Efficacy of Chlorhexidine after Oral Surgery Procedures on Wound Healing: Systematic Review and Meta-Analysis

Citation: Romero-Olid, M.d.N.; Bucataru, E.; Ramos-García, P.; González-Moles, M.Á. Efficacy of Chlorhexidine after Oral Surgery Procedures on Wound Healing: Systematic Review and Meta-Analysis. Antibiotics 2023,12, 1552. https://doi.org/10.3390/ antibiotics12101552 Academic Editor: Marc Maresca Received: 21 September 2023 Revised: 14 October 2023 Accepted: 18 October 2023 Published: 20 October 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). antibiotics Article Efficacy of Chlorhexidine after Oral Surgery Procedures on Wound Healing: Systematic Review and Meta-Analysis María de Nuria Romero-Olid 1,2, Elena Bucataru 1,2, Pablo Ramos-García1,2,* and Miguel Ángel González-Moles 1,2 1School of Dentistry, University of Granada, 18071 Granada, Spain; [email protected] (M.d.N.R.-O.); [email protected].es (E.B.); [email protected] (M.Á.G.-M.) 2Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain *Correspondence: [email protected] Abstract: Our objective was to evaluate qualitatively and quantitatively, through a systematic review and meta-analysis, available evidence on the efficacy of chlorhexidine (CHX) when applied after oral surgery on wound healing and related clinical parameters. MEDLINE/PubMed, Embase, CENTRAL, Web of Science, and Scopus were searched for studies published before January 2023. The quality of the methodology used in primary-level studies was assessed using the RoB2 tool; meta-analyses were performed jointly with heterogeneity and small-study effect analyses. Thirty-three studies and 4766 cases were included. The results point out that the application of CHX was significantly more effective, compared to controls where CHX was not employed, providing better wound healing after oral surgery (RR = 0.66, 95% CI = 0.55–0.80, p< 0.001). Stratified meta-analyses confirmed the higher efficacy of 0.20% CHX gel vs. other vehicles and concentrations (p< 0.001, respectively). Likewise, the addition of chitosan to CHX significantly increased the efficacy of surgical wound healing (p< 0.001). The use of CHX has also been significantly beneficial in the prevention of alveolar osteitis after any type of dental extraction (RR = 0.46, 95% CI = 0.39–0.53, p< 0.001) and has also been effective when applied as a gel for a reduction in pain after the surgical extraction of third molars (MD = − 0.97, 95% CI = − 1.26 to − 0.68, p< 0.001). In conclusion, this systematic review and meta-analysis demonstrate on the basis of evidence that the application of CHX exerts a beneficial effect on wound healing after oral surgical procedures, significantly decreasing the patient’s risk of developing surgical complications and/or poor wound healing. This benefit was greater when CHX was used at 0.20% in gel form with the addition of chitosan. Keywords: chlorhexidine; wound healing; oral surgery; systematic review and meta-analysis 1. Introduction Wound healing in oral surgery is a complex and dynamic process that culminates in the restitution of the tissue’s integrity [ 1 , 2 ]. During the healing process, a series of successive events occurred, starting with local hemostasis, followed by inflammation, tissue proliferation (mainly of fibroblasts, epithelial and endothelial cells), neoangiogenesis, repithelialization, synthesis, union and the alignment of collagen fibers, formation of granulation tissue, and definitive tissue remodeling [ 2 – 4 ]. These events can be altered by several factors, such as diseases (e.g., diabetes mellitus [ 5 ], hypothyroidism [ 6 , 7 ], or rheumatoid arthritis [ 8 ]), drug intake (e.g., bisphosphonates [ 7 , 9 ]), tobacco use [ 10 ]) or infections as a consequence of bacterial imbalance in the wound site [ 11 – 13 ]. Consequently, patients undergoing oral surgery are at an increased risk of developing complications during postoperative wound healing [ 14 , 15 ], such as delayed or the absence of healing, pain and, particularly, after the extraction of third molars, the development of alveolar osteitis [ 16 – 20 ]. The establishment of improvement strategies to minimize wound healing complications after oral surgery is currently a priority line of clinical research in modern dentistry [21,22]. Antibiotics 2023,12, 1552. https://doi.org/10.3390/antibiotics12101552 https://www.mdpi.com/journal/antibiotics Antibiotics 2023,12, 1552 2 of 18 One of the strategies that has received the most attention is the application of chlorhexidine (CHX) to wounds after oral surgical procedures [ 23 ]. This approach is justified by the broad-spectrum actions of CHX against Gram-positive and Gram-negative bacteria, with bacteriostatic properties at low doses and bactericidal properties at high concentrations [ 24 , 25 ], as well as an antifungal effect [ 23 ]. Its mechanism of action is exerted by increasing the permeability of the cell membrane of target microorganisms, which causes the precipitation of macromolecules in the cytoplasm and subsequent microbial death via cell lysis [ 23 ]. Therefore, the effect of CHX is mainly based on bacterial load reduction, playing an anti-infection role, which seems essential in the early stages of wound healing. Nevertheless, the problem of healing is more complicated, in which many more factors are involved. In recent years, the use of CHX has increased exponentially in the different fields of medicine, particularly in dentistry, where it is currently the most widely used antiseptic due to its antimicrobial action and other additional advantages for clinical practice and for the patient, such as its low cost and ease of application [ 23 ]. CHX can also be presented in different vehicles (mouthwash, gel, spray, toothpaste, etc.) and in variable concentrations (mainly 0.12% and 0.20%), which allows its use to be adapted to the patient’s needs [ 23 ]. Given the proven benefits of CHX, its application has been proposed to improve wound healing after oral surgical procedures [ 26 ]. However, it is surprising that, to date, there have been no scientific publications in the form of systematic reviews and meta-analyses offering a high level of evidence on the relevance of its indication. In light of the above, we propose the present study with the objective of evaluating qualitatively and quantitatively, based on the evidence, through a systematic review and meta-analysis, the efficacy of the application of CHX after oral surgery on wound healing for the improvement of clinical parameters in relation to this biological process and on the possible complications that may occur, among which we can include epithelialization, a reduction in erythema, suture dehiscence, the development of alveolar osteitis and pain. 2. Materials and Methods The present study was conducted closely by rigorously following Cochrane Collaboration criteria for systematic reviews of interventions [ 27 ]. The manuscript was prepared closely in compliance with the updated PRISMA statement (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) [28]. 2.1. Protocol A preliminary methodological protocol was designed a priori, which was later submitted to PROSPERO International prospective register of systematic reviews (ID465899/ CRD42023465899 code was assigned), with the goal of minimizing the risk of bias by reinforcing the transparency, precision, and integrity of this research. The study protocol also adhered to specific PRISMA-P reporting guidelines [29]. 2.2. Search Strategy We searched Embase, MEDLINE/PubMed, Scopus, and Web of Sciences databases, as well as registered Cochrane Central Register of Controlled Trials (CENTRAL), for primarylevel studies published before the upper limit of January 2023 without lower date filters or limits. Electronic searches were driven by combining the thesaurus with free terms, which were designed in order to maximize sensitivity (Supplementary Information [S] Table S1). Furthermore, we conducted an extra screening process by manually searching through the reference lists of the retrieved studies and utilizing Google Scholar. All references were managed using Mendeley v.1.19.8 (Elsevier, Amsterdam, The Netherlands); the duplicates’ removal process was also driven using this software. All references were organized and managed using Mendeley v.1.19.8 (Elsevier, Amsterdam, The Netherlands), and any duplicate references were removed via this software. Antibiotics 2023,12, 1552 3 of 18 2.3. Eligibility Criteria We formulated the subsequent PICO question: “Is the application of CHX effective in patients undergoing oral surgery procedures, compared to controls not exposed to CHX or other drugs, in order to improve wound healing and related clinical parameters (i.e., epithelization, erythema, wound dehiscence, alveolar osteitis, and pain)?”. Primary-level studies were strictly included according to the following eligibility criteria. Inclusion criteria: Randomized clinical trials (RCTs) or quasi-RCTs (q-RCTs), with parallel groups or split-mouth design, were used without restrictions for publication language or date, geographical area, age or sex; CHX either alone or in association with other antiseptics or antibiotics was applied as experimental intervention and placebo or no-treatment as the control arm; evaluation of the risk of wound healing complications after oral surgery procedures was conducted in study groups. When two research arms were investigated by applying CHX in different concentrations or vehicles, both were included and considered as separate analysis units. Exclusion criteria were as follows: retracted articles, non-randomized clinical trials or observational studies, case reports, preclinical experiments (animal experimentation or in vitro research), articles without scientific method and/or results (letters, editorials, personal opinions, commentaries, meeting abstracts, literature narrative reviews, or book chapters), as well as secondary/tertiary-evidence level studies (scoping reviews, systematic reviews with or without meta-analysis, overviews of reviews, umbrella studies, etc.); surgical procedures from anatomic areas distinct to the oral cavity; primary-level studies without control groups, or controls exposed to an experimental intervention with known antiseptic effect (e.g., CHX, antibiotics or other drugs); no analysis of clinical outcomes of interest or a lack of essential data for the statistical estimation of effect size metrics with their corresponding confidence intervals; inter-study overlapping populations. 2.4. Study Selection Process Two blinded authors (EB and MNRO) independently applied eligibility criteria, later resolving any discrepancies via consensus with a third supervisor author (PRG). The records were selected across two subsequent stages. In stage I, titles and abstracts were screened, looking for potential records meeting inclusion criteria. In stage II, the records were read in full text and excluded if eligibility criteria were not met. Initially, all systematic reviewers underwent training and calibration rounds by piloting 80 random papers in order to become proficient in the process of identifying and selecting studies. An optimal interagreement proportional score (relative frequency of agreement = 98.75%) was obtained. The inter-rater reliability was also measured by calculating Cohen’s kappa statistic and obtaining an almost perfect agreement (κ= 0.90). 2.5. Data Extraction Two authors (EB and PRG) systematically extracted data from included primary-level studies by employing standardized data collection forms within Excel and Word software (v.16, respectively; Microsoft. Redmond, WA, USA), solving discrepancies via a consensus. Datasets were gathered on the study’s first author, language and publication date, country, sample size, study design, type of oral surgery, CHX concentration and vehicle, control group’s intervention, recruitment and follow-up period, time intervals between checkup visits, sex, age, and outcomes of interest. 2.6. Evaluation of Quality and Risk of Bias The authors critically appraised the methodological quality and risk of bias across primary-level studies using the updated Cochrane risk-of-bias tool (aka RoB2 tool) [ 30 ]. The following five potential bias domains were explored: (1) bias arising from the derandomization process, (2) bias due to deviations from intended intervention, (3) bias due to missing outcome data, (4) bias in the measurement of the outcome, and (5) bias in the Antibiotics 2023,12, 1552 4 of 18 selection of reported result. After assessing these items, we identified each included study as low with some concerns or a high potential risk of bias for each domain. Finally, an overall score was also estimated based on the following criteria: we rated the study as “low risk of bias” if the study was critically judged as having a potentially low risk of bias for all domains for this result; “some concerns” if the study was critically judged to raise some concerns in at least one domain for this result, but not at high risk of bias for any domain; and “high risk of bias” if the study was critically judged to be at a potential high risk of bias in at least one domain for this result or if the study was judged to have some concerns for multiple domains in a way that substantially lowered confidence in the result [30]. 2.7. Statistical Analysis Pain was analyzed using primary-level studies alongside a visual analog scale and reported as the absolute difference between the mean values of the study groups. As all results were expressed as continuous outcome measurements on the same scale, the means ± SD were extracted to calculate the mean difference (MD) with their corresponding 95% confidence intervals (CI). Data were expressed as medians, interquartile ranges, and/or maximum-minimum values, which were computed and transformed, if possible, into means ± SD using the methods proposed by Luo et al. (2018) and Wan et al. (2014) [ 31 , 32 ]. When data were only expressed graphically, extraction was performed using Engauge- Digitizer 4.1. If it was desirable to combine two or more different datasets expressed as the means ± SD from subgroups into a single group, the Cochrane Handbook formula was applied [ 27 ]. This meta-analysis was conducted using the inverse–variance method under a random-effects model (based on the DerSimonian and Laird method). This approach was a priori planned in our study protocol since considerable sources of clinical heterogeneity were expected (e.g., differences among surgical approaches, variations due to patients’ subjective perception of pain and the challenge of scoring it, etc.). The rest of the parameters expressed dichotomous outcomes, generally presenting low event rates and/or small sample sizes. Therefore, relative risks (RR) with 95% CIs were pooled using the Mantel–Haenszel method (fixed-effect model), which showed better statistical properties when data were sparse. These results were also re-expressed in terms of RR reduction (RRR = [1-RR] × 100%). Forest plots were constructed in all meta-analyses in order to graphically represent the effect sizes and for subsequent visual inspection analysis. Heterogeneity between the studies was assessed using the χ2 -based Cochran’s Q-test. Given the low statistical power of the Q-test, p< 0.10 was considered significant. We also applied the Higgins I 2 statistic to estimate what proportion of variance in the observed effects reflected variation in true effects rather than a sampling error. The percentage of inter-study heterogeneity was quantified considering values of 50–75% as showcasing a moderate-to-high degree of inconsistency [ 33 , 34 ]. Preplanned subgroup meta-analyses were carried out to identify potential sources of heterogeneity and the influence of the specific study subpopulations (i.e., CHX association with other antiseptics or antibiotics, variations in vehicles or concentrations, type of oral surgery, and/or study design by parallel-group/split-mouth). Furthermore, small-study effect analyses were carried out to identify potential biases [ 35 ], such as a publication bias, the construction of funnel plots, and using the Egger regression test (performing a linear regression of the effect estimates on their standard errors, weighing using one/[variance of the effect estimate], considering ap Egger -value < 0.10 as significant) [ 36 ]. Stata software was used for all statistical analyses (v.16.1, Stata Corp, College Station, TX, USA). 3. Results 3.1. Results of the Literature Search The flow diagram (Figure 1) graphically depicts the searching and subsequent process of identification, screening, and selection studies. Overall, 2037 records were retrieved: 646 from Embase, 452 from MEDLINE, 651 from Scopus, 272 from Web of Science, 9 from Antibiotics 2023,12, 1552 5 of 18 CENTRAL, and 7 from hand-searching reference lists. After duplicates were removed, 1144 records were piloted and screened according to titles and abstracts, leaving a sample of 77 papers for full-text evaluation (in the Supplementary Information, exhibits the studies excluded jointly with their corresponding exclusion criteria). Finally, 33 studies meeting all eligibility criteria were included for qualitative evaluation and meta-analysis [37–69]. Antibiotics 2023, 12, x FOR PEER REVIEW 5 of 19 3. Results 3.1. Results of the Literature Search The flow diagram (Figure 1) graphically depicts the searching and subsequent process of identification, screening, and selection studies. Overall, 2037 records were retrieved: 646 from Embase, 452 from MEDLINE, 651 from Scopus, 272 from Web of Science, 9 from CENTRAL, and 7 from hand-searching reference lists. After duplicates were removed, 1144 records were piloted and screened according to titles and abstracts, leaving a sample of 77 papers for full-text evaluation (in the Supplementary Information, exhibits the studies excluded jointly with their corresponding exclusion criteria). Finally, 33 studies meeting all eligibility criteria were included for qualitative evaluation and meta-anal- ysis [37–69]. Figure 1. Flow diagram showing the identification and selection process of primary-level studies included in the present systematic review and meta-analysis. 3.2. Study Characteristics Table 1 summarizes the main characteristics of our study sample, and Table S2 (Supplementary Information) exhibits in detail the main variables gathered. These 33 primarylevel studies analyzed a total of 4766 cases (2525 from the intervention group and 2241 controls), ranging between 20 and 744. Twenty-three studies were designed as RCTs and ten as q-RCTs. In relation to the interventions under investigation, the single application of CHX was the most frequently used (n = 31), followed by its association with chitosan (n Records identified from: Databases (n = 2030) MEDLINE (n = 452) Embase (n = 646) CENTRAL (n = 9) Web of Science (n = 272) Scopus (n = 651) Handsearching (n = 7) Records removed before screening: Duplicate records removed (n = 895) Records marked as ineligible by automation tools (n = 0) Records removed for other reasons (n = 0) Records screened according to titles and abstracts (n = 1142) Records excluded (n = 1068) Reports sought for retrieval (n = 74) Reports not retrieved (n = 0) Full-text reports assessed for eligibility (n = 74) Full-text reports excluded, with reasons (n = 41): Inappropriate control group (n = 27) No outcomes of interest (n = 7) Inappropriate study design (nonrandomized) (n = 2) Lack of essential data (n = 2) Overlapping populations (n = 2) Off topic (n = 1) Studies included in systematic review and meta-analysis (n = 33) Identification and selection of primary-level studies Figure 1. Flow diagram showing the identification and selection process of primary-level studies included in the present systematic review and meta-analysis. 3.2. Study Characteristics Table 1summarizes the main characteristics of our study sample, and Table S2 (Supplementary Information) exhibits in detail the main variables gathered. These 33 primary-level studies analyzed a total of 4766 cases (2525 from the intervention group and 2241 controls), ranging between 20 and 744. Twenty-three studies were designed as RCTs and ten as q-RCTs. In relation to the interventions under investigation, the single application of CHX was the most frequently used (n= 31), followed by its association with chitosan (n= 4) and antibiotics (n= 4). Twenty-one of them were applied in rinse form, and the rest in a gel vehicle (n= 18), while 0.2% and 0.12% CHX were the most common concentrations (n= 26 and n= 11, respectively). Finally, the oral surgery procedures investigated were third molar (n= 28) and simple tooth extractions (n= 4), periodontal surgery (n= 4), and oral biopsies (n= 4). Antibiotics 2023,12, 1552 6 of 18 Table 1. Summarized study characteristics. Total 33 Studies Year of publication 1979–2022 Number of cases Total 4766 cases Intervention group 2525 cases Control group 2241 cases Sample size, range 20 to 744 cases Type of interventions * CHX 31 studies CHX + chitosan 4 studies CHX + antibiotics 4 studies Type of CHX vehicles * Gel 18 studies Rinse 21 studies Type of CHX concentrations * 1% 1 study 0.20% 26 studies 0.12% 11 studies 0.006% 1 study Type of oral surgery procedures * Third molar surgery 28 studies Simple tooth extraction 4 studies Periodontal surgery 4 studies Oral biopsy 3 studies Type of study design * Parallel group design 31 studies Split-mouth design 8 studies * Note that six primary-level studies reported two analysis units (total n= 39). 3.3. Qualitative Evaluation The evaluation of the risk of bias for each domain was carried out by applying the RoB2 tool (Figure 2) [30], and the following results were obtained: Domain 1 (bias arising from the randomization process) obtained a low RoB in 60.61% of the studies, some concerns in 36.36%, and a high RoB in 3.03%. The most common bias was not specifying the randomization process of the studies since many of them only mentioned the study being randomized and did not provide more information on how said randomization was carried out. The most relevant bias was a failure to blind the allocation sequence (allocation sequence concealed). Domain 2 (bias due to deviations from intended intervention) obtained a low RoB in 96.97% of the studies and some concerns in 3.03%. The most common bias did not provide clear information on whether participants and clinics knew the allocation of each group and whether that knowledge affected the results. The most relevant bias was the lack of information on whether any deviation from the planned study intervention occurred due to knowledge of the allocation sequence for each group and whether or not such deviation affected the results. Domain 3 (bias due to missing outcome data) obtained a low RoB in 100% of the studies since all of them provided data on almost the entire studied cases; missing data had a size small enough to not affect the results. Domain 4 (bias in the measurement of the outcome) obtained a low RoB in 54.55% of studies, some concerns in 36.36%, and a high RoB in 9.09%. The most relevant bias was using an inappropriate measurement method. The most frequent bias was that the person in charge of carrying out the measurements knew the assignment of each group, and the study did not provide clear information about the said knowledge. Antibiotics 2023,12, 1552 7 of 18 Domain 5 (bias in the selection of the reported result) obtained a low RoB in 27.27% of the studies and some concerns in 72.73%. The most common and most relevant bias did not provide information on the existence of a prior analysis plan or protocol completed before the analysis of the results in order to compare whether the subsequent analysis was carried out according to that protocol or not. Antibiotics 2023, 12, x FOR PEER REVIEW 8 of 19 Figure 2. Quality plot graphically representing the risk of bias across primary-level studies and critically appraised using the RoB2 tool. 3.4. Quantitative Evaluation 3.4.1. Meta-Analysis on Wound Healing A significant association was found between the application of CHX and better wound healing (RR = 0.66, 95% CI = 0.55 to 0.80, p < 0.001; RRR = 34%), although a considerable degree of heterogeneity was observed (p < 0.001, I2 = 85.9%). More homogeneous subgroups were found after stratified meta-analyses and most of them preserved the statistically significant association (CHX + chitosan: RR = 0.25, 95% CI = 0.17 to 0.37, p < 0.001; CHX gel: RR = 0.26, 95% CI = 0.18 to 0.37, p < 0.001; CHX 0.12%: RR = 1.59, 95% CI = 1.16 to 2.19, p = 0.004; CHX 0.20%: RR = 0.41, 95% CI = 0.32 to 0.53, p < 0.001; third molar surgery: RR = 0.29, 95% CI = 0.21 to 0.41, p < 0.001; parallel-group design: RR = 0.70, 95% CI = 0.57 to 0.86, p = 0.001; split-mouth design: RR = 0.41, 95% CI = 0.23 to 0.74, p = 0.003; low RoB: Figure 2. Quality plot graphically representing the risk of bias across primary-level studies and critically appraised using the RoB2 tool. 3.4. Quantitative Evaluation 3.4.1. Meta-Analysis on Wound Healing A significant association was found between the application of CHX and better wound healing (RR = 0.66, 95% CI = 0.55 to 0.80, p< 0.001; RRR = 34%), although a considerable degree of heterogeneity was observed (p< 0.001, I 2 = 85.9%). More homogeneous subgroups were found after stratified meta-analyses and most of them preserved the statistically Antibiotics 2023,12, 1552 8 of 18 significant association (CHX + chitosan: RR = 0.25, 95% CI = 0.17 to 0.37, p< 0.001; CHX gel: RR = 0.26, 95% CI = 0.18 to 0.37, p< 0.001; CHX 0.12%: RR = 1.59, 95% CI = 1.16 to 2.19, p= 0.004; CHX 0.20%: RR = 0.41, 95% CI = 0.32 to 0.53, p< 0.001; third molar surgery: RR = 0.29, 95% CI = 0.21 to 0.41, p< 0.001; parallel-group design: RR = 0.70, 95% CI = 0.57 to 0.86, p= 0.001; split-mouth design: RR = 0.41, 95% CI = 0.23 to 0.74, p= 0.003; low RoB: RR = 0.26, 95% CI = 0.17 to 0.40, p< 0.001; Some concerns RoB: RR = 0.24, 95% CI = 0.11 to 0.53, p< 0.001) (Table 2, Figures 3A and S1–S6). Antibiotics 2023, 12, x FOR PEER REVIEW 9 of 19 RR = 0.26, 95% CI = 0.17 to 0.40, p < 0.001; Some concerns RoB: RR = 0.24, 95% CI = 0.11 to 0.53, p < 0.001) (Table 2, Figures 3A and S1–S6). Figure 3. (A) Forest plot graphically represents the meta-analysis for the association between the application of CHX and wound healing. CHX, chlorhexidine; RR, relative risk; CI, confidence intervals. Fixed-effect model, Mantel–Haenszel method. An RR < 1 suggests that the application of CHX is associated with better wound healing. Diamonds indicate the pooled RRs with their corresponding 95% CIs. (B) The forest plot graphically represents a meta-analysis of the differences in pain between the CHX group and controls. CHX, chlorhexidine; MD, mean difference; CI, confidence intervals. Random-effects model, inverse-variance method. An MD < 0 suggests that pain levels were lower for the CHX group. Diamonds indicate the pooled MD with their corresponding 95% CIs. (C) The forest plot graphically represents the meta-analysis of the association between the application of CHX and alveolar osteitis. CHX, chlorhexidine; RR, relative risk; CI, confidence intervals. Fixed-effect model, Mantel–Haenszel method. An RR < 1 suggests that the application of CHX is associated with a lower risk of alveolar osteitis. Diamonds indicate the pooled RRs with their corresponding 95% CIs. 3.4.2. Meta-Analysis on Alveolar Osteitis A significant association after the application of CHX and a lower risk of alveolar osteitis (RR = 0.46, 95% CI = 0.39 to 0.53, p < 0.001) considerably reduced the incidence of alveolar osteitis when compared with the controls (RRR = 54%) and obtained homogeneous results across primary-level studies (heterogeneity: p = 0.36, I2 = 7.1%). Several subgroups also maintained this statically significant result (CHX single: RR = 0.49, 95% CI = 0.41 to 0.57, p < 0.001; CHX + antibiotics: RR = 0.35, 95% CI = 0.23 to 0.54, p < 0.001; CHX + chitosan: RR = 0.09, 95% CI = 0.01 to 1.59, p < 0.001; CHX gel: RR = 0.40, 95% CI = 0.31 to 0.51, p < 0.001; CHX rinse: RR = 0.50, 95% CI = 0.41 to 0.62, p < 0.001; CHX 0.12%: RR = 0.47, 95% CI = 0.37 to 0.59, p < 0.001; CHX 0.20%: RR = 0.46, 95% CI = 0.37 to 0.57, p < 0.001; third molar: RR = 0.48, 95% CI = 0.40 to 0.56, p < 0.001; simple extraction: RR = 0.34, 95% CI = 0.21 to 0.54, p < 0.001; parallel-group design: RR = 0.50, 95% CI = 0.42 to 0.60, p < 0.001; split-mouth design: RR = 0.35, 95% CI = 0.25 to 0.48, p < 0.001; Some concerns RoB: RR = 0.47, 95% CI = 0.38 to 0.52, p < 0.001) (Table 2, Figures 3C and S7–S12). 3.4.3. Meta-Analysis on Erythema A significant association was found between the application of CHX and better healing, with fewer erythematous wounds (RR = 0.60, 95% CI = 0.39 to 0.93, p = 0.02; RRR = 40%), although a considerable degree of heterogeneity was observed (p = 0.02, I2 = 76.3%) (Table 2, Figure S13). Subgroup meta-analyses were not performed for this variable, where only three primary-level studies entered into the meta-analysis. A B C Figure 3. ( A ) Forest plot graphically represents the meta-analysis for the association between the application of CHX and wound healing. CHX, chlorhexidine; RR, relative risk; CI, confidence intervals. Fixed-effect model, Mantel–Haenszel method. An RR < 1 suggests that the application of CHX is associated with better wound healing. Diamonds indicate the pooled RRs with their corresponding 95% CIs. ( B ) The forest plot graphically represents a meta-analysis of the differences in pain between the CHX group and controls. CHX, chlorhexidine; MD, mean difference; CI, confidence intervals. Random-effects model, inverse-variance method. An MD < 0 suggests that pain levels were lower for the CHX group. Diamonds indicate the pooled MD with their corresponding 95% CIs. ( C ) The forest plot graphically represents the meta-analysis of the association between the application of CHX and alveolar osteitis. CHX, chlorhexidine; RR, relative risk; CI, confidence intervals. Fixedeffect model, Mantel–Haenszel method. An RR < 1 suggests that the application of CHX is associated with a lower risk of alveolar osteitis. Diamonds indicate the pooled RRs with their corresponding 95% CIs. 3.4.2. Meta-Analysis on Alveolar Osteitis A significant association after the application of CHX and a lower risk of alveolar osteitis (RR = 0.46, 95% CI = 0.39 to 0.53, p< 0.001) considerably reduced the incidence of alveolar osteitis when compared with the controls (RRR = 54%) and obtained homogeneous results across primary-level studies (heterogeneity: p= 0.36, I 2 = 7.1%). Several subgroups also maintained this statically significant result (CHX single: RR = 0.49, 95% CI = 0.41 to 0.57, p< 0.001; CHX + antibiotics: RR = 0.35, 95% CI = 0.23 to 0.54, p< 0.001; CHX + chitosan: RR = 0.09, 95% CI = 0.01 to 1.59, p< 0.001; CHX gel: RR = 0.40, 95% CI = 0.31 to 0.51, p< 0.001; CHX rinse: RR = 0.50, 95% CI = 0.41 to 0.62, p< 0.001; CHX 0.12%: RR = 0.47, 95% CI = 0.37 to 0.59, p< 0.001; CHX 0.20%: RR = 0.46, 95% CI = 0.37 to 0.57, p< 0.001; third molar: RR = 0.48, 95% CI = 0.40 to 0.56, p< 0.001; simple extraction: RR = 0.34, 95% CI = 0.21 to 0.54, p< 0.001; parallel-group design: RR = 0.50, 95% CI = 0.42 to 0.60, p< 0.001; split-mouth design: RR = 0.35, 95% CI = 0.25 to 0.48, p< 0.001; Some concerns RoB: RR = 0.47, 95% CI = 0.38 to 0.52, p< 0.001) (Table 2, Figures 3C and S7–S12). Antibiotics 2023,12, 1552 9 of 18 3.4.3. Meta-Analysis on Erythema A significant association was found between the application of CHX and better healing, with fewer erythematous wounds (RR = 0.60, 95% CI = 0.39 to 0.93, p= 0.02; RRR = 40%), although a considerable degree of heterogeneity was observed (p= 0.02, I 2 = 76.3%) (Table 2, Figure S13). Subgroup meta-analyses were not performed for this variable, where only three primary-level studies entered into the meta-analysis. 3.4.4. Meta-Analysis on Epithelization A significant association was not found between the application of CHX and epithelization (RR = 1.05, 95% CI = 0.77 to 1.42, p= 0.76), and moderate heterogeneity was also observed (p= 0.06, I 2 = 55.6%) (Table 2, Figure S14). Subgroup meta-analyses were not performed for this parameter, where only five primary-level studies entered into the meta-analysis. 3.4.5. Meta-Analysis on Pain during Wound Healing Pain levels were not significantly different in the CHX group compared to the controls using a visual analog scale (MD = − 0.35, 95% CI = − 0.88 to 0.17, p= 0.19), which also showed significant heterogeneity (p< 0.001, I 2 = 80.5%) (Table 2, Figures 3B and S15– S20). More homogeneous subgroups were found after the stratified meta-analyses, and some of them showed significant differences, indicating slightly less pain in the CHX group (CHX gel: MD = − 0.97, 95% CI = − 1.26 to − 0.68, p< 0.001; Split-mouth design: MD = − 1.06, 95% CI = − 1.39 to − 0.73, p< 0.001; Low RoB: MD = − 0.45, 95% CI = − 0.90 to −0.003, p= 0.05; Some concerns RoB: MD = −1.04, 95% CI = −1.36 to −0.71, p< 0.001). 3.4.6. Small-Study Effects Analysis The visual examination of funnel plots’ asymmetry and the corresponding statistical tests were run with the same purpose affirmed for the absence of small-study effects for the variables wound healing (p Egger = 0.11) and pain (p Egger = 0.96), except for alveolar osteitis (p Egger = 0.03) for which biases, e.g., publication bias, could not be ruled out (Figures S21–S23). Table 2. Meta-analysis of the efficacy of chlorhexidine on wound healing after oral surgery procedures. Pooled Data Heterogeneity Meta-Analyses No. of Studies * No. of Cases * Stat. Model Wt ES (95% CI) p-Value phet I2 (%) Wound healing all (poor vs. better wound healing) a8 771 FEM M-H RR = 0.66 (0.55 to 0.80) <0.001 <0.001 85.9 Subgroup analysis by type of intervention b<0.001 c CHX single 4 527 FEM M-H RR = 1.10 (0.87 to 1.40) 0.43 0.02 71.3 CHX + chitosan 4 244 FEM M-H RR = 0.25 (0.17 to 0.37) <0.001 0.02 70.8 Subgroup analysis by type of vehicle b<0.001 c CHX gel 5 272 FEM M-H RR = 0.26 (0.18 to 0.37) <0.001 0.04 60.1 CHX rinse 3 499 FEM M-H RR = 1.14 (0.90 to 1.45) 0.28 0.01 77 Subgroup analysis by type of concentration b<0.001 c CHX 0.12% 1 239 — — RR = 1.59 (1.16 to 2.19) 0.004 — — CHX 0.20% 7 532 FEM M-H RR = 0.41 (0.32 to 0.53) <0.001 0.007 66.0 Antibiotics 2023,12, 1552 16 of 18 17. Ghosh, A.; Aggarwal, V.R.; Moore, R. Aetiology, Prevention and Management of Alveolar Osteitis—A Scoping Review. J. Oral Rehabil. 2022,49, 103–113. [CrossRef] [PubMed] 18. Au, A.H.Y.; Choi, S.W.; Cheung, C.W.; Leung, Y.Y. 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