Symptoms and Treatment of Angioedema
Clinical Presentation of Angioedema
Angioedema manifests as localized, non-pitting swelling of the subcutaneous or submucosal tissues that develops suddenly and can be life-threatening when it involves the upper airway. 1
Key Symptoms by Location
Cutaneous and Mucosal Swelling:
- Periorbital swelling, lip swelling, and tongue enlargement are the most common presentations 2
- Extremity swelling that can be disabling but not life-threatening 1
- Genitourinary involvement causing severe discomfort and potential urinary retention 1
Oropharyngeal and Laryngeal Symptoms (Life-Threatening):
- Change in voice quality 1, 3
- Loss of ability to swallow 1, 3
- Difficulty breathing or sensation of throat tightness 1, 3
- These symptoms carry historical mortality rates of approximately 30% or higher if untreated 4
Abdominal Symptoms:
- Severe abdominal pain requiring narcotic analgesia 1
- Nausea and vomiting requiring antiemetics 1
- Third-space fluid sequestration necessitating aggressive hydration 1
Distinguishing Features:
- Angioedema typically occurs WITHOUT urticaria (hives) in approximately 50% of cases, though concomitant urticaria suggests histamine-mediated disease 2, 5
- Pruritus (itching) suggests allergic/histaminergic origin 5
- Attacks may be preceded by premonitory signs (prodromes) 1
Treatment Algorithm Based on Angioedema Type
Immediate Assessment (All Types)
Airway evaluation is the absolute first priority regardless of angioedema type. 4, 3
- Monitor for signs of impending airway closure: voice change, inability to swallow, dyspnea 1, 3
- All patients with oropharyngeal or laryngeal involvement must be observed in a facility capable of emergency intubation or tracheostomy 1, 3
- Consider elective intubation early if airway compromise signs develop, as anatomy becomes highly distorted 1, 3
- Avoid direct airway visualization unless absolutely necessary, as trauma can worsen swelling 1, 3
- Have backup tracheostomy immediately available 3
Histamine-Mediated (Allergic) Angioedema
For allergic angioedema with significant symptoms or airway involvement, administer epinephrine 0.3 mL of 0.1% solution subcutaneously or 0.5 mL by nebulizer immediately. 3, 6
Additional first-line therapy:
- IV diphenhydramine 50 mg 3
- IV methylprednisolone 125 mg 3
- H2 blockers: ranitidine 50 mg IV or famotidine 20 mg IV 3
For chronic histamine-mediated angioedema:
- High-dose second-generation H1 antihistamines (fourfold the standard dose) 4
- Add montelukast if antihistamines alone fail 4
Hereditary Angioedema (HAE) - Bradykinin-Mediated
Critical: Standard allergic treatments (epinephrine, antihistamines, corticosteroids) are NOT effective for HAE and represent a common emergency department error. 4, 3, 7
First-line on-demand treatments (choose one):
- Plasma-derived C1 inhibitor (pdC1INH): 1000-2000 U intravenously 1, 4, 3, 7
- Icatibant: 30 mg subcutaneously 1, 4, 3, 7
- Ecallantide: administered by healthcare provider within 8 hours of attack onset 1, 4
- Recombinant human C1 inhibitor (rhC1INH): intravenous administration 1
If specific therapies unavailable:
- Fresh frozen plasma 10-15 mL/kg may be considered, though it carries risk of paradoxical worsening due to providing additional contact system substrates 1, 3
- Be prepared to manage potential exacerbation of symptoms with fresh frozen plasma 1
Emerging oral therapies:
- Sebetralstat (oral plasma kallikrein inhibitor) has completed Phase 3 trials 1
- Deucrictibant (oral bradykinin B2 receptor antagonist) is in Phase 3 trials 1
ACE Inhibitor-Induced Angioedema
Immediately and permanently discontinue the ACE inhibitor - this is non-negotiable. 3, 7
Acute management:
- Bradykinin-targeted therapies: icatibant 30 mg subcutaneously 3, 7
- Fresh frozen plasma only if icatibant or C1 inhibitor unavailable 7
- Standard allergic treatments (antihistamines, corticosteroids, epinephrine) are ineffective 4, 3
Long-term considerations:
- Never restart any ACE inhibitor (class effect) 7
- Switching to ARB carries 2-17% recurrence risk, though most patients tolerate ARBs 7
- African Americans, smokers, older individuals, and females are at higher risk 3
Symptomatic Management by Location
Abdominal Attacks:
- Narcotic analgesics for severe pain (avoid chronic opioid use - addiction risk) 1, 3
- Antiemetics for nausea/vomiting 1, 7
- Aggressive IV hydration for third-space fluid losses 1, 7
- Avoid out-of-hospital potent narcotics (fentanyl patches, oxycodone) 1
Extremity Attacks:
- No specific symptomatic therapy available 1
Genitourinary Attacks:
Prophylaxis Strategies for HAE
Short-term prophylaxis (before dental/surgical procedures):
Long-term prophylaxis (for frequent attacks):
- Androgens: danazol 100 mg on alternate days 4, 7
- Antifibrinolytic agents: tranexamic acid 30-50 mg/kg/day 7
- For children where first-line agents unavailable: tranexamic acid preferred 3
- For pregnant patients: C1-INH is the only recommended acute and prophylactic treatment 3
Critical Pitfalls to Avoid
The most dangerous error is treating bradykinin-mediated angioedema (HAE or ACE inhibitor-induced) with standard allergic therapies - these are completely ineffective and waste critical time. 4, 3, 7
- Do not delay epinephrine in true allergic angioedema with airway compromise 3
- Do not discharge patients with oropharyngeal/laryngeal involvement without adequate observation 3
- Do not use chronic potent opioids for HAE patients with frequent attacks 3
- Androgens and antifibrinolytic drugs are NOT effective for acute attacks (require days to work) 1
- Do not directly visualize the airway unless absolutely necessary 1, 3
Diagnostic Clues for Differentiation
Timing:
- Allergic angioedema develops rapidly (minutes) 5
- Bradykinin-mediated angioedema develops slowly (hours) 5
Associated features:
- Urticaria + pruritus = histamine-mediated 5
- No urticaria, slower onset = consider bradykinin-mediated 5
Medication history:
- ACE inhibitors can cause angioedema even after years of use 4
Family history:
Laboratory confirmation (when time permits):