The U.S. Food and Drug Administration (FDA) is alerting the medical community about the potential for serious hypersensitivity reactions to chlorhexidine-impregnated medical devices. Because these types of reactions are not well known to device users and because the full extent of the problem is not yet clear, the FDA is providing the information we have to date and encouraging health care workers to report such hypersensitivity reactions to us as they occur. This will help us to better evaluate the potential public health hazard these products might pose and to decide on what action, if any, should be taken.

Chlorhexidine-containing compounds have been used as topical disinfectants since the middle 1970s. An effective antimicrobial agent, chlorhexidine is used in many antiseptic skin creams, mouth rinses and disinfectants used to prepare the skin for surgical procedures. Additionally, chlorhexidine may be incorporated in cosmetic products, where it reportedly functions as a cosmetic biocide. In the early 1990s, FDA cleared three types of medical devices that incorporate chlorhexidine in the composition of the device: intravenous catheters, topical antimicrobial skin dressings and implanted antimicrobial surgical mesh.

Although the antimicrobial properties of chlorhexidine are well-known, it is not as well-known that chlorhexidine has been associated with hypersensitivity reactions. Anaphylactoid and other types of reactions have been reported with chlorhexidine used topically, intraurethrally as a lubricant on urinary catheters, and with chlorhexidine-impregnated catheters. These incidents have occurred in Japan,^1-3 Switzerland,⁴ the United Kingdom,⁵ Australia,⁶ Malaysia⁷ and the United States.^8,9

1. Immediate systemic hypersensitivity reactions to chlorhexidine gels/lubricants used during urological procedures:

Hypersensitivity reactions associated with chlorhexidine gels/lubricants used during urological procedures have been reported in several countries. (None has been reported thus far in the United States.) In one case, a 61-year-old man in the Netherlands exhibited a severe allergic reaction associated with a chlorhexidine gel used for an intrauretheral preparation.¹⁰ In another incident in Nedlands, Australia, a 52-year-old man had an anaphylactic reaction to a chlorhexidine lubricant on a urinary catheter while undergoing a temporal lobectomy.¹¹ Six cases of severe allergic reactions to chlorhexidine gel used with urinary catheters have also been reported in Melbourne, Australia.¹²

2. Immediate systemic hypersensitivity reactions to central venous catheters:

From communication with the Japanese government, FDA became aware that 13 Japanese patients experienced anaphylactoid-type adverse events while using central venous catheters impregnated with chlorhexidine. Tachycardia, hypotension and complaints of chest pain were reported. One patient subsequently died, although the exact cause of death is unknown. It is not clear why these reactions occurred in Japanese individuals but not in others; possible explanations include an increased exposure to chlorhexidine-containing products resulting in heightened sensitivity, a genetic predisposition to react to this chemical or some other factor. Sale of these central venous catheters in Japan began in 1996. The adverse events occurred between June 25, 1996, and June 24, 1997. The World Health Organization issued a notice stating that the manufacturer of the central venous catheters voluntarily withdrew the product from the market in Japan on August 19, 1997.¹³Approximately 117,000 catheters were sold. To date, FDA has not received any reports of immediate systemic hypersensitivity reactions related to central venous catheters for patients in the United States. (Of the 3 million sold worldwide since 1990, 2.5 million were in the United States.)

3. Other types of reactions:

In addition to the immediate systemic hypersensitivity reactions reported with the use of topical chlorhexidine, chlorhexidine gel/lubricant and chlorhexidine-impregnated catheters, other types of reactions have been documented. In one U.S. study, six of 10 neonates weighing under 1000 grams showed local hypersensitivity reactions to chlorhexidine gluconate-impregnated patches used to secure central venous catheters.^. Severe contact dermatitis in seven neonates with this type of dressing was also reported in another U.S. study.⁹ Two cases of occupational asthma in nurses were reported from chlorhexidine and alcohol aerosols,¹⁴ and bradycardia was reported in a neonate associated with a chlorhexidine spray used on the mother's breasts.¹⁵

• * If a patient exhibits an unexplained hypersensitivity reaction, check whether chlorhexidine was used or was impregnated in a medical device that was used.
• * If you suspect a patient may have (or has had) a hypersensitivity reaction to a drug or medical device that contains a chlorhexidine compound, monitor the reaction carefully, provide immediate respiratory and/or cardiovascular support as needed and discontinue the use of the drug or medical device as expeditiously as possible.
• * Please report any chlorhexidine hypersensitivity reactions you may discover immediately to FDA. This will help us delineate the problem and may help avoid serious reactions in the future. Please submit voluntary reports directly to MedWatch, the FDA's voluntary reporting program. Submit these reports by telephone at (800) FDA-1088, by fax at (800) FDA-0178, or by mail to: MedWatch, Food and Drug Administration, HFA-2, 5600 Fishers Lane, Rockville, MD 20857-9787.

If you have any questions about the content of this Public Health Notice, please contact Deborah Blum, R.N., Office of Surveillance and Biometrics, Division of Postmarket Surveillance, HFZ-520, 1350 Piccard Drive, Rockville, Maryland, 20850; fax (301) 594-1967; e-mail <dyb@cdrh.fda.gov>.

You can print additional copies of this notice from the Center for Devices and Radiological Health homepage at <www.fda.gov/cdrh/safety.html>. If you do not have access to the Internet and would like additional copies, call (301) 594-3060, fax (301) 594-2968, or e-mail Marian Zellner <mtz@cdrh.fda.gov>.

1. Ohtoshi T, Yamauchi N, Tadokoro K, et al. IgE antibody-mediated shock reaction caused by topical application of chlorhexidine. Clin Allergy. 1986; 16:155-161.
2. Okano M, Nomura M, Hata S, et al. Anaphylactic symptoms due to chlorhexidine gluconate. Arch Dermatol. 1989; 125:50-52.
3. Layton GT, Stanworth DR, Amos HE. The incidence of IgE and IgG antibodies to chlorhexidine. Clin Exp Allergy. 1989; 19(3):307-314.
4. Torricelli R, Wuthrich B. Life-threatening anaphylactic shock due to skin application of chlorhexidine. Clin Exp Allergy. 1996; 26(1):112.
5. Evans RJ. Acute anaphylaxis following urethral catheterization. Br J Urol. 1993; 73:613.
6. Cheung J, O'Leary JJ. Allergic reaction to chlorhexidine in an anaesthestised patient. Anaesth Intensive Care. 1985; 13(4):429-430.
7. Yaacob H, Jalil R. An unusual hypersensitivity reaction to chlorhexidine. J Oral Med. 1986; 41(3):145-146.
8. Karwowska H, Nesin M, Auld PAM. Safety and effectiveness of Biopatch™ in the reduction of catheter related sepsis in low birth weight neonates. Ped Res. 1995; 37(4):293.
9. Garland JS, Alex CP, Mueller CD, et al. Local reactions to a chlorhexidine gluconate-impregnated antimicrobial dressing in very low birth weight infants. Pediatr Infect Dis J. 1996; 15(10):912-914.
10. Ramselaar CG, Craenen A, Bijleveld RT. Severe allergic reaction to an intraurethral preparation containing chlorhexidine. Br J. Urol. 1992; 70(4):451-452.
11. Russ BR, Maddern PJ. Anaphylactic reaction to chlorhexidine in urinary catheter lubricant. Anaesth Intensive Care. 1994; 22(5):611-612.
12. Yong D, Parker FC, Foran SM. Severe allergic reactions and intra-urethral chlorhexidine gluconate. Med J Aust. 1995; 162(5):257-258.
13. World Health Organization. Central venous catheters (Arrowguard®) recalled: anaphylactic shock. Information Exchange System, Alert No. 62. Sept. 15, 1997.
14. Waclawski ER, McAlpine LG, Thomson NC. Occupational asthma in nurses caused by chlorhexidine and alcohol aerosols. BMJ. 1989; 298(6678):929-930.
15. Quinn MW, Bini RM. Bradycardia associated with chlorhexidine spray (letter). Arch Dis Child. 1989; 64(6):892-893.

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