Keywords
chlorhexidine gel - wound healing - tooth extraction
Introduction
Tooth extraction is a very common procedure that dentists perform every single day.
Postoperative complication generally do not occur; however, occasionally delayed wound
healing may arise even in normal healthy patients. The most frequent postextraction
complications documented were infection, prolonged bleeding, swelling, as well as
dry socket.[1] In addition, patient may experience pain even after a simple uncomplicated tooth
extraction.[2]
[3]
Oral healing is slower and delayed compare with dermal repair.[4] Unlike skin surface, oral environment cannot be sterilized from oral bacteria or
plaque formation, leading to persistent environmental challenge for the oral wound.
Infection is one of the significant causes of delayed wound healing; therefore, early
period of healing after tooth extraction must be facilitated and protected from infection
or any condition inhibiting healing and repair.[5]
After the procedure is performed, the site of tooth extraction may serve as a niche
for bacterial plaque formation, due to the fact that patients cannot maintain good
oral hygiene.[6] Patients may have hesitation to brush the wound site due to the pain or discomfort
and may be instructed by dentist to avoid the brush to avoid hitting the extraction
socket. To inhibit bacterial plaque accumulation, several interventions have been
incorporated in postextraction procedures such as administration of antibiotics, mouthwashes,
or topical medications, thereby preventing infection and chronicity of the wound.[7]
[8]
Unfortunately, there is emerging situation of antimicrobial resistances caused by
antimicrobial abuse, especially from systemic antibiotic use. To overcome this problem,
topical antimicrobials in wound therapy are increasing in use.[9]
[10]
[11] In this method of therapy, topical antimicrobials are directly applied to the wound,
resulting in a high concentration at the wound site, low systemic side effects, and
a low incidence of antimicrobial resistance. One of topical antimicrobial agents recently
available in the market is chlorhexidine (CHX) digluconate. Over a period of 40 years,
CHX is widely used in dentistry and considered as an excellent antiplaque agent, due
to its high substantivity and broad antimicrobial spectrum. Several forms of CHX have
been prepared, that is, mouthwash, spray, chip, cement, varnish, dentifrice, and gel.[12]
[13] It has been found to have superior antimicrobial activity compared with other active
agents.[14] Nevertheless, disadvantages remain prominent, it was found that CHX in the form
of mouthwash showed the most common side effect of tooth restoration and tongue staining.[15]
[16] In addition, there is some evidence that regular and frequent application of CHX
mouth rinses may temporarily impair the taste sensation, and promotes supragingival
calculus formation and desquamative lesion of oral mucous.[17] Other disadvantage that may occur that is rinsing 24 hours after tooth extraction
may dislodge blood clot that forms in the socket; therefore, a method of administration
of CHX that may enhance and facilitate wound healing after tooth extraction is needed.[18]
Topically applied CHX gel (Perio-Kin) has been proven to enhance wound healing in
rats both at the clinical and histological levels without any adverse effect.[19] The use of the gel preparation had also been shown to reduce the incidence of dry
sockets after third molar extraction; nevertheless, the method of treatment could
only be performed by the surgeon.[20] The present study aimed to evaluate the effect of 0.2% CHX gel on early wound healing
after tooth extraction of mandibular first molar, applied topically on the top of
the wound site by the patients.
Materials and Methods
The study design was a single blind, randomized controlled trial (RCT). The period
of the trial was from August to December 2019, and the study protocol was registered
in February 2021 at UMIN clinical trial registry with clinical trial registration
number UMIN000043357. The participants consisted of 32 healthy nonsmokers who were
about to undergo unilateral extraction of mandibular first molar at the Oral Minor
Surgery Outpatients Ward of Dental Hospital, Universitas Padjadjaran, Bandung, West
Java, Indonesia. Sample size calculation was performed by using the following formula:
(r − 1) (t − 1) ≥ 15, where t is the number of groups and r is the number of samples.
Therefore, the number of subjects was 16 participants for each group.
Prior to the start of the study, ethical clearance was obtained from the Research
Ethics Committee Faculty of Medicine Universitas Padjadjaran, Bandung, Indonesia (1497/UN6.KEP/EC/2018).
Every procedure and ethical aspect of the current research has been conducted in full
accordance with the World Medical Association's Declaration of Helsinki, and all participants
gave their consent for their participation in the current study. Inclusion criteria
of eligible participants were as follows: (1) patients who underwent tooth extraction
of mandibular first molar, (2) aged 18 to 50 years with American Society of Anesthesiologists
(ASA) physical status I, (3) did not have the medical history of being allergic to
CHX and mefenamic acid, (4) was not consuming any other antibiotic, analgesic or anti-inflammation
drug(s) at least 7 days prior to the procedure, (5) lack of infection at the tooth
indicated for extraction 3 days prior to the extraction procedure, and (6) absence
of any pathology at the area of the tooth indicated for extraction and neighboring
teeth. Participants with medically compromised condition, being pregnant, or with
tooth requires surgical extraction were excluded from the study.
Participants who fulfilled the inclusion criteria were then divided randomly into
one of the following groups: the test group that received topical administration of
0.2% CHX digluconate gel (Perio-kin, Laboratorios Kin S.A., Barcelona, Spain) and
500 mg of mefenamic acid or the control group that received topical administration
of placebo gel (Carboxymethyl Cellulose Sodium, glycerin, and aquadest) and 500 mg
of mefenamic acid. Randomization was performed by taking a closed envelope containing
the name of the group to which the participant was assigned to. The field researcher
(T.M.) was responsible for this procedure and supervised each randomization procedure.
After the participant was assigned to a group, the field researcher made the necessary
record in confidential in the research database.
All participants underwent dental extraction under local anesthesia at the Oral Minor
Surgery Outpatients Ward of Dental Hospital, Universitas Padjadjaran, Bandung West
Java, Indonesia. The procedures adhered to the standard pre- and postoperative extraction
protocols. Each removal of the mandibular first molar procedure was conducted by using
2 mL of lidocaine HCl with epinephrine as the local anesthetic and direct inferior
alveolar nerve block as the injection technique. Mandibular first molars were extracted
using simple extraction with close method, with No. 17 or No. 23 forceps. No. 17 forceps
was seated as far apically as possible. Luxation of the molar was initiated with a
buccal movement and then to the lingual. Subsequently, molar was delivered in the
bucco-occlusal direction. No tooth sectionings were done during all procedures. No
sutures have been applied to obtain wound healing by secondary intention. All the
patients received postoperative advice on good oral hygiene and information on how
to apply the topical gel. All extraction procedures were performed by a certified
dental surgeon (I.H.) who was not informed about the group of which the participant
was assigned to. All the patients were instructed to apply the assigned gel with cotton
applicators onto the extraction wound site two times (every 12 hours) for 7 days,
and take the mefenamic acid pill if necessary.
Assessments of wound diameter were performed immediately after extraction and 7 days
after procedure, in bucco-lingual and mesio-lingual widths using a vernier caliper.
Healing was assessed using the standardized index by Landry et al (1988).[21] Calculation was done by measuring the wound diameter differences between pre-extraction
(Day 1) and postextraction (Day 7) assessments.
All measurements were performed under the same conditions by one calibrated examiner
(R.R.) who was not informed about the group of which the participant was assigned
to. Reproducibility measurements in 20 other postextracted patients, 8 hours apart,
showed an intraclass correlation coefficient of 0.93 and 0.90 for wound diameter and
healing index measurements, respectively.
All of the data were subjected for normality test (Lilliefors' test). For wound diameter
analysis, pair t-test was used since it was normally distributed. Due to the fact that the data obtained
from healing index were not normally distributed, Kendall's rank correlation (Kendall's
tau) was employed to measure the association. Statistical significance was identified
by setting the p-value ≤ 0.05. Statistical analysis was performed using SPSS version 23 from IBM,
United States.
Results
A total of 32 subjects (16 in test group and 16 in control group) completed the study.
The phases of parallel RCT are shown in the Consolidated Standards of Reporting Trials
(CONSORT) flow diagram ([Fig. 1]). The mean age of the 32 subjects was 26.09 (±8.51) years without significant differences
between the groups and ranged in all the two groups between 19 and 46 years. The study
population consisted of 11 males and 21 females which was balanced distributed over
the two study groups ([Table 1]). No complication of extraction such as wound dehiscence, nerve disturbance, or
prolonged pain was registered, nor allergic reaction was experienced by participants.
Fig. 1 Consolidated Standards of Reporting Trials (CONSORT) flow of participants.
Table 1
Characteristics of participants
|
Variable
|
CHX
|
Placebo
|
p-Value
|
|
N = 16
|
N = 16
|
|
Age (y ± SD)
|
26.06 ± 9.45
|
26.13 ± 7.78
|
0.481
|
|
Sex (male/female)
|
7/9
|
4/12
|
0.457
|
Abbreviations: CHX, chlorhexidine; SD, standard deviation.
In the present study, analysis of wound closure was performed by subtracting the wound
diameter on Day 7 with wound diameter on Day 1 in buccolingual and mesiodistal directions
([Fig. 2]). The mean values of wound diameter at different evaluation times are presented
in [Table 2]. The wound diameter in the test group decreased significantly in buccolingual, as
well as mesiodistal direction compared with control group (p-value < 0.05).
Fig. 2 Wound diameter in buccolingual (A) and mesiolingual (B) direction.
Table 2
Comparison of wound closure on Days 1 and 7 after tooth extraction
|
X̄ (D1) ± SD (mm)
|
X̄ (D7) ± SD (mm)
|
∆ ± SD (mm)
|
p-Value
|
|
Buccolingual width
|
|
CHX 0.2%
|
6.69 ± 1.42
|
2.41 ± 1.13
|
4.28 ± 0.65
|
0.0000000000637[a]
|
|
Placebo
|
6.06 ± 1.81
|
3.91 ± 1.58
|
2.15 ± 0.60
|
|
Mesiodistal width
|
|
CHX 0.2%
|
9.25 ± 1.34
|
5.00 ± 1.22
|
4.25 ± 0.61
|
0.0000000000144[a]
|
|
Placebo
|
8.40 ± 1,85
|
6.56 ± 1.80
|
1.84 ± 0.72
|
Abbreviations: CHX, chlorhexidine; SD, standard deviation.
Notes: X̄ (D1) = mean wound diameter on Day 1. X̄ (D7) = mean wound diameter on Day
7. ∆ = wound diameter on D7 − D1.
a Significant difference.
Clinical features of wound healing were assessed on Day 7 by the use of Landry et
al index (1988) ([Table 3]). The frequency of healing scores experienced by subjects is presented in [Table 4].
Table 3
Wound healing index (Landry et al, 1988)
|
Healing index
|
Tissue color
|
Bleeding on palpation
|
Granulation tissue
|
Incision margin
|
Suppuration
|
|
1—very poor
Two or more signs are present
|
≥ 50% of red gingiva
|
Yes
|
Yes
|
Not epithelized, with loss of epithelium beyond incision margin
|
Yes
|
|
2—poor
|
≥ 50% of red gingiva
|
Yes
|
Yes
|
Not epithelized, with exposed connective tissue
|
No
|
|
3—good
|
25–50% of red gingiva
|
No
|
No
|
No exposed connective tissue
|
No
|
|
4—very good
|
< 25% of red gingiva
|
No
|
No
|
No exposed connective tissue
|
No
|
|
5—excellent
|
All pink tissues
|
No
|
No
|
No exposed connective tissue
|
No
|
Table 4
Results of wound healing index (Landry et al)
|
Healing index
|
N = 32
|
|
CHX
|
Placebo
|
|
1
|
Very poor
|
0
|
0
|
|
2
|
Poor
|
0
|
0
|
|
3
|
Good
|
5
|
5
|
|
4
|
Very good
|
8
|
10
|
|
5
|
Excellent
|
3
|
1
|
|
N
|
16
|
16
|
Abbreviation: CHX, chlorhexidine.
Correlation between healing score and the use of allocated gel was performed with
Kendall's tau analysis and is presented in [Table 5]. It can be seen that the use of 0.2% CHX gel had significant correlation with healing
scores (p-value < 0.05).
Table 5
Correlation of healing scores and allocated gel
|
p-Value
|
W
|
|
CHX 0.2%
|
|
Width
|
0.00000493[a]
|
0.764
|
|
Healing index
|
|
Placebo
|
|
Width
|
0.3232
|
0.071
|
|
Healing index
|
Abbreviation: CHX, chlorhexidine.
Note: W = Kendall's coefficient.
a Significant difference.
Discussion
Several local and general factors affect oral wound healing, such as trauma, thermal
damage, ischemia, wound size and location, edema, and infection. Healing within the
oral cavity is a critical aspect since it occurs in warm oral fluid containing millions
of microorganisms. Therefore, infection frequently occurs leading to poor wound healing.
The aim of the present study was to evaluate the effect of topical application of
CHX gel twice a day performed by the patients on top of the postextraction wound site.
Healing was defined as wound closure and standardized healing index evaluating clinical
appearance.
The result of the present RCT showed that 0.2% CHX gel significantly improved wound
healing at the clinical level. In the test group that was instructed to apply with
0.2% CHX gel every 12 hours for 7 days after extraction, greater wound closure and
better clinical healing were achieved as assessed by standardized healing index. This
positive effect on clinical healing was related to the use of CHX gel as revealed
by correlation analysis. In a meta-analysis study, Mínguez-Serra et al (2009) found
that 0.2% CHX gel administered twice a day for 7 days would be the best option for
preventing alveolar osteitis after extraction.[21] In the form of mouth rinse, it was shown by Halabi et al (2018) that 0.12% CHX mouthwash
was able to prevent alveolar osteitis in a population having risk of developing alveolar
osteitis (previous surgical site infection, traumatic extraction, and tobacco smoking)
after tooth extraction, whereas Hita-Iglesias et al (2008) found that CHX in the form
of gel may decrease the incidence of alveolar osteitis after mandibular third molar
extraction compared with mouth rinse (7.5 vs. 25%).[20]
[22] A recent meta-analysis of 0.2% CHX gel application intra-alveolar showed that it
was effective in preventing alveolar osteitis after third molar extraction.[23] In this present study, we evaluate CHX gel considering that the method of administration
of this gel has the main advantage of providing a greater bioavailability in the application
area, and therefore, the medication has a more prolonged release. Furthermore, administration
of CHX gel was self-administered by the participants, and not performed by operators,
so this way of administration could be considered as home care treatment.
In addition, the majority of the studies evaluating the protective effect of CHX toward
alveolar osteitis were conducted in surgery procedures with sutures to close the wounds.
However, this present study was performed in patients having tooth extraction without
sutures at the end of the procedures. Thus, the participants in this present study
had open wounds, and no dressing were applied instead of the test gel or placebo.
The results of this present study are in accordance with Palaia et al (2019) who investigated
the effect of mouthwashes containing the combination of CHX and sodium hyaluronate,
CHX alone and placebo in second intention wound healing after oral biopsy with laser
and without sutures.[24] CHX was proven to have accelerating effect on wound healing and can be recommended
as good support or adjuvant therapy after surgical procedures. Furthermore, in a recent
meta-analysis study, Armond et al (2017) suggested that the use of intra-alveolar
CHX gel after surgical removal of mandibular third molars reduces pain, edema, and
trismus after the extraction of third molars.[25]
None of the participants of the CHX group in the present study experienced adverse
events or hypersensitivity reactions after applying the gel. This could be the result
of screening for CHX hypersensitivity before the commencement of the study that only
individuals without allergic or hypersensitivity reactions to CHX could be included
as participants. Nevertheless, several publications reported adverse events associated
with prolonged use of CHX mouth rinse, ranged from mild to severe reactions including
taste changes, tooth/tongue/staining, itching mouth, sore mouth, and increased calculus,
while acute reactions had been reported as skin rash, nasal congestion, shortness
of breath, swelling of face/lips/throat, nausea, swollen glands, diarrhea, abdominal
pain, as well as anaphylactic reactions leading to death.[17]
[26]
[27] One of the study by McCoy et al (2008) reported that these adverse events occurred
in older adults with uncontrolled diabetes, while in the present study, the participants
included were younger than 50 years and systemically healthy with ASA status I.[17] Therefore, careful monitoring of adverse reactions in patients using CHX is warranted
particularly among those with multiple medical conditions and a history of allergies
or breathing problems, and the clinicians must carefully and completely advise patients
who use CHX, in any form, of possible side effects.
In the present study, smoker individuals were excluded because several studies demonstrated
that smoking is associated with delayed healing, wound infection, and dehiscence.[28]
[29]
[30] Nicotine in cigarettes has vasoconstriction effect, which may predispose to thrombotic
microvascular occlusion and consequent tissue ischemia. According to Heng et al (2007),
dry socket was found common among smokers after dental extractions as results of fibrinolytic
activity and reduced alveolar blood supply.[31] It should be remembered that this study was performed in a group of nonsmokers.
Therefore, it is currently unknown to what extent the present results can be extrapolated
to smokers.
A relevant action of CHX in promoting wound healing may be due to its ability to reduce
the bacterial load on the wound. Bacterial infection is proven to have clinical significance
in impairing wound healing since it interferes with the normal wound healing process
by stimulating the body's defense through activation of inflammatory cells and mediators,
which in turn destructs the granulation and the surrounding normal tissues.[32] If inflammation persists, it will impair therapeutic intervention as well as tissue
regeneration.[33] Back to 1970, Lindhe et al demonstrated that one daily topical application of 2.0%
to the teeth and gingiva was able to remove bacterial plaque and resolved gingival
inflammation in dogs.[34] Nevertheless, several studies on CHX have shown considerable contradiction on its
effect on wound healing. Despite its strong bactericidal action, in vitro studies showed that CHX negatively affected fibroblast and keratinocyte proliferation
in a dose-dependent manner,[35]
[36]
[37] while in vivo studies demonstrated the opposites.[38]
[39]
[40] These contrary results might be due to the different cellular and molecular interactions
occurring in vitro and in vivo. In vivo, CHX in the form of positively charged bisbiguanide can bind to different negatively
charged sites, including mucous membranes, salivary pellicle on teeth, and titanium
surfaces, as well as several components of the biofilm on the tooth surfaces, for
example, bacteria, extracellular polysaccharides, and glycoproteins.[41]
[42] Therefore, the remaining amount of CHX molecules available to bind to and harm host
cells in the wound is significantly reduced.[43]
Third molar surgery study design is usually the most validated study model to evaluate
the effects of antimicrobial products on the postoperative period after tooth extraction,[20]
[21]
[22]
[23]
[44] but since the administration of CHX gel in those trial was more complicated than
what was performed in this present study, we showed that CHX gel could also be administered
by the patients themselves without having surgeon applying the gel into the postextraction
socket. The ease and convenient way of this administration may be considered as home
care for patients who underwent noncomplicated extractions.
A limitation of the present study is the relatively short period of early wound healing
and that we only registered wound healing, while the severity of pain experienced
by the participants was not recorded.
Conclusion
In conclusion, under limitation of the present study, it is confirmed that CHX gel
has the beneficial effect in enhancing wound healing after nonsurgery tooth extraction
and may be suggested as adjuvant treatment and home care. It merits further studies
to evaluate the effect of CHX with the evaluation of clinical and radiographic examination
after tooth extraction.
