What is the management of angioedema?

Management of Angioedema

Immediate Airway Assessment is the First Priority

Assess for airway compromise immediately in every patient presenting with angioedema, as this is the single most critical first step that determines survival. 1, 2 Look specifically for change in voice, loss of ability to swallow, stridor, or difficulty breathing as signs of impending airway closure. 1, 2

• Patients with oropharyngeal or laryngeal involvement must be monitored in a facility capable of emergency intubation or tracheostomy. 1, 2
• Consider elective intubation before complete obstruction occurs if any signs of impending airway closure are present. 1, 2
• Avoid direct laryngoscopy unless absolutely necessary, as instrumentation can worsen the edema. 2
• Have backup tracheostomy equipment immediately available in case intubation fails. 2

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Determine the Type of Angioedema to Guide Treatment

The presence or absence of urticaria (hives) is the most important clinical feature that determines your treatment approach. 3

Histamine-Mediated Angioedema (WITH Hives)

• Urticaria is present in approximately 50% of allergic angioedema cases. 3, 2
• Pruritus (itching) is typically present. 2
• Responds to antihistamines, corticosteroids, and epinephrine. 1, 4

Bradykinin-Mediated Angioedema (WITHOUT Hives)

• Absence of urticaria and pruritus strongly suggests bradykinin-mediated causes. 3, 2
• Includes hereditary angioedema (HAE), ACE inhibitor-induced angioedema, and acquired C1-INH deficiency. 1, 5
• Does NOT respond to antihistamines, corticosteroids, or epinephrine. 1, 2, 5

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Treatment Based on Angioedema Type

For Histamine-Mediated Angioedema (WITH Hives)

Administer epinephrine immediately for any significant symptoms or airway involvement. 1, 3, 2

• Give epinephrine 0.3 mL (0.1% solution) subcutaneously or 0.5 mL by nebulizer. 1, 2
• Administer IV diphenhydramine 50 mg and IV methylprednisolone 125 mg. 1, 2
• Add H2 blockers: ranitidine 50 mg IV or famotidine 20 mg IV. 1, 2

For chronic management of recurrent histamine-mediated angioedema with hives:

• Start with high-dose second-generation H1 antihistamines at fourfold the standard dose. 3
• If antihistamines fail as monotherapy, add daily montelukast. 3
• If unresponsive to high-dose antihistamines plus montelukast, initiate omalizumab for 4-6 months. 3

For Bradykinin-Mediated Angioedema (WITHOUT Hives)

Standard allergy treatments (epinephrine, antihistamines, corticosteroids) are completely ineffective and should NOT be used as primary treatment. 1, 3, 2, 5

Hereditary Angioedema (HAE) Acute Treatment:

• First-line: Administer plasma-derived C1 inhibitor 1000-2000 U (or 20 IU/kg) intravenously. 1, 2
• Alternative first-line: Icatibant 30 mg subcutaneously in the abdominal area. 1, 2, 6
• If specific therapies unavailable, consider fresh frozen plasma 10-15 mL/kg. 1, 2
• Additional doses of icatibant (30 mg) may be given at intervals of at least 6 hours if response is inadequate, but do not exceed 3 injections in 24 hours. 6

ACE Inhibitor-Induced Angioedema:

• Immediately and permanently discontinue the ACE inhibitor. 1, 3, 2
• Consider icatibant 30 mg subcutaneously for acute treatment. 1, 2
• Standard allergy medications are ineffective. 5, 7

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Prophylaxis for Hereditary Angioedema

Short-Term Prophylaxis (Before Procedures)

Administer plasma-derived C1 inhibitor 1000-2000 U intravenously before dental or surgical procedures. 8, 1

The risk of angioedema after dental extraction is relatively high at 21.5%, while non-dental surgical procedures carry only a 5.7% risk. 8

When first-line C1-INH is unavailable:

• Use attenuated androgens (danazol 2.5-10 mg/kg daily, maximum 600 mg/day) starting 5 days before until 2-3 days after the procedure. 8, 1
• Alternative: Tranexamic acid 30-50 mg/kg/day (maximum 3-4.5 g daily) in 2-3 divided doses, same timing. 8, 1
• For high-risk procedures, consider combination of attenuated androgens plus fresh frozen plasma. 8

Long-Term Prophylaxis (For Frequent Attacks)

When first-line prophylactic agents are unavailable:

• Tranexamic acid 30-50 mg/kg/day (maximum 3 g/day) in 2-3 divided doses is preferred, especially in children and adolescents due to better tolerability. 8, 1
• Alternative: Attenuated androgens (danazol 100 mg on alternate days, titrated up to maximum 600 mg/day based on individual response). 8, 2
• Implement regular monitoring for patients on attenuated androgens: blood testing and periodic hepatic ultrasounds to detect side effects. 8, 1, 2

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Special Populations

Pregnant Patients with HAE:

• C1-INH (plasma-derived C1 inhibitor) is the only recommended treatment for both acute attacks and prophylaxis during pregnancy. 8, 1, 3
• Attenuated androgens are contraindicated and must be discontinued before attempting conception. 8
• Tranexamic acid or virally inactivated fresh frozen plasma can be used for long-term prophylaxis if C1-INH is unavailable. 8
• No safety data exist for icatibant, ecallantide, or recombinant C1-INH in pregnancy. 8

Children:

• Tranexamic acid is the preferred agent for long-term prophylaxis where first-line treatments are unavailable due to better tolerability. 8, 1, 3
• Fresh frozen plasma should be considered for acute treatment and short-term prophylaxis when first-line agents are unavailable. 1
• Attenuated androgens may be considered exceptionally but carry high side effect burden. 1

Contraception in Women with HAE:

• Estrogens should be avoided as they can trigger attacks. 8
• Safe options include barrier methods, intrauterine devices, and progestins. 8

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Diagnostic Workup (After Stabilization)

• Obtain detailed medication history immediately, specifically asking about ACE inhibitors, ARBs, NSAIDs, and DPP-4 inhibitors. 3, 2
• Measure C4 level first as a screening test. 3, 2
• If C4 is low, measure C1-INH antigen level and C1-INH functional activity to diagnose HAE. 3, 2
• Obtain photos, laryngoscopic evidence, or imaging during attacks to confirm true angioedema and differentiate from factitious presentations. 3

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Critical Pitfalls to Avoid

• Never delay epinephrine in histamine-mediated angioedema with airway involvement. 1, 2
• Never use antihistamines, corticosteroids, or epinephrine as primary treatment for bradykinin-mediated angioedema—they are completely ineffective. 1, 3, 2, 5
• Never discharge patients with oropharyngeal or laryngeal involvement without adequate observation, as laryngeal attacks carry historical mortality rates of approximately 30%. 1, 3
• Do not rechallenge patients with ACE inhibitors after angioedema—the discontinuation must be permanent. 1, 2
• Avoid narcotic addiction risk in HAE patients with frequent attacks by using appropriate prophylaxis and specific acute treatments. 2

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Supportive Care for All Types

• Provide analgesics and antiemetics for abdominal attacks. 2
• Administer aggressive IV hydration due to third-space fluid sequestration during abdominal attacks. 2
• Monitor vital signs and neurological status closely. 2
• Duration of observation should be based on severity and location, with extended monitoring for oropharyngeal/laryngeal involvement. 2