What is the workup and management for possible angioedema?

Workup and Management of Possible Angioedema

Immediate Airway Assessment and Stabilization

Assess for airway compromise immediately—this is the most critical first step and takes absolute priority over diagnostic workup. 1

• Monitor closely for signs of impending airway closure: change in voice, loss of ability to swallow, or difficulty breathing 2, 1
• All patients with oropharyngeal or laryngeal involvement must be observed in a medical facility capable of performing intubation or tracheostomy 2, 3, 1
• Consider elective intubation before complete airway obstruction occurs if any signs of airway compromise are present 3, 1
• Avoid direct visualization of the airway unless absolutely necessary, as trauma from the procedure can worsen angioedema 2, 3, 1
• Ensure backup tracheostomy equipment is immediately available if intubation is unsuccessful 3, 1

Rapid Clinical Differentiation: Histamine vs. Bradykinin-Mediated

The key to appropriate treatment is quickly determining whether angioedema is histamine-mediated or bradykinin-mediated, as treatments differ completely. 1

Clinical Features Suggesting Histamine-Mediated (Allergic) Angioedema:

• Concomitant urticaria (present in ~50% of cases) 2, 4
• Pruritus 5
• Rapid onset (minutes) 5
• Recent exposure to allergens (foods like eggs, shellfish, nuts; insect stings; medications) 4, 5
• Response to antihistamines, corticosteroids, or epinephrine 2, 5

Clinical Features Suggesting Bradykinin-Mediated Angioedema:

• Absence of urticaria and pruritus 2, 5
• Slower onset (hours) 5
• ACE inhibitor use (most common cause) 3, 1
• Family history of recurrent angioedema (suggests hereditary angioedema) 2, 1
• Lack of response to standard allergic treatments 3, 1, 5
• Recurrent abdominal pain attacks or unexplained swelling episodes 2

Initial Treatment Based on Type

For Histamine-Mediated (Allergic) Angioedema:

Administer epinephrine (0.1%) 0.3 mL subcutaneously or 0.5 mL by nebulizer immediately for significant symptoms or any airway involvement. 3, 1

• Give IV diphenhydramine 50 mg 3, 1
• Give IV methylprednisolone 125 mg 3, 1
• Add H2 blocker: ranitidine 50 mg IV or famotidine 20 mg IV 3, 1

For Bradykinin-Mediated Angioedema:

Standard angioedema treatments (epinephrine, corticosteroids, antihistamines) are NOT effective for bradykinin-mediated angioedema and should not be relied upon. 3, 1, 6, 5

ACE Inhibitor-Induced Angioedema:

• Permanently discontinue the ACE inhibitor immediately 3, 1
• Administer icatibant (selective bradykinin B2 receptor antagonist) 30 mg subcutaneously in the abdominal area; additional injections may be given at 6-hour intervals (maximum 3 injections in 24 hours) 3, 1
• Alternative: plasma-derived C1 inhibitor concentrate 1000-2000 U (or 20 IU/kg) intravenously 3, 1
• If specific therapies unavailable, consider fresh frozen plasma (10-15 ml/kg), though be aware of potential paradoxical worsening 2, 3, 1
• Be aware that propensity for angioedema can continue for up to 6 weeks after ACE inhibitor discontinuation 3

Hereditary Angioedema (HAE):

• Plasma-derived C1 inhibitor concentrate 1000-2000 U intravenously is the most effective first-line treatment 1, 6
• Alternative: icatibant 30 mg subcutaneously 1, 6
• Alternative: ecallantide (plasma kallikrein inhibitor), though must be administered by healthcare professional due to anaphylaxis risk 6
• Early treatment is critical—most effective when administered as early as possible during an attack 6

Diagnostic Workup (After Stabilization)

Immediate History:

• Obtain medication history immediately, specifically asking about ACE inhibitors 1
• Document timing of onset (minutes vs. hours) 5
• Ask about previous similar episodes 2
• Inquire about family history of recurrent angioedema or known HAE 2, 1
• Identify potential allergen exposures 4, 5

Laboratory Testing for Suspected Bradykinin-Mediated Angioedema:

If hereditary angioedema is suspected, measure C4 level first (screening test), followed by C1 inhibitor level and function if C4 is low. 2

• C4 level (low in HAE with C1 inhibitor deficiency) 2
• C1 inhibitor quantitative level 2
• C1 inhibitor functional assay 2
• If C1 inhibitor levels and function are normal but clinical suspicion remains high, consider targeted gene sequencing for HAE with normal C1 inhibitor (HAE-nC1INH) 2

Trial of Therapy as Diagnostic Tool:

• For patients with normal C1 inhibitor testing but recurrent angioedema without urticaria, trial high-dose second-generation H1 antihistamine (fourfold standard dose) for adequate duration 2
• If unresponsive, add daily montelukast 2
• If still unresponsive, trial omalizumab for 4-6 months (most mast cell-mediated angioedema responds) 2
• If no response to above, consider trial of bradykinin B2 receptor antagonist—prompt response supports bradykinin-mediated diagnosis 2

Observation and Disposition

• Duration of observation should be based on severity and location of angioedema, with oropharyngeal/laryngeal involvement requiring extended monitoring 2, 3, 1
• Do not discharge patients with oropharyngeal or laryngeal involvement without adequate observation 1
• Monitor vital signs and neurological status closely 1

Symptomatic Management for Non-Airway Involvement

Abdominal Attacks:

• Provide narcotic medications for pain control (but avoid out-of-hospital use of potent narcotics like fentanyl patches or oxycodone due to addiction risk) 2
• Give antiemetics for nausea and vomiting 2
• Provide aggressive IV hydration due to third-space fluid sequestration 2, 1

Genitourinary Attacks:

• Provide pain medication if discomfort is severe 2
• Consider catheterization if patient cannot urinate 2

Critical Pitfalls to Avoid

• Never delay treatment of acute attacks involving the airway—this increases morbidity and mortality 6
• Do not use standard allergic treatments (antihistamines, corticosteroids, epinephrine) as first-line for bradykinin-mediated angioedema—they are ineffective 3, 1, 6, 5
• Do not switch ACE inhibitor patients to ARBs without extreme caution—there is a 2-17% risk of recurrent angioedema 3
• Document ACE inhibitor allergy prominently in the medical record 3
• Avoid narcotic addiction in HAE patients with frequent attacks 2, 1

Follow-Up and Long-Term Management

For ACE Inhibitor-Induced Angioedema:

• Permanent discontinuation of ACE inhibitor in all cases 3
• Document allergy prominently 3
• Use extreme caution if considering ARB (2-17% cross-reactivity) 3

For Hereditary Angioedema:

• All patients should have access to on-demand HAE-specific treatment and a contingency plan for acute attacks 6
• Consider long-term prophylaxis for patients with frequent or severe attacks: plasma-derived C1 inhibitor or lanadelumab as first-line; attenuated androgens or tranexamic acid as second-line 6
• Screen all family members when HAE diagnosis is made 2, 6
• Provide short-term prophylaxis before dental work, surgical procedures, or invasive medical procedures 6