Lesion Sterilization Tissue Repair (LSTR) Approach Of Non-Vital Primary Molars With A Chloramphenicol-Tetracycline-ZOE Antibiotic Paste: A Scoping Review

Introduction

The main purpose of pulp treatment in primary dentition is to maintain the integrity, health, and functionality of the teeth and supporting tissues until their natural exfoliation [1]. Whenever it is possible, the vitality of the pulp tissue must be preserved in cases of deep caries, traumatic injuries, or other abnormal conditions. Invasive pulp treatments are therefore primordial to avoid premature tooth loss and potential subsequent abnormal changes in mastication, speech/phonetics, esthetics, and length of dental arches, and the occurrence of harmful oral habits [2, 3]. Thus, different techniques have been proposed in the dental literature for the debridement, cleansing, and disinfection of the root canal system in irreversible inflamed/infected/necrotic primary teeth [4].

Untreated decay or trauma can cause the pulp tissue of the primary tooth to become irreversibly inflamed, abscessed, or necrotic, as a result of deep caries or trauma, and other related factors that influence the endodontic treatment’s success. Treatment options include extraction, conventional root canal therapy, or the application of topical antibiotic pastes [3]. Given the complex morphology of the primary root canal system and the physiological root resorption process, both characteristic of the primary molars, and the lack of cooperation from some children, the conventional access and biomechanical instrumentation may be challenging. Considering the limitations of the primary tooth canal preparation, the use of simplified techniques employing antibiotic pastes has been encouraged during the routine clinical practice not only because they significantly reduce the operative time on the dental chair and the associated treatment costs, but also promote the reduction of pathogenic bacteria within the root canals, especially in those inaccessible locations [5]. These pastes are placed on the pulp chamber floor, performing no type of canal preparation [6]. The procedure is referred to as noninstrumental endodontic treatment and is based on the lesion sterilization and periapical tissue repair approach (LSTR). Despite LSTR has been practiced and promoted more than 25 years ago in Japan, Brazil, and other countries, it was not until recently that the AAPD has recognized it as a useful option in pediatric endodontics for irreversible inflamed or necrotic primary teeth, under several diagnostic criteria [1].

LSTR was initially promoted by Soller and Cappiello (Argentina), and by Sato and Hoshino (Japan) [4, 7]. In 1959, Soller y Cappiello described a biocompatible antibiotic mixture (called CTZ paste), composed of chloramphenicol 500 mg, tetracycline 500 mg, Zinc Oxide 1 g, and eugenol (one drop), as an alternative for traditional endodontic treatment of primary molars with irreversible pulpitis or pulp necrosis. The CTZ paste possesses good antimicrobial activity, with reported excellent clinical and radiographic outcomes; the paste application procedure is simple, can be carried out in one session, promotes stabilization of bone resorption, and does not cause tissue sensitivity [8]. Its major disadvantages are the potential pigmentation of the crown and the enamel hypoplasia in the successor premolar because of the presence of tetracycline, which exhibits a high affinity for calcified tissues [3, 9].

In this context, the present scoping review study aimed to perform a systematic scoping review with the need of exploring the actual clinical applications of the CTZ paste as an LSTR therapy agent, a simple and quick endodontic procedure for non-vital primary molars, through the most valuable current literature describing its potential clinical and radiographic effectiveness.

MATERIALS AND METHOD

The present scoping study was conducted following the framework suggested by Arksey and O’Malley [10] and Bragge et al [11] This framework comprise five steps: (i) designing the research question; (ii) identifying relevant studies through a literature search; (iii) analyzing selected studies; (iv) extracting and charting data; and (v) collating, summarizing, and reporting the results. Besides, this review used the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) reporting guideline and adjusted them to apply to a scoping review [12]. In addition, the protocol of the present review was registered in the Open Science Framework (OSF) database, under the Registration DOI 10.17605/OSF.IO/KMN7U.

First, a research question was structured based on the PICO format (Patient/Intervention/Comparison/Outcome) to scope the extent of the research available on the clinical topic and to avoid the early exhaustion of literature during the search process. Thus, the research question was: In primary molars with irreversible pulpitis or pulp necrosis, is the CTZ antibiotic paste clinical and radiographic effective when placed over the pulp canals entrance, regarding conventional pulpectomy and other LSTR pastes?

To find potentially relevant articles to answer this question, an initial electronic search was performed by three authors (CJA, MARB, and DATH) to identify appropriate titles and abstracts between January 2006 and May 2021, in the following databases: PubMed, EMBASE/Ovid, Google Scholar, the EBSCO Dentistry and Oral Sciences Source, and the Cochrane Library. This search included and combined several keywords, synonyms, and free terms; it also included subject terms from each database’s thesaurus (Medical Subject Headings or MeSH) as well as keyword searching of title and abstract fields.

The search strategy was carefully implemented by employing four major concepts: ‘CTZ paste’, ‘primary (or deciduous) teeth’, ‘pulpectomy (or endodontic treatment)’, and ‘LSTR’. This procedure was appropriately adapted for each selected database. The exact search terminology used in PubMed is described in Figure 1.

Figure 1. The used searching algorithm in PubMed for the present scoping review.

To be eligible for review, articles had to meet the following criteria: articles written in English, Spanish or Portuguese languages published in the last 15 years (January 2006 up to May 2021), whose main purpose was to study the clinical and radiographic outcomes of CTZ paste applied in primary teeth with irreversible pulpitis or pulp necrosis. The selected methodological designs were randomized clinical trials, observational studies (cohorts, case-control designs, cross-sectional studies, and clinical case-series reports), in vitro trials, or review articles; for longitudinal studies, a minimum of 4 months of follow-up was required. Clinical single-case reports, gray literature, comments, editorials, short communications, and letters were excluded from the review. The chosen articles were then retrieved in full text and were read and assessed by two experienced reviewers (JAGR and AJPG) separately to create the definitive list of studies to be included. The reference lists of selected articles were also manually screened to find other potentially eligible studies. Any discrepancy was discussed and resolved by consensus with the aid of a third examiner (MARB).

Important data from included studies were extracted and entered a predesigned and piloted standardized tracking and review form to present a narrative account of the relevant literature and avoid overlapping. From each article, the following information was recorded: general characteristics (authors, year of publication, geographical location); study methodological design; participants’ clinical features (range and mean age, gender, oral status, etc.); comparative or control endodontic material or technique; main clinical and radiographic outcomes; follow-up time and treatment success evaluation criteria; key findings or conclusions, and authors’ recommendations. A judgment was also performed concerning whether each outcome was primarily clinician-centered. Thereafter, data was collected, detailed, cross-checked, summarized, and discussed accordingly. The present scoping review process was structured as a flow diagram (Figure 2).

Figure 2. Flow diagram for literature search.

RESULTS

The initial search on January 4, 2021, yielded 37 titles of potential relevance. When the search was manually updated on May 20, 2021, an additional 4 references were identified. Eleven of them were then excluded because of duplications. Collectively, both searches resulted in 30 abstracts that were subsequently screened by two reviewers (AJPG and JAGR), and 12 of them were excluded because of non-related or irrelevant intervention. Thus, 18 full-text articles were further assessed in detail for eligibility by the same two reviewers; any conflicts were resolved with a third reviewer (MARB).

Seven articles were then excluded because of following reasons: three could not be retrieved in full-text form, one was not written in English, Spanish, or Portuguese, two were associated with other endodontic therapy different from pulpectomy (e.g. pulpotomy), and one was published in a predatory journal with notorious methodological deficiencies. As a result, 11 full-length papers were included in the present scoping review.

Eight articles were written in English, two in Spanish, and one in Portuguese; they were published between 2006 and 2021. The entire selection process is described in the flow diagram depicted in Figure 2. Table 1 exhibits the general characteristics of the studies included. Most of the studies retrieved were conducted in Latin America (mainly from Brazilian authors) and were five randomized/non-randomized controlled clinical trials [6, 13, 14, 15, 16]; five in vitro studies [5, 9, 17, 18, 19]; and one extensive case-series report [7]. After exploring the final selection of the studies, an extensive amount of relevant clinical information was condensed. The main findings from this entire process are described in the discussion section.

DISCUSSION

Scoping reviews are designed to examine the main body of available published evidence with a broad approach regarding a specific topic in dentistry and other health sciences to identify the boundaries and the context of that topic, as well as summarize the most important information and results of the included studies. Currently, many published articles use this type of review to provide a concise qualitative analysis [20]. These reviews also summarize the current knowledge to find conclusions and tendencies from the general data. In addition, scoping reviews may identify the literature gaps, directing future researches [21].

Despite the extensive implementation of several preventive and rehabilitative measures for dental caries in young children worldwide, around 50% of them still exhibit at least one primary tooth with a caries lesion needing dental treatment [22]. Primary teeth with severe carious lesions and pulp involvement, particularly those with infected root canals and periradicular tissues, are a common problem, which leads to a negative impact on the oral health-related quality of life [22, 23]. For these cases, dental literature has described and proposed diverse techniques like conventional/instrumental pulpectomy (bio or necropulpectomy). This procedure comprises a series of steps including absolute/total isolation, odontometry, chemical/mechanical preparation (debridement and modeling) of the pulp canals, profuse irrigation, and canal drying and filling. These procedures require competent clinicians’ performance and involve special instruments and materials that are not always available in public dentistry services. However, many deprived children have no choice but the extraction of the affected tooth. Private dental clinics and offices may a possibility but such treatments are often too pricey for this vulnerable population [6].

Pediatric endodontic therapy plays an important role in eliminating pathogenic bacteria, their byproducts, and substrates through the neutralization of their ecosystem by biochemical instrumentation. Those bacteria present in the superficial layers of infected root canal dentin may be easily removed, but microorganisms in the deep layers may survive and migrate to the periapical/periradicular regions and cause complications; additionally, pathogenic bacteria may smear the root canal during the endodontic instrumentation [23, 24]. LSTR approach is a simplified technique that has been proposed as a biologic alternative to conventional pulpectomy, as a long term endodontic treatment, in order to facilitate the sterilization/disinfection/healing of dentin carious lesions, necrotic/abscessed pulp canals, and periapical regions in primary teeth, with the advantages of being faster and simpler; also, it does not require multiple visits and can be applied independently of the physiologic root resorption degree [4, 24]. Taking into account that the long-term successful outcome of conventional pulpectomy has been reported in the dental literature up to 85%, the use of such alternative pulp procedures should be considered a suitable therapy with comparable or better rates; nevertheless, radiographic success is lower in the long-term follow-up [25]. Besides, and according to Coll and colleagues’ recommendations, even primary teeth with significant preoperative root resorption can be maintained in the dental arches if they are managed with LSTR therapy. This procedure should be the treatment choice over pulpectomy to save such teeth for up to 12 months; if retained longer, they have to be periodically monitored with clinical examinations and radiographs at least every 12 months [3].

LSTR strategy comprises the topical placement of a combination or mixture of antibacterial drugs in the pulp chamber floor with no mechanical instrumentation to eliminate or minimize the number of pathogenic microorganisms in the root canal system of primary teeth; thus, LSTR prevents unnecessary enlargement of root canals and irritation of periapical tissues [26]. The operative process is as follows: after opening the pulp chamber, the canal orifices are carefully enlarged with a round bur to create medication receptacles. Then, these receptacles are irrigated and cleaned, and the antibiotic paste is placed directly on them. The paste is covered with glass ionomer cement and the tooth is restored with a preformed stainless steel crown [1]. For the LSTR approach, the selected antimicrobial drugs should possess the ability to deeply penetrate the root dentin wall tubules. A single antimicrobial cannot be effective enough even if it has a broad spectrum activity; this is because of the complex polymicrobial composition inside the contaminated root canal system of primary molars mainly comprising aerobe and obligate anaerobes [23, 27, 28]. Alone, a single antibiotic is unable to eliminate bacteria, but, in combination, these drugs can to consistently sterilize the pulp canal system [28].

Different LSTR antibiotics and their combinations have been tested in clinical trials to date. The present scoping review assessed the clinical and radiographic of CTZ antibiotic paste applied on pulpally involved primary molars, following the principles of the LSTR approach. According to the retrieved results, CTZ therapy showed no significant differences regarding conventional pulpectomy, given the favorable findings from the selected studies, published fifteen years ago. This paste has evidenced both clinical and radiographic successes rate up to almost 100% and 93% respectively in previous studies, under different evaluation criteria and follow-up times [7, 16]. It has also shown equivalent clinical and radiographic results to those reported by 3-Mix paste (metronidazole or ornidazole, ciprofloxacin, and minocycline or cefaclor) and different root canal filling materials (Vitapex®, calcium hydroxide, and zinc-oxide eugenol alone) in previous studies [23, 26, 29]. On the other hand, Nakornchai and colleagues [26] do not recommend the application of LSRT pastes in children at risk of infective endocarditis and also by the potential damage to the successor tooth or cyst formation in the periapical area.

Bacteria play a crucial role in the initiation, progression, and persistence of infection inside pulp root canals. Microorganisms can remain viable deeply in dentin and cementum despite profuse irrigation with sodium hypochlorite and contribute to endodontic failure. Therefore, these bacteria must be neutralized to ensure a successful outcome [28]. As an LSTR agent, CTZ paste contains two broad-spectrum and bacteriostatic antibiotics: tetracycline and chloramphenicol. Tetracycline acts against several aerobic bacteria, facultative anaerobes, spirochetes, and Gram (+) and Gram (-) microorganisms; whereas chloramphenicol possesses bactericidal properties against Gram (+) bacteria and many anaerobes.2 Both drugs are mixed with eugenol, which also has sedative and antimicrobial (vs. Staphylococcus, Micrococci, Bacillus, and Enterobacteria for over 30 days) properties and zinc-oxide as the vehicle [30]. In this same regard, CTZ has demonstrated strong microbial growth inhibition of aerobic and anaerobic microorganisms (S. aureus, E. faecalis, P. aeruginosa, B. subtilis, and C. albicans), commonly found in infected non-vital primary teeth [5, 17]. CTZ evenly distributes throughout the primary canal system, inducing a sterilization process and promoting tissue repair and healing [7, 16]. In addition, CTZ stimulates a bone deposition in the radiolucent areas and resolves pretreatment clinical signs and symptoms [1]. In this same regard, CTZ demonstrated strong microbial growth inhibition of aerobic and anaerobic microorganisms (S. aureus, E. faecalis, P. aeruginosa, B. subtilis, and C. albicans), commonly found in infected non-vital primary teeth [5, 17].

Regarding the biocompatibility and/or possible histological harm to periapical tissues and successor premolar enamel by the CTZ paste, diverse in vitro studies have been conducted. Clinicians should consider that the furcal region in primary molars has a reduced dentin/cementum thickness with areas of resorption, and it is permeated by accessory foramen and channels. Thus, the increased permeability in this area favors the potential diffusion of drugs used in pulp therapy, which can trigger an inflammatory reaction and promote the formation of periradicular lesions involving surrounding tissues and developing successor premolar buds [9, 19]. Two studies concluded that the CTZ paste exhibited a low risk of damage to the periodontal ligament or enamel defects in premolars [9, 19]. However, Lacativa and co-workers [18], in a guinea-pig study, observed that the paste induced moderate/severe inflammation, necrotic tissue, and bone resorption after twelve weeks of the CTZ paste application, possibly due to its eugenol content; these authors rated this paste as no biocompatible, with highly irritating potential to periapical tissues.

Limitations. Unlike systematic reviews, scoping reviews do not incorporate a quality assessment of the studies included. This scoping review was aimed at collecting useful clinical information that is available and easily accessible to help pediatric dentistry practitioners during the treatment of pulpally involved primary molars. Through this approach, we intended to define the scope of the literature relevant to this clinical topic. However, as with any scoping review, a likely publication bias was present because of the selection of studies conducted only in English-or Spanish-or Portuguese-speaking countries, primarily due to limited resources for translation. Furthermore, the article search was restricted to the last 15 years; thus, our reference screening might have been underrepresented. However, we are confident that a significant number of studies included here provided an overview and useful information for the pediatric endodontics practice. Other limitations of the present study were the highly heterogeneous methodological issues of the detected articles and our limited ability to consistently summarize the details of the extracted data or findings from the retrieved articles.

CONCLUSIONS

The outcomes and findings of the available studies included in this scoping review suggest that, to date, there were no confirmed differences between topical CTZ paste, as LSTR therapy agent, and conventional instrumental pulpectomy, other antibiotic pastes, and diverse intracanal filling materials, considering the clinical, radiographic, antimicrobial activity, and periapical tissue biocompatibility outcomes. According to this, CTZ has shown excellent rates of clinical success and good radiographic results in the longterm follow-up, with appropriate antimicrobial effects; however, its periapical tissue biocompatibility could be questionable. Further research through high-quality clinical trials should be conducted before this antibiotic paste can be considered an ideal material or a substitute for instrumental pulpectomy in the treatment of primary teeth with irreversible pulp disease or pulp necrosis.

Conflict of interest.

The authors declare that they have no conflict of interest.

Ethical approval.

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent.

For this type of literature review, formal consent is not required.