II. Definitions
- Angioedema
- Localized, Non-Pitting Edema of the deep Dermis and subcutaneous tissue
- Results from intravascular fluid shift into the interstitium
- Asymmetrically affects the face, lips, Tongue, airway, extremities, and in some cases the Abdomen and genitalia
III. Pathophysiology
IV. Types
- Histamine-Mediated Angioedema (Mast Cell mediated)
- See Urticaria
- Anaphylaxis (e.g. Angioedema with Urticaria)
- Allergic Angioedema without Anaphylaxis
- Drug-induced Angioedema
- Direct Mast Cell degranulation
- Cause: NSAIDs, Aspirin, Opiates, Vancomycin, Penicillin, Dextran
- Anaphylactoid Reaction to Radiocontrast
- Immediate reaction to small dose (does not require presensitization)
- Contrast with Anaphylaxis which is IgE mediated and requires allergen presensitization
- Idiopathic Histaminergic Angioedema
- Bradykinin-Mediated Angioedema
- Angiotensin Converting Enzyme Inhibitor (ACE Inhibitor)
- Reaction may occur months to years after ACE Inhibitor initiation
- ACE inhibitor Induced Angioedema is not an Allergic Reaction (unlike typical Angioedema)
- Related to bradykinin accumulation
- Does not respond to typical Angioedema management (e.g. Corticosteroids, Antihistamines)
- More common in african american patients by factor of 2 to 4 fold
- Reaction can occur months to years after starting an ACE Inhibitor
- Treatment is withdrawal of medication and supportive care
- Reactions may be severe and life threatening with complete airway closure
- Angiotensin Receptor Blockers (ARB) do NOT appear to have increased Angioedema risk
- ARB Agents do not directly affect bradykinin metabolism (unlike ACE Inhibitors)
- ARBs appear safe in those with history of ACE inhibitor Induced Angioedema
- Wait 4 to 6 weeks after ACE-Induced Angioedema to initiate ARB
- ACE Inhibitor Angioedema was originally thought to recur with ARB agents in up to 10% of patients
- Subsequent studies demonstrate no signficant increased risk
- References
- ARB Agents do not directly affect bradykinin metabolism (unlike ACE Inhibitors)
- Hereditary Angioedema (HAE)
- Presents with recurrent facial swelling and Colicky Abdominal Pain
- Mechanism: Abnormal for Deficient C1 Esterase Inhibitor
- C1 Esterase Inhibitor suppresses the Classical Complement Pathway (C1 to C3 activation)
- C1 Esterase inhibitor also suppresses blood Coagulation Factors (Factor XII and plasma Kallikrein)
- Deficiency results in increased bradykinin (vasoactivity) and increased tissue edema
- Types
- Hereditary Angioedema Type 1 (Autosomal Dominant)
- C1 InhibitorProtein Deficiency
- Hereditary Angioedema Type 2
- Abnormal C1 Inhibitor Function
- Acquired C1 Inhibitor Deficiency
- Lymphoproliferative disorder or autoantibody consumes C1 Inhibitor
- Hereditary Angioedema Type 1 (Autosomal Dominant)
- Angiotensin Converting Enzyme Inhibitor (ACE Inhibitor)
V. Symptoms
VI. Signs
- May be associated with Anaphylaxis
- May occur with Urticaria
- Nonpitting, subcutaneous swelling
- Well demarcated
- Distribution
- Face
- Hands
- Buttocks
- Genitalia
- Abdomen
- Laryngeal Angioedema (more common in Bradykinin-Mediated Angioedema)
- Skin changes
- Pruritic Urticaria
- Associated with Histamine mediated Angioedema
- May be associated with Anaphylaxis
- Non-pruritic, Firm Papules
- Associated with bradykinin mediated Angioedema
- Pruritic Urticaria
- Associated findings
- Wheezing or Stridor
- Fever
- Lymphadenopathy
- Hypotension
- May occur with either Histamine-mediated or Bradykinin-Mediated Angioedema
- Abdominal tenderness with tense Abdomen and guarding (from bowel wall edema)
- Associated with bradykinin mediated Angioedema
VII. Labs: Distinguising Angioedema Type
- C4 Serum Complement
- Persistently low in Hereditary Angioedema
-
Serum Tryptase
- Increased in Anaphylaxis and other Mast Cell mediated conditions
VIII. Management: Acute Angioedema
-
ABC Management
- Evaluate on presentation and repeatedly for impending airway compromise
- Evaluate the lips, Tongue, Soft Palate and posterior pharynx
- Evaluate for Stridor, Hoarseness, Drooling or respiratory distress (glottic or supraglottic swelling)
- Warrants direct visualization of Larynx (e.g. fiberoptic Nasolaryngoscopy)
- Prepare for secure airway (Endotracheal Intubation) and optimize ETT first pass success
- Consider Awake Nasotracheal Intubation
- Consider Ketamine induction with Video Laryngoscopy
- Prepare for surgical airway (emergency Cricothyrotomy)
- Supraglottic Devices, Nasal Airways and NIPPV are not viable alternatives in laryngeal Angioedema
- Specific Management (choose one of the following mechanisms, and follow pathways below)
- Histamine-Mediated Angioedema
- Typically triggered by food or other allergen
- Often accompanied by Urticaria
- Treated as Anaphylaxis (Epinephrine, Antihistamines or Corticosteroids)
- Bradykinin-Mediated Angioedema Specific Management
- Urticaria and Pruritus is typically absent (although firm Papules may be present)
- More often associated with laryngeal edema
- Does not typically respond to Epinephrine, Antihistamines or Corticosteroids
- Histamine-Mediated Angioedema
IX. Management: Histamine Mediated Angioedema
- See Allergic Reaction and Anaphylaxis
- See Urticaria
- Medications (only effective in Histamine-mediated reactions, not Bradykinin-Mediated Angioedema)
- See Anaphylaxis for dosing regimens and details
- Epinephrine
- Fluid Resuscitation (if hypotensive)
- Bronchodilator Nebulizer Treatment, e.g. Duoneb (if respiratory distress or Wheezing)
- Antihistamines (Diphenhydramine and consider H2 Blockers)
- Corticosteroids
X. Management: Bradykinin-Mediated Angioedema Specific Management
- Indications
- Severe, airway compromising Hereditary Angioedema
- ACE Inhibitor Angioedema (off label use, and mixed evidence)
- Of treatments below, only Fresh Frozen Plasma (FFP) may be of benefit in ACE Inhibitor Angioedema
- Fresh Frozen Plasma (FFP) may worsen Hereditary Angioedema
- Medications
- C1 Human Esterase Inhibitor (e.g. Berinert, Cinryze )
- Selective Bradykinin B2 inhibitor (Icatibant)
- Primary Indication: Hereditary Angioedema
- Effective in one RCT for ACE Inhibitor Angioedema (symptoms resolved 19 hours faster)
- Dose: 30 mg SQ (and may repeat in 6 hours if inadequate effect, $10,000/dose)
- Bas (2015) N Engl J Med 372(5):418-25 +PMID:25629740 [PubMed]
- Icatibant did not show benefit in ACE Inhibitor Angioedema subsequent Phase III trial
- Swaminathan and Wilkerson in Herbert (2016) EM:Rap 16(3): 3-4
- Recombinant Plasma Kallikrein Inhibitor (Ecallantide)
- Indicated in Hereditary Angioedema (age 16 years old or older)
- Dose: 30 mg SQ once (and may be repeated in 24 hours)
- Risk of Anaphylactic or anaphylactoid reaction (3%)
- Fresh Frozen Plasma (FFP)
- Indicated if the above agents (C1 and B2) are unavailable in severe Hereditary Angioedema
- May also consider in ACE inhibitor Induced Angioedema
- Theoretical risk of exacerbating Angioedema (due to complement in FFP)
- Inconsistent benefit in Bradykinin-Mediated Angioedema
- Hassen (2013) J Emerg Med 44(4):764-72 +PMID:23114109 [PubMed]
- Indicated if the above agents (C1 and B2) are unavailable in severe Hereditary Angioedema
- Other medications
- Corticosteroids may be considered
- Epinephrine is unlikely to be beneficial (but often used in undifferentiated presentations)
- Antihistamines are not indicated
XI. Management: Disposition
-
General approach
- Minimal observation duration: 4-6 hours after maximal swelling has occurred
- Monitor on continuous cardiac monitor and Oxygen Saturation
- Histamine-Mediated Angioedema discharge medications (see Anaphylaxis)
- Short course (e.g. 3 days) of Corticosteroids, Antihistamines
- Epinephrine Autoinjector
- Bradykinin-Mediated Angioedema
- Discontinue ACE Inhibitor and Angiotensin Receptor Blockers
- Follow-up allergist
- Face and lip swelling
- Observe in Emergency Department and discharge home
- Anterior Tongue and oral cavity swelling
- Obtain fiberoptic examination of upper airway
- Observe in Emergency Department or on inpatient ward
- Posterior Tongue and floor of mouth swelling
- Consider intubation
- Observe on inpatient ward or Intensive Care unit
- Laryngeal and supraglottic swelling
- Strongly consider intubation
- Intensive Care admission
XII. References
- Callahan and Gingold (2019) Crit Dec Emerg Med 33(4): 3-11
- Ben Ma and Eyre (2017) Crit Dec Emerg Med 31(12): 12
- Frank in Goldman (2000) Cecil Medicine, p. 1440-5
- Kaplan in Middleton (1998) Allergy, p. 1104-18
- Habif (1996) Clinical Dermatology, p. 122-47
- Cicardi (2014) Intern Emerg Med 9(1):85-92 +PMID: 24002787 [PubMed]
- Greaves (2000) J Allergy Clin Immunol 105:664-72 [PubMed]
- Muller (2004) Am Fam Physician 69(5):1123-8 [PubMed]