Lung-Protective Mechanical Ventilation Strategies
in Pediatric Acute Respiratory Distress Syndrome
Judith Ju Ming Wong, MBBCh, BAO, MRCPCH1,2; Siew Wah Lee, MD, MRCPCH1,3;
Downloaded from https://journals.lww.com/pccmjournal by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3fgGGXf0fUkA9iyQljxcAb/xGRsLOZqMAeomBnyyej5mZBlQi/Otdsg== on 08/22/2020
Herng Lee Tan, MSc1, Yi-Jyun Ma, BSc1; Rehana Sultana, MSc (Stat)4; Yee Hui Mok, MBBS, MRCPCH1,2;
Jan Hau Lee, MBBS, MRCPCH, MCI1,2
Objectives: Reduced morbidity and mortality associated with
lung-protective mechanical ventilation is not proven in pediatric
acute respiratory distress syndrome. This study aims to determine
if a lung-protective mechanical ventilation protocol in pediatric
acute respiratory distress syndrome is associated with improved
clinical outcomes.
Design: This pilot study over April 2016 to September 2019
adopts a before-and-after comparison design of a lung-protective
mechanical ventilation protocol. All admissions to the PICU were
screened daily for fulfillment of the Pediatric Acute Lung Injury
Consensus Conference criteria and included.
Setting: Multidisciplinary PICU.
Patients: Patients with pediatric acute respiratory distress syn-
drome.
Interventions: Lung-protective mechanical ventilation protocol
with elements on peak pressures, tidal volumes, end-expiratory
pressure to Fio2 combinations, permissive hypercapnia, and per-
missive hypoxemia.
Measurements and Main Results: Ventilator and blood gas data
were collected for the first 7 days of pediatric acute respiratory dis-
tress syndrome and compared between the protocol (n = 63) and
nonprotocol groups (n = 69). After implementation of the protocol,
median tidal volume (6.4 mL/kg [5.4–7.8 mL/kg] vs 6.0 mL/kg [4.8–
7.3 mL/kg]; p = 0.005), Pao2 (78.1 mm Hg [67.0–94.6 mm Hg] vs
74.5 mm Hg [59.2–91.1 mm Hg]; p = 0.001), and oxygen satura-
tion (97% [95–99%] vs 96% [94–98%]; p = 0.007) were lower,
and end-expiratory pressure (8 cm H2O [7–9 cm H2O] vs 8 cm
H2O [8–10 cm H2O]; p = 0.002] and Paco2 (44.9 mm Hg [38.8–
53.1 mm Hg] vs 46.4 mm Hg [39.4–56.7 mm Hg]; p = 0.033)
1
Children’s Intensive Care Unit, Department of Pediatric Subspecialties,
KK Women’s and Children’s Hospital, Singapore.
2
Duke-NUS Medical School, Singapore.
3
Pediatric Intensive Care Unit, Hospital Kuala Lumpur, Kuala Lumpur,
­Malaysia.
4
Center for Quantitative Medicine, Duke-NUS Medical School, Singapore.
Copyright © 2020 by the Society of Critical Care Medicine and the World
Federation of Pediatric Intensive and Critical Care Societies
DOI: 10.1097/PCC.0000000000002324
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Copyright © 2020 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.
Unauthorized reproduction of this article is prohibited
were higher, in keeping with lung protective measures. There
was no difference in mortality (10/63 [15.9%] vs 18/69 [26.1%];
p = 0.152), ventilator-free days (16.0 [2.0–23.0] vs 19.0 [0.0–23.0];
p = 0.697), and PICU-free days (13.0 [0.0–21.0] vs 16.0 [0.0–
22.0]; p = 0.233) between the protocol and nonprotocol groups.
After adjusting for severity of illness, organ dysfunction and oxygen-
ation index, the lung-protective mechanical ventilation protocol was
associated with decreased mortality (adjusted hazard ratio, 0.37;
95% CI, 0.16–0.88).
Conclusions: In pediatric acute respiratory distress syndrome, a
lung-protective mechanical ventilation protocol improved adher-
ence to lung-protective mechanical ventilation strategies and po-
tentially mortality. (Pediatr Crit Care Med 2020; 21:720–728)
Key Words: acute lung injury; artificial respiration; intermittent
positive-pressure ventilation; pediatric intensive care unit; tidal
volume
T
he mainstay of treatment in acute respiratory distress
syndrome (ARDS), an inflammatory pulmonary con-
dition associated with severe hypoxemia, is supportive
mechanical ventilation (MV) (1). However, MV in itself has
the potential to initiate and/or aggravate lung injury. The
detrimental effects of MV is evident in experimental mod-
els as disruption of the pulmonary epithelium and endothe-
lium, pulmonary inflammation with release of inflammatory
mediators and pneumocyte dysfunction which is very sim-
ilar to ARDS itself (2–5). This knowledge has translated
into clinical practice in the development of lung-protective
mechanical ventilation (LPMV) strategies. With the aim of
minimizing ventilator-induced lung injury, LPMV strategies
were associated with a reduction of local and systemic cy-
tokine response (6–8), survival benefit and other improved
clinical outcomes (9–12).
Based on varying levels of evidence, LPMV strategies con-
sist of limiting plateau pressures (or driving pressure), low
tidal volumes (Vts), high positive end-expiratory pressure
(PEEP), and acceptance of some degree of hypercapnia and
hypoxemia (10, 13–15). Given the evidence of benefit gleaned

from individual LPMV strategies in adults, it seems logical to
extrapolate LPMV to children, to confer the same benefits to
the vulnerable pediatric acute respiratory distress syndrome
(PARDS) population. Although the evidence for critically ill
children remains limited, these key strategies have been col-
lectively incorporated into the Pediatric Acute Lung Injury
Consensus Conference (PALICC) recommendations in the
management of children with PARDS (16).
Specifically, the beneficial effects of LPMV in PARDS has not
been firmly established and it is unknown whether the applica-
tion of all key elements of LPMV would synergistically improve
outcomes. In addition, a pediatric study controversially showed
that higher Vt were associated with greater ventilator-free days
(VFDs), particularly for children with less severe disease (17).
Given the lack of data on the impact of LPMV strategies in chil-
dren with PARDS, we conducted a pilot study to determine if
the implementation of a LPMV protocol comprising all the five
key elements would result in 1) a greater adherence to LPMV
strategies and 2) estimate its impact on mortality in PARDS.
MATERIALS AND METHODS
Design, Setting, and Patients
This pragmatic pilot study examined the adherence of ven-
tilator management to the LPMV strategies in patients with
PARDS, before-and-after the implementation of a PARDS
ventilation protocol. The “non-protocol (before)” group con-
sisted of a retrospective cohort of patients, identified through
manual review of the PICU admission log from April 2016 to
March 2018 (2 yr). The “protocol (after)” group consisted of a
prospective group of patients with PARDS admitted from April
2018 to September 2019 (18 mo). All patients on invasive MV
were eligible, regardless of mode of ventilation. In both peri-
ods, patients were included if they fulfilled the PALICC defi-
nition on two separate blood gases four hours apart (16, 18).
This study was conducted in a 16-bedded multidisciplinary
PICU. In the prospective/protocol arm, all PICU admission
were screened daily for inclusion criteria and consented under
the institutional review board reference number 3076/2017/E.
This study was registered on ClinicalTrials.gov under reference
number: NCT03504176. Reporting was in accordance with
the Strengthening the Reporting of Observational Studies in
Epidemiology guidelines (19).
PARDS Ventilation Protocol
In December 2017, a PARDS ventilation protocol was devel-
oped and approved by PICU medical and nursing stakehold-
ers and fully implemented by April 2018. The protocol was
championed by a team consisting of respiratory therapists and
intensivists. Training/education sessions were held regularly
during that month and regular updates were held at PICU ad-
ministrative meetings thereafter. Posters and reminders were
also displayed across the PICU to encourage compliance.
The details of the PARDS ventilation protocol are pro-
vided in Supplementary Table 1, a, b, and c (Supplemental
Digital Content 1, http://links.lww.com/PCC/B288). Briefly, it
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Feature Articles
consisted of five essential ventilation elements: 1) peak inspir-
atory pressures (PIPs) less than 28 cm H2O, 2) Vts 3–6 mL/kg,
3) incremental PEEP to Fio2 table, 4) permissive hypercapnia
(pH, 7.20–7.30) for moderate/severe PARDS, and 5) permissive
hypoxemia (pulse oximetry [Spo2] 93–97% and 88–92% for
mild and moderate/severe PARDS, respectively). The PARDS
ventilation protocol also encouraged the use of predicted
body weight (PBW) for calculation of Vt but did not mandate
it. PBW tables for each gender based on the 50th percentile
for measured height on locally developed Health Promotion
Board, Ministry of Health, Singapore growth charts for calcu-
lation of Vt were provided in the protocol (20).
Measurement and Data Collection
Demographic and clinical data were collected. This included
admission severity scores (Pediatric Index of Mortality [PIM]
2 and Pediatric Logistic Organ Dysfunction [PELOD] scores)
(21, 22). Comorbidities were defined by the presence of com-
plex chronic conditions listed by Edwards et al (23) and catego-
rized into the most clinically affected system. Sepsis and organ
dysfunction were defined by the International Pediatric Sepsis
Consensus Conference (24). Risk factors for PARDS referred to
the triggering event for PARDS and was categorized according
to the most clinically significant contributory risk factor.
PARDS severity was defined preferably by the oxygenation
index (OI) or if an arterial cannula was absent, by the oxy-
genation saturation index (OSI)—cutoffs given by the PALICC
definition (16). Calculation of OI and OSI were done every
morning between 0600 and 0800 hours as it was routine for
blood gas sampling at this time on all patients on MV in our
unit. Detailed MV data were collected for the first 7 days of
PARDS. MV settings recorded corresponded to the blood gas
measurements at 0600–0800 hours daily. Conventional MV
(CMV) referred to both pressure-controlled (PC) and vol-
ume-controlled (VC) ventilation. Non-CMV included airway
pressure release ventilation and high frequency oscillatory
ventilation (HFOV). Use of adjuncts and other PICU support
therapies were recorded throughout the course of PARDS up
to 28 days or until PICU discharge whichever was earlier.
Outcomes and Statistical Analysis
The primary outcome was 60-day PICU mortality and was
treated as time-to-event data. Patients who survived longer than
60 days in PICU or discharged from the PICU were censored.
Secondary outcomes were VFDs and ICU-free days (IFDs) up to
28 days. Patients were analyzed in two groups: the “protocol” and
“non-protocol” groups. Patient demographics and clinical char-
acteristics were summarized as counts (percentages) and median
(interquartile range) for categorical and continuous variables, re-
spectively. Comparisons between the protocol and nonprotocol
groups were done using the chi-square test and Wilcoxon rank-
sum tests for categorical and continuous variables, respectively.
Compliance to the essential ventilation elements (1)–(3) were
measured for CMV days only. Compliance to elements (4) and
(5) were measured for all MV days, regardless of mode of ventila-
tion. We analyzed these for the first 7 days of PARDS to determine
 Wong et al
the number of days each ventilation element was adhered to, be-
fore and after the implementation of the ventilation protocol.
The use of either actual body weight (ABW) or PBW in chil-
dren is controversial and as such, not mandated in the protocol.
An a priori determined sensitivity analysis was planned for cal-
culation of Vt utilizing both measurements. The differences be-
tween the median (interquartile range) of ABW and PBW, as well
as Vt calculated using these two measurements for all the sub-
jects were compared using the Wilcoxon rank-sum test. A Bland-
Altman plot was used to visualize the individual agreement.
Sixty-day survival rate based on protocol versus nonproto-
col groups were plotted using Kaplan-Meier model and were
compared using the log-rank test. Both univariate and mul-
tivariate Cox Proportional Hazard (CPH) regression model
were used to quantify association between 60-day mortality
and other covariates (PIM 2 score, PELOD score, and severity
of PARDS). In an a priori manner, these covariates were chosen
based on its known impact on clinical outcomes in PARDS
(25). Association from CPH was characterized as hazard ratio
(HR) with corresponding 95% CI. VFD and IFD were also ana-
lyzed with respect to protocol versus nonprotocol groups.
Analysis was performed on STATA software, Version 15.1
(StataCorp, College Station, TX) and SAS Version 9.3 software
(SAS Institute, Cary, NC). All tests were two-tailed and p value
of less than 0.05 was accepted as statistically significant.
RESULTS
One hundred thirty-four patients were identified for this
study. However, two patients declined consent, leaving 63 of
132 (47.7%) and 69 of 132 (52.3%) patients analyzable in the
protocol and nonprotocol groups, respectively. Overall me-
dian age and OI at diagnosis was 2.4 years (0.5–7.7 yr) and 10.7
(7.5–15.4), respectively. There was no difference in PARDS eti-
ology, severity of illness (PIM 2 and PELOD scores), severity of
PARDS, or use of adjunctive therapies between the two groups
(Table 1). There was a total of 752 analyzable MV days consist-
ing of 522 of 752 (69.4%) and 230 of 752 (30.6%) CMV days
and non-CMV days, respectively (Supplementary Table 2, Sup-
plemental Digital Content 1, http://links.lww.com/PCC/B288).
After implementation of the ventilation protocol, compli-
ance to PIP and Vt limits were marginally increased but did
not reach statistical significance (Table 2). When daily venti-
lation elements were examined, median Vt was found to be
significantly lower in the protocol group compared with the
nonprotocol group (6.0 mL/kg [4.8–7.3 mL/kg] vs 6.4 mL/
kg [5.4–7.8 mL/kg]; p = 0.005) (Table 3). This decrease was
mainly driven by days in the moderate-severe PARDS cate-
gory (5.6 mL/kg [3.6–6.7 mL/kg] vs 6.2 mL/kg [5.1–7.7 mL/kg];
p = 0.008). In the sensitivity analysis using PBW, there was no
difference between the median ABW and PBW (11.1 kg [6.3–
21.0 kg] vs 11.5 kg [6.6–21.5 kg]; p = 0.731) nor the calculated
Vt utilizing these two measurements (6.2 mL/kg [4.9–7.5 mL/
kg] vs 6.1 mL/kg [4.8–7.5 mL/kg]; p = 0.708) (Supplementary
Fig. 1, Supplemental Digital Content 2, http://links.lww.com/
PCC/B289; legend, Supplemental Digital Content 1, http://
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links.lww.com/PCC/B288). Comparing the protocol and
nonprotocol group, there was also no increase in compli-
ance to Vt (per PBW) targets nor the median Vt (per PBW)
(Supplementary Table 3, Supplemental Digital Content 1,
http://links.lww.com/PCC/B288).
Compliance to incremental PEEP/Fio2 combinations
remained the same after implementation of the ventilation
protocol. Median Fio2 remained the same in the protocol and
nonprotocol group; however, PEEP was found to be signifi-
cantly higher after implementation of the ventilation protocol
(8 cm H2O [8–10 cm H2O] cm H2O vs 8 cm H2O [7–9 cm H2O];
p = 0.002). This increase was also mainly driven by days in the
moderate-severe PARDS category (10 cm H2O [8–12 cm H2O]
vs 9 cm H2O [8–10 cm H2O]; p = 0.011).
Permissive hypoxemia in moderate/severe PARDS
improved (41/140 [29.3%] vs 30/172 [17.4%] ventilation days;
p = 0.031) in the protocol group compared with the nonpro-
tocol group. Permissive hypoxemia was observed more often
on days where the OI/OSI fell within the moderate-severe
PARDS category (Spo2 88–92%) in the protocol versus non-
protocol group (41/140 [29.3%] vs 30/172 [17.4%]; p = 0.031)
(Table 2). This improvement was not seen on mild or at-risk
PARDS days (Spo2 93–97%). However, in patients ventilated
on non-CMV modes, there was a significant decrease in me-
dian Spo2 toward permissive hypoxemia in the protocol versus
nonprotocol group (94% [91–96%] vs 96% [93–98%]; p <
0.001) (Table 3). Correspondingly, there was a reduction in
median Pao2 (64.7 mm Hg [57.8–80.5 mm Hg] vs 75.3 mm Hg
[62.2–88.0 mm Hg]; p = 0.015) in the protocol versus non-
protocol groups. These improvements were also driven by the
moderate-severe PARDS days on non-CMV modes.
Permissive hypercapnia was observed only in approximately a
quarter of patients in both protocol and nonprotocol groups on
moderate-severe PARDS days (40/139 [28.8%] vs 42/168 [25.0%];
p = 0.457) (Table 2). Median Paco2 was significantly increased
(53.0 mm Hg [45.2–63.5 mm Hg] vs 46.2 mm Hg [39.7–54.9 mm
Hg]; p < 0.001) in the protocol group on non-CMV days; however,
there was no significant difference in the median pH (Table 3).
The overall 60-day mortality, VFD, and IFD were 28 of 132
(21.2%), 17.5 days (0.0–23.0 d), and 14.0 days (0.0–21.0 d), re-
spectively (Table 4). A decrease in mortality (10/63 [15.9%] vs
18/69 [26.1%]; p = 0.152) was seen in the protocol group com-
pared with the nonprotocol group, but this did not reach statistical
significance. There was no increase in VFD and IFD after imple-
mentation of the protocol (Table 4). After adjusting for the PIM 2
score, PELOD score and PARDS severity in the multivariate CPH
model, the LPMV protocol was associated with lower mortality
risk (adjusted HR, 0.37; 0.16–0.88; p = 0.025) (Table 5 and Fig. 1).
DISCUSSION
This pragmatic pilot before-and-after study demonstrated an
improvement in adherence to LPMV strategies in PARDS with
the implementation of a LPMV protocol. Postimplementation
of the protocol, median Vt was decreased, indicating improved
adoption of low Vt ventilation. Despite the use of similar Fio2,
 Feature Articles

TABLE 1. Patient Characteristics in the Lung-Protective Mechanical Ventilation Protocol

and Nonprotocol Groups
Nonprotocol Group Protocol Group
Characteristics All (n = 132) (n = 69) (n = 63) p

Age, yr 2.4 (0.4–8.3) 1.8 (0.4–7.7) 2.8 (0.5–9.6) 0.558

Male gender 78 (59.0) 38 (55.1) 40 (63.5) 0.326
Comorbidities 91 (68.9) 45 (65.2) 46 (73.0) 0.333
Extrapulmonary etiology 29 (22.0) 17 (24.6) 12 (19.0) 0.438
PARDS etiology 0.287
 Pneumonia 88 (66.7) 47 (68.1) 41 (65.1)
 Aspiration 10 (7.6) 2 (2.9) 8 (12.7)
 Drowning 5 (3.8) 3 (4.3) 2 (3.2)
 Sepsis 23 (17.4) 13 (18.8) 10 (15.9)
 Others 6 (4.5) 4 (5.8) 2 (3.2)
Pediatric Index of Mortality 2 score 7.1 (3.3–17.4) 6.4 (3.2–14.5) 7.4 (4.3–22.2) 0.222
Pediatric Logistic Organ Dysfunction score 10.0 (2.0–21.0) 11.0 (4.0–21.0) 8.0 (1.0–21.0) 0.118
Oxygenation indexa 7.7 (4.7–12.0) 8.1 (4.4–12.0) 7.3 (4.9–12.2) 0.828
  Severe PARDS b
53 (40.2) 28 (40.6) 25 (39.7) 0.916
High frequency oscillatory ventilation 38 (28.8) 19 (27.5) 19 (30.2) 0.740
Pulmonary vasodilators 23 (17.4) 11 (15.9) 12 (19.0) 0.638
Prone position 43 (32.6) 24 (34.5) 19 (30.2) 0.532
Systemic steroid 72 (54.5) 36 (52.2) 36 (57.1) 0.567
Neuromuscular blockade 41 (31.1) 20 (29.0) 21 (33.3) 0.590
Diuretics 113 (85.6) 57 (82.6) 56 (88.9) 0.305
Transfusion 78 (59.1) 37 (53.6) 41 (65.1) 0.181
Extracorporeal membrane oxygenation 15 (11.4) 8 (11.6) 7 (11.1) 0.957
Air leak 14 (10.6) 10 (14.5) 4 (6.3) 0.129
Multiple organ dysfunction 108 (81.8) 59 (85.5) 49 (77.8) 0.250
PARDS = pediatric acute respiratory distress syndrome.
a
Day 2 of PARDS diagnosis.
b
On any of the first 7 d of PARDS.
Continuous and categorical variables summarized in medians (interquartile ranges) and counts (percentages), respectively.

median PEEP was higher postimplementation of the protocol
indicating an improved acceptance of open lung ventilation.
There was also a greater acceptance of permissive hypercapnia
(Paco2) and permissive hypoxemia (both Spo2 and Pao2) while
on non-CMV modes of ventilation and especially on moder-
ate-severe PARDS days. LPMV strategies were also shown to
improve mortality risk in our cohort of patients with PARDS.
There is a scarcity of evidence for LPMV in PARDS com-
pared with adult ARDS (16). In adults with ARDS, the sentinel
Acute Respiratory Distress Syndrome Network (ARDSNet)
trial (n = 861) comparing low versus high Vt for ARDS was
stopped early for a statistically significant mortality benefit
(31% vs 40%; p = 0.007) and also showed increased VFD in
the low Vt arm (1). Consistently, patients randomized in this
trial to low Vt also developed a greater attenuation in the sys-
temic inflammatory response (evidenced by a decrease in in-
terleukin-6 of 26% [95% CI, 12–37%] and interleukin-8 of
12% [95% CI, 1–23%]) compared with the high Vt group
(7). Together with a handful of other smaller randomized tri-
als, a Cochrane meta-analysis (n = 1,297) concluded that the
mortality risk favored low Vt ventilation (relative risk [RR],
0.74; 95% CI, 0.61–0.88) (9). Till date, there are no similar
trials in the pediatric population. In critically ill children, a
trial comparing high versus low Vt may not gather sufficient
clinical equipoise to be undertaken. As such, a bundle/pro-
tocol approach, as conducted in our pilot study, is an attrac-
tive study design to investigate the optimal CMV settings for
children with PARDS.

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 Wong et al

TABLE 2. Compliance to Ventilation Elements in the Lung-Protective Mechanical

Ventilation Protocol and Nonprotocol Groups
No. of Days Compliant to Ventilation
Elementsa, n (%)

Nonprotocol Group Protocol Group

Ventilation Elements Target Patients (n = 393) (n = 394) p

Peak/plateau pressure, < 28 cm H2O All CMV 217/224 (96.7) 288/291 (99.0) 0.088
Tidal volume, 3–6 mL/kg actual body weight All CMV 78/228 (34.2) 114/291 (39.2) 0.245
Incremental positive end-expiratory pressure/Fio2 All CMV 53/224 (23.7) 72/292 (24.7) 0.793
combinations
Permissive hypercapnia, pH 7.20–7.30 Moderate/severe PARDS 42/168 (25.0) 40/139 (28.8) 0.457
Permissive hypoxia
Spo2 93–97% Mild/at risk PARDS 71/198 (35.9) 91/227 (40.0) 0.613
Spo2 88–92% Moderate/severe PARDS 30/172 (17.4) 41/140 (29.3) 0.031
CMV = conventional mechanical ventilation, PARDS = pediatric acute respiratory distress syndrome, Spo2 = pulse oximetry.
Numbers may not add up exactly due to missing data (please see Supplementary Table 1, Supplemental Digital Content 1, http://links.lww.com/PCC/B288:
a

Ventilation day grid).

Boldface values indicate p < 0.05.

Although we did demonstrate a reduction in peak pres-
sures, Vt, oxygen saturations and an increase in PEEP and
Paco2, the adherence to protocol targets were only marginally
improved (Table 2). To investigate the impact of low Vt in a
more robust manner, we will need to await the completion
of the trial of low Vt ventilation in prone versus supine po-
sition and HFOV in prone versus supine position in PARDS
that is currently being investigated in a four-by-four factorial
design randomized controlled trial (ClinicalTrials.gov identi-
fier: NCT03896763). Controlling Vt is more challenging with
PC ventilation as opposed to VC ventilation. As opposed to
the ARDSNet trial on low Vt ventilation which predominantly
used VC ventilation, the majority of CMV days in this current
study consisted of PC ventilation (only 5/522 d [< 1.0%] were
VC ventilation) (1). Another important consideration with
PC ventilation is the inability to obtain reliable plateau airway
pressures, a critical component of the original ARDSNet trial.
In the current study, the set PIP was treated interchangeably
with plateau pressures during PC ventilation, although this is
only true under certain assumptions: the inspiratory time is set
three to five times the inspiratory time constant, during which
the airflow decreases to zero (obviating airflow resistance) and
the patient’s inspiratory effort is negligible (26, 27).
Although thought to be of importance (28), the ideal method
of calculating Vt based on ABW or PBW in children is unclear
(29). Furthermore, the difference between ABW and PBW are
usually more profound in larger children or adults (29), calling
into question the need to routinely use PBW for Vt calcula-
tions in small children or infants. Thus far, there are no studies
to show that use of either ABW or PBW is superior in children
(30). Nevertheless, as a sensitivity analysis, we attempted to eval-
uate Vt calculation based on both ABW and PBW to determine
if a significant difference exists. In this study of Asian children,
comparing both measurements of weight and calculations of Vt,
there were minimal differences in children smaller than 25 kg. It
is however observed that in patients who were greater than 25 kg,
the Bland-Altman plot splays out. We also note that there were
limited changes in Vt/PBW in the protocol versus nonprotocol
group; hence, its impact on the outcome was also unclear. There
is insufficient evidence to conclude whether PBW for calcula-
tion of Vt in PARDS is of benefit or not. However, one needs to
pragmatically balance the added step of determining recumbent
height for PBW calculation with its potential impact for future
trial design and clinical implementation.
The optimal PEEP setting remains controversial in patients
with PARDS. It is believed that maintaining open alveoli
throughout the ventilatory cycle and minimizing excess supple-
mental oxygen produces the least pulmonary inflammation (8).
Studies examining the effects of PEEP on clinical outcomes (e.g.,
high vs low PEEP [31], PEEP to Fio2 combinations [32], and var-
ious PEEP titration maneuvers targeting 2–3 cm H2O above a
clinically determined de-recruitment point [8, 33]) have reported
varying results. In a meta-analysis of adult patients with ARDS
(n = 1,892), the use of high versus low PEEP was associated with
a borderline reduced hospital mortality (adjusted RR, 0.90; 95%
CI, 0.8–1.0) (14). In contrast, in PARDS, retrospective analysis
(n = 1,134) demonstrated that PEEP lower than recommended by
the ARDSNet protocol was independently associated with higher
mortality (odds ratio [OR], 2.1; 95% CI, 1.3–32) (34). PEEP/Fio2
combinations were used in our LPMV protocol; however, due to
poor adherence to these combinations, we are unable to attribute
the survival benefit to this ventilation parameter. Of note, how-
ever, we found that a higher PEEP was used given the same Fio2 in
the protocol group compared with the nonprotocol group.
In LPMV, hypercapnia is to be expected in conjunction with
lower Vt (35). Complex physiologic effects of hypercapnic ac-
idosis occur on the cardiopulmonary system (15, 36, 37), and
at the cellular level which attenuates lung injury by various

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 Feature Articles

TABLE 3. Ventilation Parameters on Conventional and Nonconventional Mechanical

Ventilation Days
CMV Days (n = 522), Median (IQR) Non-CMV Days (n = 230), Median (IQR)

Ventilation Nonprotocol Protocol Group Nonprotocol Protocol

Elements Target Patients Group (n = 229) (n = 293) p Group (n = 154) Group (n = 76) p

Peak inspiratory All 20 (17–23) 20 (17–23) 0.383

pressure, cm
H2O At risk and mild 20 (16–22) 19 (16–22) 0.047
Moderate and 23 (21–25) 24 (20–26) 0.877
severe
Tidal volume, mL/ All 6.4 (5.4–7.8) 6.0 (4.8–7.3) 0.005
kg actual body
weight At risk and mild 6.4 (5.5–7.8) 6.1 (5.1–7.6) 0.153
Moderate and 6.2 (5.1–7.7) 5.6 (3.6–6.7) 0.008
severe
Positive end- All 8 (7–9) 8 (8–10) 0.002
expiratory
pressure, cm At risk and mild 8 (7–9) 8 (7–9) 0.129
H2O
Moderate and 9 (8–10) 10 (8–12) 0.011
severe
Fio2, % All 35 (30–50) 35 (30–50) 0.548
At risk and mild 30 (25–35) 30 (30–40) 0.128
Moderate and 65 (50–80) 60 (50–85) 0.892
severe
pH All 7.39 (7.32–7.43) 7.38 (7.30–7.43) 0.332 7.38 (7.28–7.42) 7.34 (7.26–7.42) 0.087
At risk and mild 7.40 (7.34–7.44) 7.39 (7.33–7.44) 0.540 7.42 (7.39–7.47) 7.39 (7.19–7.44) 0.089
Moderate and 7.36 (7.28–7.41) 7.32 (7.24–7.39) 0.086 7.36 (7.26–7.41) 7.33 (7.26–7.40) 0.505
severe
Paco2, mm Hg All 45.0 (38.7–52.0) 45.3 (38.7–53.2) 0.417 46.2 (39.7–54.9) 53.0 (45.2–63.5) < 0.001
At risk and mild 44.0 (38.1–51.4) 44.7 (38.6 52.5) 0.427 41.0 (37.8–52.1) 53.4 (42.3–65.2) 0.026
Moderate and 46.6 (41.9–59.3) 48.3 (39.7–63.2) 0.794 47.8 (40.5–55.1) 52.6 (45.2–62.0) 0.004
severe
Pao2, mm Hg All 82.7 (70.0–100.8)79.6 (65.0–97.5) 0.066 75.3 (62.2–88.0) 64.7 (57.8–80.5) 0.015
At risk and mild 85.9 (74.5–103.5)83.5 (69.7–98.7) 0.072 86.5 (75.5–99.3) 91.0 (70.6–121.8) 0.511
Moderate and 72.3 (62.8–81.2) 68.3 (53.8–87.8) 0.338 73.4 (60.5–84.8) 64.0 (56.8–74.5) 0.012
severe
Pulse oximetry, % All 98 (95–99) 97 (95–99) 0.135 96 (93–98) 94 (91–96) < 0.001
At risk and mild 98 (96–100) 98 (95–99) 0.105 98 (96–100) 98 (96–100) 0.937
Moderate and 95 (93–97) 94 (90–98) 0.273 95 (93–98) 94 (90–96) 0.002
severe
CMV = conventional mechanical ventilation, IQR = interquartile range.
Boldface values indicate p < 0.05.

mechanisms including a reduction in inflammatory media-
tors (38–40). However, there are limited studies in patients
with ARDS, empirically evaluating the direct effect of hyper-
capnia on clinical outcomes (35, 41). A post hoc analysis of
the ARDSNet low Vt trial found that permissive hypercapnia
(pH < 7.35 and Pco2 > 45 mm Hg) was protective in the set-
ting of high Vt (adjusted OR for mortality, 0.14; 95% CI, 0.03–
0.70; p = 0.016) but not in the setting of low Vt (adjusted OR
for mortality, 1.18; 95% CI, 0.59–2.35; p = 0.639). Our study
demonstrated a greater adoption of permissive hypercapnia in
the protocol group ventilated on non-CMV modes with higher
Pco2 (53.0 mm Hg [45.2–63.5 mm Hg] vs 46.2 mm Hg [39.7–
54.9 mm Hg]; p < 0.001) and nonsignificantly lower pH (7.34
[7.26–7.42] vs 7.38 [7.28–7.42]; p = 0.087).
High oxygen exposure is associated with toxic effects in
patients with lung injury (42, 43). As such, we included per-
missive hypoxemia in our LPMV protocol. Data from critically
ill adults (n = 434) randomized to conservative oxygen targets

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 Wong et al

TABLE 4. Outcomes of Patients in the Lung-Protective Mechanical Ventilation Protocol

and Nonprotocol Groups
Total Nonprotocol Group Protocol Group
Outcomes (n = 132) (n = 69) (n = 63) p

60-d mortality, n (%) 28 (21.2) 18 (26.1) 10 (15.9) 0.152

Ventilator-free days, median (IQR) 17.5 (0.0–23.0) 19.0 (0.0–23.0) 16.0 (2.0–23.0) 0.697
Ventilator duration, d, median (IQR) 7.0 (4.0–13.0) 6.0 (3.0–11.0) 8.0 (4.0–15.0) 0.070
PICU-free days, median (IQR) 14.0 (0.0–21.0) 16.0 (0.0–22.0) 13.0 (0.0–21.0) 0.233
PICU duration, days, median (IQR) 9.5 (5.0–17.0) 8.0 (4.0–13.0) 13.0 (6.0–25.0) 0.018
IQR = interquartile range.
Boldface value indicates p < 0.05.

TABLE 5. Cox Proportional Hazard Regression Model for Outcome of 60-Day Mortality
Unadjusted HR Adjusted HR
Covariates (95% CI) p (95% CI) p

Pediatric Index of Mortality 2 score 1.03 (1.02–1.04) < 0.001 1.02 (1.01–1.04) 0.001
Pediatric Logistic Organ Dysfunction score 1.04 (1.03–1.06) < 0.001 1.02 (1.00–1.05) 0.046
Lung-protective mechanical ventilation 0.57 (0.26–1.22) 0.151 0.37 (0.16–0.88) 0.025
protocol (Reference: nonprotocol)
Pediatric acute respiratory distress syndrome severity (Reference: mild)
 Moderate 0.54 (0.18–1.67) 0.290 0.51 (0.16–1.64) 0.260
 Severe 1.89 (0.76–4.68) 0.169 1.76 (0.64–4.85) 0.275
HR = hazard ratio.
Boldface values indicate p < 0.05.

(Spo2 94–98% vs 97–100%) demonstrated an association with
reduced mortality (RR, 0.6; 95% CI, 0.4–0.9) (44). A similar
but smaller randomized trial in critically ill children (n = 159),
Kaplan−Meier survival estimates
1.00
however, did not find any differences in mortality or other out-
comes (45). The impact of permissive hypoxemia specifically in
children with PARDS has yet been subjected to rigorous clin-
ical trials. After implementing the LPMV
protocol in this study, a lower target Spo2
reading was accepted in moderate-severe

PARDS on non-CMV (94% [91–96%] vs

96% [93–98%]; p < 0.001) modes.
Based on the current evidence, and de-
0.75

spite the majority of intensivists reporting

Log−rank=0.092
the use of LPMV strategies in their prac-
0.50

tice, numerous studies have shown that in

reality, adherence remains low (approxi-
mately 30%) (46–48). Pediatric intensivists
0.25

are not exempt from this lack of adherence

despite publication of authoritative rec-
0.00

ommendations (49). Surveys of intensive

0 20 40 60 care providers noted that failure to recog-
Days after PARDS diagnosis nize ARDS, and role ambiguity (whereby
Number at risk the clinician, nursing and respiratory ther-
Non−protocol 69 53 51 51
Protocol 63 55 54 54 apists believe they do not have the respon-
sibility for ensuring adherence) were more
Non−protocol Protocol
likely causes of poor adherence, rather than
a knowledge deficit per say (46). As such,
Figure 1. Kaplan-Meier model comparing the lung-protective mechanical ventilation protocol and
this ventilation protocol, being driven by
nonprotocol groups. PARDS = pediatric acute respiratory distress syndrome. respiratory therapists for screening and

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implementation of the protocol elements, addresses these root
causes. Despite this, stricter observance to the protocol limits
were more evident in the moderate-severe PARDS days indicat-
ing that perhaps there is still a lack of confidence in the benefits
of lung protection in those who were less ill.
In this current study, the overall 60-day mortality of 22.0%
is comparable with other contemporary studies which use the
PALICC criteria for PARDS (50). After adjusting for admission se-
verity of illness (PIM 2 score), organ dysfunction (PELOD score)
and PARDS severity, implementation of the LPMV was associated
with a reduction in mortality risk (adjusted HR, 0.37; 0.16–0.88).
The relative contribution or interaction of each LPMV element
toward this survival benefit, however, cannot be disentangled.
Given the consistent indirect evidence from adult ARDS trials, our
findings provide fairly strong preliminary data that extrapolation
of LPMV strategies to PARDS is likely beneficial.
This study has several strengths. Through this pilot study,
we demonstrated that a ventilation protocol may improve
compliance to the LPMV strategies in PARDS. However, these
improvements in adherence were mainly seen on moderate-
severe PARDS days. This highlights that more needs to be
done to track and maintain compliance on at-risk and mild
PARDS days. We established a comprehensive screening pro-
cedure which enabled us to identify all patients who fulfilled
the PALICC criteria. The single-center before-and-after design
over a 3.5-year study period, allowed us to compare the inter-
vention with limited confounding by center or time. However,
our pilot data should be interpreted within the context of the
study’s limitations. First, being a pilot study, there was no a
priori sample size calculation determined to power the study.
Utilizing a conservative reduction in mortality of one-third, in
a multicenter setting with some degree of variability, approx-
imately 360 subjects in each arm is required to provide 80%
power. Second, the “before-and-after” study design is suscep-
tible to bias from unknown prognostic/risk factors which can
only be eliminated by randomization. Third, contribution of
the respiratory therapists in this study was paramount in pro-
tocol implementation, thus limiting the generalizability of this
study to centers without respiratory therapists. Nevertheless,
we believe that, with appropriate training and empowerment,
this pragmatic protocol can also be used by nurses/junior resi-
dents. Last, we utilized surrogates including PIP in place of pla-
teau pressure (as the cohort was predominantly ventilated on
PC ventilation) and OSI instead of OI in the absence of arterial
blood gas measurements, accepting their accompanying limi-
tations (26, 51).
CONCLUSIONS
This pilot study demonstrated that a PARDS ventilation pro-
tocol may potentially improve adherence to LPMV strate-
gies and reduce mortality. More attention needs to be paid
to improve compliance of such a protocol in at-risk and mild
PARDS days. In order to validate our preliminary findings of
the positive impact of lung-protective ventilation in children
with PARDS on clinical outcomes, an appropriately designed
and adequately powered trial is justified.
Pediatric Critical Care Medicine www.pccmjournal.org 727
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Feature Articles
Drs. Wong, Tan, Ma, and J. H. Lee contributed substantially to the con-
ception and design of the study. Drs. Wong, S. W. Lee, Tan, and Ma
were responsible for the execution of the study and acquisition of data.
Dr. Wong and Ms. Sultana performed the analysis of data. Drs. Wong
and S. W. Lee were responsible for drafting the article. All authors con-
tributed substantially to the interpretation of data and revising the ar-
ticle critically for important intellectual content. All authors approved
the version submitted for publication and agree to be accountable for
all aspects of the work in ensuring that questions related to the accu-
racy or integrity of any part of the work are appropriately investigated
and resolved.
Supplemental digital content is available for this article. Direct URL cita-
tions appear in the printed text and are provided in the HTML and PDF
versions of this article on the journal’s website (http://journals.lww.com/
pccmjournal).
Ms. Ma disclosed work for hire. Dr. J. H. Lee received funding from KK
Women’s and Children’s Hospital. The remaining authors have disclosed
that they do not have any potential conflicts of interest.
Address requests for reprints to: Judith Ju Ming Wong, MBBCh, BAO,
MRCPCH, Children’s Intensive Care Unit, Department of Pediatric Sub-
specialties, Level 2 Children’s Tower, KK Women’s and Children’s Hos-
pital, 100 Bukit Timah Road, Singapore 229899. E-mail: judith.wong.jm@
singhealth.com.sg
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