Angioedema

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.

Histamine-mediated angioedema (mast cell-mediated angioedema) ^[1][2]

• Direct mast cell activation
  • Non-IgE-mediated
  • Possible triggers: NSAIDs (most commonly aspirin) , opiates, radiocontrast media
• Allergic reactions
  • IgE-mediated
  • Possible triggers: food, insect bites/stings, antibiotics, latex, NSAIDs (less commonly), other allergens, physically-induced
  • Family history of atopy

Bradykinin-mediated angioedema ^[1][2]

• Hereditary angioedema (inherited C1 inhibitor deficiency )
  • 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 ^[3][4]
• 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 ^[1][2]

• Idiopathic angioedema
  • Recurrent episodes without known cause
  • Possible triggers: cold, heat, stress, and exercise
  • More commonly follows a histaminergic pattern
• Infections
  • More common in children
  • Possible triggers: common cold, streptococcal pharyngitis, urinary tract infections
• Drug-induced: calcium channel blockers, fibrinolytics, immunosuppressive agents (e.g., tacrolimus)

Common symptoms

• 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)

Histamine-mediated angioedema

• Often associated with urticaria and pruritus
• Other associated with clinical findings of allergic reactions (see type 1 hypersensitivity reaction)
• Onset within 30 minutes to 2 hours of exposure and resolution over hours to days

Bradykinin-mediated angioedema

• 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

References:^[5]

Approach

• Emergency management
  • Treat anaphylaxis, if present.
  • Airway management
  • Stop any potential triggers.
• Once the patient has been stabilized, identify and treat the cause of angioedema
  • Histamine-mediated angioedema treatment
  • Bradykinin-mediated angioedema treatment

Emergency management ^[1][2][6]

• Evaluate for anaphylaxis:
  • If there is concern for anaphylaxis:
    • Give IM epinephrine
    • Start aggressive supportive care (e.g., IV fluids, supplemental oxygen)
• Airway management
  • If airway compromise is present:
    • Call anesthesia/otolaryngology for help.
    • Prepare for difficult airway with rescue devices and set up for surgical airway.
      • Awake fiberoptic intubation is preferred; RSI with paralytics should be avoided if possible.
      • A supraglottic airway (e.g., laryngeal mask) is not appropriate.
    • Only attempt unassisted intubation if the risk of death is imminent and there is no expert available.
• 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 ^[1][2]

• ABCs intact and no airway compromise: Proceed with histamine-mediated angioedema treatment.
• Poor response to repeated IM epinephrine administration: Consider bradykinin-mediated angioedema treatment.

Treatment of histamine-mediated angioedema and treatment of idiopathic angioedema

• Standard therapy
  • IV antihistamines: e.g., diphenhydramine
  • IV glucocorticoids: e.g., methylprednisolone
    • Positive response: Continue standard treatment.
    • Poor response: Consider bradykinin-mediated angioedema treatment.
• Idiopathic angioedema typically responds well to standard anaphylaxis treatment
• If the initial response to standard therapy is followed by progression to anaphylaxis

Treatment of bradykinin-mediated angioedema and treatment of hereditary angioedema

• First-line: administer one of the following targeted therapies
  • Purified C1-INH concentrate (protein replacement):
    • Plasma-derived ^[1]
    • Recombinant
  • Kallikrein inhibitor: ecallantide
  • Bradykinin-B2 receptor antagonist: icatibant
• Second-line or suspected ACE inhibitor-induced etiology: fresh frozen plasma (FFP)

Epinephrine, glucocorticoids, and antihistamines are usually not effective in acute hereditary angioedema attacks!