- Email: [email protected]
Adverse events associated with chlorhexidine use
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Adverse events associated with chlorhexidine use Results from the Department of Veterans Affairs Dental Diabetes Study Linda C. McCoy, RDH, MS; Carolyn J. Wehler, RDH, MPH; Sharron E. Rich, MPH; Raul I. Garcia, DMD, MMedSc; Donald R. Miller, ScD; Judith A. Jones, DDS, MPH, DScD
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Background. The authors report adverse events (AEs) related to the use of chlorhexidine gluconate N C U mouthrinse in a clinical trial of the efficacy of periA ING EDU 4 odontal treatment in older adults with diabetes. RT ICLE Methods. Participants were U.S. veterans with uncontrolled diabetes (hemoglobin A1c value ≥ 8.5 percent) and periodontal disease. Treatment included periodontal scaling, 0.12 percent chlorhexidine lavage during ultrasonic scaling and use of chlorhexidine mouthrinse at home. Results. Forty-four (31 percent) of 140 subjects reported having AEs. Most common were taste changes and tooth staining, sore mouth and/or throat, tongue irritation and wheezing/shortness of breath; the latter was reported more commonly before chlorhexidine use than after. Only body mass index greater than 30 was significantly related to AEs. Conclusions. AEs are common among subjects using chlorhexidine mouthrinse. Most AEs (taste change and staining) were resolved easily by subjects’ discontinuing mouthrinse use and receiving dental prophylaxis. No serious AEs were reported. Clinical Implications. Clinicians should advise patients using chlorhexidine mouthrinse of possible side effects. If necessary, patients should discontinue mouthrinse use and obtain medical care. Careful monitoring of AEs in patients using chlorhexidine is warranted. Key Words. Chlorhexidine gluconate; mouthrinse; periodontal disease; diabetes. JADA 2008;139(2):178-83. I
DISCLOSURE: Dr. Miller received research funding from Sanofi-Aventis, Bridgewater, N.J.; Merck & Co., Whitehouse Station, N.J.; and GlaxoSmithKline, Research Triangle Park, N.C.
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ntimicrobial agents, such as chlorhexidine gluconate, are used often as an adjunctive therapy for periodontal treatment.1-3 Since the 1970s, chlorhexidine has been used successfully in dentistry.2,4 An effective bactericidal agent against gramnegative and gram-positive organisms, as well as against yeasts and other organisms,2,4-7 chlorhexidine is considered the gold standard of antimicrobial mouthrinses in dentistry.2 Dental applications include use as a mouthrinse,2,8-10 bactericidal spray for topical use,7 preoperative irrigation,8 denture disinfectant for systemic candidiasis,8,11 impregnation of surgical dressings,12 lavage during periodontal procedures7,13 and use as a postsurgical rinse.7 Dental delivery systems include periodontal chips,3 varnish,14 gel and dentifrices.15,16 Some nondental applications include aqueous solutions for topical ophthalmic use,17 surgical skin disinfectant18,19 and use in burn treatment.1,5 Any use of chlorhexidine, or any other medications, carries with it the risk of experiencing adverse events (AEs).
Ms. McCoy is a health science specialist, Center for Health Quality, Outcomes and Economic Research, Edith Nourse Rogers Memorial Veterans Hospital, 200 Springs Road (152), Bedford, Mass. 01730, e-mail “[email protected]”. Address reprint requests to Ms. McCoy. Ms. Wehler is an assistant professor, Boston University Goldman School of Dental Medicine. Ms. Rich is a senior analyst, Boston University Goldman School of Dental Medicine. Dr. Garcia is the director, VA Dental Longitudinal Study, VA Boston Healthcare System, and a professor and chair, Department of Health Policy and Health Services Research, Boston University Goldman School of Dental Medicine. Dr. Miller is a senior research scientist, Center for Health Quality, Outcomes and Economic Research, Bedford, Mass., and an associate professor, Boston University School of Public Health. Dr. Jones is a professor and chair, Department of General Dentistry, Boston University Goldman School of Dental Medicine.
February 2008
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Because we were conducting a clinical trial using chlorhexidine as an adjunctive therapy in the treatment of periodontal disease, we examined the rate of AEs in our study population. We report on the frequency of AEs related to the use of chlorhexidine in this clinical trial of periodontal treatment of U.S. veterans with poorly controlled diabetes and periodontal disease. SUBJECTS AND METHODS
The Department of Veterans Affairs Dental Diabetes Study20 is a randomized, single-blind, controlled clinical trial that examined periodontal treatment and the improvement in glycemic control among veterans with poorly controlled diabetes. The clinical portion of the study was conducted between December 2000 and November 2004. Institutional review boards at each of the four study facilities approved this study. Each participant gave written informed consent. The study staff (L.C.M., C.J.W., M. Puccio) recruited veterans with poorly controlled diabetes and periodontal disease from four Veterans Affairs (VA) medical centers in New England. All subjects had a hemoglobin A1c (HbA1c) value greater than or equal to 8.5 percent as well as periodontal disease. Inclusion criteria required that all subjects had Community Periodontal Index of Treatment Needs21 scores of 3.5 or greater in at least two sextants, meaning all had some form of chronic periodontitis, as well as eight or more teeth. Further information about the study sample is published elsewhere.22 The study hygienist (L.C.M.) administered periodontal therapy according to the study protocol, including ultrasonic scaling with subgingival lavage of 0.12 percent chlorhexidine; hand scaling; and adjunctive chemotherapy, including chlorhexidine mouthrinse (0.12 percent oral rinse twice per day for four months at home) and systemic doxycycline (100 milligrams per day for 14 days). The study staff gave subjects oral and written instructions regarding how to take each medication, told them of the known side effects and instructed them to report any side effects immediately. Subjects completed surveys at baseline about existing symptoms and at follow-up about AEs they experienced. When they reported experiencing an AE, subjects were told to stop taking the medication (that is, the chlorhexidine and/or the doxycycline) immediately. The list of AEs provided to participants included all previously
reported, known side effects of chlorhexidine use. AE incidence. The primary outcome of interest for this report was the incidence of AEs among subjects using chlorhexidine in the dental diabetes study.20 In distinguishing AEs associated with chlorhexidine from those associated with the other study drug (doxycycline), we noted that the possible symptoms associated with each drug are unique. In addition, subjects used chlorhexidine for a much longer period (four months) than they did doxycycline (14 days). Thus, we attributed all AEs reported after the doxycycline therapy ended to chlorhexidine use (when reported on the fourmonth follow-up questionnaire or as obvious symptoms appeared, whichever occurred sooner). Because subjects took doxycycline for only 14 days, we expected that any AEs attributable to this medication would develop in less than one month. Only 7 percent of subjects reported an AE in the first month of chlorhexidine use; therefore, we are confident that the information regarding these AEs can be attributed to chlorhexidine therapy. All AEs were self-reported. We obtained data regarding demographics, HbA1c levels and diagnostic codes23 for comorbid medical conditions from the VA outpatient clinic file and the VA computerized patient record system. From the lists of comorbid medical conditions, we calculated the Selim comorbidity index (CI),24 a measure of disease burden, and the Diabetes Complications Index (DCI),25 a measure of the severity of diabetes. The DCI is a sum of diabetes complications, including microvascular, macrovascular and metabolic conditions. Baseline data collection. The study’s calibrated hygienist (C.J.W.) assessed the subject’s periodontal condition during clinical examinations. She obtained baseline symptom data from subjects during interviews in which she asked if they had experienced the symptoms listed in Table 1. These data are available for only a subset of the sample, however, because midway through the study, we recognized that the rates of AEs were higher than expected. In response, we added a list of questions about the occurrence of symptoms (that is, known side effects associated
ABBREVIATION KEY. AE: Adverse event. BMI: Body mass index. CI: Comorbidity index. DCI: Diabetes Complications Index. HbA1c: Hemoglobin A1c. VA: Veterans Affairs.
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TABLE 1
Self-reported adverse events, according to symptom. SYMPTOM AT FOLLOW-UP
NO. OF SUBJECTS REPORTING ADVERSE EVENT
AMONG SUBJECTS USING CHLORHEXIDINE (N = 140) (% OF SUBJECTS)
AMONG SUBJECTS REPORTING ADVERSE EVENT (n = 44) (% OF SUBJECTS)
BASELINE GROUP (n = 63)† NO. (%) OF SUBJECTS*
Taste Changes
27
19.3
61.4
2 (3.2)†
Stain: Teeth/Tongue/Dentures
26
18.6
59.1
6 (9.5)
Sore Mouth/Tongue/ Throat
10
7.1
22.7
18 (28.6)‡
Tongue-Tip Irritation
10
7.1
22.7
5 (7.9)
Wheezing/Shortness of Breath
10
7.1
22.7
20 (31.7)‡
Nasal Congestion
9
6.4
20.4
27 (42.9)‡
Swelling of Face/Lips/ Throat
6
4.3
13.6
5 (7.9)
Skin Rash/Hives/Itching
6
4.3
13.6
20 (31.7)‡
Swollen Glands
5
3.6
11.4
2 (3.2)
Increased Calculus
5
3.6
11.4
6 (9.5)
Diarrhea
3
2.1
6.8
14 (22.2)‡
Nausea/Burning/ Upset Stomach
3
2.1
6.8
14 (22.2)‡
Loss of Appetite
3
2.1
6.8
0
Itching Mouth
3
2.1
6.8
7 (11.1)
Abdominal Pain
1
0.7
2.3
7 (11.1)†
* Baseline comparison group versus all subjects using chlorhexidine. † P < .001. ‡ P < .0001.
with chlorhexidine) to the baseline data collection to facilitate comparisons at follow-up. Baseline and follow-up surveys. We should point out that the two questionnaires were worded and administered slightly differently. The baseline survey asked if the subject had had symptoms within the last four weeks. The dental hygienist administered the survey via an inperson interview. The follow-up survey stated no time frame with regard to the duration of symptoms, but it asked whether the subject currently had any symptoms. We administered the followup survey via a self-reported questionnaire. We obtained additional study data from the selfreported questionnaires. We entered clinical data into a laptop computer at chairside and later synchronized the data to the database. Statistical analyses included the use of t tests, χ2 tests or the Fisher exact test, as appropriate; 180
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frequency distributions; multiple variable logistic regression; and power calculations with the use of statistical software (SAS, version 9.1.3, SAS Institute, Cary, N.C.). We used P < .05 as a cutoff for statistical significance and P < .15 to indicate trends. RESULTS
One hundred forty subjects used chlorhexidine for four months (mean age, 59.5 years; 96.4 percent were male). Of these, 44 (31.4 percent) reported that they experienced AEs. No serious AEs were reported. The U.S. Department of Veterans Affairs defines serious AEs as “unanticipated problems involving risks needing medical or surgical intervention to prevent a life-threatening experience.”26 The most common AEs reported were taste changes (27 [19.3 percent] of 140 subjects) and stains on the teeth, tongue and/or den-
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tures (26 [18.6 percent] of 140) (Table 1). Sore mouth, sore tongue and/or throat and tongue-tip irritation were reported by 10 subjects each (7.1 percent). Ten subjects (7.1 percent) also reported wheezing and shortness of breath. For comparison with the follow-up findings, we asked 63 subjects at baseline whether they had had any AE symptoms within the previous four weeks. We compared these subjects with all subjects using chlorhexidine with regard to age, race, education, type of diabetes medications taken and baseline HbA1c levels, and we found no differences. When we compared the incidence of each symptom of note (sore mouth, tongue and/or throat; wheezing and/or shortness of breath; nasal congestion; diarrhea; nausea, burning and/or upset stomach; abdominal pain; skin rash, hives and/or itching), we found that they all were significantly more common among those queried at baseline than they were at follow-up. However, subjects reported taste changes significantly more often at follow-up than at baseline. Table 224,25,27 shows comparisons between subjects who reported having an AE and those who did not. Subjects reporting an AE were less likely to have a high body mass index (BMI) (> 30) (56.8 percent of those with an AE had a high BMI versus 74.7 percent of those without an AE had a high BMI) (P = .03). BMI remained significant even after we performed multiple variable logistic regression analyses. We adjusted for covariates that showed a trend toward significance at the P < .20 level (that is, number of prescriptions, mouthrinse use, problems taking medications, CI, DCI and number of teeth). Of interest is our finding in the multiple variable logistic regression that DCI and use of any mouthrinse also were associated significantly with AEs. Nonsignificant trends are reported in Table 2; however, we have insufficient power to detect differences using the small numbers in the study. To detect significant differences at α = .05 and a power of .80, we would need between 150 and 400 subjects per group, except for self-reported general health and drug abuse, for which 1,600 to 7,000 subjects would be needed per group. There were no differences between the study groups or study sites. In addition, no subjects withdrew from the study owing to chlorhexidine use. DISCUSSION
AEs were common in medically compromised veterans with poorly controlled diabetes treated
with chlorhexidine mouthrinse in this clinical trial of periodontal care and its effects on glycemic control. The results show a high incidence of taste changes and oral stains, which are consistent with known AEs associated with this drug.9,28-31 We also observed sore mouth, tongue and/or throat, tongue-tip irritation and wheezing or shortness of breath in 7.1 percent of subjects. However, it is unclear whether this group of symptoms was caused by chlorhexidine, because they were almost as commonly reported or more commonly reported at baseline. Chlorhexidine use, while eliciting AEs, was reasonably welltolerated in this clinical trial of adults who had diabetes with poor glycemic control and multiple comorbidities. Subjects who experienced AEs were less likely to have a BMI greater than 30. It is unclear why this is so. Nonsignificant trends showed that subjects with AEs were more likely to have more comorbidities than other subjects, have more complications from diabetes, report pre-existing allergies, experience problems taking other medications and need prophylactic antibiotics before dental procedures. At baseline, they also had more teeth and were more likely to use mouthrinses than were other subjects. Finally, more nondrinkers and heavy drinkers (as opposed to moderate drinkers) were in the group that experienced AEs. Baseline versus follow-up symptoms. When comparing baseline symptoms with those at follow-up, we found that many symptoms had a higher incidence at baseline. This may be due to the variation in the way the questions were worded and the surveys were administered. The baseline survey asked if the subject had had symptoms within the last four weeks and was administered via an in-person interview, while the follow-up survey stated no time frame and was administered via a self-reported questionnaire. We did not use a placebo, because this study was not designed to evaluate the effectiveness of mouthrinse, but rather the effectiveness of periodontal treatment in improving glycemic control in subjects with poorly controlled diabetes. Thus, one cannot infer that any AEs reported by subjects in our study stemmed from chlorhexidine use alone, but could have arisen from other ingredients in the mouthrinse (for example, alcohol, flavoring). Given the relative frequency with which we observed such AEs as wheezing and shortness of breath, a placebo-controlled trial
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TABLE 2
Selected subject characteristics at baseline,* by AE† status. NO. OF SUBJECTS (N = 140)
MEAN (SD‡) OR PERCENT OF SUBJECTS§
AEs = NO, % OF SUBJECTS§ (n = 96)
AEs = YES, % OF SUBJECTS§ (n = 44)
Mean Age, Years
140
59.5 (11.0)
59.2
60.4
Married Subjects
139
54.7
55.8
52.3
White Subjects
138
84.8
83.0
88.6
53 83
39.0 61.0
38.7 61.3
39.5 60.5
Male Subjects
140
96.4
97.9
93.2
Took Both Study Medications (Chlorhexidine and Doxycycline)
140
90.7
89.6
93.2
Total No. of Medications Taken
131
9.1 (4.8)
8.8
9.6
Self-Reported Allergies to Any Medications
137
16.8
12.9
25.0¶
Any Medications That Cause Problems
136
17.6
14.1
25.0#
Takes Antibiotics Before Dental Treatment (Self-Reported)
135
28.9
23.9
39.5¶
Mouthrinse Use (Prescription)
137
6.6
4.3
11.4#
Mouthrinse Use (Nonprescription)
138
70.3
66.0
79.6#
Diabetes Medications: Takes Insulin and Oral Medications
136
26.5
29.4
20.4
Alcohol Consumption # Nondrinker < 1 drink/day ≥ 1 drink/day
80 45 12
58.4 32.8 8.8
55.9 37.6 6.4
63.6 22.7 13.6
Smoking Status Current Former Never
25 72 30
19.7 56.7 23.6
17.2 56.3 26.4
25.0 57.5 17.5
Mean Body Mass Index (BMI)
139
33.1 (6.6)
33.8
31.7¶
BMI > 30
139
69.1
74.7
56.8**
BMI < 25
139
10.1
7.4
15.9#
Selim Comorbidity Index 24
140
5.7 (3.2)
5.4
6.3¶
Self-Reported Poor General Health (GH1 ††)
136
44.8
44.1
46.5
Diabetes Complications Index 25
140
2.7 (1.8)
2.5
3.1¶
Geriatric Oral Health Assessment Index 27
137
30.1 (4.3)
30.0
30.4
Hemoglobin A 1c Level, Percent
140
9.7 (1.3)
9.7
9.6
Total No. of Teeth
140
20.9 (6.1)
20.2
22.2¶
% of Sites With Pockets > 3 mm ‡‡
139
13.5 (14.9)
14.3
11.8
% of Sites With Pockets > 5 mm
139
2.5 (5.4)
2.6
2.3
Mean Loss of Attachment, mm
139
3.2 (1.1)
3.2
3.0
Mean Loss of Attachment (Change From Baseline to Follow-Up), mm
126
-0.2 (0.3)
-0.2
-0.2
Mean Probing Depth, mm
139
2.4 (0.6)
2.5
2.4
Mean Probing Depth (Change From Baseline to Follow-Up ), mm
127
-0.3 (0.3)
-0.3
-0.3
Total No. of Periodontal Treatments
139
1.6 (1.0)
1.7
1.5
VARIABLE
Education At least some high school At least some college
* † ‡ § ¶ # ** †† ‡‡
Unless otherwise stated. AE: Adverse event. SD: Standard deviation. Unless otherwise stated. P < .1. P < .15. P < .05. GH1: General Health Exam 1 (from study survey). mm: Millimeter.
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among medically compromised older adults may be warranted. Study limitations. One limitation of this study is that there were few women in the sample as a result of the nature of the VA population (10.26 percent female).32 Another limitation is that we collected baseline symptom data only after observing a high rate of AEs among subjects at follow-up. As a result, we have baseline data for only 45 percent of subjects and cannot make strong comparisons between those who reported baseline symptoms and those who did not. Any future studies should collect baseline data for all participants. CONCLUSION
Clinicians must carefully and completely advise patients who use chlorhexidine, in any form, of possible side effects. They should request that patients report any symptoms to their health care providers, immediately discontinue use when side effects arise, and obtain medical care when necessary. Careful monitoring of AEs in patients using chlorhexidine is warranted, particularly among those with multiple medical conditions and a history of allergies or breathing problems. ■ The views expressed in this article are strictly those of the authors and do not represent the views of the U.S. Department of Veterans Affairs. This study was supported by grants VA HSR&D QUERI DII-99.206, NIH K24-DEO18211, NIH K24-DEOO419 and VA CSP #711 and by Boston University Goldman School of Dental Medicine. Questionnaires used in this study are available from Ms. McCoy on request. 1. Fardal O, Turnbull RS. A review of the literature on use of chlorhexidine in dentistry. JADA 1986;112(6):863-9. 2. Jones CG. Chlorhexidine: is it still the gold standard? Periodontol 2000 1997;15:55-62. 3. Killoy W. The use of locally delivered chlorhexidine in the treatment of periodontitis: clinical results. J Clin Periodontol 1998;25(11 part 2):953-8. 4. Löe H, Schiott CR. The effect of mouthrinses and topical application of chlorhexidine on the development of dental plaque and gingivitis in man. J Periodontal Res 1970;5(2):79-83. 5. Flotra L, Gjermo P, Rolla G, Waerhaug J. Side effects of chlorhexidine mouth washes. Scand J Dent Res 1971;79(2):119-25. 6. Yaacob H, Jalil R. An unusual hypersensitivity reaction to chlorhexidine. J Oral Med 1986;41(3):145-6. 7. Addy M, Moran JM. Clinical indications for the use of chemical adjuncts to plaque control: chlorhexidine formulations. Periodontol 2000 1997;15:52-4. 8. Albandar J, Gjermo P, Preus HR. Chlorhexidine use after two decades of over-the-counter availability. J Periodontol 1994;65(2): 109-12. 9. Grossman E, Reiter G, Sturzenberger O, et al. Six-month study of
the effects of a chlorhexidine mouthrinse on gingivitis in adults. J Periodontal Res 1986;21(supplement):33-43. 10. Siegrist B, Gusberti F, Brecx M, Weber H, Lang N. Efficacy of supervised rinsing with chlorhexidine digluconate in comparison to phenolic and plant alkaloid compounds. J Periodontal Res 1986;21 (supplement):60-73. 11. al-Tannir MA, Goodman HS. A review of chlorhexidine and its use in special populations. Spec Care Dentist 1994;14(3):116-22. 12. Ashoe-Jorgensen V, Attstrom R, Lang N, Loe H. Effect of chlorhexidine dressing on healing after periodontal surgery. J Dent Resh 1972;51(supplement 5):314. 13. Beiswanger BB, Mallat ME, Jackson RD, et al. Clinical effects of 0.12% chlorhexidine rinse as an adjunct to scaling and root planing. J Clin Dent 1992;3(2):33-8. 14. Jenatschke F, Elsenberger E, Welte HD, Schlagenhauf U. Influence of repeated chlorhexidine varnish applications on mutans streptococci counts and caries increment in patients treated with fixed orthodontic appliances. J Orofac Orthop 2001;62(1):36-45. 15. Flotra L. Different modes of chlorhexidine application and related local side effects. J Periodontal Res Suppl 1973;12:41-4. 16. Ciancio SG. Chemotherapeutics in periodontics. Dent Clin North Am 1980;24(4):813-26. 17. Hamill MB, Osato MS, Wilhelmus KR. Experimental evaluation of chlorhexidine gluconate for ocular antisepsis. Antimicrob Agents Chemother 1984;26(6):793-6. 18. Bendig JW. Surgical hand disinfection: comparison of 4% chlorhexidine detergent solution and 2% triclosan detergent solution. J Hosp Infect 1990;15(2):143-8. 19. Rosenberg A, Alatary SD, Peterson AF. Safety and efficacy of the antiseptic chlorhexidine gluconate. Surg Gynecol Obstet 1976;143(5):789-92. 20. Jones JA, Miller DR, Wehler CJ, et al. Study design, recruitment, and baseline characteristics: the Department of Veterans Affairs Dental Diabetes Study. J Clin Periodontol 2007;34(1):40-5. 21. Cutress TW, Ainamo J, Sardo-Infirri J. The community periodontal index of treatment needs (CPITN) procedure for population groups and individuals. Int Dent J 1987;37(4):222-33. 22. Jones JA, Miller DR, Wehler CJ, et al. Does periodontal care improve glycemic control? The Department of Veterans Affairs Dental Diabetes Study. J Clin Periodontol 2007;34(1):46-52. 23. International classification of diseases, 9th revision, clinical modification. 5th ed. Salt Lake City: Medicode; 1996. 24. Selim AJ, Fincke G, Ren XS, et al. Comorbidity assessments based on patient report: results from the Veterans Health Study. J Ambul Care Manage 2004;27(3):281-95. 25. Fincke BG, Clark JA, Linzer M, Spiro A 3rd, et al. Assessment of long-term complications due to type 2 diabetes using patient selfreport: the diabetes complications index. J Ambul Care Manage 2005;28(3):262-73. 26. U.S. Department of Veterans Affairs. Reporting unanticipated problems and adverse events to institutional review boards; 2006. Available at: “www1.va.gov/oro/docs/Memo-UPR-AERpts-12-06-06.rtf”. Accessed Jan. 7, 2008. 27. Atchison KA, Dolan TA. Development of the Geriatric Oral Health Assessment Index. J Dent Educ 1990;54(11):680-7. 28. Löe H, Schiott CR, Karring G, Karring T. Two years oral use of chlorhexidine in man, I: general design and clinical effects. J Periodontal Res 1976;11(3):135-44. 29. Lang NP, Hase JC, Grassi M, et al. Plaque formation and gingivitis after supervised mouthrinsing with 0.2% delmopinol hydrochloride, 0.2% chlorhexidine digluconate and placebo for 6 months. Oral Dis 1998;4(2):105-13. 30. Hase JC, Attstrom R, Edwardsson S, Kelty E, Kisch J. 6-month use of 0.2% delmopinol hydrochloride in comparison with 0.2% chlorhexidine digluconate and placebo, I: effect on plaque formation and gingivitis. J Clin Periodontol 1998;25(9):746-53. 31. Ernst CP, Prockl K, Willershausen B. The effectiveness and side effects of 0.1% and 0.2% chlorhexidine mouthrinses: a clinical study. Quintessence Int 1998;29(7):443-8. 32. United States Department of Veterans Affairs. VA Programs for women veterans: demographic trends; 2007. Available at: “www1. va.gov/wvhp/page.cfm?pg=26”. Accessed Dec. 12, 2007.
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Adverse events associated with chlorhexidine use Results from the Department of Veterans Affairs Dental Diabetes Study Linda C. McCoy, RDH, MS; Carolyn J. Wehler, RDH, MPH; Sharron E. Rich, MPH; Raul I. Garcia, DMD, MMedSc; Donald R. Miller, ScD; Judith A. Jones, DDS, MPH, DScD
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Background. The authors report adverse events (AEs) related to the use of chlorhexidine gluconate N C U mouthrinse in a clinical trial of the efficacy of periA ING EDU 4 odontal treatment in older adults with diabetes. RT ICLE Methods. Participants were U.S. veterans with uncontrolled diabetes (hemoglobin A1c value ≥ 8.5 percent) and periodontal disease. Treatment included periodontal scaling, 0.12 percent chlorhexidine lavage during ultrasonic scaling and use of chlorhexidine mouthrinse at home. Results. Forty-four (31 percent) of 140 subjects reported having AEs. Most common were taste changes and tooth staining, sore mouth and/or throat, tongue irritation and wheezing/shortness of breath; the latter was reported more commonly before chlorhexidine use than after. Only body mass index greater than 30 was significantly related to AEs. Conclusions. AEs are common among subjects using chlorhexidine mouthrinse. Most AEs (taste change and staining) were resolved easily by subjects’ discontinuing mouthrinse use and receiving dental prophylaxis. No serious AEs were reported. Clinical Implications. Clinicians should advise patients using chlorhexidine mouthrinse of possible side effects. If necessary, patients should discontinue mouthrinse use and obtain medical care. Careful monitoring of AEs in patients using chlorhexidine is warranted. Key Words. Chlorhexidine gluconate; mouthrinse; periodontal disease; diabetes. JADA 2008;139(2):178-83. I
DISCLOSURE: Dr. Miller received research funding from Sanofi-Aventis, Bridgewater, N.J.; Merck & Co., Whitehouse Station, N.J.; and GlaxoSmithKline, Research Triangle Park, N.C.
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CON
ntimicrobial agents, such as chlorhexidine gluconate, are used often as an adjunctive therapy for periodontal treatment.1-3 Since the 1970s, chlorhexidine has been used successfully in dentistry.2,4 An effective bactericidal agent against gramnegative and gram-positive organisms, as well as against yeasts and other organisms,2,4-7 chlorhexidine is considered the gold standard of antimicrobial mouthrinses in dentistry.2 Dental applications include use as a mouthrinse,2,8-10 bactericidal spray for topical use,7 preoperative irrigation,8 denture disinfectant for systemic candidiasis,8,11 impregnation of surgical dressings,12 lavage during periodontal procedures7,13 and use as a postsurgical rinse.7 Dental delivery systems include periodontal chips,3 varnish,14 gel and dentifrices.15,16 Some nondental applications include aqueous solutions for topical ophthalmic use,17 surgical skin disinfectant18,19 and use in burn treatment.1,5 Any use of chlorhexidine, or any other medications, carries with it the risk of experiencing adverse events (AEs).
Ms. McCoy is a health science specialist, Center for Health Quality, Outcomes and Economic Research, Edith Nourse Rogers Memorial Veterans Hospital, 200 Springs Road (152), Bedford, Mass. 01730, e-mail “[email protected]”. Address reprint requests to Ms. McCoy. Ms. Wehler is an assistant professor, Boston University Goldman School of Dental Medicine. Ms. Rich is a senior analyst, Boston University Goldman School of Dental Medicine. Dr. Garcia is the director, VA Dental Longitudinal Study, VA Boston Healthcare System, and a professor and chair, Department of Health Policy and Health Services Research, Boston University Goldman School of Dental Medicine. Dr. Miller is a senior research scientist, Center for Health Quality, Outcomes and Economic Research, Bedford, Mass., and an associate professor, Boston University School of Public Health. Dr. Jones is a professor and chair, Department of General Dentistry, Boston University Goldman School of Dental Medicine.
February 2008
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R E S E A R C H
Because we were conducting a clinical trial using chlorhexidine as an adjunctive therapy in the treatment of periodontal disease, we examined the rate of AEs in our study population. We report on the frequency of AEs related to the use of chlorhexidine in this clinical trial of periodontal treatment of U.S. veterans with poorly controlled diabetes and periodontal disease. SUBJECTS AND METHODS
The Department of Veterans Affairs Dental Diabetes Study20 is a randomized, single-blind, controlled clinical trial that examined periodontal treatment and the improvement in glycemic control among veterans with poorly controlled diabetes. The clinical portion of the study was conducted between December 2000 and November 2004. Institutional review boards at each of the four study facilities approved this study. Each participant gave written informed consent. The study staff (L.C.M., C.J.W., M. Puccio) recruited veterans with poorly controlled diabetes and periodontal disease from four Veterans Affairs (VA) medical centers in New England. All subjects had a hemoglobin A1c (HbA1c) value greater than or equal to 8.5 percent as well as periodontal disease. Inclusion criteria required that all subjects had Community Periodontal Index of Treatment Needs21 scores of 3.5 or greater in at least two sextants, meaning all had some form of chronic periodontitis, as well as eight or more teeth. Further information about the study sample is published elsewhere.22 The study hygienist (L.C.M.) administered periodontal therapy according to the study protocol, including ultrasonic scaling with subgingival lavage of 0.12 percent chlorhexidine; hand scaling; and adjunctive chemotherapy, including chlorhexidine mouthrinse (0.12 percent oral rinse twice per day for four months at home) and systemic doxycycline (100 milligrams per day for 14 days). The study staff gave subjects oral and written instructions regarding how to take each medication, told them of the known side effects and instructed them to report any side effects immediately. Subjects completed surveys at baseline about existing symptoms and at follow-up about AEs they experienced. When they reported experiencing an AE, subjects were told to stop taking the medication (that is, the chlorhexidine and/or the doxycycline) immediately. The list of AEs provided to participants included all previously
reported, known side effects of chlorhexidine use. AE incidence. The primary outcome of interest for this report was the incidence of AEs among subjects using chlorhexidine in the dental diabetes study.20 In distinguishing AEs associated with chlorhexidine from those associated with the other study drug (doxycycline), we noted that the possible symptoms associated with each drug are unique. In addition, subjects used chlorhexidine for a much longer period (four months) than they did doxycycline (14 days). Thus, we attributed all AEs reported after the doxycycline therapy ended to chlorhexidine use (when reported on the fourmonth follow-up questionnaire or as obvious symptoms appeared, whichever occurred sooner). Because subjects took doxycycline for only 14 days, we expected that any AEs attributable to this medication would develop in less than one month. Only 7 percent of subjects reported an AE in the first month of chlorhexidine use; therefore, we are confident that the information regarding these AEs can be attributed to chlorhexidine therapy. All AEs were self-reported. We obtained data regarding demographics, HbA1c levels and diagnostic codes23 for comorbid medical conditions from the VA outpatient clinic file and the VA computerized patient record system. From the lists of comorbid medical conditions, we calculated the Selim comorbidity index (CI),24 a measure of disease burden, and the Diabetes Complications Index (DCI),25 a measure of the severity of diabetes. The DCI is a sum of diabetes complications, including microvascular, macrovascular and metabolic conditions. Baseline data collection. The study’s calibrated hygienist (C.J.W.) assessed the subject’s periodontal condition during clinical examinations. She obtained baseline symptom data from subjects during interviews in which she asked if they had experienced the symptoms listed in Table 1. These data are available for only a subset of the sample, however, because midway through the study, we recognized that the rates of AEs were higher than expected. In response, we added a list of questions about the occurrence of symptoms (that is, known side effects associated
ABBREVIATION KEY. AE: Adverse event. BMI: Body mass index. CI: Comorbidity index. DCI: Diabetes Complications Index. HbA1c: Hemoglobin A1c. VA: Veterans Affairs.
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TABLE 1
Self-reported adverse events, according to symptom. SYMPTOM AT FOLLOW-UP
NO. OF SUBJECTS REPORTING ADVERSE EVENT
AMONG SUBJECTS USING CHLORHEXIDINE (N = 140) (% OF SUBJECTS)
AMONG SUBJECTS REPORTING ADVERSE EVENT (n = 44) (% OF SUBJECTS)
BASELINE GROUP (n = 63)† NO. (%) OF SUBJECTS*
Taste Changes
27
19.3
61.4
2 (3.2)†
Stain: Teeth/Tongue/Dentures
26
18.6
59.1
6 (9.5)
Sore Mouth/Tongue/ Throat
10
7.1
22.7
18 (28.6)‡
Tongue-Tip Irritation
10
7.1
22.7
5 (7.9)
Wheezing/Shortness of Breath
10
7.1
22.7
20 (31.7)‡
Nasal Congestion
9
6.4
20.4
27 (42.9)‡
Swelling of Face/Lips/ Throat
6
4.3
13.6
5 (7.9)
Skin Rash/Hives/Itching
6
4.3
13.6
20 (31.7)‡
Swollen Glands
5
3.6
11.4
2 (3.2)
Increased Calculus
5
3.6
11.4
6 (9.5)
Diarrhea
3
2.1
6.8
14 (22.2)‡
Nausea/Burning/ Upset Stomach
3
2.1
6.8
14 (22.2)‡
Loss of Appetite
3
2.1
6.8
0
Itching Mouth
3
2.1
6.8
7 (11.1)
Abdominal Pain
1
0.7
2.3
7 (11.1)†
* Baseline comparison group versus all subjects using chlorhexidine. † P < .001. ‡ P < .0001.
with chlorhexidine) to the baseline data collection to facilitate comparisons at follow-up. Baseline and follow-up surveys. We should point out that the two questionnaires were worded and administered slightly differently. The baseline survey asked if the subject had had symptoms within the last four weeks. The dental hygienist administered the survey via an inperson interview. The follow-up survey stated no time frame with regard to the duration of symptoms, but it asked whether the subject currently had any symptoms. We administered the followup survey via a self-reported questionnaire. We obtained additional study data from the selfreported questionnaires. We entered clinical data into a laptop computer at chairside and later synchronized the data to the database. Statistical analyses included the use of t tests, χ2 tests or the Fisher exact test, as appropriate; 180
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frequency distributions; multiple variable logistic regression; and power calculations with the use of statistical software (SAS, version 9.1.3, SAS Institute, Cary, N.C.). We used P < .05 as a cutoff for statistical significance and P < .15 to indicate trends. RESULTS
One hundred forty subjects used chlorhexidine for four months (mean age, 59.5 years; 96.4 percent were male). Of these, 44 (31.4 percent) reported that they experienced AEs. No serious AEs were reported. The U.S. Department of Veterans Affairs defines serious AEs as “unanticipated problems involving risks needing medical or surgical intervention to prevent a life-threatening experience.”26 The most common AEs reported were taste changes (27 [19.3 percent] of 140 subjects) and stains on the teeth, tongue and/or den-
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R E S E A R C H
tures (26 [18.6 percent] of 140) (Table 1). Sore mouth, sore tongue and/or throat and tongue-tip irritation were reported by 10 subjects each (7.1 percent). Ten subjects (7.1 percent) also reported wheezing and shortness of breath. For comparison with the follow-up findings, we asked 63 subjects at baseline whether they had had any AE symptoms within the previous four weeks. We compared these subjects with all subjects using chlorhexidine with regard to age, race, education, type of diabetes medications taken and baseline HbA1c levels, and we found no differences. When we compared the incidence of each symptom of note (sore mouth, tongue and/or throat; wheezing and/or shortness of breath; nasal congestion; diarrhea; nausea, burning and/or upset stomach; abdominal pain; skin rash, hives and/or itching), we found that they all were significantly more common among those queried at baseline than they were at follow-up. However, subjects reported taste changes significantly more often at follow-up than at baseline. Table 224,25,27 shows comparisons between subjects who reported having an AE and those who did not. Subjects reporting an AE were less likely to have a high body mass index (BMI) (> 30) (56.8 percent of those with an AE had a high BMI versus 74.7 percent of those without an AE had a high BMI) (P = .03). BMI remained significant even after we performed multiple variable logistic regression analyses. We adjusted for covariates that showed a trend toward significance at the P < .20 level (that is, number of prescriptions, mouthrinse use, problems taking medications, CI, DCI and number of teeth). Of interest is our finding in the multiple variable logistic regression that DCI and use of any mouthrinse also were associated significantly with AEs. Nonsignificant trends are reported in Table 2; however, we have insufficient power to detect differences using the small numbers in the study. To detect significant differences at α = .05 and a power of .80, we would need between 150 and 400 subjects per group, except for self-reported general health and drug abuse, for which 1,600 to 7,000 subjects would be needed per group. There were no differences between the study groups or study sites. In addition, no subjects withdrew from the study owing to chlorhexidine use. DISCUSSION
AEs were common in medically compromised veterans with poorly controlled diabetes treated
with chlorhexidine mouthrinse in this clinical trial of periodontal care and its effects on glycemic control. The results show a high incidence of taste changes and oral stains, which are consistent with known AEs associated with this drug.9,28-31 We also observed sore mouth, tongue and/or throat, tongue-tip irritation and wheezing or shortness of breath in 7.1 percent of subjects. However, it is unclear whether this group of symptoms was caused by chlorhexidine, because they were almost as commonly reported or more commonly reported at baseline. Chlorhexidine use, while eliciting AEs, was reasonably welltolerated in this clinical trial of adults who had diabetes with poor glycemic control and multiple comorbidities. Subjects who experienced AEs were less likely to have a BMI greater than 30. It is unclear why this is so. Nonsignificant trends showed that subjects with AEs were more likely to have more comorbidities than other subjects, have more complications from diabetes, report pre-existing allergies, experience problems taking other medications and need prophylactic antibiotics before dental procedures. At baseline, they also had more teeth and were more likely to use mouthrinses than were other subjects. Finally, more nondrinkers and heavy drinkers (as opposed to moderate drinkers) were in the group that experienced AEs. Baseline versus follow-up symptoms. When comparing baseline symptoms with those at follow-up, we found that many symptoms had a higher incidence at baseline. This may be due to the variation in the way the questions were worded and the surveys were administered. The baseline survey asked if the subject had had symptoms within the last four weeks and was administered via an in-person interview, while the follow-up survey stated no time frame and was administered via a self-reported questionnaire. We did not use a placebo, because this study was not designed to evaluate the effectiveness of mouthrinse, but rather the effectiveness of periodontal treatment in improving glycemic control in subjects with poorly controlled diabetes. Thus, one cannot infer that any AEs reported by subjects in our study stemmed from chlorhexidine use alone, but could have arisen from other ingredients in the mouthrinse (for example, alcohol, flavoring). Given the relative frequency with which we observed such AEs as wheezing and shortness of breath, a placebo-controlled trial
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TABLE 2
Selected subject characteristics at baseline,* by AE† status. NO. OF SUBJECTS (N = 140)
MEAN (SD‡) OR PERCENT OF SUBJECTS§
AEs = NO, % OF SUBJECTS§ (n = 96)
AEs = YES, % OF SUBJECTS§ (n = 44)
Mean Age, Years
140
59.5 (11.0)
59.2
60.4
Married Subjects
139
54.7
55.8
52.3
White Subjects
138
84.8
83.0
88.6
53 83
39.0 61.0
38.7 61.3
39.5 60.5
Male Subjects
140
96.4
97.9
93.2
Took Both Study Medications (Chlorhexidine and Doxycycline)
140
90.7
89.6
93.2
Total No. of Medications Taken
131
9.1 (4.8)
8.8
9.6
Self-Reported Allergies to Any Medications
137
16.8
12.9
25.0¶
Any Medications That Cause Problems
136
17.6
14.1
25.0#
Takes Antibiotics Before Dental Treatment (Self-Reported)
135
28.9
23.9
39.5¶
Mouthrinse Use (Prescription)
137
6.6
4.3
11.4#
Mouthrinse Use (Nonprescription)
138
70.3
66.0
79.6#
Diabetes Medications: Takes Insulin and Oral Medications
136
26.5
29.4
20.4
Alcohol Consumption # Nondrinker < 1 drink/day ≥ 1 drink/day
80 45 12
58.4 32.8 8.8
55.9 37.6 6.4
63.6 22.7 13.6
Smoking Status Current Former Never
25 72 30
19.7 56.7 23.6
17.2 56.3 26.4
25.0 57.5 17.5
Mean Body Mass Index (BMI)
139
33.1 (6.6)
33.8
31.7¶
BMI > 30
139
69.1
74.7
56.8**
BMI < 25
139
10.1
7.4
15.9#
Selim Comorbidity Index 24
140
5.7 (3.2)
5.4
6.3¶
Self-Reported Poor General Health (GH1 ††)
136
44.8
44.1
46.5
Diabetes Complications Index 25
140
2.7 (1.8)
2.5
3.1¶
Geriatric Oral Health Assessment Index 27
137
30.1 (4.3)
30.0
30.4
Hemoglobin A 1c Level, Percent
140
9.7 (1.3)
9.7
9.6
Total No. of Teeth
140
20.9 (6.1)
20.2
22.2¶
% of Sites With Pockets > 3 mm ‡‡
139
13.5 (14.9)
14.3
11.8
% of Sites With Pockets > 5 mm
139
2.5 (5.4)
2.6
2.3
Mean Loss of Attachment, mm
139
3.2 (1.1)
3.2
3.0
Mean Loss of Attachment (Change From Baseline to Follow-Up), mm
126
-0.2 (0.3)
-0.2
-0.2
Mean Probing Depth, mm
139
2.4 (0.6)
2.5
2.4
Mean Probing Depth (Change From Baseline to Follow-Up ), mm
127
-0.3 (0.3)
-0.3
-0.3
Total No. of Periodontal Treatments
139
1.6 (1.0)
1.7
1.5
VARIABLE
Education At least some high school At least some college
* † ‡ § ¶ # ** †† ‡‡
Unless otherwise stated. AE: Adverse event. SD: Standard deviation. Unless otherwise stated. P < .1. P < .15. P < .05. GH1: General Health Exam 1 (from study survey). mm: Millimeter.
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among medically compromised older adults may be warranted. Study limitations. One limitation of this study is that there were few women in the sample as a result of the nature of the VA population (10.26 percent female).32 Another limitation is that we collected baseline symptom data only after observing a high rate of AEs among subjects at follow-up. As a result, we have baseline data for only 45 percent of subjects and cannot make strong comparisons between those who reported baseline symptoms and those who did not. Any future studies should collect baseline data for all participants. CONCLUSION
Clinicians must carefully and completely advise patients who use chlorhexidine, in any form, of possible side effects. They should request that patients report any symptoms to their health care providers, immediately discontinue use when side effects arise, and obtain medical care when necessary. Careful monitoring of AEs in patients using chlorhexidine is warranted, particularly among those with multiple medical conditions and a history of allergies or breathing problems. ■ The views expressed in this article are strictly those of the authors and do not represent the views of the U.S. Department of Veterans Affairs. This study was supported by grants VA HSR&D QUERI DII-99.206, NIH K24-DEO18211, NIH K24-DEOO419 and VA CSP #711 and by Boston University Goldman School of Dental Medicine. Questionnaires used in this study are available from Ms. McCoy on request. 1. Fardal O, Turnbull RS. A review of the literature on use of chlorhexidine in dentistry. JADA 1986;112(6):863-9. 2. Jones CG. Chlorhexidine: is it still the gold standard? Periodontol 2000 1997;15:55-62. 3. Killoy W. The use of locally delivered chlorhexidine in the treatment of periodontitis: clinical results. J Clin Periodontol 1998;25(11 part 2):953-8. 4. Löe H, Schiott CR. The effect of mouthrinses and topical application of chlorhexidine on the development of dental plaque and gingivitis in man. J Periodontal Res 1970;5(2):79-83. 5. Flotra L, Gjermo P, Rolla G, Waerhaug J. Side effects of chlorhexidine mouth washes. Scand J Dent Res 1971;79(2):119-25. 6. Yaacob H, Jalil R. An unusual hypersensitivity reaction to chlorhexidine. J Oral Med 1986;41(3):145-6. 7. Addy M, Moran JM. Clinical indications for the use of chemical adjuncts to plaque control: chlorhexidine formulations. Periodontol 2000 1997;15:52-4. 8. Albandar J, Gjermo P, Preus HR. Chlorhexidine use after two decades of over-the-counter availability. J Periodontol 1994;65(2): 109-12. 9. Grossman E, Reiter G, Sturzenberger O, et al. Six-month study of
the effects of a chlorhexidine mouthrinse on gingivitis in adults. J Periodontal Res 1986;21(supplement):33-43. 10. Siegrist B, Gusberti F, Brecx M, Weber H, Lang N. Efficacy of supervised rinsing with chlorhexidine digluconate in comparison to phenolic and plant alkaloid compounds. J Periodontal Res 1986;21 (supplement):60-73. 11. al-Tannir MA, Goodman HS. A review of chlorhexidine and its use in special populations. Spec Care Dentist 1994;14(3):116-22. 12. Ashoe-Jorgensen V, Attstrom R, Lang N, Loe H. Effect of chlorhexidine dressing on healing after periodontal surgery. J Dent Resh 1972;51(supplement 5):314. 13. Beiswanger BB, Mallat ME, Jackson RD, et al. Clinical effects of 0.12% chlorhexidine rinse as an adjunct to scaling and root planing. J Clin Dent 1992;3(2):33-8. 14. Jenatschke F, Elsenberger E, Welte HD, Schlagenhauf U. Influence of repeated chlorhexidine varnish applications on mutans streptococci counts and caries increment in patients treated with fixed orthodontic appliances. J Orofac Orthop 2001;62(1):36-45. 15. Flotra L. Different modes of chlorhexidine application and related local side effects. J Periodontal Res Suppl 1973;12:41-4. 16. Ciancio SG. Chemotherapeutics in periodontics. Dent Clin North Am 1980;24(4):813-26. 17. Hamill MB, Osato MS, Wilhelmus KR. Experimental evaluation of chlorhexidine gluconate for ocular antisepsis. Antimicrob Agents Chemother 1984;26(6):793-6. 18. Bendig JW. Surgical hand disinfection: comparison of 4% chlorhexidine detergent solution and 2% triclosan detergent solution. J Hosp Infect 1990;15(2):143-8. 19. Rosenberg A, Alatary SD, Peterson AF. Safety and efficacy of the antiseptic chlorhexidine gluconate. Surg Gynecol Obstet 1976;143(5):789-92. 20. Jones JA, Miller DR, Wehler CJ, et al. Study design, recruitment, and baseline characteristics: the Department of Veterans Affairs Dental Diabetes Study. J Clin Periodontol 2007;34(1):40-5. 21. Cutress TW, Ainamo J, Sardo-Infirri J. The community periodontal index of treatment needs (CPITN) procedure for population groups and individuals. Int Dent J 1987;37(4):222-33. 22. Jones JA, Miller DR, Wehler CJ, et al. Does periodontal care improve glycemic control? The Department of Veterans Affairs Dental Diabetes Study. J Clin Periodontol 2007;34(1):46-52. 23. International classification of diseases, 9th revision, clinical modification. 5th ed. Salt Lake City: Medicode; 1996. 24. Selim AJ, Fincke G, Ren XS, et al. Comorbidity assessments based on patient report: results from the Veterans Health Study. J Ambul Care Manage 2004;27(3):281-95. 25. Fincke BG, Clark JA, Linzer M, Spiro A 3rd, et al. Assessment of long-term complications due to type 2 diabetes using patient selfreport: the diabetes complications index. J Ambul Care Manage 2005;28(3):262-73. 26. U.S. Department of Veterans Affairs. Reporting unanticipated problems and adverse events to institutional review boards; 2006. Available at: “www1.va.gov/oro/docs/Memo-UPR-AERpts-12-06-06.rtf”. Accessed Jan. 7, 2008. 27. Atchison KA, Dolan TA. Development of the Geriatric Oral Health Assessment Index. J Dent Educ 1990;54(11):680-7. 28. Löe H, Schiott CR, Karring G, Karring T. Two years oral use of chlorhexidine in man, I: general design and clinical effects. J Periodontal Res 1976;11(3):135-44. 29. Lang NP, Hase JC, Grassi M, et al. Plaque formation and gingivitis after supervised mouthrinsing with 0.2% delmopinol hydrochloride, 0.2% chlorhexidine digluconate and placebo for 6 months. Oral Dis 1998;4(2):105-13. 30. Hase JC, Attstrom R, Edwardsson S, Kelty E, Kisch J. 6-month use of 0.2% delmopinol hydrochloride in comparison with 0.2% chlorhexidine digluconate and placebo, I: effect on plaque formation and gingivitis. J Clin Periodontol 1998;25(9):746-53. 31. Ernst CP, Prockl K, Willershausen B. The effectiveness and side effects of 0.1% and 0.2% chlorhexidine mouthrinses: a clinical study. Quintessence Int 1998;29(7):443-8. 32. United States Department of Veterans Affairs. VA Programs for women veterans: demographic trends; 2007. Available at: “www1. va.gov/wvhp/page.cfm?pg=26”. Accessed Dec. 12, 2007.
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