Therapeutic Irrigant Procedures for Treating Apical Periodontitis (TIPTAP): A triple-blinded parallel-group randomized controlled phase I/II trial

Abstract

Background: Solubilized endogenous dentine extracellular matrix components (dECMs) are potent mediators in pulp regeneration and could potentially promote similar healing effects in diseased periradicular tissues by upregulating local mesenchymal stem cell-derived regenerative events.

Aims: (1) Determine if endodontic treatment outcomes with irrigation regimes promoting dECM release (17% ethylenediaminetetraacetic acid [EDTA]) are equivalent to conventional regimes (5.25% sodium hypochlorite [NaOCl]) in mature permanent teeth with asymptomatic apical periodontitis. (2) Explore changes in pain scores, expressions of periradicular tissue fluid (PTF)-derived inflammatory mediators, and volumtric changes in lesion size between the different irrigant regimes.

Methods: Forty single-rooted teeth, from 37 healthy adults, were block randomized into parallel groups of irrigation with either 17% EDTA, optimized for dECM solubilization, or 5.25% NaOCl (n = 20). All other aspects of the endodontic protocol were standardized over two visits with 14 days of calcium hydroxide intracanal medicament. Patient-reported pain scores were recorded at six hours and then daily for one week post-instrumentation and post-obturation. PTF samples were collected pre-instrumentation and pre-obturation, where analyte profiles (pg/TPC) were determined using an O-link Target-48 cytokine array. Treatment outcomes were clinically and radiographically assessed with cone beam computed tomography at 1 year using dichotomous criteria (favourable/unfavourable) based on volumetric change in lesion size. Participants, operators and assessors were blinded, and per-protocol analyses were conducted using binary logistic regression models with initial alpha values for statistical comparisons set at p < .05.

Results: A 90% recall rate was achieved at one year (NaOCl: 19; EDTA: 17). Favourable outcomes were observed in 89.5% of treatments using NaOCl and 94.1% of treatments using EDTA irrigation, with median lesion volume reductions of 92.5% (IQR: 67.33-99.13) and 95.84% (IQR: 78.81-100), respectively, (p > .05). Odds of unfavourable periradicular healing with EDTA irrigation were 0.53 [95% CI: 0.04-6.44; p > .05]. No serious adverse effects or atypical pain patterns were reported, although two acute exacerbations occurred post-instrumentation with NaOCl irrigation (p > .05). Target-48 panels consistently detected 15 inflammatory analytes in both groups (CCL-2, -3, -4; CSF-1; CXCL-8; HGF; IL-1β, -6, -18; MMP-1, -12; OLR-1; OSM; TNFSF-10; VEGF-A), all of which reduced pre-obturation. At this stage, IL-6 and -18 were significantly more abundant in the intervention group (p < .05).

Conclusions: Therapeutic irrigant regimes promoting dECM solubilization resulted in one-year treatment outcomes equivalent to conventional irrigant protocols with no serious adverse effects reported.

Keywords: apical periodontitis; biomarkers; cone beam computed tomography; dentine extracellular matrix components; postoperative pain; regenerative endodontics.

FIGURE 1

PRIRATE Flow Chart. Sample sizes represent participants at the tooth and patient level (t; p).

FIGURE 2

Pain intensity scores at several time points post‐instrumentation [a; 5.25% NaOCl n = 19; 17% EDTA n = 20] and ‐obturation [b; 5.25% NaOCl n = 19; 17% EDTA n = 18] following irrigation using conventional irrigant regimes (5.25% NaOCl) and those that promote the release of dentine extracellular matrix proteins (17% EDTA). Pain intensity categorized as No Pain = NRS 0; Mild = NRS 1–3; Mod = NRS 4–6; and Severe = NRS 7–10.

FIGURE 3

Volumetric (a) and percentage change (b) in periapical lesion size based on cone beam computed tomography scans of teeth diagnosed with asymptomatic apical periodontitis undergoing root canal treatment with conventional irrigant regimes and those that promote release of dentine extracellular matrix proteins. Data presented as box and whisker plots where central bars represent the median alongside upper and lower interquartile ranges at the edge of boxes and minimum and maximum values for the whiskers. Statistically significant comparisons within groups (p < .01; Wilcoxon Matched Paired tests) presented as horizontal lines.

FIGURE 4

Longitudinal volumetric cone beam computed tomography analysis of periapical lesions following root canal treatment of the UL1. The example represents the axial [a,d,g], sagittal [b,e,h] and coronal [c,f,i] views alongside the preoperative volumetric analysis [j] of a lesion that has completely resolved following 17% EDTA irrigation at the 12 months review interval [g,h,i]. The corresponding pre‐ and postoperative periapical radiographs are depicted in [k] and [l], respectively. Scale bars represent 1 cm.

FIGURE 5

Longitudinal volumetric cone beam computed tomography analysis of periapical lesions following root canal treatment of the UR1. The example represents the axial [a,d,g,j], sagittal [b,e,h,k] and coronal [c,f,i,l] views alongside the pre‐ [m] and postoperative [n] volumetric analysis of a lesion that has increased in size following 5% NaOCl irrigation at the 12 months review interval [g–l]. The corresponding pre‐ and postoperative periapical radiographs are depicted in [o] and [p], respectively. Scale bars represent 1 cm.

FIGURE 6

Longitudinal volumetric cone beam computed tomography analysis of periapical lesions following root canal treatment of the UR1. The example represents the axial [a,d,g,j], sagittal [b,e,h,k] and coronal [c,f,i,l] views alongside the pre‐ [m] and postoperative [n] volumetric analysis of a lesion that has reduced in size following 17% EDTA irrigation at the 12 months review interval [g–l]. The corresponding pre‐ and post‐operative periapical radiographs are depicted in [o] and [p], respectively. Scale bars represent 1 cm.