emDOCs Podcast – Episode 133: Angioedema

What is it?

• Non-pitting, non-dependent, transient edema affecting the skin and mucous membranes; due to accumulation of vasoactive substances (e.g., bradykinin, histamine).^1-8
  • Results in increased vascular permeability with swelling of the deep dermal, submucosal, and subcutaneous tissues of the face, neck, lips, oropharynx, extremities, urogenital tract, and gastrointestinal tract.
• Angioedema may be categorized several ways: bradykinin mediated versus histamine mediated and hereditary (bradykinin-mediated) versus acquired (bradykinin- or histamine-mediated).
  • Type affects the clinical presentation and the treatment.

How common is this?

• Up to 117,000 ED visits for angioedema annually; up to 30% of patients with angioedema use the ED at least once during their lifetime.^17-21
• Histamine-mediated angioedema most common form (40-70% of cases). Second is drug-induced angioedema (most commonly angiotensin-converting enzyme inhibitors; develops in less than 0.7% of patients), and third hereditary angioedema (estimated prevalence of 1-in-50,000 persons).^{1,2,4,5,8,12,20,31}
• Most patients with hereditary angioedema have first episode between 4-26 years.^32-35
• If not treated, angioedema can result in significant morbidity and mortality, especially with laryngeal involvement which may cause airway obstruction (mortality rates 15-56%).^9,36,37

How should we assess these patients?

• First step: assess airway, cardiovascular system, mental status.
  • Asphyxiation most common cause of mortality with acute angioedema^1,14,38-40 Up to 15% experience airway obstruction; may progress rapidly.^{1,4,6,16,39,40}
  • Over half of patients with hereditary angioedema experience at least one episode of laryngeal edema during their lifetime; accounts for over 30% of deaths.^39,40
• Look for lip and tongue swelling, pharyngeal swelling, change in voice (hoarseness, stridor), drooling, difficulty swallowing, shortness of breath, and inability to lie flat. Ask about lightheadedness, pruritus, rash, and GI symptoms (pain, vomiting, diarrhea).^3,4,14,33-35
• Obtain history of prior angioedema attacks and treatments, medications, and family history.
• Assess for exposure to a trigger.
  • Stress, medical procedures, trauma, infection, and medications (hormone therapies, oral contraceptives, opioids).^{3,4,14,16,35,41}
• Exam: assess for swelling of the lips or face and evidence of airway obstruction (swelling of the tongue, floor of the mouth, and palate).^3,4,14,35,43
• Several studies evaluate common findings in angioedema.
  • 2025 retrospective study of ACEI-induced angioedema found lip swelling occurred in 87.5% and tongue swelling in 43.6%⁴²
  • Study of 311 patients found several factors were associated with need for airway intervention: presentation within 4 hours of symptom onset; signs/symptoms including dysphagia, dysphonia, drooling, respiratory distress, and globus sensation; and involvement of the tongue, soft palate, vallecula, aryepiglottic folds, and true vocal cords.⁴³
  • 2020 study found rapid progression of symptoms within 6 hours of angioedema onset, anterior tongue swelling, voice changes, drooling, and dyspnea were associated with intubation in ACEI-induced angioedema; isolated lip swelling was not.⁴⁴
• Non-pitting edema may affect the head, neck, extremities, genitals, or abdomen; edema is typically non-contiguous.^{1-7,10,11,45,46}
• Histamine mediated form may present with urticaria and pruritus (less common in bradykinin-mediated angioedema, though may develop erythematous rings known as erythema marginatum).^22,38,47,48
• Abdominal symptoms may occur.

What should we be focusing on for the ED evaluation?

• Focus on the airway; in those with swelling of the tongue, floor of the mouth, or soft palate on initial examination, flexible endoscopy/scope is best means of assessing airway edema.
• May also use hyperangulated or standard geometry video laryngoscopy with appropriate topical analgesia to visualize the glottic structures if flexible endoscopy not available.
• X-ray/CT can reveal tongue, glottic, and airway swelling; do not use these to assess airway integrity if concerned about imminent airway obstruction.⁵²
• POCUS has been evaluated with the high frequency linear transducer in the submandibular region; evaluate for airway edema as move the probe in the transverse orientation until the anterior base of the neck is reached.^53-55
• Laboratory testing will no change management in isolated angioedema; outpatient testing can include C4, C1 esterase inhibitor (C1-INH), and tryptase levels.

Where do we start with management?

• If evidence of airway obstruction (stridor, drooling, dyspnea, marked edema in the larynx), need definitive airway. If angioedema involves the external face and lips only; airway intervention is rarely needed.^49,50,56-61
  • Do not wait for angioedema specific medications if intervention necessary, but while preparing for intubation, may attempt inhaled epinephrine.
• If you have 15-20 minutes, consider awake intubation strategy with flexible intubating endoscopy.
• If not feasible, use video laryngoscopy.
• When intubating, avoid excessive physical manipulation (worsens airway edema).
• Prepare for surgical airway. Cricothyrotomy or tracheostomy is needed in up to 50% of patients with angioedema who need emergent airway intervention. Use double set up.
• Consider using non-invasive positive pressure ventilation to temporize the patient and for preoxygenation, but this is not a long-term solution.
• Supraglottic airway devices may be displaced due to progressive swelling and may worsen airway edema.^{1,3,6,10,14,56,64}

What medications are available?

• If unsure of etiology or concerned for histamine-mediated angioedema: administer epinephrine, antihistamines, steroids.^1,3,4,14,65
• These medications are not usually effective in bradykinin-mediated forms.
  • Allergy guidelines recommend against their routine use in patients with a definite diagnosis of bradykinin-mediated angioedema (they have not been shown to be effective, but they have not been associated with harm).^{1,3,4,33,38,66}
• For known bradykinin-mediated angioedema (e.g., hereditary angioedema), there are several available medications that reduce the production or activity of bradykinin (peptide that increases vascular permeability and inflammation).^3,4,33,66-72
  • Administer as soon as possible in bradykinin-mediated angioedema.
  • C1 esterase inhibitor (C1-INH) replacements: inhibit proteases like kallikrein and the complement system to reduce bradykinin production (Berinert®, Cinryze®, Ruconest®).^68-70
  • Kallikrein inhibitors: reduce production of bradykinin (ecallantide/Kalbitor®).⁷¹
  • Bradykinin B2 receptor antagonists: prevent bradykinin from binding the B2 receptor, limits the symptoms associated with angioedema (icatibant acetate/Firazyr®) (Table 3).^3,4,33,68-72
• Literature suggests treatment within 6 hours of onset improves outcomes.^33,66,67,73
• Follow individualized treatment plan if available.^{3,4,66,67,74-76}
• C1-INH concentrates are currently the first-line recommended therapies for bradykinin-mediated angioedema in those over 2 years of age; they can be expensive.^{1,3,4,14,38,67-70,74-76}
  • Ruconest®: only available human recombinant C1-INH; can be self-administered.⁶⁸
  • Plasma-derived C1-INHs: Berinert® and Cinryze®.^3,4,67,69,70
  • Patients with recurrent attacks may need higher doses of plasma-derived C1-INH (C1-INH concentrates may become less effective over time).^{1,3,4,14,38,74-76}
• Ecallantide; kallikrein inhibitor used in those ≥ 12 years.⁷¹
• Icatibant: bradykinin antagonist; can be self-administered.⁷²
• May also use these for patients with acquired angioedema.
• If concerned for ACEI-related angioedema, may administer epinephrine, antihistamines, and steroids. Usually not effective because underlying pathophysiology is bradykinin.^{3,14,66,77,78}
  • C1-INH replacement, ecallantide, and icatibant have been evaluated in literature for ACEI-related angioedema. Case reports demonstrate a possible benefit with C1-INH therapy.^66,79,80 RCT with 30 patients with ACEI-related angioedema found no benefit with C1-INH therapy.⁸¹
  • Icatibant can improve symptoms; no studies demonstrate reduction in ICU admissions or intubation.⁸²
• TXA is another option, especially for ACEI induced angioedema.^{3,14,38,79,83,84}
  • Inhibits conversion of plasminogen to plasmin.
  • Several retrospective studies suggest TXA may reduce symptoms with no severe adverse events reported.^14,38,84-89
  • Dose: 1 g IV over 2-10 minutes, followed by a second dose if necessary.⁹⁰
  • TXA is cheap, safe, and universally available.
• FFP is another proposed treatment.
  • FFP contains angiotensin-converting enzyme (degrades bradykinin and C1-INH). ^{1,3,4,14,38,67,74-76}
  • Retrospective studies suggest benefit with FFP if other therapies are not available; no high-quality RCTs show benefit..^79,91-95
  • Potential problem: FFP contains varying levels of C1-INH and substrates of the kallikrein system, which may worsen the angioedema^79,91-95 However, no case reports suggest an exacerbation of angioedema with FFP.
  • If no access to other medications, or attempted TXA and there’s no improvement, consider FFP.
  • Dose: 15 mg/kg IV or 2 units.
• Medication summary: many limitations with the individual studies.
  • While there might be an improvement in symptoms and edema with medications, individual studies have low sample sizes and bias and heterogeneity in patient selection, comparators, medication dosing, study design, and outcomes.^{1,3,4,6,14,67,79,96-98}
  • Medications have a delayed onset of action and variable efficacy; focus on the airway.
  • If histamine-mediated or unclear, treat as anaphylaxis with epinephrine.
  • If known bradykinin-mediated, administer C1-INH replacement as soon as possible if available.
  • TXA is worth attempting if limited access to other medications.

What should we consider for disposition?

• If airway involved, admit patient to ICU.
• Disposition can be more difficult for other patients; several studies have tried to predict airway compromise.^42,56
• Ishoo staging system was derived from a retrospective study of 80 patients with 93 episodes of angioedema; categorizes severity based on the location of angioedema (Table 4).⁵⁶

• 2021 ED retrospective chart review with 320 patients found patients with stage 4 findings required airway intervention in 67% of cases, but 16% of stage 3 and 8.6% of stage 2 patients needed airway intervetnion.⁶⁴
  • Issues with the score: limited by the need to directly visualize laryngeal structures.
  • If using the score, patients with stage 1 may be discharged with follow-up after observation for several hours; stage 2 or higher should be admitted.^11,60,64,74
• 2025 retrospective study with 94 patients found throat symptoms or throat/neck edema including difficulty speaking were associated with admission.⁴²
• Observe patients with angioedema for several hours to monitor progression.¹⁴ Any worsening of angioedema despite treatments warrants admission.
• If patient appropriate for discharge, consider referring the patient to allergy/immunology specialist (especially recurrent angioedema).^{1,3,6,66,67,99-101}
  • May diagnose the underlying etiology, educate the patient on triggers, prescribe prophylactic medications.
• Must remove any triggers and discontinue medications that may be a causative agent (ACEIs, NSAIDs, and aspirin).^{1,3-7,10-12,14,66,74}
  • If on an ACEI, list it as an allergy; switch the patient to another agent.^{1,3,14,42,102-105}
  • Incidence of angioedema with an ARB approximates 0.11% (no different than placebo). While an ARB is likely safe in those with ACEI-induced angioedema, there may be a higher baseline risk of ARB angioedema in these patients.^104,105
• If improve withtherapy for anaphylaxis, discharge with an epinephrine autoinjector; prior to discharge, educate on how to use it and potential triggers. If unsure of underlying trigger, follow up with allergy/immunology.^3,66,67,101

Summary:

• Angioedema is non-dependent, non-pitting edema that can occur at a variety of sites including the external face, lips, and oropharyngeal structures.
• There are histamine-mediated and bradykinin-mediated forms.
• Initial evaluation and management has to focus on the airway.
• If concerned but you have time, perform flexible endoscopy. If this is not available, go with VL but prep for cricothyrotomy.
• If don’t know the etiology or concerned for histamine-mediated angioedema, treat with epinephrine, antihistamines, and steroids.
• For bradykinin mediated forms, first line treatment is C1 esterase inhibitor replacements. There are also kallikrein inhibitor, and bradykinin receptor antagonists.
• TXA and FFP may be effective in bradykinin mediated forms.
• Disposition depends on patient’s airway status and the involved sites.

References:

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