MD Yannick Hourmant

MD Arnaud Mailloux

MD Sandrine Valade

MD Virginie Lemiale

MD, PhD Elie Azoulay

MD, PhD Michael Darmon
email: michael.darmon@aphp.fr

Impact of early ICU admission on outcome of critically ill and critically ill cancer patients: A systematic review and meta-analysis

Keywords: intensive care unit, cancer, admission, delay, outcome, mortality 4

ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Over the last two decades, survival of critical ill patients admitted in ICU has increased.

Bellomo et al. found a decreased mortality in septic patients [START_REF] Kaukonen | Systemic inflammatory response syndrome criteria in defining severe sepsis[END_REF] and similar results were shown for patients requiring mechanical ventilation [START_REF] Esteban | Evolution of mortality over time in patients receiving mechanical ventilation[END_REF]. Similar trend was observed in critically ill cancer patients with septic shock [START_REF] Zuber | Impact of case volume on survival of septic shock in patients with malignancies*[END_REF] or acute respiratory distress syndrome (ARDS) [START_REF] Azoulay | Acute respiratory distress syndrome in patients with malignancies[END_REF]. More generally, in-ICU survival, in-hospital survival, 1-year survival of critically ill cancer patients was found to have increased [START_REF] Shimabukuro-Vornhagen | Critical care of patients with cancer[END_REF], and this survival improvement remains after adjustment and in the subgroup of cancer patients [START_REF] Darmon | Changes in critically ill cancer patients' short-term outcome over the last decades: results of systematic review with meta-analysis on individual data[END_REF].

Triage, ICU admission policy and early ICU admission strategy are among the many factors participating to this improved outcome. Thus, some studies suggested an increased survival in patients admitted early to the ICU both in the general population [START_REF] Chalfin | Impact of delayed transfer of critically ill patients from the emergency department to the intensive care unit*[END_REF][START_REF] Restrepo | Late admission to the ICU in patients with community-acquired pneumonia is associated with higher mortality[END_REF] and in immunocompromised patients [START_REF] Mokart | Delayed intensive care unit admission is associated with increased mortality in patients with cancer with acute respiratory failure[END_REF][START_REF] De Montmollin | Outcomes in critically ill cancer patients with septic shock of pulmonary origin[END_REF].

In this systematic review of the literature, we sought to report the results of studies assessing relationship between early ICU admission and outcome in patients with and without underlying malignancy. Secondary endpoint was to assess reasons for delayed ICU admission.

Methods

Systematic review

This systematic review was performed according to PRISMA statements and PRISMA checklist is reported [START_REF] Shamseer | Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation[END_REF] (supplementary appendix, table S1).

The protocol of the systematic review was registered to the PROSPERO database NEOPLASM) (figure 2).

Any reference cited in the analyzed articles and reviews were scrutinized and searched.

Research limits were set between 1970 and July 2017.

Study population

Adult patients (>17 year) admitted to the ICU.

Time to ICU admission was defined by the estimation of time between hospital and ICU stay.

The outcomes of interest were hospital mortality or in its absence ICU and then 1-year mortality rates.

Study selection and inclusion exclusion criteria

Two investigators (YH and AM) screened titles and abstracts from all identified articles by both electronic and manual searches. Articles that did not meet the inclusion criteria were excluded. All remaining articles were obtained and full-text reviewed independently by YH and AM based on the following criteria: 1/ inclusion criteria confirmed; 2/ available data regarding delay between hospital and ICU admission; 3/ available data regarding mortality.

For six articles, the two investigators disagreed on their reading of the reported data.

Disagreements were resolved by discussion between investigators and a consensus was reached in every case. The flow diagram of the literature search is displayed in figure 1 for general ICU patients and figure 4 for critically ill cancer patients.

Data extraction

The texts of the potentially relevant studies were systematically evaluated. Data were extracted, synthesized, and analyzed. For each study, the following parameters were recorded: authors' names, date of publication, study design, journal publication, sample size and included subjects and RCTs, main results on association between delayed admission and mortality.

Early ICU admission definition

Early ICU admission was defined either according to authors' definitions or as the group with the lowest delay between first assessment and ICU admission.

Late ICU admission was defined according to authors' group or as the group with the longest delay between first assessment and ICU admission When more than 2 groups (early and late ICU admission) were described by authors, groups with intermediate delay between ICU admission and outcome were excluded from the analysis.

Statistical analysis

Overall mortality of included patients and mortality in included studies are reported as medians (interquartile ranges). Publication bias was assessed by visually inspecting the funnel plot and summary estimates of relative risk and their 95% confidence interval were calculated using both fixed and random-effects model.

Cochran's Chi² test and I² test for heterogeneity were used to assess inter-study heterogeneity [START_REF] Higgins | Measuring inconsistency in metaanalyses[END_REF]. The Chi² test assesses whether observed differences among results are compatible with chance alone, and the I² describes the percentage of the variability in effect estimates that results from heterogeneity rather than from sampling error. An I² test for heterogeneity above 0.25 was considered to indicate moderate heterogeneity. Statistically significant heterogeneity was considered present at Chi² P < 0.10 and I² > 50%. All effect sizes with a p < .05 were considered significant. Tests were two-sided.

In way to explain heterogeneity, a meta-regression was performed.

Last, three sensitivity analyses were performed in way to assess impact of publication bias in the observed results using namely trim and fill method [START_REF] Peters | Performance of the trim and fill method in the presence of publication bias and between-study heterogeneity[END_REF][START_REF] Duval | Trim and Fill: A Simple Funnel-Plot-Based Method of Testing and Adjusting for Publication Bias in Meta-Analysis[END_REF], Copas method [START_REF] Copas | A sensitivity analysis for publication bias in systematic reviews[END_REF] and Outcome Reporting bias method [START_REF] Copas | Model-based sensitivity analysis for outcome reporting bias in the meta analysis of benefit and harm outcomes[END_REF].

As sensitivity analysis an updated research was performed on February 2020.

All analyses were carried out with software R, version 3.4.4. The 'Meta', the 'metasens' and 'metaphor' packages were used to produce forest plots and run meta-regression and sensitivity analyses.

Results

General ICU population

Our initial search yielded 663 citations, of which 16 were excluded due to duplication and 576 were excluded as irrelevant for the scope of this review. All abstracts of the remaining records were carefully checked and 71 full text articles were scrutinized for further evaluation.

Twelve studies were excluded as not focusing on critically ill patients or ICU setting, and 28

as not focusing on ICU admission process. Thirty-one studies were ultimately included in this analysis (Figure 1) [START_REF] Chalfin | Impact of delayed transfer of critically ill patients from the emergency department to the intensive care unit*[END_REF][START_REF] Restrepo | Late admission to the ICU in patients with community-acquired pneumonia is associated with higher mortality[END_REF].

Characteristics of the studies are reported in table S2 and table S3.

These studies were published between 1990 and 2017. A total of 122, 475 patients were included in these studies, of whom 66,797 and 6,416 patients were considered as early ICU admission and delayed ICU admission respectively. For 49,262 patients, no classification was available between early or delayed ICU admission group. There were 14 prospective studies, every of them being cohort studies. The majority of the studies (n=23, 74%) had a monocentric design.

In the general ICU population early ICU admission was associated with decreased mortality with risk ratio of 0.66 [95%CI 0.59-0.74] while using fixed effect model and 0.70 [95%CI 0.67-0.72] while using random effect model. Significant heterogeneity was noted (I²=66%) (Figure 3).

The funnel plot shown in Figure S1 and linear regression test for funnel plot asymmetry did not suggest any publication bias.

Critically Ill cancer patients

Our initial search yielded 932 citations, of which 24 were excluded due to duplication and 865 were excluded as irrelevant for the scope of this review. All abstracts of the remaining records were carefully checked and 43 full text articles were scrutinized for further evaluation. Fifteen studies were excluded as not focusing onco-hematology population, eleven studies without assessment on timing of ICU admission and 4 studies were didactic review (Figure 2) [START_REF] Mokart | Delayed intensive care unit admission is associated with increased mortality in patients with cancer with acute respiratory failure[END_REF][START_REF] De Montmollin | Outcomes in critically ill cancer patients with septic shock of pulmonary origin[END_REF][START_REF] Hung | Determining delayed admission to the intensive care unit for mechanically ventilated patients in the emergency department[END_REF][START_REF] Soares | Characteristics and outcomes of patients with cancer requiring admission to intensive care units: A prospective multicenter study*[END_REF][START_REF] Azoulay | Outcomes of Critically Ill Patients With Hematologic Malignancies: Prospective Multicenter Data From France and Belgium--A Groupe de Recherche Respiratoire en Reanimation Onco-Hematologique Study[END_REF][START_REF] Groeger | Probability of mortality of critically ill cancer patients at 72-h of intensive care unit (ICU) management[END_REF][START_REF] Thiery | Outcome of Cancer Patients Considered for Intensive Care Unit Admission: A Hospital-Wide Prospective Study[END_REF][START_REF] Peigne | Continued survival gains in recent years among critically ill myeloma patients[END_REF][START_REF] Hampshire | Admission factors associated with hospital mortality in patients with haematological malignancy admitted to UK adult, general critical care units: a secondary analysis of the ICNARC Case Mix Programme Database[END_REF][START_REF] Lengliné | Intensive care unit management of patients with newly diagnosed acute myeloid leukemia with no organ failure[END_REF][START_REF] Song | Early intervention on the outcomes in critically ill cancer patients admitted to intensive care units[END_REF][START_REF] Lee | Effect of Early Intervention on Long-Term Outcomes of Critically Ill Cancer Patients Admitted to ICUs[END_REF][START_REF] Doukhan | Respiratory events in ward are associated with later intensive care unit (ICU) admission and hospital mortality in onco-hematology patients not admitted to ICU after a first request[END_REF][START_REF] Bird | Outcomes and prognostic factors in patients with haematological malignancy admitted to a specialist cancer intensive care unit: a 5 yr study[END_REF].

Characteristics of the studies are reported in table S4 and table S5. These studies were published between 1998 and 2017. A total of 12, 751 patients were included in these studies, including: 1272 patients considered as early ICU admission and 1142 considered as delayed ICU admission. For 10, 337 patients, no classification was available between early or delayed ICU admission Overall, 8 of these studies (62%) were prospective, 7 (50%) were monocentric studies and none was randomized.

In this subset of patients, early ICU admission was associated with decreased mortality with risk ratio of 0.69 [95%CI 0.62-0.76] while using fixed effect model and 0.69 [95%CI 0.52-0.9] while using random effect model. Significant heterogeneity was noted (I²=80%) (Figure 5).

The funnel plot shown in Figure S2 and linear regression test for funnel plot asymmetry did not suggest any publication bias.

Meta-regression and sensitivity analysis.

In order to explain the vast heterogeneity observed in both meta-analyses, meta-regressions and sensitivity analyses were performed.

In the general ICU population, characteristics of the trials (prospective vs. retrospective, monocenter vs. multicenter) had no impact on findings. However, publication after 2010 (median) was associated with a lower effect of early admission (log risk-ratio of early ICU In the onco-hematological patients, characteristics of the trials (prospective vs.

retrospective, monocenter vs. multicenter) and year of publication had no impact on findings.

In the general ICU population, results were unchanged in sensitivity analyses used to adjust for funnel plot outlier (Trim and fill analysis and Copas methods) or analysis for Outcome Reporting Bias (supplementary appendix, Table S6).

In the Onco-Hematological ICU population, neither Copas methods nor sensitivity analysis for Outcome Reporting Bias, changed results (supplementary appendix, Table S7). Trim and fill method to adjust for funnel plot outlier led absence of impact of early ICU admission on outcome (OR 0.84; 95%CI [0.64-1.10]) (supplementary appendix, Table S7).

Last, an updated analysis was performed on February 2020 as sensitivity analysis. A single study was found relevant for this meta-analysis in the general ICU population. Results of the updated analysis were unchanged and are reported in supplementary appendix (Figure S3 and

Figure S4

). No study was found relevant in the Onco-Hematological ICU group.

Discussion

To the best of our knowledge, this is the first systematic review to address the relationship between time to ICU admission and outcomes with a special focus for critically ill cancer patients. Delayed ICU admission is believed to be associated with higher mortality or unfavorable outcomes. This assumption is however poorly supported by high degree evidences, except in very specific conditions. Hence, fast implementation of treatment is a standard of care for septic patients [START_REF] Rhodes | Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016[END_REF], and delay between event and management (treatment or transfer to an intensive care unit) well validated in patients with myocardial infarction [START_REF] Van De Werf | Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: The Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology[END_REF],

stroke [START_REF] Furie | Guidelines for the Early Management of Patients With Acute Ischemic Stroke[END_REF] or major trauma [START_REF] Sampalis | Direct Transport to Tertiary Trauma Centers versus Transfer from Lower Level Facilities: Impact on Mortality and Morbidity among Patients with Major Trauma[END_REF]. According to our results, a shorter delay between hospitalization and ICU admission is associated with lower mortality in the general ICU population and in critically ill cancer patients.

In general ICU population, a large multicentric cohort [START_REF] Chalfin | Impact of delayed transfer of critically ill patients from the emergency department to the intensive care unit*[END_REF] published in 2007 showed a better outcome for patients considered with an early ICU admission (emergency department boarding < 6 hrs.): a decrease in hospital length of stay, a decrease in ICU and in hospital mortality. In a recent retrospective study [START_REF] Hung | Determining delayed admission to the intensive care unit for mechanically ventilated patients in the emergency department[END_REF], delayed ICU admission (waiting > 4 hours in emergency department) affected the outcomes of 21-ventilator-day mortality and prolonged hospital stay. Some studies however show inconsistent results and O'Callaghan [START_REF] O'callaghan | An observational study to determine the effect of delayed admission to the intensive care unit on patient outcome[END_REF] showed no difference for ICU length of stay or in ICU mortality in a retrospective study between delay (> 3hrs from referral to admission) or no delay-group. As underlined by this review, difference in definition and publication bias in favor of positive study publication may explain these discrepant results.

In critically ill cancer patients, results are more consistent, a single study failing to demonstrate benefit of early ICU admission [START_REF] Doukhan | Respiratory events in ward are associated with later intensive care unit (ICU) admission and hospital mortality in onco-hematology patients not admitted to ICU after a first request[END_REF]. This study however included a limited sample size, and secondary endpoints were in favor of early ICU admission. More importantly, studies in this setting, concurrently suggested difficulty to assess patients' severity, a high rate of clinical worsening after initial assessment by physician and a high mortality in patients initially considered too well to benefit from ICU admission and requiring subsequent ICU admission [START_REF] Thiéry | Outcome of Cancer Patients Considered for Intensive Care Unit Admission: A Hospital-Wide Prospective Study[END_REF]. For acute respiratory failure patients [START_REF] Mokart | Delayed intensive care unit admission is associated with increased mortality in patients with cancer with acute respiratory failure[END_REF], a delayed ICU admission (> 2 days between respiratory symptoms onset and ICU admission) was an independent predictor of day-28 mortality. A prospective cohort showed [START_REF] Lee | Effect of Early Intervention on Long-Term Outcomes of Critically Ill Cancer Patients Admitted to ICUs[END_REF] an increase of long-term outcome in early intervention group after clinical derangement on general wards (< 1.5 hours) and reduced 1-year mortality compared to late intervention. However, no high degree of evidence study was recorded, raising doubt as regard to causality of the findings in this setting.

Several limits deserve to be noted. First, both results in general ICU population and critically ill cancer patients reported a high heterogeneity across studies. The performed metaregression failed to identify characteristics of the studies as associated with the observed effect. Hence, only date of publication was found to be associated with a lower effect for studies published more recently. Another limit is related to definition of early ICU admission definition which was inconsistent across studies, mainly relying on time between hospital or Emergency Department and ICU admission. Another limit is that most of the reported studies being low level evidence studies, patient characteristics and study design varying across publication. Thus, clustering effect related to unrecorded variable may explain timing of ICU admission, these variables ranging from patients' severity, disease course, ICU admission policy, every of which may have influenced our findings. For example, availability of ICU beds, influence of rapid response team, health care system organization and their interaction with prompt ICU admission or outcome were infrequently assessed [START_REF] Song | Early intervention on the outcomes in critically ill cancer patients admitted to intensive care units[END_REF] and could not be specifically evaluated in this study. In the same line, reason for ICU admission may influence timing of ICU admission and therefore findings. Despite our best efforts, it was impossible to adjust for this limit in this meta-analysis on aggregated data. Underlying reason for ICU admission may therefore act as a confounder which may have influenced our findings.

Moreover, timing of ICU admission may be viewed as a continuous variable rather than a binary variable. Additional studies may be required to assess whether timing as continuous variable may influence outcome and if patients' case-mix may interact with this association, different case-mix being potentially associated with different patterns. Thus, despite these encouraging results, benefit of early ICU admission needs to be validated by low risk of bias studies.

This systematic review suggest that early ICU admission is associated with decreased mortality in the general ICU population and in Critically ill Cancer Patients. These data however arise from studies at high risk of bias, and a high heterogeneity was noted.

Additional studies are required to confirm potential benefit of multifaceted strategies aiming to decrease delay between early sign of organ dysfunction and ICU admission, to assess impact of such strategy in real life practice and on hard clinical endpoints, while taking into account patients' and patients' next of kin reported outcome on one hand and cost-benefit ratio for the health care system on the other.

Figures captionsFigure 1 -Figure 2 -

 12 Figures captions Figure 1 -Flow chart of study selection for studies in general ICU population Figure 2 -Flow chart of study selection for studies in critically ill cancer patients.

Figure 3 -

 3 Figure 3 -Impact of early ICU admission in the general ICU population.

Figure 4 -

 4 Figure 4 -Impact of early ICU admission in critically ill cancer patients.

The other authors declare having no conflict of interest related to this manuscript.


Natacha Linas

Nicolas Decerle

Marie-Laure Munoz-Sanchez

Denise Faulks

Valérie Collado

Emmanuel Nicolas

Prof Martine Hennequin
email: martine.hennequin@uca.fr

Pierre-Yves Cousson

Long-term Outcomes of Full Pulpotomy in Permanent Molars for Patients Treated in a Single, Short Session under Special Conditions

ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

INTRODUCTION

For the purposes of this article, 'special conditions' is a term characterizing a medical, social or environmental context that imposes restrictions on the provision of conventional dental treatment. These restrictions may include limited intervention time, need for rehabilitation in a single, short session, particular ergonomic conditions, difficulty in reaching a precise diagnosis, availability of low cost materials only, and need for easily handled materials. Such special conditions are encountered during pandemic periods due to the need to limit high-risk contamination by saliva, blood, mucosal secretions and physical contact; during dental care under general anaesthesia (GA); and during humanitarian dental interventions. Reversible and irreversible pulpitis due to deep carious lesions or injury are the most common complaint reported in these situations [START_REF] Yu | Characteristics of Endodontic Emergencies during COVID-19 Outbreak in Wuhan[END_REF]. In order to avoid extractions, endodontic procedures should be adapted to the context of the special conditions, whilst aiming to obtain the same outcome as conventional academic procedures, i.e. maintenance of an asymptomatic and functional tooth in the mouth [START_REF]Guide to Clinical Endodontics -Sixth Edition[END_REF].

In past years, convergent results from the literature suggest that permanent vital teeth with pulpitis (3) may be treated using full pulpotomy. A recent systematic review reported a clinical success rate of pulpotomy performed on permanent teeth with irreversible pulpitis of 93.97%, and a radiological success rate of 88.39% after 36 months follow-up [START_REF] Cushley | Pulpotomy for mature carious teeth with symptoms of irreversible pulpitis: A systematic review[END_REF]. Several studies have shown similar success rates for full pulpotomy compared to root canal treatment (RCT) [START_REF] Cushley | Pulpotomy for mature carious teeth with symptoms of irreversible pulpitis: A systematic review[END_REF][START_REF] Asgary | Two-year results of vital pulp therapy in permanent molars with irreversible pulpitis: an ongoing multicenter randomized clinical trial[END_REF]. It might be expected that full pulpotomy will become the endodontic treatment of choice for affected teeth with a vital pulp, instead of RCT. This may be particularly true for difficult endodontic cases [START_REF] Azim | The Tennessee study: factors affecting treatment outcome and healing time following nonsurgical root canal treatment[END_REF] and when treatment is undertaken in special conditions limiting the operatory time and subsequent intervention. Patients consulting dental services during pandemic periods, those treated under GA, and those treated during humanitarian crises share the same special conditions for treating vital teeth with deep carious lesions.

Performing endodontic under special conditions is a challenge as RCT is time-consuming and requires advanced technology [START_REF] Alsaleh | Is endodontic treatment performed under general anaesthesia technically acceptable?[END_REF]. These conditions are neglected in the international guidelines. Local protocols established in these contexts indicate extraction, abstinence and/or prescription instead of endodontic treatment. Consequently, being treated under special conditions implies degraded treatment outcomes with extractions being preferred to minimally invasive endodontics. Ethical issues impose however that patients receive equitable quality of care, and equitable treatment outcomes, whether treated conventionally or under certain constraints [START_REF] Boeckxstaens | The equity dimension in evaluations of the quality and outcomes framework: a systematic review[END_REF]. In this context, it is legitimate to investigate whether full pulpotomy can be indicated instead of RCT. Answering this question implies reviewing the literature to define which procedures and materials could be used for full pulpotomy and coronal restoration in a single session, and then verifying the outcomes of these adapted procedures by clinical trial. Data from dental treatment under GA might be considered as a reference for full pulpotomy under special conditions, potentially offering an opportunity to evaluate this conservative solution for treating patients during pandemic periods or humanitarian crises.

Literature reviews on materials for full pulpotomy report radicular pulp capping with Calcium Hydroxide (CaOH2), CaOH2 covered with Zinc Oxide Eugenol cement (ZOE) or reinforced zinc oxide-eugenol cement IRM® (Intermediate Restorative Material), ZOE, Calcium-Enriched Mixture (CEM), Mineral Trioxide Aggregate (MTA) or Biodentine™ [START_REF] Zanini | Which procedures and materials could be applied for full pulpotomy in permanent mature teeth? A systematic review[END_REF][START_REF] Alqaderi | Coronal pulpotomy for cariously exposed permanent posterior teeth with closed apices: A systematic review and meta-analysis[END_REF]. It has previously been suggested that the removal of the most inflamed part of the pulp followed by cavity sealing to avoid reinfection, is a reliable means to obtain pulp sedation [START_REF] Hasselgren | Emergency pulpotomy: pain relieving effect with and without the use of sedative dressings[END_REF]. Overall, there is agreement that calcium silicate cements, such as MTA, CEM and Biodentine™, are pulpal regenerative materials that can result in both pulp healing and clinical success. However, positive clinical results have also been reported with CaOH2 [START_REF] Kumar | Comparative evaluation of plateletrich fibrin, mineral trioxide aggregate, and calcium hydroxide as pulpotomy agents in permanent molars with irreversible pulpitis: A randomized controlled trial[END_REF] or CaOH2 covered with ZOE [START_REF] Cousson | A follow-up study of pulpotomies and root canal treatments performed under general anaesthesia[END_REF] or IRM® [START_REF] Mcdougal | Success of an alternative for interim management of irreversible pulpitis[END_REF], despite the lack of regular tertiary dentinogenesis induction. Thus procedural arguments, instead of biological ones, may be considered when proposing materials for radicular pulp capping under special conditions. The chosen pulp capping material should be easy to handle, have a fast setting time and be compatible with immediate coronal restoration. The setting time of MTA is long, over two hours, leading to a delay in the permanent restoration and increasing the risk of immediate post-operative contamination. Of the these materials reported for pulpotomy in permanent teeth, only Biodentine™ and IRM® allow the tooth to be restored immediately. The setting times of Biodentine®, MTA Angelus® or MM-MTA® are much longer than that of IRM® and their costs are much higher. All these considerations tend to indicate IRM® as an appropriate pulp capping material for full pulpotomy performed under special conditions. However, IRM® is not currently considered to be a pulp capping material except for deciduous teeth [START_REF] Hui-Derksen | Retrospective record review: reinforced zinc oxide-eugenol pulpotomy: a retrospective study[END_REF] and there is a need to assess the long-term outcome of pulpotomies undertaken using this material.

The decision to use stainless steel crowns for the coronal restoration of teeth with deep carious lesions following pulpotomy under GA was also based on previous studies. Survival rates of teeth with carious cavities on more than three surfaces have been shown to be higher when restored with full or partial crowns rather than with composite restorations [START_REF] Dammaschke | Influence of coronal restorations on the fracture resistance of root canal-treated premolar and molar teeth: a retrospective study[END_REF]. Teeth being restored with composite [START_REF] Desai | Comparison of fracture resistance of teeth restored with ceramic inlay and resin composite: an in vitro study[END_REF][START_REF] Ozakar-Ilday | Three-year clinical performance of two indirect composite inlays compared to direct composite restorations[END_REF] had worse fracture resistance and marginal integrity, increased cervical marginal micro-leakage, more surface roughness, postoperative sensitivity and soft-tissue irritation than those restored with indirect full or partial crowns. Indirect restoration is not feasible under special conditions, direct bonded restorations are time consuming and incompatible with IRM, amalgam restorations are generally to be avoided for ecological reasons. The use of pulpotomy with IRM® followed by the immediate placement of a stainless steel crown could thus be a conceivable alternative procedure for the treatment of vital teeth under special conditions [START_REF] Sigal | Stainless steel crowns as a restoration for permanent posterior teeth in people with special needs: A retrospective study[END_REF][START_REF] Linas | Conservative and endodontic treatment performed under general anesthesia: A discussion of protocols and outcomes[END_REF].

This study aims to assess the long-term outcome of pulpotomies performed with IRM® on permanent molars and immediately restored using stainless steel crowns under GA.

MATERIALS AND METHODS

Type of study

This retrospective study was approved by the local ethical committee (CE-CIC-GREN-5044-11/17) and was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments.

Data collection

The study population consisted of all patients from the special care unit of the Dental University Hospital of Clermont-Ferrand, treated under GA between November 2008 and July 2017. Local protocols impose a conservative full-mouth rehabilitation approach with as few extractions as possible. Indications included patients presenting anxiety disorders and high levels of carious disease, medically-compromised patients, patients with disability (physical, cognitive or mental) and patients presenting with a severe gag reflex. For all patients, a full record is kept of the dental status and diagnoses at the start of the intervention, and of the treatment provided during that session. Patients were excluded if the treatment did not include at least one permanent molar treated by full pulpotomy and stainless steel crown placement.

The beginning of the follow-up period (T0) was defined as the date at which the pulpotomy was performed under GA. The immediate post-operative radiograph was collected.

After GA, patients are routinely scheduled for a one-month post-operative appointment. They are then free to come back to the hospital for regular annual check-ups if they wish. Clinical and radiographic evaluations were undertaken at each check-up appointment. Regular checkups were undertaken in the dental surgery with or without conscious sedation, or under subsequent GA depending on the level of patient cooperation. No systematic recall of patients was carried out, except for the one-month post-operative appointment. For each patient, the radiological and clinical data recorded at the longest follow-up period (T1) were retained to assess pulpotomy outcome.

Pulpal status

Performing all diagnostic tests pre-operatively was not systematically possible due to medical, physical, cognitive or mental conditions of the patients. Pulpal status was evaluated during the intervention under GA, and the tooth was categorized as either vital or non-vital according to clinical and radiological criteria. During the clinical examination, the absence of a sinus tract or swelling were verified. Radiographically, peri-apical health was determined on retroalveolar radiography using the Peri-Apical Index (PAI), described by Orstavik et al. in 1986 (20). Pulpotomies were performed on teeth with a PAI of 1, 2 or 3. Pulp vitality was confirmed per-operatively by presence of bleeding in the pulp chamber and from the canal orifices. Conventional root canal treatment was performed for non-vital teeth and these were not included in the study.

Procedure for pulpotomy

After rubber dam placement, carious tissue was removed under irrigation with a round tungsten carbide bur in a slow-speed hand-piece. Once the pulp chamber was opened, constant irrigation with 2.5% hypochloride solution was used for each further step. Shaping of the access cavity was undertaken with a Zekrya bur in a high-speed hand-piece. Preparation of the canal orifices was undertaken with a no. 3 or 4-sized Gates Glidden bur in a slow-speed hand-piece. Bleeding had to stop within 6 minutes. After final hypochloride irrigation and drying, pulp capping was performed by placing zinc oxide-eugenol cement (IRM®) into the access cavity and all canal orifices. The definitive restoration was undertaken immediately after the pulpotomy procedure, using stainless steel preformed crowns sealed with glass ionomer cement (GIC).

Outcome evaluation criteria

Outcome evaluation included a combination of clinical and radiographic examination (Table 1) [START_REF] Zanini | A Review of Criteria for the Evaluation of Pulpotomy Outcomes in Mature Permanent Teeth[END_REF]. Radiographically, the evolution of PAI [START_REF] Orstavik | The periapical index: a scoring system for radiographic assessment of apical periodontitis[END_REF] was assessed between T0 (post-operative radiograph taken immediately following treatment) and T1 (radiograph taken during the latest check-up appointment). For a tooth with multiple root canals, the root with the highest PAI is taken into account. For immature teeth, further physiological root growth was verified between T0 and T1.

Clinical assessment was undertaken by the patient's usual practitioner at a regular check-up appointment. Data regarding presence of pain, sinus tract, or swelling were recorded in the patient's medical file. Due to the ethical frame of this observational study, it was not possible to blind the assessors to the collection of clinical data. However, blind assessment was respected for radiological assessments. PAI scores at T0 and T1 were assessed using the immediate postoperative and long-term follow-up radiographs. The calibrated investigators scored the PAI for each tooth independently. Preoperative radiographs were not considered for outcome assessment in order to blind assessors between T0 and T1 images.

For the evaluation of radiological criteria, all radiographs collected at T0 and T1 were proposed in a random order to be interpreted by two calibrated investigators. If there was a disagreement, a consensual decision was made between both readers and a third calibrated investigator. For calibration, both investigators were trained to interpret PAI scores with a test and retest 15 days apart on 100 X-rays illustrating the five score categories. The intra-class correlation coefficient (ICC) for inter-rater assessment was 0.95 (p<0.001) for the test phase and 0.93 (p<0.001) for the retest at 15 days. Intra-rater validity was 0.87 (p<0.001) for the first expert and 0.90 (p<0.001) for the second expert. The first examiner's reliability was 0.87 (p<0.001) relative to the expert panel on the test and 0.89 (p<0.001) on the retest at 15 days and for the second examiner, the reliability relative to the expert panel was 0.86 (p<0.001) on the test and 0.88 (p<0.001) on the retest.

Factors potentially affecting treatment outcomes

Aetiology

The dental pathology or indication for endodontic treatment were grouped into four categories: carious disease, molar-incisor hypomineralisation, bruxism, and endodontic treatment in preparation of prosthetic rehabilitation.

Tooth maturity

Teeth were dichotomized into two categories with regards apical growth (mature/immature teeth) [START_REF] Nolla | The development of permanent teeth[END_REF].

Potential difficulty of endodontic treatment

Evaluation of the potential difficulty of RCT was performed using the American Association of Endodontists form [START_REF]Endodontic Case Difficulty Assessment Form and Guidelines[END_REF][START_REF] Simon | Endodontic case difficulty assessment: the team approach[END_REF]. Only three criteria were applicable for pulpotomies: coronal shape, root canal shape, and root canal radiographic appearance.

Statistical analysis

Descriptive analysis was performed using Excel and the statistics were undertaken using IBM SPSS Statistics version 25 (Statistical Package for the Social Sciences). Student's t-tests were used to compare the whole group to the follow-up group with respect to age, average duration of the intervention under GA, and average number of teeth treated under GA. Pearson chisquared tests were used to compare the whole group to the follow-up group with regards sex, patient typology, data on the type of treated teeth and also to analyse the impact of aetiology, tooth maturity and endodontic difficulty criteria on pulpotomy outcomes.

RESULTS

Participants

The distribution of included teeth (patients) is presented in Figure 1. The whole study group consisted of 338 patients (age range: 7-93 years old; of which 96 were <16 years-old) presenting 608 permanent molars treated with full IRM® pulpotomy and immediately restored with stainless steel crowns.

The follow-up group consisted of 143 patients (age range: 9-64 years old; of which 21 were <16 years-old), presenting 263 treated teeth, who attended a follow-up check-up during which a complete clinical and radiological examination could be performed. The patient follow-up rate was 42.3%. The average follow-up time was 29.9 ± 26.6 months (min = 1, max = 88).

The median follow-up time was 24 months. Comparisons between whole and follow-up groups are reported in Table 2 in terms of patients and in Table 3 in terms of teeth.

Follow-up evaluation

Of the 263 evaluated treatments, 234 (89%) were effective, 20 (7.6%) were of uncertain outcome and 9 (3.4%) were ineffective. The rate of effectiveness was 91.7% within 24 months and 86.2% after a follow up period of over 24 months. The distribution of the treatments' outcome is presented in Table 4. Of the factors tested, no criteria statistically influenced the outcome (Pearson Chi square test, NS).

DISCUSSION

Treating vital teeth using IRM® full pulpotomy and stainless steel crown placement in a single session is effective in the long term. This study was conducted in patients treated under GA, but its findings concern other special conditions in which patients require treatment in a single, short session. In such special conditions, This procedure allows vital teeth to be managed with a long-term goal, avoiding both extraction and the need for a second appointment. Time constraints and one-off service access are special conditions that often exclude conventional endodontic procedures, particularly if several teeth need to be treated.

Pulpotomy and immediate stainless steel crown placement in vital permanent teeth are adapted procedures that should be considered as validated alternatives to conventional "academic" procedures in such conditions. This study demonstrated that these alternative procedures attain the outcomes of academic treatments i.e. maintenance of an asymptomatic and functional tooth in the mouth. Moreover, the opportunity remains to replace stainless steel crowns with conventional crowns at a later stage, when the causes determining the special conditions relent. In terms of public health, this implies that there is no loss of equity in treatment outcomes as patients retain all the benefits of preserving their teeth.

Beside the public health implications, it is of interest to discuss the results of this study in light of previous studies on full pulpotomy. Based on clinical and radiological criteria, this study reports unexpectedly positive results from full pulpotomy with IRM®. A previous study reported strong evidence for the use of MTA, CEM or Biodentine™ for pulp capping [START_REF] Zanini | A Review of Criteria for the Evaluation of Pulpotomy Outcomes in Mature Permanent Teeth[END_REF].

Differences between criteria used to evaluate the success of pulpotomy could explain this situation. Some authors focus on the biological effect of the pulpotomy material on the pulp and evaluate the development of a dentinal bridge as a criterion of success [START_REF] Taha | Assessment of Mineral Trioxide Aggregate pulpotomy in mature permanent teeth with carious exposures[END_REF][START_REF] Nosrat | A preliminary report on histological outcome of pulpotomy with endodontic biomaterials vs calcium hydroxide[END_REF][START_REF] Kunert | Permanent teeth pulpotomy survival analysis: retrospective follow-up[END_REF]. However, the radiological evaluation of the development of a dentinal bridge is not reliable and even if it is detected, neither the quality of the bridge nor the pulpal status under the bridge can be tested [START_REF] Zanini | A Review of Criteria for the Evaluation of Pulpotomy Outcomes in Mature Permanent Teeth[END_REF]. Moreover, a dentinal bridge is not always created under calcium silicate basedcements, such as MTA and Biodentine™ [START_REF] Taha | Full Pulpotomy with Biodentine in Symptomatic Young Permanent Teeth with Carious Exposure[END_REF]. Such criteria assess the biological impact of the material on pulpal tissues, considered as a sign for biocompatibility of material, rather than the effectiveness of the pulpotomy. Other authors consider preservation of a functional tooth as a successful outcome [START_REF] Zanini | A Review of Criteria for the Evaluation of Pulpotomy Outcomes in Mature Permanent Teeth[END_REF]. In this case, as for conventional RCT, evaluation criteria combine both a clinical and a radiological examination. The state of the radicular pulp cannot be objectively assessed. Indeed, vitality tests do not faithfully reflect the histological state of pulpal tissues [START_REF] Ricucci | Correlation between clinical and histologic pulp diagnoses[END_REF][START_REF] Mejàre | Diagnosis of the condition of the dental pulp: a systematic review[END_REF][START_REF] Dummer | Clinical signs and symptoms in pulp disease[END_REF]. Moreover, pulp vitality tests are not reliable once a material has been placed over the pulp canal orifices and it may be difficult to evaluate pulp vitality [START_REF] Zanini | A Review of Criteria for the Evaluation of Pulpotomy Outcomes in Mature Permanent Teeth[END_REF]. In the absence of bacterial contamination, asymptomatic irreversible pulpitis and necrobiosis would not evolve toward further disease [START_REF] Kakehashi | The effects of surgical exposures of dental pulps in germ-free and conventional laboratory rats[END_REF]. The efficiency of pulpotomy is thus assessed clinically and radiographically with the evaluation of the absence of signs of failure. Clinically, failure is expressed by signs and symptoms of acute disease (spontaneous pain, pain on percussion, pain on apical palpation, swelling) or chronic disease (sinus tract). Radiologically, failure is expressed by the development of a periapical lesion, or with an increase in size of a preexisting periapical lesion. In this study, no apical disease was recorded for 89% of cases and radiological uncertainty was recorded for 7.6%. The absence of evolution of a pre-existing periapical lesion suggests that the treatment outcome is uncertain and needs further follow-up [START_REF] Simon | Endodontic case difficulty assessment: the team approach[END_REF] [START_REF] Zanini | A Review of Criteria for the Evaluation of Pulpotomy Outcomes in Mature Permanent Teeth[END_REF].

The composition of the pulp capping material is not the main factor for the successful outcome of pulpotomy. The key concept for effective pulpotomy is the prevention of bacterial infection [START_REF] Zanini | A Review of Criteria for the Evaluation of Pulpotomy Outcomes in Mature Permanent Teeth[END_REF]. During the current study, initial vital pulp status was verified by the absence of clinical and radiological signs of infection and by the presence of bleeding in the pulp chamber and all canal orifices. Aseptic conditions were maintained during all pulpotomy procedures as rubber dam was systematically placed before removal of carious tissue and disinfection was ensured using sodium hypochlorite irrigation. Placement of IRM® as a pulp capping material allowed immediate seal of the radicular pulp segments. Finally, an immediate hermetic coronal restoration was guaranteed by the placement of stainless steel crowns, providing long-term sealing of the pulpotomy. The combination of all these elements, and particularly the immediate hermetic coronal restoration [START_REF] Zanini | Which procedures and materials could be applied for full pulpotomy in permanent mature teeth? A systematic review[END_REF][START_REF] Kunert | Permanent teeth pulpotomy survival analysis: retrospective follow-up[END_REF][START_REF] Taha | Full Pulpotomy with Biodentine in Symptomatic Young Permanent Teeth with Carious Exposure[END_REF][START_REF] Solomon | Coronal Pulpotomy Technique Analysis as an Alternative to Pulpectomy for Preserving the Tooth Vitality, in the Context of Tissue Regeneration: A Correlated Clinical Study across 4 Adult Permanent Molars[END_REF][START_REF] Simon | Should pulp chamber pulpotomy be seen as a permanent treatment? Some preliminary thoughts[END_REF][START_REF] Alqaderi | MTA pulpotomy as an alternative to root canal treatment in children's permanent teeth in a dental public health setting[END_REF], are probably the factors that best explain the high level of effectiveness for pulpotomy reported here. The peripheral seal achieved with glass ionomer cement (GIC) and stainless steel crowns is efficient enough to avoid postoperative contamination, GIC dissolution being limited under the crown. It has been reported that the survival of posterior permanent teeth restored with stainless steel crowns is 79.2% after 10 years and this therefore represents a viable treatment choice for severely carious or fractured posterior permanent teeth [START_REF] Sigal | Stainless steel crowns as a restoration for permanent posterior teeth in people with special needs: A retrospective study[END_REF]. However, serious concerns are raised regarding the ability of preformed stainless steel crowns to satisfy the same specifications as those required from a conventional crown. The quality of the cervical margin of the coronal restoration could affect the long-term outcome of pulpal therapy. Indeed, high adaptation of the cervical limits might induce coronal contamination and radicular contamination is a risk if the margin is too low. Additional studies are needed to determine the tooth survival rate and the degree of periodontal morbidity induced by preformed crowns.

CONCLUSION

The treatment of vital teeth under special conditions should be cause for reflection in endodontic communities. Full pulpotomy with IRM® followed by immediate placement of a stainless steel crown cemented with GIC is a validated alternative procedure to conventional RCT and offers a satisfactory treatment outcome when performed under GA. This procedure should not be restricted to patients treated under GA however, as it is relevant for all special conditions that impose the provision of endodontic treatment in a single, short session, such as dental care emergencies during humanitarian crises or pandemic periods. [START_REF] Zanini | A Review of Criteria for the Evaluation of Pulpotomy Outcomes in Mature Permanent Teeth[END_REF]. (The condition for ineffective pulpotomy with PAI (T0) ≥ 3 and PAI (T1) > 3 could be checked only for teeth with PAI (T0) =3, as PAI (T0) >3 were not included in the cohort).

FIGURE CAPTIONS

Clinical examination Radiographic evolution

Figure 1 :

 1 Figure 1: Distribution of included teeth (patients) over the duration of follow-up for the

  Effective pulpotomy Absence of signs and symptoms after pulpotomy -PAI (T0) and PAI (T1) = 1 -or PAI (T0) = 2 and PAI (T1) ≤ 2 -or PAI (T0) ≥ 3 and PAI (T1) ≤ 2 -and lack of radicular lacunae -for immature teeth: further physiological root growth Uncertain pulpotomy Absence of signs and symptoms after pulpotomy -PAI (T0) = 1 and PAI (T1) = 2 -or PAI (T0) and PAI (T1) = 3 -and lack of radicular lacunae Ineffective pulpotomy Presence of signs and symptoms after pulpotomy -PAI (T0) = 1 or 2 and PAI (T1) ≥ 3 -or PAI (T0) ≥ 3 and PAI (T1) > 3 -and/or presence of radicular lacunae -for immature teeth: no further physiological root growth

Table 1 :

 1 Clinical and radiological criteria used to assess pulpotomy outcome

Table 3 :

 3 Comparison of the teeth of the whole group and the follow-up group in terms of criteria for the difficulty of endodontic treatment (American Association of Endodontists, 2006)[START_REF] Zanini | A Review of Criteria for the Evaluation of Pulpotomy Outcomes in Mature Permanent Teeth[END_REF].

	Whole group No. of teeth	Follow-up group No. of teeth	Pearson Chi Square Test
	(n=608)	(n=263)
	% (n)	% (n)

Table 4 :

 4 Outcome of pulpotomy performed on permanent molars immediately restored with stainless steel crowns according to the follow up period in months (n = 263).

		Follow up evaluation (t = time in months)
		t ≤ 6	6 < t ≤12	12 < t ≤24	24 < t	Total
				% (n)
	Effective pulpotomy	32% (75)	7.7% (18) 12.4% (29)	47.9% (112)	89% (234)
	Uncertain pulpotomy	25% (5)	5% (1)	10% (2)	60% (12)	7.6% (20)
	Ineffective pulpotomy	0	22.2% (2) 11.1% (1)	66.7% (6)	3.4% (9)
	Total per follow-up period	30.4% (80)	8% (21) 12.2% (32)	49.4% (130)	100% (263)

ACKNOWLEDGMENTS

This study did not receive any specific grant or other financial support. The authors deny any conflicts of interest related to this study.

KEYWORDS

Full pulpotomy; Permanent molar; General anaesthesia; Preformed crowns; Follow-up study;

Single session