Angioedema in the Emergency Department: An Evidence-Based Update (Pharmacology CME)

Table of Contents

 

About This Issue

When a patient presents to the ED with complaints of nonpitting edema, difficult breathing, and/or abdominal pain, angioedema may be at the top of your differential, but determining which of the 3 types of angioedema is presenting will be key to proper management. In this issue, you will learn:

The differences in presentation of histamine-mediated, bradykinin-mediated, and idiopathic angioedema.

The medications most likely to produce histamine-mediated angioedema.

How the presence – or absence – of urticaria will be a clue to the cause.

How C1-INH levels and function affect hereditary angioedema, how it can be measured in the ED, and how medications can manage the effects of decreased C1-INH levels or function.

How to assess the patient’s airway and be on guard for potentially life-threatening laryngeal swelling.

Which medications most effectively manage each type of angioedema, including the newer drug therapies.

The evidence for and against the use of corticosteroids and fresh frozen plasma.

Special cautions and management options for pediatric and pregnant/lactating patients.

How staging of the disease can inform disposition decisions.

1. About This Issue
2. Abstract
3. Case Presentations
4. Introduction
5. Critical Appraisal of the Literature
6. Etiology and Pathophysiology
   1. Histamine-Mediated Angioedema
   2. Bradykinin-Mediated Angioedema
      1. Hereditary Angioedema
      2. Acquired Angioedema
      3. Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema
      4. Tissue Plasminogen Activator-Induced Angioedema
   3. Idiopathic Angioedema
7. Differential Diagnosis
8. Prehospital Care
9. Emergency Department Evaluation
   1. Initial Management and Stabilization
   2. History
   3. Physical Examination
10. Diagnostic Studies
    1. Laboratory Studies
    2. Imaging Studies
11. Treatment
    1. Airway Management
    2. Pharmacologic Treatment
       1. Pharmacologic Treatment for Histamine-Mediated Angioedema
          • Epinephrine
          • Antihistamines
          • Corticosteroids
       2. Pharmacologic Treatment for Bradykinin-Mediated Angioedema
          • C1 Esterase Inhibitor Replacement Therapy
            • Berinert® and Cinryze®
          • Recombinant C1 Esterase Inhibitor
          • Non–C1 Esterase Inhibitor Concentrate Therapy
            • Icatibant
            • Ecallantide
    3. Fresh Frozen Plasma
    4. Prophylactic Medications
12. Special Populations
    1. Pediatric Patients
    2. Pregnant and Lactating Patients
13. Controversies and Cutting Edge
14. Disposition
    1. Staging and Treatment Location
    2. General Disposition Recommendations
15. Summary
16. Risk Management Pitfalls in Managing Angioedema in the Emergency Department
17. Time- And Cost-Effective Strategies
18. 5 Things That Will Change Your Practice
19. Case Conclusions
20. Clinical Pathway for Emergency Department Management of Patients With Angioedema
21. Tables and Figures
22. References

Abstract

Angioedema is a histamine-or bradykinin-mediated response that can be acquired, hereditary, or idiopathic. Manifestations include nonpitting edema of the subcutaneous layer of the skin or submucosal layers of the respiratory or gastrointestinal tracts. While acute presentations are typically transient and localized, angioedema can result in acute airway compromise, requiring immediate stabilization. It can also result in abdominal pain that is commonly misdiagnosed, resulting in unnecessary and potentially harmful procedures. This review assesses current literature on the etiology and management of angioedema in the emergency department. An analysis of the most recent evidence on therapeutic options is provided, while addressing barriers to use.

Case Presentations

A 23-year-old man presents by EMS with abdominal pain…

• The patient reports that for the past 4 hours he has had generalized abdominal pain that is sharp, constant, and increasing in intensity. He has associated nausea and nonbloody emesis. He denies fever, back pain, urinary complaints, chest pain, shortness of breath, or penile discharge. He denies recent NSAID, antibiotic, or drug or alcohol use, as well as recent travel or sick contacts. He states his father’s lips occasionally swell but does not know any other details of the condition. He does report having multiple similar occurrences of this abdominal pain, but with negative lab testing and imaging.
• His vital signs are: temperature, 36.6°C; heart rate, 112 beats/min; blood pressure, 104/70 mm Hg; respiratory rate, 22 breaths/min; and oxygen saturation, 100% on room air.
• His abdomen is soft, moderately distended, and diffusely tender to palpation without guarding or rebound. His genital exam is unremarkable. You are concerned for a surgical abdomen, but the recurrent nature of the presentation makes you suspicious that something else is going on…

A 48-year-old woman presents to the ED with lip swelling…

• She states her lips felt “heavy” when she woke up this morning, but over the past 8 hours, she has noticed significant swelling. She denies shortness of breath, voice change, rash, or prior history of similar occurrences, as well as fever or infection, any known allergies, or significant family history. She said she has had no recent exposures, travel, or trauma.
• The patient’s past medical history includes hypertension, diabetes mellitus type 2, and hyperlipidemia. She reports that she currently takes lisinopril, metformin, and atorvastatin.
• Her vital signs are: temperature, 37°C; heart rate, 82 beats/min; blood pressure, 138/78 mm Hg; respiratory rate, 16 breaths/min; and oxygen saturation, 100% on room air.
• On examination, the patient is in no distress, but she has significant upper and lower lip swelling, with no oropharyngeal involvement. The rest of her examination is unremarkable. You wonder whether her condition will progress and whether you should administer corticosteroids and antihistamines and proactively intubate her…

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Clinical Pathway for Emergency Department Management of Patients With Angioedema

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Tables and Figures

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Key References

Following are the most informative references cited in this paper, as determined by the authors.

3. * Long BJ, Koyfman A, Gottlieb M. Evaluation and management of angioedema in the emergency department. West J Emerg Med. 2019;20(4):587-600. (Review) DOI: 10.5811/westjem.2019.5.42650

8. * Depetri F, Tedeschi A, Cugno M. Angioedema and emergency medicine: from pathophysiology to diagnosis and treatment. Eur J Intern Med. 2019;59:8-13. (Review) DOI: 10.1016/j.ejim.2018.09.004

11. * Bernstein JA, Cremonesi P, Hoffmann TK, et al. Angioedema in the emergency department: a practical guide to differential diagnosis and management. Int J Emerg Med. 2017;10(1):15. (Review) DOI: 10.1186/s12245-017-0141-z

53. * Zuraw BL, Busse PJ, White M, et al. Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema. N Engl J Med. 2010;363(6):513-522. (Two randomized controlled trials; 68 patients) DOI: 10.1056/NEJMoa0805538

54. Takeda Pharmaceuticals. Highlights of prescribing information: Cinryze. 2008. Accessed September 10, 2022. (Drug package insert)

57. Pharming Americas B.V. Highlights of prescribing information: Ruconest. 2020. Accessed September 10, 2022. (Drug package insert)

59. * Lumry WR, Li HH, Levy RJ, et al. Randomized placebo-controlled trial of the bradykinin B2 receptor antagonist icatibant for the treatment of acute attacks of hereditary angioedema: the FAST-3 trial. Ann Allergy Asthma Immunol. 2011;107(6):529-537. (Randomized controlled trial; 88 patients) DOI: 10.1016/j.anai.2011.08.015

61. Shire Orphan Therapies Inc. Highlights of prescribing information: Firazyr. 2011. Accessed September 10, 2022. (Drug package insert)

67. Dyax Corp. Highlights of prescribing information: Kalbitor. 2014. Accessed September 10, 2022. (Drug package insert)

85. * Cicardi M, Banerji A, Bracho F, et al. Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema. N Engl J Med. 2010;363(6):532-541. (Randomized controlled trial; 74 patients) DOI: 10.1056/NEJMoa0906393

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Keywords: histamine, bradykinin, edema, swelling, urticaria, tPA, ACE inhibitor, airway, stridor, epinephrine, prophylaxis