This 25-year-old African American female presents to the emergency department (ED) 2 hours after the onset of lip swelling that has progressed to difficulty in breathing. Her past medical history is unremarkable, with the exception of newly diagnosed hypertension. Last week, her primary care physician began a course of a new antihypertensive medication, lisinopril. She has had no previous history of tissue swelling and there is no family history of disorders characterized by tissue swelling. Her ED vital signs are heart rate 100 bpm, respiratory rate 22 breaths per minute, blood pressure 165/90 mm Hg, temperature 37°C, and SpO₂ is 99% on 2 L·min⁻¹ of oxygen by nasal prongs.

The patient is seated (Figure 26–1) with markedly edematous lips. She has a muffled voice (“hot potato voice”) and is unable to swallow her own secretions. There is no stridor. The remainder of the physical examination is within normal limits.

What Is the Pathophysiology of Angioedema? Are There Different Etiologies?

Angioedema is defined as the abrupt onset of transient, well-demarcated, non-pitting swelling of the skin, mucous membranes, and deep subcutaneous tissues, including the linings of the upper respiratory and gastrointestinal tracts.^1–3 Angioedema develops because of a local increase in permeability of the submucosal or subcutaneous capillary vessels, causing local plasma extravasation into the interstitial space.^1,3 This is exacerbated by the release of vasoactive substances such as histamines, prostaglandins, cytokines, and bradykinin.⁴

Angioedema can be divided into hereditary angioedema (HAE) and acquired angioedema. HAE is extremely rare, affecting in the range of 1:30,000 to 1 in 80,000 people.^4,5 It develops due to a C1 esterase inhibitor deficiency, which is inherited in an autosomal dominant pattern with almost complete penetrance.⁵ This deficiency results in an abnormal increase in the activation of C1 and subsequent excessive formation of the enzyme kallikrein. The excess kallikrein transforms kininogen into kinins, including bradykinin. Bradykinin, the primary biologic mediator of angioedema,⁵ is highly vasoactive and produces the characteristic tissue swelling seen in angioedema.⁴ HAE is commonly precipitated by trauma and emotional stress. Frequently, the trauma is considered to be minor and can be as innocuous as prolonged sitting on a hard surface or clapping of the hands. Dental and surgical trauma are well-recognized precipitators of an acute attack.⁵

Patients with known HAE should have a predetermined comprehensive management plan that includes access to treatment in acute attacks and a prophylactic strategy, when indicated, such as prior to elective surgery. Bradykinin-mediated angioedema is not responsive to standard angioedema treatment modalities used for mast cell-mediated anaphylactic angioedema such as corticosteroids, antihistamines, and epinephrine and must be treated with C1 inhibitor replacement and drugs that act on the bradykinin pathway directly.⁵ Treatment with fresh frozen plasma (FFP) can be beneficial, as it contains C1 esterase inhibitor (C1INH). However, FFP can occasionally induce an acute exacerbation of the attack as it contains uncleaved high-molecular-weight kininogen. Therefore, caution is warranted when using FFP for the treatment of an HAE attack. Three medications are available in the United States that act on the kallikrein–bradykinin pathway directly and been proven to be beneficial in the treatment and prophylaxis of recurrent HAE attacks. These include pasteurized, nanofiltered, plasma-derived C1 inhibitor concentrate (Berinert), and bradykinin pathway antagonists (ecallantide and icatibant). A recombinant human C1INH (Ruconest) is available in Europe.^4,6

Acquired angioedema comprises several types, including:

• 
  

  acquired C1 inhibitor deficiency (C1INH) mediated by bradykinin,⁵

  
  
• 
  

  anaphylaxis mediated by IgE, precipitated by exposure to a previously sensitized allergen (such as antibiotics, peanuts, and shellfish), and

  
  
• 
  

  anaphylactoid reactions mediated by direct mast cell degranulation as elicited by agents such as morphine, vancomycin (“red man syndrome”), and radio-contrast media; or by altering arachidonic acid metabolism as seen in reactions caused by benzoates and nonsteroidal anti-inflammatory agents (NSAIDs).^7,8

Anaphylaxis is characterized by the acute onset of a spectrum of effects that may include angioedema of the upper airway. Varying degrees of systemic effects manifested by wheeze secondary to bronchoconstriction and hypotension secondary to vasodilation and plasma leakage into the interstitial space may also occur.^1,9

The development of angioedema secondary to ACEIs is of particular interest in the case presented.^10,11 In addition to inhibiting the conversion of angiotensin I to angiotensin II, the suppression of angiotensin-converting enzyme (ACE) results in reduced degradation of bradykinin and substance P. ACE is a dual-specificity dipeptidase that cleaves bradykinin and substance P into inactive peptides. Therefore, inhibition of this activity will result in increased levels of bradykinin and subsequent tissue swelling.⁵ The association between ACEIs and angioedema has been well described. Angioedema has also been demonstrated to occur with the angiotensin II receptor blockers (ARBs)^7,8 albeit with a much attenuated incidence. There is a modest increase in risk for ARB-induced angioedema in patients who have previously experienced ACEI-induced angioedema, though most patients with ACEI-induced angioedema will not develop ARB-induced angioedema.¹⁸

ACEI-induced angioedema has a predilection for the head and neck, rendering it a particular challenge in airway management.⁴ Epinephrine is the mainstay of acute treatment of allergy-induced angioedema. Adjunctive therapy includes antihistamines and corticosteroids. However, none of these agents are effective in HAE and of limited use in ACEI- and ARB-induced angioedema.^8,12 There is no role for FFP in ACEI- or ARB-induced angioedema. However, as mentioned above, FFP can be useful in the treatment of HAE due to the presence of C1 inhibitor.⁵

ACEI-induced angioedema is the most common cause of angioedema seen in US EDs, accounting for 17% to 38% of all angioedema cases.¹³ In the omapatrilat versus enalapril (OCTAVE) antihypertensive trial, the investigators identified independent risk factors including increased incidence in African Americans, age greater than 65, history of drug rash, and history of seasonal allergies.¹⁴ Other risk factors include female gender, history of smoking, increasing age, transplant recipients, and patients on immunosuppressive therapy.^3,5 According to the literature, the incidence of ACEI-induced angioedema ranges from 0.1% to 1% of all patients taking this class of drugs.^2,4,6,14 As many as half of the patients affected are African American,¹⁵ resulting in hospitalization rates ≥2 times higher in African American patients compared to non-African American patients in the United States.¹⁶ Approximately 50% of all ACEI-induced angioedema cases occur within 1 week of starting the medication, with the remainder occurring anywhere from weeks to years after starting the drug.⁴ Discontinuation of the ACEI will resolve the angioedema, though the risk of recurrent angioedema attacks may persist for weeks. Patients who have experienced an angioedema attack and who continue with ACEI therapy are at significant risk of recurrence within 5 years.⁶

What Is the General Clinical Course of Angioedema?

The clinical course of angioedema is unpredictable and largely dependent on the underlying etiology. Patients with HAE usually report trauma, often minor (e.g., dental visit), followed by tissue swelling. They can present with swelling in variable anatomic areas such as the face, hands, arms, legs, GI tract, and genitalia. Abdominal symptomatology is a frequent cause of significant morbidity due to severe abdominal pain, intractable vomiting, and hypotension due to third-spacing. Inappropriate surgical investigations in unrecognized HAE have been reported.⁵ In one large series, 10% of the patients with HAE required definitive airway intervention because of upper airway edema.¹⁷

The onset of IgE-mediated anaphylaxis is rapid and often life threatening if not treated appropriately.⁴ The clinical course of ACEI-induced angioedema is often subacute but extremely unpredictable, and life-threatening presentations requiring airway interventions do occur and are reported in up to 20% of these patients.⁴ According to the literature, between 0% and 2.2% of patients with angioedema are intubated.¹⁵ This variability may reflect a spectrum of patients from those with acute severe disease to those with a less acute presentation who were intubated for concerns of disease progression. It is extremely difficult to predict which patients who present with a stable airway will progress to a requirement for airway intervention. Researchers from Boston retrospectively analyzed cases of ACEI-related angioedema and determined that increasing age and oral cavity/oropharyngeal involvement predicted the need for airway intervention.¹⁵