Risk Stratification in Pediatric Acute Respiratory

Distress Syndrome: A Multicenter Observational

Study
Judith Ju-Ming Wong, MBBCh BAO, MRCPCH1,2; Huu Phuc Phan, MD3; Suwannee Phumeetham, MD4;
Jacqueline Soo May Ong, MB BChir, MRCPCH5; Yek Kee Chor, MD, MRCPCH6;Suyun Qian, MD7;
Rujipat Samransamruajkit, MD8; Nattachai Anantasit, MD9; Chin Seng Gan, MBBS, MMed10;
Feng Xu, MD11; Rehena Sultana, MSc (Statistics)12; Tsee Foong Loh, MBBS, MRCPCH1,2;
Jan Hau Lee, MBBS, MRCPCH, MCI1,2; for the Pediatric Acute & Critical Care Medicine Asian Network
(PACCMAN)

1
Childrens Intensive Care Unit, Department of Pediatric Subspecialities, Objectives: The Pediatric Acute Lung Injury Consensus Confer-
KK Womens and Childrens Hospital, Singapore.
ence developed a pediatric specic denition for acute respi-
2
Duke-NUS Medical School, Singapore.
ratory distress syndrome (PARDS). In this definition, severity of
3
Pediatric Intensive Care Unit, National Childrens Hospital, Hanoi, Vietnam.
lung disease is stratified into mild, moderate, and severe groups.
4
Department of Pediatrics, Faculty of Medicine, Siriraj Hospital, Mahidol
University, Bangkok, Thailand.
We aim to describe the epidemiology of patients with PARDS
5
Pediatric Intensive Care Unit, Department of Pediatrics, Khoo Teck across Asia and evaluate whether the Pediatric Acute Lung Injury
Puat-National University Childrens Medical Institute, National Univer- Consensus Conference risk stratification accurately predicts out-
sity Hospital, Singapore. come in PARDS.
6
Department of Pediatrics, Sarawak General Hospital, Kuching, Malaysia. Design: A multicenter, retrospective, descriptive cohort study.
7
Pediatric Intensive Care Unit, Beijing Childrens Hospital, Capital Medi- Setting: Ten multidisciplinary PICUs in Asia.
cal University, Beijing, China.
Patients: All mechanically ventilated children meeting the Pediat-
8
Division of Pediatric Critical Care, Department of Pediatrics, King Chul-
alongkorn Memorial Hospital, Bangkok, Thailand. ric Acute Lung Injury Consensus Conference criteria for PARDS
9
Pediatric Department, Ramathibodi Hospital, Mahidol University, Bang- between 2009 and 2015.
kok, Thailand. Interventions: None.
10
Department of Pediatrics, University Malaya Medical Centre, University Measurements and Main Results: Data on epidemiology, ven-
of Malaya, Kuala Lumpur, Malaysia.
tilation, adjunct therapies, and clinical outcomes were col-
11
Childrens Hospital of Chongqing Medical University, Chongqing, China.
lected. Patients were followed for 100 days post diagnosis of
12
Center for Quantitative Medicine, Duke-NUS Medical School, Singapore.
PARDS. A total of 373 patients were included. There were 89
Supplemental digital content is available for this article. Direct URL citations
appear in the printed text and are provided in the HTML and PDF versions (23.9%), 149 (39.9%), and 135 (36.2%) patients with mild,
of this article on the journals website (http://journals.lww.com/ccmjournal). moderate, and severe PARDS, respectively. The most com-
Supported, in part, by the Khoo Pilot Research Award (from the Estate of mon risk factor for PARDS was pneumonia/lower respiratory
Tan Sri Khoo Teck Puat). tract infection (309 [82.8%]). Higher category of severity of
Presented, in part, at the Society of Critical Care Medicines (SCCM) PARDS was associated with lower ventilator-free days (22
46th Critical Care Congress, Honolulu, Hawaii, January 21-25, 2017.
[1725], 16 [023], 6 [019]; p < 0.001 for mild, moderate,
Dr. Wong disclosed that this study was funded by the Khoo Pilot Research
Award (from the Estate of Tan Sri Khoo Teck Puat, Singapore). Fund money and severe, respectively) and PICU free days (19 [1124], 15
was used solely for the purposes of the study and none were paid to the [022], 5 [020]; p < 0.001 for mild, moderate, and severe,
authors or the institution. Dr. Lee received funding from KK Womens and
Childrens Hospital. The remaining authors have disclosed that they do
respectively). Overall PICU mortality for PARDS was 113 of
not have any potential conflicts of interest. 373 (30.3%), and 100-day mortality was 126 of 317 (39.7%).
Address requests for reprints to: Judith Ju-Ming Wong, MBBCh BAO, After adjusting for site, presence of comorbidities and severity
MRCPCH, Department of Pediatrics, Childrens Intensive Care Unit, of illness in the multivariate Cox proportional hazard regression
Level 2 Childrens Tower, KK Womens and Childrens Hospital, 100
Bukit Timah Road, 229899 Singapore. E-mail: Judith.wjm@gmail.com model, patients with moderate (hazard ratio, 1.88 [95% CI,
Copyright 2017 by the Society of Critical Care Medicine and Wolters 1.033.45]; p = 0.039) and severe PARDS (hazard ratio, 3.18
Kluwer Health, Inc. All Rights Reserved. [95% CI, 1.68, 6.02]; p < 0.001) had higher risk of mortality
DOI: 10.1097/CCM.0000000000002623 compared with those with mild PARDS.

Critical Care Medicine www.ccmjournal.org 1

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Wong et al
Conclusions: Mortality from PARDS is high in Asia. The Pedi-
atric Acute Lung Injury Consensus Conference definition of
PARDS is a useful tool for risk stratification. (Crit Care Med
2017; XX:0000)
Key Words: acute hypoxemic respiratory failure; acute lung injury;
children; mortality; pediatric intensive care units
T
here are marked differences in mortality rates in pediatric
acute respiratory distress syndrome (ARDS) around the
world (1). In Asia, mortality rates range from 44% to 75%
(13). This contrasts with the lower mortality rates (1735%)
reported in North America, Europe, and Australia-New Zealand
(46). A recent meta-analysis of pediatric ARDS showed that
studies performed in Asia had a higher overall mortality (51.0%;
95% CI, 41.562.7%) compared with those performed in the
Western hemisphere (27.3%; 95% CI, 22.333.5%) (7). Reasons
postulated for this difference were differences in resources, case
mix, socioeconomic conditions, and management strategies.
There remains a paucity of description of the epidemiology of
pediatric ARDS across multiple centers/countries in Asia. This
current gap in epidemiologic data is a barrier for investigation of
plausible reasons for the difference in pediatric ARDS mortality
rates in Asia compared with other regions of the world.
In 2015, the Pediatric Acute Lung Injury Consensus Conference
(PALICC) developed a pediatric specic denition for acute respi-
ratory distress syndrome (PARDS) (8). The PARDS definition
included: (1) hypoxemia with oxygenation index (OI) 4 or oxy-
genation saturation index (OSI) 5; (2) new radiological lung infil-
trates; (3) occurred within 7 days of a known clinical insult; and
(4) not explained by cardiac failure or fluid overload. This defini-
tion also allowed children with congenital cyanotic heart disease,
chronic lung disease and left ventricular dysfunction to be included
as long as they fulfilled the criteria above and the acute deteriora-
tion in oxygenation and pulmonary infiltrates cannot be explained
by their pre-existing diseases. Perinatal lung disease was excluded.
However, to date, a comprehensive validation of this definition is
lacking. Given the current limitations in the medical literature, we
undertook this multicenter retrospective study to 1) determine the
epidemiology of PARDS in Asia, 2) describe the mechanical ventila-
tion (MV) strategies and adjunct therapies in children with PARDS,
and 3) evaluate whether the newly proposed PALICC risk stratifica-
tion categories accurately predict clinical outcomes in PARDS.
MATERIALS AND METHODS
This is a retrospective study of children with PARDS admitted
to PICUs in the Pediatric Acute and Critical Care Asian Medi-
cine Network (PACCMAN) centers. PACCMAN is a collabora-
tion network formed in 2016 by dedicated pediatric intensivists
from Asia with the aims of sharing experience, developing best
practices, and promoting research within the region. This study
was approved by all participating hospitals institutional review
boards, and waiver of consent was granted in all sites.
Patients who fulfilled the PALICC criteria for PARDS over
the study period 20092015 were included. A list of patients was
2 www.ccmjournal.org XXX 2017 Volume XX Number XXX
Copyright 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
generated using International Classification of Diseases (International
Classification of Diseases, 9th Edition, Clinical Modification [before
2012] or International Classification of Diseases, 10th Edition,
Australian Modification [from 2012 onward]) diagnostic codes,
discharge diagnosis with keywords of ARDS or acute lung injury
(ALI), or by manually screening through the PICU registry at the
respective centers. Patients were included if they met the inclusion/
exclusion criteria described below. A secure online central database
using the Research Electronic Data Capture system was developed
by the main coordinating center in Singapore and was accessible
to all site investigators (9). This was used for remote multisite data
entry and centralized data management.
Management of PARDS among centers was at the discretion
of individual sites and physicians. All data were kept secure fol-
lowing local regulations. Data were then merged and analyzed
at the coordinating site.
Patients
We included patients 1 month to 18 years old who fulfilled the
PALICC definition for PARDS and intubated (8). Patients on
noninvasive ventilation (NIV) were excluded. Premature neo-
nates with corrected age less than 35 weeks, neonates being cared
for in the neonatal ICU and neonates deemed to have perina-
tal lung disease were excluded. Multiple organ dysfunction was
defined as more than one extrapulmonary organ dysfunction
according to the International Pediatric Sepsis Consensus Con-
ference criteria for each organ dysfunction (10).
Data Collection
The data collection form was adapted from a previous single-
center pediatric ARDS study (2). Data extracted included demo-
graphics, severity scores (Pediatric Index of Mortality 2 [PIM
2] score and Pediatric Logistic Organ dysfunction score), pres-
ence of organ dysfunction, MV data, adjunct PARDS therapies,
and PICU supportive therapies. MV data included ventilation
mode, peak inspiratory pressures (PIPs), positive end-expi-
ratory pressure (PEEP), mean airway pressure (MAP), tidal
volume (TV), and Fio2 for days 17 of PARDS. For standard-
ization, routine morning blood gasses (measured at 6:00 am to
8:00 am) and corresponding MV settings were recorded on each
day of PARDS. Patients were classified into mild, moderate, and
severe groups according to the PALICC oxygenation index (OI)
or OSI criteria on day 1 of PARDS. Conventional MV referred
to both pressure-controlled and volume-controlled ventilation.
Driving pressure was the difference between PIP and PEEP. 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
Primary outcome was 100-day mortality. Patients with 100-
day mortality were patients who died within 100 days from
PARDS diagnosis. In survivors, the most recent hospital-
wide medical records were retrieved and the last hospital visit
(inpatient or outpatient) was taken as the last date of contact.
If this occurred beyond 100 days, the patient was analyzed as

a survivor. Patients who were transferred to another medical
facility or lost to follow-up (last date of contact prior to 100 d)
were censored. Secondary outcomes included PICU mortality,
28-day ventilator-free days (VFDs), and 28-day ICU-free days
(IFDs). VFD is defined as days alive and free from invasive MV
up to 28 days. IFD is defined as days alive and discharged from
the PICU up to 28 days. This is to eliminate mortality as a com-
peting interest in evaluating MV and PICU duration.
Statistical Analysis
Categorical variables were presented as frequency with corre-
sponding proportion. Continuous variables were presented as
mean (sd) or as median (interquartile range [IQR]) as appro-
priate depending on distribution of data. Differences between
categorical and continuous variables between PARDS severity
were tested using the chi-square test and Mann-Whitney U
test, respectively. Hundred-day survival rate based on severity
groups were plotted using Kaplan-Meier model and were com-
pared using log-rank test. Both univariate and multivariate
Cox proportional hazard (CPH) regression model were used
to quantify association between 100-day mortality and other
covariates (site, presence of comorbidities, and severity of ill-
ness [PIM 2 score]). Association from CPH was characterized
as hazard ratio (HR) with corresponding 95% CI. VFD and
IFD were also analyzed with respect to PARDS severity groups.
Statistical significance was taken as p value of less than 0.05 for
all tests. SAS version 9.3 software (SAS Institute, Cary, NC) was
used for the analysis.
RESULTS
Characteristics of Patients
Data were entered for 438 patients with PARDS between 2009
and 2015 from 10 multidisciplinary PICUs (Supplementary
Table 1, Supplemental Digital Content 1, http://links.lww.
com/CCM/C774). However, after data verification, 427 were
confirmed to fulfill the PALICC definition. There were 54 of
427 patients (12.6%) on NIV on day 1 of PARDS and thus
excluded. Hence, a total of 373 patients were included in this
study (Supplementary Fig. 1, Supplemental Digital Content 2,
http://links.lww.com/CCM/C775; legend, Supplemental Digi-
tal Content 1, http://links.lww.com/CCM/C774).
There were 89 of 373 (23.9%), 149 of 373 (39.9%), and
135 of 373 (36.2%) patients with mild, moderate, and severe
PARDS, respectively (Table 1). The median OI and OSI were
12.8 (8.219.6) and 10.3 (6.816.1), respectively. Pneumonia/
lower respiratory tract infection (309/373 [82.8%]) was the
most common risk factor for PARDS.
MV and Adjunct Therapies in PARDS
On day 1 of PARDS, 309 of 373 (82.8%) were supported on
conventional MV (Table 2). Over the duration of PARDS, the
severe and moderate groups received high-frequency ventila-
tion more frequently compared with the mild group (66/135
[48.9%], 45/149 [30.2%], and 10/89 [11.2%], respectively;
[p >0.001]). Patients with greater severity of PARDS were
Critical Care Medicine www.ccmjournal.org 3
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Feature Article
ventilated with higher PIP throughout the first 7 days (Fig. 1A).
These patients also had higher driving pressures throughout the
first 7 days (Fig. 1D). However, there were no differences in TV
between the severity groups of PARDS (Fig. 1E). Approximately
one fifth (68/309 [22.0%]) of patients were ventilated with high
PIP (> 28cm H2O). Compared with patients exposed to PIP less
than 28cm H2O, patients ventilated with high PIP had reduced
VFD and IFD (11.0 [0.021.0] vs 19.0 [0.023.0] d; p = 0.0125
and 9.0 [0.020.0] vs 17.0 [0.022.0]; p = 0.0235, respectively).
There was, however, no difference in PICU or 100-day mor-
tality between these two groups. Majority of patients (51/139
[63.3%]) were ventilated with high TVs (> 8mL/kg actual body
weight). However, high TV itself was not adversely associated
with any of the primary or secondary outcomes.
PEEP and MAP were observed to be higher with increasing
PARDS severity throughout the first 7 days (Figs. 1B and 1C).
Majority of patients were ventilated with PEEP less than 10cm
H2O regardless the severity of PARDS. Overall median Fio2
was high in our cohort (60 [5095] %), and there was step-
wise increase across the severity groups. However, there was no
association between the trend of Fio2 and mortality in the three
severity groups.
Among those with arterial blood gas measurements
(311/373[83.4%]), pH and Pao2 worsened with increasing
severity of PARDS but not Paco2 (Table2). Distribution of pH,
Pao2, and Paco2 throughout the 7 days showed a normal dis-
tribution with mean (sd) of 7.4 (0.11), 83.25 (37.10) mm Hg,
and 48.1 (16.9) mm Hg, respectively (Supplementary Fig. 2,
Supplemental Digital Content 3, http://links.lww.com/CCM/
C776; legend, Supplemental Digital Content 1, http://links.
lww.com/CCM/C774). Oxygen saturation distribution, as
expected, was skewed with median (IQR) as 96.0 (92.099.0)
% (Supplement Digital Content - Figure 2).
The commonly used adjunct therapies were diuretics
(252/373 [67.6%]), blood product transfusions [245/373
(65.7%)], and systemic steroids (192/373 [51.5%]) (Table2).
A total of 12 of 373 (3.2%) patients required extracorporeal
membrane oxygenation (ECMO). Of these, 9 of 12 (75.0%)
were on veno-arterial ECMO with a mortality of seven of nine
(77.8%). The remainder, three of 12 (25.0%) were on veno-
venous ECMO, and all survived.
Outcomes
Overall PICU mortality for PARDS was 113 of 373 (30.3%).
There was a stepwise increase in mortality rate across the severity
groups (Table 3). After PICU discharge, an additional 14 patients
died. Twenty patients were transferred to another hospital, and
36 patients were lost to follow-up after discharge from the PICU
(censored). Thus, 100-day mortality was 126 of 317 (39.7%).
After controlling for site, presence of comorbidities and PIM 2
score in the multivariate CPH regression model, 100-day mor-
tality stratied according to the PARDS severity groups dem-
onstrated an adjusted HR (95% CI) of 1.88 (1.033.45) in the
moderate group and 3.18 (1.686.02) in the severe group. The
Kaplan-Meier curves showed a stepwise decrease in survival in
the moderate and severe groups compared with the mild group
Wong et al

TABLE 1. Characteristics of Patients With Pediatric Acute Respiratory Distress Syndrome

Mild PARDS, Moderate PARDS, Severe PARDS,
Characteristics (n = 89) (n = 149) (n = 135) All, (n = 373) p

Age (yr), median (IQR) 1.0 (0.34.3) 1.0 (0.34.1) 2.3 (0.75.5) 1.4 (0.45.1) 0.008
Gender, male, n (%) 52 (58.4) 77 (51.7) 67 (49.6) 196 (52.5) 0.419
Weight (kg), median (IQR) 8.4 (4.714) 7.8 (515) 11 (720) 9 (5.517) 0.001
Pediatric Index of Mortality 6.9 (2.813.7) 7.4 (3.518.3) 9.8 (4.430) 8.3 (3.821.5) 0.038
2 score, median (IQR)
Pediatric Logistic Organ 3 (112) 3 (1, 12) 11 (216) 10 (113) 0.048
Dysfunction score,
median (IQR)
Presence of comorbidities, 36 (40.4) 77 (51.7) 84 (62.2) 197 (52.8) 0.006
n (%)
Risk factors for PARDS, n (%)
Pneumonia 73 (82.0) 124 (83.2) 112 (83.0) 309 (82.8) 0.971
Sepsis 16 (18.0) 35 (23.5) 46 (34.1) 97 (26.0) 0.018
Aspiration 6 (6.7) 8 (5.4) 6 (4.4) 20 (5.4) 0.757
Transfusion 1 (1.1) 1 (0.7) 3 (2.2) 5 (1.3) 0.514
Trauma 0 (0) 1 (0.7) 2 (1.5) 3 (0.8) 0.465
Near drowning 5 (3.5) 6 (4.0) 3 (2.2) 14 (3.8) 0.414
Others 4 (4.5) 17 (11.4) 14 (10.4) 35 (9.4) 0.185
Bacteremiaa, n (%) 9 (10.1) 30 (20.1) 22 (16.3) 61 (16.4) 0.129
Organ dysfunction, n (%)
Cardiovascular 13 (14.6) 45 (30.2) 54 (40.0) 112 (30.0) < 0.001
Neurologic 4 (4.5) 12 (8.1) 12 (8.9) 28 (7.5) 0.450
Hematologic 9 (10.1) 35 (23.5) 49 (36.3) 93 (24.9) < 0.001
Renal 14 (15.7) 28 (18.8) 27 (20.0) 69 (18.5) 0.718
Hepatic 14 (15.7) 24 (16.1) 34 (25.2) 72 (19.3) 0.095
Multiple organ 20 (22.5) 54 (36.2) 68 (50.4) 142 (38.1) < 0.001
dysfunction
Inotropesa, n (%) 43 (48.3) 84 (56.4) 101 (74.8) 228 (61.1) < 0.001
Continuous renal replace- 3 (3.4) 10 (6.7) 13 (9.6) 26 (7.0) 0.195
ment therapya, n (%)
Pao2-to-Fio2 ratio, median 204.0 (177.0241.6) 126.8 (103.1155.3) 71.8 (60.597.3) 117.8 (78.5172.9) < 0.001
(IQR)
O2 saturation-to-Fio2 ratio, 200.0 (166.7245.0) 156.7 (122.5180.0) 100.0 (91.0132.0) 146.7 (100.0186.0) < 0.001
median (IQR)
Oxygenation index, median 5.9 (4.96.7) 11.3 (9.813.6) 25.2 (18.533.2) 12.8 (8.219.6) < 0.001
(IQR)
Oxygen saturation index, 5.52 (4.57.2) 9 (7.011.2) 17.1 (14.122.2) 10.3 (6.816.1) < 0.001
median (IQR)
IQR = interquartile range, PARDS = pediatric acute respiratory distress syndrome.
On any day throughout the PICU stay.
a

Oxygenation index = (mean airway pressure Fio2 ratio)/Pao2.

Oxygen saturation index = (mean airway pressure Fio2 ratio)/oxygen saturation.

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 Feature Article

TABLE 2. Ventilator Management and Adjunct Therapies in Pediatric Acute Respiratory

Distress Syndrome
Mild PARDS, Moderate PARDS, Severe PARDS,
Characteristics (n = 89) (n = 149) (n = 135) All, (n = 373) p

Ventilator settings, day 1 PARDS

Ventilator mode, n (%) < 0.001
Pressure-controlled ventilation 82 (92.1) 127 (85.2) 90 (66.7) 299 (80.2)
Volume-controlled ventilation 3 (3.4) 5 (3.4) 2 (1.5) 10 (2.7)
Airway pressure release 3 (3.4) 13 (8.7) 22 (16.3) 38 (10.2)
ventilation
High-frequency oscillatory 0 (0.0) 4 (2.7) 21 (15.6) 25 (6.7)
ventilation
Neurally Adjusted Ventilatory 1 (1.1) 0 (0.0) 0 1 (0.3)
Assist
Fio2, median (IQR) 45 (40, 60) 60 (50, 80) 95 (70, 100) 60 (50, 95) < 0.001
Peak inspiratory pressure (cm 21 (19, 25) 24 (20, 27) 28 (24, 32) 24 (20, 28) < 0.001
H2O)a, median (IQR)
Positive end-expiratory pressure 6 (5, 7) 7 (6, 8) 9.5 (7, 12) 7 (6, 9) < 0.001
(cm H2O)a, median (IQR)
Driving pressure (cm H2O)a, 15 (14, 20) 18 (15, 19.5) 20 (16, 23) 17 (14, 20) 0.0002
median (IQR)
Mean airway pressure (cm H2O), 11.2 (10.15, 13.0) 13.6 (11.3, 16.0) 19.0 (16.0, 24.0) 14.0 (11.4, 18.0) < 0.001
median (IQR)
Tidal volume, mL/kg actual body 8.9 (6.9, 10.3) 8.4 (6.2, 10.3) 10.0 (5.1, 10.9) 9.0 (6.3, 10.6) 0.905
weighta, median (IQR)
Gas exchange, day 1 PARDS
No. of patients with arterial blood 76 (85.4) 111 (74.5) 124 (91.9) 311 (83.4) 0.001
gas, n (%)
pH, median (IQR) 7.35 (7.28, 7.41) 7.33 (7.23, 7.4) 7.31 (7.21, 7.4) 7.33 (7.23, 7.4) 0.064
Pao2 (mm Hg), median (IQR) 87.6 (69.6, 125.1) 70.7 (57.2, 95) 61.2 (54.4, 70.9) 69.2 (57.2, 91) < 0.001
Paco2 (mm Hg), median (IQR) 41.9 (35.5, 55.8) 48.9 (40.5, 56.8) 47.9 (38.4, 60.3) 47.2 (37.7, 57.5) 0.011
Pulse oximetry (%), median (IQR) 98 (95, 100) 95 (91, 98) 93 (87, 98) 95 (91, 98) < 0.001
Adjunct therapies , n (%)
b

Diuretics 42 (47.2) 99 (66.4) 111 (82.2) 252 (67.6) < 0.001

Blood product transfusion 42 (47.2) 96 (64.4) 107 (79.3) 245 (65.7) < 0.001
Systemic steroids 40 (44.9) 81 (54.4) 71 (52.6) 192 (51.5) 0.353
Beta agonists 44 (49.4) 76 (51.0) 67 (49.6) 187 (50.1) 0.9625
Neuromuscular blockade 15 (16.9) 57 (38.3) 78 (57.8) 150 (40.2) < 0.001
Prone position 23 (25.8) 43 (28.9) 28 (20.7) 94 (25.2) 0.286
Pulmonary vasodilator 7 (7.9) 26 (17.4) 31 (23.0) 64 (17.2) 0.014
Surfactant 0 (0) 3 (02.0) 5 (03.7) 8 (02.1) 0.172
Extracorporeal membrane 0 (0) 3 (02.0) 9 (06.7) 12 (03.2) 0.062
oxygenation
IQR = interquartile range, PARDS = pediatric acute respiratory distress syndrome.
Only for patients on pressure-controlled and volume-controlled ventilation.
a

Adjunct therapies used throughout the course of pediatric acute respiratory distress syndrome up to 28 d or PICU discharge whichever earlier.
b

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Wong et al

Figure 1. Ventilation variables throughout the first 7 days of pediatric acute respiratory distress syndrome; (A) peak inspiratory pressure over 7 days, (B)
mean airway pressure over 7 days, (C) positive end expiratory pressure over 7 days, (D) driving pressure over 7 days, (E) tidal volume over 7 days

(Fig. 2). A sensitivity analysis conducted to evaluate the PARDS
classification according to OI and OSI classification showed that
both oxygenation indices were good at discriminating mortality.
OI was, however, more robust with better differentiation of the
moderate and severe groups (Figs. 2B and 2C).
The overall VFD and IFD were 16.0 (0.023.0) and 11.0
(6.022.0) days, respectively. There was a stepwise increase in
ventilator duration and PICU duration in increasing severity
groups (Table3). Correspondingly, there was also a reduction
in VFD and IFD in increasing severity groups. A sensitivity
analysis was conducted excluding patients on volume-con-
trolled mode (10/373 [2.7%]). The PIP, PEEP, MAP, Fio2, and
TV trend over 7 days remain unchanged. In this sensitiv-
ity analysis, results of the primary and secondary outcomes
remain unchanged.
DISCUSSION
This first multicenter study of PARDS in Asia demonstrated
that the PALICC criteria for stratification into mild, moderate,
and severe groups was associated with a stepwise decrease in

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TABLE 3. Outcomes of Patients by Severity of Pediatric Acute Respiratory Distress
Syndrome
Mild PARDS,
Outcomes (n = 89)
Ventilator-free days, median (IQR) 22 (1725)
Duration of invasive ventilation, median (IQR) 6 (39)
PICU free days, median (IQR) 19 (1124)
Duration of PICU stay, median (IQR) 9 (516)
PICU mortality, n (%) 11 (12.4)
100-d mortality, n (%)a 14 (18.7)
IQR = interquartile range, PARDS = pediatric acute respiratory distress syndrome.
a
Patients transferred or lost to follow up prior to 100 d were censored.
VFD and IFD with increase in short-term and intermediate-
term mortality. After adjusting for site, presence of comorbidi-
ties and severity of illness, patients with moderate and severe
PARDS had approximately two and three times increased risk
of dying, respectively, compared to children with mild PARDS.
Higher ventilatory pressures were associated with reduced VFD
and IFD, but we did not find any association between driving
pressures and TV with poor clinical outcomes.
The PICU mortality rate in this study (30.3%) is compa-
rable with the overall PARDS mortality reported by the recent
meta-analysis that included patients identified by the American-
European Consensus Conference or Berlin definition (7). To
date, there are only two retrospective studies using the PALICC
definition for mortality reporting and risk stratification (11, 12).
The first study (n = 254) showed that mild and moderate PARDS
groups had similar mortality (16.7% vs 18.6%, respectively),
but the severe PARDS group had significantly higher mortality
(37.0%) (11).The second study (n = 211) of PARDS in children
with pediatric allogeneic hematopoietic stem cell transplant
demonstrated that mortality increased with increasing sever-
ity (36.4%, 47.2%, and 75.4%; p < 0.001 in the mild, moderate
and severe groups, respectively) (12). Taken collectively with our
study, the predictive ability of the PALICC definition with mor-
tality based on severity groupings was fairly robust.
In children, the beneficial effects of low TV have not been
shown to be consistent. A retrospective study of 160 children
with ALI showed that a higher TV (10.21.7 vs. 8.11.4mL/
kg; p < 0.001) was associated with mortality (odds ratio, 1.59;
95% CI, 1.202.10; p < 0.001) (13). However, a meta-analysis
of mechanically ventilated children (n = 1756) including a sub-
group analysis of pediatric ALI/ARDS (n = 799) failed to show
any association between TV (up to 12mL/kg) and mortality
(14). The findings from our study echo the lack of association
between higher TV and mortality. As the predominant mode
of ventilation was pressure-limited, one would expect lower
TVs as lung injury worsened. TV, however, remained constant
across PARDS severity groups except on day 7 when the severe
group received lower TV. In this ventilation approach, TV did
not vary because the pressure limit was increased as lung com-
pliance (lung injury) worsened.
Critical Care Medicine www.ccmjournal.org 7
Copyright 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Feature Article
Moderate PARDS, Severe PARDS,
(n = 149) (n = 135) All, (n = 373) p
16 (023) 6 (019) 16 (023) < 0.001
10 (516) 11 (521) 9 (416) < 0.001
15 (022) 5 (020) 14 (022) < 0.001
12 (724) 13 (625) 11 (622) 0.010
46 (30.9) 56 (41.5) 113 (30.3) < 0.001
50 (39.1) 62 (54.4) 126 (39.7) < 0.001
Alveolar recruitment from the use of high PEEP is an open
lung strategy that leads to reduction in sheer stress during lung
over-inflation (15). A meta-analysis in adult ALI/ARDS showed
that the use of high PEEP was associated with improvements
in oxygenation (16). However, a subgroup analysis of ARDS
patients alone (n = 205) showed a reduction in mortality (risk
reduction [RR] 0.67; 95% CI, 0.480.95) with high PEEP.
Despite recommendations for the use of moderate levels of
PEEP (1015cm H2O) in severe PARDS, the levels of PEEP used
in pediatric studies remained relatively low (610cm H2O) (17,
18). Our study showed that higher levels of PEEP was used in
the moderate and severe PARDS groups, but even in the severe
category, it remained relatively low (median PEEP of 9.5 [7
12]). Instead, overall Fio2 in the entire cohort was relatively high
(median Fio2 of 60 [5095] %). This current practice in our
cohort suggests a preference for the use of Fio2 to treat hypox-
emia rather than PEEP which is not consistent with current
recommendations that emphasize minimizing Fio2 and using
PEEP effectively (8). However, the clinical impact of using high
Fio2 remains controversial (19, 20). We did not find any associa-
tion between higher Fio2 and mortality. We postulate that one
possible reason for this practice is the lack of established PEEP-
adjusted Fio2 values for different age groups/sizes in the pediat-
ric population and perhaps PEEP phobia.
A post hoc analysis of 3,562 adult ARDS patients demon-
strated that the individual beneficial changes in TV and PEEP
were due to mediation effects of driving pressure (21). Each
one sd increments in driving pressure (7cm H2O) conferred an
increased risk of mortality (RR, 1.4 [95% CI, 1.311.51]; p <
0.001). Driving pressure was also demonstrated to be indepen-
dently associated with mortality in a prospective observational
PARDS study (18). Our study showed no differences in driving
pressures across severity groups in our cohort (Fig. 1D) and no
association between higher driving pressures and mortality. It
is possible that this difference is because the prior study had a
lower proportion of pulmonary PARDS (54/84 [64.3%]) com-
pared with our study (309/373 [82.8%]). Further larger studies
are required to address this issue in a more robust manner.
This study is the first multicenter study on PARDS in Asia,
and it included a large cohort of patients. It provided data to
Wong et al

Figure 2. Kaplan-Meier curve for 100-day mortality based on (A) overall pediatric acute respiratory distress syndrome (PARDS) severity (B) oxygen-
ation index alone, and (C) oxygenation saturation index alone.

validate the recent PALICC definition for PARDS. Detailed
MV data over the first 7 days of PARDS allowed us to examine
the pattern of use and effect of each ventilation variable. We
also determined intermediate-term mortality (100-d mortal-
ity) which was higher than short-term mortality (PICU mor-
tality) indicating that PARDS has an impact on survival even
beyond the PICU stay. Data were verified by manual review
for gross inconsistencies at the coordinating center and cor-
rected prior to analysis. Despite the strengths, the results of this
study must be viewed in light of its limitations. First, patients
with PARDS were retrospectively identified and stratified.
Identifying PARDS especially in mild cases, by diagnostic
codes/keywords, may have led to under-recognition as many
patients were coded according to their underlying disease (e.g.,
pneumonia, sepsis) (22). With this limitation in mind, a man-
ual search of the PICU registry was conducted at centers which
could not reliably identify patients solely by diagnostic codes.
The retrospective design also precluded us from making any
cause-and-effect association. We can only surmise that there
was an association between ventilation strategy of higher TV,
higher Fio2, and relatively lower PEEP and higher mortality in
our cohort. Future trials are needed to investigate the impact of

8 www.ccmjournal.org XXX 2017 Volume XX Number XXX

Copyright 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

these MV strategies on improving mortality in PARDS. Second,
electronic medical records that facilitate patient identification
and data retrieval were only available at some participating
sites. Hence, these sites may have contributed data for a greater
number of patients and compared with other sites, leading to
selection bias. Sites were not mandated to recruit consecutive
patients throughout the 6-year study period. Third, MV strat-
egies and other interventions were not standardized between
centers. We attempted to control for this by including site as
a covariate in our multivariate analysis. The lack of data on
exact cause of death in nonsurvivors and development of new
morbidities in survivors is also another limitation of this study.
Last, results derived from data from these 10 centers may not
be representative of all centers across Asia.
CONCLUSION
This study demonstrates that PARDS carry a high mortal-
ity (30.1%) in Asia and that the severity groups of PARDS as
defined by the PALICC criteria are robust in risk stratification
with stepwise worsening of clinically significant outcomes
from mild to severe. Future therapeutic studies in PARDS
should consider using the PALICC risk classification to guide a
stepwise increase in management across the severity spectrum
of PARDS.
ACKNOWLEDGMENTS
We acknowledge the administrative support from Academic
Medicine Research Institute, Singhealth and Duke-NUS Medi-
cal School, and the National University of Singapore. We thank
the network team from Singapore Clinical Research Institute
for setup up and maintenance of the electronic data capture
system and website. We thank Ira M. Cheifetz (Duke Childrens
Hospital, Durham, NC) for critically appraising this article.
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