How is angioedema treated?

Treatment of Angioedema

Immediately assess for airway compromise and determine the type of angioedema, as treatment differs completely between histamine-mediated and bradykinin-mediated forms—standard allergy treatments (epinephrine, antihistamines, corticosteroids) are completely ineffective for hereditary angioedema (HAE) and ACE inhibitor-induced angioedema. 1, 2

Immediate Airway Assessment

• Monitor all patients with oropharyngeal or laryngeal involvement in a facility capable of performing intubation or tracheostomy, as laryngeal attacks carry historical mortality rates approaching 30% without proper management 1, 3
• Consider elective intubation if signs of impending airway closure develop: voice changes, loss of ability to swallow, or difficulty breathing 1, 3
• Avoid direct visualization of the airway unless absolutely necessary, as trauma can worsen angioedema 3

Determine Angioedema Type

Key Clinical Distinctions

• Histamine-mediated angioedema presents with urticaria (hives), pruritus, and responds to antihistamines and epinephrine 3, 4
• Bradykinin-mediated angioedema (HAE, ACE inhibitor-induced) has no urticaria, no pruritus, and does NOT respond to standard allergy treatments 3, 4
• Obtain detailed medication history, particularly ACE inhibitors, which cause angioedema in 0.1-0.7% of users and can occur even after years of continuous therapy 5

Treatment by Type

Histamine-Mediated Angioedema

Administer intramuscular epinephrine 0.3 mL (0.1%) immediately for significant symptoms or any airway involvement 1, 3

• Give IV diphenhydramine 50 mg and IV methylprednisolone 125 mg as adjunctive therapy 1, 3
• Add H2 blockers: ranitidine 50 mg IV or famotidine 20 mg IV 1
• For chronic management, use high-dose second-generation H1 antihistamines (fourfold the standard dose) 5, 1
• Add montelukast if antihistamines alone fail 5, 1
• If unresponsive to high-dose antihistamines plus montelukast, trial omalizumab for 4-6 months 5

Bradykinin-Mediated Angioedema (HAE)

First-line treatment is plasma-derived C1 inhibitor (1000-2000 U intravenously) or icatibant 30 mg subcutaneously 1, 2, 6

• Icatibant is FDA-approved for acute HAE attacks in adults ≥18 years; if response is inadequate or symptoms recur, additional 30 mg injections may be given at intervals of at least 6 hours 6
• Do not administer more than 3 icatibant injections in 24 hours 6
• Epinephrine, antihistamines, and corticosteroids are NOT effective and should not be used 5, 1, 2
• Fresh frozen plasma (10-15 mL/kg) may be considered if specific targeted therapies are unavailable, though it may acutely exacerbate some attacks 5, 1
• Patients may self-administer icatibant upon recognition of an HAE attack, which significantly reduces time to treatment 2, 6

ACE Inhibitor-Induced Angioedema

Immediately and permanently discontinue the ACE inhibitor 5, 1, 2

• Consider icatibant 30 mg subcutaneously for acute treatment 5, 1, 2
• Discontinuation is the cornerstone of therapy, though there may be a significant time lag (1-2 months or longer) between stopping the drug and resolution of angioedema propensity 5
• Antihistamines, corticosteroids, and epinephrine have not been shown to be efficacious 5

Prophylaxis for HAE Patients

Short-Term Prophylaxis (Before Procedures)

Administer plasma-derived C1 inhibitor (1000-2000 U intravenously) before dental or surgical procedures 1, 2

• Alternative options include attenuated androgens (danazol 2.5-10 mg/kg) or tranexamic acid 1
• For high-risk procedures when first-line therapies are unavailable, consider fresh frozen plasma 1

Long-Term Prophylaxis

For patients with frequent attacks, use androgens (danazol 100 mg on alternate days) or tranexamic acid (30-50 mg/kg/day) 1, 2

• Plasma-derived C1 inhibitor provides effective and safe long-term prophylaxis 5
• Regular monitoring for side effects with blood testing and periodic hepatic ultrasounds is required for patients receiving attenuated androgens 1
• Dose and effectiveness should be based on clinical criteria, not laboratory parameters 5

Special Populations

Children

Tranexamic acid is the preferred drug for long-term prophylaxis in children where first-line C1-INH replacement is unavailable 1, 3

• Fresh frozen plasma should be considered for acute treatment and short-term prophylaxis where first-line agents are unavailable 1
• Attenuated androgens may exceptionally be considered but carry high side effect burden 1, 3

Pregnant Patients

C1-INH is the only recommended acute and prophylactic treatment for pregnant patients with HAE 1

Diagnostic Workup for Recurrent Angioedema

When evaluating recurrent angioedema without hives, follow this stepwise approach 5:

1. Confirm clinical history with photos and laryngoscopic/imaging evidence to differentiate true angioedema from factitious cases 5
2. Measure C4, C1INH antigen, and C1INH function to exclude C1INH deficiency 5
3. Stop suspected medications and assess response over 1-2 months 5
4. Obtain detailed family history for evidence of recurrent angioedema or HAE diagnosis in relatives 5
5. Trial high-dose H1 antihistamines (fourfold standard dose) plus montelukast to exclude mast cell-mediated angioedema 5
6. Consider targeted gene sequencing if unresponsive to antihistamines and omalizumab 5
7. Trial bradykinin B2 receptor antagonist if pathogenic variant not found but clinical suspicion remains high 5

Critical Pitfalls to Avoid

• Never delay epinephrine in histamine-mediated angioedema with airway involvement 1, 3
• Never use standard allergy treatments for confirmed or suspected HAE, as they are ineffective and waste critical time 1, 2, 3
• 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
• Recognize that ACE inhibitor-induced angioedema can occur even after years of continuous therapy, and the relationship is often missed and underestimated 5, 7