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.

Etiology:

• 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:

• Onset minutes to hours; resolution hours to days.
• Asymmetric, non-pitting swelling of face, lips, mouth, uvula, larynx, throat, genitalia and/or bowel wall. (See https://emergencycarebc.ca/clinical_resource/anaphylaxis-diagnosis-treatment/).
• Bowel wall angioedema: abdominal pain, N/V/D, and may be seen on CT or U/S.
• May present as a surgical abdomen.

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

Diagnosis is clinical.

History:

• 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⁾.

Evaluation:

• 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.

• Complement protein C4 and C1 inhibitor levels can be sent off for community follow-up if desired.
• With Urticaria: See clinical summary https://emergencycarebc.ca/clinical_resource/acute-urticaria/

Imaging: Abdo CT or US if indicated.

• 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:
  • Difficult airway management: https://emergencycarebc.ca/clinical_resource/difficult-airway-management/
  • Rapid sequence intubation: https://emergencycarebc.ca/clinical_resource/rapid-sequence-intubation/
• 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.

• 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.

Dependent on resources available.

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

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

1.  

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

   Anaphylaxis (Pediatric)

   
   

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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

   
   

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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