Chlorhexidine and IN BRIEF • Describes the history of chlorhexidine use in medicine and dentistry. PRACTICE hypersensitivity reactions • Highlights the spectrum of reported hypersensitivity reactions to chlorhexidine. • Reports two cases of death due to in dentistry anaphylaxis following the use of chlorhexidine in post-extraction tooth M. N. Pemberton1 and J. Gibson2 socket care. VERIFIABLE CPD PAPER Immunological reactions to chlorhexidine, including allergy (Type I hypersensitivity) and allergic contact dermatitis/stoma‑ titis (Type IV hypersensitivity), have been recognised for many years. This potential safety issue, however, is not well known within dentistry. The purpose of this paper is to alert dentists and dental care professionals to the potential of chlorhex‑ idine in causing hypersensitivity reactions and to consider this possibility if unexplained hypersensitivity reactions occur. INTRODUCTION skin creams and disinfectants used to pre- Table 1 Mild allergy – signs, symptoms and management13 In the 1970s, seminal studies on the value pare the skin for surgical procedures. In the of chlorhexidine mouthwash in the control early 1990s, chlorhexidine also began to be Key symptoms and signs of mild allergy of plaque and gingivitis were undertaken.1,2 incorporated into the composition of medi- Urticaria and rash, particularly of chest, Following these studies, 0.1‑0.2% chlorhex- cal devices including intravenous catheters, hands and feet idine mouthwash has become a frequently topical antimicrobial skin dressings and Rhinitis, conjunctivitis 4 recommended or prescribed treatment in implanted antimicrobial surgical mesh. No difficulty breathing the management of gingivitis. Studies have From use in all of these medical applica- Key management principles of mild allergy shown its benefit over other potentially use- tions, it has become apparent that chlo- ful plaque inhibiting agents and indicated rhexidine has the potential to produce Assess the patient specific situations in which chlorhexidine hypersensitivity reactions. Hypersensitivity Give oral antihistamine (for example, chlorphena‑ is of particular benefit.3 As well as being reactions are generally known to occur in mine 4 mg tablet or loratadine 10 mg tablet in adults. Refer to BNF or BNFC available in a mouthwash form, chlorhex- four main forms, I–IV, with Type I (imme- for child doses) idine is also available in other vehicles for diate and mediated chiefly by immuno- Reassess the patient. If severe reaction use in oral healthcare including toothpastes, globulin E) and Type IV (delayed and developing, treat as for anaphylaxis sprays and gels. Common side effects, such mediated by the cells of the immune sys- Refer patient to their general medical practitioner as staining of teeth are well recognised; tem) being the reactions of greatest con- however, rarer, but potentially more severe cern in the orofacial region. side effects including hypersensitivity, are The Type IV hypersensitivity reaction manage mild Type 1 hypersensitivity (aller- less well known. of contact dermatitis to chlorhexidine has gic) reactions and anaphylaxis are given in been reported in both adults and children Tables 1 and 2.12,13 The true prevalence of CHLORHEXIDINE HYPERSENSITIVITY with confirmation by patch testing in many these reactions remains unknown. In the AND MEDICAL PRODUCTS cases.5–7 This delayed type of hypersensi- medical literature, reactions have mainly For many years, chlorhexidine-containing tivity has most frequently followed the been recorded in case reports with these products have also been used in other areas use of chlorhexidine-containing topical cases falling into three broad categories.14 of medicine because of chlorhexidine’s medicinal creams used to treat inflamed Type I hypersensitivity reactions have beneficial effects as a topical antimicrobial skin. It has also followed the use of cos- been reported when chlorhexidine has agent. These products include antiseptic metic products containing chlorhexidine. been applied to damaged skin surfaces.8,10,14 Type I hypersensitivity reactions These instances include wounds and burns 1*Consultant in Oral Medicine and Honorary Lecturer, have been reported especially where or when the skin was cut in surgical pro- University Dental Hospital of Manchester and School of Dentistry, Higher Cambridge Street, Manchester, M15 chlorhexidine has been used topically, cedures and a chlorhexidine containing 6FH; 2Consultant and Honorary Senior Lecturer in Oral intra-urethrally, and with chlorhexidine- product had been used in the prepara- Medicine, Department of Oral Medicine, Dundee Dental Hospital & School, Dundee, DD1 4HN impregnated catheters. Incidents of this tion of the skin. Anaphylactic reactions *Correspondence to: Michael Pemberton immediate allergic type of hypersensitiv- have been reported. There have also been Email: [email protected] ity have been reported from all over the a few cases in which chlorhexidine use on Refereed Paper world, with the reactions reported ranging unbroken skin has also led to immediate Accepted 10 October 2012 14 DOI: 10.1038/sj.bdj.2012.1086 from localised urticaria to life-threatening type hypersensitivity reactions. These ©British Dental Journal 2012; 213: 547-550 anaphylactic shock.8–11 Details of how to include when chlorhexidine has been BRITISH DENTAL JOURNAL VOLUME 213 NO. 11 DEC 8 2012 547 © 2012 Macmillan Publishers Limited. All rights reserved. PRACTICE applied to pre-existing hand dermatitis, early 1970s, many studies were carried Table 2 Anaphylaxis – signs, symptoms acne or to erythematous skin. out looking at the utility of chlorhex- and management12,13 Type I hypersensitivity reactions, includ- idine mouthwash as part of dental care. Key symptoms and signs of anaphylaxis ing anaphylaxis, have been reported when Radiolabelling of chlorhexidine was used may include chlorhexidine has been applied to mucous to identify the retention and distribu- Facial flushing, swelling and paraesthesia membranes.11,14–16 In the majority of cases, tion of 10 ml of a chlorhexidine 0.2% Generalised urticaria or itching these have been associated with chlo- mouthwash used in healthy volunteers. It rhexidine-containing gels and lubricants was found that an average of 4% of the Wheezing, stridor or difficulty breathing inserted into the urethra before catheteri- compound was swallowed by the adults Abdominal pain sation or cystoscopy. Other cases have been studied and an average of 30% retained Sense of impending doom reported following chlorhexidine lubricant in the mouth.19 There was a rapid fall in applied intra-vaginally before gynaeco- the chlorhexidine concentration found Rapid, weak or impalpable pulse logical examination and chlorhexidine- in the mouth over the first few hours, Falling blood pressure containing ophthalmic wash solution. but with some activity still present after Type I hypersensitivity reactions have 24 hours. While chlorhexidine appeared Key management principles of anaphylaxis been reported when chlorhexidine has to be a poorly absorbed drug, radiola- Assess the patient using an ABCDE approach been impregnated into central venous belled chlorhexidine was detected in the Call ambulance catheters.14,17,18 In 1996, such catheters kidney and liver in animal studies, indi- 20 Secure the airway and give 100% oxygen were introduced into practice and within cating some absorption had occurred. In (10‑15 litres per minute flow rate) the next few years, there were reports of 1971, a study looked at the side effects of Lay patient flat and raise legs to support patients experiencing anaphylactic-like chlorhexidine mouthwashes in a group of blood pressure 21 adverse effects. Reports came from sev- 50 soldiers over a period of four months. Administer 0.5 ml of 1:1000 adrenaline eral countries, but the majority were from The study found some cases where chlo- (adrenaline) in adults via intramuscular Japan. It is not clear why the majority of rhexidine mouthwash caused irritation injection and repeat at 5 minute intervals if needed. (For children, child 6‑12 years give these reactions occurred in the Japanese and damage to the oral mucosa with 0.3 ml of 1:1000 adrenaline, child less than population. Possible explanations include resultant chemically-induced trauma. The 6 years give 0.15 ml of 1:1000 adrenaline) a genetic predisposition or an increased frequency of this side effect appeared to Monitor patient and if cardiac arrest occurs, start exposure to chlorhexidine-containing increase with increasing chlorhexidine basic life support immediately products resulting in heightened sensitiv- concentration. ity. The catheter was subsequently with- In the early 1970s, no cases of sensitisa- shortly after an upper lip injury was dis- drawn from use in Japan, and the United tion to chlorhexidine used in the mouth infected with 0.05% chlorhexidine gluco- States Food and Drug Administration had yet been observed.21 Since then, immu- nate.16 The patient subsequently showed a issued an alert concerning potential hyper- nological reactions to chlorhexidine when positive response to an intra-dermal test. sensitivity reactions to chlorhexidine- used in the mouth have been infrequently Recently we have become aware of impregnated medical devices.4,17 The alert documented in the medical and dental liter- two cases of anaphylaxis in the UK, recommended that if a patient exhibited ature. Allergic contact stomatitis (Type IV thought to be triggered by chlorhexidine an unexplained hypersensitivity