Tranexamic acid for surgical bleedingBMJ 2014; 349 doi: https://doi.org/10.1136/bmj.g4934 (Published 13 August 2014) Cite this as: BMJ 2014;349:g4934
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It is frustrating to find anything in your journal.
Recently I read one abstract in the Anesthesiology (see the attached) and is very interested to read the whole paper. However, it is so hard to find the originals in your journal. Instead of using continuous numbers for all the pages, you use gxxxx. It took me lots of time and efforts and finally found the original paper and its editorial.
Also there is a serious error in the PDF of the editorial too. Please read at the top of this editorial just above the red line: (Published 12 August 2104). I know this is most likely a typo. I do not think it is a good idea to have this kind of mistake.
Competing interests: No competing interests
The dangerous face of ACE inhibitors and an associated advantage of tranexamic acid therapy in facial aesthetic surgery
We were very interested in the August 2014 BMJ Editorial on Tranexamic Acid BMJ 2014;349:g4934 and in the wake of the following interesting discussion concerning the use of tranexamic acid as an effective anti-inflammatory, we have changed our standard drug protocol in Aesthetic Surgery.
A patient in our unit who following a minifacelift procedure developed profound swelling of the whole perioral area due to ACE inhibitor induced angioedema (AGO) was treated with Tranexamic acid, as part of a multi modal approach to treatment.
At pre-assessment the patient was noted to be borderline hypertensive having been started on the ACE inhibitor Ramipril (ACEi) (Sanofi-AventisS.p.a, Italy), 2.5 mg bd only 2 weeks prior to surgery.
Postoperatively our patient developed clearly visible and inappropriate progressive oedema of the perioral area. As a first line treatment, her head bandage dressing was released, and cooled facial packs were applied and 200mg of IV hydrocortisone was given. About 2.5 hours later, a further 100mg of hydrocortisone was given. Her normal dosage of Ramipril was omitted, 6 hourly 200mg hydrocortisone (IV) and 4 hourly Chlorphenamine piriton were commenced.
When the diagnosis of AGO was considered as a possibility Tranexamic Acid was considered suitable for its action as an anti-inflammatory agent. By the time of transfer to a high dependency monitoring unit, oedema had spread to involve the patient’s lower lip and face but stabilized and caused no respiratory difficulty (Fig 1). The C2 complement levels alone were significantly elevated and thus the diagnosis of AGO confirmed. The next day a B-blocker was substituted for her ACE inhibitor as she remained hypertensive. She made a slow but gradual improvement and was fit for discharge on day 4 post operatively.
Angioedema (AGO) is known as a potential side effect of Angiotensin converting enzyme inhibitors (ACEi) and may be life threatening with rapid appearance of facial and laryngeal oedema. ACEi induced AGO appears to be linked to uncontrolled bradykinin release. Recent evidence-based studies advise the withdrawal of the ACE inhibitor, administration of antihistamines, corticosteroids and icatibant, a bradykinin B2 receptor inhibitor and complement (C1) inhibitor concentrate. For practical purposes angioedema (AGO) can be differentiated into allergic and non-allergic groups (2, 3). Whereas allergic AGO (urticarial associated AGO) is mediated by histamine and mast cell degranulation (3), the non-allergic types are understood to be ultimately caused by the tissue accumulation of Bradykinin. In normal physiology, activated clotting factor XII leads to the production (by cleavage) of Bradykinin, and C1 esterase inhibitor prevents the production of Bradykinin (4). C1 esterase inhibitor deficiency (C1INH) and increased levels of factor XII are therefore likely culprits of non-Allergic types of AGO, by increasing tissue levels of Bradykinin.
Angiotensin converting enzyme (ACE) is a kininase normally acting in the body to convert Angiotensin 1 to Angiotensin 2 and it also rapidly metabolizes Bradykinin. When ACE is inhibited, Bradykinin levels rise (5). It has been previously reported that a patient with ACE i -induced AGO had a 10 fold increase in measured plasma Bradykinin levels which resolved after withdrawal of medication (6). McLean-Tooke (2014), however, demonstrated that ACEi -induced AGO is specifically not caused by C1INH deficiency (6, 7). Based on this finding, the use of antihistamines and steroids are argued as having no benefit in non-allergic AGO (4). It also follows, that treatment for non-allergic (Bradykinin induced) AGO should be based on C1 inhibitor infusions and bradykinin reduction.
We reviewed the literature for current algorithms on the first line management of acute onset angioedema and adopted the following general approach given that the underlying cause of AGO may initially be unclear. Although rare, AGO related to ACE-i is potentially fatal and thus deserves a place in the common consciousness of surgical and anaesthetic practice (8). Steroids, antihistamines and Tranexamic acid were administered to our patient. Given that ACEi -induced AGO is in the non allergic category of AGO, steroids and antihistamines are arguably of no benefit (1, 4), however they are still endorsed for treatment of acute ACEi -induced AGO in current emergency medicine algorithms. Although a lack of evidence exists regarding the drugs used for treatment of ACEi -induced AGO (9), the first line assessment and treatment of all AGO remains the same:-
1) Secure the airway and remove the offending agent (in this case an ACE inhibitor), give supplemental oxygen and obtain IV access. Although debatable, conventional treatment still involves the consideration of H1 and H2 blockade (antihistamines) and corticosteroids in ACEi-induced AGO (1, 4).
2) Fresh frozen plasma is widely available and rapidly accessible for administration. There are no studies evaluating its effectiveness, but multiple case reports appear to support its use in acute attacks of hereditary and ACEi -induced AGO (10, 11, 12, 13).
3) Use of new Bradykinin receptor blockers such as icatibant. As antihistamines and corticosteroids do not directly reduce or block Bradykinin they may be futile in the management of non-allergic AGO.
4) Tranexamic acid is not a part of any published algorithm we identified for management of ACE-i related AGO, however it was administered in this reported case because of its anti-inflammatory anti-bradykinin effects. It has however been shown to be effective in idiopathic cases of AGO (6).
Tranexamic acid has become a notable adjunct in the treatment of traumatic haemorrhage in recent times and is commonly given to patients undergoing Surgery within many specialties but especially Orthopaedic, Cardiac, Urological and Plastic Surgery (13). It acts early in the coagulation pathway by reversibly blocking plasminogen and thus effectively blocks the interaction of plasminogen and fibrin to prevent the breakdown of fibrin clot (14). The reduced formation of plasmin reduces bradykinin production thus dampening inflammation (6). Although Tranexamic acid has been shown to be of benefit in the treatment of acute spontaneous idiopathic AGO (6), it’s role is now mainly accepted as a prophylactic agent in the treatment of Hereditary Angioedema (HAE) (15). Antifibrinolytics such as Tranexamic acid are thought not to be as effective as androgens (such as danazol) for hereditary angioedema, but they are considered first-line agents for prophylaxis in children with hereditary AGO) due to the reduced side-effect profile in comparison to androgen therapy.
It is now routine practice on our unit for all facelift patients to be prescribed Tranexamic acid, 500mg 8 hourly, for 24 hours. AGO and specifically ACEi -induced AGO may be unfamiliar concepts however, patients on ACE inhibitor therapy undergoing elective surgery carry risks that both Surgeons and Anaesthetists should be aware of. The benefits of reducing or preventing bradykinin release and subsequent development of secondary inflammatory oedema, together with the stabilizing of clot formation without inherent risk of thrombosis or untoward side effects (16), is compelling.
DAVID O’HARA, FRCA, Consultant Anaesthetist, Springfield Hospital, Chelmsford, CM1 7GU
CARA CONNOLLY, FRCS (PLAST), Consultant Plastic Surgeon, Springfield Hospital, Chelmsford, CM1 7GU
RONAN FENTON, FRCA, Consultant Anaesthetist, Springfield Hospital, Chelmsford, CM1 7GU
JAMES FRAME, FRCS(PLAST), Professor of Aesthetic Plastic Surgery, Consultant Plastic Surgeon, Postgraduate Medical Centre, Anglia Ruskin University, Chelmsford, CM1 1SQ
1. Ker K, Roberts I. Editorial Tranexamic acid for surgical bleeding. BMJ. 2014; 349: g4934.
2. Bas M, Adams V, Suvorava T, et al. Nonallergic angioedema: role of bradykinin. Allergy. 2007; 62: 842-56.
3. Kanani A, Schellenberg R, Warrington R. Urticaria and angioedema. Allergy Asthma Clin Immunol. 2011; Nov 10: 7 Suppl 1:S9.
4. Nussberger J, Cugno M, Amstutz C, et al. Plasma bradykinin in angio-oedema. Lancet. 1998; 351(9117): 1693-1697.
5. Du-Thanh A, Raison-Peyron N, Drouet C, et al. Efficacy of tranexamic acid in sporadic idiopathic bradykinin angioedema. Allergy. 2010; 65: 793-5. doi: 10.1111/j.1398-9995.2009.02234.x. Epub 2009 Nov 3.
6. McLean-Tooke A. Angioedema secondary to angiotensin converting enzyme inhibitors is not due to C1 esterase inhibitor deficiency. Pediatr Radiol. 2014 ; 44(3) :258-64.
7. Moldovan D, Reshef A, Fabiani J, et al. Efficacy and safety of recombinant human C1-inhibitor for the treatment of attacks of hereditary angioedema: European open-label extension study. Clin Exp Allergy. 2012 ; 42: 929-35.
8. Winters ME1, Rosenbaum S, Vilke GM, et al. Emergency department management of patients with ACE-inhibitor angioedema. J Emerg Med. 2013 Nov; 45(5): 775-80. doi: 10.1016/j.jemermed.2013.05.052. Epub 2013 Aug 26.
9. Khudari S, Loochtan MJ, Peterson E, et al. Management of angiotensin-converting enzyme inhibitor-induced angioedema. Laryngoscope. 2011; 121(11): 2327-2334.
10. Pekdemir M, Ersel M, Aksay E, et al. Effective treatment of hereditary angioedema with fresh frozen plasma in an emergency department. J Emerg Med. 2007;33(2):137-39.
11. Warrier MR, Copilevitz CA, Dykewicz MS, et al. Fresh frozen plasma in the treatment of resistant angiotensin-converting enzyme inhibitor angioedema. Ann Allergy Asthma Immunol. 2004; 92(5): 573-575.
12. Bolton MR, Dooley-Hash SL. Angiotensin-converting Enzyme Inhibitor Angioedema. J Emerg Med. 2011.
13. Roberts I, Shakur H, Coats T, et al. The CRASH-2 trial: a randomised controlled trial and economic evaluation of the effects of tranexamic acid on death, vascular occlusive events and transfusion requirement in bleeding trauma patients. Health Technol Assess. 2013; 10: 1-79. doi: 10.3310/hta17100.
14. Bowen T, Cicardi M, Farkas H, et al . International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema Allergy Asthma Clin Immunol. 2010; 6(1): 24.Published online Jul 28, 2010. doi: 10.1186/1710-1492-6-24
15. Bas M, Greve J, Stelter K,et al.Therapeutic efficacy of icatibant in angioedema induced by angiotensin-converting enzyme inhibitors: a case series. Ann Emerg Med. 2010 ; 56(3): 278-82. doi:10.1016/j.annemergmed.2010.03.032. Epub 2010 May 5
16. Poeran J, Rasul R, Suzuki S, et al Tranexamic acid use and postoperative outcomes in patients undergoing total hip or knee arthroplasty in the United States: retrospective analysis of effectiveness and safety. BMJ 2014;349:g4829
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Competing interests: No competing interests