Table of Contents

 

1. Abstract
2. Case Presentations
3. Introduction
4. Critical Appraisal Of The Literature
5. Etiology And Pathophysiology
   1. Mediators Of Angioedema
      1. Bradykinin
      2. Histamine
   2. Causes Of Angioedema
      1. Hereditary Angioedema
      2. Acquired Angioedema
      3. Immunologic/Allergic Angioedema
      4. ACE Inhibitor-Induced Angioedema
      5. Physically Induced Angioedema
      6. Idiopathic Angioedema
6. Differential Diagnosis
7. Prehospital Care
8. Emergency Department Evaluation
   1. Initial Stabilization
   2. History
   3. Physical Examination
9. Diagnostic Studies
10. Treatment
    1. Pharmacologic Treatment
       1. Epinephrine
       2. Glucagon
       3. Terbutaline
       4. Antihistamines
       5. Steroids
       6. Fresh Frozen Plasma
       7. C1 Inhibitor Concentrate
          • Berinert® (CSL Behring; Marburg, Germany)
          • Cinryze® (ViroPharma, Inc.; Exton, PA)
          • Rhucin® (Pharming; Leiden, The Netherlands)
          • Ecallantide (Kalbitor®/DX-88; Dyax; Burlington, MA)
          • Icatibant (Firazyr®/HOE-140; Shire Human Genetic Therapies, Inc.; Lexington, MA)
       8. Prophylactic Medications
          • Androgens
          • Antifibrinolytic Agents
11. Controversies And Cutting Edge
    1. Controversies In Treatment
    2. Use Of Angiotensin Receptor Blockers
12. Disposition
13. Summary
14. Risk Management Pitfalls For Angioedema
15. Time- And Cost-Effective Strategies
16. Case Conclusions
17. Clinical Pathway For The Management Of Patients With Angioedema
18. Tables and Figures
    1. Table 1. Complement Profile Testing For Different Causes Of Angioedema
    2. Table 2. Comparison Of New Medications For Treatment Of Angiodema
    3. Table 3. Ishoo Staging Of Angioedema
    4. Figure 1. Interaction Of Kallikrein-Kinin System, Coagulation Pathway, And Common Complement Pathway
19. References

Abstract

Angioedema is the end result of a variety of pathophysiological processes resulting in transient, localized, nonpitting swelling of the subcutaneous layer of the skin or submucosal layer of the respiratory or gastrointestinal tracts. It is now generally accepted that the swelling is mediated by either histamine or bradykinin. Angioedema may result in severe upper airway compromise or—less commonly recognized—compromise in the gastrointestinal tract often associated with severe abdominal pain. A variety of new therapeutic options are becoming available for use in the United States that have the potential to greatly impact the management and outcomes for those with severe clinical manifestations. This review assesses the evidence on the causes and treatments of angioedema in the emergency department and reviews the new therapeutic options available for treatment of angioedema based on their effectiveness, price, and availability.

Case Presentations

In the middle of an unusually slow evening shift, a 52-year-old black male presents to the ED from walk-in triage with a complaint of lip swelling. He states that he noticed a tingling in his lips shortly after waking that morning, but it wasn’t until he brushed his teeth that he noticed how large his lips had become. He decided to come to the hospital almost 12 hours later only after family members insisted that he get “checked out.” He denies any recent trauma, infection, or known exposures to possible allergens. He denies any pain or itching. His past medical history is significant for hypertension and borderline diabetes. He is unable to remember the name of the medication that he takes for his blood pressure, but he says he has been taking it for years. His vital signs are: heart rate, 74 beats per minute; blood pressure, 156/82 mm Hg; respiratory rate, 16 breaths per minute; temperature, 36.8°C; and oxygen saturation, 98% on room air. He is comfortable and in no apparent distress. It would be impossible to miss the rather impressive size of his lips. The upper lip looks to be about 10 times the normal size and the lower lip is only somewhat less enlarged. You are able to examine his oropharynx and find no further swelling of the uvula or posterior pharynx. The rest of his examination is unremarkable. Your nurse checks the airway cart out of concern that the patient will need to be immediately intubated. Your medical student asks the following logical questions:

• What is the cause of his lip swelling?
• Is there a diagnostic test to determine the cause?
• What is the appropriate treatment?
• Should the patient be intubated immediately to protect his airway?

The next week, you see a 19-year-old white female who is brought in by EMS for severe diffuse abdominal pain. She states that the pain began 8 hours earlier. She has had nausea with multiple episodes of vomiting. She denies fever, recent antibiotics, foreign travel, or sick contacts. She does state that she has had similar presentations multiple times in the past but never this pronounced. She denies any past medical history other than recurrent abdominal pain similar to how she is currently presenting. She was recently started on oral contraceptives, but she denies being sexually active. Her vital signs are: heart rate, 112 beats per minute; blood pressure, 92/64 mm Hg; respiratory rate, 22 breaths per minute; temperature, 36.9°C; and oxygen saturation, 100% on room air. She is obviously uncomfortable and actively retching. Her physical exam is remarkable for a soft but markedly distended abdomen with evidence of shifting dullness. She is diffusely tender to palpation without guarding or rebound. A pelvic exam is unremarkable. After reviewing her vital signs and performing her physical exam, you are much more concerned about this patient. You pull over the portable ultrasound to take a look and are immediately impressed by a large amount of free fluid in the abdomen. You ask yourself several questions:

• What is the cause of her recurrent abdominal pain?
• Does she need an abdominal CT scan, and, if yes, does it need to be with contrast?
• Does she need emergent surgical consultation?
• Other than treating the pain, is there any medication that is indicated?

Introduction

Angioedema is the clinical manifestation of transient, localized, nonpitting swelling of the subcutaneous layer of the skin or submucosal layer of the respiratory or gastrointestinal tracts. The first widely recognized description of angioedema was by Heinrich Quincke in 1882. In honor of his contribution, it is sometimes referred to as Quincke edema.

Angioedema is not a disease; rather, it is a physical manifestation of a variety of pathophysiological processes. These processes have the end result of either mast cell degranulation or formation of bradykinin. The incidence of angioedema, overall, is not known. For patients taking angiotensin-converting enzyme (ACE) inhibitors, the incidence is between 0.1% and 0.7%. The prevalence of the various forms of hereditary angioedema is estimated to be between 1 in 10,000 and 1 in 50,000.¹

The emergency clinician must understand the various causes of angioedema and tailor the treatment of the patient based on the likely etiology. In this issue of Emergency Medicine Practice, the various causes of angioedema are discussed as well as different diagnostic and treatment strategies.

Critical Appraisal Of The Literature

A literature search was performed using PubMed from 1964 to present, using the search term angioedema and limited to English-language articles that were systematic reviews, meta-analyses, multicenter studies, clinical trials, or randomized clinical trials. Using this approach, 269 articles were found and assessed for review. In addition, 1502 case reports were identified in the search; however, it was determined that they would add little to the evidence provided by the better-quality resources, and, therefore, these case reports were not systematically reviewed.

A search of the National Guidelines Clearinghouse (www.guideline.gov) produced no additional practice guidelines focused on angioedema. There was 1 guideline for urticaria that resulted when a search for angioedema was performed.² A review of the Cochrane Database of Systemic Reviews failed to find any completed reviews. There is a protocol in place for a review of “angiotensin-converting enzyme inhibitor-induced angioedema in patients with primary hypertension,” but it has not been completed.

Risk Management Pitfalls For Angioedema

1. “The patient had been on an ACE inhibitor for years. I assumed the angioedema was due to another cause, so I did not tell the patient to stop taking it.”

   ACE inhibitor-induced angioedema can develop at any time, although most cases are reported to occur in the weeks following initiation of treatment. There are multiple cases of angioedema developing after years of being on the ACE inhibitor. If a patient is on an ACE inhibitor and develops angioedema, the patient should be told to stop taking that medication immediately.

2. “The patient had no family history of hereditary angioedema, so I thought it must be due to some other cause.”

   Not all patients with hereditary angioedema have a family history of the disease. While the disease is due to a genetic defect and is therefore considered hereditary, up to 25% of these mutations occur de novo. An investigation for hereditary angioedema should be undertaken in patients with recurrent angioedema even if there is no family history.

3. “I didn’t give this patient epinephrine because I thought this was angioedema and not anaphylaxis.”

   It is important to remember that angioedema is a physical manifestation of a disease process. This may include allergic reactions and anaphylaxis. If the patient is having an anaphylactic reaction and epinephrine is indicated, then the presence of angioedema does not change the need for epinephrine.

4. “The patient’s swelling only involved the lips, so I sent him home after an hour of observation.”

   Patients with angioedema should be observed in the ED for a minimum of 4 to 6 hours before there is any consideration for discharge. The swelling of angioedema may present with a benign initial evaluation but then significantly worsen in a short period of time.

5. “The patient wasn’t on an ACE inhibitor or an ARB, there was no family history, and there was no sign of an allergic reaction. I didn’t think she needed follow-up.”

   It is important to remember that there are multiple causes of angioedema. One possible cause, although rare, is acquired angioedema. This is usually associated with a lymphoproliferative or autoimmune disease. Angioedema may be the presenting complaint for some of these patients. For recurrent angioedema without an obvious cause, an investigation into possible malignancy or autoimmune disease should be initiated.

6. “I knew the patient had a history of hereditary angioedema, but she presented with a rigid, tender abdomen and elevated WBC, so I thought emergency surgery was indicated.” Angioedema affects not only the subcutaneous tissue but also the submucosal layer of the gastrointestinal tract. Patients with hereditary angioedema often have recurrent abdominal pain. The presentation may be so profound that unnecessary surgical exploration may be undertaken. An elevated WBC count is unlikely to be helpful in differentiating an acute infectious abdominal process from abdominal angioedema. These patients present a diagnostic challenge to the treating physician.
7. “The tongue swelling was getting worse, but I thought I could wait to secure the airway.”

   The airway is of paramount importance in any patient presenting with swelling that involves the head or neck. It is better to err on the side of caution and secure the airway before the edema prevents the use of normal airway devices. At times, the progression of swelling can be rapid. A case of death from asphyxiation within 20 minutes of onset of laryngeal edema has been reported. Once there is significant swelling, the airway may only be secured with either fiber-optic means or by using a surgical technique.

8. “I had given steroids, diphenhydramine, cimetidine, and epinephrine. The patient didn’t get better, so I didn’t think that there was any other therapeutic option.”

   The FDA has approved many new therapeutic options over the past few years. It is important for the emergency clinician to stay current on available medications and their indications and to establish a protocol on the use of these new agents, proactively, with other services.

9. “This patient with hereditary angioedema was complaining of shortness of breath. I didn’t see any sign of swelling after observing her for 4 hours, so I thought she was OK to be discharged.”

   Some patients with hereditary angioedema are placed on antifibrinolytic agents such as sigma-aminocaproic acid and tranexamic acid as prophylaxis against angioedema episodes. There is an increased risk of thromboembolic events with the use of these medications. Alternative diagnoses unrelated to angioedema should be considered in these patients.

10. “I didn’t think that the patient needed any further medications because her angioedema and urticaria resolved in the ED.”

    Patients with allergic/immunologic angioedema who respond to initial therapy and are able to be discharged should be sent home with a prescription for at least 3 days of steroids and instructions to continue antihistamines. Despite initial improvement, there is always a concern for a second episode. This is due to a biphasic nature of up to 20% of allergic reactions. The second phase may be delayed as much as 72 hours after the initial presentation.

Tables and Figures

References

Evidence-based medicine requires a critical appraisal of the literature based upon study methodology and number of subjects. Not all references are equally robust. The findings of a large, prospective, randomized, and blinded trial should carry more weight than a case report.

To help the reader judge the strength of each reference, pertinent information about the study will be included in bold type following the reference, where available. In addition, the most informative references cited in this paper, as determined by the authors, are noted by an asterisk (*) next to the number of the reference.

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