SHOCK, Vol. 53, No. 5, pp.

544–549, 2020

DEMOGRAPHICS, TREATMENTS, AND OUTCOMES OF ACUTE

RESPIRATORY DISTRESS SYNDROME: THE FOCUSED OUTCOMES
RESEARCH IN EMERGENCY CARE IN ACUTE RESPIRATORY DISTRESS
SYNDROME, SEPSIS, AND TRAUMA (FORECAST) STUDY

Seitaro Fujishima, * Satoshi Gando, †‡ Daizoh Saitoh, § Shigeki Kushimoto, jj

Hiroshi Ogura, ô Toshikazu Abe, # ** Atsushi Shiraishi, †† Toshihiko Mayumi, ‡‡
Junichi Sasaki, §§ Joji Kotani, jjjj Naoshi Takeyama, ôô Ryosuke Tsuruta, ##
Kiyotsugu Takuma, *** Norio Yamashita, ††† Shin-ichiro Shiraishi, ‡‡‡
Hiroto Ikeda, §§§ Yasukazu Shiino, jjjjjj Takehiko Tarui, ôôô Taka-aki Nakada, ###
Toru Hifumi, **** Yasuhiro Otomo, †††† Kohji Okamoto, ‡‡‡‡ Yuichiro Sakamoto, §§§§
Akiyoshi Hagiwara, jjjjjjjj Tomohiko Masuno, ôôôô Masashi Ueyama, ####
Satoshi Fujimi, ***** Kazuma Yamakawa, ***** and Yutaka Umemura ô, on behalf of
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JAAM FORECAST ARDS Study Group

*Center for General Medicine Education, Keio University School of Medicine, Japan; † Division of Acute
and Critical Care Medicine, Department of Anesthesiology and Critical Care Medicine, Hokkaido
University Graduate School of Medicine, Japan; ‡ Department of Acute and Critical Care Medicine,
Sapporo Higashi Tokushukai Hospital, Japan; §Division of Traumatology, Research Institute, National
Defense Medical College, Japan; jjDivision of Emergency and Critical Care Medicine, Tohoku University
Graduate School of Medicine, Japan; ôDepartment of Traumatology and Acute Critical Medicine, Osaka
University Graduate School of Medicine, Japan; #Department of General Medicine, Juntendo University,
Japan; **Health Services Research and Development Center, University of Tsukuba, Japan; †† Emergency
and Trauma Center, Kameda Medical Center, Japan; ‡‡ Department of Emergency Medicine, School of
Medicine, University of Occupational and Environmental Health, Japan; §§Department of Emergency and
Critical Care Medicine, Keio University School of Medicine, Japan; jjjjDivision of Disaster and Emergency
Medicine, Department of Surgery Related, Kobe University Graduate School of Medicine, Japan;
ôô
Advanced Critical Care Center, Aichi Medical University Hospital, Japan; ##Advanced Medical
Emergency & Critical Care Center, Yamaguchi University Hospital, Japan; ***Emergency & Critical Care
Center, Kawasaki Municipal Hospital, Japan; ††† Department of Emergency & Critical Care Medicine,
School of Medicine, Kurume University, Japan; ‡‡‡ Department of Emergency and Critical Care Medicine,
Aizu Chuo Hospital, Japan; §§§Department of Emergency Medicine, Trauma and Resuscitation Center,
Teikyo University School of Medicine, Japan; jjjjjjDepartment of Acute Medicine, Kawasaki Medical
School, Japan; ôôôDepartment of Trauma and Critical Care Medicine, Kyorin University School of
Medicine, Japan; ###Department of Emergency and Critical Care Medicine Chiba University Graduate
School of Medicine, Japan; ****Department of Emergency and Critical Care Medicine, St. Luke’s
International Hospital, Japan; †††† Trauma and Acute Critical Care Center, Medical Hospital, Tokyo
Medical and Dental University, Japan; ‡‡‡‡ Department of Surgery, Center for Gastroenterology and Liver
Disease, Kitakyushu City Yahata Hospital, Japan; §§§§Emergency and Critical Care Medicine, Saga
University Hospital, Japan; jjjjjjjjCenter Hospital of the National Center for Global Health and Medicine,
Japan; ôôôôDepartment of Emergency and Critical Care Medicine, Nippon Medical School, Japan;
####
Department of Trauma, Critical Care Medicine, and Burn Center, Japan Community Healthcare
Organization, Chukyo Hospital, Japan; and *****Division of Trauma and Surgical Critical Care, Osaka
General Medical Center, Japan

Received 13 Apr 2019; first review completed 6 May 2019; accepted in final form 11 Jul 2019

Address reprint requests to Seitaro Fujishima, MD, Center for General Medicine
Education, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku,
Tokyo 160-8582, Japan. E-mail: fujishim@keio.jp
This study was funded by the Japanese Association for Acute Medicine.
SF reports grants and personal fees from Asahi Kasei Japan Co., personal fees
from Thermofisher Diagnostics Co., grants from Chugai Pharmaceuticals Co. Ltd.,
grants from Daiichi-Sankyo Co., Ltd., grants from Pfizer, Inc., grants from Shionogi
& Co., Ltd., outside the submitted work; SG reports personal fees from Asahi Kasei
America Cooperation, personal fees from Asahi Kasei Japan Cooperation, outside
the submitted work; TA reports grants from Grant-in-Aid for Challenging Explor-
atory Research JP 16K15388, personal fees from Asahi Kasei Pharma Co., personal
fees from Japan Blood Products Organization, personal fees from Janssen Phar-
maceutical K.K., outside the submitted work; SS reports personal fees from
Nobelpharma Co., outside the submitted work; YO reports personal fees from
Asahi Kasei Japan Corporation, outside the submitted work; YS reports personal
fees from Japan Blood Product Corporation, personal fees from Asahi Kasei Japan
Corporation, outside the submitted work; YU reports personal fees from Asahi
Kasei Pharma Corporation, personal fees from Japan blood products organization,
outside the submitted work. The remaining authors have disclosed that they do not
have any conflicts of interest.
Supplemental digital content is available for this article. Direct URL citation
appears in the printed text and is provided in the HTML and PDF versions of this
article on the journal’s Web site (www.shockjournal.com).
DOI: 10.1097/SHK.0000000000001416
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544
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SHOCK MAY 2020 EPIDEMIOLOGY, TREATMENTS, AND OUTCOMES OF ARDS 545
ABSTRACT—Purpose: Acute respiratory distress syndrome (ARDS) remains a major cause of death. Epidemiology
should be continually examined to refine therapeutic strategies for ARDS. We aimed to elucidate demographics, treatments,
and outcomes of ARDS in Japan. Methods: This is a prospective cohort study for ARDS. We included adult patients
admitted to intensive care units through emergency and critical care departments who satisfied the American–European
Consensus Conference (AECC) acute lung injury (ALI) criteria. In addition, the fulfillment of the Berlin definition was
assessed. Logistic regression analyses were used to examine the association of independent variables with outcomes.
Results: Our study included 166 patients with AECC ALI from 34 hospitals in Japan; among them, 157 (94.6%) fulfilled the
Berlin definition. The proportion of patients with PaO2/FIO2  100, patients under invasive positive pressure ventilation
(IPPV), and in-hospital mortality was 39.2%, 92.2%, and 38.0% for patients with AECC ALI and 38.9%, 96.8%, and 37.6%
for patients with Berlin ARDS, respectively. The area of lung infiltration was independently associated with outcomes of
ARDS. Low–mid-tidal volume ventilation was performed in 75% of patients under IPPV. Glucocorticoid use was observed in
54% patients, and it was positively associated with mortality. Conclusions: Our study included a greater percentage of
patients with ARDS with high severity and found that the overall mortality was 38%. The management of ARDS in Japan was
characterized by high the utilization rate of glucocorticoids, which was positively associated with mortality.
KEYWORDS—Acute lung injury, area of lung infiltration, chest X-rays, glucocorticoid, positive end-expiratory pressure

INTRODUCTION We performed a prospective multicenter cohort study for

Acute respiratory distress syndrome (ARDS) is a rapidly
progressive hypoxic condition with bilateral infiltration on
chest roentgenogram, which develops after various diseases
or insults, and is characterized by increased microvascular
permeability and diffuse alveolar damage. A mortality rate
higher than 50% was initially observed for ARDS (1), and a
large retrospective analysis of ARDS in the United States
reported a mortality reduction between 1999 and 2013 (2).
A prospective worldwide cohort study of ARDS as per the
Berlin definition reported an in-hospital mortality rate of 40.0%
(LUNG SAFE study) (3). However, as the LUNG SAFE study
revealed, significant geo-economic variations (4), regional
variations in underlying diseases/predisposing conditions,
quality of care, social health systems, and so on can affect
the outcome of patients with ARDS. Previous studies also
revealed the influence of racial differences in ARDS (5–7).
Thus, the present situations in individual areas or countries,
including Japan, must be scrutinized for clinicians to refine
their therapeutic strategy for ARDS.
The definition of ARDS by the American–European Consen-
sus Conference (AECC) was revised to the Berlin definition in
2012 (8). This revision, especially the introduction of PaO2
measurements with positive end-expiratory pressure (PEEP)
of 5 cmH2O may affect patient population and epidemiology.
However, only few prospective studies from this point of view
have been published. Furthermore, the Berlin definition should
be continuously validated in various clinical settings to compare
it appropriately with the previous AECC definition (3, 9–12).
Bilateral infiltration on chest roentgenogram is prerequisite
for diagnosing ARDS, and its qualitative recognition has been
incorporated in the successive ARDS definitions. By contrast,
although chest roentgenogram has been used intuitively to
speculate severity at the bedside, and attempts have been made
to show its objective efficacy (13), the inclusion of its quanti-
tative criteria was passed on in the AECC and Berlin definitions
because of its poor reliability (7, 14). However, a recent report
showed the efficacy of chest roentgenogram in assessing
severity using digital imaging (15). In this study, we assessed
an area of lung infiltration on chest roentgenogram with a
semiquantitative scoring method that is used in lung injury
score by Murray et al. to assess its quantitative efficacy and
correlation with outcomes (16).
ARDS, diagnosed as per the AECC and Berlin definitions, as a
part of the Focused Outcomes Research in Emergency Care in
Acute Respiratory Distress Syndrome, Sepsis, and Trauma
(FORECAST) study to comprehensively describe the demo-
graphics, quality of care, and outcomes in Japan.
METHODS
Study population
This prospective multicenter cohort study was registered at the University
Hospital Medical Information Network Clinical Trial Registry (UMIN-CTR ID:
UMIN000019701). We included adult patients (16 years old) who were
admitted to the intensive care unit through the emergency and critical care
departments of participating hospitals and who satisfied all of the following
criteria: (1) onset within 1 week after predisposing diseases/injuries, (2)
bilateral infiltration on chest roentgenogram, PaO2/FIO2 300 with any PEEP,
and (4) no clinical signs of overt heart failure or overhydration (8, 12). Among
these criteria, (2) and (4) were components of both the AECC and Berlin
definitions; (1) was a component of Berlin definition; and (3) was a component
of AECC definition. We considered the patient population selected by the
current inclusion criteria as fulfilling the ALI criteria of the AECC definition.
Patients were diagnosed as fulfilling the Berlin definition when PaO2/FIO2 was
300 with PEEP at  cmH2O. We excluded patients who were judged unsuit-
able for this study by the principal investigator.
We collected data using a web-based database (the Internet Data and
Information Center for Medical Research, which is a division of the University
Hospital Medical Information Network). This study collected patients’ data,
including demographics, vital signs, laboratory data, time to fulfill Berlin
ARDS definition if it occurred, artificial ventilation/oxygen therapy, and
pharmacological treatment. Chest roentgenogram was evaluated by an expert
emergency and critical care physician. Primary outcome was in-hospital
mortality. Secondary measures included percentage of patients with Berlin
ARDS, ventilator-free days, and ICU-free days.
We recruited patients from JAAM interim committee hospitals and JAAM
board-approved hospitals that applied to the present study (Supplementary file,
Supplemental Digital Content, http://links.lww.com/SHK/A920). All institutes
and hospitals obtained approval from their ethics committees and recruited
patients. The incidence or distribution of demographic indices, severity of
hypoxia, area of lung infiltration on chest roentgenogram, scores, organ
dysfunction, artificial ventilation, pharmacological treatments, and outcomes
were analyzed in all patients with AECC ALI and Berlin ARDS. Each organ
dysfunction was defined as a sequential organ failure assessment (SOFA) score
2 (17).
Statistical analyses
Pearson’s chi-square test was used to compare categorical data, and the
Mann–Whitney U test was used to compare medians between two subgroups.
To evaluate the correlation of variables with survival outcomes, univariate and
multivariate logistic regression analyses were applied. All statistical analyses
were conducted using IBM SPSS statistics (V24) software (International
Business Machines Corp., NY), and the level of significance was set at
P < 0.05 or Bonferroni-adjusted P values.

Copyright © 2020 by the Shock Society. Unauthorized reproduction of this article is prohibited.
546 SHOCK VOL. 53, No. 5 FUJISHIMA ET AL.

167 patients in ICU registered

(1)Onset within 1 week after predisposing diseases/injuries
(2)Bilateral infiltration on chest roentgenogram
(3)PaO2/FIO2 ratio of ≤300 on any PEEP
(4)No clinical signs of overt heart failure or overhydration

1 patient was removed as a duplicate case

166 patients with AECC ALI included

136 patients fulfilled the definition at the time of inclusion

21 patients were later shown to meet the definition

157 patients fulfilled the Berlin ARDS definition

(PaO2/FIO2 ratio of ≤300 on PEEP ≥5 cmH2O)

FIG. 1. Flow diagram for the patient enrollment process. AECC ALI indicates American–European Consensus Conference definition of acute lung injury,
Berlin; ARDS, Berlin definition of acute respiratory distress syndrome; PEEP, positive end-expiratory pressure.

RESULTS TABLE 1. Demographics of patients with AECC ALI and Berlin ARDS
Between April 1, 2016 and July 31, 2017, 167 patients were Variables AECC ALI Berlin ARDS
registered in the database from 34 hospitals. The patients’ Patient, n 166 157
enrollment process is summarized in Figure 1. One patient Age, y, median (IQR) 73.0 (60.0–79.0) 73.0 (60.0–78.0)
was removed as a duplicate case, and we finally included 166 Sex: male, n (%) 106 (63.9) 102 (65.0)
BMI, median (IQR) 22.6 (19.7–25.0) 22.6 (20.0–25.1)
patients with AECC ALI in the analysis. Among them, 136 Smoking history, yes 67/163 (41.1) 66/154 (42.9)
patients (81.9%) simultaneously fulfilled the Berlin definition (%)
at the time of inclusion. Additional 21 patients (12.7%) were CCI, median (IQR) 1.0 (0–2.0) 1.0 (0–2.0)
Etiology: indirect, n (%) 69 (41.6) 64 (40.8)
later shown to meet the Berlin definition during the PaO2/FIO2, median 118.9 (76.7–167.4) 122.0 (76.7–167.8)
observation period. (IQR)
Severity, n (%)
Table 1 summarizes the demographics of patients with 200 < PaO2/FIO2 23 (13.9) 22 (14.0)
AECC ALI and Berlin ARDS. Males comprised 64% of 300 (mild)
ALI patients. The patients displayed various etiologies, but 100< PaO2/FIO2 78 (47.0) 74 (47.1)
200 (moderate)
pneumonia of diverse origin accounted for 79.4% of direct PaO2/FIO2 100 65 (39.2) 61 (38.9)
injuries, and sepsis accounted for 75.4% of indirect injuries. In (severe)
Area of lung infiltration 3.0 (2.0–3.0) 3.0 (2.0–3.0)
total, 86% of patients had a PaO2/FIO2 ratio 200. ALI patients on chest
often had comorbidities with other organ dysfunctions, most roentgenogram,
frequently neurological and cardiovascular dysfunctions. The median (IQR)
Scores
demographics of patients with Berlin ARDS and AECC ALI SIRS score, median 3.0 (2.0–3.0) 3.0 (2.0–3.0)
were almost the same. (IQR)
SOFA score, median 9.0 (7.0–13.0) 9.0 (7.0–13.0)
The univariate analysis revealed that smoking history, the (IQR)
Charlson comorbidity index (CCI), PaO2/FIO2, the area of lung Nonpulmonary SOFA 6.0 (3.0–9.0) 6.0 (4.0–10.0)
infiltration on chest roentgenogram, SOFA score, nonpulmonary score, median
(IQR)
SOFA score, and acute physiology and chronic health evaluation APACHE II score, 24.0 (19.0–29.0) 25.0 (20.0–29.0)
(APACHE) II score were positively correlated with mortality median (IQR)
(Table 2). We performed a multivariate analysis further with six Organ dysfunction (SOFA score 2), n (%)
Neurological 92/163 (56.4) 90/154 (58.4)
independent covariates with P < 0.2, but SOFA and APACHE II Cardiovascular 86/154 (55.8) 85/145 (58.6)
scores were excluded because of their multicollinearity with Hepatic 27/162 (16.7) 27/153 (17.6)
Renal 39/161 (24.2) 36/152 (23.7)
other indices (Table 2). Among the six covariates, area of lung Hematological 43/163 (26.4) 41/154 (26.6)
infiltration, PaO2/FIO2, nonpulmonary SOFA score, and age Number of MODS 3.0 (2.0–4.0) 3.0 (2.0–4.0)
were significantly correlated with mortality. AECC ALI indicates American–European consensus conference
Table 3 summarizes the treatments and outcomes of patients definition on acute lung injury; APACHE II, acute physiology and
with AECC ALI and Berlin ARDS. Overall, 92.2% of the chronic health evaluation; BMI, body mass index; CCI, Charlson
comorbidity index; IQR, interquartile range; MODS, multiple organ
patients were receiving invasive positive pressure ventilation dysfunction syndrome; SIRS, systemic inflammatory response
(IPPV), including 7.2% of the patients receiving simultaneous syndrome; SOFA, sequential organ failure assessment.

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SHOCK MAY 2020 EPIDEMIOLOGY, TREATMENTS, AND OUTCOMES OF ARDS 547
TABLE 2. Independent characteristics associated with in-hospital mortality in AECC ALI and Berlin ARDS by univariate and multivariate
analyses
A) Univariate analysis
AECC ALI Berlin ARDS
Covariates OR (95% CI) P OR (95% CI) P

Age, y 1.024 (1.002–1.048) 0.036 1.019 (0.996–1.042) 0.105

Smoking history 0.488 (0.251–0.950) 0.035 0.508 (0.258–1.001) 0.050
CCI 1.230 (1.017–1.488) 0.033 1.230 (1.013–1.493) 0.036
Etiology: indirect 0.665 (0.348–1.270) 0.217 0.793 (0.409–1.537) 0.492
PaO2/FIO2 0.992 (0.986–0.997) 0.004 0.992 (0.986–0.998) 0.007
Area of lung infiltration (1/4–4/4) 1.914 (1.339–2.737) <0.0005 1.873 (1.294–2.710) 0.001
Scores
SIRS score 1.290 (0.858–1.941) 0.221 1.398 (0.918–2.127) 0.118
SOFA score 1.104 (1.017–1.198) 0.018 1.132 (1.035–1.238) 0.007
Nonpulmonary SOFA score 1.097 (1.006–1.197) 0.036 1.120 (1.020–1.229) 0.017
APACHE II score 1.067 (1.022–1.114) 0.003 1.070 (1.023–1.119) 0.003

B) Multivariate analysis
AECC ALI Berlin ARDS
Covariates OR (95% CI) P OR (95% CI) P

Area of lung infiltration (1/4–4/4) 2.058 (1.316–3.218) 0.002 2.011 (1.270–3.186) 0.003
PaO2/FIO2 0.991 (0.983–0.998) 0.010 0.991 (0.984–0.999) 0.022
Nonpulmonary SOFA score 1.116 (1.009–1.234) 0.032 1.136 (1.022–1.263) 0.018
Age, y 1.027 (1.001–1.054) 0.045 1.020 (0.993–1.047) 0.144
Smoking history 0.482 (0.209–1.110) 0.086 0.558 (0.239–1.299) 0.176
CCI 1.196 (0.928–1.541) 0.167 1.172 (0.906–1.517) 0.226
95% CI indicates 95% confidence interval; AECC ALI, American–European consensus conference definition on acute lung injury; APACHE II, acute
physiology and chronic health evaluation; BMI, body mass index; CCI, Charlson comorbidity index; SIRS, systemic inflammatory response syndrome;
SOFA, sequential organ failure assessment.

treatment with ECMO, and 55.1% of the patients under IPPV tidal volume of 9 mL/kg PBW. A total of 53.6% patients were
were ventilated with a tidal volume (TV) 8 mL/kg predicted treated with glucocorticoids. The in-hospital mortality of
body weight (PBW), and the IQR of TV was 6.7 to 9.0 mL/kg AECC ALI was 38.0%, which was equivalent to that of septic
PBW, indicating that 75% of the patients were ventilated with a ALI in our previous study (18). Males tended to have a higher
mortality rate than that of females, but there was no statistical
TABLE 3. Treatments and outcomes of patients with AECC ALI and significance between males and females (41.5% vs. 31.7%,
Berlin ARDS respectively, P ¼ 0.209). The treatments and outcomes of
AECC ALI Berlin ARDS
patients with Berlin ARDS and AECC ALI were almost the
Variables (n ¼ 166) (n ¼ 157) same. The overall in-hospital mortality rate was 37.6%, which
was comparable with that of other high-income countries (4).
PEEP, median (IQR) 10.0 (5.0–12.0) 10.0 (6.0–12.0)
Artificial ventilation, n (%) The mortality increased in a parallel manner with severity (mild
None 8 (4.8) 2 (1.3) 18.2%, moderate 33.8%, and severe 49.2%).
NPPV 5 (3.0) 3 (1.9)
IPPV 153 (92.2) 152 (96.8) Low TV ventilation either with 8 or 6 mL/kg did not
ECMOþIPPV 12 (7.2) 12 (7.6) affect the outcome in AECC ALI or Berlin ARDS (Table 4).
TV/PBW, mL/kg, median (IQR) 7.9 (6.7–9.0) 7.8 (6.7–9.1)
Low TV ventilation, n (%) Glucocorticoid use was positively associated with mortality.
8 mL/kg PBW 76/138 (55.1) 76/137 (55.5) Furthermore, patients with ARDS were categorized into sub-
6 mL/kg PBW 24/138 (17.4) 24/137 (17.5)
Prone position ventilation 13/165 (7.9) 13/157 (8.3) groups according to the level of glucocorticoid dose as follows:
HFOV 2/165 (1.2) 2/157 (1.3) no glucocorticoids (77 patients [46.4%]), 200 mg/d hydrocor-
Pharmacological treatments, n (%)
Glucocorticoids 89 (53.6) 85 (54.1) tisone [18 (10.8%)], 1 to 2 mg/kg/d methyl-prednisolone
Sivelestat 18 (10.8) 18 (11.5) (mPSL) [26 (15.7%)], 1 g/d mPSL [18 (10.8%)], and other
Outcomes, median (IQR)
In-hospital mortality, n (%) 63 (38.0) 59 (37.6) doses [26 (15.7%)]. These subgroups showed mortality rates of
200< PaO2/FIO2 300 (mild) 4/23 (17.4) 4/22 (18.2) 27.3%, 44.4%, 42.3%, 66.7%, and 38.5%, respectively. There
100< PaO2/FIO2 200 (moderate) 27/78 (34.6) 25/74 (33.8)
PaO2/FIO2 100 (severe) 32/65 (49.2) 30/61 (49.2) was a positive association between the level of glucocorticoid
Hospitalization days, median (IQR) 32.0 (15.3–57.0) 33.0 (16.0–58.5) dose and mortality (Table 4). We then performed a multivariate
Ventilator-free days, median (IQR) 8.0 (0–20.0) 8.0 (0–19.0)
ICU-free days, median (IQR) 8.5 (0–17.0) 8.0 (0–17.0) analysis to examine the combined effects of glucocorticoid
*P < 0.05 vs. Berlin ARDS subgroup. dose and disease severity on outcomes and noted an indepen-
AECC ALI indicates American–European consensus conference dent association between the level of glucocorticoid dose and
definition on acute lung injury; ECMO, extracorporeal membrane outcomes (Table 4). To identify the subpopulation of ARDS in
oxygenation; HFOV, high frequency oxygen ventilation; IPPV, invasive
positive pressure ventilation; IQR, interquartile range; PBW, predicted which glucocorticoid use might be unfavorable, we performed
body weight; PEEP, positive end-expiratory pressure; TV, tidal volume. stratified analysis according to the etiology. Glucocorticoid use

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548 SHOCK VOL. 53, No. 5
TABLE 4. Treatments associated with in-hospital mortality in AECC ALI and Berlin ARDS by univariate analysis
A) Univariate analysis
AECC ALI
Covariates OR (95% CI)
Low TV ventilation
8 mL/kg PBW 1.061 (0.527–2.133)
6 mL/kg PBW 1.321 (0.538–3.244)
Pharmacological treatments
Glucocorticoids 2.383 (1.242–4.572)
Level of glucocorticoid dose (0–3) 1.531 (1.119–2.094)
Sivelestat 1.045 (0.383–2.854)
B) Multivariate analysis
AECC ALI
Covariates OR (95% CI)
Level of glucocorticoid dose (0–3) 1.498 (1.057–2,124)
SOFA score 1.089 (0.994–1.194)
95% CI indicates 95% confidence interval; AECC ALI, American–European consensus conference definition on acute lung injury; PBW, predicted body
weight; SOFA, sequential organ failure assessment; TV, tidal volume.
was found to be positively associated with mortality in patients
with direct injuries (odd ratio [OR], 3.329; 95% confidence
interval [CI], 1.425–7.778; P ¼ 0.005]; however, this associa-
tion was not observed in patients with indirect injuries (OR,
1.540; 95% CI, 0.544–4.360; P ¼ 0.416). The above-men-
tioned correlations were similarly observed in patients who
fulfilled the Berlin definition.
DISCUSSION
The current prospective multicenter cohort study included 166
patients with AECC ALI. Among these, 157 (94.6%) patients
fulfilled the Berlin definition. Overall, 40% of the patients were
classified to severe ARDS, and the in-hospital mortality was
38%. Logistic regression analyses revealed that area of lung
infiltration was independently associated with outcomes. Low–
mid TV ventilation was performed in 75% patients under IPPV.
Glucocorticoid use was noted in more than half of the patients,
and it was positively associated with mortality.
The in-hospital mortality rate was 37.6% for patients with
Berlin ARDS in our analysis, which was slightly better than the
mortality rate of 40.0% reported by the LUNG SAFE study,
particularly considering our higher percentage of moderate and
severe patients (86.0% vs. 70.0%, respectively) (3). By con-
trast, the percentage of ventilation with a TV of 8 mL/kg
PBW in our study was 55.5%, which was 10% lower than that in
the LUNG SAFE study. There was no significant difference in
mortality between the two subgroups with and without low TV
ventilation, which agreed with the results of the LUNG SAFE
study (19). As 75% of patients were ventilated with a TV of
at 9 mL/kg PBW in our study, our results do not indicate
the inefficacy of low TV ventilation; instead, they show popu-
larization of a low–mid TV ventilation strategy. In our study,
nonpulmonary SOFA score was associated with outcome,
confirming the results of previous studies showing that
dysfunction in organs other than the lungs had significant
effects on the outcome of ARDS (20).
Copyright © 2020 by the Shock Society. Unauthorized reproduction of this article is prohibited.
FUJISHIMA ET AL.
Berlin ARDS
P OR (95% CI) P
0.869 1.034 (0.513–20.83) 0.925
0.543 1.304 (0.531–3.201) 0.565
0.009 2.480 (1.262–4.871) 0.008
0.008 1.603 (1.159–2.217) 0.004
0.931 1.065 (0.389–2.917) 0.903
Berlin ARDS
P OR (95% CI) P
0.023 1.581 (1.097–2.279) 0.014
0.068 1.123 (1.015–1.244) 0.025
We assessed two pharmacological treatments available in our
study. Glucocorticoids were administered in more than half of the
patients, and their use was associated with poor outcomes in our
study. Furthermore, the level of glucocorticoid dose was posi-
tively associated with mortality, independent of severity. The
efficacy of glucocorticoids for ARDS has long been a topic of
debate and remains controversial even in the guidelines (21–23).
However, the inefficacy or harmfulness of high-dose therapy for
ARDS was established and reconfirmed by a recent large-scale
retrospective analysis (24, 25). Thus, we should be extremely
cautious before the administration of high-dose glucocorticoid,
which is often called pulse therapy. Stratified analysis showed
that glucocorticoid use was positively associated with mortality
in patients with direct injuries, but not in patients with indirect
injuries; therefore, the etiology of ARDS might be useful in
deciding glucocorticoid use in patients with ARDS. However,
because the present study was observational and the timing,
duration, and reasons for glucocorticoid use varied, our findings
do not hamper glucocorticoid use for ARDS.
In the present study, the simple quadrant-based planimetry of
lung infiltration predicted in-hospital mortality appropriately.
Using a similar semiquantitative method, Lagier et al. showed
that the extent of pulmonary infiltration on the first chest
roentgenogram was the most relevant early predictive factor
of the severity of ARDS in patients with hematological diseases
(26). Furthermore, Wallet et al. showed that they could quan-
titatively evaluate a change in recruited lung volume at the
inspiratory plateau pressure after a change in PEEP using a
bedside digital chest roentgenogram (15). Thus, in developed
countries where high-resolution digital imaging is popularized
and a routine radiological confirmation by computed tomogra-
phy is performed, the recognition and quantification of lung
opacities even by a single expert has become more objective
and reproducible in critically ill patients, including those with
ARDS (27). Although chest roentgenogram has historically
played an auxiliary role, our results suggest that its significance
for ARDS in the era of digital imaging must be re-evaluated.
SHOCK MAY 2020
There are several limitations in our study. First, our study
recruited patients from the emergency and critical departments of
participating hospitals; therefore, fewer patients were included
than those in ICU-based multicenter studies, which reduced the
statistical power of our analysis. However, this study, for the first
time, clarified the epidemiology of patients with ARDS admitted
through these departments in Japan. Second, our inclusion
criteria were not identical to those of the original AECC defini-
tion. However, we believe that this difference did not affect the
ARDS population included in this study. Third, clinical indices,
including the area of lung infiltration on chest roentgenogram,
were mostly evaluated by a single expert physician, which could
have induced evaluator bias.
In the current prospective multicenter study, patients with
ARDS with a greater percentage of high severity were included
through emergency and critical care departments. The overall
in-hospital mortality was 38%, which was comparable with that
of high-income countries. The Berlin definition recognized
95% of ARDS population identified by the AECC definition.
The management of ARDS in Japan was characterized by high
utilization rate of glucocorticoids, which was positively asso-
ciated with mortality.
ACKNOWLEDGMENTS
The authors thank Prof Toshiaki Iba for the helpful comments and Mr. Shuta
Fukuda (JAAM) for his support in the administrative work.
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