What is the management for angioedema (rapid swelling of the dermis, subcutaneous tissue, mucosa, and submucosal tissues)?

Management of Angioedema

Immediately assess for airway compromise and determine whether the angioedema is histamine-mediated or bradykinin-mediated, as this distinction fundamentally determines treatment—standard allergic therapies (epinephrine, antihistamines, corticosteroids) work only for histamine-mediated angioedema and are completely ineffective for bradykinin-mediated forms. 1, 2

Immediate Airway Assessment and Stabilization

• Assess airway patency first in every patient presenting with angioedema, as this is the most critical initial step regardless of etiology 1, 2
• Monitor closely for signs of impending airway closure: change in voice, loss of ability to swallow, or difficulty breathing 1, 2
• Consider elective intubation early if any of these warning signs are present, before complete obstruction occurs 1, 2
• All patients with oropharyngeal or laryngeal involvement must be observed in a facility capable of performing emergency intubation or tracheostomy 1, 2
• Avoid direct visualization of the airway unless absolutely necessary, as instrumentation trauma can worsen the edema 1
• Have backup tracheostomy equipment immediately available if intubation is unsuccessful 1
• Awake fiberoptic intubation is the optimal technique when intubation is required, as it minimizes risk of worsening edema 1

Rapid Clinical Differentiation: Histamine vs. Bradykinin-Mediated

The presence or absence of urticaria is the most important clinical clue:

• Concomitant urticaria and pruritus strongly suggest histamine-mediated angioedema (occurs in approximately 50% of histamine-mediated cases) 1, 3
• Absence of urticaria and pruritus suggests bradykinin-mediated angioedema 1
• Obtain medication history immediately, specifically asking about ACE inhibitors, as these are the most common cause of bradykinin-mediated angioedema 1, 4, 5
• Ask about family history of recurrent angioedema or unexplained abdominal pain attacks, which suggest hereditary angioedema 1, 4
• Recurrent abdominal pain attacks or unexplained swelling episodes are characteristic of bradykinin-mediated forms 1

Treatment for Histamine-Mediated Angioedema

For histamine-mediated angioedema with significant symptoms or any airway involvement:

• Administer epinephrine (0.1%) 0.3 mL subcutaneously or 0.5 mL by nebulizer immediately 1, 2
• Give IV diphenhydramine 50 mg 1, 2
• Give IV methylprednisolone 125 mg 1, 2
• Add H2 blockers: ranitidine 50 mg IV or famotidine 20 mg IV 1, 2
• Do not delay epinephrine administration if there is any concern for airway compromise—this is a critical pitfall to avoid 1, 2

For chronic management of histamine-mediated angioedema:

• Use high-dose second-generation H1 antihistamines (fourfold the standard dose) 2
• Add montelukast if antihistamines alone fail 2

Treatment for Bradykinin-Mediated Angioedema

Hereditary Angioedema (HAE)

First-line acute treatment options:

• Plasma-derived C1 inhibitor concentrate 1000-2000 U (or 20 IU/kg) intravenously 1, 2, 4
• Icatibant 30 mg subcutaneously in the abdominal area 1, 2, 4, 6
  • 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 injections in 24 hours 6
  • Patients may self-administer upon recognition of an HAE attack 2, 6
  • For laryngeal attacks treated with icatibant, advise patients to seek immediate medical attention 6
• Fresh frozen plasma (10-15 mL/kg) may be considered if specific targeted therapies are unavailable 1, 2, 4

Critical point: Standard allergic treatments (epinephrine, antihistamines, corticosteroids) are completely ineffective for HAE—using these wastes precious time and provides no benefit 1, 2, 4

Early treatment is critical for HAE attacks, as outcomes improve significantly when therapy is administered as early as possible 2, 4

ACE Inhibitor-Induced Angioedema

• Immediately and permanently discontinue the ACE inhibitor—this is the cornerstone of treatment 1, 2, 4
• Never restart the ACE inhibitor, as patients who react to one ACE inhibitor will typically react to all others (class effect) 4
• Consider bradykinin pathway-targeted therapies such as icatibant 30 mg subcutaneously 1, 2, 4
• Fresh frozen plasma (10-15 mL/kg) may be considered if icatibant or C1 inhibitor are unavailable 1, 4
• If switching antihypertensive therapy, note that ARBs carry a modest recurrence risk (2-17%), though most patients tolerate them without recurrence 4
• Symptoms can recur for weeks to months after ACE inhibitor discontinuation 7

Supportive Care for All Types

• Provide analgesics and antiemetics for abdominal attacks 1, 2
• Provide aggressive IV hydration for abdominal attacks due to third-space fluid sequestration 1
• Monitor vital signs and neurological status continuously 1
• Avoid narcotic addiction risk in patients with frequent HAE attacks 1

Observation and Disposition

• Duration of observation should be based on severity and location of angioedema 1
• Oropharyngeal or laryngeal involvement requires extended monitoring in a facility capable of emergency airway management 1, 2
• Do not discharge patients with oropharyngeal or laryngeal involvement without adequate observation—this is a critical safety pitfall 2
• Laryngeal attacks are potentially life-threatening with historical mortality rates of approximately 30% or higher 2

Prophylaxis for HAE Patients

Short-Term Prophylaxis (Before Dental or Surgical Procedures)

• Plasma-derived C1 inhibitor 1000-2000 U intravenously 2, 4
• Alternative options include attenuated androgens (danazol 2.5-10 mg/kg) or tranexamic acid 2
• For high-risk procedures when first-line therapies are unavailable, consider attenuated androgens, fresh frozen plasma, or combination therapy 2

Long-Term Prophylaxis (For Frequent Attacks)

• Androgens (danazol 100 mg on alternate days) 2, 4
• Tranexamic acid (30-50 mg/kg/day) where first-line treatments are unavailable 2, 4
• Regular monitoring for side effects with blood testing and periodic hepatic ultrasounds is required for patients receiving attenuated androgens 2

Special Populations

Children

• Tranexamic acid is the preferred drug for long-term prophylaxis where first-line agents are unavailable 1, 2
• Fresh frozen plasma should be considered for acute treatment and short-term prophylaxis where first-line agents are unavailable 2
• Attenuated androgens may exceptionally be considered for long-term prophylaxis but side effect burden is likely to be high 2

Pregnant Patients

• C1-INH is the only recommended acute and prophylactic treatment for pregnant patients with hereditary angioedema 1, 2

High-Risk Populations for ACE Inhibitor-Induced Angioedema

• African American patients, smokers, older individuals, and females are at higher risk 1

Diagnostic Workup (After Stabilization)

• Measure C4 level first as a screening test 1
• If C4 is low, follow with C1 inhibitor level and function testing for suspected hereditary angioedema 1
• Consider targeted gene sequencing for HAE with normal C1 inhibitor (HAE-nC1INH) if clinical suspicion remains high 1