Loe H, Schiott CR The effect of mouthrinse and topical applications of chlorhexidine on the developments of dental plaque and gingivitis in man. J Periodont Res. 1970; 5:79-83
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Nshioka K, Doi T, Katayama I Histamine release in contact urticaria. Contact Derm. 1984; 11
Ohtoshi T, Yamauchi N, Tadokoro K IgE antibody-mediated shock reaction caused by topical application of chlorhexidine. Clin Allergy. 1986; 16:155-161
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Chisholm DG, Calder I, Peterson D Intranasal chlorhexidine resulting in anaphylactic circulatory arrest. Br Med J. 1997; 315
Stephens R, Mythen M, Kallis P Two episodes of life-threatening anaphylaxis in the same patient to a chlorhexidine-sulphadiazine coated central venous catheter. Br J Anaesth. 2001; 87:306-308
Central venous catheters (Arrowguard®) recalled: anaphylactic shock.Geneva: World Health Organization; 1997
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Chlorhexidine is an effective antiseptic which is widely used in dentistry. Over recent years, it has also been used in other healthcare products as well as in cosmetics. Anaphylaxis to chlorhexidine has been increasingly reported throughout the world, including two incidents in the UK where chlorhexidine-containing mouthwash had been used to wash tooth sockets following recent tooth extraction. Chlorhexidine is under-recognized as a cause of anaphylaxis and dentists should be aware of its potential for serious adverse effects. Dentists need to consider whether the washing out of a tooth socket with chlorhexidine solution should be avoided in the treatment of established dry socket. On current evidence the potential risks of using chlorhexidine as irrigation solution for treating an established dry socket appears to outweigh any known benefit.
CPD/Clinical Relevance: Chlorhexidine has the potential to cause anaphylaxis in the dental surgery.
Article
Over the last 50 years, chlorhexidine has become widely used in dentistry, in healthcare in general, and in cosmetics, and it is likely that its use will continue to grow. With this increase in use there are increasing possibilities for adverse effects of which the dental practitioner should be aware.
Chlorhexidine in healthcare and other products
Chlorhexidine is a widely used antiseptic with which all dental practitioners are familiar. It has been extensively used in dentistry, most frequently for the control of dental plaque and reduction of gingivitis since the 1970s, following studies showing 0.1–0.2% chlorhexidine mouthwash to be of benefit.1,2 Chlorhexidine has also become available for oral use in toothpaste, sprays, gels and periodontal chips.
Chlorhexidine is also widely used as an antiseptic on the skin. In the early 1990s, chlorhexidine began to be incorporated into the composition of medical devices including catheters, skin dressings and surgical mesh.
Outside of the healthcare setting, chlorhexidine may be used in cosmetics as a preservative or antimicrobial agent. In Europe, chlorhexidine is allowed in cosmetic products at a concentration of up to 0.3%, as set by the European Cosmetics Directive (now regulations).3 A study in Finland found chlorhexidine in 1.9% of cosmetic products, whilst a recent study in Denmark found chlorhexidine in 3.6% of cosmetic products, including hair products and facial cream and ointments.4,5 Chlorhexidine was mainly found in products from international companies and in products aimed at the female market.
Chlorhexidine and hypersensitivity
Serious adverse effects resulting from chlorhexidine use are rare, but chlorhexidine can cause both Type I and Type IV hypersensitivity reactions. Type IV hypersensitivity is a delayed reaction mediated by cells of the immune system. Its most common manifestation is as contact dermatitis. Type I hypersensitivity is an acute reaction mediated by immunoglobulin E. A mild reaction can manifest itself as simple skin urticarial, whilst a severe systemic reaction manifests as anaphylaxis, with a risk of cardiac arrest and death. Type IV hypersensitivity reactions to chlorhexidine are more frequently reported than Type I hypersensitivity reactions and are most frequently reported following the use of chlorhexidine-containing topical medications used on the skin. Type IV reactions have also been reported following application of cosmetic products containing chlorhexidine.
Over time we have become increasingly aware of Type I hypersensitivity reactions to chlorhexidine since the first report of anaphylaxis to chlorhexidine in 1984.6 Type 1 reactions, including anaphylaxis in some cases resulting in death, have most frequently been reported in the following circumstances:
Following application of chlorhexidine to damaged skin surfaces. This includes wounds and burns and also antiseptic skin preparation followed by surgical incision.7,8
Following application of chlorhexidine to mucous membranes outside of the mouth. This includes following application of chlorhexidine containing gels and lubricants into the urethra, vagina, eye and nose.9,10,11,12
Following insertion of medical devices impregnated with chlorhexidine.13 Chlorhexidine-containing central venous catheters were introduced into clinical practice in 1996. Shortly afterwards reports of anaphylaxis emerged from several countries, with the majority originating in Japan. The chlorhexidine-impregnated central venous catheter was subsequently withdrawn from use in Japan, and in the USA the Food and Drug Administration issued an alert concerning potential hypersensitivity reactions to chlorhexidineimpregnated devices.14,15
A recent literature review identified 65 published case reports of chlorhexidine-related anaphylaxis since 1994, however, true incidence is likely to be higher.16 Several of the reports identified that the affected patients had experienced mild urticarial reactions to chlorhexidine at a time previous to the anaphylactic event. These warning reactions appear to have been missed, perhaps because awareness of allergy to chlorhexidine is not as widely known as it deserves. Delayed recognition of chlorhexidine as a cause of anaphylaxis has also created problems with resuscitation where anaphylaxis occurs. Awareness and labelling of latex products has grown considerably, however, chlorhexidine is not always as prominently labelled as is necessary so that, even in patients with known chlorhexidine allergy, chlorhexidineimpregnated devices have unknowingly been inserted.13
In January 2012, the UK Medicines and Healthcare Products Regulatory Agency (MHRA) released a drug safety update to all healthcare workers on the potential for chlorhexidine to induce hypersensitivity as a reminder of this risk.17 In October 2012, the MHRA followed this with a medical device alert concerning all medical devices and medicinal products containing chlorhexidine.18 Healthcare workers were advised to ensure that all known allergies are recorded in patient notes. They were also advised to check the labels and instructions for use, to establish if products contained chlorhexidine, prior to use on patients with a known allergy. They were further advised that, if a patient experiences an unexplained reaction, to check whether chlorhexidine was used or was impregnated in a medical device that was used. Any allergic reactions to products containing chlorhexidine should be reported to the MHRA.
The use of chlorhexidine in healthcare products and hospital disinfection is increasing. According to the MHRA licensing records, the percentage of products containing chlorhexidine has increased substantially over the last 20 years, from 21 chlorhexidine-containing products in 2000 to 45 products available for use by 2015.19 Alongside this, the heightened awareness of hospital acquired infections has encouraged frequent hand decontamination amongst healthcare workers. Many of these hand disinfectants now contain chlorhexidine and the concern has been raised that the incidence of allergy to this product will increase in parallel with increased exposure to the antiseptic.
Chlorhexidine allergy in dentistry
Since the introduction of chlorhexidine-containing mouthwash in the 1970s, immunologically mediated reactions to chlorhexidine-containing products used in the mouth have only been occasionally reported in the literature. It is not always clear from the reports, however, exactly what type of immunological reaction has occurred in this situation. Type IV hypersensitivity has been reported following the use of chlorhexidine-containing mouthwash.20 Type I hypersensitivity has been reported following treatment with an antiseptic dental gel containing 1% chlorhexidine gluconate.21 Type I hypersensitivity has also been reported after a lip injury was disinfected with 0.05% chlorhexidine gluconate.22 In a further case, urticarial skin lesions followed the use of chlorhexidine-containing mouthwash.23
Most recently in the UK, two cases of anaphylaxis to chlorhexidine, resulting in death, have been reported (Boxes 1 and 2). In both cases, chlorhexidine-containing mouthwash was being used to treat a tooth socket following recent tooth extraction.24
Anaphylaxis to chlorhexidine in the dental surgery Case 1.25
In October 2009, a 63-year-old male patient attended his dentist with symptoms following recent extraction of a tooth. The tooth socket was washed with chlorhexidine mouthwash. The patient developed anaphylactic shock to the chlorhexidine. The attending dentists recognized the symptoms of anaphylaxis while the patient was in the dental chair, summoned paramedics and administered adrenaline by injection. Unfortunately, despite the attention of the dental staff and paramedics, the patient deteriorated, suffered a respiratory arrest and died. At the subsequent inquest, the dental practice was praised for their management of the patient. It also came to light that the patient had suffered an unexplained allergic reaction 7 years earlier in the local hospital which had not been sufficiently investigated at the time.
It is reported that the practice owner has since stated his considerations for other dental practitioners in the light of his experience:
Pre-register your location with ambulance control. (The practice was a new build and as such was not recognized in the satellite navigation system. Ambulance control had become regionalized with loss of local knowledge, slowing down the arrival of the ambulance);
Ensure a comprehensive allergy history as part of the medical history;
Use hypo-allergenic products where possible to minimize the risk of adverse allergic reactions;
Have a signed and updated medical history at the start of each treatment;
Ensure the ‘next of kin’ contact details are correct and updated;
Use the knowledge and training that dentists possess to deal with emergencies;
Undertake regular medical emergency training with the whole practice staff.
Anaphylaxis to chlorhexidine in the dental surgery Case 2.26,27
In February 2011, a 30-year-old female patient attended her dentist with symptoms following a recent tooth extraction. The tooth socket was washed with chlorhexidine mouthwash. The patient had anaphylactic shock to the chlorhexidine. Within minutes of chlorhexidine administration, the patient began to feel unwell and complained of feeling hot and had an itchy back and leg. The patient collapsed but the anaphylactic shock was not recognized and adrenaline was not administered. The patient subsequently died. At the subsequent inquest the coroner suggested that ‘failure to recognize anaphylactic shock was regrettable but understandable in light of the extraordinary speed of the illness.’ There was nothing in the patient's history to suggest an allergy to chlorhexidine.
Chlorhexidine and alveolar osteitis (dry socket)
Chlorhexidine has been used in several trials to see if it can reduce the risk of development of a dry socket following tooth extraction. Chlorhexidine gel and mouthwashes of between 0.1% and 0.2% in concentration have been trialled by application immediately pre-operatively, immediately post-operatively and for several days post extraction to observe the effect on the incidence of dry socket. In 2012, two independent systematic reviews were published having analysed the data from multiple trials. Yengopal and Michenautsch specifically looked at trials using chlorhexidine in the prevention of alveolar osteitis.28 They analysed 10 trials and found two application protocols favoured chlorhexidine over placebo, however, they felt the trials were of high risk of bias and concluded that the review could not identify sufficient evidence for supporting the use of chlorhexidine for the prevention of dry socket. A Cochrane review published in the same year also analysed all trials where local interventions (including chlorhexidine) had been used in the prevention of dry socket and came to different conclusions.29 It was felt that there was some evidence that perioperative rinsing with chlorhexidine mouthwash (0.12% and 0.2%) or placing chlorhexidine gel (0.2%) in the sockets of extracted teeth provides a benefit in preventing dry socket. These two reviews did not look at exactly the same group of studies as different inclusion criteria were used.
The Cochrane review also analysed trials where local interventions had been used in the treatment of dry socket, once it had become established. No trials were found where chlorhexidine had been investigated as a treatment for dry socket.
Conclusion
The use of chlorhexidine as a constituent of both healthcare and nonhealthcare products is growing. The rate of patients sensitized to chlorhexidine remains unknown. Chlorhexidine allergy can initially present with mild cutaneous urticarial symptoms which may be missed by the attending clinician. Over the last 30 years, increasing numbers of reports of anaphylactic reactions to chlorhexidine, some with fatal results, have been published. Chlorhexidine is under-recognized as a cause of anaphylaxis and should always be considered in perioperative anaphylaxis. Dentists should be aware of this potential adverse reaction to chlorhexidine.
There appears to be some evidence, albeit inconclusive, that use of chlorhexidine may help prevent development of a dry socket if used perioperatively. There is no evidence however that chlorhexidine is of benefit in the treatment of dry socket once established. In both cases of anaphylaxis described in this paper, chlorhexidine solution was used to rinse out a tooth extraction socket, days after removal of the tooth. With respect to patient safety, dentists need to consider whether chlorhexidine should be avoided as an irrigation solution when treating an established dry socket. On current evidence, the potential risks of using chlorhexidine as irrigation solution for treating a dry socket appears to outweigh any known benefit.
