Bradykinin-induced angioedema in the emergency department

Abstract

Background: Acute airway angioedema commonly occurs through two distinct mechanisms: histamine- and bradykinin-dependent. Although they respond to distinct treatments, these two potentially life-threatening states present similarly. Poor recognition of the bradykinin-dependent pathway leads to treatment errors in the emergency department (ED), despite the availability of multiple pharmacologic options for hereditary angioedema (HAE) and other forms of bradykinin-induced angioedema. Here, we consider the pathophysiology and clinical features of bradykinin-induced angioedema, and we present a systematic literature review exploring the effectiveness of the available therapies for managing such cases.

Methods: PubMed searches using 'emergency', 'bradykinin' and various therapeutic product names identified studies reporting the efficacy of treatments for bradykinin-induced angioedema in the ED setting. In all, 22 studies met prespecified criteria and are analysed here.

Findings: Whereas histamine-induced angioedema has a faster onset and often presents with urticaria, bradykinin-induced angioedema is slower in onset, with greater incidence of abdominal symptoms. Acute airway angioedema in the ED should initially be treated with anaphylactic protocols, focusing on airway management and treatment with epinephrine, antihistamine and systemic steroids. Bradykinin-induced angioedema should be considered if this standard treatment is not effective, despite proper dosing and regard of beta-adrenergic blockade. Therapeutics currently approved for HAE appear as promising options for this and other forms of bradykinin-induced angioedema encountered in the ED.

Conclusion: Diagnostic algorithms of bradykinin-induced angioedema should be followed in the ED, with early use of approved therapies to improve patient outcomes.

Keywords: Angioedema; Bradykinin; Emergency; Histamine.

Fig. 1

Mechanisms of angioedema [, –8]. A Histamine induced. Upon exposure to an allergen, it is taken up by antigen-presenting cells (e.g. dendritic cells) and proteolyzed to produce small peptides. These peptides are then presented with major histocompatibility (MHC) class II antigen as a complex on the cell surface and recognised by T-helper (Th) lymphocyte receptors. This leads to the activation of T cells and release of Th2 cytokines that promote the differentiation of B cells to plasma cells and the production of specific IgE antibodies that recognise the original antigen. These antibodies bind to high-affinity IgE receptor FcεRI on mast cells and persist for weeks, months or years. Upon re-exposure to the allergen, the allergenic peptide is recognised by these bound IgEs, activating the mast cells to release bioactive mediators such as histamine. Binding of histamine on selective receptors of the vascular endothelium causes vasodilation and increased permeability. Mast cells can also be activated and triggered to produce histamine mediators through non-IgE-mediated response. B Bradykinin-induced. The contact pathway is initiated when factor XII (or Hageman factor) binds to damaged tissue and converts to factor XIIa, which then converts prekallikrein to plasma kallikrein. Finally, kallikrein cleaves HMWK to form bradykinin, which binds B2 receptors on the vascular endothelium, triggering vasodilation and increased permeability. Plasmin from the fibrinolytic system can convert factor XII into factor XIIa, accelerating the bradykinin production from HMWK. Multiple biological and pharmacological inhibitors can be used to treat bradykinin-induced angioedema. C1-INH can act on multiple stages of the contact and fibrinolytic system to inhibit the production of bradykinin. Ecallantide is a kallikrein inhibitor that blocks the cleavage of HMWK into bradykinin, and icatibant is an antagonist that prevents bradykinin from binding to its receptor

Fig. 2

ED response to localised airway angioedema, consistent with published algorithms [1, 3, 4]. When a patient presents at the ED with localised angioedema, airway management should be performed and intubation, tracheotomy or cricothyrotomy procedures should be prepared for worsening symptoms. Unless the patient is known to have HAE or reports prior experience of ACEi- or similar drug-induced angioedema, it is usually difficult to differentiate between histamine- or bradykinin-induced angioedema by clinical presentation alone. Because histamine-induced angioedema is more common, the patient should receive standard treatment (epinephrine, antihistamine and/or corticosteroids). If the symptoms subside, this helps confirm the aetiology as histamine-induced angioedema. Conversely, if symptoms do not resolve or begin to worsen, and beta-adrenergic blockade has been excluded, bradykinin-induced angioedema becomes more likely. Although approved treatments are currently for HAE, some studies have reported that patients with suspected bradykinin-induced angioedema in the ED respond well to these treatments. However, more studies are required to establish their efficacy and use in emergency situations. The patient’s primary care physician should be notified, and the patient should be referred to a specialist if appropriate for long-term management

Fig. 3

Consort diagram of systematic literature search. Search terms on PubMed generated a total of 137 studies. Those that were not conducted in the ED setting, related to treatment efficacy and/or bradykinin-induced angioedema were excluded (n = 122). Seven additional papers relevant to the discussion of the review were included in the analysis. The final 22 studies reported on the effectiveness of current treatments for resolving acute bradykinin-induced angioedema attacks in the ED