Pharmacovigilance for chlorhexidine anaphylaxis: a preventable adverse reaction

Clinical record

A 73‐year‐old man underwent a right total right knee replacement for osteoarthritis. He had a background of ischaemic heart disease with previous coronary artery bypass grafting, diabetes mellitus and gout. His medications before surgery were aspirin, metformin, frusemide, atorvastatin, paracetamol, sotalol, ramipril and allopurinol. Sixteen minutes after spinal anaesthesia comprising bupivacaine, fentanyl and morphine in addition to intravenous (IV) midazolam, cefazolin and tranexamic acid, he developed anaphylaxis characterised by hypotension (systolic blood pressure, 60 mmHg), and generalised pruritus requiring IV metaraminol and adrenaline. His condition stabilised to allow completion of the procedure.

Postoperative assessment revealed elevated serum tryptase levels during his reaction (9.4 ng/mL compared with a baseline level of 2.5 ng/mL 24 hours later). Skin testing elicited a positive response to chlorhexidine and found an elevated level of specific IgE to chlorhexidine. Skin test responses to other agents used perioperatively (ropivacaine, fentanyl, morphine, midazolam, cefazolin, tranexamic acid) as well as potentially cross‐reactive agents, penicillin and amoxycillin, were negative. A medical alert bracelet was fashioned stipulating his chlorhexidine allergy.

One year later, the patient underwent a left total knee replacement at the same hospital under general anaesthesia with propofol, cephazolin, tranexamic acid and rocuronium. Operating staff were aware of the chlorhexidine allergy and a chlorhexidine‐free environment was established, including removal of topical antiseptic agents and placement of warning signs in the theatre room. However, an antiseptic gel containing 2% lignocaine gel and 0.5% chlorhexidine from a prefilled syringe labelled as containing chlorhexidine was inadvertently used for urethral catheter insertion. Anaphylaxis occurred 20 minutes after induction, with hypotension (systolic blood pressure, 57 mmHg), and a generalised urticarial rash requiring IV metaraminol and IV adrenaline. He was stabilised and the operation completed. Acute and convalescent serum tryptase measurements confirmed an anaphylactic reaction.

Discussion

An estimate of the incidence of perioperative anaphylaxis is 1 in 4500–20 000, with mortality rates as high as 6%.1 The current incidence of chlorhexidine anaphylaxis in the perioperative setting in Australia is unknown but is 9% in the United Kingdom and 9.6% in Denmark.2 The chlorhexidine products responsible for allergic reactions are predominantly indwelling urinary catheter‐containing lubricants (44%), central venous catheters (35%) and topical antiseptics (16%).1 However, it should be stressed that chlorhexidine is a ubiquitous antiseptic also found in surgical skin preparations, skin wipes, mouthwashes, toothpastes, contact lens solutions, cosmetics, medical devices and certain wound dressings. Lack of awareness or incomplete labelling can inadvertently result in anaphylaxis.3

Pharmacovigilance can minimise the incidence of potentially fatal chlorhexidine anaphylaxis. The first task is assessing its necessity as an antiseptic. Evidence for the use of chlorhexidine‐infused urethral gels is weak, with no significant difference in the rate of associated urinary tract infections between antiseptic lubricants and non‐antiseptic‐impregnated lubricants.3 The United States Centers for Disease Control and Prevention advises against the routine use of antiseptic urethral lubricants,4 and in Australia, the Therapeutic Goods Administration issued a warning in 2009 of the risk of chlorhexidine anaphylaxis with the application of chlorhexidine–lignocaine urethral gels.5 Rates of chlorhexidine anaphylaxis decreased in two large perioperative allergy clinics in Australia following discontinuation of chlorhexidine‐impregnated urethral gels.2 As indwelling urinary catheters containing lubricants account for almost half of chlorhexidine allergic reactions, abrogation of their use would significantly reduce the incidence of these reactions. In 2019, the Parliamentary Standing Committee on Health, Aged Care and Sport recommended consistent labelling for all products containing chlorhexidine.6

The Australian and New Zealand College of Anaesthetists (ANZCA) has released guidelines on the management of patients with chlorhexidine hypersensitivity, including the following recommendations.7

• Documenting an allergy to chlorhexidine before exposure with clear signage in the patient notes and on the door of the room.
• Using a single room to ensure no disadvantage to other patients, with removal of all chlorhexidine‐containing products.
• Developing a chlorhexidine product register for each site, with a copy placed in the patient’s room.
• Checking the contents of each product for chlorhexidine before use.
• Ensuring that medical alert devices remain on patients, or that patients display a plastic alert band stating “Anaphylaxis to chlorhexidine”.
• Ensuring handover of chlorhexidine avoidance when a patient is transferred to other locations in the health care facility, and informing patients to be vigilant towards potential chlorhexidine exposures.

The ANZCA has recommended that operating theatres provide a “chlorhexidine‐free box” which contains a chlorhexidine‐free register listing chlorhexidine‐free alternatives for procedures; for example, lubricants such as 2% lignocaine for indwelling catheter insertion.7

Our case highlights the life‐threatening risk of chlorhexidine anaphylaxis and the need for pharmacovigilance. The risk can be mitigated by adherence to national warnings to withdraw non‐essential chlorhexidine‐containing products, improved labelling, and following ANZCA‐endorsed preventive measures. Epidemiological data are required to monitor the effectiveness of such strategies with in vivo and in vitro testing.