emDocs Cases: Angioedema Evaluation and Management

Authors: Brit Long, MD (@long_brit, EM Attending Physician, San Antonio, TX) and Michael Gottlieb, MD (EM Attending Physician, Rush Medical Center, Chicago, IL) // Edited by: Alex Koyfman, MD (@EMHighAK)

Today on emDocs Cases we have case-based discussion on a core EM topic, with a look at some controversy and cutting-edge treatments.

Case 1:

A 23-year-old female presents with face, lip, and tongue swelling after eating shellfish. She has diffuse urticaria as well. Though vital signs are normal, she has noted significant voice changes. On oral examination, you can only see a large tongue.

Case 2:

A 52-year-old male with a history of C1-INH factor deficiency presents with lip and tongue swelling and voice changes. He forgot to take his prophylactic medication and woke with this swelling. He has never required definitive airway in the past.


Angioedema can present in a variety of ways, but most commonly with transient, non-dependent, non-pitting edema. It typically affects deep dermal, submucosal, and subcutaneous tissues in the face, lips, neck, extremities, and GI system (1-8). What we worry about in the patient in angioedema is airway obstruction.

It’s difficult to determine the prevalence, but angioedema accounts for anywhere from 80,000 to 112,000 ED visits per year. For those taking ACE inhibitors, 0.1-0.7% of patients are affected by angioedema, and hereditary angioedema (HAE) affects 1 in 10,000 to 50,000 persons (6-14).

Why does it occur?

You can think of angioedema in several different ways: bradykinin- or histamine-mediated, or hereditary (bradykinin) or acquired (bradykinin or histamine) (Table 1) (1-4,7,8,14). The underlying cause can impact the presentation and management in angioedema. Bradykinin-mediated forms are usually longer-lasting, more severe, and tend to affect the upper airway (1,12-14).


The most common form of angioedema is histamine-mediated. The pathophysiology is similar to that of allergic reactions and anaphylaxis with IgE (1,4,5). Allergen exposure can result in a rapid presentation, and resolution, of symptoms. The most common triggers include food, medications, bites/stings, exercise, and latex.  A physically-induced form can also occur due to temperature extremes, UV radiation, and vibration (15-20).


Bradykinin is a vasoactive substance that primary acts on endothelial cells, as well as the coagulation, complement, and tissue contact pathways. Bradykinin can accumulate from excess production, increased release, or reduced metabolism and breakdown (4,13,21,22). Drug-induced angioedema, hereditary angioedema, and several other forms of angioedema comprise this form (12,23).

One of the classic medications associated with this bradykinin-mediated form is the ACE inhibitor class. This accounts for up to 30% of ED visits for angioedema, with most symptoms localized to the lips and tongue (5,13,14,23-28). Risk factors for ACE inhibitor mediated angioedema include those on immunosuppressants and African Americans (1-4,13,14,28). Angioedema rates are highest in the first 30 days of starting the medication, though it can occur at any point (29-31).

The hereditary form is thought to be autosomal dominant (1-4). Type I is associated with reduced and defective C1-INH (85% of cases), while type II is associated with dysfunctional C1-INH (1,2,7,8,32-34). The majority of patients with HAE present before age 10 with their first episode (1-4,35). Patients with this form typically will not have urticaria, but they may have erythema marginatum.  The hereditary form more commonly affects females with more severe swelling, compared to males. Pregnancy and estrogen-containing medications can increase the number and severity of episodes (1,2,7,8).

The acquired bradykinin-mediated form affects those > 40 years and typically is due to catabolism of C1-INH, though it can occur in those with autoimmune or lymphoproliferative disorders (1,2,7,8).

Finally, other causes of bradykinin-mediated angioedema include NSAIDs, antibiotics, and ARBs. Angioedema due to exposure to tPA therapy in acute ischemic stroke can affect 1.2-5.1% of patients, though most cases are mild and resolve within a day (35-45).


Finally, the idiopathic form is associated with >3 attacks in a 6-12 month period but no known etiology (2,5,44,45). Many patients with idiopathic angioedema will improve with standard therapies for anaphylaxis (epinephrine, steroids, antihistamines), though some may not (1,2,7,8). These patients typically have a bradykinin-mediated form.

Case 1 and Case 2

Case 1 seems to be histamine-mediated and Case 2 bradykinin-mediated based on the history and examination. What are key components of the history and exam?

Presentation, History, and Physical Examination

We are most concerned with airway obstruction and asphyxiation in these patients. Ultimately, presentation depends on the underlying subtype (histamine vs bradykinin). Approximately half of patients with HAE will have at least 1 episode of laryngeal edema during their lifetime (46,47). Key history and exam findings include lip/tongue swelling, voice changes, and GI symptoms. Evaluation of patient medications, prior episodes of angioedema, and airway interventions, as well as family history, can provide important clues (1-5).  Patients may have prodromal symptoms including swelling, fatigue, and rash. While swelling can affect the head, face, oropharynx, extremities, and abdomen, swelling may be non-contiguous (1-5,12,14,47-49.  Histamine-mediated forms usually have faster onset, while HAE more often has a slower-progressive onset with GI tract involvement in over 90% of patients (1-5,12,49-51). While urticaria can occur in histamine-mediated forms (50%), it is rare in bradykinin-mediated angioedema (1,12,52).

Stridor, voice changes, hoarseness, and dyspnea suggest need for definitive airway. Evaluate for wheezing, which is more common in histamine-mediated forms. A patient who is able to phonate a high-pitched “E” is not likely to have laryngeal edema (1,2,7,8).  Table 2 provides key differentiating factors in histaminergic versus bradykinin-mediated angioedema.

What kind of diagnostic testing is warranted?

To be honest, angioedema is a clinical diagnosis. WBC counts > 30,000/mm3 have been found, but WBC elevation is not reliable (53). CRP can be elevated in ACE inhibitor associated angioedema (1-4). Labs including tryptase, C4, and C1-INH can be utilized to determine the specific type of angioedema. Histamine-mediated forms can have an elevated tryptase level. For angioedema associated with HAE, C4 levels will be less than 30% of normal. Type I HAE will demonstrate low C1-INH levels and decreased function, while Type II will have decreased function (and normal levels) (1-4,12,54). C1q levels are typically decreased in acquired angioedema. No tests are useful for ACE inhibitor angioedema (1-4,7,8).

Imaging is only warranted in specific situations. Those with abdominal pain associated with angioedema can present with peritoneal findings, and CT and ultrasound can reveal bowel wall edema and ascites (55-57). Ultrasound can also be utilized for laryngeal edema. Other imaging tests (ie, chest x-ray) are usually normal.

Case 1 and 2

You decide to forgo laboratory and imaging assessment and instead focus on management, as you are confident this is angioedema.

Management – The Airway

As the killer in angioedema is airway obstruction, initial focus is the airway. Even if a definitive airway is needed, vital signs can be normal (1-4,7,8).  Airway obstruction can occur in up to 15% of patients with angioedema (1,2,7,8). If an emergent definitive airway is required, literature suggests a high rate of cricothyrotomy or tracheostomy (up to 50% of cases) (46,47,56,58). Factors associated with requiring a definitive airway include prior history of intubation and severe angioedema. Swelling of the tongue, floor of the mouth, or soft palate should be evaluated further with visualization of the airway with a fiberoptic device.  If this reveals edema of the epiglottis, laryngeal, and/or aryepiglottic region, definitive airway is recommended. Edema involving structures such as the lips only can be observed (50,51,58-63).  However, fiberoptic devices are not always available. Thus, if your exam is concerning for airway edema, obtain a definitive airway. Always prepare for a surgical airway, as laryngeal edema may prevent ETT passage (1,2,4,7,8). While noninvasive measures such as CPAP or BiPAP can provide temporary improvement, these are not definitive. Supraglottic devices should not be used, as they may worsen edema. In fact, physical trauma to an airway with swelling due to angioedema may cause further worsening of symptoms (1,4,7,8,59).

Management – Medications

There are prophylactic medications such as danazol, but this post will focus on management of the acute episode. If histamine-mediated angioedema is suspected, start by removing the trigger and provide standard anaphylaxis medications (ie, epinephrine, steroids, H1/H2 antagonists) (1,4,7,8). These therapies can be attempted for bradykinin-mediated forms, but they are unlikely to be effective (1,2,64,65).

Fresh frozen plasma (FFP) has been previously recommended based on case reports in HAE and ACE inhibitor-induced forms, as it contains C1-INH in varying amounts (66-70). While it may assist in these forms, type II HAE may worsen with FFP. FFP contains kallikrein and kininogen, which may worsen angioedema. Most cases report dosing of 1-4 units IV. Most of the case reports focus on use in ACE-inhibitor induced angioedema, with improvement in 4 hours (68-80).

Medications – Targeted Therapies for Bradykinin-mediated Angioedema

Several medications can assist in bradykinin-mediated angioedema,with three C1-INH concentrates (2 plasma-derived and 1 recombinant), 1 kallikrein inhibitor, and 1 bradykinin-2-receptor antagonist (Table 3) (1,4,7,8,12,71,81,82).

C1 Inhibitor Concentrate

This class was first introduced in 1973, with two plasma derived formulations (Berinert and Cinryze) and one recombinant form (Ruconest) available, administered intravenously. These are approved for HAE, but not ACE-I induced forms. Studies (the IMPACT trials funded by CLS Behring and several others) suggest improvement anywhere from 30 minutes to several hours for patients with HAE episodes when compared to placebo (71,81-89).

Kallikrein Inhibitor

This class includes ecallantide, a recombinant plasma inhibitor of kallikrein, which prevents cleavage of kininogen. This medication is provided via the subcutaneous route for HAE and ACE I induced angioedema, though studies (the EDEMA trials) regarding its efficacy demonstrate controversial results (71,90-95).  Some studies suggest symptom improvement within 4 hours, while others demonstrate no benefit. This medication is also associated with a risk of anaphylaxis of approximately 3% of patients (1,4,7,8).

Bradykinin B2 Receptor Antagonist

Icatibant functions as a selective bradykinin B2 receptor antagonist. Studies (the FAST trials) evaluating its use demonstrate symptom improvement ranging from minutes to 7 hours (1,4,7,8,71). Of these studies demonstrating improvement, half of patients demonstrate reduced angioedema within 30 minutes of administration, with complete resolution occurring in 30 minutes to 16 hours (40% demonstrate complete resolution in 4 hours) (71,96-105).

A 2017 systematic review stated icatibant has the highest level of evidence for therapy, though this is based on case reports, case series, a prospective observational study, and a randomized controlled trial with low quality evidence, significant heterogeneity, poor reporting of patient-centered outcomes, and severe publication bias (71). Following this systematic review, Sinert et al. found no clinical difference in time to discharge or symptom relief for icatibant (106), and a randomized trial comparing icatibant with placebo found similar results with no difference in reduction of symptom duration or severity (107).

Thus, if the patient’s airway is at risk, focus on managing the airway and order the medications (1,4,7,8,108,109). Do not rely on a variable efficacy and time to symptom relief from these medications. If the angioedema is severe but the airway is not at risk, medications may be beneficial.

Case 1

You provide epinephrine IM, methylprednisolone, diphenhydramine, and ranitidine to the patient, who appears to improve. She is now able to speak, her urticaria has almost disappeared, and her tongue is decreased in size.

Case 2

Fortunately, your hospital has icatibant. You ask the nurse and technician to ready the airway equipment, you call ENT, and you call the pharmacist with an order for icatibant 30 mg subcutaneous. Even though you think anaphylaxis therapies will have little benefit, you administer epinephrine, steroids, and diphenhydramine/ranitidine. The pharmacist races over with the icatibant, and the nurse administers it.  ENT calls back, and you discuss the case with them hurriedly while the patient is given nebulized lidocaine to prepare for awake intubation. Your videoscope and preparations for cricothyrotomy are ready at bedside.


Disposition is primarily affected by airway involvement. Most are familiar with using some form of the Ishoo Staging system (1,4,7,8,59). Of note in the original studies pertaining to the Ishoo system, wheezing, voice changes, hoarseness, and stridor predicted the need for airway intervention. However, this system requires laryngeal visualization, and further validation studies are needed (59,109).

Patients with airway or respiratory disease or those with stage III or IV angioedema should be admitted to a monitored setting. If the patient has stage I or II angioedema, observation for several hours is recommended to evaluate for progression. Patients with further progression should be admitted. Those with stage I can be discharged after several hours of monitoring, while those with stage II should be observed for longer (1-8,62). If angioedema affects over 3 sites, the risk of airway involvement is greater, and patients should be admitted to a monitored setting (59,62).

Patients who are discharged can benefit from allergy/immunology evaluation, especially if attacks are recurrent or there is family history of similar episodes. If the etiology was histamine-mediated, then discharge the patient with an epinephrine autoinjector (5-8). If an ACE inhibitor is the suspected agent, the medication should be discontinued. Finally, education on triggers and return precautions is recommended.

For an algorithm that incorporates your treatment options, see Figure 1:

Figure 1. Angioedema Management.

Key Points:

Transient, non-dependent, non-pitting edema is the most common presentation of angioedema. Commonly involved sites include the face, lips, extremities, and GI system.

– Two forms include histamine- and bradykinin-mediated forms. Histamine-mediated angioedema presents similarly to anaphylaxis, while bradykinin-mediated angioedema is slower in onset, more severe, and more commonly affects the oropharynx.

– Management should focus on the airway initially.

– Histaminergic-mediated angioedema can be treated with medications such as epinephrine, antihistamines, and steroids. However, these medications are not as effective for bradykinin-mediated angioedema.

C1-INH protein replacement, kallikrein inhibitor, and bradykinin receptor antagonists are agents that may benefit bradykinin-mediated angioedema.

– Airway management can be challenging and is improved with fiberoptic or video laryngoscopy, with preparation for cricothyrotomy.

– Disposition is also challenging, dependent on the involved sites.

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