pISSN 2383-9309❚eISSN 2383-9317

Review Article J Dent Anesth Pain Med 2021;21(6):527-545❚https://doi.org/10.17245/jdapm.2021.21.6.527

Success rate of nitrous oxide-oxygen procedural

sedation in dental patients: systematic review and
meta-analysis
Marco Rossit, Victor Gil-Manich, José Manuel Ribera-Uribe
Department of Geriatric Dentistry, Oral Medicine, and Care for Patients with Special Needs, Universitat Internacional de Catalunya
(UIC), Barcelona, Spain

The aim of this systematic review was to determine the success rate of nitrous oxide-oxygen procedural sedation
(NOIS) in dentistry. A systematic digital search was conducted for publications or reports of randomized controlled
trials evaluating the clinical performance of NOIS. Abstracts of research papers were screened for suitability,
and full-text articles were obtained for those who met the inclusion and exclusion criteria accordingly. The
quality of the studies was assessed using the revised Cochrane risk-of-bias tool (RoB 2). A total of 19 articles
(eight randomized clinical trials with parallel intervention groups and 11 crossover trials), published between
May 1988 and August 2019, were finally selected for this review. The studies followed 1293 patients reporting
NOIS success rates, with a cumulative mean value of 94.9% (95% CI: 88.8–98.9%). Thirteen trials were conducted
on pediatric populations (1098 patients), and the remaining six were conducted on adults (195 patients), with
cumulative efficacy rates of 91.9% (95% CI: 82.5–98.1%) and 99.9% (95% CI: 97.7–100.0%), respectively. The
difference was statistically significant (P = 0.002). Completion of treatment and Section IV of the Houpt scale
were the most used efficacy criteria. Within the limitations of this systematic review, the present study provides
important information on the efficacy rate of NOIS. However, further well-designed and well-documented clinical
trials are required and there is a need to develop guidelines for standardization of criteria and definition of
success in procedural sedation. Currently, completion of treatment is the most used parameter in clinical practice,
though many others also do exist at the same time. To maximize NOIS efficacy, clinicians should strictly consider
appropriate indications for the procedure.

Keywords: Conscious Sedation; Dental Care; Nitrous Oxide; Procedural Sedation.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License
(http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in
any medium, provided the original work is properly cited.

INTRODUCTION American Society of Anesthesiologists (ASA) classifi-

cation [6]. The administration of N2O-O2 can induce
procedural sedation due to the potential unspecific
In dentistry, nitrous oxide-oxygen mixture (N2O-O2) is depression of the central nervous system caused by this
used to induce procedural sedation (previously termed gas mixture. Nitrous oxide delivered at a concentration
“conscious sedation” [1,2]) in patients unable to receive < 50% is accepted as a minimal sedation drug by the
standard dental treatments [3] or merely to complete ASA [2] and at a concentration ≤ 50% by the American
therapies comfortably for both the professional and the Academy of Pediatrics (AAP) [7]. In concentrations >
patient [4]. Procedural sedation is defined as a state of 50%, the AAP cautions that "the likelihood for moderate
minimal or moderate sedation [5] according to the or deep sedation increases" [8]. Therefore, when the

Received: August 16, 2021•Revised: October 18, 2021•Accepted: November 7, 2021

Corresponding Author: Marco Rossit, DDS, Department of Geriatric Dentistry, Oral Medicine, and Care for Patients with Special Needs, Universitat Internacional
de Catalunya (UIC), Barcelona, Spain, Via dello Stadio 3/C, Cortona (AR), 52044, Italy
E-mail: [email protected]
Copyrightⓒ 2021 Journal of Dental Anesthesia and Pain Medicine

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Marco Rossit, et al

proper use of N2O-O2 is effective, the patient shows signs effectiveness in avoiding unwanted consequences for the
of depressed consciousness (e.g., relaxed, somnolent patient (e.g., aborted, traumatic, or even harmful
patient who may appear dissociated and with a feeling experience) [11,23].
of well-being and confidence) [3] but he/she remains in Therefore, the aim of this study was to systematically
verbal contact throughout treatment and maintains all review the existing scientific literature and to determine
vital functions [9] (e.g., preservation of airway patency the success rate of NOIS in dentistry.
and spontaneous ventilation [1]). However, there is a
controversy regarding the efficacy of this technique in METHODS
scientific literature [10], as it may not always be
successful [7,11].
1. Review protocol
To the best of the authors’ knowledge, the clinical
performance of nitrous oxide-oxygen procedural sedation The Cochrane Handbook Method Guidelines [24] and
(NOIS) in dentistry has not been sufficiently summarized Center for Reviews and Dissemination (CRD) guidelines
by an evidence-based method. As a matter of fact, [25] were consulted to prepare the conduct of this study.
scientific literature lacks reviews that systematically The protocol was written according to the Preferred
compare and synthesize data from existing studies to Reporting Items for Systematic Reviews and
determine the efficacy rate of NOIS in dentistry, despite Meta-Analyses (PRISMA) guidelines and checklist [26].
its wide use in this field and the importance for both According to the population, intervention, comparison,
clinicians and patients to rely on statistically calculated outcome, and study design (PICOS) approach [25,27], the
rates for therapy outcomes. Moreover, the efficacy rate guiding question of this review was: “What is the clinical
of NOIS in dentistry varies widely as reported in success rate of NOIS in dental patients from randomized
published studies. In a recent article [12], it was stated clinical trials?”.
that the efficacy rates of this procedure were placed in The full review protocol was registered in the
a range from 77% to 97%. However, this study had taken International Prospective Register of Systematic Reviews
into account few reference studies (n = 4) and did not (PROSPERO) with registration number
have any systematic analyses included therein. Indeed, CRD42020155159. The text can be accessed at
other studies showed lower (52% [13]) or higher (100% https://www.crd.york.ac.uk/prospero/display_record.php?
[14]) rates. RecordID=155159.
The importance of reporting context-specific evidence
2. Search strategy
of NOIS effectiveness following contemporary research
guidelines has been underlined by many authors [13,15– A digital systematic literature search in PubMed,
19], and the European Society of Anesthesiology (ESA) Cochrane Central Register of Controlled Trials
[20] stated that there is a need to define the most (CENTRAL), Scopus, EBSCO, LILACS, Summon, and
appropriate procedure-related effective use of nitrous Database of Abstracts of Reviews of Effects (DARE) was
oxide-oxygen. Apparently, there is a lack of information conducted on April 2, 2021. The US National Institutes
about NOIS efficacy in dental private offices rather than of Health Ongoing Trials Register (clinicaltrials.gov) and
in the hospital settings [15,21], as this sedation technique World Health Organization International Clinical Trials
has been mostly studied in relation to medical procedures Registry Platform (apps.who.int/trialsearch) were
other than dental care [22]. In dentistry, it has been searched on the same date for ongoing studies.
described that NOIS is successful in most cases, but not The search strategy was implemented using the
in all, which justifies the importance of investigating its following keywords: “nitrous oxide” AND “dental”. No

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limits were applied to the year of study; however, when 3. Comparison: None.
possible, search filters were used to find only studies of 4. Outcome:
interest (trials) and articles published in English, Spanish, 4.1. NOIS success was not defined by trialists or by
or Italian. The digital search was implemented by literature regarding the specific evaluation
manually searching the reference lists from full-text method used.
articles and related reviews. 4.2. Impossibility of extracting data for cumulative
efficacy rate calculation (e.g., grouped data
3. Inclusion criteria
presented only as means and/or medians,
The PICOS criteria related to research question are neglected data, trials that do not evaluate NOIS
detailed below: efficacy).
1. Population: Adult or child who required procedural 5. Study Design: Any study design except an RCT.
sedation for dental treatment.
5. Selection process
2. Intervention: Inhalation of nitrous oxide-oxygen
mixture. Two reviewers (MR and VG) independently screened
3. Comparison: One or more other drugs, sedation the above-mentioned databases to select studies that met
technique, or placebo that was used by dental team the inclusion criteria. In order to do this, these authors
professionals. As this category of PICOS approach independently assessed each study found in the review
is optional [28,29], comparison outcomes were not process by grading it as “eligible,” “not eligible” or
analyzed, these being irrelevant in this review. “might be eligible” [30]. A study was included if both
4. Outcome: reviewers independently assessed it to be satisfying the
4.1. Primary: Clinical success rate of NOIS. inclusion criteria based on the full-text article. Trials’
4.2. Secondary: Clinical methods (e.g., scales) for authors were contacted, if necessary, to request clarifi-
defining NOIS success were listed to create a cations, raw data, or additional data to those already
dataset of efficacy criteria prevalence in reported.
published trials. In case of disagreement, the full text was analyzed and
5. Study Design: Randomized controlled clinical trials discussed by all the reviewers to find a consensus.
(RCTs), including crossover trials.
6. Data extraction
4. Exclusion criteria
A data extraction form was created using Excel
Studies presenting at least one of the following software (version 16.46, Microsoft, Redmond WA, USA)
characteristics were excluded from this review: to collect information of interest from articles and
1. Population: Patients with special needs (i.e., patients facilitate comparison between studies. The two reviewers
with physical, medical, developmental, or cognitive responsible for screening databases independently used
conditions who require special consideration when this tool to record all the studies found in the review
receiving dental treatment). process. Therefore, data from each study were collected
2. Intervention: in duplicate and compared at the end of the process.
2.1. Combination of nitrous oxide-oxygen with other For included studies, information on trial design, type
drugs (except for local anesthetics), sedation of interventions, sample size, characteristics of patients,
techniques, or placebo. main outcome data, and criteria used to evaluate NOIS
2.2. Administration of nitrous oxide-oxygen through efficacy were collected accordingly. Main outcome data
any device other than nasal hood. were extracted as “number of events / population”

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proportion (i.e., “number of sedated patients / total heterogeneity among studies [36]. Heterogeneity was
number of patients”), in order to obtain an efficacy rate considered low if the I² value was < 50%, moderate
for each trial. Thus, binary data were extracted from these between 50% and 75%, and high if ≥ 75%. A
studies. random-effects model was used in cases of moderate/high
A “three stage” decision process for inclusion of heterogeneity and a fixed-effect model was used in cases
crossover data in meta-analysis [24,31,32] was followed of mild heterogeneity.
in the case of crossover trials. To calculate a pooled
11. Synthesis of results
estimate, reviewers were required to use the same method
to analyze data from all included crossover trials [32]. Main outcome data were pooled after Freeman-Tukey
The third reviewer (JMR) checked collected data for double arcsine transformation for proportions close to the
consistency and clarity. 0 and 1 values [37] and the NOIS efficacy rate was
calculated as previously detailed. Outcomes were
7. Quality assessment
combined and calculated using the packages “meta” and
The methodological quality of the included studies was “metaprop” [38] for meta-analysis within the statistical
assessed using the Revised Cochrane risk-of-bias tool for R software (version 4.0.1, FOAS, Boston MA, USA). For
randomized trials (RoB 2, 2019 version) [33]. The authors the objective of this review, the efficacy rates of NOIS
independently completed the related form for each were grouped and reported as an event rate with a 95%
included study, grading each trial as being at low, high, confidence interval (95% CI).
or unclear risk of bias. A comparison of the evaluations The included trials were divided into two groups
allowed the reviewers to find a consensus. depending on the patients’ type: adult population (≥ 16
years old) and pediatric population (< 16 years old). This
8. Measurement of treatment effect
differentiation was performed in order to perform a
NOIS success was defined according to the criteria subgroup analysis of NOIS efficacy in those populations,
(e.g. scales) specified in the individual studies. Sedation which was completed with the same synthesis methods
scales may be ordinal or dichotomous [34]: as ordinal used for the meta-analysis of the total population. The
scales have generally a threshold or cutoff score to chi-square test was used to calculate statistical
establish achievement of procedural sedation state [35], significance when comparing the results. The level of
it was possible to collect and group binary data also from significance was set at P = 0.05 .
included trials that used this type of evaluation (i.e., final The results were visually represented with forest-plot
dichotomous evaluation: “Yes”=Sedated patient [SP]; diagrams created with R software, which also allowed
“No”=Non-sedated patient [NSP]). Hence, it was feasible for visual expression of heterogeneity among the included
to obtain proportions of NOIS efficacy, expressing them studies.
as percentages (SP/(SP + NSP) × 100), and to combine
trial outcomes, allowing meta-analysis to be carried out. RESULTS
9. Unit of analysis
1. Search results
The statistical unit was the patient undergoing NOIS
for dental treatment. Initial searches using MeSH terms and title/abstract
words resulted in 1647 potential studies. After removing
10. Assessment of heterogeneity
duplicates, a total of 1149 references were identified from
The I² index was used to describe the degree of the digital sources. Screening of titles and abstracts

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Fig. 1. Flow chart (PRISMA, preferred reporting items for systematic reviews and meta-analyses) of the screening and selection of studies process.

allowed the selection of 54 full-text studies. Hand populations (195 patients, 15.1%). Of the 726 patients
searches of the bibliographies of full-text articles treated with NOIS, 582 (80.2%) were children and 144
identified 28 additional articles. After full-text evaluation, (19.8%) were adults. Eight studies had parallel
19 RCTs [13,39–56] published between May 1988 and intervention groups, while the remaining trials had a
August 2019 were finally selected for the review. The crossover design.
study screening, selection process, and reasons for In most studies, it was reported that the initial behavior
exclusion are depicted in Fig. 1, as per the PRISMA of patients was assessed as uncooperative, with
guidelines. preoperative anxiety, and potentially collaborative under
sedation, often using the Frankl scale [57] or the Corah
2. Included studies
Dental Anxiety Scale (DAS) questionnaire [58].
The details of the included studies are listed in Table The gas mixture was administered with slow induction
1. A total of 1321 patients were enrolled in the trials; and regular increases in nitrous oxide amount in 14
the number of drop-outs was 28, and 1293 patients could intervention groups (70.0%). The rapid induction
be completely followed. Of the 19 included studies, 13 technique was used in six intervention groups: in four
were conducted on pediatric populations (1098 patients, groups (20.0%), the gas proportions were maintained
84.9%) and the remaining six were conducted in adult fixed during the whole process and in two groups (10.0%)

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Marco Rossit, et al

Fig. 2. Administration techniques in included trials: use of adjustable (dark blue) or fixed (light blue) proportions of gases

the proportions were maintained fixed in the first phase

of sedation and then adjusted according to the patient’s
condition during treatment (Fig. 2). The proportion of
nitrous did not exceed 50% in any trial and in all trials,
local anesthesia was used to complete all the therapies.

3. Quality analysis

Of the 19 trials included in this review, only one [48]

was assessed as having a low overall risk of bias using
the Cochrane RoB 2 tool. Two trials (10.5%) [41,42] were
assessed to be at unclear risk of bias, and in the remaining
16 studies (84.2%), at least one domain was assessed as
being at high risk of bias (Fig. 3).

4. Measures (success criteria)

The main outcome variables used in the trials were

ordinal or dichotomous. Trialists mostly used the first
type of measure (16 studies, 84.2%), employing various
ordinal scales: Section IV of Houpt Behavioral Rating
Scale [59] was the most common (seven trials, 36.8%).
The remaining three studies used the same dichotomous
Fig. 3. Evaluation of the quality of the included studies with Cochrane
measure: completion of treatment (Yes/No) (Table 1). RoB 2 (I: bias arising from the randomization process; II: bias due to
In total, 10 different measurement scales were used to deviations from intended interventions; III: bias due to missing outcome
data; IV: bias in measurement of the outcome; V: bias in selection of
determine the efficacy of NOIS (Fig. 4). the reported result; Ov: Overall bias).

5. NOIS intervention effect (success rates)

In one study [40], both the intervention and control
The proportions of successful sedations with the groups received NOIS but they were administered the
N2O/O2 mixture were variable, ranging from 52.3% to mixture using two different techniques. The two groups
100% (Table 1). Of all the studies, 10 had a success rate had a success rate of 100%.
of 100% (five with adults and five with children), while
6. Meta-analysis
three trials had relatively low efficacy rates (52.3% [13],
55.0% [46], and 66.7% [49]; all with children). Treatment arms from included crossover trials were

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Table 1. Studies included in this systematic review: characteristics according to PICOS approach
Author Participants Intervention Control Outcome Study Design
Gupta P, et al. · Adults (≥ 18 y.o.) Slow induction Local anesthesia alone MDAS (< 19): N. I. on blinding,
(2019) [39] · MDAS 19-25 (max: 50% N2O) · NOOS: 100.0% Parallel groups
· n = 60 (30/group) · Control: 96.7%
Samir PV, et al. · Children (5-12 y.o.) Slow induction Rapid induction, adjustable proportions (max: RASS (≤ -2): N.I. on blinding,
(2017) [40] · Frankl 3-4 (max: 40% N2O) 40% N2O) (NOOS 2) · NOOS 1: 100.0% Parallel groups
· n = 60 (30/group) (NOOS 1) · NOOS 2: 100.0%
Subramaniam P, · Children (5-10 y.o.) Slow induction Oral triclofos sodium (70 mg.kg-1) Houpt, pt. IV (≥ 3): Non-blinded,
et al. (2017) [41] · Anxious, potentially cooperatives (max: 40% N2O) · NOOS: 83.3% Parallel groups
· n = 60 (30/group) · Control: 90.0%
Takkar D, et al. · Children (7-10 y.o.) Slow induction Placebo (O2 100%) OAA/S (≤ 4): Double-blind,
(2015) [42] · Frankl 2-3 (max: 40% N2O) · NOOS: 90.0% Parallel groups
· n = 40 (20/group) · Control: 5.0%
Allen M, · Adults (18-62 y.o.) Slow induction Sevoflurane (max: 0.3%) DSTG (≤ 2): Single-blind,
Thompson S. · Anxious, potentially cooperatives (max: 40% N2O) · NOOS: 94.7% Parallel groups
(2014) [43] · n = 40 (NOOS: 19; Control: 21) · Control: 95.2%
Guelmann M, et al. · Children (5-8 y.o) Rapid induction, Placebo (O2 100%) OSUBRS (< 3) Double-blind,
(2012) [44] · Anxious, potentially cooperatives adjustable · NOOS: 100.0% Cross-over
· n = 17 proportions (max: · Control: 94.1%
50% N2O)
Zhang G, et al. · Adults (18-42 y.o.) Rapid induction, Video-eyewear + 30% N2O Houpt, pt. IV (≥ 3): Non-blinded,
(2012) [45] · DAS-R 9-12 fixed proportions · NOOS:100.0% Cross-over
· n = 38 (30% N2O) · Control: 100.0%
Özen B, et al. · Children (4-6 y.o.) Rapid induction, · 1: Intranasal midazolam (0.20 mg.kg-1) + Treatment completion: N.I. on blinding,
(2012) [46] · Frankl 1-2 fixed proportions 50% N2O · NOOS: 55.0% Parallel groups
· n = 240 (60/group) (50% N2O) · 2: Oral midazolam (0.75 mg.kg-1) + · Control 1: 86.6%
50% N2O · Control 2: 78.3%
· 3: Oral midazolam (0.50 mg.kg-1) + · Control 3: 71.6%
50% N2O
Abdullah WA, et al. · Adults (18-30 y.o.) Slow induction Methoxyflurane (max: 0.4%) RSS (≥ 2): Non-blinded,
(2011) [47] · DAS-R 9-14 (max: 50% N2O) · NOOS: 100.0% Cross-over
· n = 20 · Control: 100.00%
Soldani F, et al. · Children (6-15 y.o.) Slow induction Sevoflurane (max: 0.3%) Treatment completion: Double-blind,
(2010) [48] · Anxious, potentially cooperatives (max: 30% N2O) · NOOS: 89.7% Cross-over
· n = 29 · Control: 89.3%
Baygin O, et al. · Children (5-8 y.o) Slow induction · 1: Oral hydroxyzine hydrochloride RSS (≥ 2): Double-blind,
(2010) [49] · Frankl 1-2 (max: 40% N2O) (1 mg.kg-1) + 40% N2O · NOOS: 66.7% Parallel groups
· n = 60 (15/group) · 2: Oral midazolam (0.70 mg.kg-1) + 40% · Control 1: 66.7%
N2O · Control 2: 74.0%
· 3: Oral ketamine (3 mg.kg-1) + oral · Control 3: 66.7%
midazolam (0.25 mg.kg-1) + 40% N2O
Wilson KE, et al. · Children (10-15 y.o.) Slow induction Transmucosal midazolam (0.2 mg.kg-1) Houpt, pt. IV (≥ 3): Non-blinded,
(2007) [50] · Anxious, potentially cooperatives (max: 30% N2O) · NOOS: 100.0% Cross-over
· n = 36 · Control: 100.0%
Wilson KE, et al. · Children (5-10 y.o.) Slow induction Oral midazolam (0.3 mg.kg-1) Houpt, pt. IV (≥ 3): Non-blinded,
(2006) [51] · Anxious, potentially cooperatives (max: 30% N2O) · NOOS: 100.0% Cross-over
· n = 35 · Control: 100.0%
Wilson KE, et al. · Children (12-16 y.o.) Slow induction Intravenous midazolam (max: 5.0 mg) Houpt, pt. IV (≥ 3): Non-blinded,
(2003) [52] · Anxious, potentially cooperatives (max: 30% N2O) · NOOS: 97.5% Cross-over
· n = 40 · Control: 95.0%
Wang CY, et al. · Adults (19-43 y.o.) Slow induction Sevoflurane (max: 1%) VAS (≤ 3): Single-blind,
(2002) [53] · Anxious, potentially cooperatives (max: 50% N2O) NOOS: 100.00% Cross-over
· n = 17 Control: 100.00%

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Marco Rossit, et al

(continued)
Author Participants Intervention Control Outcome Study Design
Wilson KE, et al. · Children (10-16 y.o.) Slow induction Oral midazolam (0.5 mg.kg-1) Houpt, pt. IV (≥ 3): Non-blinded,
(2002, a) [54] · Anxious, potentially cooperatives (max: 30% N2O) · NOOS: 97.7% Cross-over
· n = 44 · Control: 97.7%
Wilson KE, et al. · Children (10-16 y.o.) Slow induction Oral midazolam (0.5 mg.kg-1) Houpt, pt. IV (≥ 3): Non-blinded,
(2002, b) [55] · Anxious, potentially cooperatives (max: 30% N2O) · NOOS: 96.1% Cross-over
· n = 26 · Control: 96.1%
Lahoud GY, · Children (3-10 y.o.) Rapid induction, fixed Sevoflurane (max: 0.3%) Treatment completion: Non-blinded,
Averley PA. · Dedicated clinic for anxiety proportions (40% N2O) · NOOS: 52.3% Parallel groups
(2002) [13] management · Control: 89.2%
· n = 411 (NOOS: 170, Control: 241)
Rodrigo MR, · Adults (18-31 y.o.) Rapid induction, fixed Isoflurane (max: 0.5%) Custom scale: Double-blind,
Rosenquist JB. · Anxious, potentially cooperatives proportions (33% N2O) · NOOS: 100.0% Cross-over
(1988) [56] · n = 20 · Control: 100.0%
DSTG, Sedation Score from Dental Sedation Teachers Group; Houpt, Houpt Behaviour Rating Scale; MDAS, Modified Dental Anxiety Scale; N2O, Nitrous
Oxide; O2, Oxygen; OAA/S, Observer’s Assessment of Alertness/Sedation; OSUBRS, Ohio State University Behavioral Rating Scale; RASS, Richmond
Agitation-Sedation Scale; RSS, Ramsay Sedation Score; VAS, Visual Analogue Scale.

Fig. 4. Ordinal (dark blue) or dichotomous (light blue) success criteria prevalence in the included trials. DSTG, Sedation Score from Dental Sedation
Teachers Group; Houpt, Houpt Behavior Rating Scale; MDAS, Modified Dental Anxiety Scale; OAA/S, Observer’s Assessment of Alertness/Sedation;
OSUBRS, Ohio State University Behavioral Rating Scale; RASS, Richmond Agitation-Sedation Scale; RSS, Ramsay Sedation Score; T.C., Treatment
Completion; VAS, Visual Analogue Scale.

considered as independent, following a "three stage" and moderate (I2 = 64.6%), respectively. Therefore, a
decision process for inclusion of crossover data in fixed-effects model was used for the adult population and
meta-analysis [24,31,32], as using results from paired a random-effects model was used for the pediatric
analysis was impossible and not all of these studies population.
reported data from the first crossover period.
The resulting overall success rate was 94.9% (95% CI: DISCUSSION
88.8–98.9%) (Fig. 5). Heterogeneity among all trials was
moderate (I2 = 58.6%); thus, a random-effects model was
used to perform the calculation. The purpose of this systematic review and meta-
The success rate of NOIS in trials with adults was analysis was to determine the success rate of NOIS in
99.9% (95% CI: 97.7–100.0%) (Fig. 6), and in studies dental patients by analyzing RCTs, as they are one of
with pediatric population 91.9% (95% CI: 82.5–98.2%) the most reliable sources of information for clinical
(Fig. 7), with a statistically significant difference (P = practice. After an exhaustive literature search, 19 RCTs
2
0.002). Heterogeneity among studies was mild (I = 0.0%) were identified following the application of the inclusion

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Fig. 5. Efficacy rate of nitrous oxide-oxygen procedural sedation

Fig. 6. Efficacy rate of nitrous oxide-oxygen procedural sedation in the adult population

and exclusion criteria. Cochrane RoB 2 tool gave similar results to those of
many other systematic reviews [19,62,63], wherein the
1. Quality
general quality of included articles was mostly
Open-label clinical trials and observational studies disappointing. In the Cochrane review by Ashley et al.
were not included in this review, as knowledge of the [19] on sedation techniques, the proportions of trials with
treatment assignments by patients, clinicians, or high, unclear, and low risk of bias were very similar to
evaluators could influence the measurement or those of the present review (81%, 18%, and 1%,
communication of the results, thus introducing biases respectively). In the present study, the poor information
[60]. Indeed, according to the hierarchy of evidence, only reporting of included articles was an undoubted problem:
systematic reviews of randomized trials provide the this implied low scores in the evaluation of design,
highest level of scientific evidence [61]. completion, and outcome communication of the trials
Careful assessment of the risk of bias using the (Fig. 3). In general, the overall risk of bias for most

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Fig. 7. Efficacy rate of nitrous oxide-oxygen procedural sedation in the pediatric population

studies was at best a mix of low and unclear or likely 3. Characteristics of the included studies
to have at least one domain with high risk.
The proportion of nitrous oxide in the gas mixture did
2. Main outcomes not exceed 50% in any trial. Although ASA considers
a concentration of < 50% as minimal sedation [2], this
According to this systematic review and meta-analysis,
maximum was just slightly overpassed by some trialists
the estimated efficacy rates of NOIS in global, adult, and
[39,44,46,47,53] and it was always maintained within the
pediatric populations were 94.9% (95% CI: 88.8–98.9%),
limit established by AAP (≤ 50%) [7]. Furthermore, this
99.9% (95% CI: 97.7–100.0%), and 91.9% (95% CI: 82.5
proportion was reached only in some patients.
–98.2%), respectively. The difference between the adult
In all trials, local anesthesia was used to complete all
and pediatric populations was statistically significant (P
the therapies. Therefore, it is safe to assume that all the
= 0.002). These results highlight the high efficacy of
performed treatments were comparable in terms of pain
NOIS in dental patients, with means and data types that
and comfort perceived by the patient, or that they had
were not present in literature.
negligible differences. Furthermore, the manifestations of
The findings of this study are consistent with those of
dental anxiety are independent of the actual pain
other systematic reviews on NOIS. In 2018, Ashley et
experienced by the patient, and conversely, dental anxiety
al. [19] analyzed mean data from published RCTs and
may underlie the pain perceived throughout the entire
observed a behavior improvement in children undergoing
period of dental treatment [64].
dental treatment with NOIS. Nevertheless, the authors
stated that the results had limited reliability, since the 4. Possible reasons for sedation failures
number of included studies was very low and their quality
The two studies with the lowest success rates in this
was excessively poor. In 2017, another systematic review
review (52.3% [13] and 55.0% [46]) also had the largest
[62] did not identify a statistically significant difference
samples among all RCTs; thus, the highest w (“weight”)
in overall cooperation using NOIS and midazolam, in
value. This had an impact on the meta-analysis
combination or separately. Thus, the authors concluded
calculation, causing an inclination of the overall results
that these different techniques could be considered
through those rates. The efficacy rate in the pediatric
equivalent in terms of efficacy.

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 Nitrous oxide-oxygen sedation in dentistry

population was the most affected outcome, as both trials well as incorrect local anesthesia techniques [18,71],
were conducted in children. The reason for this evident could negatively affect procedural sedation. Therefore,
discrepancy in results (Fig. 5 and 7) is probably due to the patient’s response to sedative and anesthetic
the NOIS indications considered in these two studies. medications should be carefully evaluated in practice
Indeed, Özen et al. [46] included patients classified as [8,72]. In pediatric population, it may be common for
Frankl 1 (“Definitely Negative”, refusal of treatment, or the nasal hood to not fit perfectly, thus not creating an
any other overt evidence of extreme negativism), in airtight seal [73,74]. Moreover, children, as extremely
addition to Frankl 2. The study by Baygin et al. [49] was uncollaborative adults, may not accept the nasal mask or
the other publication that described the inclusion of they may uncontrollably move during the initial phases
Frankl 1 patients: this trial obtained the third lowest of sedation [41]. Some patients (usually children) may
efficacy rate in this review (66.7%, pediatric population), not use the mask as instructed, limiting the absorption
with an evident discrepancy from all the other studies, of the drug: oral breathers, for example, are not
too (Fig. 5 and 7). On the other hand, Lahoud and Averley considered an appropriate patient profile for this type of
[13] completed their trial in a dedicated clinic for dental sedation [50]. Furthermore, pediatric nasal anatomy may
anxiety management. Therefore, it is expected that the result in unavoidable air entertainment when delivering
profile of patients from this trial was similar to that of nitrous oxide–oxygen. In accordance with Subramaniam
the two above-mentioned studies. Contrary to these et al. [41], these issues imply that there will always be
trialists, Abdullah et al. [47] excluded Frankl 1 patients, a small number of patients for whom treatment with NOIS
and they obtained an efficacy rate of 100.00% (Table 1). will be unsuccessful. In many of these situations, if
As described by Clark and Brunick [65], among NOIS sedation is mandatory, deep sedation or general
contraindications, there is an inability to understand the anesthesia is the procedure of choice [65].
procedure, the unwillingness to consent to procedure, the Patients should have the correct set of expectations on
impossibility of establishing communication, and patients procedural sedation, as often they have the impression
who are completely uncooperative (e.g., extreme claustro- that they will be ‘‘gently asleep” [75]. Conversely, they
phobia, psychosomatic behavior problems, inflexible must collaborate and participate in every phase of the
temperament [66] and extremely high anxiety before procedure. Clinicians’ experience with this aspect, both
treatment [67]). The importance of patient selection with for the ability to use the technique [46] and for affecting
NOIS is also underlined by other authors [66–68], patients’ anxiety [76], is hence important.
specifying, for example, that NOIS efficacy is low in
5. Clinical success criteria
cases of severe anxiety or fear [69,70]. These
characteristics seem to be compatible with the patients Procedural (or conscious) sedation lacks a clear
included in the previously described RCTs [13,46,49], consensus on the definition of success [19,77] thus, it
that recorded the lowest efficacy rates in this review. currently exists more than a singular description [78].
Hence, the poor success obtained in those studies is The ESA [1] describes that procedural sedation is
probably attributable to inappropriate selection of the effective when “the use of hypnotic and/or analgesic
patients to be sedated with NOIS. medications enables effective performance of diagnostic
Besides this main rationale, scientific literature outlines or therapeutic procedures”. The ASA in conjunction with
other possible factors that may result in NOIS failure. other relevant associations [2] listed a series of parameters
Coyle et al. [4] reported that the incidence of adverse to define moderate sedation efficacy: induction time,
effects caused by this drug (e.g., vomiting, inability to duration of sedation, successful therapy, patient/family
communicate during the procedure, or oversedation), as satisfaction, and proceduralist satisfaction. Nevertheless,

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Marco Rossit, et al

different criteria and methods are used for this scope [15], cortisol levels [89] and vital signs [90,91].
depending, for example, on the geographical area [79]. Although different scales may be used to evaluate
Similar to the findings of other systematic reviews [19], procedural sedation, all of them evaluate the same
Section IV of the Houpt scale [59] was the most used domain: procedural sedation state achievement [35],
evaluation method by trialists. The various sections of defined as a state of minimal or moderate sedation [5]
the Houpt scale allow the monitoring and assessment of that can be induced by the administration of nitrous
different patient aspects during sedation (alertness, oxide-oxygen. Therefore, it is reasonable to realize a
movement, crying, and completion of treatment). Every methodical synthesis of existing RCT results, despite the
section showed high degrees of correlation between fact that criteria or scales used for outcome evaluation,
expert and/or non-expert evaluators [80] thus the scale may differ among trials. The use of different criteria to
has recognized scientific validity. Section IV assesses evaluate the same outcome is also common in other fields
treatment completion in an ordinal form (grade 1 to 6); of dentistry and medicine. A typical example is
nevertheless, treatment completion can also be represented by implantology, where this issue is managed
successfully evaluated in a dichotomous form (Yes/No), in well-known systematic reviews and meta-analyses with
and this type of evaluation was the second most used methods that have inspired those of this review [92–95].
assessment method in this review (Fig. 4).
6. Crossover trials
Completion of dental treatment has been widely used
as success criterion for sedation procedures in dentistry Careful quality analysis with validated tools [33,96]
[77,81–84]. The advantage of this parameter is that it is revealed a modest level of scientific availability. In this
objective and reproducible [42] (unlike, for example, context, eight RCTs with parallel groups were identified,
patient cooperation evaluated with scales such as VAS), however the other included reports were related to
and it demonstrates a high degree of correlation between crossover trials.
expert and non-expert evaluators [80]. On the other hand, Crossover trials were included following statistically
this parameter should always be accompanied by an validated methods [24,31,32]. The most appropriate use
independent assessment of patient's behavior to avoid of this type of study relates to the investigation of
situations in which treatment completion is considered symptomatic treatment of conditions and/or diseases that
successful despite, for example, a significant physical are chronic or relatively stable (e.g., dental anxiety) and
restriction [77]. The consequences of interrupted when treatment effects are likely to be reversible and
treatment, which could be relevant, as well as patient and short-lived [31,32] (i.e., cases in which the “carry-over”
clinician satisfaction for completing the therapy, effect [97] cannot exist). NOIS can be considered among
demonstrate the importance of this criterion [85]. For these situations [5,32].
example, the impossibility to conclude planned treatment Furthermore, crossover trials are often used with
could imply the need for more powerful sedative drugs clinical pharmacology [32] and pediatrics [98]. Meta‐
or referral of the patient to units equipped for general analyses regarding these topics may consequently require
anesthesia [13]. the combination of results from trials with crossover and
Scientific literature describes a wide range of other parallel design [31]. Moreover, the power of a
success criteria, some of which were used in the included meta-analysis may decrease by combining only trials of
RCTs, such as the Ramsay Sedation Scale [86] or the same type [99].
Richmond Agitation-Sedation Scale [87]. Some methods
7. Implications of key findings and recommendations
are based on physiological parameters, such as the
bispectral index system [88] or the evaluation of serum The present review systematically explored the

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available scientific evidence on the clinical success rate sedation failure, especially in those studies that recorded
of NOIS. By gathering and summarizing data from RCTs, the lowest efficacy rates. The found data suggest a
the findings from this study provide further evidence on potential increase in the risk of NOIS failure in extremely
the clinical performance of this procedure, providing anxious groups, who may have the highest demand for
useful data to dental professionals for clinical activity and sedation procedures. Clinicians and researchers should
communication with patients on expected outcomes. strictly follow the most appropriate indications for NOIS
Indeed, statistically calculated rates are often used to that scientific literature has already demonstrated, in order
guide clinical decision making and to provide a more to make procedural sedation the most effective. Indeed,
accurate patient-specific prognosis of the procedure to be this technique can be recommended as a viable and
performed [95]. minimally invasive approach for all patients who comply
Moreover, the findings of this review highlight with the correct indications, as it demonstrates remarkable
interesting issues for future research and clinical practice. efficacy rates if the interventions are appropriately
The variety of clinical criteria used in the trials to define selected.
NOIS success was an important finding of this review.
8. Limitations
As a matter of fact, in scientific literature a wide range
of efficacy criteria exists [19,77,78], each with recognized The relatively low evidence grading was the main
scientific validity or less. Given the evidence found, limitation of this systematic review. However, the quality
completion of treatment (ordinally or dichotomously assessment was performed using the Cochrane RoB 2
evaluated) was demonstrated to be the most widely used tool, which has recognized validity, but it implies a strict
parameter for sedation success, due to its validity and evaluation [96]. Since there is a lack of available RCTs
objectivity [42,80]. Nevertheless, there is a need to with parallel groups, many of the included studies were
develop guidelines to standardize efficacy criteria and crossover trials. Nevertheless, the only RCT with a low
evaluation methods in procedural sedation, thereby overall risk of bias had a crossover design.
facilitating communication and comparison of data and Some other limitations can also be considered in this
prospectively defining success. review. For instance, abstracts of studies published in
There is a need for further well-designed and languages other than English, Spanish, or Italian were not
well-documented clinical trials to evaluate NOIS examined, which might have led to selection bias.
performance. In designing future studies, trialists should Furthermore, as there is a lack of standardized NOIS
consider reference guidelines (e.g., CONSORT) and the processes for clinicians, some variables that are difficult
evaluation with the RoB 2 tool, and they need to develop to be comprehensively evaluated, such as administration
reasonable evidence-based assumptions regarding the procedures, clinician experience, and equipments, may
handling of missing data. have increased the heterogeneity among the included
Most of the included trials were of the crossover type studies.
and they were conducted in pediatric populations.
9. Conclusions
Considering that evidence provided by interventions on
parallel groups is unquestionable, future RCTs should Within the limitations of this systematic review, the
evaluate NOIS effects with such kind of design, and, to present study provides important information on the
a greater degree, in adult populations. efficacy rate of NOIS. Further well-designed and
The importance of correct patient selection is well-documented clinical trials are required, and there is
underlined by the results of this systematic review. a need to develop guidelines for standardization of criteria
Inappropriate selection was likely the main reason for and definition of success in procedural sedation, since

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Marco Rossit, et al

completion of treatment is the most used parameter, but Preferred Reporting Items for Systematic Reviews and
many others also exist. To maximize NOIS efficacy, Meta-Analyses (PRISMA) guidelines and checklist.
clinicians should strictly consider the appropriate According to the population, intervention, comparison,
indications for the procedure. outcome, and study design (PICOS) approach, the guiding
It is important for clinicians to rely on statistically question of this review was: “What is the clinical success
calculated rates to be fully aware of the expected rate of NOIS in dental patients from randomized clinical
outcomes and to provide more accurate patient-specific trials?”. The full review protocol was registered in the
prognosis of the procedure, thus helping in the International Prospective Register of Systematic Reviews
decision-making process and communication with the (PROSPERO) with registration number CRD42020155159.
patient. The text can be accessed at
https://www.crd.york.ac.uk/prospero/display_record.php?
AUTHOR ORCIDs RecordID=155159.
Marco Rossit: https://orcid.org/0000-0003-2545-5637
Victor Gil-Manich: https://orcid.org/0000-0001-9597-071X
REFERENCES
José Manuel Ribera-Uribe: https://orcid.org/0000-0002-9919-3281

AUTHOR CONTRIBUTIONS
1. Hinkelbein J, Lamperti M, Akeson J, Santos J, Costa J,
Marco Rossit: Conceptualization, Data curation, Methodology, Writing
De Robertis E, et al. European Society of Anaesthesiology
– original draft, Writing – review & editing
Victor Gil-Manich: Conceptualization, Data curation, Formal analysis, and European Board of Anaesthesiology guidelines for
Methodology, Supervision, Writing – original draft, Writing – review procedural sedation and analgesia in adults. Eur J
& editing Anaesthesiol 2018; 35: 6-24.
José Manuel Ribera-Uribe: Conceptualization, Data curation,
2. Practice guidelines for moderate procedural sedation and
Methodology, Supervision, Writing – review & editing
analgesia 2018: a report by the American Society of
Anesthesiologists task force on moderate procedural
ACKNOWLEDGMENTS, CONFLICT OF INTEREST, AND sedation and analgesia, the American Association of Oral
SOURCES OF FUNDING STATEMENT: The authors declare and Maxillofacial Surgeons, American College of
that there are no conflicts of interest in this study. Radiology, American Dental Association, American Society
NOTE: *A first partial version of this review was of Dentist Anesthesiologists, and Society of Interventional
presented at the CED/IADR (Continental European Radiology. Anesthesiology 2018; 128: 437-79.
Division of the International Association for Dental 3. Samir PV, Fere SS. Nitrous oxide-oxygen inhalation
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