Interventions for the endodontic management of non-vital traumatised immature permanent anterior teeth in children and adolescents: a systematic review of the evidence and guidelines of the European Academy of Paediatric Dentistry

A comprehensive search was developed for ensuring that as many studies as possible were identified through a structured electronic search, hand search, and personal contacts.

The subject search used a combination of controlled vocabulary and free text terms. There was no restriction on the language of publication.

The following databases were searched via OVID gateway:

All reports identified electronically were scanned on the basis of the title, keywords and abstract to exclude reports that were non-relevant to the review question as well as case reports, in vitro, animal studies, and retrospective studies. In order to ensure that the appraisal criteria were applied consistently, electronically identified trials, appearing to meet the inclusion criteria, were independently reviewed by two calibrated reviewers. Full text articles were obtained from the University of Leeds Health Science Library if the title or the abstract did not provide enough information about the study to make a decision or there was no abstract available.

When a controlled clinical trial was identified, the Cochrane methodology assessment for quality of RCTs (Cochrane Collaboration 2011) was used in this systematic review of interventions for non-vital immature teeth. The following describes the criteria that were used for studies considered for inclusion into this review.

The methodological quality of included RCT studies was assessed using the criteria described in the Cochrane Handbook for Systematic Reviews of Interventions 4.2.8. (Cochrane Collaboration 2011) Two reviewers assessed the included trials independently for quality and in duplicate without blinding the name of authors, institutions or journals. The grading for the recommendations in evidence considering all usable studies was performed according to the Scottish Intercollegiate Guidelines Network (SIGN) guidelines (2008).

A data extraction proforma was developed, agreed and tested at the start of data collection stage. The following was included:

Completed searches from all sources identified 200 reports on apexification. Following scanning of the titles and abstracts of these reports; 33 electronically identified reports were not relevant to the review topic and were rejected leaving 167 reports of different study designs to be assessed. The abstracts and full text were obtained whenever there was a doubt that the article could not be definitely rejected. Only six studies were suitable to be assessed as clinical trials and these were assessed in detail, are presented in Table 1.

Out of those six studies three (Roberts and Brilliant 1975; Coviello and Brilliant 1979; Mackie et al. 1994), met most of the review’s methodological quality assessment criteria. The results reported by Roberts and Brilliant (1975) showed 87.5% (7 out of 8 teeth) successful apical barrier formation using Ca(OH)₂ powder compared to 75% (6 out of 8 teeth) treated with tricalcium phosphate (TCP). The small numbers of participants in both groups did not allow identification of any difference between materials. One case in the Ca(OH)₂ group dropped out which would have reduced the success rate to 75% in this group if an intention to treat (ITT) analysis had been performed.

Coviello and Brilliant (1979) reported success in apical barrier formation of 82.9% (29 teeth out of 35) in the apical plug group which had one failure, seven drop-outs and five questionable teeth. The calculated ITT = 69% success. In the apexification group there were nine failures, seven cases dropped out and 10 questionable teeth with a success of 63.5%. The calculated ITT = 55.9% success. There was no reported significant difference between treatment groups or materials used employing Chi-square tests at p<0.05 probability. The relative effectiveness of the single appointment technique using both materials compared to the multi-appointment technique using the same materials cannot be evaluated based on the data presented in this study. The difference in providing treatment to both groups may explain the large number of failures seen in the multi-appointment group which denotes a high risk of performance bias. The same conclusion can be applied to the number of visits needed to complete any treatment in this group. The small numbers of the positive controls in both groups would not allow for identifying any difference between both materials using either technique.

Mackie et al. (1994) compared two Ca(OH)₂ (Reogan Rapid to Hypo-cal) paste preparations. The success for both brands was 100% based on available patients at the time of final analysis (33 children with 38 teeth out of 36 children with 41 teeth). Cases that dropped out (1 patient with 1 tooth) and excluded cases (2 patients with 2 teeth) were not included in the final analysis. ITT analysis if completed would change the total success rate into 92.7%, which would still be a favourable outcome. It should be noted that both comparison groups were Ca(OH)₂ preparations and the results should be interpreted on the basis of comparing the two pastes and not to be applied as a general success rate for Ca(OH)₂ material in multi-visit apexification.

The overall success rates reported in these studies is summarised in Fig. 1.

Calcium hydroxide apexification has been used over many decades as the treatment of choice for non-vital immature incisors where it has been essential to obtain a root end barrier in order to facilitate the placement of a root filling. However, it can be seen from the review that evidence for this technique cannot be deduced from well conducted RCTs.

Therefore the level of recommendation for Ca(OH)₂ apexification is = C/D.

It has been suggested that due to its highly alkaline pH, Ca(OH)₂ can cause desiccation of dentinal proteins thereby leading to the weakening of the tooth structure and predisposing these teeth to fractures. Prolonged dressing of the immature tooth with non-setting Ca(OH)₂ has been shown to result in a reduction in the fracture strength of dentine. A retrospective study of luxated non-vital maxillary incisors treated with Ca(OH)₂ in the root canal found that the frequency of cervical fracture was higher in these teeth (Al-Jundi 2004; Cvek 1992).

Level of Evidence = 2+.

In the last decade there have been a number of laboratory studies that have also shown a significant reduction of resistance to fracture of teeth following prolonged use of Ca(OH)₂. These are:

Andreasen et al. 2002.

Level of Evidence = 2++

Doyon et al. 2005; Rosenberg et al. 2007; Twati et al. 2009b.

Level of Evidence = 3.

In view of these findings clinicians should consider discarding the traditional approach of using prolonged dressing of root canals with Ca(OH)₂ to achieve apexification and consider alternative methods of managing these teeth.

Mineral trioxide aggregate (MTA) first received Food and Drug Administration of the USA (FDA) approval in 1998. It was later used in achieving an apical barrier in non-vital immature teeth. This treatment can be completed in one or two visits depending on the MTA used, thereby reducing the time needed for completion of treatment and restoring the tooth.

MTA is a powder that consists of fine hydrophilic particles that set in the presence of moisture. Hydration of the powder results in a colloidal gel with a pH of 12.5 that solidifies to a hard structure. MTA is available as grey or white and is made mainly of tricalcium silicate, dicalcium silicate, tricalcium aluminate, calcium sulphate dehydrate and bismuth oxide.

There are many favourable characteristics of MTA that indicates its use for managing non-vital immature teeth, these include:

MTA can be used to physically create a barrier at the root end thereby allowing the root canal obturation to be carried out in the same or the next visit. The following procedure is currently recommended:

Powder: sterile water (3:1).

In reviewing the evidence for MTA use it became very clear that the current available evidence does not meet the strict criteria set out by Cochrane collaboration. Most studies are in the form of case reports, case control/cohort or retrospective evaluations of cases (Table 2). However in our opinion these substantial numbers of studies supporting the use of MTA should not be overlooked. Conducting a prospective RCT on treatment outcome comparing Ca(OH)₂ with MTA for managing non-vital immature permanent incisor teeth with an appropriate follow-up period is not only difficult but also expensive to undertake. Despite all the limitations in the reported studies, most if not all have demonstrated excellent clinical outcomes for non-vital immature teeth where MTA was used to create an apical plug, followed by root canal obturation. This is also supported by a recent systematic review and meta-analysis (Nicoloso et al. 2016) which concluded that MTA apexification appears to produce overall better clinical and radiographic success rates among endodontic treatment available in immature necrotic permanent teeth.

In view of these findings clinicians should consider using MTA routinely as a method for creating an apical barrier to allow root canal obturation to be carried out.

The level of recommendation for MTA = C.

Two potential problems have been reported with the use of MTA.

Level of Evidence = 3.

Level of Evidence = 3.

It is important to reinforce the coronal portion of a tooth at the time of final restoration in order to increase the fracture resistance of endodontically managed immature teeth. There is a high frequency of coronal fractures reported for such teeth. (Cvek 1992).

Level of Evidence = 2+.

There is some evidence that fibre posts might be superior to other forms of restorations. (Bateman et al. 2003; Al-Ansari 2007).

Level of Evidence = 1+.

It is important to create a leak-proof coronal seal in order to prevent reinfection of the root canal with microorganisms as there is some evidence that coronal leakage contributes to the failure of endodontic treatment. (Quality guidelines for endodontic treatment 2006).

Level of Evidence = 3/4.

In the last few years there seems to have been a paradigm shift in the way it is proposed to manage teeth with incomplete root development that have become non-vital as a result of trauma, caries or developmental anomalies such as dens-in-dente. The new way of thinking seems to have been prompted by the limitations of the use of Ca(OH)₂ or MTA. Both of these methods allow root canal obturation to be performed through generating a physical barrier against which the root filling can be condensed. However, neither of these methods contributes to any qualitative or quantitative improvement in root dimensions. Rather the evidence reviewed above suggests that both methods can have a detrimental effect on dentine and might make the root more prone to fractures, in particular with the prolonged use of Ca(OH)₂. If any further deposition of dentine or cementum is to be achieved, in order to provide a qualitative improvement of root structure, then vital tissue has to be generated, as only cellular activity can result in any such tissue being deposited. Recently there has been an attempt to re-establish the blood supply in those teeth, which have already become non-vital and the technique is commonly known as the Regenerative or Revitalisation Endodontic Therapy or technique (RET).

Through the repopulation with vital tissue of the root canal space, the RET technique aims to promote continued root development and/or thickening of the dentinal walls, thereby improving the long-term prognosis of the tooth.

The technique is based on the following prerequisites:

There are several sources of stem cells in the oral cavity (Hargreaves et al. 2013) with some researchers implying that stem cells of the apical papilla (SCAP) have a major role in regeneration techniques (Huang et al. 2008). Recently it has been shown that stem cells exist in the apical area of incomplete roots in children and adolescents (Sonoyama et al. 2008). The entity in which these cells exist has been called as stem cells of the apical papilla (SCAP). Sonoyama and co-workers (2008) demonstrated that isolated SCAP grown in cultures have the ability to undergo dentinogenic differentiation when stimulated with dexamethasone supplemented with L-ascorbate-2 phosphate and inorganic phosphate. SCAP cells have also been shown to be capable of differentiating into functional dentinogenic cells in vivo, using implantation techniques in animal experimental models. In summary SCAP have been shown to be similar to dental pulp progenitor cells and therefore, if their potential can be harnessed they could be induced to differentiate into dental pulp cells. Stem cell population growth into the root canal system is achieved mainly through induction of bleeding from the periapical area, which has been achieved in 77% of the work published until May 2014 (Kontakiotis et al. 2015). This has been supported by the work of Lovelace et al. (2011)who showed a 400-600 fold increase in mesenchymal stem cell markers in blood collected from root canals in comparison to those levels found in systemic blood samples.

Following this understanding a technique has been proposed which could harness the potential of the SCAP cells leading to repopulation of the root canal space with vital tissue. This technique has been referred to as revitalisation, revascularisation, repopulation, regeneration or even maturogenesis (Wigler et al. 2013). The exact nature of the tissue repopulating the root canal system is still unclear with histological studies reporting desirable tissues such as fibroblasts, blood vessels and collagen and undesirable tissues such as cementoblasts and osteoblasts (Wigler et al. 2013).

The use of sodium hypochlorite, with concentrations of 1–6%, has been used either as the only irrigant (65% of studies) or in combination with other irrigants in 97% of RET studies published before May 2014 (Kontakiotis et al. 2015). This irrigant has been shown to be a potent antimicrobial material that dissolves organic matter (Martin et al. 2014).

Some laboratory studies have investigated the effect of sodium hypochlorite on stem cells. Martin et al. (2014) assessed the effect of different sodium hypochlorite concentrations (0.5, 1.5, 3 and 6%) followed by either 17% EDTA or normal saline and reported negative effects of high concentration of sodium hypochlorite on the survival and differentiation of SCAP. They recommended the use of 1.5% sodium hypochlorite followed by 17% EDTA. The use of EDTA following irrigation with sodium hypochlorite is now widely recommended (Wigler et al. 2013). Trevino et al. (2011) assessed the effect of different combinations of irrigants on SCAP and reported the best outcome, in terms of cell survival, was following irrigation with only 17% EDTA. Therefore the use of 1.5% sodium hypochlorite followed by 17% EDTA is currently the recommended irrigation system in RET and should be employed in future studies.

The use of an antibiotic paste had been reported in 80% of studies published (Kontakiotis et al. 2015). A tri-antibiotic paste containing 100 mg Metronidazole, 100 mg Minocycline and 100 mg Ciprofloxacin has been shown to have a sufficient bactericidal efficacy and potency to eradicate bacteria from the infected dentine of root canals (Hoshino et al. 1996). Recently, Minocycline has been eliminated from the mixture due to its potential to discolour the tooth (Kim et al. 2010) which was further supported by recent work conducted showing similar antimicrobial effects of the tri-antibiotic and bi-antibiotic pastes (Twati et al. 2011).

Achieving a hermetical coronal seal is also crucial in maintaining a sterile root canal environment. The use of MTA in achieving a hermetic coronal seal, hence preventing future contamination, had been associated with crown discolouration. The most commercially available MTA contains agents used to enhance its radio-opacity, such as bismuth oxide, which is known to cause discolouration of teeth. There are currently several types of contemporary materials with similar biocompatibility and biomineralisation that are recently gaining popularity as suitable materials as a viable replacement for MTA. These include materials e.g. Biodentine^®, EndoSequence^® Root Repair Material and Portland cement (Lenherr et al. 2012; Nazzal et al. 2015). In vitro and in vivo studies have used bioceramics to demonstrate antibacterial effects (Elshamy et al. 2016), biocompatibility to pulp tissue and induction of dental pulp cells proliferation and reparative dentine bridge formation (Liu et al. 2015), whilst producing significantly less discolouration. It is certain that the recommendations for coronal seal material will change as more information on the suitability of these materials become available.

There are an increasing number of commercial scaffolds available for tissue engineering in the medical field but these are too expensive for use in dental practice. A biological scaffold is required within the root canal, which would serve two purposes. Firstly it would provide a matrix into which the cells from SCAP could differentiate. Secondly it should act as a scaffold rich in growth and differentiation factors that are essential to aid with the in-growth of viable tissue into the pulpal space. Currently a blood clot is considered as a favourable scaffold for this technique. The use of blood clot as a scaffold has been used in 75% of RET protocols published before May 2014 (Kontakiotis et al. 2015). Various other scaffolds have been suggested and/or used, such as platelet rich plasma (PRP) and platelet rich fibrin (REF) but these have not shown any added advantage over the use of a blood clot.

Despite the recently published American Association of Endodontics RET protocol, different modifications of RET have been used by researchers (Kontakiotis et al. 2015).

The outline of the technique proposed in general is as follows:

The original idea as proposed by Nygaard-Ostby (1961) regained popularity since its use by Banchs and Trope (2004). In the last few years, several studies have been published including a few RCTs comparing different types of scaffolds or RET against other non-vital immature teeth management techniques such as apexification or MTA apical plug technique. An analysis of the studies that are relevant is given in Table 3.

At present there is insufficient evidence available for this technique to be recommended for use routinely by clinicians for the management of non-vital immature teeth in children. However, it is suggested that clinicians should give due consideration to the use of this method especially in cases where the root development is very immature and even the use of MTA is unlikely to improve the prognosis of the tooth.

The level of recommendation for RET = D.