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A single-centre investigator-blinded randomised parallel-group study protocol to investigate the influence of an acclimatisation appointment on children’s behaviour during N2O/O2 sedation as measured by psychological, behavioural and real-time physiological parameters

Aims and objectives To describe a study protocol of a randomised control trial (RCT) assessing the effectiveness, in reducing dental anxiety, of an acclimatising nitrous oxide sedation (N2O) session prior to actual dental treatment with N2O. Materials and methods A single-centre investigator-blinded parallel-group RCT conducted in a postgraduate dental hospital in Dubai, United Arab Emirates (UAE). Anxious children requiring N2O (aged 5–15 years) will be randomly assigned to; a study group: children who will have a preparatory N2O trial experience or; a control group: children who will only have N2O explained to them. Treatment with N2O for both groups will start at the second visit. The following outcomes will be recorded: completion of dental treatment, anxiety scores at baseline and after treatment (using the Modified Child Dental Anxiety Scale faces), behaviour of the child (using Frankl Rating Behaviour Scale) and the acquisition of real-time physiological anxiety-related parameters (using E4® electronic wrist devices). Results The data will be analysed statistically. Discussion There is a paucity of research regarding dental N2O acclimatising appointments. This RCT will supplement existing literature. Conclusions This RCT will report whether prior acclimatising of a child to N2O sedation is effective, or not, in improving dental treatment behaviour.

No previous study has investigated the effect of an N 2 O/O 2 sedation acclimatisation visit on children's anxiety and stress levels as measured by psychological, behavioural and realtime physiological parameters.
• This study will provide evidence to support the experts' opinion regarding the implementation of an acclimatisation visit.
• The study will establish an effective method in the child's pharmacological behaviour management.

INTRODUCTION
Nitrous oxide inhalation sedation (nitrous oxide/oxygen-N 2 O/O 2 or N 2 O for short) is a mild method of anxiolytic sedation. It is a combination of nitrous oxide and oxygen breathed through a snugly fitting nosepiece, using a special delivery device with robust safety features. This aids the anxious child to feel at ease and allow for dental treatment. 1,2 It is a known fact that fear and anxiety from dentistry are the most commonly known barriers to receiving actual dental treatment, 3 with millions of patients reporting that they, if offered some type of anxiolysis/sedation, would be more amenable to accepting dental procedures. 4 The utilisation of N 2 O or general anaesthesia (GA) is advised by contemporary guidelines to enable the performance of dental treatment in children. This is the case when nonpharmacological behaviour shaping methods fail to lessen children's anxiety and fear, 2 and where invasive dental treatment (such as extractions and restorations) are needed particularly in countries that have a very high rate of dental decay such as the United Arab Emirates. 5,6 The application of N 2 O for dental procedures is essentially reliant on the child's cooperation, allowance of and maintenance of the N 2 O nasal piece to remain securely in position. If N 2 O is gradually titrated to the appropriate levels for the said child, it provides a mild plane of sedation and anxiolysis to allow for dental treatment. 1,2 It is suggested that the use of an acclimatisation (familiarisation) visit, defined to be a session in which N 2 O sedation is solely provided, with no or minimal dental intervention, would enhance the acceptability and the efficacy of N 2 O success. 2 This principle may be contentious. It may increase treatment success and compliance, based on the concepts of graded exposure and cognitive behaviour therapy, 7 which are behind many well-utilised behaviour shaping modalities. However, it may expose the child patient to further pharmacological intercession and increase patient-dentist contact time, subsequently impacting adversely on patient compliance.
The use of an acclimatising N 2 O session had historically been suggested. 8 While the sedation guidelines of the Royal Colleges of Surgeons and the Royal College of Anaesthetists in the United Kingdom in 2015 proposed two visits for N 2 O-an assessment session without the use of N 2 O-and a treatment session, they recommended N 2 O to be administered at the first visit in cases of dental emergencies only. 9 Nevertheless, and most recently, other authorities reverted back to the classical viewpoint. For example, the Scottish Dental Clinical Effectiveness Programme (SDCEP) as recent as 2017 recommended the use of an introductory visit stating "a brief trial of nitrous oxide/oxygen at the assessment appointment may be helpful for the psychological preparation of some children". 2 Therefore, the aforementioned guidelines have advocated the use of an N 2 O accustoming appointment. Nevertheless, and to our awareness, there are no clinical studies that have investigated the effectiveness of such an acclimatisation visit of N 2 O sedation on the acceptance of the child patients of dental procedures. In addition, no robust, methodically designed and objective randomised control trials exist, to our knowledge, to assess if this preparatory appointment would lead to an enhancement in the patients' performance and behaviour during the dental procedure.

THE AIMS OF THE STUDY
This study is a randomised controlled two-arm trial with a singlecentre, single-blinded, parallel-group design. The aims of this clinical research project are to assess the outcome and effect of conducting a short acclimatising preparatory appointment, of 15min duration using N 2 O sedation, on the objectively assessed behaviour of child dental patients and their perceived and measured levels of anxiety during dental treatment. In addition, this study aims to relate and compare this effect in the study group, with that of a group of children who undergo standard dental treatment without the preparatory accustoming appointment of N 2 O sedation.
The null hypothesis The employment of an acclimatising appointment of N 2 O sedation, preceding the instigation of dental treatment will not bring about an enhancement in the child's behaviour and will not lead to a decrease in anxiety levels throughout dental treatment.

MATERIALS AND METHODS
The outline of the suggested study is that of a single-centre, single-blinded (to dental surgeon and physiologist investigators), parallel-group randomised controlled two-arm clinical trial, adhering to the guidelines of the CONSORT Group (Schulz et al., 2010) 10 and to reporting checklist for protocol of a clinical trial based on the SPIRIT guidelines. The overall trial start date (from idea conception) is 01/02/2018, and the proposed end date will be 15/10/2020.

Primary outcome
The changes in the child's behaviour and anxiety levels. The primary outcome measures will be assessed by Heart rate (HR), • Surface skin temperature.
(b) Dental anxiety scores at baseline before the (acclimatisation session) and after treatment (second session) using the Modified Child Dental Anxiety Scale-face version (MCDASf). 11 (c) Children's behaviour score will be recorded using the Frankl Behaviour Rating Scale (FBRS). 12

Secondary outcomes
The following clinical outcomes will be obtained and considered as indications of a beneficial effect of the acclimatisation N 2 O session: (a) The successful completion of the required dental procedure as measured by reviewing the clinical notes documents obtained from the electronic dental records system. (b) The children's and parents' acceptance of the treatment with or without acclimatisation session as measured by guardian/child quantitative questionnaire (see below -Children whose parents refuse to participate in the study. -Patients with contraindications for the use of N 2 O, such as patients who have upper respiratory tract infections (common cold), mouth breathers due to nasal adenoids.
-Patients with obvious skin conditions such as eczema or psoriasis that may impede the use of the E4 ® wrist bands and impair their conductivity.
Study flow and layout A layout of the clinical study is presented in the flowchart seen in Fig. 1. After the initial examination by the clinical investigator, A single-centre investigator-blinded randomised parallel-group study. . . M Kowash et al.
eligibility verification, participant's assent and parents'/guardian's signing the informed consent, the study participants will be randomly assigned to either the control or study group (33 patients per group). The study group will include families (children and parents) who are in need of N 2 O sedation at DDH (Dubai, UAE), who would attend a visit for prevention where N 2 O sedation will be introduced and experienced while the control group will be the families who would attend for a prevention visit and discussion of the sedation procedure only without any actual introduction to N 2 O. A 1:1 allocation-based block randomisation method will be employed. The method of allocation concealment will be attained by using matching, sealed, serially numbered, non-transparent envelopes that will contain group allocation. The envelopes will be opened in sequence by a non-investigator (dental assistant), only after the envelope has been conclusively dispensed to each partaker and will continue to be anonymous to the clinical team.
At the initial screening visit, the anxiety level will be recorded using MCDASf (Fig. 2) to determine the need for N 2 O sedation and subsequently invite the child and parents to participate in the study. Once enroled, an acclimatising visit will be carried out by a single paediatric dentist who will not be involved in the subsequent treatment of the patients. To be constant, an information script will be organised and rehearsed so that the same preoperative instructions about N 2 O sedation will be delivered to all the children and their parents. The patient's physiological signs will be recorded using the E4 ® wrist band (Fig. 3). For the study group only, 15 min of N 2 O sedation will be administered without any dental treatment procedures at the acclimatisation visit.
Throughout the second visit, the dental treatment for both study and control groups will include administering local anaesthesia and restoration of carious teeth, pulp treatment if needed and/or tooth/teeth extractions. The dental treatment will be carried out by the same paediatric dentist. However, a second paediatric dentist blinded to which group the child belongs to will record the FBRS of children while receiving the treatment under N 2 O sedation.
The MCDASf (see Fig. 2) using the SDCEP endorsed and condensed version of the MCDASf questionnaire, 11 not including the last two questions on dental sedation and GA, will be used for all anxious children. The MCDASf is a validated tool that had been used to assess dental anxiety. [14][15][16] The language of the MCDASf questionnaire will be English or Arabic. The English version was translated into Arabic using the forward and backward translation method. The translation was checked by an independent bilingual expert who resolved concerns and discrepancies. To make sure that the translation was effective, a back-translation to the English language was done by an independent translator who back-translated the questionnaire and discrepancies in the translation version were resolved. The total score range of MCDASf is 6-30. Children with a score ≥19 will be considered to have severe dental anxiety (dental phobia), while those with a score of <19 will be considered to have none to moderate anxiety (Table 2). 7 The treatment complexity rank score (Table 3) records the medical status classification, based on the patient's (ASA) classification. 13 In addition to the MCDASf, physiological anxiety-related changes will be recorded using E4 ® wrist bands (see Fig. 3). The wrist band will be placed 5 min before the patient comes into the surgery for treatment and will be taken off 5 min after the completion of treatment. This will enable recording physiological parameters continuously before, during and after the dental treatment. E4 ® wrist bands will provide real-time parameters (Fig. 4) such as EDA also known as GSR, BVP, acceleration, HR, and temperature. E4 ® wrist bands are small, simulate wearing a wristwatch, and we do not anticipate any increase in the children's anxiety as a result of wearing these wrist bands. The E4 ® wrist band was validated 17 and approved by the United States Food and Drug Administration as a medical device. It is used in a wide range of research settings with configurations for palmar skin conductance measurement or using gelled electrodes secured under the band. Additional evaluation of behaviour (Table 4) will be documented using the numerical FBRS scores (FBRS: 1-4, where 1 is very uncooperative). 12 Parents and children will be asked to fill in the survey questionnaire after completion of dental treatment visit to assess their perception and approval (or lack of) How did we look after you when you had your treatment?
How friendly were we when you came to see us?
How well did the dentist explain everything about treating your tooth?
Was it ok having your tooth fixed/extracted?
A single-centre investigator-blinded randomised parallel-group study. . . M Kowash et al. of dental treatment with or without an accustoming session (Table 1a, b).

Calculation of the study's sample size
The study is sized to have an 80% power to detect a statistically significant difference in children's behaviour and anxiety level between the two groups. As there are no previous similar studies, the primary outcome measure is a change in anxiety (a reduction mainly). To our knowledge, no studies had investigated the effect of an acclimatising session of N 2 O on the child's behaviour to base our sample size calculation on. Our biostatistician used Houpt et al. study in 1996 (effects of nitrous oxide on diazepam sedation of young children) to predict the sample size. 18 The predicted sample size is 33 participants in each group and to compensate for dropouts a total of 70 participants will be recruited for both groups.

Role of the participants and the general public in the study
What was the research question, the outcome and outcome measures of the study and how were they developed? A pilot questionnaire to explore the usefulness of an N 2 O acclimatising appointment prior to actual treatment, from the participants' point of view was carried out in a group of 15 child participants (range: 5-15 years). The outcome of this survey was indecisive with 8 out of 15 children expressing a predilection for commencing treatment without an acclimatising session to N 2 O. This resulted in the formulation of the primary outcome measure of our study on investigating the differences in the participants reported dental anxiety scale in children belonging to the study and control groups. What were the preferences and experiences of the participants and their influence in designing the study? We asked the aforementioned children regarding their feeling in carrying out the completion of the MCDASf (anxiety survey). All the children in this survey mentioned that completing MCDASf was acceptable to them. In addition, we showed and placed the E4 watch on their wrists and asked if they would be happy to wear the watch throughout the treatment. Out of 15 children, 13 were happy with wearing the E4 watch; 2 children found it uncomfortable.
Involvement of participants in the recruitment to and conduct of the study. The potential participants will already be patients indicated for N 2 O sedation and are on the DDH sedation list.
Ethical aspects and approval This study will be conducted in full conformance with principles of the "Declaration of Helsinki", Good Clinical Practice, and within the laws and regulations of the UAE/Dubai Healthcare City. Participants (legal guardians and children) who meet the aforementioned inclusion criteria will be enroled in this study. An informed consent (verbal and written) will be provided to the parents/ Fig. 1 Flowchart of the study design.
A single-centre investigator-blinded randomised parallel-group study. . . M Kowash et al. caregivers of the child before the N 2 O sedation and enrolment in the study. Partakers and their parents/guardians will be appropriately informed about the set objectives of the study; each participant will be ensured anonymity. Following data analysis, consolidated results will be published. A signed, informed consent form will be required for participation from the parents/caregivers.

Dissemination of the study's results
The detailed results and conclusive outcome(s) of the study will be disseminated through peer-reviewed publication/s, conference presentations and the MBRU web site. Additional events will be conducted by inviting stakeholders and groups of interest in inhalation sedation (such as dental teams including general dental practitioners, dental nurses, paediatric dental specialists and consultants to discuss our findings as it will be relevant to all those who manage children who have dental anxiety generally and those using N 2 O specifically).
The study's statistical analysis We will conduct deep statistical analysis after consideration of the data's distribution normality, with the appropriate parametric or non-parametric statistical tests using the statistical software SPSS™ 24.0.0 (SPSS © Inc., USA). The utilisation of standard descriptive statistics and quantitative data will be reported; if normally distributed, means and standard deviations shall be used; and if skewed, medians and interquartile ranges will be reported. The score of dental anxiety will be calculated for each participant and test for normality by using the Shapiro-Wilk test. Categorical data will be tested for independency by using Chi-square or Fisher's exact test when appropriate. The difference in the means between the two groups will be tested using either t-test or Mann-Whitney test depending on the normality of the data. The comparison of the means of more than two variables will be tested by using ANOVA or Kruskal-Wallis depending on the normality of the   measurements. A p-value of <0.05 will be considered significant in all tests.

DISCUSSION
The purpose of this study/protocol is to provide an evidence supported answer regarding the clinical value of the use of an additional acclimatising visit for N 2 O prior to the actual planned dental treatment. Nitrous oxide inhalation sedation has been employed in dentistry for over 170 years. Recently, there has been interest for stronger evidence to back its use both generally and in dentistry. 19 Nevertheless, N 2 O use has been strongly advocated by major international paediatric dentistry organisations. For example, the American Academy of Pediatric Dentistry (AAPD) recognises nitrous oxide/oxygen inhalation as a safe and effective anxiolytic technique proven to reduce dental anxiety that provides mild analgesia and enhances effective communication between a child patient and dental health care provider (AAPD 2015). 1 The SDCEP (2017) recommends the use of inhalation sedation with nitrous oxide/oxygen as the preferred method for conscious sedation. 2 These endorsements echo the guidelines of other entities such as the UK dental faculties of the Royal Colleges of Surgeons and the Royal College of Anaesthetists. The latter, in 2015, recommended two visits for inhalation sedation-one preparatory (for assessment purposes for suitability for sedation only) and the other one for the actual treatment. 9 The employment of an acclimatisation session prior to dental treatment under N 2 O has been suggested by some authors of Fig. 4 The screenshot from the real-time physiological parameter interface obtained from the E4 ® watch analytical software.  20,21 However, the specific advantages of the use of this technique have not been investigated properly. An additional resource that recommended the use of accustoming visit was the SDCEP in 2017. 2 They issued the following statement without specific supportive evidence: "A brief trial of nitrous oxide/oxygen at the assessment appointment may be helpful for the psychological preparation of some children". Thus, currently, the guidelines recommendations are based on collective expert opinion and are not evidence based.
The outcomes of this research will provide some evidence on whether or not a separate session for acclimatisation to N 2 O/O 2 sedation should be offered and whether such extra visit increases the effectiveness of this safe method of sedation to treat anxious children in the clinic. In addition, the requirement of a lengthy time of no oral feeding renders GA a challenge in some young and medically compromised children. [22][23][24] Furthermore, dental treatment under N 2 O will decrease treatment costs by about a third, thus avoiding expensive GA hospital admissions. 25 Although a recent Cochrane report 26 highlighted that evidence to support the superiority of GA over N 2 O sedation for providing dental care to children is lacking, the safety of the latter is not in question. Our research aims at improving our knowledge in relation to the use of N 2 O, a time-tested method that has cemented its position in the armamentarium available in dealing with anxious dental patients.
Data statement Anonymous participants' data may be shared on request to promote a culture of openness and an increased sharing of research data. Our information sheet and informed consent clearly state that the collected data are intended to be used for research purposes, and possibly published in dental journals and presented at conferences. All the anonymously collected data can be shared upon request from the primary investigator once the study is completed. The data will be stored for 5 years after the final publication to be shared upon request.