Angioedema is a self-limited, localized swelling of the dermis, subcutaneous tissues, and/or submucosal tissues caused by fluid leakage into the interstitial tissue. It is mediated by vasoactive substances and can be classified as histamine-mediated (often secondary to allergic reactions and NSAIDs), bradykinin-mediated (due to ACE inhibitor use or enzyme deficiencies), or unknown (idiopathic). Patients usually present with swelling of the eyelids, lips, and tongue. However, life-threatening laryngeal edema may occur, which requires immediate airway protection. Treatment generally consists of aggressive supportive care and avoidance of triggers, if applicable. In acute cases, histamine-mediated angioedema is treated with systemic glucocorticoids, antihistamines, and, if necessary, epinephrine for anaphylaxis. Bradykinin-mediated angioedema is treated with C1 inhibitor (C1-INH) concentrate, bradykinin-B2-receptor antagonists, or kallikrein inhibitors.
|Differentiation between histamine-mediated angioedema and bradykinin-mediated angioedema|
|Histamine-mediated angioedema ||Bradykinin-mediated angioedema |
|Hereditary angioedema types I–III||Acquired angioedema|
|Onset|| || |
|Duration|| || |
|Usual age|| || |
|Family history|| || || |
| || || |
|Laryngeal edema|| || |
|Extremity or truncal edema|
|Bronchospasm|| || |
|Response to standard anaphylaxis treatment|| || |
- Direct mast cell activation
- Allergic reactions
Hereditary angioedema (inherited )
- Autosomal-dominant inheritance
- Clinical manifestations in childhood or adolescence
- Possible triggers: estrogen fluctuation (e.g., OCPs, hormone replacement, menstruation, ovulation, and pregnancy), infection (e.g., H. pylori), mental stress/fatigue, physical exertion, trauma, surgical and dental procedures, drugs (e.g., ACE inhibitors), and weather changes 
Acquired angioedema (acquired C1 inhibitor deficiency)
- Presents in advanced or middle age (usually in or after the fourth decade of life)
- Often associated with lymphoproliferative diseases and B-cell malignancies
- ACE inhibitor-induced (rarely ARB-induced): impaired bradykinin breakdown
Angioedema of unknown cause 
- Recurrent episodes without known cause
- Possible triggers: cold, heat, stress, and exercise
- More commonly follows a histaminergic pattern
- Drug-induced: calcium channel blockers, fibrinolytics, immunosuppressive agents (e.g., tacrolimus)
- Facial edema (mouth, eyelids, tongue)
- Laryngeal involvement: dyspnea; and inspiratory stridor; potentially life-threatening
- Possible swelling of extremities and urogenital area (e.g., hands, feet, scrotum)
- Often associated with urticaria and pruritus
- Other associated with clinical findings of allergic reactions (see )
- Onset within 30 minutes to 2 hours of exposure and resolution over hours to days
- Family history often present (hereditary angioedema)
- Abdominal symptoms : colicky abdominal pain, nausea/vomiting, diarrhea
- Angioedema of the extremities or trunk
- Not associated with urticaria or pruritus
- The diagnosis is mainly based on history and clinical findings.
- Flexible fiberoptic laryngoscopy should be performed if there is no clear obstruction but clinical suspicion of angioedema is high. 
Further evaluation: indicated for follow-up or if the etiology is unclear 
- Laboratory studies
- Imaging: not routinely recommended
|Laboratory findings in bradykinin-mediated angioedema |
|Hereditary angioedema||Acquired angioedema|
|Type I||Type II||Type III||ACE-inhibitor induced||C1-INH deficiency|
|C4 level||↓ During acute attacks||↓ During acute attacks||Normal||Normal||↓|
- Anaphylaxis is the most important differential diagnosis (see ).
The differential diagnoses listed here are not exhaustive.
- Emergency management
- Once the patient has been stabilized, identify and treat the cause of angioedema
Emergency management 
- Evaluate for anaphylaxis: See .
- If airway compromise is present:
- See .
- Call anesthesia/otolaryngology for help.
- Prepare for difficult airway with rescue devices and set up for surgical airway.
- Only attempt unassisted intubation if the risk of death is imminent and there is no expert available.
- If airway compromise is present:
- Stop any potential triggers: Remove potential exposures or offending medications (e.g., ACE inhibitors).
If airway compromise is suspected (stridor, wheezing, diminished air movement) or the patient is in shock, administer IM epinephrine immediately, start oxygen and IV fluids, and consider intubation to protect the airway. Once acute therapy has been initiated, the type and cause of angioedema should be determined.
Intubation is very risky in patients with angioedema and should only be performed by an expert. If there is no time for help, then preparation for the procedure must also include rescue devices and surgical airway equipment.
Case-based specific treatment 
- ABCs intact and no airway compromise: Proceed with .
- Poor response to repeated IM epinephrine administration: Consider .
Treatment of histamine-mediated angioedema and treatment of idiopathic angioedema
- Standard therapy
- Idiopathic angioedema typically responds well to standard anaphylaxis treatment
- If the initial response to standard therapy is followed by progression to anaphylaxis : see and acute management checklist for anaphylaxis.
Treatment of bradykinin-mediated angioedema and treatment of hereditary angioedema
- Administer one of the following targeted therapies:
- Second-line or suspected ACE inhibitor-induced etiology: fresh frozen plasma (FFP)
- Angioedema associated with tPA: requires special treatment algorithm; See “Complications of thrombolysis.”
Epinephrine, glucocorticoids, and antihistamines are usually not effective in acute hereditary angioedema attacks! If these have been given empirically (e.g., for suspected anaphylaxis with airway compromise) and there is a poor response, then targeted therapy for bradykinin-mediated angioedema should be considered as the next step.
- Treat anaphylaxis if present at any time (see acute management checklist for anaphylaxis).
- Administer supplemental oxygen and perform basic airway maneuvers.
- Urgent anesthesia and/or ENT consult if the airway is compromised
- Prepare for a difficult airway and surgical airway as a backup.
- Administer case-based specific treatment.
- If histamine-mediated angioedema is suspected or the etiology is unknown: Administer standard therapy with antihistamines and steroids.
- If bradykinin-mediated angioedema is suspected: Administer targeted therapy with C1-INH protein replacement, ecallantide, or icatibant.
- If an ACE inhibitor-induced etiology is suspected: Administer FFP.
- Remove potential exposures or offending medications (e.g., ACE inhibitors).
- Continuous telemetry and pulse oximetry (with or without capnography)
- ICU consult
- Trigger avoidance (e.g., allergens, offending medications, environmental factors)
- Counseling on symptom recognition and instructions for when to return to the hospital
- Prespecified treatment action plans
- Hereditary angioedema 
- Histamine-mediated angioedema