Accepted Article

DR LUC VANLINTHOUT (Orcid ID : 0000-0002-4541-5037)

MR JOHAN M.A BERGHMANS (Orcid ID : 0000-0002-3835-562X)

Article type : Systematic reviews

Editor : Prof Brian Anderson

Neuromuscular blocking agents for tracheal intubation in pediatric patients: A systematic review
and meta-analysis 1,2
Article category: Meta-analysis.

Luc E. Vanlinthout,1,2 Bénédicte Geniets,2 Jacques J. Driessen,3 Vera Saldien,4 Raphaël Lapré,1 Johan
Berghmans,5 Germaine Uwimpuhwe,6,7 and Niel Hens7

1Department of Anesthesiology and Algology, University Hospital Gasthuisberg, Belgium

2Department of Anesthesiology and Algology, GZA Hospitals, Antwerp, Belgium
3Department of Anesthesiology, Radboud University Medical Centre Nijmegen, Nijmegen,
The Netherlands
4Department of Anesthesiology, University Hospital of Antwerp, Antwerp, Belgium
5Department of Anesthesiology, Erasmus MC - Sophia Children’s Hospital, Rotterdam, The Netherlands
6 Durham Research Methods Centre, Durham University, Durham, United Kingdom
7Interuniversity Institute for Biostatistics and statistical Bioinformatics (I-BIOSTAT), Universities of Leuven
and Hasselt, Leuven and Diepenbeek, Belgium

Corresponding author: Dr. Luc E. Vanlinthout (vanlinthout.l@skynet.be)

Department of Anesthesiology and Algology
University Hospital Gasthuisberg

1 Has been presented at Euroanaesthesia in Vienna, June 01-03, 2019

2 PROSPERO registration number: CRD42018097146

This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process, which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1111/PAN.13806
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 Herestraat 33
Accepted Article
3000-LEUVEN
Belgium
E-mail address: Vanlinthout.l@skynet.be

Short running title: Muscle relaxants for tracheal intubation

Acknowledgements

We are grateful to Shihao Bao, MD for the translation from Chinese to English. We are indebted to Mrs.
Geertruida Bekkering for reviewing the manuscript. She is affiliated to the Centre of Evidence Based
Medicine (CEBAM) at the University of Leuven (Belgium), who represents the Belgian Branch of the
Cochrane Collaboration.

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 Abstract
Accepted Article
Background: The benefit of using neuromuscular blocking agents to facilitate tracheal intubation in
children remains unclear due to variations in design, treatments, and results among trials. By combining the
available evidence, we aimed to establish whether scientific findings are consistent and can be generalized
across various populations, settings and treatments.
Methods: A systematic search for randomized controlled trials (RCTs), related to the use of neuromuscular
blocking agents for tracheal intubation in ASA Class I-II participants (0-12 y) was performed. We
considered all RCTs that studied whether intubation conditions and hemodynamics obtained by using
neuromuscular blocking agents were equivalent to those that were achieved without neuromuscular
blocking agents. We combined the outcomes in Review Manager 5.3 (RevMan, The Cochrane Collaboration) by
pair-wise random-effects meta-analysis using a risk ratio for intubation conditions and mean difference for
hemodynamic values (mean [95%CI]). Heterogeneity among trials was explored using sensitivity analyses.
Results: We identified 22 eligible RCTs with 1651 participants. Overall, the use of a neuromuscular
blocking agent was associated with a clinically important increase in the likelihood of both excellent
(RR=1.41 [1.19-1.68], I²=76%) and acceptable (RR=1.13 [1.07-1.19], I²=68%) intubating conditions. There
is strong evidence that both, unacceptable intubation conditions (RR=0.35 [0.22-0.46], I²=23%) and failed
first intubation attempts (RR=0.25 [0.14-0.42], I²=0%) were less likely to occur when a neuromuscular
blocking agent was used compared to when it was not. Higher systolic or mean arterial pressures (mean
difference=13.3 [9.1-17.5] mmHg, I²=69%) and heart rates (mean difference=15.9 [11.0-20.8] beats∙min-1,
I²=75%) as well as a lower incidence of arrhythmias were observed when tracheal intubation was facilitated
by neuromuscular blocking agents.
Conclusion: The use of a neuromuscular blocking agent during light to moderate depth of anesthesia can
improve the quality as well as the success rate of tracheal intubation and provides better hemodynamic
stability during induction of anesthesia.

Key words:
Clinical trials; Induction of anesthesia; Airway; neuromuscular blocking
drugs, Drugs; intravenous agents, Drugs; inhaled agents, Drugs

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 Introduction
Accepted Article
Surveys conducted among pediatric anesthesiologists show that avoiding neuromuscular blocking agents
(NMBAs) for airway management in children is still a common practice.1 Concerns about the dangers of
succinylcholine particularly after induction with inhaled anesthetics, prolonged paralysis following exposure
to long-acting neuromuscular blocking agents, and possible anaphylactic reactions, have discouraged the
use of NMBAs in children.2
However, NMBAs can improve the quality of intubation and reduce the incidence of critical
respiratory events, especially when airway instrumentation is performed at inadequate levels of
anaesthesia.3-6 Cases of bradycardia and airway damage have been reported when relaxant-free methods
have been used.7,8 According to the Pediatric Difficult Airway Society guidelines adequate paralysis should
be established in cases of unanticipated problematic airway management.9 In recent years, short-acting
NMBAs characterized by minimal side effects have become available. Despite the various advantages that
are afforded by these newer agents, the need for NMBAs in pediatric induction protocols is still a subject of
ongoing debate.10,11
Proper trials on the safety and efficacy of many drugs used in children are surprisingly scarce.
Methodological issues which relate specifically to research in children include a smaller and more
heterogeneous population.12 From the available evidence, the benefit of using NMBAs to facilitate tracheal
intubation in children has not yet been firmly established due to variations in design, treatment and results
among studies. In a recent meta-analysis that included 7 randomized controlled trials (RCTs), the statistical
power was insufficient to determine whether excellent intubation conditions were more likely when either
NMBAs or opioids were used to facilitate tracheal intubation.13
Systematic reviews establish whether scientific findings are consistent and can be generalized
across populations, interventions and settings, or whether findings vary meaningfully by particular
subsets.14 For the purpose of reducing variability, a previous meta-analysis has been confined to a smaller
and more homogeneous group of studies13 A limitation of such a reductionist scope and restricted focus is
the limited inference that is possible outside of the narrowly specified settings or treatments (NMBAs vs
opioids), whereas using more liberal inclusion criteria (that can better simulate “real-world” clinical practice)
might allow broader generalization with increased sample size/statistical power and precision of estimates
of intervention effect.15 The clinical diversity of multiple reviewed studies obtained with the latter approach,
provides an interpretative context that is not available in the previous study.13
The aims of the present study were to determine the impact of NMBAs on tracheal intubating
conditions and hemodynamic responses in ASA class I-II children aged 0-12 y. For that purpose we
considered all eligible RCTs that studied whether intubation conditions and hemodynamics obtained by
using NMBAs were equivalent to those that were achieved when they were not.

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 Methods
Accepted Article
Search strategy and selection criteria
The current meta-analysis was conducted according to guidelines from the Cochrane Handbook for
Systematic Reviews16 and the PRISMA statements for reporting of systematic reviews.17
We searched for RCTs published in any language that compared different doses of intravenous
rocuronium, succinylcholine, mivacurium, atracurium, vecuronium and cis-atracurium vs no muscle relaxant
at all from January 1990 until December 2018 in five databases: PubMed, Embase Cochrane Central
Register of Controlled Trials, the EU Clinical Trials Register and Web of Science. We combined the free
text terms ‘rocuronium', ‘succinylcholine’, 'mivacurium', 'atracurium', 'vecuronium', 'cis-atracurium',
‘intubation conditions’, ‘infants’, ‘children' and 'pediatrics'. We manually reviewed reference lists of the
retrieved trials to search for additional relevant studies that were not picked up by the electronic search.
Reports of eligible trials were published as a peer reviewed full-text article or as an abstract. We excluded
doctoral dissertations, letters, reviews, and trials that were not peer-reviewed.
We included RCTs that studied healthy ASA class I-II patients who were aged 0-12 y. Participants
of included trials were scheduled for elective or emergency surgery that required tracheal intubation. We
accepted all trials in which anesthesia was induced with inhaled or intravenous routes of administration
either with or without opioids.
Studies that enrolled participants who had known psychiatric, neurological, neuromuscular, hepatic,
renal, and endocrine diseases as well as trials in which NMBAs were administered by any other route other
than IV were excluded.

Outcomes
We assessed intubating conditions using the Goldberg scale.18 This is a widely used three-point scale that
allocates a categorical score for the following items: ease of intubation, vocal cord movement, and patient
response to intubation. We converted studies to this scale if it was not directly reported but sufficient detail
was available to do so.
The primary outcome was ‘excellent intubation conditions’, which was defined by three criteria:
easy tube insertion, immobile open vocal cords and no patient movement during laryngoscopy and tracheal
intubation. With the complete absence of muscular activity, ‘excellent intubation conditions’ can be
considered as a hard endpoint in which interpretation bias could be avoided. The secondary outcome was
'clinically acceptable intubation conditions' in which the score for each of the three items, i.e. ease of
intubation, vocal cord movement, and patient response to intubation was graded either excellent or good.
Further outcomes included blood pressure and heart rate before and at 1 min following laryngoscopy and
intubation.

Quality assessment—risk of bias

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 To assess the risk of bias, we used the Cochrane risk of bias assessment tool,19 which includes the
Accepted Article
following items: random sequence generation, allocation concealment, personnel and outcome assessors'
blinding, completeness of outcome data, and selective outcome reporting. Risks were categorized as
present, absent or unclear.
Two authors (LV and BG) independently selected studies, assessed the risk of bias and extracted
data. We resolved all disagreements by consensus. If we could not reach a consensus, then a third author
(JD) was available to give a final decision.

Statistical analysis
For both excellent and acceptable intubation conditions, the unit of analysis was the intubation score
provided by each of the treatment arms of included trials. These scores were dichotomized, i.e.
transformed into binary variables (1/0) according to whether an event (excellent or acceptable intubation
conditions) occurred (1) or not (0). We used relative risk and a 95% confidence interval (95% CI) for both
excellent and acceptable intubation conditions, to measure the magnitude and direction of intervention
effects. Blood pressure and heart rate were considered as continuous variables with a mean value,
standard deviation and/or 95% CI for each treatment group.
We used random effects model20 in Review Manager 5.3 to pool the estimates of the risk ratios
(RRs) of intubation conditions as well as the mean differences of hemodynamic parameters (arterial blood
pressure and heart rate). A pairwise meta-analysis was performed to compare the outcomes from both
induction techniques, either including (intervention) or excluding (control) the use of NMBAs. The results of
included trials were weighted by the precision (1/variance) of their association with intubation conditions
and hemodynamic outcomes.

Exploring heterogeneity in outcome data

Heterogeneity in the outcome data was assessed using Cochrane’s Q test and inconsistency across trials
was quantified with I2, using a random effects model and inverse variance. I2 thresholds of 25%, 50% and
75% indicate mild, moderate and high degrees of inconsistency, respectively.21 We explored the causes of
clinically important heterogeneity using subgroup analyses and meta-regression.22 A sensitivity analysis
was done to determine whether the results were sensitive to restrictions on the data included. The sample
size required for logistic metaregression was accepted to be 5 for each covariable23 that was selected by
backward stepwise regression (fit criterion p<0.05). Reporting bias was assessed by visual inspection of a
funnel plot of the incorporated trials.

Trial sequential analysis

Trial sequential analyses were done to determine whether the amount of available information (that is the
number of participants needed in a meta-analysis to detect or reject a certain intervention effect) was
sufficient or further studies were needed.24 In the current study, the number of participants required was
computed for the primary, secondary and other study outcomes assuming α=0.05, β=0.20 and a treatment

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 effect, i.e. relative risk reduction (RRR) and mean difference, of 20% between NMBA and muscle relaxant-
Accepted Article
free techniques.

Data analysis was carried out using Stata version 15.0 (StatCorp®, College Drive, Texas, USA), Review
Manager version 5.3 (RevMan, Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration), and Trial
Sequence Analyzer version 0.9.5.9 Beta (Copenhagen Trial Unit, Centre for Clinical Intervention Research,
Rigshospitalet, Copenhagen, Denmark.). We considered a
value of p < 0.05 as statistically significant.

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 Results
Accepted Article
Exploratory data analysis
We identified 22 RCTs with 1651 ASA class I-II patients in 62 treatment groups (Figure 1 and Table 1) that
were conducted between 1993 and 2018. Clinical reports of all studies25-46 were published as peer-
reviewed full journal articles. Participants were recruited over a period of 26 y (1993-2018) from different
parts of the world. About 80% of them were submitted to studies that were published after 2000 (Figure
S1). Cumulative distribution of participants by age is shown in Figure S2.
For each study, methodological details were assessed for risk of bias. A summary of our
judgements of bias can be found in Figure S3 and Figure S4. The exact method of random number
generation and allocation concealment was not always described. In 3/22 studies,39,43,46 there was
insufficient information about outcome assessor’s blinding. In 2 RCTs attrition of outcome data could have
biased the intervention effect estimate.27,40 Selective reporting was uniformly low-risk. The method to
calculate the sample size required before embarking on data collection was not reported in 6/22 of the
enrolled studies.25,34,35,37,40,46 Intubation conditions were assessed using either a 3-item (7/22)25,34-37,40,42,43
or 5-item (15/22) 26-33,36,38,39,41,44-46 scoring system. In 3 trials primary outcome (excellent intubation
conditions) was not addressed35,38,46. Several studies reported no30-32,36,43 or only partial
hemodynamic26,29,42,43 data. Magnitude and time course of neuromuscular block was monitored in 5 studies,
i.e by mechanomyography30,34 or by acceleromyography.29,31,32
Anesthesia was induced either intravenously or by facemask using inhaled agents. Either propofol
(957 pts) or thiopentone (130 pts) was used as a IV hypnotic, and sevoflurane (604 pts) and halothane
(238 pts) were used as inhaled anesthetic agents. In a number of studies, opioids, i.e., fentanyl (258 pts),
alfentanil (173 pts), remifentanil (339 pts) or morphine (64 pts) were added to the induction sequence. In a
number of studies, anesthesia induction was preceded by midazolam 0.50 mg∙kg-1 PO (410
pts)30,31,33,35,37,41 , 0.3-1 mg∙kg-1 rectal (98 pts)32,34 or 0.10 mg∙kg-1 IV (120 pts)46. Anticholinergic medication
was administered after intravenous access was established (579pts)27,28,35,37,41,42 or as appropriate to treat
hypotension or bradycardia34,36.
Endotracheal intubation was facilitated by either atracurium (14 pts)34, mivacurium (28 pts)27,
rocuronium (290 pts)29-33,36,37, succinylcholine (398 pts)25,26,28,35,38-45, vecuronium (30 pts)46, or no muscle
relaxant at all (821 pts). No placebo controlled RCTs could be found regarding intubation conditions
obtained by cis-atracurium in children.

Heterogeneity analysis

Effects of the interventions were reported as RRs (intubation conditions) and mean differences
(hemodynamic values) (mean [95% CI]).
Overall, the use of NMBAs was associated with a clinically important increase in the likelihood of
both excellent (RR=1.41 [1.19-1.68], I²=76%)(p<0.0001) and acceptable (RR=1.13 [1.07-1.19],
I²=68%)(p<0.0001) intubating conditions (Figure 2). In the subgroup analysis, there was no evidence of a

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 difference in excellent intubation conditions created by either nondepolarizers or techniques that did not
Accepted Article
include the use of a relaxant (RR=1.33 [0.93-1.90], I²=76%)(p=0.12). This latter result can be explained by
the inclusion of a trial in which ease of tracheal tube insertion, facilitated by either 0.4 mg∙kg-1 rocuronium or
high dose remifentanil (4 µg∙kg-1) were compared. By excluding this study from the meta-analysis, the
advantage of using nondepolarizers for the creation of excellent intubations during light/moderate depth of
anaesthesia became apparent (RR=1.49 [1.03-2.15], I²=71%)(p<0.04).
There was insufficient evidence to determine whether, when using a relaxant, either intravenous
(RR=1.33 [1.06-1.68], I²=80%) / (RR=1.11 [1.01-1.21], I²=77%) or inhalational anesthesia (RR=1.49 [1.12-
1.97], I²=61%) / (RR=1.11 [1.02-1.19], I²=61%) improved excellent/acceptable conditions for tracheal
intubation (p=0.57/0.98)(Figure S5).
There is very strong evidence that the use of NMBAs compared to when they were not was
associated with 1) less closing/closed vocal cords, i.e. 27/738(3.7%) vs 79/713(11.1%), respectively,
(RR=0.27 [0.17-0.41], I²=6%)(p<0.0001); 2) less unacceptable conditions, i.e 54/771(7.0%) vs
177/880(20.1%), respectively, (RR=0.35 [0.22-0.46], I²=23%)(p<0.0001); and 3) less failed first pass
attempts, i.e. in 13/796(1.6%) vs 64/855(7.5%)(p<0.0001), respectively, (RR=0.25 [0.14-0.42],
I²=0%)(p<0.0001). No significant differences could be demonstrated between the effect of using
depolarizing rather than nondepolarizing NMBAs on the incidence of unacceptable intubation conditions,
closing/closed vocal cords or failed intubations (Figure S6).
In some relaxant free treatment arms, failure rates of up to 20% have been observed, i.e., in the
propofol/alfentanil group, in 7/30 participants25; in the propofol/remifentanil1 group, in 6/28 participants27; in
the sevoflurane 8% in O2 group, in 7/27 participants29, in the sevoflurane 8% in N2O/O2 group, in 7/20
participants31 and in the sevoflurane8%/alfentanil group, in 5/23 participants29 (Figure S6).
For those aged≤24 months in the NMBA and muscle relaxant free groups, respectively, the
incidence of unacceptable conditions (20/127(15.8%) and 43/160(26.9%)) and failed first pass attempts
(4/127(3.2%) and 25/160(15.6%)) was higher25,28,29,32,34 than that obtained for these same outcomes in
their older counterparts (aged>24 months), i.e. unacceptable conditions (70/764(9.2%) and 97/600(16.2%))
and first attempt failures (9/676(1.3%) and 39/702(5.6%)).
Random effects metaregression analysis demonstrated that, within the age range 0-12y excellent
intubation conditions for rocuronium (17 study arms, 326 participants, R²=71.4 and I²=26.8%)29 were more
likely with higher NMBA dose, younger participants and increasing time to intubation. (Figure 4, Table S1).
Clinically important decreases in mean arterial (MAP) or systolic arterial pressure (SAP) (mean
difference=13.3 [9.1-17.5] mmHg, I²=69%)(p<0.0001) and heart rate (mean difference=15.9 [11.0-20.8]
beats∙min-1, I²=75%)(p<0.0001) were measured when NMBAs were not used compared to when they
were (Figure 3). One minute after intubation these values were (mean difference=17.4 [13.8-21.1] mmHg,
I²=56%)(p<0.0001) and (mean difference=17.3 [14.7-19.9] beats∙min-1, I²=76%)(p<0.0001) for blood
pressure and heart rate, respectively.
Despite prophylactic anticholinergics, the reduction in heart rate with propofol was more
pronounced in the muscle relaxant free groups when alfentanil or remifentanil was also given, (mean

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 difference=19.4 [13.6-25.2] beats∙min-1) compared to that when they were not used (mean difference=7.9
Accepted Article
[0.2-15.7] beats∙min-1) (p=0.028).
The overall incidence of dysrhythmias without atropine in one study was 0/30 (0%), 8/28(29%) and
6/28(21%) participants in the thiopental/succinylcholine, propofol/alfentanil and halothane in N2O/O2
groups, respectively. In another study,35 junctional rhythm was the most commonly recorded cardiac
dysrhythmia, occurring in 32/100 participants who received halothane in N2O/O2, of which 23/50(46%)
were in the 2% halothane group and 9/50(18%) were in the succinylcholine 1 mg∙kg-1/1% halothane group.
In a study with infants (0-2yr)29 in which prophylactic administration of anticholinergics was omitted,
bradycardia and/or hypotension (defined as more than 30% variation from baseline) occurred in 2/27(7%)
of the sevoflurane, in 8/27(30%) of the sevoflurane/alfentanil and in 1/25(4%) of the sevoflurane/rocuronium
treatment groups.
There were significantly more infants with respiratory adverse events (13/50(26%)) and arterial
desaturation (7/50(14%)) in the muscle relaxant-free groups as compared to those receiving rocuronium
(0/25 for both).29
Masseter muscle rigidity was observed in 1/50(2%) participants receiving 1% halothane in 70%
N2O combined with succinylcholine 1 mg∙kg-1.35
Halothane was used in 4/22 studies.25,34,35,40 However, excluding these studies did not significantly
alter the results regarding the primary and other outcomes.
Drug allergy was listed as an exclusion criterion in 4 studies29,41-43. No symptoms of allergic
reactions were reported in the reviewed studies.
Post-operative sore throat was recorded 7/30(23%), 3/30(10%), 3/30(10%), and 2/30(7%) of
participants, following induction sequences in which sevoflurane 3% was supplemented with remifentanil 1,
2, 3 µg∙kg-1, and vecuronium 0.1 mg∙kg-1, respectively.46

Quality of evidence
In current meta-analysis 8/22 trials were at high risk of bias of which 6 studies failed to report
appropriate sample size calculations25,34,35,37,46 and 2 were at high risk for incomplete outcome
reporting.27,40 However, excluding these studies did not meaningfully alter the results regarding the primary
and other outcomes.
There was heterogeneity in the pair-wise meta-analyses, as was demonstrated by Chi-squared test
for heterogeneity and graphically with the 95% CIs of each trial (Figure 2, Figure 3, Figure S5 and Figure
S6). An analysis of the influence on consistency demonstrated that no single trial, regardless of its size,
meaningfully altered the I² statistic. We therefore decided that the sources of heterogeneity were clinical
and methodological diversity which contributed to the generalizability of the results.
We assessed publication bias using a funnel plot. Visual inspection revealed a symmetrical
distribution of trials on either side of the effect estimate.

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Accepted Article Trial sequential analysis24 confirmed sufficient statistical power (Figure S7 and Figure S8), allowing
to make robust inferences about the primary (excellent intubation conditions), secondary (acceptable
intubation conditions) and other outcomes (blood pressure and heart rate).

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 Discussion
Accepted Article
The current meta-analysis, which summarizes the results of 22 trials including 1651 ASA I-II participants in
62 dose groups, demonstrated that, during light to moderate depth of anesthesia, the use of neuromuscular
blocking agents can improve the quality as well as the success rate of tracheal intubation and was
associated with better hemodynamic stability, i.e. smaller reduction in blood pressure and heart rate as well
as a lower incidence of arrhythmias, during induction of anesthesia.
Avoidance of a NMBA never improves the quality of intubation and is associated with a higher
incidence of unacceptable conditions, failed first intubation attempts and respiratory adverse events.29,47
Particularly in those, aged 24 months or less25,28,29,32,34, intubation can be difficult or fail, especially when
this is attempted in the absence of muscular paralysis.48 Some trials reported failure rates and adverse
events of up to 20% when NMBAs are omitted25,27,29,31. This is inadmissible even in patients in whom
intubating is difficult.49 However, in many relaxant free study arms, tracheal intubation has been carried out
at light to moderate planes of anesthesia in which airway reflexes can be enhanced. Adequate CNS
depression is necessary to obtain an optimal attempt at intubation. With coughing or movement during
laryngoscopy, glottic exposure can be difficult. Airway instrumentation attempted at these inadequate levels
of anesthesia can be complicated with vocal cords’ closure, resulting in partial or complete loss of the
patients’ airway3-5,50. Pediatric patients with difficult tracheal intubation are at risk for complications, such
as laryngeal morbidity,51 and esophageal intubations. The high metabolic rate, high cardiac output, and
small functional residual capacity of these patients predispose them to the rapid development of oxygen
desaturation in the presence of airway obstruction.29,51,52
Not unexpectedly, the dose of the neuromuscular blocking agent is an important factor in
determining the quality of intubation. Rocuronium 0.90-1.20 mg·kg-1 in anaesthetized children produces
neuromuscular blockade almost as rapidly and profoundly as does succinylcholine 1.00-1.50 mg·kg-1, albeit
at the cost of a prolonged recovery.53,54 Using lower doses of a nondepolarizing muscle relaxant during a
light/moderate depth of anesthesia can create adequate conditions with minimal potential for adverse
effects, even for short procedures.12,30,31 Small amounts of rocuronium (0.15-0.30 mg·kg-1), are suitable to
improve intubation conditions during sevoflurane anaesthesia.30,31,55 By potentiation of the muscular
blocking effect during administration of sevoflurane and reversal of this potentiation upon withdrawal of the
short-acting inhaled agent, NMBA dose requirements for intubation might be reduced with a decreased risk
for residual postoperative curarization.
Timing of intubation is crucial for the ease with which airway management can be performed. Onset
and magnitude of neuromuscular block depend upon delivery of sufficient molecules at enough receptors to
prevent acetylcholine from causing neuromuscular transmission. Even in the younger age group with
greater cardiac output per kilogram body weight and more rapid distribution of drugs to and from their sites
of action,56 higher proportions of excellent intubating conditions have been obtained by delaying the
intubation, especially when lower doses of NMBA have been administered.30,31,36
As compared to infants32, children of 5-12 y33,36,37, needed higher doses of rocuronium for achieving
similar conditions of tracheal intubation. Although anesthetic requirement tends to decrease in upgrowing

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 children57,58, those aged 5-12 y, on a mg∙kg-1 basis, need more of all nondepolarizing NMBAs than do
Accepted Article
infants or adolescents for a given degree of neuromuscular block.59,60 Developmental changes at
neuromuscular synapses between 5-12y are likely to increase margin of safety for the relay of motor nerve
signals to muscle, requiring higher amounts of nondepolarizing NMBAs to effectively block transmission.61
Changes in distribution volume cannot offer a proper explanation because ECF only changes little after the
first year of life.62
We found insufficient evidence to determine whether intravenous or inhaled anesthesia is
superior in improving the conditions for tracheal intubation. Both, sevoflurane and propofol can profoundly
depress pharyngeal and laryngeal reflexes and muscular movement at deeper planes of anaesthesia.57
While Halothane has long been the mainstay of pediatric anesthesia, this role has been challenged.
Today, sevoflurane has replaced halothane for induction and maintenance of pediatric anesthesia because
of its rapid induction and recovery characteristics, acceptable cardiovascular profile and lower incidence of
side-effects. Although halothane has been abandoned in western anesthesia, it is still preferred in low- or
medium income countries having large pediatric populations.63
We agree that, with sufficient depth of anesthesia, a relaxant-free technique can, in the right
experienced hands and in the right patient group, be an acceptable technique.1,2,8 In the reviewed studies,
the most useful techniques are remifentanil 2-4 µg∙kg-1 supplementation of a propofol 3-4 mg∙kg-1 27,28,32,37,39
or sevoflurane 8%46 induction.
Compared with the i.v. barbiturates and etomidate, relaxation of the jaw and attenuation of
laryngeal reflexes were increased by propofol such that clinicians started to consider omitting the use of
NMBAs putatively to avoid their side-effects.48,63,65 However, IV agents demonstrate high interindividual
variability. In some studies, the proportion of acceptable intubation conditions in patients who were given a
propofol/alfentanil induction was found to be remarkably low.25,26, These results confirm earlier observations
66,67 but differ from the findings of other studies that, when using a similar propofol/alfentanil dose, found a
higher proportion of acceptable intubating conditions.68 The issue of ensuring adequate depth of IV
anesthesia in all situations has yet to be resolved.69
With propofol as an induction agent, remifentanil 2-4 μg∙kg-1 27,28,32,37,39 appeared to be the adjuvant
of choice to improve the quality of intubation. Although remifentanil 3-4 μg∙kg-1 in combination with propofol
or sevoflurane is able to provide excellent37 and acceptable intubating conditions27,28,37,46 in >80% of
children, the time to return of spontaneous respiration can be prolonged and can exceed that of short-
acting muscle relaxants, such as mivacurium 0.15-0.20 mg∙kg-1 27 and rocuronium 0.15 mg∙kg-1 31,32 hence,
limiting the usefulness of the technique for short procedures where a very rapid return of spontaneous
respiration is desired.
Although both nondepolarizers and opioids have been combined with inhalational induction, neither
of these drugs provides sufficient relaxation and depth of anesthesia to achieve suitable conditions for
airway insertion while allowing rapid return of spontaneous ventilation.29-31,36,65 Therefore inhalational
anesthesia has been combined with iv propofol to rapidly create excellent conditions for tracheal
intubation.33,34,57,70

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Accepted Article We confirmed that the doses and combinations of drugs used to facilitate laryngoscopy and
airway insertion in muscle relaxant free inductions can reduce heart rate and blood pressure. Similar to
previous observations,9,71 despite prophylactic anticholinergics, reduction in heart rate with propofol was
more likely when alfentanil or remifentanil was also given. The higher blood pressure and heart rate could
be explained by the light to moderate level of anesthesia at the time of intubation. However, it is

notoriously difficult to define 'hypotension' or 'hypertension' in a pediatric population because normal

ranges are quite wide.72,73 It is probably not unreasonable to assume that healthy ASA class I-II patients
can well tolerate a small degree of hemodynamic depression during induction/intubation.

Potential risks and limitations of the current meta-analysis have to be considered.

In a number of studies, the induction sequence was preceded by midazolam 30-35,37,41,46 which might
have improved the quality of intubation.
Infants and neonates are not the same as older, pre-teenage children and anesthetic techniques as
well as airway management do differ. However, treatment efficacy of NMBAs in each of the specific
pediatric age classes (1-12y) was currently assessed by analyzing the outcomes from RCTs using clearly
defined inclusion criteria (e.g. narrow age range) and experimental protocol (Table 1).
Proper trials for anesthetic agents in childhood are scarce. The reasons for this scarcity relate to
complex ethical issues, parental consent, the smaller burden of disease and trauma in children. Higher
costs are a major disincentive for the pharmaceutical industry to fund trials in children, particularly when the
market size is small and return on investment is limited. Methodological issues which relate specifically to
research in children include fragmented information from smaller and more heterogeneous populations.12,74
Meta-analysis can be conducted with two fundamentally different options in mind, resulting in the
use of contrasting approaches.15 The first of these options, applied previously13, is exemplified by the
Cochrane PICO (population, intervention, comparator, outcome) framework, in which specification of each
of these elements is central to the purpose of the synthesis.75 The second quite different option, used
currently, is to reach a general statement across larger numbers of outcomes from a range of
populations/research approaches.76 A limitation of a reductionist scope is the limited inference that is
possible outside of a narrowly specified population and/or setting.13 A more holistic approach, on the other
hand, can increase recruitment potential and generalizability of conclusions15, such that physicians treating
patients in real-world settings have the appropriate evidence upon which to base their clinical decisions.
Both of these methodologies can be limited or even biased. A collection of many narrowly focused reviews
of what is essentially the same intervention can generate spurious results, as can the opposite approach of
‘fishing’ for significance among potential effect modifiers or covariates in an excessively broad study.15
The conclusions of current meta-analysis cannot be applicable to debilitated/compromised or more
complex patients that make up an important part of a pediatric anesthetist's practice.

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Accepted Article Participants were recruited over a 26-year period (80% were submitted to studies that were
published after 2000) and from many countries. This factor might be a strength as much as a weakness in
determining robust inferences supported by consistency across subgroup analyses.
In conclusion, the use of neuromuscular blockers during light to moderate depth of anesthesia can
improve the quality and the success rate of tracheal intubation and provides better hemodynamic stability
during induction of anesthesia. Avoiding a NMBA never improves the quality of intubation and is associated
with a higher incidence of unacceptable conditions, failed first pass attempts and respiratory adverse
events. As part of the induction sequence, muscle relaxants reduce the amount of anesthetic agent
required, resulting in fewer anesthesia related side-effects and more rapid recovery of consciousness.10,11

Funding
This research was carried out without funding.

Conflicts of interest
No conflicts of interests declared.

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Accepted Article

Dose Delay Age Premedication Anticholinergic

Author NMBA Induction sequence n EIC AIC
(mg·kg-1) (s) (months)

1. Annila [25] Sux 1.50 ? ~60 † 23 (11) T 5 mg·kg-1; 30 22 29

- - - 25 (8) None None P 3 mg·kg-1 and Alf 10 µg·kg-1; 30 1 13

- - - 24 (8) H 5% (IC int) in N2O 70% 30 22 30

2. Blair [26] Sux 1.00 60 90 [36-151] P 3 mg·kg-1 and N2O 70%; 40 28 39

- - - 85 [39-150] None None Alf 10 µg·kg-1 and P 3 mg·kg-1; 40 3 21

- - - 86 [36-155] S 4.2 % (ET int) in N2O 50%, 40 18 35

3. Blair [27] Miv 0.20 90 97 [53-154] None Atrp 10 µg∙kg-1 P 3 mg·kg-1 and N2O 70% 28 16 27

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Accepted Article - - - 94 [46-145] Remi 1 µg·kg-1, P 3 mg·kg-1 and N2O 70%; 28 8 14

- - - 87 [46-132] Remi 2 µg·kg-1, P 3 mg·kg-1 and N2O 70%; 26 9 18

- - - 97 [47-154] Remi 3 µg·kg-1, P 3 mg·kg-1 and N2O 70%; 27 13 22

4. Crawford [28] Sux 2.00 90 L 0.2 mg·kg-1, P 4 mg·kg-1 and N2O 70%; 12 12 12

6 (3) None Glyp 10 µg∙kg-1

- - - L 0.2 mg·kg-1, P 3 mg·kg-1, Remi 3 µg·kg-1 and N2O
70%; 11 12 12

5. Devys [29] Roc 0.30 90 12 (6) S 5.2% (ET int) 25 16 23

12 (6) None None S 5.2% (ET int) 27 4 17

11 (7) S 5.0% (ET int) and Alf 20 µg·kg-1 23 7 16

6. Eikermann [30] Roc 0.15 120 10 6 7

Roc 0.22 120 10 7 9

[24-84] Mdz 0.5 mg∙kg-1 po None S 2% (ET int) in N2O 60%
Roc 0.30 120 10 8 10

Roc 0.50 120 10 8 10

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Accepted Article Roc 1.00 120 10 9 10

- - - 10 0 1

7. Eikermann [31] Roc 0.10 120 20 8 8

Roc 0.15 120 20 13 15

Roc 0.22 120 20 17 19

[24-84] Mdz 0.5 mg∙kg-1 po None S 8% (IC int) in N2O 60%
Roc 0.33 120 20 18 20

Roc 0.60 120 20 19 20

- - - 20 1 7

8. Gelberg [32] Roc 0.2 60 2 [1-4] L 1 mg·kg-1 and P 3 mg·kg-1; 36 31 35

Mdz 0.3 mg∙kg ir
-1 None
- - - 2 [1-4] L 1 mg·kg-1 , P 3 mg·kg-1 and Remi 2 µg·kg-1 34 27 31

9. Gera [33] Roc 0.60 60 57 (26) S 3 % (ET int) and Fent 1 µg·kg-1; 25 19 24
Mdz 0.5 mg∙kg po
-1 None
- - - 55 (23) S 3 % (ET int), Fent 1 µg·kg-1 and P 1.5 mg·kg-1 25 19 24

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Accepted Article
10. Grubhoher [34] Atr 0.4 120 6 (6) H 2% (IC int) in N2O 67%; 14 10 12
Mdz 1.0 mg∙kg-1 ir None ‡
- - - 7 (3) H 2% (IC int) in N2O 67% and P 3 mg·kg-1 14 11 13

11. Hansen [35] Sux 1.60 45 34 (19) H 1% (ET int) in N2O 67%; 50 - 48
Mdz 0.5 mg∙kg-1 po Atrp 10 µg∙kg-1
- - - 34 (18) H 2% (ET int) in N2O 67% 50 - 48

12. Huh [36] Roc 0.15 120 90 (26) 25 11 24

P 2.5 mg·kg-1 and Fent 2 µg·kg-1
Roc 0.30 120 100 (25) None None ‡ 25 20 25
S 5% (IC) in O2 after loss of eyelash reflex
- - - 92 (28) 25 5 18

13. Klemola [37] Roc 0.20 60 64 (22) P 3.5 mg·kg-1 and Remi 2 µg·kg-1; 20 13 19

Roc 0.40 60 63 (23) P 3.5 mg·kg-1; 20 7 20

Mdz 0.5 mg∙kg-1 po Atrp 15 µg∙kg-1
- - - 68 (23) P 3.5 mg·kg-1 and Remi 2 µg·kg-1; 20 11 18

- - - 57 (17) P 3.5 mg·kg-1 and Remi 4 µg·kg-1 20 17 20

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Accepted Article
14. Morgan [38] Sux 1.00 60 106 (42) P 4 mg·kg-1; 30 - 26
None None
- - 60 103 (42) P 4 mg·kg-1, Remi 1.25 µg·kg-1 and I 2% (IC int) 30 - 20

15. Naziri [39] Sux 1.50 60 81 (26) P 3 mg·kg-1; 30 30 30

None None
- - - 71 (32) P 3 mg·kg-1 and Remi 2 µg·kg-1 30 26 30

16. Ng [40] Sux 2.00 60 56 (5) H 2-3% (IC int) in N2O 60%; 20 15 20
None None
- - - 55 (4) H 2-3% (IC int) in N2O 60% and Alf 20 µg·kg-1 20 15 18

17. Rizanović [41] Sux 1.00 60 [48-144] P 3 mg·kg-1; 40 39 40

Mdz 0.5 mg∙kg-1 po Atrp 10 µg∙kg-1
- - 60 Fent 3 µg·kg-1 and P 3 mg·kg-1 40 34 38

18. Salawu [42] Sux 1.5 91 (27) 71 (26) L 0.2 mg∙kg-1, P 2.5 mg·kg-1 and Fent 2 µg∙kg-1; 33 28 33
None Atrp 10 µg∙kg-1
- - 67 (24) S 8% (IC int) and Fent 2 µg∙kg-1 33 15 31

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Accepted Article
19. Shaikh [43] Sux 1.00 60 95 (34) P 3 mg·kg-1; 40 36 40
None None
- - - 106 (29) Fent 4 µg·kg-1 and P 3 mg·kg-1 40 14 38

20. Steyn [44] Sux 1.50 55 85 [37-162] L 0.2 mg·kg-1, P 3-4 mg·kg-1; 40 - 35
None None
- - - 82 [26-163] L 0.2 mg·kg-1, P 3-4 mg·kg-1, Alf 15 µg·kg-1 40 - 32

21. Twaites [45] Sux 2.00 152 60 [36-120] P 3-4 mg·kg-1 and Morphine 0.1 mg·kg-1; 33 27 33
None None
- - - S 8% (IC int) and Morphine 0.1 mg·kg-1 31 17 31

22. Wei [46] Vec 0.10 120 79 (23) S 3% (ET int) in N2O 60%; 30 - 28

- - - 79 (22) S 3% (ET int) in N2O 60% and Remi 1 µg·kg-1; 30 - 21

Mdz 0.1 mg∙kg-1 IV Atrp 10 µg∙kg-1
- - - 86 (19) S 3% (ET int) in N2O 60% and Remi 2µg·kg-1; 30 - 26

- - - 82 (19) S 3% (ET int) in N2O 60% and Remi 3µg·kg-1 30 - 27

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Accepted Article
Table 1. Variables in 22 incorporated RCTs of 1651 participants in 53 treatment groups. NMBA: neuromuscular blocking agent administered. Author: first author of
article [reference].Roc: rocuronium; Sux: suxamethonium; Miv: mivacurium; Vec: vecuronium; and Atr: atracurium. Dose: dose of neuromuscular blocking agent
administered ( mg·kg-1); Delay: mean time interval between administration of the relaxant and insertion of airway (s); Age: average age of patients included in
treatment group (months); Values are number, mean (SD), (95CI%), [range]; Induction sequence: agents used to induce anaesthesia i.e. T: thiopentone; P:
propofol; Eto: etomidate; Fent: fentanyl; Alf: alfentanil; Remi: remifentanil; K: ketamine; Mdz: midazolam; L: lidocaine; S: sevoflurane; H: halothane; IC int:
inspiratory concentration at intubation; ET int: end-tidal concentration at intubation; Atrp: atropine; Glyp: glycopyrrolate; po: by mouth; ir: intrarectal use. n= total
numbers of patients exposed; EIC: numbers of patients with excellent intubation conditions; AIC: numbers of patients with acceptable intubation conditions; and †
estimated delay; ‡: anticholinergic medication was administered as appropriate to treat hypotension or bradycardia.

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 Figure captions.
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Figure 1 Flowchart of retrieved, excluded and analysed trials.

Figure 2 Forest plots of excellent (upper panel) and acceptable intubation conditions (lower panel)
achieved when neuromuscular blocking agents were not used compared to when they were. Intubation
conditions created by depolarizing and nondepolarizing neuromuscular blocking agents were analysed
separately. The squares represent the mean risk ratio for individual trials, and the corresponding horizontal
line is the 95%CI. The diamond shaped lozenges represent the pooled risk ratio (95%CI) for, respectively,
the depolarizers, the nondepolarizers and for the trial population as a whole. Subgroup differences were tested
for significance.

Figure 3 Forest plots of blood pressures (upper panel) and heart rates (lower panel) achieved when
neuromuscular blocking agents were not used compared to when they were. Blood pressures and heart
rates were recorded immediately before laryngoscopy and intubation. Haemodynamic effects of
depolarizing and nondepolarizing neuromuscular blocking agents were analysed separately. The squares
represent the mean difference for individual trials, and the corresponding horizontal line is the 95%CI. The
diamond shaped lozenges represent the pooled mean difference (95%CI) for, respectively, the
depolarizers, the nondepolarizers and the trial population as a whole. Subgroup differences were tested for
significance. †: patients were given an anticholinergic in the premedication. ‡ Systolic arterial pressure
arterial pressure was compared.

Figure 4. Relationship between rocuronium dose (mg.kg-1, log scale) and the probability of excellent
intubation conditions (%, logit scale) in 17 treatment arms. Each circle represents a treatment group, the
diameter of which is proportional to the number of participants. Some of the treatment groups are not
displayed as they are overlapped by others.22

Figure captions of Supplementary Data

Figure S1 Entry of participants to included randomized controlled trials.

Figure S2 Cumulative distribution of participants by age.

Figure S3 Risk of bias summary: reviews authors’ judgements about risks of bias in seven methodological
domains for each included study.19 Scores for each item are ranked as yes (+), no (-) or unsure (?),
reflecting low, high or unclear risk of bias.

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 Figure S4 Risk of bias graph: reviews authors’ judgements about each risk of bias item presented as
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percentages across all included studies.19

Figure S5 Forest plots of excellent (upper panel) and acceptable intubation conditions (lower panel)
achieved when neuromuscular blocking agents were not used compared to when they were. Intubation
conditions created by neuromuscular blocking agents were analysed for both, the intravenous and
inhalational induction techniques, separately. The squares represent the mean risk ratio for individual trials,
and the corresponding horizontal line is the 95%CI. The diamond shaped lozenges represent the pooled
risk ratio (95%CI) for, respectively, the intravenous, the inhalational and the trial population as a whole.
Subgroup differences were tested for significance.

Figure S6 Forest plots of failed first intubation attempts reported when neuromuscular blocking agents
were not used compared to when they were. The squares represent the mean risk ratio for individual trials,
and the corresponding horizontal line is the 95%CI. The diamond shaped lozenges represent the pooled
mean risk ratios (95%CI) for, respectively, the depolarizers, the nondepolarizers and for the trial population
as a whole. Subgroup differences were tested for significance.

Figure S7. Trial sequential analysis of, respectively 16 (excellent intubations conditions, upper panel) and
22 (acceptable intubations conditions, lower panel) RCTs (black square fill icons). The graph demonstrates
that the cumulative z-curve (blue line, cumulative statistical summary obtained by sequentially including the
findings of successive studies) crosses the trial sequential monitoring boundary (sloping red dotted lines,
corresponding to p=0.05), before reaching the required information size (vertical red dotted line). These
results provide conclusive evidence for a specific intervention effect (α=0.05,1-β=0.8). The X-axis indicates
the cumulative number of patients randomized and the Y-axis the cumulative 2-sided Z-Score.24

Figure S8. Same graph for the haemodynamic parameters. Trial sequential analysis of, respectively 13
(blood pressure after induction, upper panel) and 14 (heart rate after induction, lower panel) RCTs (black
square fill icons). The graph demonstrates that the cumulative z-curve (blue line, cumulative statistical
summary obtained by sequentially including the findings of successive studies) crosses the trial sequential
monitoring boundary (sloping red dotted lines, corresponding to p=0.05), before reaching the required
information size (vertical red dotted line). These results provide conclusive evidence for a specific
intervention effect (α=0.05,1-β=0.8). The X-axis indicates the cumulative number of patients randomized
and the Y-axis the cumulative 2-sided Z-Score.24

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