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    Cardiovascular, Critical Care / Resuscitation, Ears, Eyes, Nose, and Throat, Gastrointestinal, Inflammatory, Respiratory, Toxicology

    Last Updated Dec 15, 2023
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    By Willem De Vynck, Francois Van Wyk

    First 5 Minutes

    If patient is in respiratory distress or presents with hemodynamic instability with angioedema, treat for anaphylaxis and prepare for airway management.

    Respiratory distress can occur rapidly and may create a difficult intubation. Get help EARLY, including ED staff, RT, and/or anesthesia/ENT. Surgical airway may be needed in some cases.

    There are essentially two distinct types of angioedema based on pathogenesis: histamine mediated and non-histamine (bradykinin) mediated.

    Histamine-mediated angioedema should be treated with epinephrine, antihistamine (anti-H1) and steroids.

    These medications are not effective for bradykinin mediated angioedema, instead:

    • C1 inhibitor protein replacement (berinert, purified C1 inhibitor concentrate, Fresh frozen plasma).
    • Kallikrein inhibitor, ecallantide (not currently licensed in Canada but may be requested through the Special Access Program of Health Canada).
    • Bradykinin receptor antagonists (Icatibant).


    Pathogenesis: Increased vascular permeability leading to extravascular fluid leak into subcutaneous sand submucosal tissues most notably face, lips, mouth, uvula, larynx, throat, genitalia, and bowel wall.


    • Histaminergic (mast cell related):
      • Often associated with urticaria and pruritis. Classic IgE mediated: allergic reactions – but other causes exist.
    • Non-histaminergic (bradykinin related):
      • Often associated with pain and pressure rather than pruritis.

    Four subtypes:

    • Decreased degradation:
      • Angiotensin-converting enzyme inhibitors (ACEi) up to 32% of presentations (1). Typically within weeks of starting but can be years later.
      • Dipeptidyl peptidase 4 inhibitors (DPP-4i) (gliptins): alogliptin, saxagliptin, sitagliptin and linagliptin.

    ∗∗ACEi treatment can uncover C1 inhibitor deficiency: beware of multifactorial causes of angioedema (2)**

    • C1 inhibitor deficiency (increased bradykinin production):
      • Acquired – may be associated with an underlying lymphoma, or monoclonal gammopathy.
      • Hereditary Angioedema (HAE).
    • Non-C1 inhibitor related: Hereditary angioedema (HAE).
    • Idiopathic/Other:
      • Infections (esp. in children).
      • Idiopathic nonhistaminergic angioedema.
      • Other drugs:
        • Calcium channel blockers.
        • Fibrinolytic agents – tPa, TNK etc. – rare but recognized complication. Treat as allergic reaction (even epinephrine if indicated).

    Clinical Features:

    Images acquired from: Category:Angioedema – Wikimedia Commons [Internet]. commons.wikimedia.org. [cited 2023 Nov 29]. Available from: https://commons.wikimedia.org/wiki/Category:Angioedema

    Diagnostic Process

    Diagnosis is clinical.


    • Assess for rashes, locations of swelling.
    • Recent insect bites/allergen exposures.
    • Medication history: specifically, ACEi, DPP-4i, NSAIDs/Aspirin, estrogens, antibiotics,
    • Any previous incidences of angioedema.
    • FamHx of angioedema.

    Physical Exam:

    • Assess upper airway.
    • Assess for anaphylactic shock.
    • Assess for allergic symptoms – histaminergic features: urticaria (hives), itchy rash.
    • Assess for lymphadenopathy as angioedema may be a first presentation of lymphoma (3).


    • If no mast-cell activation (allergic) related signs, the most likely etiology is bradykinin mediated.

    Recommended laboratory testing: Limited value – may help with future work-up in community.

    Imaging: Abdo CT or US if indicated.

    Recommended Treatment

    • If a. signs of respiratory distress or b. hemodynamic instability, treat as anaphylaxis. See Anaphylaxis clinical summary.
    • Get the help that you need EARLY, including ED staff (nurses, additional ERP), RT, and/or anesthesia/ENT if needed.
    • Difficult airway identification: https://emergencycarebc.ca/clinical_resource/difficult-airway-identification-in-the-emergency-department/?_rt=NHwxfGludHViYXRpb258MTcwMTM2MzkzOQ&_rt_nonce=cfb63b3b0d
    • Early intubation is recommended. Follow the appropriate clinical resource:
    • When cause is unknown (often the case) treat for both allergic and non-allergic angioedema.
    • Stop offending medications.
    • Specific treatments:
      • ACEi induced angioedema
        • Stop ACEi.
        • Consider treatment with Tranexamic acid (TXA) 1g IV over 10 minutes (5).
        • If severe, treatment with Icatibant 30mg SC q6h, max 90mg over 24 hours is indicated (a bradykinin B2 receptor antagonist).
        • Treatment with 2 units of Fresh frozen plasma has shown some efficacy for the presence of ACE. which contains a C1 inhibitor, has been reported to be effective in acute attacks; however, there are rare reports of exacerbation of the angioedema by FFP.
      • Anaphylaxis: See clinical summary. https://emergencycarebc.ca/clinical_resource/anaphylaxis-diagnosis-treatment/
      • Allergic angioedema:
        • H1 Antihistamines: eg. cetirizine up to 20 mg BID.
        • Glucocorticoids: Prednisone in adults, prednisolone in children.
      • Known or suspected hereditary angioedema: Treatment with a C1 inhibitor concentrate is indicated (icatibant most common) (4).
      • BERINERT® (C1-Esterase Inhibitor) is a plasma-derived C1 Esterase Inhibitor (Human) indicated for the treatment of HAE attacks in adult and pediatric patients. Berinert is delivered intravenously and is approved for self-administration.
      • FIRAZYR® (icatibant injection) is a bradykinin B2 receptor antagonist indicated for treatment of acute attacks of HAE in adults, adolescents and children aged 2 years and older with C1-esterase inhibitor deficiency. Firazyr is delivered by subcutaneous injection.
      • A second line treatment is fresh frozen plasma, however this treatment has lower evidence and efficacy.
      • Follow-up with hematologist/allergist.

    Underlying illness (e.g., Infection): treatment with antihistamines/glucocorticoids along with treatment of the illness, e.g., Antibiotics.

    Criteria For Hospital Admission

    • Respiratory distress, hemodynamic instability.
    • Poor resolution or recurrence of symptoms if in areas of concern – airway or significant pain.
    • Severe episodes can last for 3-5 days.

    Criteria For Transfer To Another Facility

    Dependent on resources available.

    Criteria For Close Observation And/or Consult

    • Impending respiratory failure.
    • Hemodynamic instability.
    • Resolved respiratory or hemodynamic instability – with/without treatment.

    Criteria For Safe Discharge Home

    • Patients should be monitored until symptoms are clearly resolving.
    • Patients with allergic or anaphylactic angioedema have been provided education and requisition for EpiPen.

    Quality Of Evidence?


    This is a well described and documented topic, the majority of evidence is derived from high quality studies.


    Related Information



      Hereditary Angioedema (HAE) Canada: https://haecanada.org/

      Anaphylaxis (Pediatric)

    Reference List

    1. Gandhi J, Jones R, Teubner D, Gabb G. Multicentre audit of ACE-inhibitor associated angioedema (MAAAA). Aust Fam Physician. 2015;44(8):579–83.

    2. Ricketti AJ, Cleri DJ, Ramos-Bonner LS, Vernaleo JR. Hereditary angioedema presenting in late middle age after angiotensin-converting enzyme inhibitor treatment. Ann Allergy Asthma Immunol [Internet]. 2007;98(4):397–401. Available from: http://dx.doi.org/10.1016/S1081-1206(10)60889-7

    3. Gunatilake SSC, Wimalaratna H. Angioedema as the first presentation of B-cell non-Hodgkin lymphoma – an unusual case with normal C1 esterase inhibitor level: a case report. BMC Res Notes [Internet]. 2014;7(1). Available from: http://dx.doi.org/10.1186/1756-0500-7-495

    4. Zuraw BL. Hereditary angioedema. N Engl J Med [Internet]. 2008;359(10):1027–36. Available from: http://dx.doi.org/10.1056/nejmcp0803977

    5. Stoldt J, Cox C, Matusz E. Tranexamic acid use in the setting of ACE inhibitor induced angioedema. Am J Emerg Med [Internet]. 2022;55:230.e3-230.e4. Available from: http://dx.doi.org/10.1016/j.ajem.2022.01.041

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