EM@3AM – Angioedema

Author: Erica Simon, DO, MHA (@E_M_Simon, EM Chief Resident, SAUSHEC, USAF) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UT Southwestern Medical Center / Parkland Memorial Hospital) and Brit Long, MD (@long_brit, EM Attending Physician, SAUSHEC, USAF)

Welcome to EM@3AM, an emdocs series designed to foster your working knowledge by providing an expedited review of clinical basics. We’ll keep it short, while you keep that EM brain sharp.

A 38-year-old African American female presents to the emergency department with mouth swelling. Upon initial examination, the patient is protecting her airway. She reports symptom onset one hour prior to arrival, with hoarseness and difficulty swallowing prompting her desire for evaluation and treatment. The patient denies known food and medication allergies. She denies a personal and familial history of similar symptoms. She denies exposure to new environments, foods, cosmetics, detergents, and medications. She reports initiating enalapril three weeks prior for the treatment of hypertension.

VS: HR 134, BP 132/82, RR 14, T 99.8 Oral, SpO2 98% on room air

What do you suspect as a diagnosis? What’s the next step in your evaluation and treatment?

Answer: Angioedema (AE)^1-8

• Presentation: Non-pitting, non-demarcated edema of the dermis and subcutaneous tissues that may be localized to the face, lips, larynx, glottis, tongue, abdomen, genitalia or extremities.^1,2
  • Numerous associated signs and symptoms have been reported: urticaria, pruritus, dyspnea, wheezing, and hypotension, to name a few.³

• Pathophysiology:^1-3
  • Angiotensin Converting Enzyme Inhibitor (ACEI) induced AE:
    • Angiotensin converting enzyme (ACE) is responsible for the degradation of bradykinin. As ACEIs inhibit ACE, bradykinin levels increase thereby resulting in an increase of vasoactive mediators => angioedema, vasodilation, cough, etc.
    • Represents 30-45% of AE cases presenting to the ED.⁴ More than half of patients experience symptoms within the first week of ACEI therapy, but case reports detail AE as occurring years after the initiation of therapy.⁵ The incidence of ACEI is up to 5x higher in patients of African American descent.⁵
  •  Hereditary AE:
    • An autosomal dominant disorder resulting from a deficiency in functional C1 esterase inhibitor. C1 esterase inhibitor regulates the conversion of prekallikrein to kallikrein (components of the pro-inflammatory kallikrein-kinin cascade). C1 inhibitor deficiency  manifests as increased kallikrein, which results in increased bradykinin production.
    • Hereditary AE affects an estimated 1 in 50,000 individuals in the U.S., with the mean age of onset between 8 and 12 years.⁴ Attacks may be triggered by local trauma or psychological stress.
  •  Acquired AE:
    • An acquired deficiency of C1 esterase inhibitor associated with B cell lymphoproliferative disorders and autoimmune pathology. The majority of patients present without associated urticaria.
    • Acquired C1 esterase deficiency presents in the fourth decade of life or later.⁶
  •  Histamine-Mediated (Allergic) AE:
    • Antigen exposure results in IgE cross linking and mast cell degranulation releasing histamine, serine proteases, thromboxane, prostaglandins and leukotrienes resulting in vasodilation and endothelial activation.
  •  Idiopathic AE:
    • Histamine and non-histamine variants reported in the literature. Histamine mediated forms are commonly accompanied by urticaria.³

• Evaluation:^1-3
  • Address ABCs. Be mindful of signs of impending airway compromise: hoarseness, stridor, difficulty tolerating secretions, etc.
    • Awake fiberoptic intubation advised (with cricothyrotomy as a  back-up plan).

• Treatment:^1-3
  • Assume anaphylaxis and treat with IM/IV epinephrine (1:1,000), glucocorticoids, and H1/H2 antagonists.
    • ACEI AE: epinephrine, glucocorticoids, H1/H2 antagonists unlikely to be effective as the reaction is not histamine mediated.  Therapies include: icatibant and ecallantide (off-label use). If unavailable, FFP and purified C1 esterase inhibitor concentrate have demonstrated effectivity for ACEI AE.³
    • Hereditary AE: Treat with C1 esterase inhibitor concentrate, icatibant, or ecallantide. FFP may be utilized if the aforementioned are unavailable.
    • Acquired AE: Treat with C1 esterase inhibitor concentrate, recombinant human C1 inhibitor, icatibant, ecallantide, or FFP.
      • Note: patients with acquired AE who experience recurrent attacks often develop resistance to C1 esterase inhibitor concentrate, requiring higher doses for symptom control.⁸

• Pearls:
  • Each year more than 100,000 patients present to the ED for angioedema in the U.S.⁹
  • Patients may present without oropharyngeal edema: episodes may be isolated to the abdomen, genitalia, or the extremities.¹

References:

1. Fermann G. (2013). Angioedema in the Emergency Department. [PowerPoint slides]. Retrieved from http://1bf1a1c4390778f48601-8bc17ee13ddec5a8abc07f9a0b95e48f.r91.cf1.rackcdn.com/0830%20Tuesday%20Fermann%20Angioedema%20in%20ED%20Presentation.FINAL%20sm.pdf
2. Frigas E, Park M. Acute urticaria and angioedema: diagnostic and treatment considerations. 2009; 10(4):239-250.
3. Kulthanan K, Jiamton S, Boochangkool K, Jongjarearnprasert K. Angioedema: clinical and etiological aspects. Clin Dev Immunol. 2007; 2007:26438.
4. Longhurst H, Cicardi M. Hereditary angio-oedema. Lancet. 2012; 379:474-481.
5. Malde B, Regalado J, Greenberger P. Investigation of angioedema associated with the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Ann Allergy Asthma Immunol. 2007; 98(1):57.
6. Gelfand J, Boss G, Conley C, Reinart R, Frank M. Acquired C1 esterase inhibitor deficiency and angioedema: a review. Medicine. 1979; 58(4);321.
7. Cicardi M, Zingale L, Pappalardo E, Folcioni A, Agostoni A. Autoantibodies and lymphoproliferative disease in acquired C1-inhibitor deficiencies. Medicine. 2003;82(4):274.
8. Kelly M, Donnelly J, McAnnally J, Wang H. National estimates of emergency department visits for angioedema and allergic reactions in the United States. Allergy Asthma Proc. 2013; 34(2):150-154.

For Additional Reading:

 Review of Awake Endotracheal Intubation:

Awake Endotracheal Intubation

Review of Emergency Cricothyrotomy:

The Sphincter Series: Emergent Cricothyrotomy