Evaluation of intra-alveolar chlorhexidine dressings after removal of impacted mandibular third molars Pete G. Fotos, DDS, PhD, L%L!?,~ Gerard F. Koorbusch, DDS, LVBA,~ Daniel S. Sarasin, DDS,’ and Richard J. Kist, DDS,d Iowa City, Iowa, and Charleston, S.C. UNIVERSITY

OF IOWA COLLEGE

OF DENTISTRY

AND MEDICAL

UNIVERSITY

OF SOUTH

CAROLINA Chlorhexidine gluconate (CHX) has been investigated for its possible benefit in the prevention of alveolar osteitis complicating third molar removal. In a double-blind, placebo-controlled clinical study, 70 randomly selected healthy patients were subjected to uncomplicated mandibular third molar removal followed by CHX-gelatin sponge and saline solution-gelatin sponge intra-alveolar dressings. Each patient was followed for 6 days for postoperative discomfort and complications, and scored accordingly. The results demonstrated that patients receiving 0.2% CHX intra-alveolar dressings exhibited a significant reduction in postoperative discomfort and complications when compared with saline solution-treated control sites (p < 0.005). Further, this phenomenon was not found to be related to patient factors including age, sex, and race, nor did any correlation exist between treated or control sites, and surgical factors including performing surgeon, surgeon’s dominant hand, time of surgery, surgical site, and difficulty of the removal. These findingIs warrant further studies concerning the apparent clinical benefit of postextraction intra-alveolar CHX dressings for the reduction of postoperative alveolar osteitis. (ORAL SURC ORAL MED ORAL PATHOL 1992;73:383-8)

P

ostextraction alveolar osteitis (AO) is a relatively common local complication that can occur after any tooth extraction in the permanent dentition.lm4 After the surgical removal of third molar teeth from the mandible, the incidence of A0 has been reported to occur in up to 30% of such surgical sites, depending on the factors used to identify this condition.‘, 3 Clinically, postoperative: discomfort can range from simple local inflammation to classic AO, including haliSupported by the DOW’S Institute for Dental Research and the University of Iowa. College of Dentistry. Preliminary report presented at the annual meeting of the American Academy of Oral alnd Maxillofacial Surgery, Sept. 9, 1989, San Francisco, Calif. aProfessor, Department of Oral Pathology, Radiology, and Medicine, University of Iowa College of Dentistry. bAssistant Professor, Department of Oral and Maxillofacial Surgery, University of Iowa College of Dentistry. CResident, Oral and Maxillofacial Surgery, Medical University of South Carolina. din private practice, Clinton, Iowa. 7/17/30287

tosis, regional trismus, and dull throbbing pain. A variety of causes have been suggested for unusual postoperative discomfort and AO, including foreign body responses,4, 5 organic disease,4>6 nutritional factors,7-9 drug therapy,tO surgical technique,2r 4, It, I2 and poor postoperative care.t3, l4 However, the strongest body of evidence points to the role of microbial inhabitants of the oral cavity, belonging specifically to the genus Treponema, and their possible role in causing premature clot lysis. 2, I53l6 The reduction of normal oral flora before oral surgery has been shown to mitigate postextraction symptoms.17>I* Consistent with the strongly suspected microbial pathogenesis of AO, a variety of antibacterial therapeutic modalities have been studied in clinical trials to determine an acceptable preventive routine for use after extraction.‘9-26 Of particular interest is the past use of chlorhexidine (CHX) as an antimicrobial mouthrinse.25-33 CHX digluconate (a polybiguanide) is water soluble and readily dissociates, releasing the positively

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charged CHX at physiologic pH. The bacteriocidal effect of the drug is due to cationic molecular binding to extramicrobial complexes and negatively charged microbial cell walls. This has a net effect of altering the osmotic equilibrium of the cell, resulting in electrolyte loss followed by cell lysis.34-35The safety of CHX use in laboratory animals and in human beings has been well documented. This agent is poorly absorbed after oral administration, is well tolerated after parenteral administration, and exhibits minimal percutaneous absorption, with 90% being excreted in feces and the remainder eliminated through the urinary tract. Extrapolation of experimental data from rodent studies suggestthat the median lethal dose in human beings for CHX is approximately 126,000 mg.37The daily use of mouthrinses for as long as 2 years has not demonstrated any significant hematologic or immunologic changesin healthy human subjects.38 Furthermore, investigations into the mutagenic potential of CHX with rodent models at CHX concentrations 200 times the chemically therapeutic concentration used in oral rinse therapy have also failed to provide sufficient reason for concern.37M40 The broad antimicrobial spectrum of CHX is enhanced through its ability to bind to mucous membranes and to be subsequently released during a 12hour period.3’, 4* Now commercially available as an oral rinse in a 0.12% concentration, CHX has been suggestedfor the treatment of a wide variety of oral conditions including aphthous ulcers, sore mouth as a result of dentures, and gingivostomatisis; as a pronhylaxis in immunocompromised persons; and as an active component of periodontal dressings.29-34T 42-4s The primary disadvantages of CHX when used as an oral cavity includes the bitter taste and the potential for staining the dentition. Additionally, delays in wound healing have been reported with CHX concentrations greater than 0.2%, which suggeststhat in clinical applications CHX should be used at dilutions of 0.2% or less.46,47 Several studies have examined the use of CHX as an adjunctive treatment in periodontal therapy and to reduce postsurgical complications.3’, 34,43,48,49 The use of 0.12% CHX as a preoperative rinse before dental extractions also has been shown to transiently reduce both the total oral microflora and the number of postoperative complications, when usedin conjunction with systemic antibiotic therapy.25Studies on inflammatory exudates accompanying wound sites have shown reductions in leukocytes when CHX was used as a surgical irrigant. 5oInvestigations into the effects of CHX on alveolar bone have shown inhibition of resorption in rodent models.51$52CHX irrigation of periodontal defects produced in the root bifurcation of

posterior teeth of dogs aiso have demonstrated no adverse effect on connective tissue repair or alveolar bone regeneration.53A recent study comparing CHX with a surfactant (cetylpyridinium)-containing antimicrobial has also confirmed previous findings indicating the value of CHX for reducing postextraction A0.28 It has been suggestedthat a more direct application of CHX to the surgical site may produce a greater reduction of postoperative complications such as AO.S4 The potential for direct toxic or inflammatory responsesto CHX when placed in extraction sites has not been well studied, although a recent report has described six casesof immediate hypersensitivity reactions to CHX after topical dermal application.55 Therefore this investigation was designed to explored the benefits of CHX placement into postextraction sites immediately after surgery, to assessthe benefits of intra-alveolar delivery for reducing postoperative discomfort. MATERIAL

AND METHODS

Seventy patients seen at the University of Iowa College of Dentistry for elective mandibular third molar removal participated in this study. All subjects were fully informed as to the purpose and procedures planned and any perceived risks. All study participants were assuredthat any information gained about them would be kept completely confidential and not affect their dental treatment, according to the institutional guidelines for the use of human subjects. Medical histories were closely examined for the purpose of excluding persons who were medically compromised by systemic diseasesor medications. Patients seenfor bilateral mandibular third molar removal were selected from the general patient population at the college of dentistry. All patients seenfor removal of impacted teeth were asymptomatic at the time of surgery and had no acute inflammation or infection at the surgical sites. The seven participating oral and maxillofacial surgeonswere given two solutions to use for each case,one containing 2 ml of normal saline solution (0.9%) and the other containing either of two CHX concentrations (0.1% or 0.2%) diluted in pyrogen-free sterile water (Sigma Chemical Co., St. Louis, MO.). These were furnished in paired sterile single-dosevials, with each pair coded as to the identity of its contents (double-blind format). In a split-mouth placebo-controlled experimental design, each subject was treated at one extraction site with a saline solution control whereas the other site received CHX. Immediately after each extraction, the solutions were absorbed onto a 1 cm gelatin sponge (Gelfoam; Henry Schein Inc., Port Washing-

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Surgeon handedness Right Left Case difficulty Uncomplicated Mild difficulty Modera.te difficulty Severe difficullty Surgical site Right more difficult Left more dithcult Surgeon f.requency Surgeon 1 Surgeon 2 Surgeon 3 Surgeon 4 Surgeon 5 Surgeon 6 Surgeon 7 Surgical time (nun): Control site 45 Surgical time (nun): CHX site 45

385

Table II. Correlation

Table I. Surgical variables Variable

chlorhexidine

%*

coefficients between patient and surgical variables and surgical site discomfort

85 15 19 71

36 64 4 40 13 11 13 11 8 2 45 34 19

41 32 19

*n = 70 subjects, 14C1surgical sites.

ton, N.Y.) and placed into the surgical defects, followed by closure with sutures for retention. Identical po;stoperative instructions, provided for each test subject after surgery, consisted of abstention from smoking, the use of saline solution rinses, and a soft diet for 48 hours. Evaluation of the postsurgical benefits obtained through the use of each solution was assessedon the basis of a subjective rating (by the patient) of pain intensity and local inflammation, measured on a continuous scale of 0 through 5; lower scores denote less severe signs and symptoms. Postoperative signs and symptoms were also monitored and noted by the surgeons, and included pain, trismus, swelling, erythema, lymphadenopathy, and clot formation to sockNetgranulation characteristics. Scores were recorded by participating surgeons for a period of 5 days postoperatively for each extraction site on each patient. Secondary patient and surgical variables were also monitored to assure study validity. These included age,, sex, and race, and identity of surgeon, dominant handedness of the surgeon, surgical time, surgical site, and case difficulty (angle-position classification of the impaction, proximity to critical structures, difficulty in obtaining hemostasis, and

Variable Patient variables Sex Race Age Surgeon variables Surgical time at control site Surgical time at CHX site Surgeon handedness Operating surgeon Site difficulty Case difficulty

m

0.05 -0.15 -0.10

-0.22 -0.09 0.01

0.09

0.16

-0.16 0.15 0.14 -0.06 -0.29*

0.22 0.10 0.25 -0.11 0.25

*Significant negative correlation at p < 0.05, where n = 140.

unusual root curvature), which were all ranked by scores of 1 to 4. A comparison of postoperative signs and symptoms between placebo (saline solution-treated) sites and the CHX test sites at either concentration was carried out with a chi-square analysis (SAS, SAS Institute, Cary, N.C.). The difference between the two CHX concentrations was analyzed by Student’s t test (SAS). Secondary patient variables and surgical variables were evaluated with a Pearson product-moment correlation (SAS). RESULTS

The study population had a male/female ratio of approximately 1:2, a mean age of 22 years, and a median age of 30 years. Race was predominantly white (93%), and five patients were of Asian descent. Table I lists the percentages of patients or surgical sites falling under each surgical variable. Most surgeons were right handed, and left-sided surgical sites were generally perceived as more difficult procedures (64%). An comparison of mean scores across control and medicated sites reported by each surgeon were also compared. These means ranged from 1.1 to 3.2 and were not found to be significantly different. The procedure times for control and medicated sites were similar. No patient variable showed a significant correlation with either control or medicated site discomfort (Table II). There was a moderate, significant negative correlation (-0.29) between the surgical variable, case difficulty, and control site discomfort (p < 0.05) (Table II). No other surgical variables exhibited significant relationships to either control or medicated sites. Table III shows that no significant difference

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~RAL%JRG~RAL?v~ED

ORALPATHOL

March 1992

Table III. Postoperative complications between saline solution- and CHX-treated

I Medication Sterile saline 0.9% CHX 0.1% Sterile saline 0.9% CHX 0.2%

n

Mean discomfort* score {SD) 1.85 2.11 2.16 1.62

21 43

*Mean discomfort score range is 0 to 5, with 0 = no discomfort tSignificant difference by E &t (p < 0.005).

(1.58) (1.67) (1.64) (1.43)

third molar extraction sites

Mean difference

0.25 -0.53

p value

0.182 0.002t

and 5 = severe discomfort.

existed between the control sites that accompanied either CHX concentration. When both CHX medication groups (0.1% and 0.2%) were combined, no significant difference in postoperative discomfort was observed. The same was true when control site discomfort was compared with medicated sites treated with the lower CHX concentration (0.1%). However, the higher concentration (0.2%) resulted in significantly less discomfort (1.62) than the untreated control sites (2.16) (JJ < 0.005). DlSCUSSlON Many techniques have been advocated for the prevention of postoperative complications after third molar removal. Numerous clinical investigators have advocated the use of oral rinses, socket packing, intra-alveolar placement of medicaments or antibiotics, systemic antibiotics, ointments, and so forth. None of these procedures are without their own morbidity, nor are any so effective that their use has eliminated the presence of AO. This study has addressed the prevention of A0 on the assumption that its etiology is predominantly microbial.2> 15,t6 In view of past applications of antimicrobial agents for the treatment of oral diseases, the use of CHX as an intrasulcular dressing logically follows the recent clinical studies that suggest that such agents should be used with a vehicle and placed direct!y into the socket after dental extractions.28, 54 The intrasulcular placement of CHX obviates two of the potential problems in using this agent: its bitter taste and its potential for staining the dentition. Because the etiology of A0 remains somewhat controversial, the experimental design controlled for both patient and surgical variables that can be related to the frequency of complications associated with third molar removal. Attention was also taken to prevent potential bias induced by biologic variation and differences in individual pain perception, through the use of a split-mouth design for each CHX concentration used. Such considerations are especially important in sample sizes less than 100. In this research none of the patient surgical variables analyzed signif-

icantly contributed to the observed benefits obtained with 0.2% CHX-medicated sites. Interestingly, the 0.1% CHX concentration did not significantly reduce postoperative discomfort whereas the use of the higher 0.2% concentration was significantly efficacious in reducing these symptoms and often alleviating pain 24 to 48 hours sooner than control sites in the same patient (descriptive data not shown). The negative correlation between control sites and case difficulty also infers that the surgical sites receiving CHX were, on balance, the more difficult surgical procedures. One may speculate that a higher concentration of CHX might provide an even greater benefit. However, in vitro and in vivo studies have demonstrated that CHX in high concentrations is a cytotoxin and can produce delays in wound granulation and healing, respectively.46> 47,56,j7 F or these reasons the use of this agent at concentrations greater than 0.2% may require further experimental justification before human trials. Alternatively, one must consider that the total drug volume employed in this study was relatively low (2 ml) and that both the concentration and volume of CHX that remains in the wound defect are expected to decrease after placement, because of the local effects of salivary influx and intrasocket hemorrhage. Therefore the true drug delivery at the surgical site remains quantitatively vague after initial hemostasis (perhaps 30 minutes postoperatively). An additional area that requires further consideration is the use of gelatin sponge as the absorptive vehicle for CHX. Although essentially an inert material, several problems related to this material make it less than ideal for use in intra-alveolar CHX delivery. Gelatin sponge has a degree of hydrophobicity that precludes efficient absorption of CHX before intraalveolar placement. In addition, its structured (preshaped) form does not allow for passive placement to the full depth of the socket. A more appropriate vehicle may be microfibrillar or sponge bovine collagen. Future studies are currently under way to evaluate these alternatives further.

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Volume 73 Number 3

The efficacy of CHX cannot be fully assessedas an adjunctive agent in the prevention of A0 on the basis of this study. Larger numbers of patients must be treated with tlhe agent, and the results of this study replicated, before any long-term conclusions can be rendered on its use as an intra-alveolar dressing. However, the (data indicate that CHX holds promise as an intra-alveolar antimicrobial medicament for the reduction of postoperative AO. The use of CHX in combination with antibiotics or anti-inflammatory agents for intra-alveolar application may also deserve future evaluation in clinical designs similar to that employed in this study, to develop the most effective combination possible. We express gratitude to Drs. Kirk L. Fridrich, Bradly T. Porter, Scott A. Preisller, Bruce E. Rotter, Robert A. Rudman, Patrick J. Vezea.u, and John M. Wise for their interest and clinical participation, which helped make this research possible.

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Reprint requests: Pete G. Fotos, DDS, MS, PhD Department of Oral Pathology, Radiology, and Medicine University of Iowa College of Dentistry Iowa City, IA 52242