European Archives of Paediatric Dentistry (2021) 22:989–1002

https://doi.org/10.1007/s40368-021-00660-z

INVITED REVIEW

Best clinical practice guidance for conscious sedation of children

undergoing dental treatment: an EAPD policy document
P. Ashley1 · P. Anand2 · K. Andersson3

Received: 19 July 2021 / Accepted: 12 August 2021 / Published online: 28 August 2021
© The Author(s) 2021

Abstract
Background Due to fear and/or behaviour management problems, some children are unable to cooperate for dental treatment
using local anaesthesia and psychological support alone. Sedation is required for these patients in order for dentists to be
able to deliver high quality, pain-free dental care.
The aim of this guideline is to evaluate the efficacy and relative efficacy of conscious sedation agents and dosages for behav-
iour management in paediatric dentistry and to provide guidance as to which sedative agents should be used.
Methods These guidelines were developed using a multi-step approach adapted from that outlined by the National Institute
for Clinical Excellence (NICE (2020) Developing NICE Guidelines: the manual. https://​www.​nice.​org.​uk/​proce​ss/​pmg20/​
chapte​ r/i​ ntrod​ uctio​ n#m
​ ain-s​ tages-o​ f-g​ uidel​ ine-d​ evelo​ pment. Accessed 7 Oct 2020). Evidence for this guideline was provided
from a pre-existing Cochrane review (Ashley et al. Cochrane Database Syst Rev 12:CD003877, 2018) supplemented by an
updated search and data extraction up to May 2020.
Results Studies were from 18 different countries and had recruited 4131 participants overall with an average of 70 partici-
pants per study. Ages ranged from 0 to 16 years with an average age of 5.6 years across all included studies. A wide variety of
drugs or combinations of drugs (n = 38) were used and delivered orally, intranasally, intravenously, rectally, intramuscularly,
submucosally, transmucosally or by inhalation sedation. Twenty-four different outcome measures for behaviour were used.
The wide range of drug combinations and outcome measures used greatly complicated description and analysis of the data.
Conclusion Oral midazolam is recommended for conscious dental sedation. Midazolam delivered via other methods or
nitrous oxide/oxygen sedation could be considered, but the evidence for both was very low.

Keywords Sedation · Dental · Paediatric · Midazolam · Nitrous oxide

Aim to evaluate the efficacy and relative efficacy of conscious

sedation agents and dosages for behaviour management in
The European Association of Paediatric Dentistry (EAPD) paediatric dentistry and to provide guidance as to which sed-
proposes this clinical guideline for practitioners wanting to ative agents should be used. In addition, this guideline will
use conscious sedation to support delivery of dental care provide a clinical protocol to guide dentists on the use of rec-
in children and adolescents. The aim of this guideline is ommended dental sedative agents. This document replaces
the former EAPD statement developed by Hallonsten et al.
(2005) and incorporates the Cochrane review on sedation of
* P. Ashley children undergoing dental treatment (Ashley et al. 2018).
[email protected]
1
Paediatric Dentistry, UCL Eastman Dental Institute,
Rockefeller Building, University St, London WC1E 6DE, Selection of the guidance topic
UK
2
Royal National ENT and Eastman Dental Hospitals, UCLH There are two main dimensions to paediatric oral care: (1)
NHS Trust, 47‑49 Huntley Street, London WC1E 6DG, UK to keep the oral environment healthy, and (2) to keep the
3
Department of Dental Medicine, Division of Orthodontics patient capable of, and willing to utilize the dental service.
and Pediatric Dentistry, Karolinska Institutet, POB 4064, Maintenance of good oral health will often require operative
SE‑141 04 Huddinge, Sweden

13
Vol.:(0123456789)
990 European Archives of Paediatric Dentistry (2021) 22:989–1002

intervention. Due to dental fear and/or dental behaviour This updated guideline will continue to only consider
management problems, some children may not be able to drugs and techniques that produce conscious sedation.
cooperate for treatment using local anaesthesia and psy-
chological support alone. Treatment can be performed with
delivery of general anaesthesia, however this should be Legislation, training and governance
avoided due to the associated need of specialist resources
and potential risk of death (Ashley et al. 2018). The rules and regulations governing dental practice differ
Sedation is an alternative for these child patients in order widely between European countries. Important differences
for dentists to be able to deliver high quality, pain-free dental as to the rights of the dentist to utilize various methods of
care in a safe way without the need for general anaesthesia. It sedation also exist. This guideline will present evidence-
also has the potential to help the patient cope with continued based recommendations on the efficacy of sedative agents
use of paediatric dental services. and expert-based recommendations on appropriate train-
ing and governance for dentists practising sedation. These
will need to be interpreted and used within the legislative
framework of individual nation states.
Objectives for sedation in paediatric
dentistry

Objectives for sedation in paediatric dental care consider Education and training
both the needs of the child and the dentist:
Training of paediatric dentists in sedation should be the-
The child oretical and practical. EAPD Guidelines for postgradu-
ate training in paediatric dentistry should be followed in
• Reduce fear and perception of pain during the treatment developing appropriate training programmes in sedation
• Facilitate coping with the treatment (EAPD 1997).
• Prevent development of dental fear and anxiety Theoretical training should cover all the subjects
referred to in the present document. Practical training
should include knowledge of the drugs and equipment used
The dentist for conscious sedation and must be completed before the
clinical training. Knowledge of management of complica-
• Facilitate accomplishment of dental procedures tions due to conscious sedation is essential. Training and
• Reduce stress and unpleasant emotions experience should be regularly updated and maintained.
Documented, contemporaneous supervised hands-on
In recognition of the expanding need for both the elective experience must be acquired for each conscious sedation
and emergency use of sedative agents and the importance of technique used. The minimum number of documented
delivering painless treatment to children, guidelines for the supervised cases completed should be no less than those
use of sedative agents among children are important. specified by appropriate authorities.
Paediatric dentists should be aware that sedation repre- Dental auxiliary personnel assisting during conscious
sents a continuum. Thus, a patient may move easily from a sedation sessions shall also have appropriate training.
light level of sedation to a deeper level, which may result in All clinical staff require theory and practical training
the loss of the patient’s protective reflexes. The distinction in basic life support. Basic life support must conform to
between conscious sedation and deep sedation is made for contemporary guidelines issued by national authorities
the purpose of describing the level of monitoring needed, and dental associations. Training can be through informal
as well as the responsibility of the dentist. Techniques that courses where clinical training is included or in theoretical
cannot be safely delivered by an operator/sedationist are courses with clinical demonstrations in combinations with
unlikely to be ‘conscious’. clinics where conscious sedation is regularly performed
Conscious sedation can be defined as for hands-on supervision.
Those arranging such training have a duty to ensure that
• Minimally depressed consciousness the quality of training and trainers is appropriate, and that
• Ability to maintain open airway all theoretical and practical training is documented.
• Protective reflexes maintained
• Response to verbal and physical stimulation

13
European Archives of Paediatric Dentistry (2021) 22:989–1002 991

Conscious sedation agents and dosages • Cochrane Central Register of Controlled Trials
for behaviour management in paediatric • Medline OVID
dentistry in children up to the age • Embase OVID
of 16 years
The search was updated for this review by the informa-
Methodology tion specialist at the Karolinska Institutet using the same
search strategy. The following databases were searched up
These guidelines were developed using a multi-step to 20 May 2020.
approach adapted from that outlined by the National Institute
for Clinical Excellence (NICE 2020). Input from children • Medline OVID
and young people was not taken into account in this review. • Embase OVID
Resource implications were also not considered.
A draft revision of the guideline was written by the Risk of Bias was assessed using Cochrane’s risk of bias
authors. We started the process from the evidence review tool (Higgins 2011).
stage. Moving from evidence to draft recommendations was
undertaken following the GRADE methodology (Guyatt
et al. 2008). This was then submitted to the Clinical Advi- Data synthesis
sory Group of the European Association of Paediatric Den-
tistry before presentation to the membership at the EAPD Outcomes considered to be most important to the aim of
Interim meeting in 2021. this review were

• Completion of treatment (yes/no)

Evidence review • Difference in behaviour between test and control groups
• Difference in post-operative anxiety between test and
Evidence for this guideline was provided from a pre-exist- control groups
ing Cochrane review (Ashley et al. 2018) supplemented by • Adverse events
an updated search and data extraction (up to May 2020).
Details of the methodology can be found in the pre-existing Trials included in the review presented with complex
Cochrane review. A summary of the evidence review meth- data, very different interventions and a wide range of out-
odology follows. come measures. Therefore to aid description and analysis
we separated studies into three groups:
Selection criteria and types of studies
• Active treatment vs placebo
Studies were selected if they met the following criteria: ran- • Different doses of the same agent
domised controlled trials of conscious sedation comparing • Different agents vs each other
two or more drugs/techniques/placebo undertaken by the
dentist or one of the dental team in children up to 16 years Data were predominantly presented in a narrative
of age. Quasi-randomised trials were excluded. We also format as there were few options to combine data into a
excluded cross-over trials from this review, as they are not meta-analysis.
an appropriate study design when the intervention can have a The certainty of the evidence was assessed using
long-lasting effect (Higgins 2011) or for studies investigating GRADE methodology. We produced 'Summary of find-
the efficacy of sedative agents (Gomes et al. 2019). ings' tables for the main comparisons of the review and
the following outcomes: mean Houpt/other behavioral
score and good or better behaviour, and adverse events.
Search strategy
We used GRADE methods and the GRADEpro online tool
for developing the 'Summary of findings' tables (www.​
Searches were carried out by the Cochrane Oral Health
guide​lined​evelo​pment.​org). We assessed the certainty of
Information Specialist in the following databases (up to 22
the body of evidence for each comparison and outcome by
Feb 2018). There were no language or publication status
considering the overall risk of bias of the included studies,
restrictions. Details of the search strategy are reported in
the directness of the evidence, the inconsistency of the
the Cochrane review.
results, the precision of the estimates, and the risk of pub-
lication bias. We categorised the certainty of each body of
• Cochrane Oral Health Trials Register

13
992 European Archives of Paediatric Dentistry (2021) 22:989–1002

evidence as high, moderate, low, or very low. Economic this should always be recorded and then compared to levels
factors were not considered. of anxiety after sedation. Baseline values of anxiety were not
uniformly reported and very few studies recorded anxiety
Clinical evidence at the end. Outcome measures recorded from the updated
search are in Supplement 5.
Results of the search are summarised below, data from the The wide range of drug combinations and outcome meas-
original Cochrane review and the updated search have been ures used greatly complicated description and analysis of the
combined. More detailed description of the original data data. Therefore, studies were separated into three categories:
can be found in the Cochrane review (Ashley et al. 2018),
detailed results from the updated search can be found in the • Studies where test drug(s) were compared to a placebo.
supplements to this guideline as indicated below. • Studies where differing dosages of the same drug(s) were
compared.
• Studies comparing different drugs or combinations of
Results of the search drugs.

Six additional studies were included in the review and added Placebo studies
to those studies already identified in the Cochrane review
bringing the total number to 56 (Prisma flowchart of the There were 12 placebo studies which looked at oral chloral
search results and excluded studies is in Supplement 1). hydrate, intranasal dexmedetomidine, oral diazepam, mela-
Studies were from 18 different countries with India being tonin, intramuscular meperidine, oral midazolam, intrave-
the most common (n = 16, 18%). Studies had recruited 4131 nous midazolam, midazolam/ketamine and nitrous oxide
participants overall all with an average of 70 participants (Table 1). No additional studies were found in the updated
per study. Ages ranged from 0 to 16 years with an average search.
age of 5.6 years across all included studies. Characteristics
of the included studies from the updated search are in Sup- Dosage comparison studies
plement 2.
A wide variety of drugs or combinations of drugs (n = 38) There were 11 studies which compared different dosages
were used and delivered orally, intranasally, intravenously, or routes of admission of sedative agents: one used hydrox-
rectally, intramuscularly, submucosally, transmucosally or yzine, one looked at different dosages and methods of
by inhalation sedation. Supplemental nitrous oxide/oxygen delivering dexmedetomidine (Patel et al. 2018, added from
in combination with a papoose board was used in 23% of updated search), the remaining nine varied dosage or method
the studies. Dental treatment was poorly described on the of midazolam with six primarily using intranasal midazolam
whole. Drugs recorded from the updated search are in Sup- and three oral midazolam (Table 2). Data from studies from
plement 3. the updated search are in Supplement 6.
Most of the included papers did not state explicitly
whether they were practicing conscious or deep sedation, Drug comparison studies
sleeping was also poorly reported. We believe that in some
of these papers deep sedation was undertaken, as partici- There were 35 studies that compared different drugs or com-
pants were reported as falling asleep and mouth props were binations of drugs which are summarised in Table 3. Five
used. of these were added following the updated search with one
Sequence generation and allocation concealment were comparing IV dexmedetomidine with ketamine/atropine,
generally poorly reported and often scored as unclear. Nine one comparing IV ketamine with IV propofol and IV keta-
of the studies (16%) had no blinding at all, in three (5%) it mine and propofol, three looking at oral midazolam/keta-
was unclear and in seven (13%) only the outcome assessor mine compared to either nitrous oxide/oxygen, dexmedeto-
was blinded. Risk of bias assessments of the studies included midine/fentanyl, dexmedetomidine/ketamine, midazolam
from the updated search are in Supplement 4. (oral) or intranasal midazolam ketamine).
A range of outcome measures were originally proposed
for this review however meaningful data could only be col- Adverse effects
lected for behaviour. Completion of treatment was not used
as in most studies both arms successfully completed treat- There is insufficient evidence from trials in this review to
ment. Twenty-four different outcome measures for behaviour support the effectiveness of either chloral hydrate or keta-
were used. The efficacy of a particular agent will be influ- mine. However, it should be noted that chloral hydrate was
enced by the baseline anxiety of the child involved. Ideally associated with significant adverse effects, specifically

13
 Table 1  Summary of Findings; sedative compared to placebo for children needing dental care
Patient or population: children needing dental care
Setting: hospital
Intervention: sedative
Comparison: placebo
Outcomes Anticipated absolute effects (95% CI) Relative effect (95% CI) Number of Certainty of Comments
participants the evidence
Risk with Placebo Risk with Sedative (studies) (GRADE)

Houpt/other behavioural The Houpt/other behavioural score in the midazolam (oral) 202 (6 RCTs) ⊕  ⊕  ⊕  ⊝ As a rule of thumb 0.2 SD repre-
score—Midazolam (oral) group was on average 1.96 SDs higher (1.59 higher to MODERATE1 sents a small difference, 0.5 a
SD units: investigators measure 2.33 higher) than the placebo group moderate difference, and 0.8 a
behaviour using different large difference
scales—Higher values mean Adverse events: vomiting/hic-
better behaviour cupping reported in one study.
Amnesia reported in one study
Oral midazolam probably
improves behaviour
European Archives of Paediatric Dentistry (2021) 22:989–1002

Houpt/other behavioural The Houpt/other behavioural score in the midazolam (intra- 20 (1 RCT) ⊕  ⊝  ⊝  ⊝ As a rule of thumb 0.2 SD repre-
score—Midazolam (intrave- venous) group was on average 1.21 SDs higher (0.24 VERY ­LOW1, 2 sents a small difference, 0.5 a
nous) higher to 2.18 higher) than the placebo group moderate difference, and 0.8 a
SD units: investigators measure large difference
behaviour using different No adverse events reported
scales—Higher values mean Uncertain whether intravenous
better behaviour midazolam improves behaviour
Houpt/other behavioural The Houpt/other behavioural score in the nitrous oxide 52 (1 RCT) ⊕  ⊝  ⊝  ⊝ As a rule of thumb 0.2 SD repre-
score—Nitrous oxide group was on average 0.69 SDs higher (0.13 higher to VERY ­LOW1, 3 sents a small difference, 0.5 a
SD units: investigators measure 1.26 higher) than the placebo group moderate difference, and 0.8 a
behaviour using different large difference
scales—Higher values mean No adverse events reported
better behaviour Uncertain whether nitrous oxide
improves behaviour
Houpt/other behavioural The Houpt/other behavioural score in the diazepam (oral) 20 (1 RCT) ⊕  ⊝  ⊝  ⊝ As a rule of thumb 0.2 SD repre-
score—Diazepam (oral) group was on average 0.62 SDs higher (0.28 lower to VERY ­LOW1, 2 sents a small difference, 0.5 a
SD units: investigators measure 1.53 higher) than the placebo group moderate difference, and 0.8 a
behaviour using different large difference
scales—Higher values mean No adverse events reported
better behaviour Uncertain whether oral diazepam
improves behaviour
Good or better behaviour— Study population RR 1.33 (0.80–2.22) 60 (1 RCT) ⊕  ⊝  ⊝  ⊝ Adverse events: associated with
Chloral hydrate 533 per 1000 709 per 1000 (427–1000) VERY ­LOW3, 4 airway problems
Uncertain whether chloral
hydrate improves behaviour

13
993
 Table 1  (continued)
994

Patient or population: children needing dental care

Setting: hospital

13
Intervention: sedative
Comparison: placebo
Outcomes Anticipated absolute effects (95% CI) Relative effect (95% CI) Number of Certainty of Comments
participants the evidence
Risk with Placebo Risk with Sedative (studies) (GRADE)

Good or better behaviour— Study population RR 5.33 (1.45–19.64) 60 (1 RCT) ⊕  ⊕  ⊝  ⊝ Adverse events: nausea, vomiting
Meperidine LOW5 and unmanageable behaviour
133 per 1000 711 per 1000 (193–1000) were associated with meperi-
dine use
Meperidine may improve behav-
iour

GRADE Working Group grades of evidence

High certainty: we are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect
Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
CI confidence interval; RCT​randomised controlled trial; RR risk ratio; SD standard deviation; SMD standardized mean difference
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI)
1
Downgraded for risk of bias (lack of blinding and randomisation processes unclear)
2
Downgraded for imprecision (large confidence interval and small numbers)
3
Downgraded for imprecision (large confidence interval)
4
Downgraded for risk of bias (randomisation unclear and incomplete outcome assessment)
5
Downgraded for risk of bias (randomisation unclear) and imprecision
European Archives of Paediatric Dentistry (2021) 22:989–1002
European Archives of Paediatric Dentistry (2021) 22:989–1002 995

Table 2  Summary of findings: Sedative compared with different dosage (or method application) of the same sedative for children needing dental
care
Patient or population: children needing dental care
Setting: hospital
Intervention: sedative
Comparison: placebo
Outcomes Number of Certainty of Comments
participants the evidence
(studies) (GRADE)

Any behavioural score 394 (10) ⊕  ⊝  ⊝  ⊝ There is insufficient evidence to determine whether any specific dose
Midazolam (any mode of delivery) VERY ­LOW1 of intranasal midazolam is effective
There is weak evidence from two trials that oral midazolam at a dose
of 0.5–0.75 mg/kg is an effective sedative for children. However,
one trial administered both nitrous oxide and midazolam so it is
difficult to attribute benefit to midazolam alone
Any behavioural score 30 (1) ⊕  ⊝  ⊝  ⊝ There is insufficient evidence to determine whether any specific dose
Hydroxyzine VERY ­LOW1 of hydroxyzine is effective
Any behavioural score 44 (1) ⊕  ⊝  ⊝  ⊝ There is insufficient evidence to determine whether any specific dose
Dexmedetomidine VERY ­LOW1 of dexmedetomidine is effective or whether intranasal administra-
tion is more or less effective than oral administration

GRADE Working Group grades of evidence

High certainty: we are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there
is a possibility that it is substantially different
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect
Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of
effect
1
Downgraded for risk of bias, inconsistency and/or imprecision

airway issues especially when high doses (> 50 mg/kg) were Weak
combined with the use of inhalational nitrous oxide. Keta-
mine was also associated with significant adverse effects. We suggest nitrous oxide/oxygen is used for sedation of chil-
dren needing dental treatment.
Draft clinical recommendations
Remarks Nitrous/oxide oxygen only has very low quality
Due to the poor quality of data from both the drug compari- evidence supporting its use. We have recommended it as a
son groups and dosage groups, we decided not to use these conscious sedation agent due to its well-known anxiolytic
to develop recommendations. and sedative effects combined with rapid onset and recov-
ery and its overall safety. It is already in widespread use in
Strong dentistry and medicine as a sedative agent for children and
adults.
We recommend oral midazolam for sedation of children
needing dental treatment. We suggest midazolam delivered by IV or any transmu-
cosal route is used for sedation of children needing dental
Remarks Oral midazolam for dental sedation in children is treatment.
supported by moderate quality evidence and at appropri-
ate dosages is safe to use and acceptable to children. This Remarks Midazolam delivered by IV or any transmucosal
review did not consider whether or not placing an IV can- route only has very low-quality evidence supporting its use.
nula for delivery of flumazenil was required when giving We have recommended it as a conscious sedation agent due
oral midazolam. to its well-known anxiolytic and sedative effects combined
with rapid onset and recovery and its overall safety. It is
already in widespread use in dentistry and medicine as a
sedative agent for children and adults.

13
996 European Archives of Paediatric Dentistry (2021) 22:989–1002

Table 3  Summary of findings: Sedative compared with a different sedative for children needing dental care
Patient or population: children needing dental care
Setting: hospital
Intervention: sedative
Comparison: placebo
Outcomes Number of Certainty of Comments
participants the evidence
(studies) (GRADE)

Any behavioural score 235 (6) ⊕  ⊝  ⊝  ⊝ Very few studies evaluated the same intervention and comparisons.
Chloral hydrate/hydroxyzine versus VERY ­LOW1 No studies that did evaluate similar interventions and compari-
Any behavioural score 24 (1) ⊕  ⊝  ⊝  ⊝ sons found the same effect. There is insufficient evidence to draw
Chloral hydrate/promethazine versus VERY ­LOW1 any conclusions
Any behavioural score 160 (3) ⊕  ⊝  ⊝  ⊝
Dexmedetomidine versus VERY ­LOW1
Any behavioural score 569 (9) ⊕  ⊝  ⊝  ⊝
Ketamine vs VERY ­LOW1
Any behavioural score 175 (4) ⊕  ⊝  ⊝  ⊝
Ketamine/midazolam vs VERY ­LOW1
Any behavioural score 654 (7) ⊕  ⊝  ⊝  ⊝
Midazolam (oral) vs VERY ­LOW1
Any behavioural score 70 (2) ⊕  ⊝  ⊝  ⊝
Midazolam (intravenous) vs VERY ­LOW1
Any behavioural score 90 (1) ⊕  ⊝  ⊝  ⊝
Midazolam (rectal) vs VERY ­LOW1
Any behavioural score 1140 (3) ⊕  ⊝  ⊝  ⊝
Sevoflurane vs VERY ­LOW1

GRADE Working Group grades of evidence

High certainty: we are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there
is a possibility that it is substantially different
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect
Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of
effect
1
Downgraded for risk of bias, inconsistency and/or imprecision

Chloral hydrate and meperidine were not recommended between studies difficult or impossible. They are predomi-
as agents for the dental sedation of children because of the nantly clinician centred and focussed on the ease of treat-
risk of adverse events. Diazepam was not recommended as ment provision. They are often based on movement or
an agent for the dental sedation of children as compared to obvious signs of distress, therefore may have little value
midazolam it has high tissue solubility, prolonged elimi- in studies where children are restrained or heavily sedated.
nation time (24–48 h) and active metabolites. It may be Patient satisfaction, reduction in anxiety or other patient
better for preoperative anxiolysis the day before surgery centred measures are rarely used. Demographic variables
rather than on the day of the operative procedure. are often incompletely reported. Depth of sedation is
unclear and definitions of conscious or deep sedation are
inconsistently applied (if used at all). Use of restraint or
Research recommendations adjunctive nitrous oxide/oxygen is unclear in some studies.

Develop a core outcome set to measure dental

sedation effectiveness in children

Rationale

Currently a large number of different outcomes are used in

studies investigating dental sedation making comparison

13
European Archives of Paediatric Dentistry (2021) 22:989–1002 997

Investigate the effectiveness of new dental sedation Indications and contraindications

agents by comparing to a placebo or widely used
reference technique A combined consideration of the following two groups of
factors may be appropriate for identification of children in
Rationale need of conscious sedation.

Drugs were commonly compared to other combinations 1. Children unable to cope, e.g., dental anxiety, special
of drugs that themselves had no significant evidence base. needs.
New drugs or drug combinations for conscious dental seda- 2. Treatment required, e.g., emergency or large volume.
tion should be tested against standard and commonly used
techniques. Sedation of children below the age of 1 year or < 10 kg
is hardly ever relevant in the dental setting and should not
Investigate the effectiveness of dental sedation be performed without consulting with an anaesthesiologist
in reducing dental anxiety (Kapur and Kapur 2018). Conscious sedation during preg-
nancy requires careful assessment of risks versus the benefits
Rationale and represents a relative contraindication to extensive elec-
tive dental care, particularly during the first trimester.
Dental sedation could be used to facilitate the introduction
of treatment to anxious children with a view to reducing or Patient information
removing sedation in subsequent visits (an approach taken
by Veerkamp 1993). Written and oral information and consent

Investigate the effectiveness of dental sedation The child and the parent or guardian should have oral and
in different age groups written pre- and postoperative instructions in advance of the
procedure. Informed consent should follow the legislation
Rationale of the country. The child should always be escorted to and
from treatment by a responsible adult who is well known to
The majority of studies involved sedation in children less the child. Provided the parents have consented, schoolchil-
than 6 years of age, probably because this age range belongs dren can get treatment with nitrous oxide/oxygen without the
to a 'pre-co-operative' group. Treatment needs and man- presence of an adult escort in the context of school dental
agement of children will vary as they grow and develop. clinics.
Techniques that are appropriate in a 3-year-old may not be
appropriate in a 12-year-old and vice versa. Patient monitoring

Continuous clinical observation

Using midazolam and nitrous oxide—clinical
protocol Paediatric dental patients under conscious sedation must be
monitored continuously clinically, as this is the most impor-
Patient selection and assessment tant element in patient monitoring. Clinical monitoring can
include:
Patient assessment must include a full medical, dental and
social history. Each patient should be classified according to • Level of consciousness/depth of sedation
the ASA Physical Status Classification System (ASA 1963). • Airway patency
Patients who are ASA Class I or Class II may be considered • Observe breathing including movements of the thorax
candidates for conscious sedation as outpatients. Patients • Respiraton-rate and depth
in ASA Class III and Class IV represent special problems • Observing skin colour
requiring individual consideration and are best treated in a • Pulse rate, rhythm and volume
hospital environment. Medical colleagues should be con- • Adequate pain control including adequate local anaesthe-
sulted where appropriate. sia

The clinical team must be able to recognise a deterio-

rating patient and manage accordingly. It is vital that staff
are adequately trained in the use of clinical monitoring and

13
998 European Archives of Paediatric Dentistry (2021) 22:989–1002

electronic monitoring. Any electronic monitoring used must procedure conducted including appropriate diet, medica-
be age appropriate. tions, level of activity and management of possible postop-
erative bleeding.
Pulsoximetry and blood pressure monitoring

In the case of conscious sedation, oxygen desaturation below Documentation and records
95% in children is rare. Nevertheless the use of pulse oxi-
metry has been widely discussed. Pulsoximetry and blood It is recommended that the documentation include
pressure monitoring is not usually deemed necessary for
conscious sedation with nitrous oxide/oxygen but is nor- • Medical history including prescribed medication
mally expected for benzodiazepine sedation. When pulse • Previous dental history
oximetry is used, the alarms may show false positive due to • History of previous conscious sedations and general
movement artefacts, sensor displacement or other reasons. anaesthesia
Young children especially may react with increased anxiety • Indication for the use of conscious sedation
to the placement of the pulsoximeter. • Pre-sedation assessment
• Written instructions provided pre- and post-operatively
Fasting • Presence of an accompanying responsible adult
• Arrangements for suitable post-operative transportation
Fasting prior to sedation continues to be a controversial and supervision
topic and each country’s legislation for this must be followed • Compliance with pre-treatment instructions
according to the local guidance. There is only low evidence • The course of the treatment
available for this (NICE 2010; IACSD 2015; SDCEP 2017). • Monitoring
For conscious sedation, an individual assessment needs to be
made on the basis of the dental procedure, patient’s medical – Dose, and route of administration of sedative drugs
assessment and the sedation technique being used. Depend- of Dental treatment performed
ing on the circumstances, it may or may not be appropri- – Sedation evaluation (sedation scale)
ate for the patient to modify food and drink intake before – Acceptance of sedation and treatment (behavioural
sedation. scale)
After carefully considering all factors for a patient: – Complications
• Post-sedation assessment and time of discharge home
• If the decision is to not fast, a patient should be advised
that although they can eat and drink on the day, they need
Some examples of possible scales that could be used to
to avoid alcoholic drinks and large meals.
monitor the effect of the sedation are in Table 4.
• If there is a significant risk of aspiration, or another indi-
cation, consider fasting prior to sedation. The 2–4–6 fast-
ing rule is recommended in this situation. Using Nitrous oxide

It is advisable to confirm and record food and fluid intake Nitrous oxide is a gas with anxiolytic and sedative effects
on the day of sedation. combined with varying degree of analgesia and muscular
relaxation. It has been suggested that both GABA a and
NMDA- receptors are affected by nitrous oxide (Jevtovic-
Discharge Todorovic et al. 1998; Fujinaga and Maze 2002; Sanders
et al. 2008). To safeguard the patient’s oxygen supply during
The recovery of a child must be assessed before discharge. inhalation, nitrous oxide must be given in a mixture with
At time of discharge, the patient should be alert and oriented oxygen (> 30%). Nitrous oxide is non-irritant to the respira-
(or have returned to an age-appropriate base line). A respon- tory tract, has a low tissue solubility, and a minimum alve-
sible adult must be present to observe the child for compli- olar concentration (MAC) value of more than one atmos-
cations after discharge. In case of midazolam sedation, this phere. Therefore, nitrous oxide has an onset and recovery
adult should ensure that the child is in a position to facilitate within minutes, and is a poor anaesthetic.
breathing. If the responsible adult is driving, another adult
must be present if the child is young.
The adult must be given written and oral instructions not
only related to the sedation technique, but also the dental

13
European Archives of Paediatric Dentistry (2021) 22:989–1002 999

Table 4  Recommended Sedation records during and after sedation according to Wilson et al. (1990) and DSTG (2020)
Sedation techniques
IV Intravenous sedation

RA Inhalation sedation
O Oral sedation
TM Transmucosal
Sedation scoring

1 Fully awake and orientated

2 Drowsy
3 Eyes closed, responds promptly on verbal command
4 Eyes closed, rousable on mild physical stimulus
5 Eyes closed, unrousable on mild physical stimulus
Assessment of operating conditions

1 Good Patient fully cooperative with optimum degree of sedation

2 Fair Minimal interference from patient due to over/under sedation
3 Poor Operating difficult due to over/under sedation
4 Impossible Action taken (e.g., GA)
Recovery

Normal Within the timescale expected

Rapid Sooner than normal—action taken
Prolonged Longer than normal—action taken

Indications • Patients with sinusitis or recent ENT operations

(within 14 days)
Nitrous oxide/oxygen sedation is useful in children who can • Patients in bleomycin chemotherapy
cope with nasal breathing instructions, often 3 years and • Severe emotional or drug-related dependencies
older. • Chronic obstructive pulmonary disease
Further to the general indications for conscious sedation • Raised intraocular pressure, retinal surgery, intestinal
mentioned previously, nitrous oxide/oxygen can be used in obstructive surgery
patients with a strong gag reflex, as well as in patients with • Untreated B12 deficiency (Stach 1995; Haas 1999;
muscular tone disorders such as cerebral palsy, to avoid AAPD 2018)
unintentional movements.
Patients belonging to ASA Class III and Class IV can be Whenever possible and appropriate, medical specialists
treated with the help of nitrous oxide/oxygen sedation pro- should be consulted before administering nitrous oxide to
vided other indications are present, but treatment of these patients with significant underlying medical conditions.
patients should be in conjunction with responsible medical
colleagues and in a hospital setting.
Adverse effects
Contraindications
Observed side effects of nitrous oxide are over sedation,
Nitrous oxide/oxygen sedation should not be used in nausea, vomiting, sweating, dysphoria, restlessness,
panics and headache (Jastak 1975; Hallonsten 1982;
• Pre-co-operative children Veerkamp 1990).
• Patients with upper airway problems as common cold,
tonsillitis, sinusitis or nasal blockage
• Middle ear infection

13
1000 European Archives of Paediatric Dentistry (2021) 22:989–1002

Technique • Children with any form of acute disease

• Children with respiratory or cardiac disease that affects
Sedation is initiated by inhalation of pure oxygen for daily life
2–5 min. Following that, the nitrous oxide concentration • Children with neuromuscular diseases as myasthenia
is gradually increased every second minute. The maximum gravis
recommended concentration of nitrous oxide is determined • Children with allergy to BZD
by national regulations, and varies between the Europe coun- • Children with sleep apnoea
tries from 50 to 70%. The commonly effective dosage for • Children with liver dysfunction (dose adjustment may be
most children tends to be 30–40%. At the end of the session necessary)
the child is given pure oxygen for 5 min before discharge. • Children with hepatic dysfunction (dose adjustment may
be necessary)
Potential interactions • Children with porhyria

Nitrous oxide may amplify the effects of other sedatives, Whenever appropriate, medical specialists should be
e.g., opioids, benzodiazepines, leading to CNS depression. consulted before administering midazolam to patients with
There are no known potential interactions with other drugs. significant underlying medical conditions (e.g., cardiac, pul-
monary, kidney or liver dysfunction or current medication
Safety for the staff with centrally acting analgesics).

Chronic exposure to certain environmental concentrations Adverse effects

of nitrous oxide has been reported to constitute an health
risk for the dental staff (Rowland et al. 1992, 1995; Zaffina The following side effects have been noted:
et al. 2019). Consequently, the dental staff must follow strict
indications for the use of nitrous oxide, only use nitrous • Hiccups
oxide delivery systems with an efficient scavenging system, • Nausea
have appropriate technique for disconnection of the delivery • Respiratory depression
system, and have methods for testing the integrity of the • Interactions with other medication
breathing system. • Paradoxical reaction
• Over sedation
Using midazolam • Hallucinations

Midazolam is a short-acting benzodiazepine with rapid onset

of action. It has anxiolytic, sedative, hypnotic, anticonvul- Clinical considerations
sant and muscle relaxant activity and frequently induces
anterograde amnesia. Midazolam binds to the benzodi- All drugs in use in the treatment area must be clearly
azepine receptor in the CNS and enhances the inhibitory labelled and each drug should be given according to
action of the neurotransmitter GABA. The inhibitory effect accepted recommendations.
of GABA is caused by increasing the flux of chloride ions Flumazenil should be available in case needed to reverse
through the ion channels of the nerve cell. The increase of the effects of midazolam in an emergency.
chloride ions into the cell decreases its ability to initiate an
action potential (Nordt and Clark 1997). Routes

Indications • Oral midazolam can be administered as a sweetened mix-

ture for delivery either in a cup or drawn into a needleless
See general indications for sedation. Where moderate seda- syringe and deposited in the retromolar area. A prefor-
tion as opposed to only mild sedation is required. mulated flavoured syrup is also available for use.
• Intravenous midazolam can be administered via a cannula
Contraindications directly into circulation and titrated to affect.
• Transmucosal administration (rectal and intranasal) of
Midazolam must not be given to the following groups of midazolam has the advantage of depositing the drug
children directly into the systemic circulation.

• Children under the age of 1 year or body weight < 10 kg

13
European Archives of Paediatric Dentistry (2021) 22:989–1002 1001

• Rectal administration requires syringes and a rectal appli- intravenously for rapid onset and reversal of effects of ben-
cator. In some countries, rectal administration is uncom- zodiazepines like midazolam.
mon due to cultural attitude. The elimination half-time of Flumazenil is however
• Intranasal sedation can be sprayed into one nostril. shorter than that of midazolam. Hence patients must be care-
fully monitored to prevent recurrence of overdose symp-
toms. Repeat doses of flumazenil may be required for this
Dosage reason too.

Oral Children under 25 kg of weight shall have 0.3–0.5 mg • Recommended dose of flumazenil (in child > 1 yr) given
midazolam per kilogram bodyweight. Maximum dose: as intravenous administration: 10 µgm/kg, up to 200 µgm,
10–12 mg based on local legislation. over 15 s
Children over 25 kg of weight shall have 10–12 mg mida- • Repeat every 1 min × 4, Max 1 mg, i.e., two ampoules of
zolam based on local legislation. 500 µgm or 50 µgm/kg, whichever is less
Oral mixtures are given approximately 15–20 min before. • 5 yr, 20 kg child; max 1000 µgm (2 amps)
The duration of effect is usually 30–50 min. • 12 yr, 40 kg child; max 1000 µgm (2 amps)

Rectal Children under 25 kg of weight shall have 0.3– Mandatory equipment for emergency situations
0.4 mg midazolam per kilogram bodyweight. Maximum during sedation with midazolam
dose 10 mg midazolam.
Children over 25 kg of weight shall have 10 mg Mandatory equipment as would be required by legislation
midazolam. of the country should include all equipment for a medical
Rectal solution is administered approximately 10 min emergency, which would include age appropriate.
before treatment starts.
• Oxygen equipment
Intranasal Intranasal sedation can be sprayed into one nos- • Ventilation mask
tril, using mucosal atomizer device (MAD). • Pulsoximeter
Formulation made up for this purpose needs to be quite
concentrated to allow a small volume to be effective while
being deposited in the nostril. Supplementary Information The online version contains supplemen-
Dosage 0.2 mg/kg, maximum dose 10 mg. tary material available at https://​doi.​org/​10.​1007/​s40368-​021-​00660-z.
The effect of the sedation takes place in approximately
10–15 min. The duration of effect is usually around 30 min. Acknowledgements Thank-you to Sabina Gillsund, Karolinska Insti-
tutet for the updated evidence search.

Intravenous 1 mg initial loading dose over 60 s followed by Author contributions All authors contributed equally to the preparation
60 s increment of 1 mg until patient is ready for treatment. of this manuscript.
Dosage usually ranges from 2 to 7.5 mg. The effect of the
sedation takes place in 1–2 min. The duration of effect is Funding No funds, grants, or other support was received.
usually 30–50 min.
The effect of sedation may exhibit an interpersonal and Availability of data and material Not applicable.
intrapersonal variation.
Code availability Not applicable.

Potential interactions Contemporaneous intake of erythro-

Declarations
mycin, hypnotics, anxiolytics, antidepressants, some anti-
fungals, some antivirals, antipsychotics, antiepileptics, anti- Conflict of interest The authors have no conflicts of interest to declare
histamines, opioids, grapefruit juice, clonidine and alcohol that are relevant to the content of this article.
can enhance the effect. Drug interactions should be followed
by the practitioner in their respective national databases. Open Access This article is licensed under a Creative Commons Attri-
bution 4.0 International License, which permits use, sharing, adapta-
tion, distribution and reproduction in any medium or format, as long
Flumazenil–midazolam antidote as you give appropriate credit to the original author(s) and the source,
provide a link to the Creative Commons licence, and indicate if changes
Flumazenil is a selective GABA receptor antagonist. It were made. The images or other third party material in this article are
acts as an antagonist and antidote to benzodiazepines included in the article's Creative Commons licence, unless indicated
otherwise in a credit line to the material. If material is not included in
through competitive inhibition. It is mostly administered the article's Creative Commons licence and your intended use is not

13
1002 European Archives of Paediatric Dentistry (2021) 22:989–1002

permitted by statutory regulation or exceeds the permitted use, you will NICE. Sedation in under 19s: using sedation for diagnostic and thera-
need to obtain permission directly from the copyright holder. To view a peutic procedures (CG112). National Institute for Health and Care
copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/. Excellence. 2010. www.n​ ice.o​ rg.u​ k/g​ uidan​ ce/c​ g112. Accessed 17
Jan 2021.
NICE. Developing NICE Guidelines: the manual. https://​www.​nice.​
org.u​ k/p​ roces​ s/p​ mg20/c​ hapte​ r/i​ ntrod​ uctio​ n#m
​ ain-s​ tages-o​ f-g​ uide​
line-​devel​opment. Accessed 7 Oct 2020.
References Nordt S, Clark R. Midazolam: a review of therapeutic uses and toxicity.
J Emerg Med. 1997;15(3):357–65.
American Academy of Pediatric Dentistry (AAPD). Use of Nitrous Patel V, Singh N, Saksena AK, Singh S, Sonkar SK, Jolly SM. A
oxide for pediatric dental patients. 2018. https://​www.​aapd.​org/​ comparative assessment of intranasal and oraldexmedetomidine
media/​Polic​ies_​Guide​lines/​BP_​Useof​Nitro​us.​pdf. Accessed 20 for procedural sedation in pediatric dental patients. J Indian Soc
Jan 2021. Pedod Prev Dent. 2018;36(4):370–75.
American Society for Anesthesiologists. New classification of physical Rowland AS, Baird DD, Weinberg CR, Shore DL, Shy CM, Wilcox
status. Anesthesiology. 1963;24:111. AJ. Reduced fertility among women employed as dental assis-
Ashley PF, Chaudhary M, Lourenço-Matharu L. Sedation of chil- tants exposed to high levels of nitrous oxide. N Engl J Med.
dren undergoing dental treatment. Cochrane Database Syst Rev. 1992;327(14):993–7.
2018;12:CD003877. https://​doi.​org/​10.​1002/​14651​858.​CD003​ Rowland AS, Baird DD, Shore DL, Weinberg CR, Savitz DA, Wilcox
877.​pub5. AJ. Nitrous oxide and spontaneous abortion in female dental assis-
Dental Sedation Teachers Group . DSTG Logbook of clinical experi- tants. Am J Epidemiol. 1995;141(6):531–8.
ence in conscious sedation. 2015. Available online at https://w ​ ww.​ Sanders RD, Weimann J, Maze M. Biologic effects of nitrous
dstg.c​ o.u​ k/i​ ndex.p​ hp/​docum​ents/​docum​ent/s​ edat​ionlog​ book-​doc. oxide: a mechanistic and toxicologic review. Anesthesiology.
Accessed Apr 2020. 2008;109(4):707–22.
European Association of Paediatric Dentistry. Curriculum guidelines Scottish Dental Clinical Effectiveness Programme. Conscious Sedation
for education and training in paediatric dentistry. Int J Paediatr in Dentistry: Dental Clinical Guidance. 2017. https://​www.​sdcep.​
Dent. 1997;7:273–81. org.u​ k/w
​ p-c​ onten​ t/u​ pload​ s/2​ 018/0​ 7/S​ DCEP-C ​ onsci​ ous-S
​ edati​ on-​
Fujinaga M, Maze M. Neurobiology of nitrous oxide-induced antino- Guida​nce.​pdf. Accessed 25 Jan 2021.
ciceptive effects. Mol Neurobiol. 2002;25(2):167–89. Stach DJ. Nitrous oxide sedation: understanding the benefits and risks.
Gomes HS, Daher A, Costa PS, Batista AC, Costa LR. Crossover stud- Am J Dent. 1995;8(1):47–50.
ies of pediatric dental sedation are inappropriate. Braz Dent J. Standards for Conscious Sedation in the Provision of Dental Care
2019;30(4):404–9. https://d​ oi.o​ rg/1​ 0.1​ 590/0​ 103-6​ 44020​ 19028​ 52. (V1.1): Report of the Intercollegiate Advisory Committee for
Guyatt GH, Oxman AD, Vist GE, Kunz R, Faick-Ytter Y, Alonso- Sedation in Dentistry (IACSD). 2015; www.​rcseng.​ac.​uk/​den-
Coello P, Schunemann HJ. GRADE: an emerging consensus on tal-​facul​ties/​fds/​publi​catio​ns-​guide​lines/​stand​ards-​for-​consc​
rating quality of evidence and strength of recommendations. BMJ. ious-​sedat​ion-​in-​the-​provi​sion-​of-​dental-​care-​and-​accre​ditat​ion/.
2008;336:924. Accessed 17 Jan 2021.
Haas DA. Oral and inhalation conscious sedation. Dent Clin North Am. Veerkamp JS, Gruythuysen RJ, van Amerongen WE, Hoogstraten
1999;43(2):341–59. J. Dental treatment of fearful children using nitrous oxide.
Hallonsten A-L. Nitrous oxide-oxygen sedation in dentistry. Swed Dent Part 3: Anxiety during sequential visits. ASDC J Dent Child.
J Suppl. 1982;14:5–44. 1993;60(3):175–82 (PMID: 8340519).
Hallonsten AL, Jensen B, Raadal M, Veerkamp J, Hosey MT, Poulsen Veerkamp JS. Nitrous oxide, happy air or hot air. University of Amster-
S. EAPD Guidelines on Sedation in Paediatric Dentistry. 2005. dam; 1990.
https://​www.​eapd.​eu/​uploa​ds/​5CF03​741_​file.​pdf. Accessed Sept Wilson E, David A, MacKenzie N, Grant IS. Sedation during spi-
2020 nal anaesthesia: comparison of propofol and midazolam. Br J
Higgins JP, Green S, editor(s) Cochrane Handbook for Systematic Anaesth. 1990;64:48–52.
Reviews of Interventions Version 5.1.0 (updated March 2011). Zaffina S, Lembo M, Gilardi F, Bussu A, Pattavina F, Tucci MG,
The Cochrane Collaboration, 2011. Available from handbook. Moscato U, Raponi M, Derrico P, Galeotti A, Camisa V. Nitrous
cochrane.org. oxide occupational exposure in conscious sedation procedures in
Jastak JT, Paravecchio R. An analysis of 1,331 sedations using inha- dental ambulatories: a pilot retrospective observational study in an
lation, intravenous, or other techniques. J Am Dent Assoc. Italian pediatric hospital. BMC Anesthesiol. 2019;19:42.
1975;91(6):1242–9.
Jevtović-Todorović V, Todorović SM, Mennerick S, Powell S, Dikra- Publisher's Note Springer Nature remains neutral with regard to
nian K, Benshoff N, Zorumski CF, Olney JW. Nitrous oxide jurisdictional claims in published maps and institutional affiliations.
(laughing gas) is an NMDA antagonist, neuroprotectant and neu-
rotoxin. Nat Med. 1998;4(4):460–3.
Kapur A, Kapur V. Conscious sedation in dentistry. Ann Maxillofac
Surg. 2018;8(2):320–3.

13