Evaluation and Management of Angioedema in the Emergency Department

Angioedema is defined by non-dependent, non-pitting edema that affects several different sites and is potentially life-threatening due to laryngeal edema. This narrative review provides emergency physicians with a focused overview of the evaluation and management of angioedema. Two primary forms include histamine-mediated and bradykinin-mediated angioedema. Histamine-mediated forms present similarly to anaphylaxis, while bradykinin-mediated angioedema presents with greater face and oropharyngeal involvement and higher risk of progression. Initial evaluation and management should focus on evaluation of the airway, followed by obtaining relevant historical features, including family history, medications, and prior episodes. Histamine-mediated angioedema should be treated with epinephrine intramuscularly, antihistaminergic medications, and steroids. These medications are not effective for bradykinin-mediated forms. Other medications include C1-INH protein replacement, kallikrein inhibitor, and bradykinin receptor antagonists. Evidence is controversial concerning the efficacy of these medications in an acute episode, and airway management is the most important intervention when indicated. Airway intervention may require fiberoptic or video laryngoscopy, with preparation for cricothyrotomy. Disposition is dependent on patient’s airway and respiratory status, as well as the sites involved.


INTRODUCTION
Angioedema is a condition defined by non-dependent, non-pitting, transient edema lasting up to seven days due to

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Evaluation and Mangement of Angioedema in the ED types I and II, and several forms of acquired and idiopathic angioedema. 13,20,42,43 ACEi-mediated angioedema accounts for up to 30% of ED visits for angioedema of all types. 16,21,[44][45][46][47][48][49] ACEis prevent the conversion of angiotensin I to angiotensin II and reduce bradykinin metabolism, which increases the risk of angioedema. Most cases are localized to the lips and tongue. 14,15 Patients at greatest risk for developing ACEi-mediated angioedema include African Americans and those taking immunosuppressants or dipeptidyl peptidase-IV inhibitors (a class of diabetic medications) in addition to the ACEi. 14,15,49 The rate of angioedema is highest within the first 30 days of starting an ACEi, although the risk of angioedema remains for the duration of the ACEi use, with cases of ACEi-mediated angioedema documented in patients with prolonged courses of multiple years. 50-52 If a patient continues taking an ACEi after developing ACEi-mediated angioedema, the average time to recurrence is approximately 10 months. 50,53 Angiotensin II receptor blockers (ARB) and renin antagonists can also cause angioedema, but this is not due to bradykinin. [1][2][3][4][5] If angioedema develops in a patient on an ACEi, the ACEi should be discontinued and a different antihypertensive class used.
Differentiating histamine and bradykinin-mediated angioedema can be difficult. One retrospective study evaluated 188 patients, with one point assigned to age > 65 years, dyspnea, no itching or erythema, laryngeal involvement, and intake of ACEi/AT-II antagonist, and two points assigned if there was no response to steroid therapy. 97 If the score was > 3 points, the patient was treated with C1-INH or B2 receptor antagonist for suspicion of bradykinin-mediated angioedema. This resulted in a sensitivity of 96% and specificity of 84% for the diagnosis of bradykinin-mediated angioedema. 97 While this tool can help to differentiate the underlying etiology, it requires further validation before routine use.

Diagnostic Testing
Angioedema is a clinical diagnosis, with no required testing in the ED. 1,2,4 Leukocyte counts cannot reliably differentiate if an infection is present, as leukocytosis over 30,000 per cubic millimeter has been observed. 98 C-reactive protein may be elevated in ACEi-mediated angioedema. 1,4 Determining the specific type of angioedema involves specialized laboratory testing not available in the ED, including tryptase, C4, and C1-INH. [1][2][3][4] These tests can be obtained in the outpatient setting and should not be routinely obtained in the ED, as they do not guide management. Histamine-mediated forms can display elevated tryptase levels during attacks, while patients with HAE will display normal tryptase levels. 3 C4 levels serve as a sensitive screening test for C1-INH deficiency. 1,3 Serum C4 levels will typically be < 30% of normal in acute episodes of angioedema from HAE types I and II, although the laboratory values may be normal between attacks. 23,100,101 Type I HAE often involves low C1-INH levels and decreased function, while type II HAE includes normal levels but decreased function. 13,19,102 C1q levels, a component of the complement system, can be used to differentiate acquired and hereditary forms, as C1q is decreased in acquired angioedema and normal in HAE. 1,3,4,100,103 Type III HAE has normal levels and function of C1-INH but is usually identified by a positive family history. [1][2][3][4]7,8 No tests can confirm ACEi-mediated angioedema. 1,7,19,23 Patients with abdominal symptoms may demonstrate segmental bowel wall edema, straightening of intestinal segments, and ascites on computed tomography (CT). 4,104,105 Ultrasound may similarly reveal bowel wall thickening or ascites. 106 Ultrasound can be used to evaluate for laryngeal edema, although this requires further study. 4 Chest radiography, if obtained, is typically normal. Neck radiographs and CT of the neck with intravenous (IV) contrast can evaluate for mimics of angioedema, but they should not be ordered routinely for patients with suspected angioedema. 104 Fiberoptic visualization of laryngeal and airway structures is recommended if concern for laryngeal or airway involvement is present.

Management
The primary focus of ED management is assessment of the airway and evaluation for anaphylaxis, which is the most common mimic. [1][2][3][4]7,8 Figure 1 depicts an algorithm for management. Vital signs should not be relied upon in isolation to determine the need for airway intervention.

Airway Management
Patients with angioedema involving the tongue or larynx require consideration of definitive airway management. Angioedema can progress rapidly within hours, and airway obstruction occurs in up to 15% of patients with angioedema. 1,4,17,18 For patients with angioedema who require a definitive airway, cricothyrotomy or tracheostomy is needed in up to 50% of cases. 17,87,105 Prior history of intubation or severe angioedema should raise the concern for a difficult airway which may require early airway intervention. 1,4,107 Evidence of upper airway involvement on examination includes stridor, change in patient voice, and hoarseness. If physical examination reveals swelling of the tongue, floor of the mouth, or soft palate, directly visualize the tongue base and airway with fiberoptics. The presence of epiglottic, aryepiglottic, or laryngeal edema suggests need for definitive airway. 1,2 If the angioedema exclusively involves structures anterior to the teeth such as the lips, intubation is generally not needed. [85][86][87][88][89][90][91][92] Noninvasive positive pressure ventilation can also assist with temporization; however, this is not a definitive therapy for patients with airway involvement. Supraglottic and extraglottic airway devices are common rescue devices; however, they are not recommended in patients with angioedema, as the device will remain above the site of airway obstruction. 1,4,7,8,85 If placed, these devices may also worsen edema due to the associated trauma with placement.
Physical manipulation of the airway may worsen edema, especially in bradykinin-mediated angioedema. 1,4,7,8 In patients with history or evidence on examination of a difficult airway, video laryngoscopy or fiberoptic awake intubation is recommended, as this allows the patient to maintain his/her airway reflexes during airway visualization and the intubation attempt. 1,4,[107][108][109] Topical anesthetics and ketamine are optimal agents for awake intubation. Severe edema may prohibit passage of an endotracheal tube through the glottis, even with the use of fiberoptic or video laryngoscopy guidance. Thus, the resuscitation team must prepare for cricothyrotomy before an attempt at intubation is started, known as a double setup. [1][2][3][4][5] If the patient does not require immediate airway intervention, transfer to the operating room may be beneficial with anesthesia and otolaryngology consultation, similar to pediatric epiglottitis.

Evaluation and Mangement of Angioedema in the ED
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Targeted Therapies for Bradykinin-mediated Angioedema
Bradykinin-mediated forms of angioedema are typically resistant to therapies effective in histamine-mediated reactions. 1,4,7,8,13,135,136,147 At the time of construction for this review, several medications have been FDA approved for treatment of acute bradykinin-mediated angioedema: three C1-INH concentrates (two plasma-derived and one recombinant), one kallikrein inhibitor, and one bradykinin-2-receptor antagonist (Table 3). 1,4,7,8,13,135,136 C1 Inhibitor Concentrate C1-INH concentrate for HAE episodes was first described in 1973, and there are two plasma-derived formulations currently available (Berinert and Cinryze), as well as one recombinant form (Ruconest), all administered intravenously. [1][2][3][4][5]7,8,135,136,148 They are currently approved for acute HAE, although these medications have been used for ACEi-mediated forms. [1][2][3][4][5]7,8,135,136,148 Berinert and Cinryze provide native plasma protein that regulates kallikrein and Factor XII activity, reducing bradykinin production. Bork 151 Cinryze has also been evaluated in HAE, with a double-blind placebo-controlled trial of 68 patients finding no statistically significant improvement in time to relief, although a double-blind crossover trial of 21 patients demonstrated decrease in attack number, duration, and severity. 4,136,152 A study that was

Long et al.
Evaluation and Mangement of Angioedema in the ED not placebo controlled found 68% of patients had improvement at one hour, while 87% experienced relief at four hours. 153 Other trials evaluating Berinert and Cinryze for HAE and ACEimediated angioedema have found that the time to symptom improvement from administration varies from 0.5-5 hours, with complete resolution occurring within 1-10 hours. 136 Ruconest is a recombinant form of C1INH. One open-label study with no placebo control found time to symptom relief of 30 minutes. 154 A double-blind, placebo-controlled trial found time to symptom relief of 66 minutes in patients receiving 100 units/kg, vs 495 minutes in controls. 155 Another randomized trial found time to symptom relief of 75 minutes in treated patients vs 303 minutes in patients receiving placebo. 156 Kallikrein Inhibitor Ecallantide (Kalbitor) is a recombinant plasma inhibitor of kallikrein provided subcutaneously and approved for use in HAE. 1,4,7,8,136 This agent reduces bradykinin synthesis by preventing the cleavage of kininogen. 1,4,7,8,136 It is associated with up to a 3% risk of anaphylaxis, necessitating close observation during administration and for up to one hour after. 1,4,7,8 The EDEMA trials evaluated ecallantide for HAE. [157][158][159][160] The EDEMA1 trial evaluated ecallantide at various doses vs placebo, finding the 40 mg/m 2 dose improved symptoms at four hours, although other doses did not. 157 The phase 2 EDEMA2 trial found subcutaneous dosing had improved outcomes vs IV dosing. 158 EDEMA3 was an open label and double-blind phase 3 trial evaluating ecallantide vs placebo, with improvement in treatment score at four hours in patients receiving ecallantide. 159 EDEMA4 found improved symptom scores vs placebo. 160 A triple-blind phase 2 randomized controlled trial compared ecallantide at three different subcutaneous doses with placebo for ACEi-mediated angioedema and found no difference in patients meeting criteria for discharge. 161 Lewis et al. conducted a double-blind phase 2 study with patients randomized to placebo or ecallantide. 162 Most patients received therapy for histamine-mediated angioedema as well. The study found no difference in patients meeting criteria for discharge within six hours with ecallantide administration. 162

Bradykinin B2 Receptor Antagonist
Icatibant acetate (Firazyr) is a selective and competitive bradykinin B2 receptor antagonist. 1,4,7,8,136 Icatibant was evaluated in three clinical trials: FAST-1, FAST-2, and FAST-3. 136,163,164 FAST-1 was a double-blind, placebo-controlled trial that demonstrated faster symptom relief (0.8 vs 16.9 hours) but no difference in the degree of symptom relief. 4,163 The FAST-2 study demonstrated improved time to symptom relief in a doubleblind study comparing icatibant to oral tranexamic acid (onset of symptom improvement 0.9 vs 7.8 hours). 4,163 FAST-3 was a phase 3 double-blind, randomized, placebo-controlled trial that found a decrease in the time to primary symptom relief (2.0 vs 19.8 hours) and complete symptom relief (median 8.0 vs 36 hours). 4,164 The literature suggests that the time to symptom improvement ranges from several minutes up to seven hours for icatibant. Of studies reporting improvement, approximately half of patients improve within 30 minutes, while time to complete symptom resolution ranges from 0.5-16 hours. 136  A systematic review published in 2017 evaluating medication use in ACEi-mediated angioedema concluded icatibant possessed the highest level of evidence due to better study quality, while FFP has limited evidence demonstrating benefit and inconsistent dosing strategies for ACEi-mediated angioedema. 136 This systematic review incorporated case reports, case series, a prospective observational study, and one randomized controlled trial. However, the recommendations were limited by low quality evidence and significant heterogeneity with respect to the severity of angioedema and clinical outcomes. 175 Most of the included studies evaluated time to discharge and time to symptom relief, rather than the need for definitive airway, peak symptoms severity, duration of mechanical ventilation, and hospital/ ICU admission. 136,175 Publication bias was also severe, limiting conclusions. Studies following the publication of this systematic review from 2017 suggest no difference in time to discharge with icatibant. 175 Sinert et al. evaluated icatibant vs placebo in a phase III, double-blind clinical trial. 176 Time to discharge was four hours in both groups, with similar time of symptom relief. 176 A second prospective, randomized study published by Straka et al. compared icatibant and placebo, finding no difference in symptom severity or duration. 177 The current literature evaluating targeted therapy for bradykinin-mediated angioedema suffers from several limitations, including significant heterogeneity in patient selection, outcomes, comparators, dosing, and study design, as well as low numbers of included patients and high risk of bias. 1,4,136,175 Medication efficacy is controversial with delayed onset of action, variable relief of symptoms, and limited availability depending on the institution. 136,175 Rather than primarily focus on administering medications that may or may not improve symptoms in bradykinin-mediated forms of angioedema, EPs should focus on managing the patient's airway. 1,4,175

Disposition
Disposition is mainly determined by airway involvement. Several studies have sought to predict airway compromise in patients with acute angioedema. [1][2][3][4][5]85,178 Ishoo et al. performed a retrospective study of 80 patients with 93 acute episodes of angioedema. 85 Wheezing, voice change, hoarseness, and stridor predicted the need for airway intervention. This study categorized patients based on the anatomic location of angioedema (Table 4). 85 A subsequent study published one year later found the same factors predict need for definitive airway. 178 Importantly, these factors require further validation and laryngeal visualization for staging.
Patients with respiratory or airway distress require ICU admission, as well as those with stage III and IV edema due to risk of progression. [1][2][3][4][5]7,8,89 Patients with stable or improving stage I or II edema of the face, lip, or soft palate should be monitored for several hours to evaluate for worsening of the angioedema. [1][2][3][4][5]7,8,89,102 Patients with stage I angioedema can be discharged with follow-up after evaluation for progression. Patients with stage II angioedema are often discharged home within 24 hours, and ED observation units provide an optimal setting for monitoring of these patients. 1,4 However, if edema involves > 3 sites (lips, tongue, mouth floor, soft palate, and larynx), admission is recommended due to greater risk of airway involvement. 89 Patients with acute and recurrent angioedema may benefit from consultation with allergy/immunology specialists to discuss laboratory testing and arrange follow-up, particularly in patients with HAE. [1][2][3][4][5]7,8,102 Patients with a first episode of angioedema, no response to anaphylaxis treatment, or family history of HAE require follow-up with an allergy/immunology specialist. These specialists can help diagnose a specific cause, evaluate and educate the patient concerning triggers, and provide prophylactic medications, which may prevent the need for ED care. 1,4,179,180 Patients with known HAE and a recurrent attack may present with an action plan and recommended therapies, which should be followed when possible. 102,181,182 Patients discharged from the ED with histamine-mediated angioedema and those with unclear etiology or first-time episode should be prescribed epinephrine autoinjectors and educated on potential triggers. 69,102 Family and friends should also be educated on these factors. Patients with respiratory distress or airway swelling after discharge should use the epinephrine autoinjector and immediately return to the ED. The patient with ACEimediated angioedema must discontinue his or her medication, and an alternative agent should be discussed with the patient's primary care provider. [1][2][3][4][5]7,8,102 Most patients can use calcium channel blockers or angiotensin receptor blockers without developing a recurrence of their angioedema. 1,183,184 The literature suggests the incidence of angioedema with ARB is 0.11%, which is not statistically different than placebo. 185

Stage
Site

CONCLUSION
Angioedema is non-dependent, non-pitting edema at a variety of sites. Its forms can be divided into histamine-mediated and bradykinin-mediated types. Histamine-mediated forms can present similarly to anaphylaxis, while bradykinin-mediated angioedema is slower in onset, presents with greater face and oropharyngeal involvement, and has higher risk of progression. Initial evaluation and management should focus on the airway, followed by an evaluation for family history, medications, and prior episodes. Histamine-mediated angioedema is treated like anaphylaxis with epinephrine, antihistamines, and steroids. These medications are not effective for the bradykinin-mediated forms, although they can be attempted in the absence of effective therapy. Other medications include C1-INH protein replacement, kallikrein inhibitor, and bradykinin receptor antagonists. Several studies have evaluated these for angioedema, but the evidence is lacking for efficacy. The focus should be on airway management rather than medications in bradykinin-mediated angioedema. This may require fiberoptic or video laryngoscopy, with preparation for cricothyrotomy. Disposition depends on patient's airway and respiratory status, as well as the involved sites.