A c u t e R e s p i r a t o r y D i s t res s

S y n d ro m e
Definition, Diagnosis, and Routine Management

a, b
Philip Yang, MD, MSc *, Michael W. Sjoding, MD, MSc

KEYWORDS
 Acute respiratory distress syndrome  Heterogeneity  Phenotypes
 Lung-protective ventilation

KEY POINTS
 Acute respiratory distress syndrome (ARDS) is an acute inflammatory lung injury charac-
terized by severe hypoxemic respiratory failure, bilateral opacities on chest imaging, and
low lung compliance.
 ARDS is a heterogeneous syndrome that is the common end point of a wide variety of pre-
disposing conditions, with complex pathophysiology and underlying mechanisms.
 Routine management of ARDS is centered on lung-protective ventilation strategies such
as low tidal volume ventilation and targeting low airway pressures to avoid exacerbation of
lung injury, as well as a conservative fluid management strategy.
 Advancements in molecular diagnostics and informatics tools may lead to a refined ARDS
definition, improved understanding of ARDS heterogeneity and ARDS subphenotypes,
and facilitate the development of novel therapeutic approaches.

INTRODUCTION

Acute respiratory distress syndrome (ARDS) is a rapidly progressive form of acute in-
flammatory lung injury associated with non-hydrostatic pulmonary edema and severe
acute hypoxemic respiratory failure (AHRF).1 It represents approximately 10% of all
intensive care unit (ICU) admissions and 23% of all patients requiring mechanical
ventilation.2 However, clinicians frequently fail to recognize patients with ARDS in clin-
ical practice and implement appropriate treatment strategies.2 Furthermore, ARDS is
a clinically heterogeneous syndrome with complex pathophysiology and underlying

a
Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University, 6335
Hospital Parkway, Physicians Plaza Suite 310, Johns Creek, GA 30097, USA; b Division of Pul-
monary and Critical Care Medicine, University of Michigan, 2800 Plymouth Road, NCRC,
Building 16, G027W, Ann Arbor, MI 48109, USA
* Corresponding author. 6335 Hospital Parkway, Physicians Plaza Suite 310, Johns Creek, GA
30097.
E-mail address: philip.yang@emory.edu

Crit Care Clin 40 (2024) 309–327

https://doi.org/10.1016/j.ccc.2023.12.003 criticalcare.theclinics.com
0749-0704/24/ª 2023 Elsevier Inc. All rights reserved.
Descargado para Anonymous User (n/a) en National Autonomous University of Mexico de
ClinicalKey.es por Elsevier en marzo 16, 2024. Para uso personal exclusivamente. No se
permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos
reservados.
310 Yang & Sjoding

mechanisms, which has significantly limited the development of simple diagnostic

tests or targeted pharmacologic therapies for ARDS that improve patient outcomes.3
As such, ARDS continues to be associated with high mortality of up to 46% in severe
cases.1,2 The current management strategies for ARDS are largely limited to a few
supportive measures that are centered around mechanical ventilation strategies
aimed at avoiding further lung injury (“lung-protective ventilation” [LPV]). This article
first reviews the current conceptual and clinical definitions of ARDS, current limitations
in ARDS definition and diagnosis, and strategies to address those limitations. Then, it
reviews the routine management strategies for ARDS, including noninvasive forms of
respiratory support, invasive mechanical ventilation (IMV) with LPV strategies, and
conservative fluid management.

CURRENT ACUTE RESPIRATORY DISTRESS SYNDROME DEFINITION, LIMITATIONS,

AND PROPOSED CHANGES
Acute Respiratory Distress Syndrome Definition
ARDS is conceptually understood as an acute, diffuse, inflammatory lung injury lead-
ing to increased pulmonary vascular permeability and non-hydrostatic pulmonary
edema, causing loss of aerated lung tissue, increased physiologic dead space,
increased lung weight, and decreased lung compliance.1 ARDS can arise from one
of the many risk factors and predisposing conditions, which have historically been
divided into “direct” and “indirect” causes of lung injury (Table 1).4,5 Among the poten-
tial causes, pneumonia, aspiration of gastric contents, and sepsis are the most com-
mon causes of ARDS.4 These conditions are heterogeneous in nature but eventually
lead to the common pathway of acute inflammatory lung injury, resulting in the clinical
findings of severe hypoxemic respiratory failure and bilateral pulmonary opacities on
chest imaging.1
The formal clinical definition of ARDS has been updated several times because the
initial description of the syndrome in a case series by Ashbaugh and colleagues.6 This
article focuses on the Berlin definition of ARDS published in 2012 (Table 2),1 whose
criteria are retained in the recently published Global Definition of ARDS7 that builds
on the Berlin definition. The Berlin definition was developed to address several limita-
tions of its immediate predecessor, the American-European Consensus Conference
(AECC) definition5 for acute lung injury (ALI), and ARDS. Specifically, the Berlin defini-
tion explicitly defined “acute” as a 7-day period following a known clinical insult,
required a positive end-expiratory pressure (PEEP) 5 cmH2O (or continuous positive
airway pressure [CPAP] 5 cmH2O for patients with mild ARDS on noninvasive venti-
lation [NIV]) when evaluating oxygenation, and provided clarifications regarding

Table 1
Risk factors and predisposing conditions for acute respiratory distress syndrome

Direct Lung Injury Indirect Lung Injury

 Pneumonia (bacterial, viral, or fungal) Sepsis from non-pulmonary source
Aspiration of gastric contents Trauma or burn injury
Toxic inhalational injury Pancreatitis
Near drowning Drug overdose
Pulmonary contusion Transfusion of blood products (transfusion-related
acute lung injury [TRALI])
Cardiopulmonary bypass
Reperfusion edema after lung transplantation or
embolectomy

Descargado para Anonymous User (n/a) en National Autonomous University of Mexico de

ClinicalKey.es por Elsevier en marzo 16, 2024. Para uso personal exclusivamente. No se
permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos
reservados.
 Acute Respiratory Distress Syndrome 311

Table 2
The Berlin definition of acute respiratory distress syndrome and mortality rates for different
severity categories

Criteria Definition
Timing Within 1 week of a
known clinical
insult or new or
worsening
respiratory
symptoms
Chest imaging Bilateral opacities
that are not fully
explained by
effusions, lobar/
lung collapse, or
nodules
Origin of edema Respiratory failure
not fully
explained by
cardiac failure or
fluid overload
Hypoxemia Mortality (Ranieri Mortality (Bellani
et al,1 2012) et al,2 2016)
Mild 200 mm Hg < PaO2/ 27% 34.9%
FiO2  300 mm Hg
with PEEP or CPAP
 5 cmH2O
Moderate 100 mm Hg < PaO2/ 32% 40.3%
FiO2  200 mm Hg
with PEEP 
5 cmH2O
Severe PaO2/FiO2  100 mm 45% 46.1%
Hg with PEEP 
5 cmH2O

Abbreviations: CPAP, continuous positive airway pressure; PaO2/FiO2, partial pressure arterial oxy-
gen to fraction of inspired oxygen ratio; PEEP, positive end-expiratory pressure.

exclusion of hydrostatic edema without the use of pulmonary artery catheters (PACs).1
It also defined three mutually exclusive severity categories of hypoxemia based on
partial pressure of arterial oxygen to fraction of inspired oxygen (PaO2/FiO2) ratio,
with more severe categories of hypoxemia correlating with increased mortality and
decreased ventilator-free days (see Table 2).1,2

Limitations of the Berlin Acute Respiratory Distress Syndrome Definition

Although the Berlin definition of ARDS was developed to address some of the limita-
tions of its predecessors, it is also not without its own shortcomings. First, the Berlin
definition requires a patient to receive positive pressure ventilation, undergo arterial
blood gas (ABG) sampling, and have either a chest radiograph or computed tomogra-
phy (CT) performed to satisfy all of its diagnostic criteria. However, such diagnostic
and therapeutic modalities may be difficult to obtain for all patients who are at risk
of developing ARDS, especially in those who are being treated outside of ICU or in set-
tings with limited resources.8,9
Descargado para Anonymous User (n/a) en National Autonomous University of Mexico de
ClinicalKey.es por Elsevier en marzo 16, 2024. Para uso personal exclusivamente. No se
permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos
reservados.
312 Yang & Sjoding

Second, a stated goal of the Berlin definition task force was to improve the reliability
of the ARDS definition, particularly the interpretation of chest radiographs for bilateral
opacities that has low interobserver reliability even among ARDS experts.10 However,
recent studies continue to demonstrate low interobserver reliability of chest radio-
graph interpretation for bilateral airspace opacities, which is the main driver of dis-
agreements between physicians when identifying ARDS.11 Efforts to improve
reliability by training physicians and clinical research coordinators with a set of stan-
dard chest radiographs developed by the ARDS definition task force were ineffec-
tive,12,13 highlighting the problematic nature of this essential criterion of the ARDS
definition.
A third limitation of the Berlin definition is that it encompasses a heterogeneous syn-
drome with complex pathophysiology and underlying mechanisms and is inherently
broad, nonspecific, and imprecise.3 As a result, there is no standardized, gold-
standard diagnostic test for ARDS.3 The clinical manifestations of ARDS have been
correlated with the histopathologic finding of diffuse alveolar damage (DAD) charac-
terized by capillary congestion, pulmonary edema, injury to alveolar lining and endo-
thelial cells, and hyaline membrane formation.6,14 However, DAD is not the sole
pathologic correlate of ARDS and was present in only 45% of patients with ARDS in
an autopsy series.15 Although DAD was more common in patients who met criteria
for severe ARDS for more than 72 hours (69%),15 it was still not a uniform finding, high-
lighting the clinical and pathologic heterogeneity of ARDS.

Underrecognition of Acute Respiratory Distress Syndrome in Clinical Practice

A related concern about the Berlin definition is that it may be difficult to operation-
alize at the bedside, resulting in poor recognition of ARDS in clinical practice and fail-
ure to administer evidence-based therapies for ARDS.16 This was most clearly
demonstrated in a large international prospective cohort study reporting that only
60% of ARDS cases were recognized by clinicians, with an increase in clinician
recognition rates with increasing severity.2 Moreover, clinician recognition of ARDS
at the time of fulfilling ARDS criteria was even lower at 34%, suggesting that
ARDS diagnosis was delayed in a substantial proportion of patients.2 Additional
studies have also reported poor clinician recognition rates of ARDS, ranging between
31% and 70%.17–19
Missed or delayed diagnoses of ARDS negatively impact the implementation of
treatment measures that improve outcomes in ARDS. Several studies have reported
overall low adherence to low tidal volume ventilation (LTVV) and substantial delays be-
tween ARDS onset and initiation of LTVV, thought to be at least partially due to poor
recognition of ARDS.2,19,20 Clinician recognition of ARDS has been associated with the
use of LTVV and higher PEEP, as well as greater use of adjunctive measures such as
prone positioning and neuromuscular blockade.2,19 Therefore, improved methods to
facilitate ARDS recognition may be important for timely implementation of appropriate
therapies.

Modifications to the Berlin Acute Respiratory Distress Syndrome Definition

To address the concerns regarding the Berlin definition of ARDS, several proposals for
modifications have been made. These proposals generally attempt to increase the
applicability of the ARDS definition to capture patients who demonstrate clinical fea-
tures of ARDS but do not strictly satisfy the current Berlin definition or are receiving
care in settings where certain diagnostic tests are unavailable. For example, high-
flow nasal oxygen (HFNO) has become increasingly popular for treatment of hypox-
emic respiratory failure and ARDS since 2012, especially during the recent COVID-
Descargado para Anonymous User (n/a) en National Autonomous University of Mexico de
ClinicalKey.es por Elsevier en marzo 16, 2024. Para uso personal exclusivamente. No se
permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos
reservados.
 Acute Respiratory Distress Syndrome 313

19 pandemic.21 However, the low-level positive pressure generated by HFNO is highly

variable and cannot reliably satisfy the PEEP requirement of the Berlin definition.22 In
addition, some of the diagnostic testing modalities specified in the Berlin definition,
such as ABG and radiographic testing, may not be readily available in settings with
limited health care resources.8,9
One of the earlier proposals for modifying the Berlin definition, called the Kigali
modification,8 tried to address some of these issues. It proposed.
1. Removal of a PEEP requirement, to allow patients to be diagnosed without positive
pressure ventilation
2. An oxygenation cutoff based on oxygen saturation by pulse oximetry (SpO2) to FiO2
ratio 315, in lieu of the PaO2/FiO2 ratio that requires ABG testing
3. The use of lung ultrasound as an acceptable imaging modality to assess for bilat-
eral opacities, in addition to plain radiograph and CT.
In the original cohort study conducted in Kigali, Rwanda, these modifications
allowed for identification of ARDS in patients who otherwise would not have fully satis-
fied the Berlin definition yet had severe hypoxemia with a high mortality of 50%.8 Even
in resource-rich settings, the Kigali modification could prove beneficial by facilitating
earlier ARDS diagnosis in patients outside of the ICU who are not receiving positive
pressure ventilation and avoiding the need for ABG testing and imaging modalities
that use ionizing radiation.9
More recently, the Global Definition of ARDS7 was published, which sought to build
on the Berlin definition and address similar concerns discussed above. It includes
components that are very similar to the Kigali modification, including.
1. Allowing HFNO with a minimum flow rate of 30 L/min, or NIV or CPAP with at least
5 cmH2O of end-expiratory pressure
2. Allowing either PaO2/FiO2 300 or SpO2/FiO2 315 with SpO2 97% to identify
hypoxemia
3. Adding ultrasound as a modality of imaging to identify bilateral opacities
4. Not requiring PEEP, oxygen flow, or specific respiratory support devices to diag-
nose ARDS in resource variable settings.
In both proposed modifications, lung ultrasound can be used to identify bilateral
opacities. However, the specific lung ultrasound findings of bilateral opacities have
varied across studies. In the Kigali modification, bilateral opacities were identified
by ultrasound findings of “B-lines” (an imaging artifact consistent with alveolar-
interstitial edema) and/or consolidation without associated effusion in at least one
area on each side of the chest.8 However, a recent study proposed a more detailed,
quantitative evaluation method called the lung ultrasound ARDS score that was vali-
dated against chest x-ray or CT images when available.23 This score is calculated
based on weighting the presence and type of abnormal ultrasound findings in 12 re-
gions of the chest (six areas in each hemithorax), including the presence of abnormal
pleural lines, B-lines, or consolidations.23 Validation studies of these approaches in
prospective studies across diverse populations will be necessary to demonstrate
generalizability and standardize the ultrasound examination to support ARDS diag-
nosis.24 Additional concerns regarding the use of ultrasound for ARDS diagnosis
include inter-operator variability depending on the sonographer’s training and external
factors that make it difficult to obtain ultrasound images, such as obesity, catheters,
and lines.23,24 Owing to these limitations, the Global Definition of ARDS does not
formally include specific ultrasound findings or scoring systems as a part of the defi-
nition.7 Nonetheless, there is growing evidence to support the use of ultrasound for
Descargado para Anonymous User (n/a) en National Autonomous University of Mexico de
ClinicalKey.es por Elsevier en marzo 16, 2024. Para uso personal exclusivamente. No se
permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos
reservados.
314 Yang & Sjoding

identifying bilateral opacities and to promote training in the use of lung ultrasound in
evaluating patients with ARDS.7

EMERGING APPROACHES FOR IMPROVING THE ACUTE RESPIRATORY DISTRESS

SYNDROME DEFINITION AND DIAGNOSIS

The above modifications to the ARDS definition will make it more inclusive and easier
to be applied in wider clinical contexts, which may allow for increased inclusion into
future epidemiologic studies, clinical research, and clinical trials for ARDS. However,
these modifications may also make the ARDS definition more nonspecific and will not
address the issues related to poor reliability and heterogeneity of the Berlin definition.
Therefore, additional methods spanning molecular diagnostics and informatics do-
mains are being studied to improve the reliability of the Berlin definition and to advance
the pathophysiologic understanding of ARDS. Although all of these techniques require
additional research before incorporation into a new ARDS definition, they all share a
common goal of improving ARDS identification and phenotyping to facilitate earlier
delivery of tailored interventions (Fig. 1).

Biomarkers for Improving Acute Respiratory Distress Syndrome Identification and

Phenotyping
Several candidate biomarkers measured in serum or plasma have been studied for
use in improving identification and risk stratification of patients with ARDS (Table 3).
Measuring several of these biomarkers together may offer better diagnostic and prog-
nostic accuracy than individual biomarkers by themselves, though studies differ with
regard to which biomarkers are measured together.25–27 Although most studies have
focused on blood biomarkers, some studies have examined biomarkers from other
body compartments, such as protein biomarkers from bronchoalveolar lavage
fluid28–30 and volatile organic compounds in exhaled breath condensates.31,32
Advanced molecular techniques such as metabolomics29,33–36 and proteomics37–39
have also been explored to help identify ARDS and understand the details of its
pathophysiology.

Fig. 1. Clinical and scientific tools being researched to improve identification and phenotyp-
ing of acute respiratory distress syndrome (ARDS).
Descargado para Anonymous User (n/a) en National Autonomous University of Mexico de
ClinicalKey.es por Elsevier en marzo 16, 2024. Para uso personal exclusivamente. No se
permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos
reservados.
 Acute Respiratory Distress Syndrome 315

Biomarkers have also played an important role in understanding the pathophysio-

logic heterogeneity of ARDS. Earlier studies in this area focused on correlating the
biomarker profiles with the clinical risk factors or etiologies of ARDS. For example, sur-
factant protein-A (SP-A) and surfactant protein-D (SP-D) levels were shown to be
higher in patients with ARDS from pneumonia than in patients with ARDS from
trauma.40 Another study demonstrated that von Willebrand factor (vWF) levels were
lower in patients with trauma-associated ARDS compared with those with other
causes of ARDS and lower in patients with indirect ARDS compared with those with
direct ARDS.41 Angiopoietin-2 (Ang-2) and SP-D were shown to correlate with
ARDS from indirect versus direct lung injury, respectively, suggesting distinct mecha-
nisms of lung injury caused by different etiologies of ARDS.42
More recently, sophisticated statistical methods analyzing both biomarker and clin-
ical data have been used to divide patients into ARDS subphenotypes, thereby
reducing the heterogeneity of patients within the groups. In secondary analyses of
several ARDS clinical trials, latent class analysis (LCA) has consistently identified
two distinct subphenotypes of ARDS based on clinical and laboratory data.43–46

Table 3
Select candidate biomarkers for acute respiratory distress syndrome identification and risk
stratification

Mechanistic Involvement in Acute

Biomarker Respiratory Distress Syndrome (ARDS)
Soluble receptor for advanced glycation Marker of lung epithelial injury.
end products (sRAGE)25,26,90–92 Extracellular domain of multiligand
receptor expressed on alveolar type
1 cells and may be a causal
intermediate in sepsis-induced ARDS.
Surfactant protein-D (SP-D)26,40,93,94 Marker of lung epithelial injury.
Synthesized in alveolar type 2 cells and
non-ciliated bronchiolar epithelium,
involved in lung inflammation.
Angiopoietin-2 (Ang-2)25,95,96 Marker of lung endothelial injury.
Binds Tie2 receptors on lung endothelial
cells and impairs endothelial barrier
function.
Von Willebrand factor (vWF)41,95 Marker of lung endothelial injury.
Glycoprotein involved with hemostasis,
released by endothelial cells in
endothelial injury.
Soluble intercellular adhesion molecule-1 Marker of both lung epithelial and
(sICAM-1)30,97 endothelial injury.
Expressed on both alveolar epithelial and
vascular endothelial cells, involved in
neutrophil recruitment into the lung.
Interleukin-6 and interleukin-825,98 Nonspecific pro-inflammatory cytokine.
Tumor necrosis factor-a (TNF-a)25,98 Nonspecific pro-inflammatory cytokine.
Soluble tumor necrosis factor receptor Binds circulating TNF-a and regulates
(sTNFR)-1 and 299 inflammatory response.
Plasminogen activator inhibitor-1 (PAI- Inhibitor of fibrinolysis contributes to
1)100,101 fibrin deposition in alveolar spaces.

Descargado para Anonymous User (n/a) en National Autonomous University of Mexico de

ClinicalKey.es por Elsevier en marzo 16, 2024. Para uso personal exclusivamente. No se
permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos
reservados.
316 Yang & Sjoding

One of the two subphenotypes was characterized by elevated levels of inflammatory

biomarkers, such as interleukin (IL)-6, IL-8, soluble tumor necrosis factor receptor
(sTNFR)-1, and plasminogen activator inhibitor (PAI)-1.43–46 This subphenotype,
labeled the “hyper-inflammatory” phenotype, was consistently associated with higher
mortality and worse clinical outcomes compared with the “hypo-inflammatory”
phenotype. More strikingly, the hyper-inflammatory subphenotype seemed to benefit
significantly from higher PEEP strategy,43 simvastatin therapy,44 and liberal fluid strat-
egy,45 whereas the hypo-inflammatory subphenotype had no benefit or even harm
from such therapies. The subphenotypes were subsequently validated in two pro-
spective observational cohorts of ARDS patients, further supporting their generaliz-
ability.47 These results indicate that biomarkers can be informative for identifying
ARDS subphenotypes with unique biological characteristics and treatment responses
and have the potential to inform future clinical trials.
However, significant challenges still remain in the application of biomarkers in clin-
ical settings. Many biomarker studies show significant variations in patient populations
and methodology, making it difficult to establish the optimal timing and method of
biomarker measurement. There is also no consensus regarding which biomarker, or
panel of biomarkers, most reliably identify ARDS or its subphenotypes. In the studies
of LCA-derived ARDS subphenotypes, attempts to develop parsimonious models us-
ing just three to five biomarkers and clinical variables (instead of > 30 variables
included in the full models) found slightly different sets of biomarkers to be useful
for identifying the ARDS subphenotypes.43,45,46 Moreover, many of the promising bio-
markers are not yet available for rapid measurement in clinical laboratories, and the
capability to measure the biomarkers in real time still needs to be developed.44,46
Further research is necessary to standardize the methods and timing of biomarker
measurement, validate the reproducibility of biomarker-based ARDS identification
and phenotyping across diverse populations, and determine whether personalized
treatment strategies based on subphenotypes can indeed improve outcomes.48

Informatics Approaches for Improving Reliability of Acute Respiratory Distress

Syndrome Recognition
The wealth of clinical data available in electronic medical record (EMR) systems has
led to the development of several promising informatics techniques to improve
ARDS detection. If deployed, these tools could help to improve the poor recognition
of ARDS in clinical practice. Although clinical scores for early identification of ARDS
such as the Lung Injury Prediction Score49 were developed previously, many of its
components required manual chart review by clinicians, making it difficult to automate
within EMR. Other earlier studies examined automated, rule-based “sniffer” tools that
analyzed EMR data to screen patients who may have ARDS, relying primarily on qual-
ifying PaO2/FiO2 ratios and keywords contained in chest imaging reports (such as
“bilateral,” “infiltrates,” and “edema”).50,51 Recent advances in machine learning
(ML) and artificial intelligence techniques have led to the further development of so-
phisticated models that can process a large amount of clinical information to identify
ARDS earlier in its course.52–55 Given the poor reliability of chest imaging interpreta-
tion, methods incorporating chest radiographs—such as natural language processing
applied to radiology reports56 and deep convolutional neural network to detect ARDS
findings on chest radiograph images57—have also been studied with promising
results.
Although most informatics tools focus on improving the reliability and timeliness of
ARDS identification, they have been used to corroborate the aforementioned hyper-
and hypo-inflammatory subphenotypes of ARDS58,59 as well as to explore a novel
Descargado para Anonymous User (n/a) en National Autonomous University of Mexico de
ClinicalKey.es por Elsevier en marzo 16, 2024. Para uso personal exclusivamente. No se
permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos
reservados.
 Acute Respiratory Distress Syndrome 317

previously undefined phenotypes of ARDS.60 These phenotypes demonstrate

different treatment responses and distinct clinical characteristics and may have impli-
cations for designing and selecting patients for future clinical trials in ARDS.
There are still numerous barriers that need to be overcome before the novel infor-
matics tools for ARDS can be implemented in clinical settings. Most existing studies
use retrospective data or secondary analyses of clinical trials, and more prospective
studies are needed to validate the model performance and generalizability, especially
across different institutions with different patient populations, data recording prac-
tices, and/or data processing capabilities.61 It is also unclear whether the ML model
predictions can facilitate meaningful clinical interventions or prevention of ARDS
that would not have been possible otherwise,61 given the rapid onset of ARDS and
narrow therapeutic window.2,62 In addition, the inner workings of the so-called
“black-box” algorithms need to be evaluated for their physiologic validity and
credibility.61

ROUTINE MANAGEMENT STRATEGIES FOR ACUTE RESPIRATORY DISTRESS

SYNDROME

Current management strategies for ARDS mainly consist of supportive care, including
various modalities of oxygen support and mechanical ventilation strategies designed
to reduce further lung injury LPV). Numerous clinical trials of potential ARDS therapies
have failed to demonstrate benefit, and no specific pharmacologic therapy currently
exists,3 which is likely explained by the significant clinical and pathophysiologic het-
erogeneity of patients meeting the current ARDS definition.

Noninvasive Modalities of Oxygen Support

The Berlin definition of ARDS specifies that a patient should be receiving positive pres-
sure ventilation with at least 5 cmH2O of PEEP to satisfy the definition of ARDS based
on the fact that PEEP can markedly affect oxygenation and the PaO2/FiO2 ratio.1 The
PEEP requirement could be met during administration of noninvasive positive pres-
sure ventilation (NIPPV) for patients with mild ARDS. HFNO, a newer modality of nonin-
vasive respiratory support that also provides variable levels of PEEP, emerged after
the Berlin definition was established. The recent increase in the use of HFNO for treat-
ment of AHRF and ARDS has resulted in the inclusion of HFNO in the new Global Defi-
nition of ARDS described above.7
However, it is important to note that the benefit of HFNO or NIPPV for improving out-
comes from ARDS has not been clearly demonstrated in clinical trials. The results of
individual clinical trials of HFNO conducted in various clinical contexts (both before
and during the COVID-19 pandemic) have not individually demonstrated a convincing
benefit of HFNO therapy, with mixed signals for mortality benefit or intubation rates
when compared with standard oxygen therapy or NIPPV.63–66 A subsequent pooled
analyses of these clinical trials and additional studies found potential benefit of
HFNO for preventing intubation, but not for reducing mortality.48 Clinical trials
comparing HFNO and NIPPV also have not demonstrated a clear mortality benefit
of either treatment modality and have produced somewhat conflicting results for
reducing intubation rates.63,64,67,68 In addition, when the results of several clinical trials
comparing conventional oxygen therapy to NIPPV were analyzed for the development
of the European Society of Intensive Care Medicine (ESICM) guidelines, there was no
significant benefit of NIPPV over conventional therapy for reducing intubation or mor-
tality, leading the guideline committee to not recommend one therapy over the other.48
Although NIPPV may have a strong physiologic rationale, these potential benefits may
Descargado para Anonymous User (n/a) en National Autonomous University of Mexico de
ClinicalKey.es por Elsevier en marzo 16, 2024. Para uso personal exclusivamente. No se
permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos
reservados.
318 Yang & Sjoding

be countered by its potential harms including poor patient tolerance, impaired ability
to clear secretions, increased risk of patient self-induced lung injury, and delayed intu-
bation.48 NIPPV via helmet interface was also explored as an alternative to the tradi-
tional face mask in a small single-center trial,69 but additional data to support its utility
are lacking.
As a consequence, the only affirmative recommendation regarding noninvasive res-
piratory support in the recent ESICM ARDS guidelines is for using HFNO over conven-
tional oxygen therapy to reduce the risk of intubation (but not to reduce mortality).48
Otherwise, the ESICM guidelines do not make a recommendation for or against the
use of HFNO versus NIPPV or NIPPV versus conventional oxygen therapy.48 For pa-
tients with AHRF or ARDS who are initiated on HFNO therapy, clinical scores such
as the respiratory rate-oxygenation index (defined as SpO2/FiO2 ratio divided by the
respiratory rate) can be helpful for evaluating the risk of HFNO failure and determining
whether or not HFNO therapy can be continued.70,71 However, many patients with
ARDS will develop worsening respiratory failure and will ultimately require endotra-
cheal intubation and IMV.

Lung-Protective Ventilation
Once a patient with ARDS is placed on IMV, supportive management is centered on
“lung-protective” mechanical ventilation strategies to mitigate several potential mecha-
nisms of ventilator-induced lung injury in ARDS. First, atelectasis and pulmonary edema
reduce aerated lung volumes in patients with ARDS. In such cases, even “normal” tidal
volumes that may be physiologic for uninjured lungs may nonetheless result in regional
overdistention of aerated lung in ARDS and cause “volutrauma.”72 A related mechanism
of injury is “barotrauma,” which also results from regional lung overdistension (with or
without increased airway pressures) and can lead to alveolar rupture, air leaks, and other
complications such as pneumothorax and pneumomediastinum.73 In addition, repetitive
opening and closing of alveoli with tidal breaths and the corresponding shearing injury to
the lungs may amplify regional lung strain, resulting in “atelectrauma.”73,74 Together,
these mechanisms exacerbate and perpetuate lung epithelial and endothelial injury
associated with ARDS, which then leads to release of pro-inflammatory mediators
and worsening systemic inflammation (“biotrauma”).4,73 As such, mechanical ventilation
strategies in ARDS should be optimized to minimize further lung injury.
This is first achieved by ensuring that patients receive low tidal volumes to reduce
volutrauma and overdistension injury. In a landmark randomized controlled trial
(RCT) from the ARDS network, patients receiving low tidal volume ventilation strategy
(initial tidal volume of 6 mL per kg of ideal body weight [IBW] and targeting plateau
pressure 30 cmH2O) had significantly lower mortality and higher 28-day ventilator-
free days compared with those receiving “traditional” tidal volume ventilation strategy
(initial tidal volume of 12 mL per kg of IBW and targeting plateau pressure
50 cmH2O), causing the trial to be stopped early.72 Of note, the low tidal volume
ventilation group had higher PEEP and FiO2 requirements as well as more respiratory
acidosis than the traditional ventilation group, but nonetheless had greater reductions
in plasma IL-6 concentrations, indicating reduced inflammatory response with lower
tidal volumes.72 Based on the results of this trial and analysis of other studies, multiple
society guidelines for ARDS all recommend strategies that limit tidal volumes (4–8 mL/
kg of IBW) and plateau pressures (<30 cmH2O).48,75
Another important consideration in minimizing further lung injury is using higher
PEEP, though the benefits of this strategy are less clearly defined than those of low
tidal volume ventilation. Although it was believed that higher PEEP may improve alve-
olar recruitment and minimize lung injury associated with cyclical alveolar collapse,
Descargado para Anonymous User (n/a) en National Autonomous University of Mexico de
ClinicalKey.es por Elsevier en marzo 16, 2024. Para uso personal exclusivamente. No se
permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos
reservados.
 Acute Respiratory Distress Syndrome 319

there were also concerns regarding the potential harms of higher PEEP such as lung
overdistension and circulatory depression.74 Three large RCTs did not demonstrate a
significant mortality benefit for the higher PEEP strategy, though there were some im-
provements in oxygenation and other secondary end points with the higher PEEP
strategy.76–78 When the individual patient data from these three trials were pooled in
a meta-analysis, there was potential benefit of higher PEEP strategy in patients with
moderate or severe ARDS (PaO2/FiO2 200 mm Hg), but not in patients with mild
ARDS.74 Secondary analysis of additional clinical trials also did not demonstrate a sig-
nificant difference in mortality or other clinical outcomes with higher PEEP strategy75
and using esophageal pressure monitoring (as an estimate of pleural pressure) to
guide PEEP titration also did not demonstrate improved outcomes from ARDS
compared with empirical high-PEEP strategy.79 As such, the ideal method for titrating
or setting PEEP is not clearly established, and the guidelines do not make clear rec-
ommendations for higher PEEP strategy (one guideline with conditional recommenda-
tion for higher PEEP strategy and another with no recommendation).48,75
Additional studies have suggested that it is not necessarily the PEEP itself, but
rather the combined effect of tidal volume and PEEP on airway pressures and lung
mechanics that may have a stronger impact on lung injury and clinical outcomes. In
a secondary analysis of individual patient data from nine ARDS clinical trials, the
driving pressure (defined as the plateau pressure minus PEEP, which is equal to the
ratio of tidal volume to respiratory system compliance and is a surrogate for cyclic
lung strain with each tidal breath) was examined as an independent variable associ-
ated with survival.80 The study showed that lower driving pressure (indicating lower
tidal volume in relation to a given respiratory system compliance) was most strongly
associated with survival and that changes in the plateau pressure or PEEP were not
individually associated with survival unless they led to a concurrent reduction in the
driving pressure. This study provided insight that higher PEEP strategy may be bene-
ficial only if the increased PEEP improves alveolar recruitment and lung mechanics
such that the same tidal volume can be delivered with a lower lung strain.80
Although the optimal strategy for adjusting ventilator settings in ARDS remains un-
clear based on available evidence, dynamic adjustment of tidal volume and PEEP to
achieve low plateau pressure and perhaps low driving pressure is a reasonable
approach. Based on the currently available guidelines,48,75 a possible starting point
would be to set a tidal volume of around 6 mL/kg of IBW (acceptable range 4–
8 mL/kg of IBW) and following the protocol for higher PEEP strategy that was used
in one of three RCTs mentioned above (ALVEOLI [Assessment of Low Tidal Volume
and Elevated End-Expiratory Volume to Obviate Lung Injury],76 LOV [Lung Open Venti-
lation] Study,77 EXPRESS [Expiratory Pressure]78), then monitoring the resulting
changes in airway pressures. Subsequently, the ventilator settings should be adjusted
incrementally to achieve plateau pressure 30 cmH2O and driving pressure
15 cmH2O while carefully monitoring for potential complications such as excessive
impairments in oxygenation, acid–base balance, or hemodynamics.

Conservative Fluid Strategy

Although it is not explicitly discussed in either of the recent ARDS guidelines, another
important supportive measure in ARDS is conservative fluid strategy. Although
restricting fluid intake and increasing urinary output are thought to be beneficial for
decreasing lung edema and improving clinical outcomes, such strategy may cause
decreased cardiac output and worsening of non-pulmonary organ function.81 This
risk–benefit balance was assessed in the FACTT trial,81 in which patients with ARDS
were assigned to either conservative versus liberal fluid strategies and either PAC
Descargado para Anonymous User (n/a) en National Autonomous University of Mexico de
ClinicalKey.es por Elsevier en marzo 16, 2024. Para uso personal exclusivamente. No se
permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos
reservados.
320 Yang & Sjoding

versus central venous catheter in a two-by-two factorial design. The participants’ cen-
tral venous pressure or pulmonary artery occlusion pressure, systemic mean arterial
pressure, urine output, and cardiac index were measured to determine their fluid sta-
tus and prescribe appropriate interventions, consisting of various combinations of
fluid, vasopressors, inotropes, and/or diuretics depending on their randomization
assignment. Although there was no difference in 60-day mortality between the conser-
vative versus liberal fluid groups, the conservative fluid group had higher 28-day
ventilator-free days and ICU-free days, as well as better lung injury scores and
oxygenation indexes, without an increase in non-pulmonary organ failures.81 A subse-
quent secondary analysis of this trial demonstrated potential differences in treatment
responses to fluid strategies between ARDS subphenotypes,45 but a separate RCT
dedicated to evaluating this matter has not been conducted. The exact protocol
used in the FACTT trial is difficult to follow, but conservative fluid strategy aimed at
reducing fluid intake and increasing urinary output is considered beneficial for
improving lung function and is generally preferred in patients with ARDS.

DISCUSSION

This article has focused on the current definition of ARDS and routine management
strategies for ARDS that should be applied to nearly all patients with ARDS with
only rare exceptions. However, such strategies entail general supportive ventilator
management and fluid strategies, rather than targeting a specific ARDS pathophysio-
logic process. Even adjunctive and rescue therapies for ARDS—such as prone posi-
tioning, neuromuscular blockade, corticosteroids, and extracorporeal membrane
oxygenation—merely seek to improve oxygenation/ventilation and reduce further
lung injury, rather than address the underlying pathologic process. This may explain,
at least partially, why mortality from ARDS has not improved significantly in recent
years82 despite some decline noted during the first decade of the 2000s.83 This stag-
nation of improvements in ARDS mortality bears some resemblance to the failure of
recent RCTs in sepsis84–86 to replicate the benefits of early goal-directed therapy,87
highlighting the need for improved recognition of ARDS as well as specific targeted
therapies to further improve outcomes.
At the heart of this problem lies the clinical and pathophysiologic heterogeneity of
patients meeting the current definition of ARDS. The AECC and Berlin definitions
proved useful for establishing a uniform definition of ALI/ARDS and creating a frame-
work for performing many of the practice-informing clinical trials. However, “lumping”
different disease processes into a single syndromic definition and then attempting
study treatments that target specific pathologic processes has proven exceedingly
difficult. This problem has even led to criticisms about the utility and validity of
ARDS as a clinical entity, along with suggestions to avoid the term “ARDS” in favor
of more specific nomenclature based on concrete pathologic processes (eg, “pneu-
mococcal respiratory distress,” or “hypo- vs hyper-inflammatory lung failure”).88,89
In some ways, this is broadly consistent with the recent trends favoring precision med-
icine approaches in ARDS research, with an increasing focus on “splitting” ARDS into
subphenotypes and endotypes that may respond differently to treatments. With the
continued advancements in molecular techniques and informatics tools, this
approach may lead to a more granular and refined understanding of the heteroge-
neous syndrome of ARDS. Such efforts could enable opportunities for innovative clin-
ical trial design using prognostic and predictive enrichment to discovery of novel
targeted therapies that may move us beyond the routine supportive therapies for
ARDS.
Descargado para Anonymous User (n/a) en National Autonomous University of Mexico de
ClinicalKey.es por Elsevier en marzo 16, 2024. Para uso personal exclusivamente. No se
permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos
reservados.
 Acute Respiratory Distress Syndrome 321

SUMMARY

In summary, ARDS is a severe form of acute inflammatory lung injury that develops
secondary to an inciting clinical event, which then leads to non-cardiogenic pulmonary
edema, severe hypoxemic respiratory failure, bilateral opacities on chest imaging, and
low lung compliance. Despite decades of research, mortality from ARDS remains high,
with further improvements in outcomes being hindered by the clinical and pathologic
heterogeneity inherent in its syndromic definition, underrecognition in clinical practice,
and lack of therapies targeting specific pathologic processes in ARDS. The main treat-
ment strategies for ARDS are supportive measures consisting of noninvasive oxygen
support and IMV, LPV strategies, and conservative fluid strategy. The proposed
changes to the clinical definition of ARDS, in combination with the advancements in
clinical, laboratory, and informatics methods for diagnosing and phenotyping ARDS,
may enable innovative approaches to ARDS clinical trials, discovery of novel ARDS
therapies, and improvements in clinical outcomes from ARDS.

CLINICS CARE POINTS

 Acute respiratory distress syndrome (ARDS) is currently defined by the Berlin definition, but
this definition may soon be updated to allow ARDS to be diagnosed with the use of (1) high-
flow nasal oxygen (HFNO), without a requirement for positive end-expiratory pressure
(PEEP); (2) SpO2/FiO2 criteria to identify hypoxia, without the need for arterial blood gas
testing; and (3) ultrasound as an additional modality of imaging to identify bilateral
opacities.
 HFNO and noninvasive ventilation are reasonable modalities of oxygen support in patients
who are developing ARDS or have mild ARDS, but many patients with ARDS will
subsequently require invasive mechanical ventilation.
 Lung-protective ventilation strategy in ARDS consists of delivering low tidal volumes (4–8 mL
per kg of ideal body weight) to avoid lung overdistension and optimizing PEEP to promote
alveolar recruitment such that plateau and driving pressures, which are surrogate measures
of mechanical stress on the lungs, are minimized.
 Conservative fluid strategy should also be applied to ARDS patients to reduce lung edema, by
reducing fluid intake and increasing urinary output within safe limits.

DISCLOSURE

The authors have no disclosures.

FUNDING

Dr Sjoding is supported by the National Heart, Lung, and Blood Institute (NHLBI) of the
National Institutes of Health (NIH) under award number R01HL158626. The content is
solely the responsibility of the authors and does not necessarily represent the official
views of the National Institutes of Health.

REFERENCES

1. Ranieri V, Rubenfeld G, Thompson B, et al. Acute respiratory distress syndrome:

the berlin definition. JAMA 2012;307(23):2526–33.
2. Bellani G, Laffey J, Pham T, et al, LUNG SAFE Investigators, ESICM Trials
Group. Epidemiology, patterns of care, and mortality for patients with acute
Descargado para Anonymous User (n/a) en National Autonomous University of Mexico de
ClinicalKey.es por Elsevier en marzo 16, 2024. Para uso personal exclusivamente. No se
permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos
reservados.
322 Yang & Sjoding

respiratory distress syndrome in intensive care units in 50 countries. JAMA

2016;315(8):788–800.
3. Reilly JP, Calfee CS, Christie JD. Acute respiratory distress syndrome pheno-
types. Semin Respir Crit Care Med 2019;40(1):19–30.
4. Thompson BT, Chambers RC, Liu KD. Acute respiratory distress syndrome.
N Engl J Med 2017;377(6):562–72.
5. Bernard G, Artigas A, Brigham K, et al. The American-European consensus con-
ference on ARDS. definitions, mechanisms, relevant outcomes, and clinical trial
coordination. Am J Respir Crit Care Med 1994;149(3 Pt 1):818–24.
6. Ashbaugh DG, Bigelow DB, Petty TL, et al. Acute respiratory distress in adults.
Lancet 1967;2(7511):319–23.
7. Matthay MA, Arabi Y, Arroliga AC, et al. A new global definition of acute respi-
ratory distress syndrome. Am J Respir Crit Care Med 2023. https://doi.org/10.
1164/rccm.202303-0558WS.
8. Riviello ED, Kiviri W, Twagirumugabe T, et al. Hospital incidence and outcomes
of the acute respiratory distress syndrome using the Kigali modification of the
berlin definition. Am J Respir Crit Care Med 2016;193(1):52–9.
9. Riviello ED, Buregeya E, Twagirumugabe T. Diagnosing acute respiratory
distress syndrome in resource limited settings: the kigali modification of the ber-
lin definition. Curr Opin Crit Care 2017;23(1):18–23.
10. Rubenfeld GD, Caldwell E, Granton J, et al. Interobserver variability in applying
a radiographic definition for ARDS. Chest 1999;116(5):1347–53.
11. Sjoding MW, Hofer TP, Co IC, et al. Interobserver reliability of the berlin ARDS
definition and strategies to improve the reliability of ARDS diagnosis. Chest
2018;153(2):361–7.
12. Peng JM, Qian CY, Yu XY, et al, China Critical Care Clinical Trial Group
CCCCTG. Does training improve diagnostic accuracy and inter-rater agreement
in applying the Berlin radiographic definition of acute respiratory distress syn-
drome? A multicenter prospective study. Crit Care 2017;21(1):12.
13. Goddard SL, Rubenfeld GD, Manoharan V, et al. The randomized educational
acute respiratory distress syndrome diagnosis study: a trial to improve the
radiographic diagnosis of acute respiratory distress syndrome. Crit Care Med
2018;46(5):743–8.
14. Katzenstein AL, Bloor CM, Leibow AA. Diffuse alveolar damage–the role of ox-
ygen, shock, and related factors. A review. Am J Pathol 1976;85(1):209–28.
15. Thille AW, Esteban A, Fernandez-Segoviano P, et al. Comparison of the Berlin
definition for acute respiratory distress syndrome with autopsy. Am J Respir
Crit Care Med 2013;187(7):761–7.
16. Bellani G, Pham T, Laffey JG. Missed or delayed diagnosis of ARDS: a common
and serious problem. Intensive Care Med 2020;46(6):1180–3.
17. Ferguson ND, Frutos-Vivar F, Esteban A, et al. Acute respiratory distress syn-
drome: underrecognition by clinicians and diagnostic accuracy of three clinical
definitions. Crit Care Med 2005;33(10):2228–34.
18. Frohlich S, Murphy N, Doolan A, et al. Acute respiratory distress syndrome: un-
derrecognition by clinicians. J Crit Care 2013;28(5):663–8.
19. Schwede M, Lee RY, Zhuo H, et al. Clinician recognition of the acute respiratory
distress syndrome: risk factors for under-recognition and trends over time. Crit
Care Med 2020;48(6):830–7.
20. Weiss CH, Baker DW, Weiner S, et al. Low tidal volume ventilation use in acute
respiratory distress syndrome. Crit Care Med 2016;44(8):1515–22.
Descargado para Anonymous User (n/a) en National Autonomous University of Mexico de
ClinicalKey.es por Elsevier en marzo 16, 2024. Para uso personal exclusivamente. No se
permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos
reservados.
 Acute Respiratory Distress Syndrome 323

21. Crimi C, Pierucci P, Renda T, et al. High-flow nasal cannula and COVID-19: a
clinical review. Respir Care 2022;67(2):227–40.
22. Parke R, McGuinness S, Eccleston M. Nasal high-flow therapy delivers low level
positive airway pressure. Br J Anaesth 2009;103(6):886–90.
23. Smit MR, Hagens LA, Heijnen NFL, et al, DARTS Consortium members. Lung ul-
trasound prediction model for acute respiratory distress syndrome: a multi-
center prospective observational study. Am J Respir Crit Care Med 2023;
207(12):1591–601.
24. Ware LB. Improving acute respiratory distress syndrome diagnosis: is lung ultra-
sound the answer? Am J Respir Crit Care Med 2023;207(12):1548–9.
25. Fremont RD, Koyama T, Calfee CS, et al. Acute lung injury in patients with trau-
matic injuries: utility of a panel of biomarkers for diagnosis and pathogenesis.
J Trauma 2010;68(5):1121–7.
26. Ware LB, Koyama T, Zhao Z, et al. Biomarkers of lung epithelial injury and
inflammation distinguish severe sepsis patients with acute respiratory distress
syndrome. Crit Care 2013;17(5):R253.
27. Ware LB, Koyama T, Billheimer DD, et al, NHLBI ARDS Clinical Trials Network.
Prognostic and pathogenetic value of combining clinical and biochemical
indices in patients with acute lung injury. Chest 2010;137(2):288–96.
28. Albertine KH, Soulier MF, Wang Z, et al. Fas and fas ligand are up-regulated in
pulmonary edema fluid and lung tissue of patients with acute lung injury and the
acute respiratory distress syndrome. Am J Pathol 2002;161(5):1783–96.
29. Evans CR, Karnovsky A, Kovach MA, et al. Untargeted LC-MS metabolomics of
bronchoalveolar lavage fluid differentiates acute respiratory distress syndrome
from health. J Proteome Res 2014;13(2):640–9.
30. Agouridakis P, Kyriakou D, Alexandrakis MG, et al. The predictive role of serum
and bronchoalveolar lavage cytokines and adhesion molecules for acute respi-
ratory distress syndrome development and outcome. Respir Res 2002;3:25.
31. Bos LDJ, Schultz MJ, Sterk PJ. Exhaled breath profiling for diagnosing acute
respiratory distress syndrome. BMC Pulm Med 2014;14:1–9.
32. Bos LDJ, Weda H, Wang Y, et al. Exhaled breath metabolomics as a noninvasive
diagnostic tool for acute respiratory distress syndrome. Eur Respir J 2014;44(1):
188–97.
33. Stringer KA, Serkova NJ, Karnovsky A, et al. Metabolic consequences of sepsis-
induced acute lung injury revealed by plasma 1H-nuclear magnetic resonance
quantitative metabolomics and computational analysis. Am J Physiol Lung Cell
Mol Physiol 2011;300(1):L4–11.
34. Stringer KA, Jones AE, Puskarich MA, et al. 1H-nuclear magnetic resonance (NMR)-
detected lipids associated with apoptosis differentiate early acute respiratory
distress syndrome (ARDS) from sepsis. Am J Respir Crit Care Med 2014;189:A5000.
35. Esper AM, Park Y, Martin GS, et al. Metabolomic analysis in sepsis and ARDS.
Am J Respir Crit Care Med 2013;187:A2223.
36. Yang P, Hu X, Iffrig E, et al. Serial metabolomic analyses in sepsis-induced acute
respiratory distress syndrome. Am J Respir Crit Care Med 2022;205:A5139.
37. Bowler RP, Dudag B, Chan ED, et al. Proteomic analysis of pulmonary edema
fluid and plasma in patients with acute lung injury. Am J Physiol Lung Cell
Mol Physiol 2004;286(6):L1095–104.
38. de Torre C, Ying SX, Munson PJ, et al. Proteomic analysis of inflammatory bio-
markers in bronchoalveolar lavage. Proteomics 2006;6(13):3949–57.
Descargado para Anonymous User (n/a) en National Autonomous University of Mexico de
ClinicalKey.es por Elsevier en marzo 16, 2024. Para uso personal exclusivamente. No se
permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos
reservados.
324 Yang & Sjoding

39. Chen X, Shan Q, Jiang L, et al. Quantitative proteomic analysis by iTRAQ for
identification of candidate biomarkers in plasma from acute respiratory distress
syndrome patients. Biochem Biophys Res Commun 2013;441(1):1–6.
40. Eisner M, Parsons P, Matthay M, et al. Plasma surfactant protein levels and clin-
ical outcomes in patients with acute lung injury. Thorax 2003;58(11):983–8.
41. Ware LB, Eisner MD, Thompson BT, et al. Significance of Von Willebrand factor
in septic and nonseptic patients with acute lung injury. Am J Respir Crit Care
Med 2004;170(7):766–72.
42. Calfee CS, Janz DR, Bernard GR, et al. Distinct molecular phenotypes of direct
vs indirect ARDS in single-center and multicenter studies. Chest 2015;147(6):
1539–48.
43. Calfee CS, Delucchi K, Parsons PE, et al, NHLBI ARDS Network. Subpheno-
types in acute respiratory distress syndrome: latent class analysis of data
from two randomised controlled trials. Lancet Respir Med 2014;2(8):611–20.
44. Calfee CS, Delucchi KL, Sinha P, et al, Irish Critical Care Trials Group. Acute res-
piratory distress syndrome subphenotypes and differential response to simva-
statin: secondary analysis of a randomised controlled trial. Lancet Respir Med
2018;6(9):691–8.
45. Famous KR, Delucchi K, Ware LB, et al, ARDS Network. Acute respiratory
distress syndrome subphenotypes respond differently to randomized fluid man-
agement strategy. Am J Respir Crit Care Med 2017;195(3):331–8.
46. Sinha P, Delucchi KL, Thompson BT, et al, NHLBI ARDS Network. Latent class
analysis of ARDS subphenotypes: a secondary analysis of the statins for acutely
injured lungs from sepsis (SAILS) study. Intensive Care Med 2018;44(11):
1859–69.
47. Sinha P, Delucchi KL, Chen Y, et al. Latent class analysis-derived subpheno-
types are generalisable to observational cohorts of acute respiratory distress
syndrome: a prospective study. Thorax 2022;77(1):13–21.
48. Grasselli G, Calfee CS, Camporota L, et al, European Society of Intensive Care
Medicine Taskforce on ARDS. ESICM guidelines on acute respiratory distress
syndrome: definition, phenotyping and respiratory support strategies. Intensive
Care Med 2023;49(7):727–59.
49. Gajic O, Dabbagh O, Park P, et al, U.S. Critical Illness and Injury Trials Group:
Lung Injury Prevention Study Investigators USCIITG-LIPS. Early identification of
patients at risk of acute lung injury: evaluation of lung injury prediction score in a
multicenter cohort study. Am J Respir Crit Care Med 2011;183(4):462–70.
50. Herasevich V, Yilmaz M, Khan H, et al. Validation of an electronic surveillance
system for acute lung injury. Intensive Care Med 2009;35(6):1018–23.
51. Koenig HC, Finkel BB, Khalsa SS, et al. Performance of an automated electronic
acute lung injury screening system in intensive care unit patients. Crit Care Med
2011;39(1):98–104.
52. Le S, Pellegrini E, Green-Saxena A, et al. Supervised machine learning for the
early prediction of acute respiratory distress syndrome (ARDS). J Crit Care
2020;60:96–102.
53. Zeiberg D, Prahlad T, Nallamothu BK, et al. Machine learning for patient risk
stratification for acute respiratory distress syndrome. PLoS One 2019;14(3):
e0214465.
54. Singhal L, Garg Y, Yang P, et al. eARDS: a multi-center validation of an interpret-
able machine learning algorithm of early onset Acute Respiratory Distress Syn-
drome (ARDS) among critically ill adults with COVID-19. PLoS One 2021;16(9):
e0257056.
Descargado para Anonymous User (n/a) en National Autonomous University of Mexico de
ClinicalKey.es por Elsevier en marzo 16, 2024. Para uso personal exclusivamente. No se
permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos
reservados.
 Acute Respiratory Distress Syndrome 325

55. Wu W, Wang Y, Tang J, et al. Developing and evaluating a machine-learning-

based algorithm to predict the incidence and severity of ARDS with continuous
non-invasive parameters from ordinary monitors and ventilators. Comput
Methods Programs Biomed 2023;230:107328.
56. Afshar M, Joyce C, Oakey A, et al. A computable phenotype for acute respira-
tory distress syndrome using natural language processing and machine
learning. AMIA Annu Symp Proc 2018;2018:157–65.
57. Sjoding MW, Taylor D, Motyka J, et al. Deep learning to detect acute respiratory
distress syndrome on chest radiographs: a retrospective study with external
validation. Lancet Digit Health 2021;3(6):e340–8.
58. Maddali MV, Churpek M, Pham T, et al, LUNG SAFE Investigators and the
ESICM Trials Group. Validation and utility of ARDS subphenotypes identified
by machine-learning models using clinical data: an observational, multicohort,
retrospective analysis. Lancet Respir Med 2022;10(4):367–77.
59. Sinha P, Churpek MM, Calfee CS. Machine learning classifier models can iden-
tify acute respiratory distress syndrome phenotypes using readily available clin-
ical data. Am J Respir Crit Care Med 2020;202(7):996–1004.
60. Bai Y, Xia J, Huang X, et al. Using machine learning for the early prediction of
sepsis-associated ARDS in the ICU and identification of clinical phenotypes
with differential responses to treatment. Front Physiol 2022;13:1050849.
61. Wong AI, Cheung PC, Kamaleswaran R, et al. Machine learning methods to pre-
dict acute respiratory failure and acute respiratory distress syndrome. Front Big
Data 2020;3:579774.
62. Shari G, Kojicic M, Li G, et al. Timing of the onset of acute respiratory distress
syndrome: a population-based study. Respir Care 2011;56(5):576–82.
63. Frat JP, Thille AW, Mercat A, et al, FLORALI Study Group, REVA Network. High-
flow oxygen through nasal cannula in acute hypoxemic respiratory failure.
N Engl J Med 2015;372(23):2185–96.
64. Azoulay E, Lemiale V, Mokart D, et al. Effect of high-flow nasal oxygen vs stan-
dard oxygen on 28-day mortality in immunocompromised patients with acute
respiratory failure: the high randomized clinical trial. JAMA 2018;320(20):
2099–107.
65. Frat JP, Quenot JP, Badie J, et al, SOHO-COVID Study Group and the REVA
Network. Effect of high-flow nasal cannula oxygen vs standard oxygen therapy
on mortality in patients with respiratory failure due to COVID-19: the SOHO-
COVID randomized clinical trial. JAMA 2022;328(12):1212–22.
66. Perkins GD, Ji C, Connolly BA, et al, RECOVERY-RS Collaborators. Effect of
noninvasive respiratory strategies on intubation or mortality among patients
with acute hypoxemic respiratory failure and COVID-19: the RECOVERY-RS ran-
domized clinical trial. JAMA 2022;327(6):546–58.
67. Grieco DL, Menga LS, Cesarano M, et al, COVID-ICU Gemelli Study Group. Ef-
fect of helmet noninvasive ventilation vs high-flow nasal oxygen on days free of
respiratory support in patients with COVID-19 and moderate to severe hypox-
emic respiratory failure: the HENIVOT randomized clinical trial. JAMA 2021;
325(17):1731–43.
68. Nair PR, Haritha D, Behera S, et al. Comparison of High-flow nasal cannula and
noninvasive ventilation in acute hypoxemic respiratory failure due to severe
COVID-19 pneumonia. Respir Care 2021;66(12):1824–30.
69. Patel BK, Wolfe KS, Pohlman AS, et al. Effect of noninvasive ventilation delivered
by helmet vs face mask on the rate of endotracheal intubation in patients with
Descargado para Anonymous User (n/a) en National Autonomous University of Mexico de
ClinicalKey.es por Elsevier en marzo 16, 2024. Para uso personal exclusivamente. No se
permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos
reservados.
326 Yang & Sjoding

acute respiratory distress syndrome: a randomized clinical trial. JAMA 2016;

315(22):2435–41.
70. Roca O, Messika J, Caralt B, et al. Predicting success of high-flow nasal can-
nula in pneumonia patients with hypoxemic respiratory failure: the utility of the
ROX index. J Crit Care 2016;35:200–5.
71. Roca O, Caralt B, Messika J, et al. An index combining respiratory rate and
oxygenation to predict outcome of nasal high-flow therapy. Am J Respir Crit
Care Med 2019;199(11):1368–76.
72. Brower R, Matthay M, Morris A, et al. Ventilation with lower tidal volumes as
compared with traditional tidal volumes for acute lung injury and the acute res-
piratory distress syndrome. N Engl J Med 2000;342(18):1301–8.
73. Slutsky AS, Ranieri VM. Ventilator-induced lung injury. N Engl J Med 2013;
369(22):2126–36.
74. Briel M, Meade M, Mercat A, et al. Higher vs lower positive end-expiratory pres-
sure in patients with acute lung injury and acute respiratory distress syndrome:
systematic review and meta-analysis. JAMA 2010;303(9):865–73.
75. Fan E, Del Sorbo L, Goligher EC, et al, American Thoracic Society, European So-
ciety of Intensive Care Medicine, and Society of Critical Care Medicine. An offi-
cial American thoracic society/European society of intensive care medicine/
society of critical care medicine clinical practice guideline: mechanical ventila-
tion in adult patients with acute respiratory distress syndrome. Am J Respir Crit
Care Med 2017;195(9):1253–63.
76. Brower RG, Lanken PN, MacIntyre N, et al, National Heart, Lung, and Blood
Institute ARDS Clinical Trials Network. Higher versus lower positive end-
expiratory pressures in patients with the acute respiratory distress syndrome.
N Engl J Med 2004;351(4):327–36.
77. Meade MO, Cook DJ, Guyatt GH, et al, Lung Open Ventilation Study Investiga-
tors. Ventilation strategy using low tidal volumes, recruitment maneuvers, and
high positive end-expiratory pressure for acute lung injury and acute respiratory
distress syndrome: a randomized controlled trial. JAMA 2008;299(6):637–45.
78. Mercat A, Richard JCM, Vielle B, et al, Expiratory Pressure Express Study
Group. Positive end-expiratory pressure setting in adults with acute lung injury
and acute respiratory distress syndrome: a randomized controlled trial. JAMA
2008;299(6):646–55.
79. Beitler JR, Sarge T, Banner-Goodspeed VM, et al, EPVent-2 Study Group. Effect
of titrating positive end-expiratory pressure (peep) with an esophageal
pressure-guided strategy vs an empirical high peep-fio2 strategy on death
and days free from mechanical ventilation among patients with acute respiratory
distress syndrome: a randomized clinical trial. JAMA 2019;321(9):846–57.
80. Amato MB, Meade MO, Slutsky AS, et al. Driving pressure and survival in the
acute respiratory distress syndrome. N Engl J Med 2015;372(8):747–55.
81. Wiedemann HP, Wheeler AP, Bernard GR, et al. Comparison of two fluid-
management strategies in acute lung injury. N Engl J Med 2006;354(24):2564–75.
82. Parcha V, Kalra R, Bhatt SP, et al. Trends and geographic variation in acute res-
piratory failure and ARDS mortality in the United States. Chest 2021;159(4):
1460–72.
83. Cochi SE, Kempker JA, Annangi S, et al. Mortality trends of acute respiratory
distress syndrome in the United States from 1999 to 2013. Ann Am Thorac
Soc 2016;13(10):1742–51.
84. Investigators A, Group ACT, Peake SL, et al. Goal-directed resuscitation for pa-
tients with early septic shock. N Engl J Med 2014;371(16):1496–506.
Descargado para Anonymous User (n/a) en National Autonomous University of Mexico de
ClinicalKey.es por Elsevier en marzo 16, 2024. Para uso personal exclusivamente. No se
permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos
reservados.
 Acute Respiratory Distress Syndrome 327

85. Pro CI, Yealy DM, Kellum JA, et al. A randomized trial of protocol-based care for
early septic shock. N Engl J Med 2014;370(18):1683–93.
86. Mouncey PR, Osborn TM, Power GS, et al, ProMISe Trial Investigators. Trial of
early, goal-directed resuscitation for septic shock. N Engl J Med 2015;
372(14):1301–11.
87. Rivers E, Nguyen B, Havstad S, et al, Early Goal-Directed Therapy Collaborative
Group. Early goal-directed therapy in the treatment of severe sepsis and septic
shock. N Engl J Med 2001;345(19):1368–77.
88. Vincent JL, Slutsky AS. We’ve never seen a patient with ARDS. Intensive Care
Med 2020;46(12):2133–5.
89. Gattinoni L, Marini JJ. Isn’t it time to abandon ARDS? The COVID-19 lesson. Crit
Care 2021;25(1):326.
90. Jones TK, Feng R, Kerchberger VE, et al. Plasma sRAGE Acts as a genetically
regulated causal intermediate in sepsis-associated acute respiratory distress
syndrome. Am J Respir Crit Care Med 2020;201(1):47–56.
91. Calfee CS, Ware LB, Eisner MD, et al, NHLBI ARDS Network. Plasma receptor
for advanced glycation end products and clinical outcomes in acute lung injury.
Thorax 2008;63(12):1083–9.
92. Jabaudon M, Futier E, Roszyk L, et al. Soluble form of the receptor for advanced
glycation end products is a marker of acute lung injury but not of severe sepsis
in critically ill patients. Crit Care Med 2011;39(3):480–8.
93. Park J, Pabon M, Choi AMK, et al. Plasma surfactant protein-D as a diagnostic
biomarker for acute respiratory distress syndrome: validation in US and Korean
cohorts. BMC Pulm Med 2017;17(1):204.
94. Determann R, Royakkers A, Haitsma J, et al. Plasma levels of surfactant protein
D and KL-6 for evaluation of lung injury in critically ill mechanically ventilated pa-
tients. BMC Pulm Med 2010;10(6).
95. Van Der Heijden M, Van Nieuw Amerongen GP, Koolwijk P, et al. Angiopoietin-2,
permeability oedema, occurrence and severity of ALI/ARDS in septic and non-
septic critically ill patients. Thorax 2008;63(10):903–9.
96. Agrawal A, Matthay MA, Kangelaris KN, et al. Plasma angiopoietin-2 predicts
the onset of acute lung injury in critically ill patients. Am J Respir Crit Care
Med 2013;187(7):736–42.
97. Calfee CS, Eisner MD, Parsons PE, et al, NHLBI Acute Respiratory Distress Syn-
drome Clinical Trials Network. Soluble intercellular adhesion molecule-1 and
clinical outcomes in patients with acute lung injury. Intensive Care Med 2009;
35(2):248–57.
98. Terpstra ML, Aman J, Van Nieuw Amerongen GP, et al. Plasma biomarkers for
acute respiratory distress syndrome: a systematic review and Meta-Analysis.
Crit Care Med 2014;42(3):691–700.
99. Parsons PE, Matthay MA, Ware LB, et al, National Heart LBIARDSCTN. Elevated
plasma levels of soluble TNF receptors are associated with morbidity and mor-
tality in patients with acute lung injury. Am J Physiol Lung Cell Mol Physiol 2005;
288(3):L426–31.
100. Ware LB, Matthay MA, Parsons PE, et al, National Heart, Lung, and Blood Insti-
tute Acute Respiratory Distress Syndrome Clinical Trials Network. Pathogenetic
and prognostic significance of altered coagulation and fibrinolysis in acute lung
injury/acute respiratory distress syndrome. Crit Care Med 2007;35(8):1821–8.
101. Prabhakaran P, Ware LB, White KE, et al. Elevated levels of plasminogen acti-
vator inhibitor-1 in pulmonary edema fluid are associated with mortality in acute
lung injury. Am J Physiol Lung Cell Mol Physiol 2003;285(1):L20–8.
Descargado para Anonymous User (n/a) en National Autonomous University of Mexico de
ClinicalKey.es por Elsevier en marzo 16, 2024. Para uso personal exclusivamente. No se
permiten otros usos sin autorización. Copyright ©2024. Elsevier Inc. Todos los derechos
reservados.