hours with placebo. [66] When used for prophylaxis, nanofiltered C1-INH concentrate reduced the number of acute attacks over a 12-week period from 12.73 to 6.26.

Subsequently, Riedl et al showed that 68% of patients achieved unequivocal relief within 1 hour after receiving nanofiltered C1-INH concentrate, and 87% achieved relief within 4 hours. [67] The median time to onset of relief was 0.75 hour. Currently, however, purified C1-INH is approved by the FDA only for prophylaxis.

In 2009, ecallantide, a potent, selective, reversible inhibitor of plasma kallikrein that suppresses bradykinin generation, was approved by the FDA for treatment of acute HAE attacks. During such attacks, unregulated plasma kallikrein activity leads to excessive bradykinin generation, resulting in swelling, inflammation, and pain. The inhibition of plasma kallikrein reduces the conversion of kininogen to bradykinin. [68]

In 2011, icatibant, a bradykinin B2 receptor antagonist, was approved by the FDA for the treatment of acute HAE attacks. [69] This agent is administered subcutaneously via prefilled syringes that can be can be carried and stored at room temperature. Icatibant can be self-injected by the patient. [70]

A 2012 guideline from the Hereditary Angioedema International Working Group includes the following management recommendations for individuals with HAE [71] :

  • For treatment of acute attacks, provide all HAE patients with access to at least 1 specific medication, such as C1 inhibitors (plasma-derived or recombinant), icatibant, or ecallantide, even if asymptomatic

  • Whenever possible, have patients keep medication on hand to treat acute attacks at home, and train patients to self-administer these medications

  • Advise patients to treat any attack, regardless of location, as soon as it is clearly recognized and to report to the hospital if laryngeal symptoms persist after initial treatment


C1-INH-HAE in Women

An international panel has proposed guidelines for management of gynecologic and obstetric issues in women with C1INH-HAE. Recommendations of this panel include the following [72] :

  • For contraception, estrogens should be avoided; barrier methods, intrauterine devices, and progestins can be used

  • Attenuated androgens are contraindicated during pregnancy and should be discontinued before attempting conception

  • During pregnancy, plasma-derived human C1-INH is preferred for acute treatment, short-term prophylaxis, or long-term prophylaxis

  • During pregnancy, tranexamic acid or virally inactivated FFP can be used for long-term prophylaxis if human plasma-derived C1-INH is not available

  • No pregnancy safety data are available on icatibant, ecallantide, or recombinant human C1-INH (rhC1INH)

  • During delivery, plasma-derived human C1-INH prophylaxis is advised before forceps or vacuum extraction or cesarean section

  • Regional anesthesia is preferred to endotracheal intubation for cesarean section



The FDA has approved various agents including C1-INHs, the kallikrein inhibitor ecallantide, lanadelumab, a monoclonal antibody that targets kallikrein, and the bradykinin-receptor antagonist icatibant for use in patients with HAE, either as prophylaxis or to treat acute attacks. (See Hereditary Angioedema.)

In August 2018, the FDA approved lanadelumab, a monoclonal antibody that targets kallikrein, for prophylaxis of HAE. Approval was based on the HELP clinical trial which investigated the efficacy and safety of lanadelumab for long-term prophylaxis against angioedema attacks in hereditary angioedema (HAE). Of 125 patients, 113 completed the trial. All lanadelumab dosing regimens significantly reduced the mean monthly attack rates of HAE compared to placebo (P < 0.001) over the 26-week duration of the study. The 300 mg SC every 2 week regimen reduced attacks by 92.8% from baseline in patient with < 2 attacks per month and by 88.2% in patients whose baseline was 2 to < 3 attacks per month. [78]

FFP has been used for short-term prophylaxis of C1-INH–related angioedema. In patients with C1-INH-AAE, treatment of the underlying disorder usually results in elimination of angioedema.

The Hereditary Angioedema International Working Group guidelines consider long-term prophylaxis to be appropriate for C1-INH-HAE patients in whom on-demand acute treatment is inadequate to minimize disease. [71] The Working Group found high levels of evidence for the efficacy of both attenuated androgens and plasma-derived C1-INH, but not for the efficacy of antifibrinolytic agents. [71]

Androgen derivatives (eg, danazol, oxandrolone) have been used in patients with HAE as a prophylactic option. These agents can be considered for nonpregnant, nonlactating patients older than 16 years, and they may also help for certain cases of C1-INH-AAE. However, androgen derivatives are not recommended if the patient cannot tolerate them or if the effective danazol dosage exceeds 200 mg/day. There is no clear benefit to the use of androgen derivatives in treating other types of angioedema. [14]

Plasma-derived C1-INH can also be considered for all patients with C1-INH-HAE. Because a dosage of 1000 units twice weekly reduces attack rates only by 50%, some patients may need higher dosages for better control. [71]

If a patient taking an ACE inhibitor experiences an attack of angioedema, the medication should be withdrawn. Most of these patients can tolerate an angiotensin II receptor blocker (ARB); however, in a very few patients, even an ARB will trigger angioedema and must therefore be avoided. Similarly, patients with a history of episodes possibly triggered by estrogen-based oral contraceptives should avoid such agents.

For patients with an established food allergy or food additive hypersensitivity, avoidance of the identified allergen is indicated. Most patients do not need activity restriction. However, physical trauma may trigger certain types of angioedema; therefore, patients should exercise caution when engaging in contact sports.

For IH-AAE, 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 the agents most commonly prescribed for this condition. Leukotriene antagonists (eg, montelukast and zafirlukast), a 5-lipoxygenase inhibitor (zileuton), and immunomodulators (eg, cyclosporine) have been used.

Corticosteroid treatment is reserved for very recalcitrant cases. Antifibrinolytics have been tried in some patients with success (those with IH-AAE, C1-INH-AAE, and HAE). Androgen derivatives and progesterone-only oral contraceptives may also be considered.



When symptoms of angioedema 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 are advisable. Allergy and immunology specialists should also be consulted (eg, to identify potential allergies, medication reactions, or changes in certain body enzymes).