What is the treatment for angioedema?

Treatment of Angioedema

Treatment of angioedema depends critically on identifying whether it is histamine-mediated (allergic) or bradykinin-mediated (hereditary/ACE inhibitor-induced), as these require completely different therapies and standard allergy treatments are ineffective and waste critical time in bradykinin-mediated cases. 1, 2

Immediate Airway Assessment

• Assess for airway compromise immediately as the first critical step in any patient presenting with angioedema. 1, 3
• Patients with oropharyngeal or laryngeal involvement require close monitoring in a facility capable of performing intubation or tracheostomy. 1, 3
• Consider elective intubation if signs of impending airway closure develop, including voice changes, loss of ability to swallow, or difficulty breathing. 1, 3
• Laryngeal attacks carry historical mortality rates approaching 30% without appropriate treatment. 1, 3

Determine Angioedema Type

The presence or absence of urticaria is the key clinical distinguishing feature:

• Histamine-mediated angioedema presents WITH urticaria and pruritus, and responds to antihistamines and epinephrine. 3, 4
• Bradykinin-mediated angioedema (hereditary angioedema or ACE inhibitor-induced) presents WITHOUT urticaria or pruritus, and does NOT respond to standard allergy treatments. 5, 3, 6

Treatment Based on Type

Histamine-Mediated (Allergic) Angioedema

For significant symptoms or any airway involvement:

• Administer epinephrine 0.3 mL of 0.1% solution subcutaneously or 0.5 mL by nebulizer immediately. 1
• Give IV diphenhydramine 50 mg and IV methylprednisolone 125 mg as adjunctive therapy. 1, 3
• Add H2 blockers such as ranitidine 50 mg IV or famotidine 20 mg IV. 1

For chronic management (symptoms >6 weeks):

• Use high-dose second-generation H1 antihistamines at fourfold the standard dose. 5, 1
• Add montelukast if antihistamines alone fail to prevent attacks. 5, 1
• Consider omalizumab (4-6 months course) if unresponsive to high-dose antihistamines plus montelukast. 5

Bradykinin-Mediated Angioedema (Hereditary Angioedema)

Critical pitfall: Epinephrine, corticosteroids, and antihistamines are NOT efficacious and are NOT recommended for HAE treatment. 5, 1, 2

Acute attack treatment (first-line):

• Administer plasma-derived C1 inhibitor concentrate (Berinert) 20 International Units per kg body weight intravenously at a rate of approximately 4 mL per minute. 7
• Alternative: Icatibant (bradykinin B2 receptor antagonist) 30 mg subcutaneously. 1, 2
• Early treatment is critical—on-demand treatment is most effective when administered as early as possible in an attack. 2
• Appropriately trained patients may self-administer upon recognition of an HAE attack, though patients should immediately seek medical attention for laryngeal attacks. 7, 1

If specific targeted therapies unavailable:

• Fresh frozen plasma (10-15 mL/kg) may be considered, though it might acutely exacerbate some attacks and caution is required. 5, 1

Short-term prophylaxis (before dental/surgical procedures):

• Plasma-derived C1 inhibitor 1000-2000 U intravenously. 1, 2
• Alternative options include attenuated androgens (danazol 2.5-10 mg/kg) or tranexamic acid. 1

Long-term prophylaxis (for frequent attacks):

• Androgens (danazol 100 mg on alternate days) with regular monitoring for side effects by blood testing and periodic hepatic ultrasounds. 1, 2
• Tranexamic acid (30-50 mg/kg/day) should be considered where first-line treatments are not available. 1
• In children, tranexamic acid is the preferred long-term prophylaxis where first-line C1-INH replacement is unavailable, as attenuated androgens carry high side effect burden. 1, 3
• In pregnant patients, C1-INH is the only recommended acute and prophylactic treatment. 1

ACE Inhibitor-Induced Angioedema

• Immediately discontinue the ACE inhibitor permanently. 1, 2
• Consider bradykinin pathway-targeted therapies such as icatibant 30 mg subcutaneously. 1, 2, 8
• One study examining off-label use of icatibant demonstrated efficacy over control treatment with corticosteroids and antihistamines. 8
• Standard allergy treatments (antihistamines, corticosteroids, epinephrine) are ineffective for ACE inhibitor-induced angioedema. 1, 9

Supportive Care for All Types

• Provide aggressive IV hydration for abdominal attacks. 2, 3
• Administer antiemetics for nausea/vomiting. 2, 3
• Give appropriate analgesia for pain control, but avoid creating narcotic dependence in patients with frequent attacks. 2, 3

Diagnostic Workup for Recurrent Angioedema

When evaluating recurrent angioedema without urticaria:

• Confirm clinical history of documented recurrent angioedema without hives using photos, laryngoscopic, and imaging evidence. 5
• Measure C4, C1INH antigen, and C1INH function to exclude C1INH deficiency. 5, 3
• Stop suspected medications (ACE inhibitors, dipeptidyl peptidase inhibitors, neprilysin inhibitors, tissue plasminogen activators, NSAIDs) and assess response for 1-3 months. 5
• If unresponsive to mast cell-directed therapy (high-dose antihistamines, montelukast, omalizumab), consider targeted gene sequencing for known HAE pathogenic variants. 5
• A prompt and durable response to a bradykinin B2 receptor antagonist early in an attack supports the diagnosis of bradykinin-mediated angioedema. 5

Critical Pitfalls to Avoid

• Never delay epinephrine administration in histamine-mediated angioedema with airway involvement. 1, 3
• Never use standard angioedema treatments (epinephrine, corticosteroids, antihistamines) for bradykinin-mediated angioedema, as they are ineffective. 5, 1, 2
• Never discharge patients with oropharyngeal or laryngeal involvement without adequate observation. 1, 3
• Never prescribe ACE inhibitors to patients with any form of angioedema, especially HAE. 3, 9
• Recognize that ACE inhibitor-induced angioedema can occur after long-term treatment, and the duration of use does not lessen the probability that the ACE inhibitor is the cause. 9