The Clinical Effectiveness of Calcium Hydroxide in Root Canal Disinfection of Primary Teeth: A Meta-Analysis.

BACKGROUND The aim of this research was to systematically analyze the effectiveness of calcium hydroxide compared to formocresol (FC) and camphor phenol (CP) in root canal disinfection of primary teeth. MATERIAL AND METHODS The meta-analysis was based on the participants, interventions, control, outcome (PICO) study design principle and 16 randomized-controlled clinical trials published from January 2000 to August 2018. The data heterogeneity of each study was assessed by the Q-test. The odds ratio and 95% confidence interval (CI) were calculated based on the heterogeneity results by Revman software. RESULTS Sixteen randomized-controlled clinical trials of 3047 primary teeth were included in this meta-analysis. There were significant differences of clinical effectiveness between calcium hydroxide and FC in root canal disinfection of primary teeth (OR=3.37; 95% CI range: 2.54-4.48, P<0.01) and endodontic inter-appointment emergencies (EIAE) after disinfection for 7 days (OR=0.26; 95% CI range: 0.16-0.42, P<0.01). However, there was no statistical difference of EIAE, after disinfection of primary teeth for 48 hours, between calcium hydroxide and FC (OR=0.62; 95% CI range: 0.34-1.11, P=0.11). There were significant differences of clinical effectiveness between the calcium hydroxide and CP in root canal disinfection of primary teeth (OR=5.50; 95% CI range: 3.36-8.98, P<0.01). CONCLUSIONS This meta-analysis indicated that the effectiveness of calcium hydroxide as root canal disinfectant in primary teeth was more effective than that of FC and CP.

Background

The root canal therapy (RCT) of deciduous teeth is considered a last approach to keeping a deciduous tooth whose pulp tissue has been irreversibly affected due to caries or tooth trauma in a child. It can preserve masticatory functions, maintain the space for the succedaneous permanent tooth, and avoid early eruption [1,2]. The success of RCT mainly depends on the decrease of microorganisms and the avoidance of reinfection; therefore, root canal disinfection is the key step to ensure the success of RCT, especially in primary teeth, which have a more complex root canal anatomy [3]. Application of ideal intracanal medicaments could significantly eliminate the intracanal microorganisms and repair damaged tissues [4,5]. There are several intracanal disinfectants that can be applied during RCT of primary teeth, such as formocresol (FC), camphor phenol (CP), and calcium hydroxide, which have their own unique characteristics, respectively. It was reported that FC had exceptional antimicrobial properties [6]. FC, which had been used most commonly as an intracanal disinfectant, makes protein denaturation to play the role of bacteriostasis with bactericidal effect. However, formaldehyde has potential antigenicity to cause the immune response of the body and has a toxic effect on the periapical tissue [7]. CP, another traditional intracanal disinfectant, has less toxicity and disinfection force than FC and could not effectively eliminate endotoxins; however, its strong permeability improves the short-term disinfectant effectiveness of an infected root canal [7,8]. Calcium hydroxide, as an intracanal disinfectant with increasing application, can release hydroxyl ions which are strongly alkaline. Its abilities have been reported to destroy the cell membrane and protein structure of bacteria and can disinfect the root canal [9,10]. Calcium hydroxide has become widely applied as a clinical root canal disinfectant in recent years because of its superior biocompatibility compared to FC and CP [7]. Rajdeep et al. [9] confirmed the effectiveness of calcium hydroxide as root canal disinfectant, and traditional intracanal disinfectants, such as FC and CP, are still applied in clinical treatment in some situations. However, there is no comprehensive, systematic evaluation of intracanal disinfectants of primary teeth. This study systematically analyzes the clinical effectiveness and endodontic inter-appointment emergencies (EIAE) of calcium hydroxide and FC and CP in root canal disinfection of deciduous teeth to provide pediatric dentists with guidance and the basis for the clinical application of root canal disinfectants.

Material and Methods

This meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [11]. In accordance with the participants, interventions, control, outcome study design (PICO) principle, the question of the clinical effectiveness of calcium hydroxide in root canal disinfection of primary teeth compared to that of the traditional intracanal disinfectants, FC and CP, was posed.

Inclusion criteria

The articles were selected following the study inclusion criteria: 1) a randomized controlled clinical trial of calcium hydroxide for root canal disinfection of deciduous teeth, 2) deciduous teeth with complex root canal anatomy and periapical periodontitis or pulpitis requiring RCT, 3) the experimental group used calcium hydroxide as intracanal disinfectant, 4) the control group used FC and/or CP as intracanal disinfectant, and 5) reporting the clinical effectiveness and/or EIAE as outcome indicators. The clinical effectiveness was divided into effectiveness (symptom disappearing or alleviated, tapping pain (− ~ ±), fistula closure or reduction, normal gums or gingival redness and swelling alleviated, no exudation or reduction of root canal) and ineffectiveness (symptoms without change or aggravation, tapping pain (+ ~ +++), fistula unclosed, gingival redness and swelling, and exudation of root canal increasing). EIAE was divided into no pain (grade I and II pain according to Mohd Sulong [12] standard) and pain (grade III and IV pain according to Mohd Sulong [12] standard).

Exclusion criteria

Studies were excluded according to the following criteria: 1) repeated documents and case reports, 2) insufficient data to be extracted, and 3) not published in English or Chinese.

Search strategy

Cochrane Library, PubMed, Ovid, ScienceDirect, Wiley, China Biology Medicine (CBM), China National Knowledge Infrastructure (CNKI), Wan Fang, and VIP Database for Chinese Technical Periodicals (VIP) databases were searched for articles dating from January 2000 to July 2018. The adequate search strategy was performed according to the following Boolean phrases: Calcium hydroxide AND (deciduous teeth OR primary teeth OR kids OR children). In addition, the references of related reviews and all selected full-text articles were cross-checked by a hand-search.

Literature screening and data extraction

Two experienced dentists identified and selected studies independently, based on inclusion and exclusion criteria by reading the title, abstract, and full text. When opinions were not united, the problems were solved by discussion or with the help of relevant experts.

The following information was extracted from each included article: the first author, year of publication, diagnosis, study design, number of teeth, control group, experiment group, and disinfected time.

Methodology quality evaluation and bias risk assessment

The previous 2 researchers conducted a methodological quality evaluation and bias risk assessment of all the included studies, based on the Cochrane Collaboration’s tool for assessing risk of bias [13], including random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other biases.

Statistical analysis

The data were combined for meta-analysis by using a statistical software package (RevMan software, version 5.3). The overall effect was estimated and reported as the odds ratio (OR) and 95% confidence interval (95% CI). The Q-test and I2 measurement were conducted to assess the heterogeneity of each selected article. A significant heterogeneity was indicated by P<0.1 because of the moderate insensitivity of the Q statistic [14]. The value of I2 ranged from 0 to 100, with larger values (≥75%) suggesting high heterogeneity [15]. The Mantel-Haenszel fixed-effects model was chosen for calculation of the OR and 95% CI if the combined overall effect of multiple included studies results showed homogeneity; otherwise, the DerSimonian Laird random-effects model was chosen [16]. A Z-test was used to assess the overall effect, and publication bias was investigated for each outcome of interest through visual asymmetry detection after analyzing the funnel plot [17].

Result

The results of the search are shown in Figure 1. After screening the initial 1755 articles, 16 randomized controlled clinical trials were included [18-33] of 3044 deciduous teeth in the systematic meta-analysis. The characteristics of all eligible researches extracted are also shown in Table 1, and all the included studies were randomized controlled clinical trials comparing of the effectiveness of calcium hydroxide versus FC and/or CP.

Figure 1

Flow chart of the process of study selection.

Table 1

Main characteristics of all studies included in the meta-analysis.

Study	Diagnosis	Study design	N	Control group	Experiment group	Disinfected time
Wang [14] 2002	Periapical periodontitis	Randomized-controlled clinical trial	126	FC, CP	Calcium hydroxide	7d
Liu [15] 2004	Chronic periapical periodontitis	Randomized-controlled clinical trial	314	FC	Calcium hydroxide	7d
Zhang [16] 2005	Chronic periapical periodontitis	Randomized-controlled clinical trial	320	FC	Calcium hydroxide	7d
Fu [17] 2006	Chronic periapical periodontitis	Randomized-controlled clinical trial	280	FC	Calcium hydroxide	7d
Liu [18] 2006	Pulpitis, periapical periodontitis	Randomized-controlled clinical trial	150	FC, CP	Calcium hydroxide	7d
Yao [19] 2007	Chronic periapical periodontitis	Randomized-controlled clinical trial	60	CP	Calcium hydroxide	14d
Jin [20] 2008	Periapical periodontitis	Randomized-controlled clinical trial	272	FC	Calcium hydroxide	7d
Li [21] 2008	Periapical periodontitis	Randomized-controlled clinical trial	268	CP	Calcium hydroxide	7d
Wei [22] 2010	Periapical periodontitis	Randomized-controlled clinical trial	248	FC	Calcium hydroxide	7d
You [23] 2010	Pulpitis, periapical periodontitis	Randomized-controlled clinical trial	101	FC	Calcium hydroxide	7d
You [24] 2011	Chemical periapical periodontitis	Randomized-controlled clinical trial	78	FC	Calcium hydroxide	7d
Zhang [25] 2011	Periapical periodontitis	Randomized-controlled clinical trial!	126	FC	Calcium hydroxide	7d
Wang [26] 2013	Periapical periodontitis	Randomized-controlled clinical trial	90	CP	Calcium hydroxide	7d
Liu [27] 2014	Not mentioned	Randomized-controlled clinical trial	64	CP	Calcium hydroxide	10d
Sha [28] 2014	Periapical periodontitis	Randomized-controlled clinical trial	254	FC	Calcium hydroxide	7d
Wei [29] 2014	Periapical periodontitis, pulpitis	Randomized-controlled clinical trial	300	CP, FC	Calcium hydroxide	7d

FC – formocresol; CP – camphor phenol.

Quality assessment

The quality of all included research studies was assessed based on the Cochrane Collaboration’s tool for assessing risk of bias. In this meta-analysis, although all the included studies were randomized controlled clinical trials, only 1 article mentioned the random number table method. Two studies used blind methods, but others did no labeling. Three studies had deviations in the text data by which to obtain information accurately and efficiently by checking the calculations (Figure 2).

Figure 2

Risk of bias graph of all studies included in the meta-analysis.

Meta-analysis results

Clinical effectiveness of calcium hydroxide compared with FC

The clinical effectiveness of calcium hydroxide compared with FC was assessed in 12 randomized controlled clinical trials, and the Q-test analysis showed that there was no heterogeneity among these studies (P=0.87, I2=0%). The meta-analysis result of a fixed-effects model showed that there was a significant difference in the clinical effectiveness of calcium hydroxide in root canal disinfection of primary teeth compared to that of the traditional intracanal disinfectant FC (OR=3.37, 95% CI range: 2.54–4.48, P<0.01) (Figure 3).

Figure 3

Forest plots of calcium hydroxide verse FC about clinical effectiveness. FC – formocresol.

EIAE after disinfection by calcium hydroxide compared with FC

The EIAE, after disinfection for 48 hours by calcium hydroxide compared with FC, was assessed in 2 randomized controlled clinical trials, and the Q-test analysis showed that there was no heterogeneity among these studies (P=0.19, I2=42%). The meta-analysis result of a fixed-effects model showed that there was no significant difference in the EIAE after disinfection for 48 hours in calcium hydroxide compared to that of FC (OR=0.62, 95% CI range: 0.34–1.11, P=0.11) (Figure 4).

Figure 4

Forest plots of calcium hydroxide verse FC about EIAE after disinfected 48 hours. FC – formocresol; EIAE – endodontic inter-appointment emergencies.

The EIAE, after calcium hydroxide disinfection for 7 days compared with FC, was assessed in 3 randomized controlled clinical trials, and the Q-test analysis showed that there was no heterogeneity among these studies (P=0.42, I2=0%). The meta-analysis result of a fixed-effects model showed significant difference in the EIAE after disinfection for 7 days in calcium hydroxide, compared to that of FC (OR=0.26, 95% CI range: 0.16–0.42, P<0.01) (Figure 5).

Figure 5

Forest plots of calcium hydroxide verse FC about EIAE after disinfected 7 days. FC – formocresol; EIAE – endodontic inter-appointment emergencies.

Clinical effectiveness of calcium hydroxide compared with CP

The clinical effectiveness of calcium hydroxide compared with CP was assessed in 7 randomized controlled clinical trials, and the Q-test analysis showed that there was no heterogeneity among these studies (P=0.63, I2=0%). The meta-analysis result of a fixed-effects model showed significant difference in the clinical effectiveness of calcium hydroxide as root canal disinfectant of primary teeth compared to that of the traditional CP intracanal disinfectant (OR=5.50, 95% CI range: 3.36–8.98, P<0.01) (Figure 6).

Figure 6

Forest plots of calcium hydroxide verse CP about clinical effectiveness. CP – camphor phenol.

Discussion

Bacteria and related products were the main sources of the pulpitis and periapical periodontitis [34,35]. One of the main goals of RCT was to clean and disinfect the root canal system [35]. The anatomy of primary teeth was more complex than that of permanent teeth. The primary teeth were smaller in terms of size and had more variation of external and internal morphology, such as connections involving furcation and horizontal anastomoses, which makes chemical preparation more important in primary tooth RCT [3,5,36]. Calcium hydroxide used as an intracanal disinfectant had finite efficacy in reducing microorganisms from the root canal but was associated with periradicular healing [36]. This study was the first time to analyze systematically the effectiveness of calcium hydroxide compared to FC and CP as root canal disinfection of primary teeth.

The results of the meta-analysis

Through analyzing the 16 randomized controlled clinical trials included, the results of this meta-analysis suggested that calcium hydroxide in root canal disinfectants of primary teeth had a better clinical effectiveness than FC and CP. The mid-1980s saw a preference for using strong phenolic intracanal disinfection such as FC and CP [37], which were confirmed to result in protein denaturation due to strong permeability and combine with putrid fat products to form soap-like substances; however, the traditional intracanal disinfectants, FC and CP, had limited antibacterial and anti-inflammatory activity against endodontic pathogens [7], in accordance with the study assessing the antibacterial effect of CP as intracanal disinfection [38]. Recently, calcium hydroxide, with its strong alkalinity, was widely used as an intracanal medication; it could effectively destroy bacteria due to its ability to release hydroxyl ions not only into the dentin tubule where bacteria and their products gathered, but also to hydrolyze lipopolysaccharides (LPS) in bacterial cell walls, destroying the cell membrane enzyme and changing the chemical structure of bacteria [39,40]. To date, controversy still existed in research about the antimicrobial property of calcium hydroxide [41]. It has been confirmed that calcium hydroxide could kill most nosogenic bacteria [42], and McGurkin et al. found that calcium hydroxide could significantly reduce the intracanal bacteria to promote prognosis [43]. However, Manzur et al. found that calcium hydroxide had a limited efficacy in eliminating root canal bacteria because the initially high pH was buffered, and bacteria which could survive in the root canal system at pH 9–10 could not be destroyed [41]. Lakhani et al. pointed out that Enterococcus faecalis was tolerant of calcium hydroxide with high pH and resided in the deeper part of the dentin tubule, which was most commonly associated with failed RCT [44]. In the clinical application, Peters et al. found that calcium hydroxide, applied as an intracanal disinfectant for 4 weeks, did not further decrease the number of bacteria [45]. Recently, many researchers have been trying to find a vehicle that might best increase the antimicrobial effect of calcium hydroxide, such as chlorhexidine and propolis [10,46]. It was noticeable that there were limitations of microbiological root canal sampling as the way to test the effectiveness of intracanal disinfectants, which should be taken into account when evaluating the effectiveness of intracanal disinfectants [47,48]. This meta-analysis, including 16 randomized controlled clinical trials, published between January 2000 and August 2018, indicated that calcium hydroxide was a better intracanal disinfectant of primary teeth than FC and CP; however, further research is still needed to look for an ideal intracanal disinfectant in primary teeth.

EIAE was a kind of acute reaction during RCT, including pain and swelling. Its incidence rate was as high as 11~40% [49,50]. The results of this systematic analysis indicated that there was no difference of EIAE after primary tooth root canal disinfection for 48 hours between calcium hydroxide and FC; however, there was significant difference of EIAE after primary tooth root canal disinfection for 7 days between calcium hydroxide and FC, and the EIAE occurrence rate was lower in calcium hydroxide tests. It was reported that the EIAE were caused by some pathogenic factors, such as vasodilation, hyperemia, and exudation of tissue fluid, which could increase local pressure and stimulate the periapical nerve; the influencing factors of EIAE included the condition of the illness, the state of the patients, the operative technique of the dentist, such as improper root canal disinfection, and so on [51,52]. Grundy et al. [53] reported that 9 cases of radiolucent lesions appeared following RCT of primary teeth treated with FC. Studies [7,54] still indicated that FC, with good permeability and antibacterial and anti-inflammatory effectiveness, had strong cytotoxicity and corrosive effects on soft tissue, which were the main reasons for the EIAE. It has been pointed out that the appropriate time of FC sealing was about 5 days to prevent EIAE [7]. Other than good disinfecting antibacterial ability, calcium hydroxide could not only activate alkaline phosphatase in periapical tissue to promote the repair of periapical tissue, it could also neutralize the acidic substance produced during inflammation that stimulated periapical tissue, and release Ca2+ to decrease exudation by reducing the permeability of the capillary that was related to the intercellular fluid [52]. Meanwhile, it could soften and dissolve the soft tissue of the root canal wall, eliminate the tissue fragments in the root canal, and remove the infectious substances in the root canal more effectively, which all reduced the incidence of EIAE during RCT [55].

Quality of the evidence

In this meta-analysis, all the included studies were randomized controlled clinical trials and were high in the quality of evidence for determining therapeutic efficacy [36], and the results of the Q-test showed that the heterogeneity of the included 16 papers was low and the meta-analysis results were real and reliable. It was rather remarkable that there were some factors that might increase the heterogeneity of the included research, for example, unclear diagnostic classification of the pulpitis or periapical periodontitis in some studies, differences of sealing medicine formulae, operation and observation time among the studies, and lack of a unified standard for judging clinical effectiveness, differences of the sensitivity, and judgment of pain in children. The included studies were performed respectively by one experienced dentist, which could reduce the possibility of systematic errors due to the operating technique level and the technical differences. Thus, the heterogeneity test results showed that there was no impact on the demonstrated strength and credibility of the results of this meta-analysis.

In addition, factors such as age, tooth type, occlusion, and preoperative periapical status significantly affected periapical healing [56]. This research suggested that more attention should be paid to the design balances of the research objects and groups in future research.

Limitations of the meta-analysis

The data of the included studies were converted from ranked data to binary data, which might increase error. The results of the methodological quality evaluation and bias risk assessment, based on the Cochrane Collaboration tool for assessing risk of bias, showed that the quality of some included research was not high, and the number of studies about EIAE was limited, which probably increased the bias of this meta-analysis to a certain extent. The languages of the included studies were only English and Chinese; some research in other languages that met the inclusion criteria might be lost which could increase the bias. Publication bias test results showed that the bias of this study was small, and the results were reliable. Although this meta-analysis accurately testified to the efficacy of calcium hydroxide in root canal disinfection of primary teeth, more studies about calcium hydroxide as a root canal disinfectant of primary teeth according to the statistical methodology design are awaited.

This meta-analysis could not make the comparison of the clinical effectiveness between calcium hydroxide and CP in preventing EIAE, because no article reported it, which might be because CP has an analgesic effect and lower toxicity [57]. More studies about EIAE due to CP, both in clinical effectiveness and mechanism, should be done in the future. It was remarkable that the studies included were all in Chinese, which meant that FC and CP were widely used in RCT of primary teeth in some areas and countries, mainly because in some areas the periapical periodontitis related to early childhood caries in children was quite prevalent [58]. The results of this meta-analysis showed that the effectiveness of calcium hydroxide as intracanal disinfectant of primary teeth was better than that of FC and CP, and calcium hydroxide was a favorable alternative to traditional intracanal disinfectants. Dentists should be aware of this clinical treatment concept and put calcium hydroxide application into clinical practice.

Conclusions

This study indicated that the effectiveness of calcium hydroxide in root canal disinfection of primary teeth was superior to the traditional FC and CP; at the same time, it provided evidence and guidance for clinicians about the selection of intracanal disinfectants and reduction of complications during the process of primary tooth RCT. The damage to periapical soft tissue was the main result of EIAE after root canal disinfection; endodontic medicine with better biocompatibility and antimicrobial effect should be explored. There were some limitations of meta-analysis, and better methodology should be established in the future.