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28 February 2024: Articles  USA

A Case of Trauma-Related Angioedema of the Airway in a Patient on an Angiotensin Receptor Blocker

Unusual clinical course, Unusual or unexpected effect of treatment, Diagnostic / therapeutic accidents, Unexpected drug reaction

Saint-Martin Allihien1ABDEF*, Sammudeen Ibrahim1AE, Swethapriya Chaparala1E, Shreyas Singireddy1E, Onoriode Kesiena1E

DOI: 10.12659/AJCR.943407

Am J Case Rep 2024; 25:e943407

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Abstract

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BACKGROUND: Angioedema is non-pitting edema that occurs in the deep layers of the skin and subcutaneous tissue due to vascular leakage of plasma resulting from 1 of 2 major pathophysiological processes: mast cell-mediated angioedema and bradykinin-mediated angioedema. While it is a well-recognized adverse reaction of angiotensin-converting enzyme inhibitors, the association of angioedema with angiotensin receptor blockers is relatively less studied. Direct local trauma, although rarely, has been suggested to induce angioedema under certain conditions. We present a unique case of direct, local, trauma-related angioedema in a patient on an angiotensin receptor blocker.

CASE REPORT: The patient, an 83-year-old woman on telmisartan for hypertension, hit her neck against the edge of a chair during a fall. Shortly thereafter, she developed progressive airway compromise due to airway angioedema, as noted on direct laryngoscopy. A contrast CT scan of the neck also noted edema of the periglottic and supraglottic regions. She required intravenous corticosteroid administration and intubation in the emergency room and was successfully extubated 3 days after admission. She had no prior history of angioedema or allergy. We hypothesize that increased levels of circulatory bradykinin in the setting of telmisartan, combined with a local release of bradykinin from trauma, was the main pathophysiologic cause of the angioedema.

CONCLUSIONS: This case report highlights the rare and often forgotten adverse reaction of angioedema with use of angiotensin receptor blockers and confirms the finding of local trauma as a possible trigger.

Keywords: angioedema, telmisartan, essential hypertension, bradykinin

Background

Angioedema is non-pitting edema that occurs in the deep layers of the skin and subcutaneous tissue due to vascular leakage of plasma. This process is reported to be mediated by vasoactive and pro-inflammatory substances that increase vascular permeability, such as bradykinin, histamine, proteases, and prostaglandins [1,2]. It is common in the face and neck regions, the extremities, and regions lined by mucous membranes, such as the intestines [3,4]. When it involves the airway, angioedema can be rapidly fatal before any emergent curative intervention can be taken [5].

While angioedema as a potentially life-threatening adverse reaction of angiotensin-converting enzyme inhibitors (ACEIs) is well-recognized, angioedema as an adverse reaction of angiotensin receptor blockers (ARBs) is relatively less studied and less reported [1,6]. Indeed, many cases of spontaneous angioedema and perioperative angioedema in patients taking ACEIs have been reported [7]. However, angioedema following local trauma in patients taking ARBs is rare in the literature, and our literature review in PubMed revealed only 1 similar case [8].

In this report we aim to illustrate a case of life-threatening angioedema induced by direct neck trauma in a nonsurgical patient on an ARB medication.

Case Report

Our patient was an 83-year-old woman with a history of systemic hypertension, paroxysmal atrial fibrillation, sick sinus syndrome status post dual-chamber pacemaker, and rheumatoid arthritis. She was on amlodipine, atorvastatin, dabigatran, carvedilol, folic acid, sulfasalazine, and telmisartan. She had been taking telmisartan 40 mg daily for several years. She presented after a fall, during in which she hit her left mandible and neck against the edge of a chair. This was shortly followed by dyspnea and dysphagia and an audible stridor. She had no known allergies or hereditary angioedema (HAE).

Initial examination at the Emergency Department revealed an elderly woman in mild respiratory distress with an audible progressive stridor, a respiratory rate of 16 breaths per minute, and an SPO2 of 94%. There was painful diffuse swelling on the chin and left mandible but no hematoma, bruise, or visible swelling on the neck. She was afebrile, and her chest and cardiovascular system examinations were clinically unremarkable. A contrast CT scan of the neck showed significant edema of the periglottic and supraglottic regions, causing marked airway narrowing (Figure 1).

She received intravenous (IV) dexamethasone (10 mg) and epinephrine racemic nebulizer (0.5 ml) and was intubated due to concerns about impending airway compromise. Direct laryngoscopy revealed angioedema of the pharynx and bilaterally mobile vocal cords during intubation. She received an additional 6 mg of IV dexamethasone for 24 h after intubation. She was managed successfully on the ventilator and was extubated on the third day of admission. She continued to experience dysphagia, which improved over time, and she was discharged on day 10 with discontinuation of the telmisartan. She had experienced no recurrence of the angioedema 1 year following the index event.

Discussion

Two major types of angioedema are described based on the pathophysiology: mast cell-mediated angioedema and brady-kinin-mediated angioedema [1]. The mast cell-mediated pathway involves the activation of immunoglobulin E (IgE)-mediated mast cell and basophil degranulation, leading to the release of vasoactive and pro-inflammatory mediators such as hista-mine [9]. This process is often associated with allergic reactions or anaphylaxis [1]. Our patient had no known allergies or signs of anaphylaxis on presentation, such as urticaria, pruritus, or hypotension, making mast cell-induced angioedema less likely. An adverse reaction to sulfasalazine, a sulfa-based medication our patient was taking at the time of this presentation, would typically follow the mast cell-induced pathway with angioedema-associated urticaria and pruritus, as already described. Such an adverse reaction often occurs within minutes to weeks of starting the medication [1,10]. The fact that our patient had been on the medication for several years without any adverse reaction makes her current presentation less likely to be a result of an adverse reaction to sulfasalazine, and this adverse reaction is not known to be potentiated by trauma.

Bradykinin-mediated angioedema is characterized by brady-kinin-mediated vasodilatation and vascular leakage [9] and is involved in angioedema induced by drugs such as ACEIs and ARBs because they cause increased circulating levels of bradykinin in the body [1,11]. Although ACEIs are the class of medication most associated with angioedema, ARBs are also known to cause angioedema, and there are reports of this rare event in the literature [6,12]. A dose-dependent relationship between ARBs and the development of angioedema has also been suggested [13]. Our patient was on telmisartan, and we suspect her presentation may have been partly due to ARB-induced angioedema.

In our assessment of this patient we also considered HAE, an inherited form of bradykinin-induced angioedema in which patients have recurrent angioedema attacks, with an average onset around 10 years old. HAE often affects the limbs and intestines and rarely manifests in the head and neck regions. Our patient was an elderly woman who had no history of angioedema or diagnosis of HAE, and her presentation involved the neck, which is a region almost exclusively affected in drug-induced angioedema (ACEIs and ARBs) instead of the hereditary form of bradykinin-induced angioedema [1]. She was on the anticoagulant dabigatran, which could have pre-disposed her to a traumatic hematoma, but her neck CT scan showed no hematoma. Also, given that she had a low-energy, ground-level fall, it seemed that factors other than trauma alone would have been involved as the cause of her angioedema requiring intubation.

The available literature contains many case reports of angioedema in surgical patients, suggesting direct injury caused by perioperative trauma (eg, intubation, lumbosacral spine surgery, c-spine surgery, shoulder surgery) as a trigger for angioedema in patients taking ACEIs or angiotensin II receptor blockers [3,7,14,15]. However, our search in PubMed (March 10, 2023) yielded only 1 case of local trauma-related angioedema outside the perioperative period, in a patient who bit her upper lip [8]. The patient was on an ACEI; no such event is reported with ARBs in a nonsurgical setting. As with ACEIs and ARBs, physical trauma causes increased circulation of bradykinin and activates the intrinsic pathway by exposing subendothelial tissues to already circulating inactive factor XII (FXII). As illustrated in Figure 2, FXII is activated through the contact/intrinsic coagulation pathway upon contact with unnatural surfaces. Activated factor XII (FXIIa) converts plasma prekallikrein to kallikrein, which liberates bradykinin from high-molecular-weight kininogen [16]. When the “perfect storm” of FXIIa-mediated bradykinin release following trauma occurs in the presence of ARB-induced increased bradykinin circulation, it can create the rare adverse reaction of bradykinin-mediated angioedema. After considering other possible factors, we conclude that our patient’s clinical presentation is a peculiar case of direct trauma-related angioedema in a patient on an ARB. In addition, our patient’s sex may have increased her risk of developing angioedema, as females are more likely to develop angioedema than males [9].

Conclusions

This is case report highlights 2 main facts. First, the risk of angioedema with ARBs is real, although it is less common than with ACEIs. Second, even minor physical trauma can trigger angioedema in patients on ARBs. Clinicians need to be aware of this potentially life-threatening adverse reaction and promptly discontinue ARBs in these patients to prevent recurrence. Given that low-velocity trauma such as ground-level falls are a predominant mechanism of injury, patients on ARBs need appropriate medication counselling to encourage them to promptly report angioedema symptoms following low-velocity trauma [17].

References:

1.. Hahn J, Hoffmann TK, Bock B, Nordmann-Kleiner M, Angioedema: Dtsch Arztebl Int, 2017; 114(29–30); 489-96

2.. Tarbox JA, Bansal A, Peiris AN, Angioedema: JAMA, 2018; 319(19); 2054

3.. Bisinotto FMB, Seabra BC, Lóes FBP, [Postoperative angioedema induced by angiotensin-converting enzyme inhibitor: case report]: Braz J Anesthesiol, 2019; 69(5); 521-26 [in Spanish]

4.. Beavers CJ, Dunn SP, Macaulay TE, The role of angiotensin receptor blockers in patients with angiotensin-converting enzyme inhibitor-induced angioedema: Ann Pharmacother, 2011; 45(4); 520-24

5.. Gilbert JD, Byard RW, Lethal manifestations of angioedema: Forensic Sci Med Pathol, 2019; 15(3); 494-97

6.. Kim H, Baik SY, Yang SJ, Clinical experiences and case review of angiotensin II receptor blocker-related angioedema in Korea: Basic Clin Pharmacol Toxicol, 2019; 124(1); 115-22

7.. Hannoodi F, Sabbagh H, ACE inhibitor-induced angioedema following cervical spine surgery: Case Rep Cardiol, 2017; 2017; 4268962

8.. Simmons BB, Folsom MA, Bryden LA, Studdiford JS, Angioedema after local trauma in a patient on angiotensin-converting enzyme inhibitor therapy: J Am Board Fam Med, 2008; 21(6); 577-79

9.. Kanani A, Betschel SD, Warrington R, Urticaria and angioedema: Allergy Asthma Clin Immunol, 2018; 14(Suppl. 2); 59

10.. Cildag S, Senturk T, Sulfasalazine-related hypersensitivity reactions in patients with rheumatic diseases: J Clin Rheumatol, 2017; 23(2); 77-79

11.. Campbell DJ, Krum H, Esler MD, Losartan increases bradykinin levels in hypertensive humans: Circulation, 2005; 111(3); 315-20

12.. Irons BK, Kumar A, Valsartan-induced angioedema: Anna Pharmacother, 2003; 37(7–8); 1024-27

13.. Niazi BA, Kaur M, Mosseri M, Lo A, A rare case of dose-dependent losartan-induced angioedema: Cureus, 2022; 14(4); e24110

14.. Alhowary A, Odat H, Alali O, Ali-Omari A, Intraoperative angioedema induced by angiotensin II receptor blocker: A case report: Patient Saf Surg, 2018; 12; 27

15.. Soghomonyan S, Fleming Q, Bhandary SP, Case report: Post-operative angioedema after a laryngeal mask airway application: Front Med (Lausanne), 2021; 8; 566100

16.. Didiasova M, Wujak L, Schaefer L, Wygrecka M, Factor XII in coagulation, inflammation and beyond: Cell Signal, 2018; 51; 257-65

17.. Roubik D, Cook AD, Ward JG, Then we all fall down: fall mortality by trauma center level: J Surg Res, 2017; 217; 36-44.e2

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American Journal of Case Reports eISSN: 1941-5923
American Journal of Case Reports eISSN: 1941-5923