Angioedema, Hereditary Angioedema, Allergic Angioedema, Histamine-Mediated Angioedema, Bradykinin-Mediated Angioedema, ACE inhibitor Induced Angioedema, Drug-Induced Angioedema and Urticaria, C1 Esterase Inhibitor Deficiency

  • Definitions
  1. Angioedema
    1. Localized, Non-Pitting Edema of the deep Dermis and subcutaneous tissue
    2. Results from intravascular fluid shift into the interstitium
    3. Asymmetrically affects the face, lips, Tongue, airway, extremities, and in some cases the Abdomen and genitalia
  • Pathophysiology
  1. See Urticaria
  2. Increased vascular permeability
  3. Fluid extravasation into tissues
    1. Edema of the deep Dermis and subcutaneous tissues
  • Types
  1. Histamine-Mediated Angioedema (Mast Cell mediated)
    1. See Urticaria
    2. Anaphylaxis (e.g. Angioedema with Urticaria)
    3. Allergic Angioedema without Anaphylaxis
    4. Drug-induced Angioedema
      1. Direct Mast Cell degranulation
      2. Cause: NSAIDs, Aspirin, Opiates, Vancomycin, Penicillin, Dextran
      3. Anaphylactoid Reaction to Radiocontrast
        1. Immediate reaction to small dose (does not require presensitization)
        2. Contrast with Anaphylaxis which is IgE mediated and requires allergen presensitization
    5. Idiopathic Histaminergic Angioedema
  2. Bradykinin-Mediated Angioedema
    1. Angiotensin Converting Enzyme Inhibitor (ACE Inhibitor)
      1. Reaction may occur months to years after ACE Inhibitor initiation
      2. ACE inhibitor Induced Angioedema is not an Allergic Reaction (unlike typical Angioedema)
        1. Related to bradykinin accumulation
        2. Does not respond to typical Angioedema management (e.g. Corticosteroids, Antihistamines)
      3. More common in african american patients by factor of 2 to 4 fold
      4. Reaction can occur months to years after starting an ACE Inhibitor
      5. Treatment is withdrawal of medication and supportive care
        1. ACE Inhibitor Angioedema will recur with ARB agents in 8% of patients
        2. Reactions may be severe and life threatening with complete airway closure
    2. Hereditary Angioedema (HAE)
      1. Presents with recurrent facial swelling and Colicky Abdominal Pain
      2. Mechanism: Abnormal for Deficient C1 Esterase Inhibitor
        1. C1 Esterase Inhibitor suppresses the Classical Complement Pathway (C1 to C3 activation)
        2. C1 Esterase inhibitor also suppresses blood Coagulation Factors (Factor XII and plasma Kallikrein)
          1. Deficiency results in increased bradykinin (vasoactivity) and increased tissue edema
      3. Types
        1. Hereditary Angioedema Type 1 (Autosomal Dominant)
          1. C1 InhibitorProtein Deficiency
        2. Hereditary Angioedema Type 2
          1. Abnormal C1 Inhibitor Function
        3. Acquired C1 Inhibitor Deficiency
          1. Lymphoproliferative disorder or autoantibody consumes C1 Inhibitor
  • Symptoms
  1. Edema
    1. Facial, Tongue or lip swelling
    2. Abdomen or genitalia swelling
    3. Extremity swelling
  2. Airway edema related symptoms
    1. Dysarthria (related to Tongue swelling)
    2. Stridor or Wheezing
    3. Dyspnea
  3. Rash
    1. See signs below
    2. Pruritus and Urticaria (if Histamine-mediated)
  4. Gastrointestinal symptoms (if edema affects intestinal tract)
    1. Nausea
    2. Vomiting
    3. Diarrhea
    4. Abdominal Pain
  • Signs
  1. May be associated with Anaphylaxis
  2. May occur with Urticaria
  3. Nonpitting, subcutaneous swelling
    1. Well demarcated
    2. Distribution
      1. Face
      2. Hands
      3. Buttocks
      4. Genitalia
      5. Abdomen
      6. Laryngeal Angioedema (more common in Bradykinin-Mediated Angioedema)
  4. Skin changes
    1. Pruritic Urticaria
      1. Associated with Histamine mediated Angioedema
      2. May be associated with Anaphylaxis
    2. Non-pruritic, Firm Papules
      1. Associated with bradykinin mediated Angioedema
  5. Associated findings
    1. Wheezing or Stridor
    2. Fever
    3. Lymphadenopathy
    4. Hypotension
      1. May occur with either Histamine-mediated or Bradykinin-Mediated Angioedema
    5. Abdominal tenderness with tense Abdomen and guarding (from bowel wall edema)
      1. Associated with bradykinin mediated Angioedema
  • Labs
  • Distinguising Angioedema Type
  1. C4 Serum Complement
    1. Persistently low in Hereditary Angioedema
  2. Serum Tryptase
    1. Increased in Anaphylaxis and other Mast Cell mediated conditions
  • Management
  • Acute Angioedema
  1. ABC Management
    1. Evaluate on presentation and repeatedly for impending airway compromise
    2. Evaluate the lips, Tongue, Soft Palate and posterior pharynx
    3. Evaluate for Stridor, Hoarseness, Drooling or respiratory distress (glottic or supraglottic swelling)
      1. Warrants direct visualization of Larynx (e.g. fiberoptic Nasolaryngoscopy)
      2. Prepare for secure airway (Endotracheal Intubation) and optimize ETT first pass success
        1. Consider Awake Nasotracheal Intubation
        2. Consider Ketamine induction with Video Laryngoscopy
      3. Prepare for surgical airway (emergency Cricothyrotomy)
      4. Supraglottic Devices, Nasal Airways and NIPPV are not viable alternatives in laryngeal Angioedema
  2. Specific Management (choose one of the following mechanisms, and follow pathways below)
    1. Histamine-Mediated Angioedema
      1. Typically triggered by food or other allergen
      2. Often accompanied by Urticaria
      3. Treated as Anaphylaxis (Epinephrine, Antihistamines or Corticosteroids)
    2. Bradykinin-Mediated Angioedema Specific Management
      1. Urticaria and Pruritus is typically absent (although firm Papules may be present)
      2. More often associated with laryngeal edema
      3. Does not typically respond to Epinephrine, Antihistamines or Corticosteroids
  1. See Allergic Reaction and Anaphylaxis
  2. See Urticaria
  3. Medications (only effective in Histamine-mediated reactions, not Bradykinin-Mediated Angioedema)
    1. See Anaphylaxis for dosing regimens and details
    2. Epinephrine
    3. Fluid Resuscitation (if hypotensive)
    4. Bronchodilator Nebulizer Treatment, e.g. Duoneb (if respiratory distress or Wheezing)
    5. Antihistamines (Diphenhydramine and consider H2 Blockers)
    6. Corticosteroids
  • Management
  • Bradykinin-Mediated Angioedema Specific Management
  1. Indications
    1. Severe, airway compromising Hereditary Angioedema
    2. ACE Inhibitor Angioedema (off label use, and mixed evidence)
      1. Of treatments below, only Fresh Frozen Plasma (FFP) may be of benefit in ACE Inhibitor Angioedema
      2. Fresh Frozen Plasma (FFP) may worsen Hereditary Angioedema
  2. Medications
    1. C1 Human Esterase Inhibitor (e.g. Berinert, Cinryze )
      1. Indicated in acute Hereditary Angioedema affecting the face, Larynx or Abdomen in any age
      2. Berinert: 20 IU/kg IV for 1 dose ($3000 per dose)
      3. Cinryze is approved for prophylaxis of Hereditary Angioedema
        1. Dose: 1000 units IV every 3-4 days
    2. Selective Bradykinin B2 inhibitor (Icatibant)
      1. Primary Indication: Hereditary Angioedema
      2. Effective in one RCT for ACE Inhibitor Angioedema (symptoms resolved 19 hours faster)
        1. Dose: 30 mg SQ (and may repeat in 6 hours if inadequate effect, $10,000/dose)
        2. Bas (2015) N Engl J Med 372(5):418-25 +PMID:25629740 [PubMed]
      3. Icatibant did not show benefit in ACE Inhibitor Angioedema subsequent Phase III trial
        1. Swaminathan and Wilkerson in Herbert (2016) EM:Rap 16(3): 3-4
    3. Recombinant Plasma Kallikrein Inhibitor (Ecallantide)
      1. Indicated in Hereditary Angioedema (age 16 years old or older)
      2. Dose: 30 mg SQ once (and may be repeated in 24 hours)
      3. Risk of Anaphylactic or anaphylactoid reaction (3%)
    4. Fresh Frozen Plasma (FFP)
      1. Indicated if the above agents (C1 and B2) are unavailable in severe Hereditary Angioedema
        1. May also consider in ACE inhibitor Induced Angioedema
      2. Theoretical risk of exacerbating Angioedema (due to complement in FFP)
      3. Inconsistent benefit in Bradykinin-Mediated Angioedema
      4. Hassen (2013) J Emerg Med 44(4):764-72 +PMID:23114109 [PubMed]
    5. Other medications
      1. Corticosteroids may be considered
      2. Epinephrine is unlikely to be beneficial (but often used in undifferentiated presentations)
      3. Antihistamines are not indicated
  • Management
  • Disposition
  1. General approach
    1. Minimal observation duration: 4-6 hours after maximal swelling has occurred
    2. Monitor on continuous cardiac monitor and Oxygen Saturation
    3. Histamine-Mediated Angioedema discharge medications (see Anaphylaxis)
      1. Short course (e.g. 3 days) of Corticosteroids, Antihistamines
      2. Epinephrine Autoinjector
    4. Bradykinin-Mediated Angioedema
      1. Discontinue ACE Inhibitor and Angiotensin Receptor Blockers
      2. Follow-up allergist
  2. Face and lip swelling
    1. Observe in Emergency Department and discharge home
  3. Anterior Tongue and oral cavity swelling
    1. Obtain fiberoptic examination of upper airway
    2. Observe in Emergency Department or on inpatient ward
  4. Posterior Tongue and floor of mouth swelling
    1. Consider intubation
    2. Observe on inpatient ward or Intensive Care unit
  5. Laryngeal and supraglottic swelling
    1. Strongly consider intubation
    2. Intensive Care admission
  • References
  1. Callahan and Gingold (2019) Crit Dec Emerg Med 33(4): 3-11
  2. Ben Ma and Eyre (2017) Crit Dec Emerg Med 31(12): 12
  3. Frank in Goldman (2000) Cecil Medicine, p. 1440-5
  4. Kaplan in Middleton (1998) Allergy, p. 1104-18
  5. Habif (1996) Clinical Dermatology, p. 122-47
  6. Cicardi (2014) Intern Emerg Med 9(1):85-92 +PMID: 24002787 [PubMed]
  7. Greaves (2000) J Allergy Clin Immunol 105:664-72 [PubMed]
  8. Muller (2004) Am Fam Physician 69(5):1123-8 [PubMed]