Assessing Angioedema: ACE-inhibitors vs Anaphylaxis

By Priyanka Iyer

Case Presentation

History: DC is a 67-year-old Afro-American female with a past medical history of hypertension, hyperlipidemia, asthma, left breast cancer s/p lumpectomy, COPD, Type 2 Diabetes Mellitus, obesity and STEMI 11/2023 s/p RCA PCI presenting to ED for tongue swelling. Patient stated she took Mucinex cough drops at 8:30pm and noticed right-sided tongue swelling at 9pm. Patient denies chest pain, SOB, rashes, itching, wheezing, nausea, vomiting, diarrhea. She had no known drug allergies. Of note, she started a lisinopril 2 months ago after her STEMI.

Physical exam: Notable for significant symmetric tongue swelling R>L, muffled voice but able to speak in full sentences. Copious secretions from mouth. No stridor/rashes/pain.

ED Course

Laboratory data:

CMP: all components in normal limits
CBC: RBC 3.82, Hemoglobin 11.1, Hematocrit 34.2, Mean platelet volume 8.9, Eosinophil % 5.0, Eosinophil absolute 0.40, all other components in normal limits

Imaging:

CXR – No acute intrathoracic abnormalities
EKG – normal sinus rhythm

Diagnosis: Lisinopril-induced Angioedema

Management:

At 1:10am given IV dexamethasone 10mg, IV diphenhydramine 50mg, IM epinephrine 0.5mg, IV famotidine 20mg
At 1:30am, ENT performed a flexible laryngoscopy showed enlarged and oedematous base of tongue extending to lingual surface of epiglottis, though remainder of supraglottic structures non-edematous with patent glottic airway (figure 1).
Patient initially improved slightly after interventions but suddenly worsened at 5am.
5:30 am ENT interval exam revealed new vocal cord edema and worsening supraglottic swelling
Given her worsening clinical trajectory, she was taken to OR for awake nasal fiberoptic intubation and then subsequently admitted to MICU.

Clinical Question: How do you differentiate ACE-inhibitor (ACEi) induced angioedema from histamine-mediated angioedema and how do you manage it in the ED?

Summary of Evidence

Angioedema can be distinguished into 2 types: histamine-mediated and bradykinin-mediated. Histamine-mediated angioedema is triggered by allergens like food, insects, and is associated with urticaria, flushing and pruritus. It causes a diffuse, symmetric swelling of the face, most commonly of the eyes and lips, that rapidly evolves over minutes. There is concern for anaphylaxis if additional organ systems are involved, i.e. respiratory compromise with wheeze, stridor or cardiovascular compromise with hypotension, syncope. Conversely, bradykinin-induced angioedema is associated with drugs like ACEi/ARB or C1 inhibitor deficiencies and commonly presents with asymmetrical swelling of the tongue that develops slowly over hours with no urticarial symptoms. A large retrospective study of 5 EDs in the USA showed that ACEi are the leading cause for drug-induced angioedema, accounting for 175 patients or ~30% of the 586 angioedema cases reported (1). ACEi directly impair degradation of bradykinin and substance P, leading to vasodilation and triggering angioedema which can occur anytime from a few weeks to a years after initiating ACEi. A large retrospective study showed that 2/3 of angioedema episodes occurred within the first 3 months of therapy, consistent with this patient’s history (2). ACEi-induced angioedema is also 5x more common in people of African descent (3), as in this patient.

In both anaphylaxis and ACEi-induced angioedema, frequent airway assessment and preparation for early intubation is imperative. The severity of angioedema can be classified with the Ishoo staging system (4), with severe obstruction requiring fiberoptic intubation, as was done in this patient near the end of the ED course.

If the angioedema is likely histamine-mediated or unclear, it is recommended to initiate IM epinephrine, IV methylprednisolone, IV diphenhydramine and IV famotidine, which is similar to anaphylaxis management. Although this patient had more of a bradykinin-mediated angioedema clinical picture, these medications were trialed in her likely as a diagnostic approach to differentiate between the two angioedema mechanisms as bradykinin mediated angioedema does not respond to epinephrine, antihistamines, or glucocorticoids (5). Additionally, it may have been administered as a safety precaution considering the extent of her tongue swelling and that anaphylaxis is often underdiagnosed, with delays in epinephrine treatment resulting in greater fatality rates (6). Interestingly, the patient displayed an apparent biphasic reaction where they initially improved slightly in response to the medications, but then markedly worsened. The worsening of their symptoms despite the trialed medications indicates that their angioedema is indeed bradykinin-mediated and not histamine-mediated. The reasons for the initial improvement in symptoms are unclear but may be due to various factors such as reducing the potential allergic response from the Mucinex cough drop.

In ACEi-induced angioedema, primary management involves airway management and discontinuing the ACEi. It is also recommended to trial 1g tranexamic acid IV and consider 2 units of fresh frozen plasma as some studies have shown them to reduce the likelihood of requiring intubation (7, 8). However, the efficacy of these drugs is still debatable, explaining perhaps why it was not trialed in our patient in the ED.

Bradykinin-mediated angioedema in the setting of hereditary angioedema can be managed with drugs like ecallantide, icatibant, and C1 inhibitor concentrate, however larger randomized controlled trials studies have shown no benefit compared to placebo of these interventions, and hence they are not routinely recommended (9, 10).

Recommendations

Anaphylaxis is a potentially fatal disorder, and the goal of therapy should be early recognition and administration of IM epinephrine and frequent airway assessments.
If it is unclear whether the angioedema is histamine- or bradykinin-mediated, administration of epinephrine, antihistamines and glucocorticoids can be trialed as a diagnostic approach.
ACE-inhibitor induced angioedema should be managed with frequent airway assessment and discontinuation of ACE-inhibitor, but tranexamic acid and FFP can also be trialed.

References

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Toh S, Reichman ME, Houstoun M, Ross Southworth M, Ding X, Hernandez AF, et al. Comparative risk for angioedema associated with the use of drugs that target the renin-angiotensin-aldosterone system. Arch Intern Med. 2012;172(20):1582-9.
Kostis JB, Kim HJ, Rusnak J, Casale T, Kaplan A, Corren J, et al. Incidence and characteristics of angioedema associated with enalapril. Arch Intern Med. 2005;165(14):1637-42.
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Lenschow M, Bas M, Johnson F, Wirth M, Strassen U. A score for the differential diagnosis of bradykinin- and histamine-induced head and neck swellings. Eur Arch Otorhinolaryngol. 2018;275(7):1767-73.
Pumphrey. Lessons for management of anaphylaxis from a study of fatal reactions. Clinical & Experimental Allergy. 2000;30(8):1144-50.
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Saeb A, Hagglund KH, Cigolle CT. Using Fresh Frozen Plasma for Acute Airway Angioedema to Prevent Intubation in the Emergency Department: A Retrospective Cohort Study. Emerg Med Int. 2016;2016:6091510.
Baş M, Greve J, Stelter K, Havel M, Strassen U, Rotter N, et al. A randomized trial of icatibant in ACE-inhibitor-induced angioedema. N Engl J Med. 2015;372(5):418-25.
Sinert R, Levy P, Bernstein JA, Body R, Sivilotti MLA, Moellman J, et al. Randomized Trial of Icatibant for Angiotensin-Converting Enzyme Inhibitor-Induced Upper Airway Angioedema. J Allergy Clin Immunol Pract. 2017;5(5):1402-9.e3.