Elsevier

Annals of Emergency Medicine

Volume 68, Issue 3, September 2016, Pages 345-348
Annals of Emergency Medicine

Neurology/case report
A Novel Approach to the Treatment of Orolingual Angioedema After Tissue Plasminogen Activator Administration

https://doi.org/10.1016/j.annemergmed.2016.02.019Get rights and content

Orolingual angioedema is a rare adverse effect of tissue plasminogen activator (tPA), with an incidence of 1% to 5%. There are currently no published reports describing resolution of tPA-induced orolingual angioedema with complement inhibitor therapy. A 72-year-old man receiving home angiotensin-converting enzyme inhibitor therapy presented to the emergency department with newly developed orolingual angioedema after treatment with tPA for acute ischemic stroke. Therapy was initiated with intravenous methylprednisolone 125 mg, famotidine 20 mg, and diphenhydramine 50 mg, without significant improvement. Because of increased concern for airway protection, plasma-derived C1 esterase inhibitor was administered. Concerns about progressive and airway-threatening orolingual angioedema subsided 2 hours after administration, and invasive airway maneuvers were avoided. Orolingual angioedema is an infrequent, severe adverse effect of tPA for treatment of acute ischemic stroke. Complement inhibitors may be an additional therapeutic option for patients presenting with orolingual angioedema with potential airway compromise that is refractory to standard anaphylactic therapies.

Introduction

Orolingual angioedema can be a life-threatening crisis initiated by genetic factors or by certain foods, medications, infections, or stress. Hereditary angioedema has edematous and inflammatory consequences similar to those of other causes, but it is due to qualitative or quantitative dysfunction of C1 esterase inhibitor.1, 2 This can result in excessive release of bradykinin and histamine, leading to increased vascular permeability and edema. Icatibant, ecallantide, and plasma-derived C1 esterase inhibitor are approved hereditary angioedema treatments that target areas to prevent and reverse orolingual angioedema.

Orolingual angioedema is a rare adverse effect of tissue plasminogen activator (tPA) treatment of acute ischemic stroke, with a reported incidence of between 1% and 5%.3, 4, 5, 6, 7, 8, 9, 10 The frontal, insular, and peri-insular regions are often involved and are believed to play a role in the pathophysiology of stroke-associated angioedema. This association is thought to be due to proximity to the facial cortex, in conjunction with increased sympathetic tone and peripheral vasoconstriction, leading to cerebral dysregulation.10, 11 Orolingual angioedema developing after tPA administration for acute ischemic stroke may manifest as unilateral swelling of the lips, tongue, and face. The resultant edema is commonly contralateral to the ischemic lesion, which is believed to be due to the infarction’s triggering autonomic dysfunction and vasomotor changes in the hemiparetic side.10 Despite this distinct presentation, available literature has demonstrated equal representation of bilateral, contralateral, and ipsilateral edema.5, 7, 11

The proposed mechanism of tPA-induced orolingual angioedema is shown in Figure 1.1, 6, 7, 9, 11 Plasminogen is activated to plasmin by tPA, which leads to fibrinolysis and activation of the complement cascade and kinin pathway. Complement cascade activation causes anaphylotoxin release, which results in bradykinin production and vasodilatation. Patients receiving angiotensin-converting enzyme inhibitors who also receive tPA may be at higher risk for angioedema.3, 4, 7, 10 Angiotensin-converting enzyme inhibitors block plasma kinases responsible for bradykinin inactivation, resulting in elevated baseline bradykinin concentrations. Complement activation, histamine release, and bradykinin release are believed to be the primary mediators of tPA-associated angioedema.1, 2, 5, 6, 7, 9, 10, 11, 12, 13 Given a lack of direct treatment for tPA-induced orolingual angioedema, the current treatment recommendations suggest supportive care, corticosteroids, epinephrine, and histamine antagonists.3, 4, 5, 7, 9 There is potential to use hereditary angioedema therapies in patients presenting with tPA-induced orolingual angioedema refractory to the first-line therapies.

Section snippets

Case Report

A 72-year-old white man with a history of coronary artery disease, myocardial infarction requiring 2 drug-eluting stents, hypertension, and hyperlipidemia presented with sudden-onset right-sided weakness, dysarthria, and a National Institutes of Health Stroke Scale score of 10. Formal medication reconciliation was performed and included atenolol 25 mg, lisinopril 20 mg, hydrochlorothiazide 12.5 mg, atorvastatin 80 mg, aspirin 81 mg, and vitamin supplements. The patient received a diagnosis of

Discussion

Because of tPA-associated orolingual angioedema’s rarity, no targeted treatment exists for it. Symptomatic management with supportive care, corticosteroids, epinephrine, and histamine antagonists is considered first-line therapy.3, 4, 5, 7, 9 Rapid progression with airway compromise and pending asphyxia may occur despite these treatments.5, 7 Food and Drug Administration–approved therapies for hereditary angioedema that antagonize bradykinin or target the kallikrein-kinin system are believed to

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      Limitations of this case are the lack of research and case studies regarding itcatibant's use for rt-PA-induced angioedema. One case report of the successful use of plasma-derived C-1 esterase inhibitor for the management of rt-PA-induced angioedema exists, and there has only been one other case report of the use of icatibant [9,10]. In patients who develop rt-PA-induced angioedema that are unresponsive to traditional therapy, icatibant may be an adjunct treatment option to improve outcomes and avoid emergent and/or invasive airway management, and warrants further investigation.

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    Supervising editors: William J. Meurer, MD, MS; Donald M. Yealy, MD

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