Delayed post-operative bradykinin-mediated angioedema: A silent airway threat and role of tranexamic acid

Dear Editor, Post-operative angioedema is a potentially fatal airway emergency in anaesthetic practice, where early recognition of the underlying mechanism is crucial. Allergic and angioedema-related reactions are usually anticipated intra-operatively or in the immediate post-operative period when clinical vigilance is often reduced. We report a case that presented on post-operative day 4. The patient was a 51-year-old male with type 2 diabetes mellitus who had met with a road traffic accident. He had sustained right 5th and 6th rib fractures and a closed right trimalleolar ankle fracture with subluxation, which was managed with closed reduction under a popliteal sciatic nerve block. The intra-operative and immediate post-operative course was uneventful. He was transferred to the ward after 24 hours of observation. On post-operative day 4, following a single febrile episode responding to intravenous (IV) paracetamol (1 g), the patient developed acute tongue and gingival swelling Figure 1a with dysphagia and slurred speech shortly after coffee consumption. There was no urticaria, rash, stridor, or respiratory distress, though a mild wheeze was noted.Figure 1: (a) Isolated angioedema of the tongue. (b) Complete resolution on the next dayMedication history included IV paracetamol, oral amoxicillin–clavulanate (last dose 48 hours earlier), and Buvalor® (buprenorphine) transdermal patch applied on post-operative day 0. He was not receiving angiotensin-converting enzyme (ACE) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, or neprilysin inhibitors. The initial treatment included nebulised salbutamol (5 mg), nebulised budesonide (0.5–1 mg), IV hydrocortisone (200 mg), and IV pheniramine (45 mg), which was administered within 15 minutes of symptom onset. No appreciable reduction in swelling was observed over 45–60 minutes. Adrenaline was not administered as the patient had no features of anaphylaxis. There was no dyspnoea or features of respiratory distress. Difficult airway equipment with readiness for tracheal intubation was kept available. In view of the absence of urticaria and poor response to anti-histaminergic therapy, a bradykinin-mediated mechanism was suspected, where adrenaline has limited benefits. Approximately 1 hour after symptom onset, tranexamic acid (TXA) 1 g (≈12 mg/kg) was administered over 10 minutes with subjective improvement within 30–60 minutes and progressive resolution over the next few hours without adverse effects Figure 1b. Beta-lactam allergy was considered less likely due to the absence of typical features. Continuous opioid exposure from the buprenorphine patch was considered a plausible trigger as opioids have been implicated in non-IgE-mediated angioedema through activation of the kallikrein–kinin system.1–3 Bradykinin-mediated angioedema is characterised by lack of wheals, poor response to standard anti-allergic therapy, and a predilection for upper airway involvement. Drugs implicated include ACE inhibitors, DPP-4 inhibitors, certain angiotensin receptor blockers, thrombolytics, and opioids.3 Other known triggers for non-IgE-mediated or hereditary angioedema include stress, trauma, infection, and temperature changes Figure 2. Nevertheless, the single febrile episode in the patient may have acted as a mild trigger.Figure 2: Algorithm for evaluation and management of angioedema. TXA: Tranexamic acid; ACE: Angiotensin converting enzyme; DPP: Dipeptidyl peptidase; ARBs: Angiotensin receptor blockers; C1-INH: C1-esterase inhibitor; IV:IntravenousTXA inhibits plasmin formation, reducing factor XII activation, kallikrein activity, and downstream bradykinin generation. This underpins its role in hereditary angioedema prophylaxis and emerging use in ACE inhibitor-induced or idiopathic non-histaminergic angioedema.3,4 Recent reports suggest that IV TXA may reduce symptom progression with a favourable safety profile, although rare hypersensitivity reactions, including angioedema, have been described.4,5 A recent retrospective multi-centre study did not demonstrate a statistically significant improvement in major clinical outcomes such as the need for airway intervention, thus highlighting inconclusive evidence.6 For acute use in adults, IV TXA 10–15 mg/kg over 10 minutes, repeated every 6–8 hours up to 3 g/day, is recommended; oral TXA for short-term prophylaxis (25–50 mg/kg/day in divided doses for 3–5 days) is generally reserved for recurrent episodes. In our patient, oral prophylaxis was not given for this isolated event.4,5 Further, to support the diagnosis of bradykinin-mediated angioedema, ideally serum complement C4 and C1-esterase inhibitor (C1-INH) levels and functions should be measured, along with serum tryptase to exclude mast-cell-mediated reactions. The present case highlights key peri-operative lessons: Not all post-operative angioedema is allergic; the absence of urticaria and poor response to antihistamines should prompt consideration of bradykinin-mediated mechanisms; delayed onset does not exclude drug-induced angioedema; TXA can be considered early in selected cases, especially where icatibant or C1-INH concentrates are unavailable; and vigilant airway monitoring remains paramount. We believe that this case will reinforce awareness of bradykinin-mediated angioedema in peri-operative practice and support the judicious and early use of TXA while awaiting further prospective evidence. Declaration of Patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient consented to the images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed. Disclosure of use of artificial intelligence (AI)-assistive or generative tools No AI tools were used. Author contributions NMM Manuscript prepration, literature search. JB Review and approval, concepts. PG Conduct of case. All the authors have participated in the review, drafting and final approval of the manuscript. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.