Australian Critical Care xxx (xxxx) xxx

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Australian Critical Care

journal homepage: www.elsevier.com/locate/aucc

Research paper

Normal saline and lung recruitment with paediatric endotracheal

suction (NARES): A pilot, factorial, randomised controlled trial
Jessica A. Schults, RN, PhD a, b, c, *
Marie Cooke, RN, PhD b
Debbie Long, RN, PhD a, b, c
Andreas Schibler, MD a, c
Robert S. Ware, PhD d
Karina Charles, RN, MNurs (PICU) b
Adam Irwin, MBChB PhD e, f
Marion L. Mitchell, RN, PhD b, g
a
Paediatric Intensive Care Unit, Queensland Children's Hospital, South Brisbane, Queensland, Australia
b
Menzies Health Institute Queensland, School of Nursing and Midwifery, Griffith University, Queensland, Australia
c
Paediatric Critical Care Research Group, Centre for Children's Health Research, The University of Queensland, South Brisbane, Queensland, Australia
d
Menzies Health Institute Queensland, Griffith University, Nathan, Queensland, Australia
e
UQ Centre for Clinical Research, The University of Queensland, Australia
f
Infection Management and Prevention Service, Queensland Children's Hospital, South Brisbane, Queensland, Australia
g
Intensive Care Unit, Princess Alexandra Hospital, Queensland, Australia

article information a b s t r a c t

Article history:
Background/objective: Endotracheal suction is one of the most common and harmful procuedres per-
Received 23 June 2020
formed on mechanically ventilated children. The aim of the study was to establish the feasibility of a
Received in revised form
17 January 2021 randomised controlled trial (RCT) examining the effectiveness of normal saline instillation (NSI) and a
Accepted 23 January 2021 positive end-expiratory pressure recruitment manoeuvre (RM) with endotracheal suction in the paedi-
atric intensive care unit.
Keywords: Methods: Pilot 2
2 factorial RCT.
Pediatrics The study was conducted at a 36-bed tertiary paediatric intensive care unit in Australia.
Endotracheal suction Fifty-eight children aged less than 16 years undergoing tracheal intubation and invasive mechanical
Normal saline ventilation.
Recruitment manoeuvre (i) NSI or no NSI and (ii) RM or no RM with endotracheal suction . The primary outcome was feasibility;
Positive end-expiratory pressure secondary outcomes were ventilator-associated pneumonia (VAP), change in end-expiratory lung vol-
Critical care ume assessed by electrical impedance tomography, dynamic compliance, and oxygen saturation-to-
fraction of inspired oxygen (SpO2/FiO2) ratio.
Results/Findings: Recruitment, retention, and missing data feasibility criteria were achieved. Eligibility
and protocol adherence criteria were not achieved, with 818 patients eligible and 58 enrolled; cardiac
surgery was the primary reason for exclusion. Approximately 30% of patients had at least one episode of
nonadherence. Children who received NSI had a reduced incidence of VAP; however, this did not reach
statistical significance (incidence rate ratio ¼ 0.12, 95% confidence interval ¼ 0.01e1.10; p ¼ 0.06). NSI
was associated with a significantly reduced SpO2/FiO2 ratio up to 10 min after suction. RMs were not
associated with a reduced VAP incidence (incidence rate ratio ¼ 0.31, 95% confidence interval ¼ 0.05
e1.88), but did significantly improve end-expiratory lung volume at 2 and 5 min after suction, dynamic
compliance, and SpO2/FiO2 ratio.
Conclusion: RMs provided short-term improvements in end-expiratory lung volume and oxygenation.
NSI with suction led to a reduced incidence of VAP; however, a definitive RCT is needed to test statistical

* Corresponding author at: School of Nursing and Midwifery, Menzies Health

Institute Queensland, Griffith University, N48 Kessels Road, Nathan, Queensland
4111, Australia.
E-mail address: j.schults@griffith.edu.au (J.A. Schults).

https://doi.org/10.1016/j.aucc.2021.01.006
1036-7314/© 2021 Australian College of Critical Care Nurses Ltd. Published by Elsevier Ltd. All rights reserved.

Please cite this article as: Schults JA et al., Normal saline and lung recruitment with paediatric endotracheal suction (NARES): A pilot, factorial,
randomised controlled trial, Australian Critical Care, https://doi.org/10.1016/j.aucc.2021.01.006
2 J.A. Schults et al. / Australian Critical Care xxx (xxxx) xxx

differences. A RCT of study interventions is worthwhile and may be feasible with protocol modifications
including the widening of participant eligibility.
© 2021 Australian College of Critical Care Nurses Ltd. Published by Elsevier Ltd. All rights reserved.

1. Introduction 2.3. Study setting

For mechanically ventilated children in the paediatric intensive
care unit (PICU), endotracheal suction (ETS) is an essential pro-
cedure to maintain airway patency.1,2 Despite its importance, ETS
can result in adverse events (AEs), with a recent observational
study showing that suction-related AEs (e.g., desaturation, brady-
cardia) occur in up to 47% of children.3 Although factors such as
diagnosis, mode of ventilation, and endotracheal tube (ETT) size
contribute to the degree of physiological compromise,4,5 the cu-
mulative effect and longitudinal impact of ETS-associated AEs such
as alveolar collapse and resultant hypoxaemia are relatively un-
known. ETS-related complications, such as atelectasis, impaired gas
exchange, decreased lung compliance,1,6 and ventilator-associated
pneumonia (VAP),1,7,8 may contribute to a prolonged duration of
mechanical ventilation and PICU admission.
ETS practice lacks standardisation, with variations in adjunct
interventions used.9,10 Many ETS interventions such as normal sa-
line instillation (NSI) and lung recruitment manoeuvres (RMs) have
not been rigorously evaluated in randomised controlled trials
(RCTs), and consequently, it is unclear whether these interventions
are causally associated with improved outcomes for children.
Because more than 40% of PICU admissions require mechanical
ventilation and ETS, improvement in ETS care could equate to
improved health outcomes for a large number of children and
substantial savings for healthcare services. Prospective phase 3 RCT
data are needed to determine the efficacy of the ETS interventions
such as NSI and RMs. Therefore, we sought to evaluate the feasi-
bility of undertaking an RCT comparing two intervention pairs (NSI
and RM) in mechanically ventilated children using predefined
criteria for eligibility, protocol adherence, and sample size esti-
mates. Our study reports effective estimates of NSI and RMs on
measures of infection, gas exchange, and lung mechanics and
impedance to inform future studies. NSI and RM interventions were
chosen as the study interventions owing to their ad hoc use in
practice, reported clinician uncertainty, and potential benefits of
application with paediatric ETS to decrease complications.
The RCT was conducted at the Queensland Children's Hospital
(QCH), Brisbane. QCH is a tertiary referral, specialist teaching fa-
cility that provides advanced life support interventions including
extracorporeal life support to infants and children. The QCH PICU
has an average annual admission rate of 2000 children.
2.4. Participants
Eligibility criteria were as follows: aged 0 (>37 weeks) to 16
years, intubated with an ETT, anticipated to require >24 h of inva-
sive ventilation, and attainment of informed consent. Patients were
ineligible for trial enrolment if they had cardiac surgery during
admission, a diagnosed air leak syndrome, been ventilated for
>48 h before screening, pulmonary hypoplasia, a current diagnosis
of VAP, tracheal reconstruction, cystic fibrosis, significantly raised
intracranial pressure, or been previously enrolled in a study at
hospital admission.
2.5. Interventions
All participants received ETS as per the existing PICU's clinical
guidelines (Supplementary material 1). In addition, children were
randomly assigned to receive a suction element from each inter-
vention pair:
1. NSI, 0.1 ml/kg of 0.9% normal saline (maximum ¼ 2.0 ml), with
ETT suction versus no normal saline:9,11e13 NSI was administered
before ETS on disconnection from the ventilator circuit. The
patient was than manually ventilated using an anaesthetic bag
before insertion of the suction catheter.
2. RM, increase in baseline positive end-expiratory pressure (PEEP)
by a factor of 2 (maximum ¼ 18 cmH2O) for 2 min after ETT
suction versus no RM.11,13e15

2. Materials and methods
2.1. Design
A 2
2 factorial, pilot RCT was undertaken at a single-centre
Australian PICU between October 2017 and October 2019. Children
receiving invasive mechanical ventilation were allocated to i) NSI
versus no NSI and (ii) RM versus no RM with ETS. The trial was
prospectively registered with the Australia New Zealand Clinical
Trials Registry (ACTRN12617000609358), and RCT methods are
published.11
2.6. Outcomes
The primary outcome was feasibility of a definitive factorial RCT
investigating NSI and RMs with ETS.11 Feasibility was determined
through composite analysis of eligibility, recruitment, retention,
protocol adherence, and missing data.16,17 Secondary outcomes
were clinically suspected VAP defined in accordance with the
Centers for Disease Control and Prevention (CDC) definition,18,19
oxygen saturation (SpO2)-to-fraction of inspired oxygen (FiO2) ra-
tio, dynamic compliance (Cdyn, ml/cmH2O), end-expiratory lung
impedance (EELI), and tidal impedance variation (VARt).20 Primary
and secondary trial outcomes are defined fully in Supplementary
material 2.

2.2. Ethical statement 2.7. Sample size

Ethical approval to undertake the trial was received from Chil- The target sample size was 100 participants. The sample size
dren's Health Queensland (HREC/16/QRCH/374) and Griffith Uni- was based on requirements for feasibility testing and calculating
versity (2017/065). primary end point effect size estimates for an efficacy trial.16,21

Please cite this article as: Schults JA et al., Normal saline and lung recruitment with paediatric endotracheal suction (NARES): A pilot, factorial,
randomised controlled trial, Australian Critical Care, https://doi.org/10.1016/j.aucc.2021.01.006
 J.A. Schults et al. / Australian Critical Care xxx (xxxx) xxx
2.8. Study procedures
Clinical research nurses (CRNs) screened all patients daily dur-
ing business hours from Monday to Friday and obtained written
informed consent. A central web-based randomisation service was
used to randomise patients and ensure allocation concealment.
Randomisation occurred twice (once for each intervention pair),
generated on in a 1:1 ratio between groups. Randomisation was
stratified by reason for intubation (respiratory versus non-
respiratory) with randomly varied block sizes (4 or 6) within each
stratum. NSI and RMs were not amenable to masking of patients,
clinical staff or CRNs. A masked infectious disease paediatrician
assessed criteria for VAP. Participants remained in the treatment
phase of the study for 48 hours, or until tracheal extubation,
whichever occurred first.
Data were collected and managed in REDCap™ (Research Elec-
tronic Data Capture version 7, Vanderbilt, USA). A screening log was
used to record patient information, including name, diagnosis,
eligibility, recruitment, and group allocation. Patient and clinical
characteristics recorded included admission source, PICU admis-
sion time, diagnosis, age, sex, weight, date and time of intubation,
ETT size, and oxygen saturation index.22 The CRN collected data on
the primary and secondary outcomes.
2.9. ETS procedures
With the exception of study interventions, ETS was performed
when clinically indicated23,24 and as per local clinical policy, with
the patient positioned in a semi-Fowler's position (30 bed head
elevation; as per VAP best practice care bundles25). Changes in
SpO2/FiO226 and Cdyn were compared at baseline (2 min pre ETS), on
reconnection post ETS, at 2 min post ETS, and at 10 min post ETS.
Secondary outcome data were collected using the bedside monitor
(Phillips IntelliVue, Nevada USA) and mechanical ventilator and
stored in the clinical information system Metavision iMDSoft, Park
Atidim TelAviv. All patients were ventilated using an Evita XL
(Dra€ger, Lübeck, Germany) or SERVO-U/i (Maquet Medical Systems,
Rastatt, Germany) in volume- or pressure-controlled modes.
Lung volume changes were assessed using electrical impedance
tomography (EIT), EELI, also referred to as the end-expiratory
level,27,28 has a strong linear correlation with changes in end-
expiratory lung volume.29,30 Similarly, regional and global tidal
volume (VT) changes are correlated with VARt.30 Therefore, the
effect of RMs and NSI at a pulmonary level can be assessed using EIT
measurements, which were performed once per day (with ETS)
during study enrolment using the PulmoVista 500 (Dra €ger Medical,
Lübeck, Germany). A frequency of 50 kHz was used, and EIT data
were filtered using a low-pass filter. Four key time points were
assessed (spontaneous or ventilated supported breathing pre ETS,
on reconnection post ETS, 2 min post ETS, and 5 min post ETS; Fig.
1). EIT files were saved on the device's hard drive and analysed
using Dr€ ager review software, version 5.1 (Lübeck, Germany. Pa-
tients were assessed in a supine or semi-Fowler's position in bed
(head of bed elevation of at least 30 ).31,32
2.10. Data analysis
Comparability of groups at baseline was assessed using clinical
parameters and reported using descriptive statistics. Means and
standard deviations were used to report normally distributed
continuous data, and medians and interquartile ranges were used
for interval data that could not be approximated using a normal
distribution. Ventilator-free days at 28 days were calculated using
published methods and censored at 28 days.33 Feasibility was re-
ported descriptively, against predefined criteria. Incidence rates
Please cite this article as: Schults JA et al., Normal saline and lung recruitment with paediatric endotracheal suction (NARES): A pilot, factorial,
randomised controlled trial, Australian Critical Care, https://doi.org/10.1016/j.aucc.2021.01.006
3
(IRs) of VAP per 1000 ventilator days and 95% confidence intervals
(CIs) were calculated using Poisson regression. Interaction effects
between NSI and RM were investigated in the regression models. In
the absence of significant interaction, Poisson regression models
were constructed, with treatment as the main effect and the pre-
suction measurement of the outcome included as a covariable.
Models were offset by the natural logarithm of the time the child
was at risk of VAP. Secondary outcomes measured using interval
data (SpO2/FiO2 and Cdyn) were analysed, adjusting for baseline
measurement, using linear regressions, in a pairwise sequential
manner to compare NSI and RM.34 To assess EELI and VARt, we used
a mixed-effects linear regression model, with time and interven-
tion (NSI or RM) included as main effects and a time-by-interven-
tion interaction. The patient was included as a random effect to
account for the repeated measures nature of the data. Analyses
were undertaken on an intention-to-treat basis. Data were ana-
lysed using StataSE version 14.1 (StataCorp Pty Ltd., College Station,
Texas).
3. Results
3.1. Recruitment and retention
Between October 2017 and October 2019, 3881 children were
admitted to PICU, and 818 (21%) children were eligible for inclusion.
Of the 818 participants, cardiac surgery was the primary reason for
exclusion (479/818; 59%), followed by readmission (123/818; 15%).
Thirty-six children were admitted outside CRN work hours; eight
were excluded owing to the treating physician's decisions, and 17
were excluded due owing to inappropriate patient circumstances
(e.g., end-of-life care). Ninety percent of families approached for
consent agreed to enrol. Seven families refused participation. Me-
dian time to randomisation from tracheal intubation was 15 h
(interquartile range [IQR]11e21), and suction was performed as per
unit policy prior to enrolment. Following randomisation, two
children required escalation of care to high frequency oscillation
ventilation after 10 and 24 hours of study enrolment. Data prior to
escalation were included in the analyses. Fig. 2 depicts the flow of
participants through the study.
NARES recruitment was ceased after 2 years, enrolling 58 par-
ticipants, for whom 599 suctions were studied performed. Twenty
patients (34%) received the randomised allocation at all times. The
remaining 38 (66%) patients received the allocated intervention for
some, but not all, of the study period. Nonadherence to protocol
included saline administration in the no saline arm (21 patients;
89/341 suctions, 26%), failure to apply RMs in the RM arm (22 pa-
tients; 87/301 suctions; 29%), nonuse of saline in the saline arm (six
patients; 19/257 suctions, 7%), and RM use in the no RM arm (1
patient; 1/297 suctions, 0.3%). Nonadherence was greater on the
day shift (07.00e19.00hours; accounting for 53% of protocol
breaches) than in the night shift (19.00 hourse07.00hours; 47%). Of
the 58 patients, 100% follow-up was achieved, with no missing data
for primary outcomes; five patients (8%) did not contribute EIT data
owing to unforeseen patient or equipment circumstances (un-
planned extubation, patient refusal [15-year-old], escalation of
care, equipment service and repair, corrupted EIT files).
Participants were on average 11 months old (IQR 2 - 43admitted
for a respiratory diagnosis (27/58; 47%), with a median paediatric
index of mortality 3 score of 1.0 (IQR 0.4e3.3) (Tables 1 and 2). The
median duration of ventilation was 2.7 days (IQR 1.8 e 4.6), with a
length of PICU stay of 4.5 days (IQR 3.3e8.1). Fifty-seven (98%)
children were intubated with a cuffed ETT, and one child (no RM
allocation) received an uncuffed ETT.
4 J.A. Schults et al. / Australian Critical Care xxx (xxxx) xxx

Fig. 1. EIT measurements and trace during a suction and PEEP recruitment. A loss of end-expiratory lung impedance is seen during the two suction procedures, indicated by the
arrows. Note that the area under the curves (marked by the first horizontal line) remains diminished compared with presuction levels after the two suction procedures, indicating a
loss of end-expiratory lung volume. End-expiratory lung impedance is seen to improve with PEEP recruitment, returning to baseline at 5 minutes. EIT ¼ electrical impedance
tomography; PEEP ¼ positive end-expiratory pressure; ETS ¼ endotracheal suction; RM ¼ recruitment manoeuvre; min ¼ minute.

Fig. 2. CONSORT flowchart.

3.2. Ventilator-associated pneumonia
The highest IR of VAP occurred in the no saline group (IR109 per
1,000 ventilator days, 95% CI41, 290). Participants in the saline
group had a reduced IR (13 per 1,000 ventilator days, 95% CI2, 96)
and were 8.1 times less likely to acquire VAP; however, this did not
reach statistical significance (incidence rate ratio [IRR]0.1, 95% CI
0.01, 1.10; p ¼ 0.06, see Table 3). When compared no RM ( IRIR 84
per 1,000 ventilator days, 95% CI27, 262), the application of an RM
resulted in a decreased risk of developing VAP; however, this was
not statistically significant (IR26 per 1,000 ventilator days, 95% CI7,
106; IRR0.31, 95% CI0.05, 1.88, p ¼ 0.20). There was no interaction
between study interventions; however, an exploratory analysis of
VAP IR across study arms is presented in Supplementary material 3.
To sufficiently power a future trial to examine the effect of saline
(alpha ¼ 0.05, power ¼ 80%), assuming an IR of 0.109 per day and an
average risk time of 1 day for participants, then, 94 children in each
group would be required to detect an IRR of 0.15 or lower. When
considering RMs, assuming an alpha of 0.05, 80% power, IR of 0.084
per day, and an average risk- time of 1 day, then, 277 children in
each group would be required to detect an IRR of 0.35 or lower.
3.3. Oxygenation indices
Group data for the measurement time points and group com-
parisons are presented in Table 4. RMs were found to result in a
significantly improved SpO2/FiO2 ratio at 2 min (þ10 mmHg, 95%
CI1, 19; p ¼ 0.02) and 10 min (þ16 mmHg, 95% CI ¼ 6, 26; p ¼ 0.01)
after ETS. When compared with no NSI, NSI led to a significantly
reduced SpO2/FiO2 ratio at 2 min (12, 95% CI21, 3; p ¼ <0.01) and
10 min (10, 95% CI20, 0.87; p ¼ 0.03). Outcome measurements
after ETS are outlined in Supplementary material 4.
3.4. Dynamic compliance
RM application increased mean Cdyn by 0.20 ml/cmH2O/kg at 10
min after ETS (95% CI 0.1, 0.3; p ¼ 0.001). No significant relationship
was found between RM and improved Cdyn at 2 min after ETS. NSI
increased mean Cdyn by 0.29 ml/cmH2O/kg at 2 min after ETS (95%
CI0.09, 0.49; p ¼ <0.01) when compared with the no NSI group. A
significant difference in Cdyn was not found with NSI at 10 min.
3.5. Impedance measures
In total, 61 EIT measurements were completed on 53 patients.
ETS resulted in a decreased mean EELI from 2054 units (standard
deviation ± 1153) by 232 units (±2226; after ETS) across all
study participants. RMs significantly increased mean EELI by 2434
impedance units (95% CI1605e3263; p < 0.001) at 2 min and
2268 units (95% CI1421e3115; p < 0.001) at 5 min after ETS,
indicating a similar increase in end expiratory lung volume
(EELV). No significant difference was found in VARt at 2- or 5-
minute measurements on comparison between RM and the
control, suggesting no significant change in tidal volume. NSI

Please cite this article as: Schults JA et al., Normal saline and lung recruitment with paediatric endotracheal suction (NARES): A pilot, factorial,
randomised controlled trial, Australian Critical Care, https://doi.org/10.1016/j.aucc.2021.01.006
 J.A. Schults et al. / Australian Critical Care xxx (xxxx) xxx 5

Table 1
Demographic characteristics of the participants.

Variable 0.9% normal saline Recruitment manoeuvre

No saline (n ¼ 28) 0.1 ml/kg (n ¼ 30) No RM (n ¼ 29) RM (n ¼ 29)

Age, median (IQR), months 15 (2e76) 11 (2e42) 19 (2e62) 9 (2e31)

Male, n (%) 13 (46) 18 (60) 14 (48) 17 (59)
Weight, median (IQR), kg 10 (4e22) 10 (4e15) 10 (4e17) 10 (4e16)
Source of admission, n (%)
Retrieval 13 (47) 18 (60) 13 (45) 18 (62)
Emergency department 6 (21) 4 (13) 6 (21) 4 (14)
Operating room 5 (18) 3 (10) 5 (17) 3 (10)
Hospital floor 2 (7) 4 (13) 3 (10) 3 (10)
Another hospital 2 (7) 1 (4) 2 (7) 1 (4)
Primary diagnosis, n (%)
Respiratory 11 (39) 16 (53) 14 (48) 13 (45)
Neurology 7 (25) 5 (17) 7 (24) 5 (17)
Medicine 5 (18) 4 (13) 4 (14) 5 (17)
Surgical 5 (18) 3 (10) 3 (10) 5 (17)
Other 0 (0) 2 (7) 1 (4) 1 (4)

IQR ¼ interquartile range; kg ¼ kilograms; RM ¼ recruitment manoeuvre.

Table 2
Clinical characteristics of the participants.

Variable 0.9% normal saline Recruitment manoeuvre

No saline (n ¼ 28) 0.1 ml/kg (n ¼ 30) No RM (n ¼ 29) RM (n ¼ 29)

ETT size, mm
3.0 10 (36) 6 (20) 7 (24) 9 (31)
3.5 3 (11) 11 (37) 5 (17) 9 (31)
4.0 6 (21) 3 (10) 5 (17) 4 (14)
4.5 2 (7) 6 (20) 6 (21) 2 (7)
5.0 0 (0) 1 (3) 1 (3) 0 (0)
5.5 2 (7) 0 (0) 1 (3) 1 (3)
6.0 5 (18) 3 (10) 4 (15) 4 (14)
Number of ETT suctions, median (IQR)b 4 (3e6) 4 (2e6) 4 (2e6) 4 (2e6)
PIM3, median (IQR) 0.98 (0.45e3.28) 1.23 (0.98e3.11) 0.98 (0.43e3.50) 1.28 (0.60e3.26)
OSI, median (IQR), D1 3.90 (3.1e5.6) 3.32 (2.6e4.5) 3.7 (2.5e4.8) 3.78 (3.0e5.3)
PARDSa severity, n (%)
Mild 4 (14) 2 (7) 0 (0) 6 (21)
Moderate 0 (0) 1 (3) 0 (0) 1 (3)
Severe 1 (4) 0 (0) 0 (0) 1 (3)
Day 1, median (IQR)
PEEP, mmHg 8 (5e8) 6 (5e8) 7 (5e8) 8 (5e8)
PIP, mmHg 18 (16e21) 19 (15e21) 17 (13e21) 19 (16e21)
FiO2 requirement, % 30 (30e35) 30 (25e35) 30 (25e35) 30 (26e35)
MAP, mmHg 11 (9e14) 10 (8e12) 10 (8e12) 10 (9e13)
Shifted to HFOV, n (%) 0 (0) 2 (7) 0 (0) 2 (7)
Mechanical ventilation, median (IQR), d 2.9 (2.4e4.5) 2.6 (1.3e4.9) 2.4 (1.5e3.7) 3.1 (2.3e5.8)
Ventilator-free days,c median (IQR), d 25 (23e25) 25 (23e26) 25 (24e26) 24 (22e25)
PICU LoS, median (IQR), 4.5 (3.4e7.3) 4.6 (3.1e8.0) 4.5 (3.1e6.3) 5.2 (3.4e10.4)
Hospital LoS, median (IQR), d 9.7 (7.4e19.6) 11.9 (7.2e27.3) 10.4 (7.9e21.5) 10.0 (6.5e20.0)
Mortality, n (%)
Death in the PICU 0 (0) 0 (0) 0 (0) 0 (0)
Death in the hospital 0 (0) 1 (3) 0 (0) 1 (3)

RM ¼ recruitment manoeuvre; ml ¼ millilitres; kg ¼ kilograms; ETT ¼ endotracheal tube; mm ¼ millimetres; IQR ¼ interquartile range; PIM3 ¼ paediatric index of mortality3
score; OSI ¼ oxygen saturation index; d ¼ days; PARDS ¼ paediatric acute respiratory disease syndrome; n ¼ number; PEEP ¼ positive end-expiratory pressure; PIP ¼ positive
inspiratory pressure; FiO2 ¼ fraction of inspired oxygen; MAP ¼ mean airway pressure; mmHg ¼ millimetres of mercury; HFOV ¼ high-frequency oscillation ventilation;
PICU ¼ paediatric intensive care unit; LoS ¼ length of stay.
a
Mild (5  OSI < 7.5), moderate (7.5  OSI < 12.3), severe (OSI  12.3) (Pediatric Acute Lung Injury Consensus Conference Group, 2015).
b
Per patient per day.
c
At 28 days.

significantly decreased mean EELI at 2 min after ETS by 1108
impedance units (95% CI -2025, 192; p ¼ 0.01). This suggests a
decrease in EELV at 2 min after suction. No significant difference
in VARt was found on comparison of the NSI and no NSI groups at
any time point after ETS. No participant had an ETT leak of 20%,
and therefore, none were excluded from the analyses.35e37 The
median time from the last suction to ETS with EIT measurement
was 3 h (IQR1e4).
3.6. Safety and AEs
No serious AEs including ETT occlusion (suspected or
confirmed), pneumothoraces, or death were observed in any
participant. There was no significant difference in heart rate, sys-
tolic blood pressure, or mean arterial pressure between groups at
2 and 10 minutes after suction (Supplementary material 4).

Please cite this article as: Schults JA et al., Normal saline and lung recruitment with paediatric endotracheal suction (NARES): A pilot, factorial,
randomised controlled trial, Australian Critical Care, https://doi.org/10.1016/j.aucc.2021.01.006
6 J.A. Schults et al. / Australian Critical Care xxx (xxxx) xxx

Table 3
VAP incidence rates for factorial groups.

Factorial groups Saline vs no saline RM vs no RM

Variable No saline (n ¼ 28) Saline (n ¼ 30) P No RM (n ¼ 29) RM (n ¼ 29) P

VAP, n (%) 4 (14) 1 (3) 3 (10) 2 (7)

VAP IR (1000 ventilator days,a 95% CI) 109 (41e290) 13 (2e96) 84 (27e262) 27 (7e106)
b
VAP IRR (95% CI) 1.00 (referent) 0.12 (0.01e1.10) 0.06 1.00 (Referent) 0.31 (0.05e1.88) 0.20b

VAP ¼ ventilator-associated pneumonia; RM ¼ recruitment manoeuvre; CI ¼ confidence interval; IR ¼ incidence rate; IRR ¼ incidence rate ratio.
a
At-risk days.
b
Poisson regression.

Table 4
Secondary outcome measure comparisons for the study groups.

Outcome measure Saline vs no saline RM vs no RM

No saline (n ¼ 28) Saline (n ¼ 30) Mean difference (95% CI) P No RM (n ¼ 29) RM (n ¼ 29) Mean difference (95% CI) P
a
SpO2/FiO2 ratio (mmHg)
Pre ETS 341 (93) 302 (92) 39 (54 to 25) <0.001 306 (96) 343 (90) 37 (23e52) <0.001
2 min post ETS 347 (86) 306 (89) 12 (22 to 3) 0.009 310 (90) 348 (85) 10 (1e19) 0.02
10 min post ETS 343 (87) 305 (90) 11 (20 to 0.8) 0.03 306 (92) 349 (84) 17 (7e26) 0.01
Cdyn (ml/cmH2O/kg)a
Pre ETS 0.9 (0.7) 0.9 (0.9) 0.1 (0.1 to 0.1) 0.77 0.9 (0.8) 0.9 (0.9) 0.0 (0.1 to 0.2) 0.97
2 min ETS post 0.9 (0.6) 1.0 (1.7) 0.3 (0.1e0.4) 0.004 1.0 (1.5) 1.0 (0.9) 0.1 (0.1 to 0.2) 0.43
10 min ETS post 0.9 (0.7) 0.8 (0.9) 0.03 (0.1 to 0.1) 0.58 0.8 (0.8) 1.0 (0.8) 0.2 (0.1e0.3) 0.001
EELI (units)a
Pre ETS 1147 (1124) 1294 (968) 147 (768 to 1064) 0.75 1275 (928) 1145 (1179) 75 (-746 to 897) 0.85
2 min ETSpost 3076 (3587) 1967 (2694) 1108 (2025 to 192) 0.01 1455 (3013) 3715 (3147) 2434 (1605e3263) <0.001
5 min ETSpost 2343 (3077) 2017 (1977) 496 (1429 to 436) 0.20 1278 (2061) 3217 (2837) 2268 (1421e3115) <0.001
Tidal variation (units)a
Pre ETS 2127 (1241) 1956 (1018) 174 (-803 to 453) 0.58 2043 (1023) 2065 (1273) 99 (664 to 465) 0.73
2 min after ETS post 2274 (1489) 2091 (1343) 187 (-815 to 440) 0.55 2132 (1248) 2257 (1587) 39 (530 to 610) 0.89
5 min ETS post 2259 (1302) 1837 (1176) 265 (-899 to 368) 0.41 1970 (1183) 2178 (1341) 155 (421 to 732) 0.59

RM ¼ recruitment manoeuvre; SpO2/FiO2 ¼ oxygen saturation-to-fraction of inspired oxygen ratio; Cdyn ¼ dynamic compliance; EELI ¼ end-expiratory lung impedance;
ml ¼ millilitres; cmH2O ¼ centimetres of water; kg ¼ kilograms; ETS ¼ endotracheal suction; min ¼ minute; CI ¼ confidence interval.
a
Mean and standard deviation.

4. Discussion internationally in paediatric studies.38,43 However, as recom-

The pilot trial demonstrated that with modification to the in-
clusion and exclusion criteria, multisite recruitment, and the in-
clusion of a process evaluation, an RCT of NSI and RMs may be
feasible. The pilot trial highlighted issues with trial recruitment,
which was stopped early owing to eligibility challenges and pro-
tocol adherence that need to be addressed for a definitive trial. A
number of barriers impeded rapid participant enrolment, including
a restrictive eligibility/inclusion criterion (pragmatic decision to
exclude high-risk populations) or missed opportunity to identify
eligible patients.38 Protocol modifications necessary to support a
large RCT feasibility would include the widening of inclusion
criteria to include cardiac surgical patients39,40 and PICU read-
missions (as long as other inclusion/exclusion criteria were met),
and following the same randomised allocation41 would double the
percentage of eligible patients at the site. Multicentre PICU
recruitment with standardised ETS procedures and improved hu-
man resource allocation (e.g., weekend and after business-hours
coverage of CRNs) would also increase the rate of recruitment and
enhance generalisability of findings. Nonadherence occurred in
two-thirds of the study participants in at least one suction; there-
fore, the inclusion of a concurrent process evaluation in the larger
trial would also facilitate formal and rigorous intervention fidelity
monitoring, addressing nonadherence as it is identified. Previous
studies have shown nurses favour historic ETS practices such as NSI
and lack of confidence with regard to the application of unfamiliar
interventions such as RMs, which may have contributed to the
moderate nonadherence rates in our study.42 Recruitment chal-
lenges encountered during the NARES trial have been reported
mended by the United Kingdom's Medical Research Council's
Framework for Developing and Evaluating Complex In-
terventions,44 this pilot RCT has provided important feasibility data
for a future efficacy trial.
As anticipated in this pilot trial, we did not find NSI or RM to be
significantly associated with a reduced risk of acquiring VAP.
However, NSI led to clinically significant differences in the number
of clinically suspected VAP cases (IRR0.12, 95% CI 0.01, 1.10, p ¼
0.06), and approached statistical significance. The findings of our
study are similar to those of the only other published work inves-
tigating the effects of NSI on VAP. In a cohort of adult oncology ICU
patients, Caruso et al45 demonstrated that saline instillation before
ETS led to a 54% (95% CI18%, 74%) risk reduction in developing VAP.
Interestingly, Caruso et al45 reported similar rates of clinically
suspected VAP across both the groups but found the incidence of
microbiologically proven VAP to be significantly lower in the NSI
group (23.5% versus 10.8%; p ¼ 0.008). Although our trial did not
investigate the incidence density of microbiologically proven VAP,
findings from Caruso et al45'’s study suggest we may have seen a
greater difference in VAP rates using this endpoint. Overall, the
findings from this study, for the first time in paediatrics, indicate
that NSI may reduce a child's risk of acquiring VAP as per the CDC
definition. This association requires testing in a definitive phase 3
RCT. It should be noted that child definitions would need to be
adapted to meet the new definitions of ventilator-associated event
46,47
, with respect to possible and probable VAP.
Trial data indicated that RMs applied after ETS were asso-
ciated with significant, short-term increases in EELI in me-
chanically ventilated children and therefore improved

Please cite this article as: Schults JA et al., Normal saline and lung recruitment with paediatric endotracheal suction (NARES): A pilot, factorial,
randomised controlled trial, Australian Critical Care, https://doi.org/10.1016/j.aucc.2021.01.006
 J.A. Schults et al. / Australian Critical Care xxx (xxxx) xxx
functional residual capacity. This is an important finding as ETS
and mechanical aspiration of secretions cause sudden and
profound loss of functional residual capacity, resulting in ate-
lectatic segments of the lung.40,48 The increase in EELV seen
with RM application could be attributed to the recruitment of
atelectatic alveoli and the prevention of further lung collapse,
as a result of the transient increase in transpulmonary pressure
generated by the increased PEEP.49,50
Despite seeing improvements in EELI, we did not find signif-
icant increases in VARt following the RM but found improve-
ments in Cdyn and SpO2/FiO2 ratio. These findings are similar to
those of the few published studies investigating RMs following
ETS.14,51 RMs have been shown to maintain EELV following ETS in
mechanically ventilated adults, with patients not receiving an RM
having significantly reduced EELV at 15 min after ETS (p ¼ 0.01).51
In mechanically ventilated children, a crossover RCT (n ¼ 60)
found that a double PEEP RM led to improved EELV and
oxygenation, particularly in children with lung pathology.14 Im-
provements in impedance and lung volumes from RMs may be
more significant in patients with pulmonary disease, who have
noncompliant lungs with closing volumes greater than functional
residual capacity and that are prone to atelectasis and desatura-
tion during ETS. This could be examined in a larger trial with
subanalyses of paediatric acute respiratory disease syndrome
severity. No adverse side effects with the application of PEEP RMs
were observed during the trial. The finding of the NARES trial
when combined with the existing evidence suggests that PEEP
RMs are a promising intervention to consider with existing ETS
practices in the general PICU population, at least with respect to
the effect on short-term lung volume recovery, oxygenation, and
Cdyn. Although we did not observe any AEs in this trial, this will
need to be evaluated in a definitive RCT. In addition, prospective
trial data are needed to determine whether re-expansion of
collapsed alveolar units can be sustained, with studies showing
RMs may only lead to transient re-expansion and improvement in
oxygenation indices and lung mechanics.7,52
ETS is frequently complicated by oxygen desaturation.3,53 In
line with current evidence, we confirmed the negative effect
NSI with ETS has on oxygenation indices, with statistically
significant reductions found in the SpO2/FiO2 ratio at all time
points for children suctioned with saline. However, compared
with current evidence, which suggests the decrease is transient
and returns to baseline at 10 min,12 our data indicated signifi-
cant differences in mean SpO2/FiO2 ratios persisting at 10 min.
This finding, however, may be due to the measurement of
different clinical endpoints; SpO2 versus SpO2/FiO2. ETS leads to
significant lung volume loss; NSI further contributes to gas
maldistribution, worsening derecruitment by increasing the
alveolar threshold opening pressure.14,54,55 If NSI has the po-
tential to prevent the development of serious healthcare- health
careeacquired infections, clinicians require improved guidance
around its application, with greater access to data allowing
clinicians to make more informed decisions. There needs to be
an increased focus on identification of secretion retention,
preventing the adverse effects of ETS, and consideration of what
is the appropriate ETS intervention for the clinical scenario in
mechanically ventilated children. Interventions such as RMs
may be used in conjunction with NSI, and in this study cohort,
were demonstrated to significantly improve measures of
oxygenation following ETS. Rerecruitment of collapsed alveoli
can improve pulmonary gas exchange and lung mechanics and
also helps protect the lung from further insult.
Please cite this article as: Schults JA et al., Normal saline and lung recruitment with paediatric endotracheal suction (NARES): A pilot, factorial,
randomised controlled trial, Australian Critical Care, https://doi.org/10.1016/j.aucc.2021.01.006
7
4.1. Strengths and limitations
This feasibility and pilot trial provided important informa-
tion with regard to study processes to inform the undertaking
of a definitive trial. It assessed predefined feasibility criteria,
including patient eligibility, recruitment, retention, protocol
adherence, and missing data. Trial interventions were informed
by literature reviews (identified gaps),9,10,12 an observational
study (site practice variability),3,42 and interviews with clini-
cians (intervention fidelity strategies).42 VAP was chosen as the
clinical endpoint owing to the significant burden it places on
patients and the health service.46 Additional clinical endpoints
should be included in a larger trial, and these should include
length of ventilation, ventilator and respiratory free days.
Despite robust methodology, our trial has a number of limita-
tions. First, the study was undertaken in a single, tertiary
paediatric facility, and the number of patients recruited to this
trial might be insufficient for multiple comparisons of two
separate interventions. Furthermore, patient eligibility for trial
enrolment was limited by eligibility criteria for RMs (no high-
risk patients), limiting the generalisability of the findings to
other critical care populations such as cardiac surgical patients,
trauma patients, or children with head injuries. Although the
pilot trial aimed to examine feasibility and had a small sample
size, investigators were able to describe significant differences
in clinical markers between RM and no RM usage in mechan-
ically ventilated children. Furthermore, we did not plan nor
conduct subanalyses of infants with altered lung mechanics due
to sample size limitations; this would be an important addition
to the statistical analysis plan in a definitive trial. In addition, it
was not possible to blind the study interventions from clinical
and research staff owing to the nature of the NSI and RM
procedures. However, the infectious disease paediatrician (who
assessed all patients against the CDC VAP criteria) was blinded
to group allocation, thus reducing the risk of bias. Finally, the
participants received the allocated intervention for 48 h or
extubation, whichever came first in a pragmatic attempt to
encourage intervention adherence; importantly, the median
duration of ventilation for the participants was 2.7 days. Similar
intervention fidelity has been reported nationally in other RCTs
examining NSI effectiveness with ETS.56 Since trial registration,
the definition of VAP (used in this study) has been superseded
by the new definition of Ventilator-Associated Events (PedVAE)
,57,58 which may limit comparability of findings. Study rigour
was promoted by following a registered trial protocol (with
registered amendment), independent randomisation, and con-
cealed allocation.
5. Conclusion
The pilot trial identified necessary protocol modifications to
support the feasibility of a future RCT of NSI and RMs. NSI was
associated with a reduced incidence of VAP, and RMs were asso-
ciated with improvements in oxygenation, lung compliance, and
EELV; however, a definitive trial is needed to determine the effect.
With targeted protocol modifications, a future RCT of NSI and RMs
may be feasible and is worthwhile.
Funding
This research was independently developed and undertaken,
with support from the Australian College of Critical Care Nurses
8 J.A. Schults et al. / Australian Critical Care xxx (xxxx) xxx
(2017), Children's Health Queensland SERTA, and the Centaur Me-
morial Fund for Nurses research and scholarship grants.
CRediT author statement
JS conceived the study, designed the protocol, secured funding,
recruited participants, performed data collection, assisted with
data analysis and prepared and approved the final version of the
manuscript. MC, DL, AS, and MM conceived the study, designed the
protocol, secured funding, contributed to results interpretation and
reviewed and approved the final version of the manuscript. RW
reviewed the protocol and designed the statistical analysis plan,
performed data analysis reviewed and approved the final version of
the manuscript. KC contributed to protocol development, per-
formed data collection and reviewed and approved the final version
of the manuscript. AI contributed to protocol development, per-
formed blinded VAP assessment and reviewed and approved the
final version of the manuscript.
Conflict of Interest
J.A.S., M.C., D.L., K.C., A.S., R.S.W., A.I., and M.L.M. have no con-
flicts of interest to disclose.
Acknowledgements
The authors would like to thank the parents and patients and
clinicians who participated in the study. The authors would also
like to thank members of the Paediatric Critical Care Research
Group for their support throughout this project, in particular
Associate Professor Kristen Gibbons and research nurses Kylie
Pearson, Kristy Price, Louise Sparkes, and Mel Kennardy. Finally, the
authors would like to acknowledge Dr. Edgar Santoz Fernandez, Ms.
Amanda Corley, and Mr. Lawrence Caruana for their assistance with
data transformation and electrical impedance tomography
reconstruction.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.aucc.2021.01.006.
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