Acute Respiratory Distress Syndrome 2022

Respiratory Disease Series:
Diagnostic Tools and Disease Managements

Series Editors: Hiroyuki Nakamura · Kazutetsu Aoshiba
Sadatomo Tasaka Editor
Acute
Respiratory
Distress
Syndrome
Advances in Diagnostic Tools
and Disease Management
Respiratory Disease Series: Diagnostic Tools
and Disease Managements
Series Editors
Hiroyuki Nakamura
Ibaraki Medical Center
Tokyo Medical University
Ibaraki, Ibaraki, Japan
Kazutetsu Aoshiba
Ibaraki Medical Center
Tokyo Medical University
Ibaraki, Ibaraki, Japan
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Sadatomo Tasaka
Editor
Acute Respiratory Distress

Syndrome
Advances in Diagnostic Tools and Disease
Management
Editor
Sadatomo Tasaka
Department of Respiratory Medicine
Hirosaki University, Graduate School of Medicine
Hirosaki, Japan
ISSN 2509-5552 ISSN 2509-5560 (electronic)

Respiratory Disease Series: Diagnostic Tools and Disease Managements
ISBN 978-981-16-8370-1 ISBN 978-981-16-8371-8 (eBook)
https://doi.org/10.1007/978-981-16-8371-8
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Preface
The spread of COVID-19, which began in December 2019, has shown no signs of
ending even after more than a year. ARDS, which was first described 60 years ago,
still has a high mortality rate of 30–40% despite intensive research on its patho-
physiology and advances in drug therapies and patient management. Since many of
the clinical trials of ARDS treatment to date have targeted patients with a variety of
background factors, there has always been a concern that the trials may not indicate
therapeutic strategy of each patient with ARDS. However, over the past year or
more, a vast amount of information on respiratory failure due to a single cause of
COVID-19 has been accumulating. In a sense, this is the largest study of ARDS
caused by respiratory infections.
The Berlin definition established in 2012 provides refined diagnostic criteria of
timing, chest imaging, origin of edema, and hypoxemia. It has been widely accepted
but still has several limitations that require further investigations to establish better
definition of ARDS. Risk factors for ARDS include pneumonia, sepsis, aspiration,
and trauma as primary diseases; chronic alcohol abuse, cigarette smoking, air pollu-
tion, and hypoproteinemia as comorbidities. The reported incidence of ARDS varies
widely from study to study, and ICU mortality is between 30% and 49%, which is
generally lower in randomized controlled trials than in observational studies.
The cardinal feature of ARDS is caused by formation of protein-rich alveolar
edema after damage to the integrity of the lung’s alveolar–capillary barrier. The
innate immune response is important in the pathogenesis of ARDS and damages
tissues via activated neutrophils and other inflammatory cells. Widespread alveolar
flooding in ARDS reduces diffusing capacity and inactivates surfactant; this, in turn,
decreases lung compliance, increases ventilation-perfusion mismatch, and produces
intrapulmonary shunt, resulting in refractory hypoxemia. It is important to evaluate
respiratory dysfunction from limited information such as arterial blood gases and
chest CT images. High-resolution CT (HRCT) is the most useful imaging tool for
ARDS, which can distinct direct injury such as pneumonia and aspiration from
indirect injury such as sepsis and trauma. In addition, the extent of fibrotic shadow
on HRCT, such as reticulation and traction bronchiectasis and volume loss, are cru-
cial findings, which indicate fibroproliferative changes in the lung and are
v
vi Preface
associated with poor prognosis. In ARDS patients, serum or plasma biomarkers

associated with coagulation/fibrinolysis, inflammatory cascade, endothelium dam-
age, and epithelium damage are shown to be predictive of prognosis.
In the current situation where no effective drug therapy for ARDS is available,
respiratory management is central to the treatment of ARDS patients. Lung protec-
tive ventilation has become a common practice in ventilatory management of ARDS
patients. However, the initial understanding that reducing tidal volume is “lung pro-
tective” is now changing to the concept that the energy loaded by mechanical venti-
lation is the damaging factor, and how to reduce the stress on the lungs is the key.
Anatomically, vertebrate rationality is maintained in the distribution of ventilation
and blood flow in the human lungs, and the prone position optimizes the distribution
of ventilation and perfusion. Because the limitations of mechanical ventilation in
the supine position cannot be easily overcome, it is necessary to consider the signifi-
cance of spontaneous respiration. In addition, noninvasive respiratory management,
such as noninvasive ventilation (NIV) and high-flow nasal cannula (HFNC) oxygen
therapy, has been drawing attention due to the possibility to prevent unnecessary
intubation and worsening of the disease severity. Although the benefits of NIV and
HFNC are limited owing to the lack of precise setting of tidal volume, they may be
effective as the respiratory management in mild or early ARDS.
Adequate fluid and nutritional managements have potentials to improve the out-
come of ARDS patients. Conservative fluid management, which uses fluid restric-
tion, diuretics, and possibly hyperoncotic albumin to avoid a positive fluid balance,
is preferable compared with liberal fluid management in terms of preventing further
pulmonary edema formation. However, conservative strategy might be associated
with the risk of cognitive impairment as a late complication. Omega-3 fatty acid is
likely to be beneficial for nutritional support during ARDS, although the results of
randomized controlled trials remain controversial.
Continuous hemodiafiltration (CHDF) may improve oxygenation and extend the
survival rate of ARDS patients, but there is little evidence to recommend CHDF in
those without renal failure. Extracorporeal membrane oxygenation (ECMO) ther-
apy for severe respiratory failure is gaining worldwide attention. Although ECMO
is highly invasive, it can minimize lung damage from mechanical ventilation and
provide a better lung environment for recovery in severe ARDS.
Because ARDS is characterized by inflammatory lung injury, anti-inflammatory
drugs including corticosteroids might serve as potential therapeutics for ARDS. Early
administration of corticosteroid may reduce duration of mechanical ventilation and
improve short-term survival, although its effect on long-term survival outcomes
remains unclear. Besides drug therapy, physiotherapy, including early active exer-
cise and mobilization, is safe and feasible, with some evidence of improved patient
outcomes.
As an innovative approach to ARDS, microRNAs and extracellular vesicles have
been attracting attentions as a novel diagnostic tool of ARDS. In addition, cell-
based therapies, primarily using mesenchymal stem/stromal cells, have been exten-
sively investigated in animal models and clinical studies as a promising approach
for the treatment of ARDS. To optimize ventilatory support, electrical impedance
Preface vii
tomography (EIT), a real-time, noninvasive monitoring tool, may be useful for visu-
alizing the distribution of ventilation.
Acute respiratory failure due to COVID-19 is the largest and most urgent issue in
the world. I believe that discussion presented here, which contain a lot of the
cutting-edge information and concepts, will be helpful and inspiring for
pulmonologists and intensivists as well as general physicians confronted with this
vital clinical challenge.
Hirosaki, Japan Sadatomo Tasaka

Contents
Part I Definition, Epidemiology, and Pathophysiology

1 Definition of ARDS: Does the Berlin Definition Fit the Clinical
Entity and Predict the Outcome? �� 3
Satoru Hashimoto
2 Epidemiology and Risk Factors of ARDS: How Many Is the Real
Incidence of ARDS? �� 19
Kiyoyasu Kurahashi
3 Pathophysiology of ARDS: What Is the Current Understanding
of Pathophysiology of ARDS? �� 33
Sadatomo Tasaka
Part II Diagnosis
4 Imaging Diagnosis of ARDS: How Can We Know the Severity
and Prognosis from the Lung Imaging?�� 55
Tomoo Kishaba
5 Serum Markers of ARDS: How Can We Know the Severity
and Prognosis from the Serum Markers?�� 67
Taku Nakashima and Noboru Hattori
Part III Management
6 Ventilatory Management for Patients with ARDS: Established
and Rapidly Evolving Strategies�� 81
Yasuhiro Norisue
7 Noninvasive Ventilation and High-Flow Oxygen Therapy
for ARDS: Does Noninvasive Ventilatory Management
Improve the Outcome of ARDS Patients? �� 89
Toshiki Yokoyama and Yasuhiro Kondoh
ix
x Contents
8 Fluid and Nutritional Management of ARDS: What Is the Ideal

Fluid and Nutritional Management for an ARDS Patient? �� 105
Shinichiro Ohshimo
9 CHDF and ECMO for ARDS: Does CHDF and ECMO Improve
the Outcome of ARDS Patients?�� 121
Shinhiro Takeda and Keisuke Ohyama
10 Physiotherapy and Early Rehabilitation for Patients
with ARDS: Does Physiotherapy Improve the Functional
Outcome of ARDS Patients? �� 127
Ryo Kozu, Masatoshi Hanada, Masato Oikawa, Hiroki Nagura,
Rina Takeuchi, and Motohiro Sekino
Part IV Current Topics

11 MicroRNAs and Extracellular Vesicles for Diagnosis of ARDS:
Can MicroRNAs and Extracellular Vesicles Be Helpful for Early
Diagnosis or Risk Evaluation of ARDS?�� 147
Mitsuhiro Yamada
12 Stem Cell Therapy and Regenerative Medicine for ARDS:
Can Stem Cell Therapy and Regenerative Medicine Contribute
to the Protection or Recovery of the Injured Lungs? �� 159
Makoto Ishii
13 Imaging Technique for Ventilatory Management
of ARDS Patients: Novel Monitoring Tool—Electrical
Impedance Tomography�� 171
Atsuko Shono and Toru Kotani
Part I
Definition, Epidemiology,
and Pathophysiology
Chapter 1
Definition of ARDS: Does the Berlin
Definition Fit the Clinical Entity
and Predict the Outcome?
Satoru Hashimoto
Abstract Acute respiratory distress syndrome (ARDS) is a collective term for the
pathological conditions that develop acutely, following preexisting underlying dis-
eases or injuries, resulting in extremely severe hypoxemia caused by non-hydrostatic
pulmonary edema due to diffuse lung injury. Ever since its first description in 1967,
the syndrome has been extensively investigated but continued as a contributor to the
high mortality of patients in ICU settings. The American-European Consensus
Conference (AECC) definition reported in 1994 was the first generally agreed-upon
definition for ARDS. Although the AECC definition facilitated the many clinical
trials, a number of limitations emerged. The Berlin definition established in 2012
was a revised version of the AECC definition maintaining a link to prior definition
with refinement of diagnostic criteria of timing, chest imaging, origin of edema, and
hypoxemia. The Berlin definition showed qualitative improvements over the AECC
definition in several aspects. Three mutually exclusive categories of mild, moderate,
and severe ARDS were validated as they were associated with higher mortality rates
from mild to severe form of ARDS. The Berlin definition has been widely accepted,
but it still has several limitations that require further investigations to establish a
better definition of ARDS.
Keywords Berlin definition · AECC definition · Clinical criteria
S. Hashimoto (*)
Department of Anesthesiology and Intensive Care Medicine, Kyoto Prefectural University of
Medicine, Kyoto, Japan
e-mail: satoru@koto.kpu-m.ac.jp
© The Author(s), under exclusive license to Springer Nature Singapore Pte 3

Ltd. 2022
S. Tasaka (ed.), Acute Respiratory Distress Syndrome, Respiratory Disease
Series: Diagnostic Tools and Disease Managements,
https://doi.org/10.1007/978-981-16-8371-8_1
4 S. Hashimoto
1 Introduction
Acute respiratory distress syndrome (ARDS) is a collective term for the pathologi-
cal conditions that develop acutely, following preexisting underlying diseases or
injuries, resulting in extremely severe hypoxemia caused by diffuse lung injury. The
pathophysiology of ARDS is a diffuse pulmonary edema that cannot be explained
by cardiac failure, renal failure, or overhydration. Namely, the edema is not caused
by an increase in capillary hydrostatic pressure but an increased alveolar permeabil-
ity due to the disruption of the lung endothelium and the alveolar epithelium [1]. In
general, patients have various kinds of risk factors that trigger the acute develop-
ment of the lung injury within several days that require tracheal intubation with the
mechanical ventilation, and sometimes extracorporeal membrane oxygenation
(ECMO). Efforts to find an effective treatment to increase survivability and decrease
mortality rates are still ongoing. Although no effective pharmaceutical measures
have not been found, it is believed that the refined critical care setting offered a
considerable decrease in mortality nowadays. Still, specific clinical definition is
imperative for the clear diagnosis, prognosis, and severity of the illness to provide
appropriate therapeutic measures for clinicians.
2 Before 1967
Laennec reported a queer condition that showed pulmonary edema without heart
failure and described it as an idiopathic anazarca in 1821. This would be the first
historically reported syndrome now recognized as acute respiratory distress syn-
drome (ARDS) [2].
Inhalation of phosgene and chlorine, chemical weapons used during the World
War I era, posed devastating risks on many casualties. Once victims were exposed
to these gases, the symptom of acute lung injury progressed gradually, usually overt
on the following day [3]. Near the end of World War II, some refractory respiratory
distress was identified among soldiers with non-thoracic injury and the syndrome
was called as “wet lung” or “shock lung.” During Vietnam war, the more casualties
were properly and promptly salvaged from battlefield, the more this strange lung
syndrome became evident. Many soldiers succumbed unexpectedly due to respira-
tory distress during convalescence from well resuscitated traumatic or hemorrhagic
shock [4]. The syndrome was called Da Nang lung as many cases were seen at a
medical center at Da Nang in Vietnam, and some doctors suspected these cases as
an endemic. Military doctors who then returned to private practice in a civilian
environment encountered similar respiratory failure among citizen of all ages in the
USA and suspected it as Da Nang lung. Then, they finally found the right answer in
the publication by Ashbaugh and colleagues in 1967 [5, 6].
1 Definition of ARDS: Does the Berlin Definition Fit the Clinical Entity and Predict… 5
3 1967–1992
3.1 First Report of ARDS by Ashbaugh and Colleagues
Ashbaugh and colleagues described 12 patients with refractory respiratory distress

followed by several clinically unrelated disorders such as viral pneumonia, severe
multiple trauma with shock, acute pancreatitis, or gastric aspiration. The abnormali-
ties have distinguished them from among 272 patients who had received respiratory
support in the intensive care units at that time period. They observed acute onset of
tachypnea, hypoxemia, and loss of lung compliance together with the effectiveness
of positive end-expiratory pressure (PEEP) to combat these symptoms. They also
postulated the lack of surfactant activity in the alveoli and suggested the use of cor-
ticosteroids, inotropes, and diuretics in some cases. At autopsy, they observed heavy
and deep reddish lung resembling liver tissue. Microscopic appearance of the lungs
showed diffuse interstitial inflammation with hyaline membranes and fibrosis was
present in patients who died after a protracted course [5]. Although they described
the syndrome as acute respiratory distress, 4 years later they coined the term “adult
respiratory distress syndrome” as ARDS [7], because they address the notion of
ARDS as an adult version of infant respiratory distress syndrome (IRDS), a syn-
drome of premature infants caused by the insufficiency of surfactant production and
lung immaturity. Table 1.1 shows six characteristic findings proposed by Petty and
Ashbaugh that became the source of concept and diagnostic criteria for ARDS defi-
nition. [7].
After this publication, no widely accepted definition of ARDS was seen for a
quarter of a century. During this period, the incidence or the mortality of ARDS
varied as it could say that each facility has its own definition of ARDS. Garber et al.
identified a total of 83 clinical ARDS studies from 1966 to 1994, and found only
49% of studies provided some definition of ARDS. At least seven substantially dif-
ferent definitions were found during this period that should cause significant varia-
tion in the incidence and mortality of ARDS [8].
Table 1.1 Clinical It occurs from an unrelated variety of direct and

features of ARDS depicted indirect lung insults.
by Petty and Ashbaugh [7] It reduces lung compliance due to alveolar and/or
interstitial fluid and loss of surfactant activity.
It shows no sign of left cardiac failure.
It causes refractory hypoxemia despite
administration of supplemental oxygen, sometimes
responding to PEEP.
It shows diffuse infiltration of the bilateral lung on
chest X-ray.
It shows diffuse alveolar infiltration at autopsy
compatible with diffuse alveolar damage.
6 S. Hashimoto
3.2 Murray’s Definition with Lung Injury Score
In 1988, Murray and colleagues reported their definition of ARDS incorporating

timing, risk factors, and severity (Table 1.2). The severity was measured by a Lung
Injury Score (LIS) also shown in Table 1.2 [9]. Although LIS remains a commonly
utilized measure of lung injury severity, there has been no report that the LIS is valid
for the marker of mortality risk [10, 11].
Table 1.2 Expanded Acute or Chronic, depending on the course mild to

definition of ARDS by moderate or severe (ARDS) lung injury, depending
Murray [9] on lung injury score (LIS) preexisting direct or
indirect disease or conditions lung injury score (LIS) Score
1. Chest roentgenogram score
No alveolar consolidation 0
Alveolar consolidation confined to 1 quadrant 1
Alveolar consolidation confined to 2 quadrants 2
Alveolar consolidation confined to 3 quadrants 3
Alveolar consolidation in all 4 quadrants 4
2. Hypoxemia score
PaO2/FlO2 ≥ 300 0
PaO2/FlO2225–299 1
PaO2/FlO2 175–224 2
PaO2/FlO2 100–174 3
PaO2/FlO2 < 100 4
3. PEEP score (when ventilated)
PEEP ≥5 cm H2O 0
PEEP 6–8 cm H2O 1
PEEP 9–11 cm H2O 2
PEEP 12–14 cm H2O 3
PEEP ≥15 cm H2O 4
4. Respiratory system compliance score (when available)
Compliance ≤80 mL/cm H2O 0
Compliance 60–79 mL/cm H2O 1
Compliance ≤19 mL/cm H2O 4
The final score is obtained by dividing the aggregate score by the
number of components that were used. Final lung injury score: no
lung injury: score 0; mild to moderate lung injury score 0.1–2.5;
severe lung injury (ARDS): >2.5
4 1992–2012
4.1 AECC Definition
In 1992, a series of meetings were held during annual conferences of the American
Thoracic Society and European Society of Intensive Care Medicine to discuss a
clear and uniform definition of ARDS. The report was published in 1994 by the
name of the American-European Consensus Conference (AECC). This so-called
AECC definition was the first widely accepted and used ARDS definition. First of
all, they decided to call ARDS as “acute” (rather than “adult”) respiratory distress
syndrome. The consensus definition consists of four components, timing, oxygen-
ation, chest XP, and pulmonary artery occlusion pressure (or no clinical sign of left
arterial hypertension) (Table 1.3). It classified lung injury by PaO2/FiO2 ratio.
Patients with PaO2/FiO2 ≤ 300 were defined as acute lung injury (ALI) and those
who showed PaO2/FiO2 ≤ 200 (severer form of ALI) were defined as
ARDS. Although ALI is an umbrella term for all patients with PaO2/FiO2 ≤ 300, it
is frequently and misleadingly used for patients with PaO2/FiO2 between 201 and
300. Namely, all patients with ARDS have ALI, but not all patients with ALI have
ARDS (see Fig. 1.1a). Thus, a milder form of ALI was sometimes called ALI with-
out ARDS.
AECC members explained that although ARDS is caused by different types of
risk factors, similar clinical features make clinicians understand ARDS as a sin-
gle entity rather than characterize the individual risk factors as separate clinical
entities. At the same time, AECC members noted that it would be useful to think
of the pathogenesis as consisting of two pathways: direct effects of an insult on
lung cells and the indirect result of an acute systemic inflammatory response
(Table 1.4).
Table 1.3 AECC definition [12]

Recommended criteria for acute lung injury (ALI) and acute respiratory distress syndrome
(ARDS)
Pulmonary artery wedge
Timing Oxygenation Chest radiograph pressure
ALI Acute PaO2/FIO2 ≤ 300 mm Bilateral infiltrates ≤18 mm hg when measured
criteria onset hg (regardless of PEEP seen on frontal or no clinical evidence of
level) chest radiograph left atrial hypertension
ARDS Acute PaO2/FIO2 ≤ 200 mm Bilateral infiltrates ≤18 mm hg when measured
criteria onset hg (regardless of PEEP seen on frontal or no clinical evidence of
level) chest radiograph left atrial hypertension
8 S. Hashimoto
AHRF
ALI
AECC
definition
ARDS
Peumonia
mild moderate severe Berlin

ARDS ARDS ARDS definition
AHRF
Fig. 1.1 Schematic explanation of conceptual difference and resemblance of ARDS between the
AECC definition and the Berlin definition based on the degree of oxygenation. Acute hypoxemic
respiratory failure (AHRF) is a general term applied for patients with refractory severe hypoxemia
usually defined as PaO2/FiO2 ≤ 300. Ketchams and colleagues reported that they identified 385
patients with AHRF and of whom 33% met criteria with Berlin definition [13]. Other causes of
AHRF would be hydrostatic lung edema, volume overload, right-to-left intracardiac shunts, or
pneumonia without fulfilling the criteria of ARDS definition, etc.
Table 1.4 Clinical Direct injury Indirect injury

disorders associated with
Common causes Common causes
the development of the
ARDS [14] Pneumonia Sepsis
Aspiration pneumonia Multiple trauma
Less common causes Less common causes
Pulmonary contusion Acute pancreatitis
Near drowning Drug overdose
Inhalation injury Cardiopulmonary bypass
Fat embolism Transfusion of blood
4.2 Limitation of AECC Definition
Although only proven therapeutic measure so far was lung protective strategy with
low tidal volume, the AECC definition was simple to apply in a clinical setting and
has been adopted for many subsequent randomized control trials for the next two
decades. Nonetheless, this definition had several flaws that challenged its reliability
and validity to conduct epidemiological studies and clinical trials. First, at autopsy,
only half of the patients diagnosed as ARDS by AECC definition revealed typical
diffuse alveolar damage, the histopathological hallmark for the acute phase of
ARDS [15]. Second, mechanical ventilatory support was not considered a require-
ment in defining ALI or ARDS, as they presumed ventilator therapy resources and
physician’s practice patterns vary considerably. But in reality, it is evident that the
level of PEEP or FiO2 can significantly influence oxygenation [16]. Third, although
the chest radiograph is essential to diagnose ARDS, high inter-observer variability
has been pointed out and sometimes makes it difficult to apply the result for proper
diagnosis [17, 18]. Fourth, the onset of respiratory failure was simply defined as
“acute,” not indicating a specific timeframe explicitly. Fifth, routine use of pulmo-
nary artery catheters lost popularity as its use was associated with increased mortal-
ity [19], and pulmonary artery catheters guided therapy for ARDS showed no benefit
compared to central venous catheter-guided therapy [20]. Also, hydrostatic edema
in the form of cardiac failure or fluid overload may coexist with ARDS [20].
4.3 DELPHI Definition
The Delphi technique is a group interaction method of gaining consensus on a par-

ticular topic. Ferguson and colleagues implemented this technique to develop a new
definition of ARDS. The definition was named after the technique as Delphi defini-
tion [21]. They also suggested that testing of sensibility, feasibility, reliability, and
validity would be needed for the making reliable definition. This structured com-
munication technique was applied afterward, such as to making of the Berlin defini-
tion or Surviving Sepsis Campaign guidelines [21, 22]. Subsequently, they compared
the diagnostic accuracy among the AECC definition, the lung injury score (LIS),
and the Delphi definition [23]. They showed that 42 out of 138 autopsied patients
who were being mechanically ventilated had diffuse alveolar damage. Only 20 of
these 42 patients had any mention of ARDS in the medical chart suggesting ARDS
is often underrecognized in clinical practice. The sensitivities were not significantly
different among three definitions. Whereas, specificity was significantly but moder-
ately higher for the LIS and Delphi definition than for the AECC definition [21].
The Delphi definition did not gain popularity but created the atmosphere that the
AECC definition should be reconsidered (Table 1.5).
10 S. Hashimoto
Table 1.5 Delphi definition of ARDS by Ferguson and colleagues, modified from original
table [21]
Timing Within 72 h
Oxygenation PaO2/FiO2 ≤ 200 mm hg with PEEP ≥10 cm H2O
Chest radiograph Bilateral airspace disease involving ≥2 quadrants
Noncardiogenic in No clinical evidence of congestive heart failure PAWP ≤ 18 mm hg or
origin LV ejection fraction ≥40%
Decreased lung Static respiratory system compliance ≤50 mL/cm H2O (with patient
compliance sedated, Vt of 8 mL/kg, IBW, PEEP ≥10)
Predisposition Presence of recognized risk factor for ARDS
PAWP Pulmonary artery wedge pressure, LV Left ventricle, Vt tidal volume, IBW ideal body weight
5 After 2012
5.1 Berlin Definition; Draft Definition
In 2011, a panel of ARDS experts convened at the 24th annual meeting of the
European Society of Intensive Care Medicine held in Berlin. They developed a con-
ceptual model of ARDS mainly based on AECC definition, maintaining a link to
prior AECC definitions with diagnostic criteria of timing, chest imaging, origin of
edema, and hypoxemia, and proposed a draft definition [24]. Using teleconferenc-
ing, in-person discussions and retrospective data for checking validity, the panel
published the final version of definition in 2012 [24]. In revising the definition of
ARDS, the panel emphasized feasibility, reliability, face validity (i.e., how clini-
cians recognize ARDS), and predictive validity (i.e., ability to predict response to
therapy, outcomes, or both).
In the draft definition, the term, acute lung injury (ALI) was eliminated. PEEP of
at least 5 cm H2O was required to obtain the value of PaO2/FiO2 ratio. ARDS was
then classified into three mutually exclusive subcategories (See Fig. 1.1 b), based on
the degree of oxygenation, as mild (200 < PaO2/FiO2 ≤ 300 with PEEP or
CPAP ≥5 cm H2O), moderate (100 < PaO2/FiO2 ≤ 200 with PEEP ≥ 5 cm H2O), and
severe ARDS (PaO2/FiO2 ≤ 100 with PEEP ≥ 5 cm H2O). As nearly all patients with
ARDS identified within 7 days, the timing for onset was proposed as within 1 week
of a clinical insult or new/worsening respiratory symptoms. As for the chest imag-
ing, bilateral opacities could be demonstrated either chest radiograph or CT scan.
The utilization of pulmonary artery catheter to measure pulmonary wedge pressure
was excluded. Patients can be diagnosed as having ARDS if they have respiratory
failure with risk factors for ARDS. If no ARDS risk factor is found, objective assess-
ment (e.g., echocardiography) will be required to exclude the hydrostatic edema or
overhydration. In addition, the panel suggested to add four ancillary variables for
severe ARDS; radiographic opacity on chest X-ray involving 3 or 4 quadrants, static
compliance of respiratory system (≤40 mL/cm H2O), positive end-expiratory pres-
sure (≥10 cm H2O), and corrected expired volume per minute (≥10 L/min).
5.2 B
erlin Definition; Empirical Evaluation
of the Draft Definition
The draft definition was then evaluated empirically using database from four multi-
center clinical studies (4188 patients with ARDS) [25–28] and three single-center
physiological studies (269 patients with ARDS) [29–31]. Using these databases,
characteristics of patients in each category of ARDS were determined and predic-
tive validity for mortality was examined. The panel convened 4 months later by
multiple teleconferences to produce a final version of the definition. The final ver-
sion of the Berlin definition for ARDS is shown in Table 1.6. While the AECC defi-
nition classified ARDS into direct and indirect lung injury categories, the Berlin
definition abandoned this idea and emphasized that knowing underlying disease
regardless of its direct or indirect nature leading to ARDS would serve to guide
therapy (Table 1.7). And risk factor was partly incorporated into the definition [32].
The four ancillary variables were revealed to have no better predictive validity of
severe ARDS for mortality and were removed from the final definition [24]. The
panel also considered to include potential diagnostic criteria, such as minimal FiO2
requirement, SpO2/FiO2 ratio, higher PEEP requirement, thoracic computed tomog-
raphy, electrical impedance tomography, extravascular lung water, inflammatory
biomarkers, genetic markers, plateau pressure, dead space, respiratory system com-
pliance, minute ventilation, and pathological finding of diffuse alveolar damage by
lung biopsy. However, they were rejected during definition development because of
a lack of association data, impact on feasibility, or both [32]. In addition, to enhance
inter-observer reliability, a reference set of chest radiographs were provided, and
illustrative vignettes were created to guide judgments whether the illustrating cases
qualify as ARDS based on ruling out hydrostatic edema [32].
Table 1.6 Berlin definition [24]

Acute respiratory distress syndrome (ARDS)
Timing Within 1 week of a known clinical insult or new/worsening respiratory
symptoms
Chest Bilateral opacities—not fully explained by effusions, lobar/lung collapse, or
imaginga nodules
Origin of Origin of edema—respiratory failure not fully explained by cardiac failure or
edema fluid overload; need objective assessment (e.g., echocardiography) to exclude
hydrostatic edema if no risk factor present
Oxygenationb Mild Moderate Severe
200 < PaO2/FiO2 ≤ 300 with PEEP or 100 < PaO2/ PaO2/FiO2 ≤ 100
CPAP ≥5 cm H2Oc FiO2 ≤ 200 with with PEEP
PEEP ≥5 cm H2O ≥5 cm H2O
a
Chest X-ray or CT scan
b
If altitude higher than 1,000 m, correction factor should be made as follows: PaO2/FiO2 × (baro-
metric pressure/760)
c
This may be delivered non-invasively in the mild ARDS group
12 S. Hashimoto
Table 1.7 Common risk Risk factors

factors for ARDS by Berlin Pneumonia
Definition [24]
Non-pulmonary sepsis
Aspiration of gastric contents
Major trauma
Pulmonary contusion
Pancreatitis
Inhalational injury
Severe burns
Non-cardiogenic shock
Drug overdose
Multiple transfusions or transfusion-associated acute lung
injury (TRALI)
Pulmonary vasculitis
Drowning
As for the predictive validity of the Berlin definition, the three mutually exclu-
sive categories of mild, moderate, and severe ARDS were validated, as they were
associated with the significant progressive higher mortality rate from mild to mod-
erate to the severe form of ARDS, 27% [95%CI, 24–30%], 32% [95%CI, 29–34%],
and 45% [95%CI, 42–48%], respectively, based on the data from four clinical trials.
The definition performed similarly in the physiological database as in the clinical
database. Likewise, ventilator-free days declined, and the median duration of
mechanical ventilation in survivors increased with stages of ARDS from mild to
moderate to severe. Although, each stage is associated with increased mortality,
prediction ability of mortality using this definition is still poor, with an area under
the curve of only 0.577, and has not been much improved compared to 0.536 for the
AECC definition [24].
5.3 Berlin Definition; Limitation of the Berlin Definition
The Berlin definition of ARDS offers several major advances over previous defini-
tions and numerous clinical trials proposed and are now in progress [33]. However,
there remains considerable controversy about the Berlin Definition whether it is
valid and meets clinicians’ need.
First, as it does not eliminate the underlying heterogeneity, some investigators are
afraid that the Berlin definition may merely contribute to generating additional nega-
tive trials [34]. Second, as for the interobserver reliability of ARDS diagnosis,
Sjoding and colleagues reported that clinicians had only moderate interobserver
agreement when diagnosing ARDS, and major cause of the variability was the inter-
pretation of chest images [35]. Third, the correlation of pathological findings of dif-
fuse alveolar damage by open lung biopsy and ARDS diagnosed by Berlin definition
is modest [36]. Still, fewer than half of patients with Berlin definition ARDS have
diffuse alveolar damage [37]. Fourth, Villar and colleagues showed that under stan-
dardized ventilator settings (VT = 7 mL/kg of predicted body weight, PEEP = 10 cm
H2O, and FiO2 0.5), measurement of PaO2/FiO2 24 h from the initial assessment
improved the stratification and resulted in better predictive validity for the mortality
[38, 39]. As they pointed out, under non-standardized assessment of oxygenation,
PaO2/FiO2 can vary considerably with PEEP and FiO2 titration, further researches
would be needed to determine whether incorporating more specific guidelines based
on a standard method of evaluating oxygenation status (i.e., a specific level of PEEP
and FiO2) add value to the definition. Fifth, most recent epidemiological data were
provided by LUNG-SAFE (Large Observational Study to Understand the Global
Impact of Severe Acute Respiratory Failure). Of 29,144 patients who were admitted
to the ICUs, 12,906 (44.3%) received mechanical ventilation upon ICU admissions,
and 3022 (10.4%) fulfilled the Berlin definition of ARDS. The clinical recognition
of ARDS was 51.3% in mild, and 78.5% in severe ARDS. These findings suggest
that ARDS was underrecognized in the ICU settings [40]. However, some investiga-
tors criticized that their observation was an overestimation of incidence caused by
incapability of Berlin definition to identify true ARDS patients [41]. Caser and col-
leagues prospectively evaluated 130 ARDS (fulfilled with AECC or Berlin defini-
tion) patients in the Brazilian ICU setting, and did not observe significant differences
in mortality among the mild, moderate, and severe ARDS based on the Berlin defini-
tion, and could not show any improvement of predictive mortality compared to
AECC definition (area under the ROC curve was 0.5625 for the AECC and 0.5664
for the Berlin definition, P = 0.9510) [42]. Finally, although noninvasive ventilation
or high-flow nasal cannula without positive pressure ventilation became popular
nowadays, definition applicable in these settings was lacking.
5.4 Future Perspective
In general, a precise and appropriate definition is absolutely necessary to facilitate

clinicians in making timely decisions for diagnosis, specific therapies or prognosis
of the disease, and investigators in proceeding reproducible clinical trials. The fun-
damental challenge to making a better definition of ARDS is the lack of a gold
standard diagnostic test for ARDS. Like other critical illness syndromes such as
sepsis, ARDS is a heterogeneous syndrome with complex pathology and mecha-
nisms. Proposed definitions so far are based on clinical criteria and did not offer
enough reliability and validity, unable to identify patients with specific disease pro-
cesses such as diffuse alveolar damage. This situation makes clinicians and research-
ers difficult to identify ARDS properly and leads to paucity of successful therapeutic
interventions in ARDS [43]. Some investigators insist that for patients who meet the
clinical definitions for ARDS, there are subgroups/subphenotypes of patients who
are more or less likely to benefit from a particular therapy. There are several factors
for identifying phenotypes based on physiological (such as PaO2/FiO2 ratio, dead
14 S. Hashimoto
space fraction, or driving pressure), clinical (age, sex, ethnicity, routine laboratory
tests, and imaging techniques), and biologic (genetic polymorphisms, genomic,
transcriptomic, proteomic, or metabolomic) data [44, 45].
As for the clinical data, if anyone would find some clinical phenotypes in ARDS
identifiable at hospital that correlate with the host response patterns and clinical
outcomes, that would facilitate clinicians for a better and tailored management of
this heterogeneous syndrome. Calfee and colleagues identified two phenotypes of
ARDS differently responding to treatment and named them as hyperinflammatory
or hypoinflammatory subphenotypes. These phenotypes were identified based on
the baseline demographics (age and sex), baseline clinical data (direct and indirect
ARDS risk factors, bilirubin, creatinine, platelet count, PaO2 to FiO2 ratio, plateau
pressure, tidal volume, and use of vasopressors), and baseline interleukin 6 and
sTNFr1 values [44, 46]. Further study will be needed to validate this strategy to
incorporate the idea into future definitions. As for the biologic phenotyping, the
researchers have just started the studies and now expanding the evidence steadily in
basic science. Comprehensive definition would be accomplished when the exact
phenotyping is established that would minimize heterogeneity of the syndrome and
enable stratification of subject selection for enrollment in clinical trial and proper
treatment.
As far as we do not have a gold standard for the recognition of ARDS or its sub-
types, any new feasible diagnostic and prognostic tools more objective and accurate
than our current bedside assessment to identify the disease process will be incorpo-
rated into new draft definition and will be evaluated in terms of its feasibility, reli-
ability, and predictive/face validity. Possibly, a new definition would maintain a link
to prior definitions to facilitate the comparison of the studies.
Another aspect of the future definition is that to develop several noninvasive
techniques detecting ARDS promptly at the bedside or limited resource environ-
ment, possibly identify the candidate of mechanical ventilation beforehand. SpO2
(pulse oximetric saturation)/FiO2 ratio has been proposed as a promising noninva-
sive alternative to PaO2/FiO2 ratio [47]. Lung ultrasound is also a noninvasive and
easy to perform tool to diagnose ARDS at the bedside. Bass reported that combina-
tion of pulse SpO2/FiO2 ratio and lung ultrasound analysis enabled clinicians to
diagnose ARDS at the bedside noninvasively in a limited resource environment
where arterial blood gas measurement and chest radiography are not routinely avail-
able [48]. Riviello and colleagues suggested the validity of this combination in
Rwanda [49]. These studies should shed light on another aspect to develop a new
definition that can be used in all settings.
6 Conclusion
In this chapter, the definition of ARDS was historically summarized. It is important

to note that ARDS, as the name implies, is a syndrome, not a disease, and there is
no laboratory, imaging, or biological gold standard at this time to diagnose
ARDS. Therefore, it has to be defined by a constellation of clinical and physiologi-

cal criteria like the AECC definition and the Berlin definition. Both definitions had
enabled clinicians to prospectively identify patients with ARDS and apply suitable
therapy such as a lung protective procedure promptly or to enroll patients in many
clinical trials. However, clinical heterogeneity observed among patients diagnosed
as ARDS based on the current definitions had likely contributed to the epidemio-
logic variations among studies and the paucity of appropriate therapies for ARDS
despite a large number of promising preclinical studies and clinical trials. Specifying
distinct ARDS subgroups by the discovery of new phenotyping may substantially
change the definition of ARDS, and hopefully leading to precision/tailored treat-
ment of ARDS.
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Chapter 2
Epidemiology and Risk Factors of ARDS:
How Many Is the Real Incidence of ARDS?
Kiyoyasu Kurahashi
Abstract The incidence of acute respiratory distress syndrome (ARDS) varies sig-
nificantly from study to study, from 5.0 to 78.9 per 100,000 persons per year regard-
less of severity. Within each study, there is a trend toward higher incidence in less
severe ARDS than more severe ARDS. Among patients admitted to ICU, 16–20%
of patients under mechanical ventilation are diagnosed as ARDS.
ICU mortality among ARDS patients is between 30% and 49%, and hospital
mortality is between 37% and 58% from data collected after the American–European
Consensus Conference (AECC) definition. Some reports conclude that trends in
mortality are declining, whereas some do that the mortality remains the same, at
least after the AECC definition. The mortality of ARDS in randomized controlled
studies is generally lower than that in observational studies. In this way, the epide-
miology of ARDS is not relatively conclusive.
Risk factors for ARDS include pneumonia, sepsis, aspiration, and trauma as pri-
mary diseases; chronic alcohol abuse, cigarette smoking, air pollution, and hypo-
proteinemia as comorbidities. Interestingly, patients with diabetes have a lower risk
of developing ARDS. Transfusion, especially from multiparous women, inadequate
antimicrobial therapy, mechanical ventilation with injurious tidal volumes, and
aspiration are hospital-based modifiable exposures. There is an interaction of fac-
tors as risk enhancement in the development of ARDS. Thus, evading as many risk
factors as possible is essential when treating ARDS patients or those at risk.
Keywords Multi-hit theory · Injurious ventilation · Transfusion-related acute lung

injury · Lung injury prediction score
K. Kurahashi (*)
Department of Anesthesiology and Intensive Care Medicine, International University of
Health and Welfare School of Medicine, Chiba, Japan
e-mail: kiyok@iuhw.ac.jp

Ltd. 2022
https://doi.org/10.1007/978-981-16-8371-8_2
20 K. Kurahashi
1 Introduction
Acute respiratory distress syndrome (ARDS) is a condition of lung injury and clini-
cal manifestations, including oxygenation impairment caused by various insults
to the lungs or other organs. The incidence and mortality of ARDS vary from study
to study. One reason is that ARDS is a syndrome that consists of multiple pathologi-
cal conditions but not a single disease. In addition, the definition of ARDS has been
changed multiple times. Another reason is that each study or database is based on a
different region, size, and organizational type, or the number of ICU beds of
hospitals.
2 Epidemiology
2.1 Incidence of ARDS
The incidence of ARDS varies from 10.6 to 78.9 per 100,000 persons per year for
mild ARDS, termed as acute lung injury (ALI) in the American–European Consensus
Conference (AECC) definition, and 5.0–58.7 per 100,000 persons per year for mod-
erate to severe ARDS (Table 2.1) [1–6].
From a retrospective review of patients admitted to two ICUs in Iceland, the
average crude incidence of moderate to severe ARDS was 6.76 per 100,000 person-
years [7]. The latest and current ARDS definition, the Berlin definition, was pub-
lished in 2012 [8]. Subsequently, the LUNG SAFE study provided valuable data in
a cross-sectional analysis of 29,144 patients in 50 countries from 5 continents dur-
ing the winter of 2014 [9]. In this study, the prevalence of ARDS in patients in
intensive care was 10.4%, and ARDS was identified in 23.4% of all ventilated
patients. In the study; however, about 40% of the patients with ARDS were not
recognized by clinicians, suggesting that ARDS is under-recognized.
2.2 Clinical Risk Factors
In nearly all large cohorts, the risk factors for ARDS demonstrate a consistent pat-
tern of primarily patients with pneumonia (35–50%), followed by nonpulmonary
sepsis (30%), aspiration (10%), and trauma (10%), with an assortment of less com-
mon risk factors and some cases with no identifiable risk [10]. In blunt and penetrat-
ing trauma, the severity and duration of shock, chest injury, the number of blood
product transfusions, the presence of traumatic brain injury, and the quantity of
crystalloid fluids (as a volume expander) can each contribute to the risk of develop-
ing ARDS [11, 12].
Table 2.1 The incidence and mortality for patients with ARDS after AECC definition
Study (First author) Luhr [1] Bersten [2] Brun-Buisson [3] Rubenfeld [4] Linko [5] Villar [6]
Year published 1999 2002 2004 2005 2009 2011
Countries Europe Australia Europe USA Finland Spain
Sites Multicenter Multicenter Multicenter Multicenter Multicenter Multicenter
Study period 8 Weeks (Oct– 2 Months (Oct– 2 Months (Feb– 1 Year (April 8 Weeks (April– 1 Year (Nov
Nov 1997) Nov 1999) Mar 1999) 1999–July 2000) June 2007) 2008–Oct 2009)
Study design Prospective Prospective Prospective Prospective Prospective Prospective
Cases (per 100,000 ALI 17.9 34 – 78.9 10.6 –
population-year) ARDS 13.5 28 – 58.7 5 7.2
ICU mortality (%) ALI 28 22.6 –
ARDS 30 49.4 42.7
Hospital mortality (%) ALI – 32.7 38.5 –
ARDS – 57.9 41.1 47.8
28-day mortality (%) ALI 32
ARDS 34
90-day mortality (%) ALI 42.2
ARDS 41.2
ALI/ 47
ARDS
ALI acute lung injury, ARDS acute respiratory distress syndrome
Note that ALI is termed as mild ARDS, a 200 < PaO2/FIO2 ≤ 300 Torr, in the American–European Consensus Conference (AECC) definition. In this context,
ARDS is defined as moderate to severe ARDS, a PaO2/FIO2 ≤ 200 Torr
2 Epidemiology and Risk Factors of ARDS: How Many Is the Real Incidence of ARDS?
21
22 K. Kurahashi
The incidence of ARDS increased with age from 16 per 100,000 person-years for
those 15–19 years of age to 306 for 75–84 [4].
2.3 Comorbidities and Susceptibility to ARDS
Several comorbidities and modifiable risk factors have been studied and identified
to be linked to the development of ARDS including chronic alcohol abuse [13–15],
cigarette smoking [16], air pollution [17, 18], and hypoproteinemia [19]. Obesity
and ARDS appear to share alterations in inflammation, endothelial dysfunction, and
oxidative stress. This raises the possibility that obese patients may be at higher risk
of developing ARDS; however, data supporting such an association are inconclusive
[20]. It is probably due to but not limited to decreased total respiratory system com-
pliance and formation of atelectasis without the development of ARDS and indis-
tinct radiographic images of lungs caused by excessive soft tissue thickness in obese
patients. In addition, obese patients may receive different care than nonobese
patients, which may impact the development of ARDS either positively or negatively.
Patients with diabetes had a lower risk of developing ARDS, the mechanism of
which is unknown. Still, three RCTs have the same trends [21–23], and a systematic
review and meta-analysis disclosed this inclination [24]. Recently, however, data
from the LUNG SAFE study showed no association between diabetes and the diag-
nosis or development of ARDS [25].
2.4 Hospital-Based Modifiable Exposures and ARDS
Adverse events were highly associated with ARDS development (odds ratio, 6.2;
95% CI, 4.0–9.7), as were inadequate antimicrobial therapy, mechanical ventilation
with injurious tidal volumes, hospital-acquired aspiration, and volume of blood
products transfused and fluids administered [26].
Transfusion-related acute lung injury (TRALI) is the leading cause of mortality
related to transfusion and is multi-factorial. Recent studies revealed that human
leukocyte antigen (HLA) and human neutrophil antigen (HNA) antibodies but not
red cells play a pivotal role in the development of ARDS [27]. The HLA and HNA-
antibodies are found mainly in blood from multiparous women; therefore, the intro-
duction of a male-only strategy for plasma donation had rapidly decreased the
incidence of TRALI. In addition, there are several risk factors on the recipient side
including recent liver surgery, chronic alcohol abuse, current cigarette smoking,
higher peak airway pressure, and positive fluid balance [28].
2 Epidemiology and Risk Factors of ARDS: How Many Is the Real Incidence of ARDS? 23
In addition to transfusion, the following are also independent risk factors of

developing ARDS for patients with blunt and penetrating trauma: the severity and
duration of shock, chest injury, the number of blood product transfusions, the pres-
ence of traumatic brain injury, and the quantity of crystalloid fluids as a volume
expander [11].
It is beyond controversy that ventilatory management is crucial; however, the
recent global observational study, LUNG SAFE, revealed only two-thirds of the
patients fell within limits for protective ventilation, defined as plateau pressure less
than or equal to 30 cm H2O and tidal volume of less than or equal to 8 mL/kg of
predicted body weight, suggesting that a considerable population of patients were
exposed to an “injurious” or rather “harmful” ventilatory condition.
2.5 Interaction of Factors as Risk Enhancement
Notably, some factors may serve as an amplifying factor in the presence of other

risks, e.g., chronic alcohol abuse with septic shock [14], air pollution with severe
trauma [17], or transfusion with hepatic surgery [27].
The Lung Injury Prediction Score (LIPS) model identifies patients at high risk
for ARDS [29]. The LIPS value, the sum of multiple predisposing conditions and
risk modifiers with weighted points, is proportional to the likelihood of ARDS
development [30]. This explains that patients exposed to various potentially harmful
factors are likely to develop ARDS. This concept is referred to as the multi-hit the-
ory of ARDS pathogenesis [31].
A paper evaluated an 8-year trend of incidence of ARDS in a relatively closed
local community [32]. During the period, they changed hospital practice including
decreased exposure to blood product transfusion, prioritizing the use of male-
predominant plasma, applying low tidal-volume mechanical ventilation, and
improved treatment of sepsis and pneumonia. They found that the incidence of
hospital-acquired ARDS decreased significantly while that of community-acquired
stays the same, suggesting that avoiding the “second hit” may reduce the develop-
ment of ARDS.
3 Mortality of ARDS
Among trials published after the AECC definition, the ICU mortality ranged from
30% to 49% and the hospital mortality from 41% to 58% (Table 2.1). Multiple fac-
tors impact the mortality of ARDS, which will be discussed.
24 K. Kurahashi
3.1 Mortality Related to Severity of ARDS
Mortality of ARDS depends on the severity of the illness, as other diseases or syn-
dromes do. From a definition standpoint, PaO2/FIO2 ratio is the only measure of
severity for ARDS. In a multicenter study of 21 hospital ICUs in Australia, the
28-day mortality of ALI and ARDS was 32% and 34%, respectively [2]. In a multi-
national cohort study conducted in 78 ICUs across 10 European countries, ICU
mortality was 22.6% and 49.4%, and hospital mortality was 32.7% and 57.9%, for
ALI and moderate to severe ARDS, respectively [3]. In the latest LUNG SAFE
study, hospital mortality was 34.9% (95%CI, 31.4–38.5%) with mild, 40.3%
(95%CI, 37.4–43.3%) with moderate, and 46.1% (95%CI, 41.9–50.4%) for those
with severe ARDS [9]. Thus, the mortality of ARDS is strongly related to the sever-
ity of ARDS, referred to as oxygenation impairment.
3.2 Mortality Related to the Cause of Lung Injury
The committee of the latest definition of ARDS, the Berlin definition, decided not

to include direct and indirect ARDS as distinct entities [33]. Patients with ARDS do
not die merely due to lung injury or hypoxemia but due to underlying conditions
including uncontrolled infection, hypotension and low output, or coagulation disor-
ders. In other words, the severity or controllability of the leading cause of ARDS
strongly contributes to mortality. Fuchs et al. demonstrated that among patients who
were ventilated on ICU admission, neither the presence, the severity, or the timing
of ARDS contribute independently to the short-term mortality risk; however, ARDS
does contribute significantly to 2-year mortality risk [34]. This implies that patients
may not die acutely from ARDS by itself but rather from the primary disease, sug-
gesting the importance of focusing on treating the conditions that led to ARDS.
3.3 Ventilatory Strategy and Mortality
It is well known that low tidal volume ventilation as compared with conventional

higher tidal volume decreases mortality among ARDS patients [35]. High PEEP had
been evaluated for its utility, especially since the benefit of low tidal-volume venti-
lation was confirmed. Multiple RCTs compared higher PEEP with the PEEP level
of the ARDSNet PEEP-FIO2 table [36–39]. None of the studies showed a benefit of
higher PEEP, and meta-analyses corroborated the fact [40, 41] with an exception by
subgroup analysis [41]. A large RCT showed increased mortality in the recruitment
maneuver with titrated PEEP arm compared with low PEEP arm [42]. A meta-anal-
ysis whose systematic reviewing process included this RCT showed no benefit or
detriment of recruitment maneuver on mortality [43]. Prone positioning for rela-
tively longer durations for moderate to severe ARDS patients is elucidated as ben-
eficial [44–46]. Veno–venous extracorporeal membrane oxygenation (v–v ECMO)
improves mortality [46, 47]. In contrast, early use of neuromuscular blocking agents
has heterogeneous results [48–50]. These ventilatory strategies for ARDS patients
are discussed in Chaps. 6 and 9.
3.4 Trends in Mortality
Even before the low tidal-volume ventilation strategy era, a number of single-center

studies that evaluated trends in mortality in association with the ARDS showed
significant declines in mortality [51, 52]. One study showed a decrease in overall
case fatality, whereas survival for those patients whose risk factor is sepsis has not
changed [53]. In a National Heart, Lung and Blood Institute (NHLBI) workshop
report published in 2010, mortality has decreased from almost 40% in studies con-
ducted in the mid to late 1990s to approximately 25% in the early 2000s [54].
However, there are conflicting results from some meta-analyses conducted over the
same period. A literature review of Zambon and Vincent shows a decrease in overall
mortality of approximately 1.1% per year from 1994 to 2006 in general populations
of patients with ARDS [55].
Regarding RCTs, Erickson and colleagues analyzed patients enrolled in the
ARDS Network clinical trials from 1996 to 2005 [56]. Crude mortality was 35% in
1996–1997 and declined during each subsequent time frame to as low as 26% in
2004–2005. When analyzed by individual causes of lung injury, there were no sta-
tistically significant temporal trends in mortality for the most common causes of
lung injury, pneumonia, sepsis, aspiration, and trauma. Phua and colleagues
searched both prospective observational studies and RCTs published between
1984 and 2006, and 18,900 patients were evaluated [57]. Mortality decreased with
time in observational studies conducted before 1994 when a consensus definition of
ALI/ARDS was published. In contrast, no temporal associations with mortality
were demonstrated in studies conducted after 1994; overall pooled weighted mor-
tality is 44.0%. In RCTs, mortality has remained relatively unchanged, whose over-
all pooled weighted mortality was 36.2%. In contrast, McNicholas et al. evaluated
hospital mortality in RCTs and prospective cohort studies of data collected from
1990 to 2014. Hospital mortality is lower and appears to have decreased signifi-
cantly over time in the RCTs, whereas mortality is higher and unchanged in pro-
spective observational studies [58]. To summarize this subject, it is difficult to
discern the temporal trends in outcomes of ARDS.
26 K. Kurahashi
3.5 Mortality Related to Organizational Factors
Raymondos et al. investigated differences in treatment and outcome of ventilated

patients with ARDS between the university and non-university hospitals in Germany
[59]. Multivariable analysis revealed odds ratio for hospital mortality in ventilated
patients with ARDS (2.89) was significantly high (p < 0.008) in non-university hos-
pitals when compared with university hospitals. The difference appears to be due to
differences in patient care including but not limited to respiratory managements such
as the use of high PEEP or low driving pressures, in which university hospitals have
higher accomplishment. Another important organizational factor, the number of ICU
beds, was independently associated with hospital survival in patients with ARDS
[60]. Having fewer ICU beds was associated with higher hospital mortality. The mor-
tality of ARDS varies according to geo-economic variations. Laffey JG and col-
leagues demonstrated that hospital survival was significantly lower in middle-income
countries than high-income European countries or high-income countries in the rest
of the world [61]. The authors stated that it might not reflect a different quality of care
but could result from differing access to critical care services or preventive medicine.
3.6 Mortality Related to Unmodifiable Factors
Mortality increased with age from 24% for patients 15–19 to 60% for patients
85 years of age or older [4]. Another meta-analysis also revealed an age-related
mortality increase [57]. It indicated that patient age (odds ratio per additional
10 years, 1.27; 95% CI, 1.07–1.50) was a factor associated with mortality. Men had
higher average ARDS-related mortality than women in two studies that analyzed
patients who died with a diagnostic code for ARDS in the United States [62, 63].
There is higher mortality for African–Americans [62], black and Hispanic [64], or
non-Hispanic Black people [65] when compared with white or other racial back-
grounds. Using a National Trauma Data Bank of the USA, Ryb et al. found that
Hispanics experienced higher odds for ARDS-associated mortality among blunt-
trauma patients [66]. In contrast, there is a protective effect of black people for
ARDS incidence using Caucasian as a reference (OR, 0.73; 95% CI, 0.58–0.91) and
there was no association between black people and ARDS-associated mortality in
those trauma patients.
3.7 Genetic Factors and ARDS
Genetic factors have been suggested; however, it is not fully understood [67]. The
genomic contribution to ARDS is not immediately apparent for several reasons:
ARDS is a complication of a significant environmental insult, and the requirement
for such a large environmental insult prevents the use of genetic linkage studies of
family pedigrees to identify genetic influences on ARDS risk or mortality; ARDS is
a heterogeneous disease with various pathogenic processes contributing differently
in different patients depending on clinical factors as well as genetics; ARDS lacks a
simple diagnostic test and is under-recognized by clinicians; and cohorts of patients
with ARDS and at-risk patients have not achieved the sample sizes typically required
for genome-wide association studies that identify multiple risk variants [68]. Despite
these difficulties, some genes have been suggested to contribute to ARDS develop-
ment, severity, or mortality. Platelets are critical cells in the pathogenesis of ARDS. A
variant in LRRC16A, which encodes a protein important in actin-based cellular pro-
cesses, associated with platelet count during critical illness [69] decreased ARDS
risk and mortality [70]. High IL-1β is associated with poor outcomes in patients with
ARDS. Variation in the IL-1 pathway gene IL1RN is associated with ARDS risk
[71]. Plasma angiopoietin-2 (Ang-2) is a biomarker of endothelial activation and
permeability with a strong potential to contribute causally to ARDS pathogenesis.
Genetic association studies have implicated genetic variation in the angiopoietin-2
gene (ANGPT2) in ARDS risk [72], which was subsequently validated in critically
ill trauma patients [73]. Furthermore, using a quantitative trait loci analysis, five
ANGPT2 genetic variants in a population with European ancestry have been associ-
ated with increased levels of plasma angiopoietin 2, and two of the five variants were
associated with increased ARDS risk; in contrast, no significant associations were
found with this gene in people with African ancestry [74]. These findings could help
propel the field toward precision medicine options for ARDS.
3.8 Outcomes Other than Mortality
Mortality is the essential endpoint in studies to measure the outcome of ARDS. Many

studies evaluate endpoints other than mortality; however, there are no proven sur-
rogate measures for mortality in ARDS. For example, studies that demonstrated the
changes in oxygenation index in ARDS confer no mortality benefit [40, 75].
Duration of mechanical ventilation and ventilator-free days are potentially biased
outcomes because the decision to discontinue mechanical ventilation is often sub-
jective unless driven by an explicit protocol [54].
3.9 Quality of Life After ARDS
There have been growing concerns about long-term outcomes of ARDS patients
including physical, psychological, and social disabilities. Survivors commonly suf-
fer from muscle weakness and neuropsychiatric problems, such that fewer than 50%
have returned to work 12 months after leaving intensive care [76]. Notably, respira-
tory function is not a predominant factor for disabilities. Among ARDS survivors,
28 K. Kurahashi
physical and psychological health states were closely associated [77]. Female,
Hispanic, and smokers had the poorest physical and mental health states 6 months
after the onset of ARDS. Furthermore, newly developed or persistent psychological
problems in both patients and family caregivers are an issue even 5 years after the
discharge of the ICU [78].
4 Conclusions
In the present chapter, a review of previously published literature defined that many
factors are controversial. This is partly explained as outcomes being affected by
multiple factors, including patient attributes, genetic background, comorbidities,
insults applied after the admission, or treatments they received. ARDS is a syn-
drome, not a single disease, and specific therapy for ARDS has not yet been discov-
ered. Ventilatory strategy aiming to protect lungs from further injury has been
introduced since the late 1990s and may have had an impact on outcomes of ARDS
patients. However, a recent observational study revealed that one-third of the
patients receive so-called injurious ventilation [9]. Ventilatory strategy is a bundle,
and each patient is given a selected combination of care, suggesting an occurrence
of heterogeneity in treatments, some of which might not be ideal. Therefore, obser-
vational studies and even some RCTs may involve some unignorable bias. We
learned that occurrence of ARDS is multi-factorial, and eliminating as many factors
that may contribute to ARDS is crucial to prevent the development, reduce the
severity, or lower the mortality of ARDS.
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NEJMoa1011802.
Chapter 3
Pathophysiology of ARDS:
What Is the Current Understanding
of Pathophysiology of ARDS?
Sadatomo Tasaka
Abstract ARDS is a non-cardiogenic pulmonary edema caused by increased per-

meability of the alveolar epithelium and pulmonary microvascular endothelium.
Because effective drug therapy has not been established, understanding the patho-
physiology is important in determining accurate diagnosis and optimal respiratory
management. The cardinal feature of ARDS is caused by formation of protein-rich
alveolar edema after damage to the integrity of the lung’s alveolar–capillary barrier.
The innate immune response is important in the pathogenesis of ARDS and dam-
ages tissues via activated neutrophils, macrophages, and dendritic cells. When lung
tissue injury occurs, accumulated neutrophils release proteolytic enzymes, reactive
oxygen species, cytokines, and neutrophil extracellular traps. In particular, damage
to type II alveolar epithelial cells, which regulate the secretion of pulmonary surfac-
tant and the water balance in the lung, is critical. Widespread alveolar flooding in
ARDS reduces diffusing capacity and inactivates surfactant; this, in turn, decreases
lung compliance, increases ventilation-perfusion mismatch, and produces intrapul-
monary shunt, resulting in refractory hypoxemia. ARDS is often associated with
pulmonary hypertension caused by pulmonary vasospasm, compression due to
interstitial edema, and microvascular obstruction due to microthrombosis, leading
to decreased right heart function and cardiac output and impaired oxygen supply to
the whole body. Routine pulmonary function tests are difficult to perform in ARDS
patients due to severe respiratory failure. It is important to evaluate dysfunction
from limited information such as arterial blood gas analysis, exhaled gas analysis,
and chest CT images, and connect it to appropriate patient management.
Keywords Innate immunity · Intrapulmonary shunt · Neutrophils · Permeability

edema · Pulmonary hypertension
S. Tasaka (*)
Department of Respiratory Medicine, Hirosaki University Graduate School of Medicine,
Hirosaki, Aomori, Japan
e-mail: tasaka@hirosaki-u.ac.jp

Ltd. 2022
https://doi.org/10.1007/978-981-16-8371-8_3
34 S. Tasaka
1 Introduction
The acute respiratory distress syndrome (ARDS) represents a spectrum of respira-

tory failure of rapid onset characterized by diffuse, bilateral lung injury and severe
hypoxemia that are caused by noncardiogenic pulmonary edema. ARDS can occur
secondary to various underlying illnesses such as sepsis, severe pneumonia, aspira-
tion of gastric contents, and trauma and is associated with severe inflammation of
the alveolar septum. ARDS is characterized by pulmonary edema due to increased
permeability of vascular endothelium and alveolar epithelium. As can be seen from
the Berlin definition, ARDS is a syndrome and includes various pathological condi-
tions [1]. Despite numerous clinical trials, the only treatment that improves survival
of ARDS patients is mechanical ventilation using a lung protective strategy in which
tidal volume (VT) is carefully titrated to ~6 mL/kg of predicted body weight [2].
Positive end-expiratory pressure (PEEP) ventilation is useful for alveolar recruit-
ment in lungs that will be prone to atelectasis. Understanding the physiological
changes during ARDS is essential for appropriate ventilatory management in
patients.
This chapter describes the etiologic and physiologic bases of ARDS and sum-
marizes the current understanding of how its molecular pathogenesis leads to the
physiologic alterations of respiratory failure, emphasizing factors known to be
involved in the development and resolution of permeability pulmonary edema. It
also provides a physiologic basis for understanding and implementing strategies for
the respiratory care and management of patients with ARDS.
2 Genetic Factors
ARDS does not always occur in patients with clinical risk factors for this disease,
which suggests that host factors such as genetic susceptibility are involved in the
immune response and the development of ARDS. To date, a number of candidate
genes associated with the development or outcomes of ARDS have been reported.
However, no specific loci with genome-wide significance for associations with
ARDS have been identified, partly because of the phenotypic complexity of ARDS
elicited by the different risk factors [3, 4]. In addition, differences in virulence fac-
tors (e.g., pneumonia pathogens), comorbidities (e.g., diabetes), and environmental
exposure (e.g., smoking habits) can influence the interpretation of genetic findings.
Like other diseases, the biological importance of genetic association is enhanced
by additional studies suggesting the same pathway. For example, a variant in the
gene encoding angiotensin-converting enzyme (ACE) is associated with overall
susceptibility to ARDS, and the ACE2 protein is the receptor for severe acute respi-
ratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019
(COVID-19) [5, 6].
3 Pathophysiology of ARDS: What Is the Current Understanding of Pathophysiology… 35
3 Innate Immunity
Innate immunity provides the first-line host defense against pathogens and may play
a key role in the development of ARDS regardless of the existence of infections.
Pattern recognition receptors (PRRs), which recognize a wide range of microbes
and endogenous ligands such as fibronectin and hyaluronic acid, play a crucial role
in the proper function of the innate immune system [7, 8] (Fig. 3.1). For instance,
PRRs expressed by immune cells recognize pathogen-associated molecular patterns
(PAMPs), which are exogenous substances peculiar to pathogenic microorganisms
such as the highly conserved lipid A portion of LPS, prokaryotic DNA, and other
microbe-derived components [8, 9].
Compared to acquired immunity, innate immunity is less specific and has no
immune memory, but has the advantage of being able to recognize pathogens and
respond quickly [7]. PRRs are mainly present in macrophages and dendritic cells.
Toll-like receptors (TLRs), a family of membrane proteins, are representative of
PRRs. TLRs are highly conserved in vertebrates, and ten types of them have been
identified in humans. In addition, NOD-like receptors (NLRs) are known as PRRs
existing in the cytoplasm. By recognizing PAMPs, PRRs activate proinflamma-
tory transcription factors, such as nuclear transcription factor-κB (NF-κB) and
activator protein-1 (AP-1), and cause production of cytokines and adhesion
Pathogen PAMPS PRR APC T cell

(e.g., TLR) Infection
Macrophage PMN
Cytokines/chemokines
Immune cell recruitment
Inflammation
Adaptive immunity
DAMP Tissue repair
receptor
Stressed
DAMPS
PRR
Tissue damage
Healthy
Fig. 3.1 Roles of pattern recognition receptors. Pattern recognition receptors recognize various
molecules derived from microbes and endogenous ligands and a crucial role in the innate immune
system. APC antigen presenting cell, DAMPs damage-associated molecular patterns, PAMPs
pathogen-associated molecular patterns, PMN polymorphonuclear neutrophil, PRR pattern recog-
nition receptor, TLR Toll-like receptor
36 S. Tasaka
molecules. In addition, PRRs are known to induce inflammation by recognizing

nuclear contents and denatured cell membrane components released from injured
cells and tissues. These endogenous substances are called damage-associated
molecular patterns (DAMPs) and, together with PAMPs, function as a danger
signal or alarmin to the immune system that the body is at stake. Mitochondrial-
derived components released by tissue damage are also associated with systemic
inflammation as DAMPs, which increase the osmotic pressure of vascular endo-
thelial cells via neutrophils. Studies in ICU patients have shown that the group of
patients with high levels of mitochondrial-derived DAMPs in plasma has a poor
prognosis [10].
TLRs and NLRs signals play various roles in the development and resolution of
ARDS, among which TLR4 mediates the mammalian response to
LPS. Polymorphisms in the TLR4 gene are associated with LPS hyporesponsive-
ness [11], but not all that are hyporesponsive to LPS have TLR4 polymorphisms and
not all TLR4 polymorphisms are hyporesponsive, suggesting that other genes are
involved in this complex biological response. It has been indicated that some
responses to LPS are modulated by MHC class II genes, such as those in macro-
phages [12], and by other TLR4-associated proteins (MyD88 and MD-2) [13, 14].
Activation of such innate immune responses generates the inflammatory mediators
and contributes to the development of ARDS.
Hyaluronic acid produced after tissue injury causes an inflammatory reaction by
acting on TLR2 and TLR4, and is also involved in tissue repair [9]. It has also been
reported that TLR4 is strongly involved in pathogenesis in experimental acute lung
injury due to hemorrhagic shock [15], and that TLR3 is involved in exacerbation of
lung injury in a high oxygen exposure model [16].
4 Cellular and Molecular Pathogenesis
4.1 Accumulation of Neutrophils in the Lungs
Neutrophils play a central role in inflammation and tissue injury in the early stages
of ARDS. This is based upon the accumulation of neutrophils in the lung tissue
(pulmonary capillaries, lung interstitium, and alveolar space) of ARDS patients and
the attenuation of experimental lung injury in animals with drug-induced neutrophil
depletion. Since ARDS is also observed in patients with neutropenia, inflammatory
cells other than neutrophils may be involved, but neutrophils are considered to play
a major role in most settings [2].
Because the diameter of neutrophils is larger than the inner diameter of the pul-
monary capillaries, the neutrophils need to be deformed or elongated to pass through
the pulmonary capillaries. When mediators, such as inflammatory cytokines and
rolling firm adhesion transmigration

-integrin (CD11/CD18)
2 PECAM-1 (CD31)
Leukocyte SLex(CD15s)
-integrin (CD49d/CD29)
1 CD44
Endothelial cell P-selectin ICAM-1 (CD54) PECAM-1 (CD31)

E-selectin VCAM-1 (CD106) hyaluronan
Vessel
Flow
inactive
neutrophil integrin
SLeX IL-8
activated
E-, P-selectin 2-integrin
PECAM-1
ICAM-1
endothelial cell
Lung tissue
Fig. 3.2 Neutrophil–endothelial interaction during the development of ARDS. Selectins mediate

tethering and rolling and can generate signal transduction pathways contributing to integrin activa-
tion. Integrins and members of the immunoglobulin superfamily participate in rolling, firm adhe-
sion, and transmigration
arachidonic acid metabolites, are released into the bloodstream due to the underly-
ing disorders, neutrophils are activated and changes occur in the cytoskeleton.
Activated neutrophils with reduced plasticity cannot pass through the pulmonary
capillaries and stay in the pulmonary capillaries, increasing the marginated pool
[17]. The first contact of neutrophils with the endothelium is mediated by selectins
and their counterreceptors, followed by rolling of neutrophils along the endothelial
wall of postcapillary venules and integrin-mediated arrest (Fig. 3.2). In parallel,
inflammatory mediators also increase the expression of intercellular adhesion mol-
ecule-1 (ICAM-1) and other adhesion molecules on the vascular endothelial side,
which results in firm adhesion between neutrophils and vascular endothelial
cells [17].
Neutrophils that adhere to the endothelial cells migrate out of the blood vessels
under the influence of chemokines such as IL-8 derived from alveolar macrophages
and other chemotactic factors. PECAM-1 (CD31) is thought to play an important
role in this process. In the pre-migration stage, cell–cell adhesion between neutro-
phils and endothelial cells is an important step, but as neutrophils migrate from the
intercellular spaces to the interstitium, the elimination of the adhesion (de-adhesion)
is an important step as well.
38 S. Tasaka
4.2 Neutrophil-Derived Substances
Neutrophils that reach the lung interstitium and alveolar space release tissue damag-
ing substances such as reactive oxygen species and proteolytic enzymes, impairing
the function of tight junctions and increasing vascular permeability [18]. These tis-
sue damaging substances induce extensive and nonspecific inflammation in the lung
tissue, including pulmonary vascular endothelial cells and alveolar epithelial cells.
In addition, permeability edema is caused by the degradation of fibronectin and
laminin, which are constituents of the cell basement membrane, and cadherin, an
intercellular junctional protein [19].
4.2.1 Reactive Oxygen Species
A large amount of reactive oxygen species (ROS) are constantly produced from
neutrophils and other inflammatory cells [20]. NADPH oxidase or xanthine oxidase
in neutrophils produces O2− (superoxide anion) from oxygen molecules (O2), and
O2− is reduced to hydrogen peroxide (H2O2) by superoxide dismutase, an antioxi-
dant enzyme. When this H2O2 receives an electron from a metal ion such as Fe3+ or
Cu2+, ·OH (hydroxyl radical), which causes peroxidation of lipids and proteins and
damages DNA, is generated. ONOO− (peroxynitrite), which is produced by reacting
O2− with NO, also has a strong DNA damaging effect.
4.2.2 Proteolytic Enzymes
Proteolytic enzymes are enzymes that hydrolyze proteins. In ARDS, serine prote-
ases and matrix metalloprotease (MMP) groups are released from neutrophils and
are involved in tissue damage. Serine proteases can have a direct pathophysiological
role in the progression of ARDS. For example, proteinase-3, cathepsin G, and neu-
trophil elastase (NE) can degrade surfactant D and A, both of which are important
in the clearance of inflammatory cells and attenuation of residual inflammation. NE
has high proteolytic ability and low substrate specificity that decomposes elastin,
collagen (types I–IV), fibronectin, laminin, and proteoglycan [21]. NE increases
alveolar epithelial permeability by altering the actin cytoskeleton of epithelial cells.
Therefore, it is considered to play an important role in the pathogenesis of ARDS
[21]. NE activity, which is increased in bronchoalveolar lavage (BAL) fluid in
ARDS patients, is correlated with decreased respiratory function and duration of
mechanical ventilation [22]. Among proteolytic enzymes other than NE, MMP-2
and MMP-9 are produced in neutrophils and increased in the BAL fluid of ARDS
patients, suggesting their roles in the development of ARDS [23]. These enzymes
are also involved in extracellular migration of neutrophils and tissue remodeling as
well as destroying extracellular matrix components.
4.2.3 Neutrophil Extracellular Traps
Neutrophils also release neutrophil extracellular traps (NETs), composed of a net-

work of extracellular DNA fibers, histones, elastase, and myeloperoxidase. NETosis
is a special type of neutrophil death which can produce NETs. NETs in BAL fluid
have been documented, indicating that transmigrated neutrophils undergo NETosis
during ARDS [24, 25]. Extracellular histones released via NETosis may accelerate
neutrophil accumulation and elicit direct destruction of the alveolar epithelium
leading to disruption of the alveolar permeability barrier.
4.3 I mpairment of Endothelial and Epithelial

Barrier Functions
In ARDS, the barrier function of the vascular endothelium and the alveolar epithe-
lium is impaired, so that the protein-rich edema fluid fills the alveolar space and
impairs gas exchange [26]. In addition, the permeability of body blood vessels is
also increased, which is a cause of multiple organ failure [27].
Vascular endothelial cadherin (VE-cadherin), which is an adhesion molecule
belonging to the cadherin superfamily, plays an important role in the adhesion
between endothelial cells of pulmonary microvessels [28]. Catenin binds to the
intracellular domain of VE-cadherin to form a complex, which is linked to the cyto-
skeleton to stabilize the adhesive structure (Fig. 3.3). Pulmonary edema occurs
when the function of VE-cadherin is inhibited by antibodies against VE-cadherin,
TNF, thrombin, and vascular endothelial growth factor (VEGF) [28, 29]. On the
contrary, stabilization of cell–cell adhesion by VE-cadherin can be expected to sup-
press pulmonary edema. In fact, it has been reported that, in mice in which
VE-cadherin is genetically replaced by a VE-cadherin-α-catenin fusion construct,
the increases in protein concentration and the cell counts in BAL fluid after LPS
administration are suppressed [30].
5 Development of Permeability Edema
Normal pulmonary capillaries are selectively permeable, with serum proteins con-
fined to intravascular spaces, while smaller molecules and water travel across endo-
thelial membranes. The Starling’s equation describes the net flow of fluid across a
semipermeable membrane (Fig. 3.4). Applied to the lung microvasculature, it can
be written as follows:
Qf = K f × éë( Pmv - Pi ) - s (p mv - p i ) ùû

40 S. Tasaka
Ang1
Alveolar Tie-2
epithelial cell Occludin stress fiber formation
Tight junction
Claudin
stabilize
JAM
E-cadherin E-cadherin
Adherens junction actin
p120 α-catenin
-catenin
basement
membrane
VE-cadherin
Vascular VE-cadherin
endothelial cell
-catenin
20
p120
-catenin
p1
-catenin
-catenin
actin Rac stabilize
actin
reconstruct
Robo4
S1Pr1
Vascular space Slit

S1P
Fig. 3.3 Barrier function of the vascular endothelium and the alveolar epithelium. VE- and
E-cadherin play important roles in the barrier function of the vascular endothelium and the alveolar
epithelium, respectively. Ang1 angiopoietin-1, S1P sphingosine 1-phosphate
where:
• Qf = net filtration of fluid from the lung microvasculature to the interstitium
• Kf = filtration coefficient for permeability of the capillary endothelium
• Pmv = hydrostatic pressure within pulmonary microvessels
• Pi = hydrostatic pressure in the perimicrovascular interstitium
• σ = protein reflection coefficient, normally 1.0 (arbitrary units)
• πmv = protein colloid osmotic pressure in the microvasculature
• πi = protein colloid osmotic pressure in the interstitium
Under normal conditions, the microvascular endothelium is somewhat leaky to
fluid, and the pulmonary interstitial pressure is slightly negative. On the other hand,
the endothelium is quite impermeable to proteins with a reflection coefficient near
1. Thus, the fluid filtered from the microvessels is low in protein compared to the
fluid in the vascular space [31]. On balance, there is normally a small net flow of
fluid from the lung microvasculature to the interstitium.
Dysfunction of the endothelial barrier has potentially catastrophic implications
for gas exchange; indeed, increased endothelial fluid (increased Kf) or protein
(decreased σ) permeability is pathognomonic of ARDS. Given the critical
mv
Pmv
Pi i
Fig. 3.4 The Starling’s equation for the capillary exchange of fluid. The Starling’s equation
describes the net flow of fluid across a semipermeable membrane. Pmv = hydrostatic pressure
within pulmonary microvessels. Pi = hydrostatic pressure in the perimicrovascular interstitium.
πmv = protein colloid osmotic pressure in the microvasculature. πi = protein colloid osmotic pres-
sure in the interstitium
importance of a functional endothelial barrier, processes controlling endothelial

permeability are highly regulated. When the permeability of the vascular endothe-
lium increases, water leaks and accumulates in the interstitium around the blood
vessels and bronchi, resulting in interstitial pulmonary edema. Furthermore, when
the alveolar epithelium is injured, exudate containing plasma components fills the
alveolar space, resulting in alveolar pulmonary edema. These cause gravitationally
dependent alveolar edema, first evident in inferior lung zones of supine patients,
worsening VA/Q mismatch and reducing PaO2. It has been reported that ARDS
severity is associated with an increase in extravascular lung water and pulmonary
vascular permeability as assessed using the transpulmonary single thermodilution
method [32].
Transendothelial fluid leak during ARDS is believed to occur largely in a para-
cellular fashion, that is, through gaps within interendothelial junctions. Consequently,
much research effort has been dedicated to understanding mechanisms regulating
endothelial cell–cell adhesion. These efforts (often performed using in vitro endo-
thelial cell monolayer models) have revealed multiple intraendothelial signaling
cascades (e.g., myosin light chain kinase regulation of the actin cytoskeleton and
regulation of adherens junction assembly) that influence endothelial gap formation
and permeability. Like every research effort in ARDS, however, identification of
these cascades has yet to translate into an effective clinical intervention.
In addition to paracellular mechanisms, nonparacellular or transcellular transport
of proteins and other macromolecules, conducted via caveolin-mediated endocyto-
sis, may contribute to ARDS endothelial hyperpermeability and can cross-talk with
control of paracellular permeability [33]. Increasing attention has been paid to the
role of the extracellular matrix in governing vascular leak. The negatively charged
42 S. Tasaka
endothelial glycocalyx (which lines the vascular intima) has been proposed to be a
key regulator of the transendothelial oncotic gradient; loss of the glycocalyx can
therefore increase both protein and fluid permeability (and facilitate inflammatory
cell extravasation).
At least three mechanisms promote fluid retention in capillaries to prevent inter-
stitial edema and alveolar flooding. First, airspace liquid is cleared by apical Na+
transporters in alveolar epithelial cells. Second, larger plasma proteins like albumin
maintain osmotic gradients favoring water reabsorption. Third, interstitial lymphat-
ics return alveolar fluid to the circulation.
6 Changes in the Pulmonary Circulation During ARDS
Various factors are considered to be involved in pulmonary hypertension and micro-

thrombus formation in ARDS [34]. Pulmonary hypertension causes right heart dys-
function, low cardiac output, and a decrease in oxygen supply to the whole body.
6.1 Hypoxic Pulmonary Vasoconstriction
Hypoxic pulmonary vasoconstriction (HPV) is known as a mechanism by which

blood flow is redistributed from the hypoxic lung region to the normal lung region
in order to maintain the VA/Q ratio. The increase in pulmonary artery pressure due
to HPV increases right ventricular load, which is a physiological response to main-
tain gas exchange capacity in the lungs and maintain systemic oxygenation. HPV is
suppressed in ARDS as compared with normal lungs possibly due to endogenous
pulmonary vasodilators such as nitric oxide (NO) and prostacyclin (PGI2) [35].
6.2 Increased Pulmonary Vascular Tone
In normal pulmonary circulation, the tension of vascular smooth muscle is regulated

by various vasoactive substances synthesized and released by endothelial cells. In
addition to NO, vascular endothelial cells produce various vasoactive substances,
including cyclooxygenase metabolites such as thromboxane A2 (TxA2) and PGI2,
leukotrienes, endothelin, a potent vasoconstrictor, and platelet-activating factor
(PAF). In ARDS, pulmonary blood vessels are exposed to various vasoconstrictors
and dilators, but the overall balance tends toward increased pulmonary vascular
tone [34].
6.3 Coagulation Abnormality
When lung tissue is injured during the development of ARDS, tissue factor is
expressed on the cell surface and the extrinsic coagulation pathway is activated [36].
This phenomenon is not limited to blood vessels, but damage to alveolar epithelial
cells enhances coagulation in the alveolar space, resulting in fibrin deposition fol-
lowing thrombin production in the alveolar space [37]. The deposited fibrin magni-
fies vascular permeability, promotes the migration of inflammatory cells and
fibroblasts, and further enhances inflammation. Thrombus formation is associated
with increased pulmonary vascular resistance as well.
In ARDS patients, the thrombin concentration in BAL fluid is elevated. Thrombin
promotes the production of inflammatory cytokines and the migration of inflamma-
tory cells, and also induces apoptosis of alveolar epithelial cells. This action is
mediated by the thrombin receptor present on the cell membrane. Receptors that are
activated by degradation by proteolytic enzymes such as thrombin and trypsin, such
as thrombin receptors, are called protease-activated receptors (PARs) and play an
important role in the interaction between the coagulation system and inflammation
[38]. To date, four types of PAR have been identified, from PAR-1 to PAR-4. When
activated, PAR-1, a receptor for thrombin, acts in the direction of hypercoagulation,
such as induction of tissue factors in the vascular endothelium. In addition, when
PAR-2, which is a receptor for activated factor X, is activated, it enhances the pro-
duction of cytokines (IL-6 and IL-8) and the expression of adhesion molecules
(P-selectin), resulting in an inflammatory reaction. In this way, in ARDS patients
with disseminated intravascular coagulation (DIC), multiple organ failure progress
due to mutual amplification of the coagulation reaction and the inflammatory reac-
tion. It has been reported that the prognosis of ARDS patients with DIC is worse
than those without DIC [39].
7 Pathophysiology
In general, the causes of impaired pulmonary gas exchange associated with lung
disease include (1) pulmonary shunt, (2) diffusion disorder, (3) ventilation-perfusion
(V/Q) mismatch, and (4) alveolar hypoventilation [40]. The hypoxemia in ARDS is
often difficult to improve even if the inhaled oxygen concentration is increased, sug-
gesting that the main cause of hypoxemia is an increase in intrapulmonary shunt,
which passes through the lung region without any ventilation. In addition, diffusion
disorders and V/Q mismatch also contribute to the impaired gas exchange. The
physiological changes occurring in the lungs of ARDS patients are described below.
44 S. Tasaka
7.1 Intrapulmonary Shunt
The VA/Q ratio distribution of ARDS patients obtained by the multiple inert gas
elimination technique shows that the ratio is clearly separated into the normal part
and the shunt (VA/Q = 0) part, in contrast to the distribution widely in the region with
hypoventilation in those with COPD [41]. When edema fluid accumulates in the
alveolar space in ARDS, the alveoli collapse due to a decrease in surface tension,
and aeration is lost. Since blood flow is kept in the collapsed alveoli, intrapulmonary
shunt increases, resulting in severe hypoxemia. Hypoxemia during ARDS is severe
and refractory to supplemental oxygen. When PEEP is applied, ventilation is
restored to the collapsed alveoli, and the shunt rate (QS/QT) decreases [41].
7.2 Changes in Ventilation Mechanics
In the early stage of ARDS, progressive hypoxemia becomes a ventilatory stimulus,

respiratory rate increases, and hypocapnia occurs. However, as the disease pro-
gresses further, ventilatory insufficiency occurs, resulting in hypercapnia. The ven-
tilatory mechanics of ARDS are characterized by decreased lung compliance and
increased respiratory resistance [42]. The more severe the lung injury, the lower the
lung compliance and the higher the respiratory resistance. The resulting ventilatory
impairment causes the accumulation of carbon dioxide, which is caused by the fol-
lowing mechanism. The driving pressure (P) required for lung ventilation is
expressed as follows:
P = V / CL + V × RL ×

CL and RL are the compliance and resistance components of the entire lung. V and
V are lung air volume and airflow rate. In advanced ARDS, airway resistance increases
due to the airway edema and outflow of edema fluid accumulated in the alveoli into
the airways, and a marked decrease in lung compliance increases the driving pressure
(P) required for respiratory movements, leading to ventilatory insufficiency.
7.2.1 Decreased Lung Compliance (Hardening of the Lungs)
Lung compliance quantifies changes in lung volumes (ΔV) that are caused by dis-
tending airway or intrapleural pressures (ΔP) as occur during spontaneous respira-
tion. In ARDS, the number of unaerated alveoli increases due to pulmonary edema
and surfactant dysfunction. As a result, the extensibility of the lungs is reduced, and
the lung weight is also increased, resulting in a decrease in compliance (ΔV/ΔP) of
the lungs as a whole [43]. Decreased compliance often leads to alveolar instability
and collapse when approaching end-expiratory pressures. As a result, the lung pres-
sure–volume curve shifted downward to the right compared to normal (Fig. 3.5),
Normal
Derecruitment point:
lung starts to recollapse
ARDS
Volume
Upper inflection point:

lung is fully recruited, and
overinflation occurs
Lower inflection point:

onset of alveolar recruitment
0 5 10 15 20 25 30 35 40
Pressure (cm H2O)
Fig. 3.5 Lung pressure–volume curve of a normal subject and an ARDS patient. The lung pres-
sure–volume curve of a patient with ARDS shifts downward to the right compared to a nor-
mal subject
and lung volumes such as total lung volume (TLC), residual volume (RV), and
functional residual volume (FRC) decrease uniformly.
The lung pressure–volume curve of ARDS patients often has two inflection
points on the inspiratory limb [43]. Overstretch of the alveoli can occur at pressures
and capacities above the upper inflection point, and alveolar collapse is likely to
occur below the lower inflection point.
7.2.2 Increased Respiratory Resistance
Airway resistance usually increases when edema fluid accumulates in the airways.
It is also increased by water retention in the interstitium around the small airways
(interstitial pulmonary edema) or swelling of the airway mucosa. Since airway
resistance is inversely proportional to the fourth power of the airway inner diameter,
even a slight change in the airway inner diameter causes a large change in airway
resistance. On the other hand, when respiratory resistance is divided by FRC to cor-
rect the effect of the decrease in lung air volume, there is no significant difference
between ARDS patients and healthy subjects [44]. For this reason, the increase in
46 S. Tasaka
respiratory resistance can be associated with the decrease in the ventilated lung area
and the maintenance of constant ventilation through a smaller number of airways,
rather than the narrowing of individual airways.
7.3 Impaired Diffusing Capacity
In ARDS, edema formation increases the distance from the alveoli to the pulmonary
capillary blood [45]. In addition, lung air volume or diffusion area is decreased due
to alveolar flooding. Pulmonary capillary bed is also decreased due to thrombosis or
hypoxic pulmonary vasoconstriction. Because of these changes, diffusion impair-
ment occurs, contributing to refractory hypoxemia. As the diffusing capacity of car-
bon dioxide is 20 times that of oxygen, even in case of diffusion impairment,
hypercapnia does not occur without hypoventilation.
7.4 Ventilation-Perfusion Mismatch
Chest computed tomography (CT) shows that, in ARDS patients, the lung lesions
are not so-called “diffuse” but are often unevenly distributed. Especially in the
dependent regions where the weight of the lungs is applied, for example, the dorsal
part if the patient is in the supine position, the ventilation of the lungs is signifi-
cantly reduced as compared with the independent regions. On the other hand, the
blood flow is large in the dependent regions, leading to the further VA/Q mismatch,
which contributes to severe hypoxemia during ARDS.
7.5 Elevated Pulmonary Vascular Resistance
In ARDS patients, pulmonary vascular resistance increases because blood vessels

are compressed from the surrounding lung tissue due to water retention in the pul-
monary interstitium [34]. Hypoxic pulmonary vasoconstriction centered on poorly
ventilated areas also contribute to the elevated pulmonary vascular resistance.
Because pulmonary arterial pressure is correlated with the degree of pulmonary
edema, compression of blood vessels by the edematous lung interstitium is consid-
ered to play a central role. In addition, hypercoagulable state during ARDS induces
thrombus formation, resulting in obstruction of pulmonary microvessels. Increased
production of inflammatory lipid mediators such as thromboxane also contributes to
elevated vascular tone. Pulmonary hypertension in ARDS is associated with
impaired right heart function and lower cardiac output, resulting in a decrease in
oxygen supply to the whole body, but no clear correlation has been shown between
the degree of pulmonary hypertension and mortality. In ARDS, pulmonary hyper-
tension can persist even after hypoxemia is improved, which is thought to be due to
remodeling of pulmonary blood vessels and progress of medial thickening and nar-
rowing of the lumen.
7.6 Pulmonary Surfactant Dysfunction
Pulmonary surfactant is a lipid–protein complex that exists at the gas–liquid inter-

face on the alveolar surface, forming the alveolar lining layer. Pulmonary surfactant
reduces the surface tension of the alveoli surface, preventing the alveolar collapse
and contributing to the maintenance of gas exchange. In ARDS patients, the pulmo-
nary surfactant system is affected by mechanical ventilation and supplemental oxy-
gen as well as inflammation and other pathological conditions, leading to alveolar
collapse with a marked decrease in oxygenation capacity [46].
7.6.1 Pulmonary Surfactant Dysfunction During ARDS
Surfactant components in BAL fluid change since the early stage of ARDS [46].
The mechanism of surfactant dysfunction in ARDS is as follows: (1) degradation of
surfactant components by tissue damaging substances derived from inflammatory
cells such as neutrophil elastase and reactive oxygen species, (2) inhibition of
adsorption of surfactant at the gas–liquid interface by fibrinogen or other serum
proteins in edema fluid, and (3) reduction of synthesis or secretion of surfactant due
to severe inflammation of the lung.
7.6.2 Influence of Respiratory Management on Pulmonary Surfactant
Mechanical ventilation or other respiratory management is often required in ARDS

patients, but such management itself can cause surfactant dysfunction. Mechanical
ventilation can remove surfactants from the gas–liquid interface and transfer it to
the lower layer of the alveolar lining fluid. It may also change the three-dimensional
structure of surfactant to that with low surface activity. Although inhalation of high-
concentration oxygen is often required for management of ARDS, it can reduce the
production of phospholipids, the main components of surfactant, by alveolar type
II cells.
48 S. Tasaka
8 Assessment of Respiratory Function of ARDS Patients
8.1 Practical Assessment of Respiratory Function
Patients with ARDS can hardly perform lung function tests such as spirometry and
lung diffusion test. Usually, arterial blood gas analysis is the only way to evaluate
respiratory function of a patient with ARDS. Gas exchange status can be estimated
by the alveolar–arterial oxygen gradient (AaDO2) or oxygenation index (PaO2/
FIO2). If the patient is intubated, decreased lung compliance and increased respira-
tory resistance can be monitored as increased airway pressure.
8.2 Exhaled Gas Analysis
Abnormalities of pulmonary blood flow and injury to the microcirculation are charac-
teristic features of ARDS. As a result, pulmonary blood flow is compromised to lung
regions that remain well ventilated, leading to an increase in the physiological dead
space. Pulmonary dead space is the component of ventilation that is wasted because it
does not participate in gas exchange, and an increase in dead space volume (VD) repre-
sents an impaired ability to excrete carbon dioxide. In addition, rapid shallow breathing
is also associated with an increase in dead space ventilation during ARDS. The dead
space fraction (VD/VE) is expressed as follows by the expiratory carbon dioxide partial
pressure (PECO2) and the arterial blood carbon dioxide partial pressure (PaCO2).
VD / VE = ( PaCO2 - PECO2 ) / PaCO2

A study of dead space ventilation in ARDS patients by exhaled gas analysis
showed that VD/VE is an independent predictor of mortality in ARDS [47].
8.3 E
valuation of Lung Volume and Regional Lung Function
by Chest CT
Chest CT is useful not only for diagnosing ARDS, but also for predicting pathologi-
cal stage, treatment response, and prognosis. Furthermore, it may be applicable to
the evaluation of lung air volume and local ventilation of the lungs. The signal
strength (CT value) of the CT pixel is determined by the X-ray absorption of the
corresponding part and is proportional to the weight density. If the target is water,
the CT value will be 0 Hounsfield Unit (HU), and if it is air, it will be −1000 HU,
so the CT value of the lungs reflects the aeration and water content. For example, if
the CT value is −500 HU, it can be seen that air occupies 50% and other tissues
occupy 50%. In pulmonary edema, the CT value approaches 0 HU, reflecting an
increase in lung tissue weight (per unit volume) including pulmonary extravascular
water content and a decrease in air content. The CT image is composed of rectangu-
lar parallelepiped pixel units (voxels) that increase the slice thickness, and the lung
air volume can be obtained by calculating the air content of each voxel from the
volume of voxels and the CT value [48]. Puybasset and colleagues evaluated FRC
of healthy subjects and ARDS patients using chest CT images and demonstrated
that FRC decreased in ARDS patients. The air content decreased especially at the
bottom of the lungs because of the abdominal pressure via the diaphragm [49].
Furthermore, FRC calculated from CT images is correlated positively with oxygen-
ation index (PaO2/FIO2) and negatively with shunt rate (QS/QT) in ARDS patients
[50]. It was suggested that, as the FRC decreases, the shunt blood flow increases and
oxygenation worsens. It is also possible to evaluate the local ventilation state with
the difference in CT values in the inspiratory and expiratory states.
9 Conclusion
The true nature of ARDS is permeability pulmonary edema due to damage to the
alveolar epithelial and endothelial cells of the lung. ARDS is characterized by
severe hypoxemia that does not improve with normal oxygen administration alone.
The main cause of oxygenation disorders is an increase in pulmonary shunts, but
diffusion disorders and ventilation–perfusion mismatch also contribute.
Understanding of the pathophysiology of ARDS has progressed, and knowledge has
been accumulated regarding its relationship with new parameters, such as biomark-
ers and imaging findings. Hopefully, the prognosis of ARDS patients will be
improved by further understanding its pathophysiology and clarifying the optimal
treatment and management for the patients.
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Part II
Diagnosis
Chapter 4
Imaging Diagnosis of ARDS: How Can
We Know the Severity and Prognosis
from the Lung Imaging?
Tomoo Kishaba
Abstract Acute respiratory distress syndrome (ARDS) is a critical syndrome and

its mortality remains high. Based on Berlin criteria for ARDS, chest imaging plays
an important role. For clinicians, evaluation of disease severity and prediction of
prognosis are quite helpful for management of ARDS. Chest radiograph is a simple
test and first stage of diagnosis for ARDS. Findings of chest radiograph are often
affected by patient status, positive pressure ventilation, and stage of ARDS itself.
Therefore, integration of clinical condition such as vital sign and ratio of partial
pressure of oxygen and fraction of inspired oxygen (P/F ratio) is important. Most
important differential diagnosis is congestive heart failure (CHF). Therefore, evalu-
ation of lung water distribution is important. Most robust point of chest radiograph
is detection of volume loss comparison with previous film. Chest high-resolution
computed tomography (HRCT) is the most useful imaging tool for ARDS. HRCT
can distinguish direct injury such as pneumonia, aspiration from indirect injury
such as sepsis, burn. Direct injury often shows asymmetric distribution such as uni-
lateral predominant consolidation with air bronchogram. On the other hand, indirect
injury more often demonstrates gravity dependent consolidation with subtle ventral
ground-glass opacity (GGO). In viewpoint of severity of ARDS, severe ARDS
patients show more extensive shadow compared to mild or moderate ARDS. In pre-
diction of prognosis, ARDS have three pathological stages which consist of exuda-
tive, fibroproliferative, and fibrotic phase. In chest HRCT, extent of fibrotic shadow
such as reticulation and traction bronchiectasis and volume loss are crucial findings
which are associated with poor prognosis.
Keywords Acute respiratory distress syndrome · Chest high-resolution computed

tomography · Fibroproliferative · Traction bronchiectasis
T. Kishaba (*)
Department of Respiratory Medicine, Okinawa Chubu Hospital, Uruma City, Okinawa, Japan

Ltd. 2022
https://doi.org/10.1007/978-981-16-8371-8_4
56 T. Kishaba
1 Introduction
Acute respiratory distress syndrome (ARDS) is a life-threatening syndrome which

consists of variable etiology such as pneumonia, sepsis, pancreatitis, trauma [1, 2].
Chest radiograph is a simple and easily applicable tool and diagnosis of ARDS will
be possible. However, evaluation of chest radiograph alone has limitation in daily
practice for ARDS. According to the Berlin criteria for ARDS, important parame-
ters are both grade of oxygenation and findings of chest imaging [3]. During ARDS,
we carefully monitor both clinical parameters such as P/F ratio, laboratory value
and extent of imaging findings for evaluation of treatment effect. For patients and
physician, crucial issue is to know severity and prognosis of ARDS, which contrib-
ute to more adequate management strategy and improve prognosis. In this chapter,
I would like to show how we could evaluate severity and prognosis for ARDS using
chest radiograph and chest HRCT.
2 Chest Radiograph
Chest radiograph is an initial step of imaging for diagnosis of ARDS. From an

imaging point of view, important differential diagnoses are atelectasis, pleural effu-
sion, pneumonia [4]. When we see acute phase of lung injury, chest radiograph
often shows normal imaging or subtle GGO. Therefore, next step is chest HRCT in
this situation. In initial phase of ARDS, patient often has poor inspiration due to
severe distress, which contributes to volume loss like findings. In intensive care
unit, we usually order portable chest imaging, cardiomegaly is overestimated and
bilateral opacity is often due to pleural effusion. Therefore, portable echo is useful
for distinction true parenchymal opacity from pleural effusion with identification of
echo-free space and B-line or comet tail artifacts [5–7]. B-line often have positive
correlation with chest CT findings of GGO, consolidation or septal thickening. B
lines are perpendicular to the pleural line and move synchronously with lung slid-
ing. The presence of 3 or more B lines in 1 intercostal space is considered abnormal
and referred to as a B pattern. By contrast, A lines constitute a basic artifact of nor-
mally aerated lung described as horizontal repetitive hyperechoic artifacts arising
from, and appearing parallel to, the pleural line. In diffuse disease such as ARDS,
there is diffuse loss of aeration with multiple B lines and/or areas of consolidation
in all lung fields. We often see rapid improvement of bilateral shadow in portable
film on positive pressure ventilation status. This phenomenon is caused by high
positive pressure end-expiratory pressure (PEEP). We should interpret patient con-
dition through improvement in clinical condition and gas exchange such as P/F ratio.
One of the important role of chest radiograph is to check the position of tracheal
tube, central venous line, naso-gastric tube, or other monitoring device [5]. Another
important role is to detect ventilator-associated complications especially pneumo-
thorax and ventilator-associated pneumonia (VAP). In patients with positive
4 Imaging Diagnosis of ARDS: How Can We Know the Severity and Prognosis… 57
pressure ventilation, we sometimes see pneumothorax. Portable chest imaging can

miss subtle pneumothorax. Therefore, when we suspect pneumothorax, we can
order chest radiograph with Trendelenburg position or erect position. Air tends to
accumulate in high area in human body. So, deep sulcus sign is easy to detect pneu-
mothorax using imaging of Trendelenburg position [8]. If we order supine imaging,
we might miss small pneumothorax because of bilateral homogeneous opacity with
pleural effusion or parenchymal shadow in ARDS patients. In terms of VAP, com-
parison of previous film and signs of respiratory infection such as fever, purulent
secretion, and elevation of inflammation marker are crucial factors for accurate
diagnosis [9]. From an imaging point of view, detection of new shadow is important
accompanying with exclusion of pleural effusion or atelectasis.
Important differential diagnosis is CHF. CHF usually shows septal lines in lower
lung field and peri-bronchovascular thickening in upper lung field [10]. In normal
lung, interlobular septum is more evident in anterior ventral portion in upper lung
field and near diaphragm. On the other hand, interlobar fissure has scarce septum.
Therefore, linear shadow from mediastinum to outer direction in upper lung field or
straight line from chest wall suggests septal thickening due to volume overload. In
addition, reversed perfusion which is shown by more significance of vascular mark-
ings in upper lung field compared to lower lung field. Careful point is acute cardio-
genic pulmonary edema often show absence of cardiomegaly. Non-cardiogenic
pulmonary edema sometimes show asymmetric fluid overload. In evaluating vol-
ume status, vascular pedicle width (VPW) is useful. VPW means distance from
outer line of azygos vein to outer line of left subclavian artery [11]. If VPW is over
5 mm, which signifies approximately 1000 ml volume overload with same film
condition. Therefore, using difference of VPW combined with physical examina-
tion including jugular venous pressure estimation, hepato-jugular reflux, and urine
output will provide useful information of volume status of ARDS patients.
In evaluation of severity, severe ARDS patients usually demonstrate more exten-
sive consolidation or GGO rather than mild or moderate ARDS. Trace of imaging
trend is quite crucial for both severity and prognosis. Chest radiograph is affected
by patient position, depth of inspiration, rotation, inspiration timing, and volume
status. Therefore, film condition should be arranged as much as we can. In exudative
phase, chest radiograph shows bilateral GGO or consolidation with air broncho-
gram based on inflammatory exudates in alveolar space [12]. If ARDS phase prog-
ress to late exudative phase, we often see more confluent consolidation. More severe
the ARDS, more extensive and dense consolidation develop. When ARDS pro-
gresses to fibroproliferative phase after 7–10 days, we usually see coarse reticula-
tion and volume loss of bilateral lower lung field [13]. Direct injury such as bacterial
pneumonia or aspiration pneumonia often cause asymmetric reticulation because of
primary focus in unilateral. On the contrary, indirect injury such as sepsis, pancre-
atitis, burn usually show symmetric reticulation and volume loss because of sys-
temic intense inflammatory substance. In fibrotic phase of ARDS, we often see
diffuse reticulation with persistent volume loss.
In estimation of prediction of prognosis for ARDS, identification of volume loss
and diffuse fibrotic change is important. In normal chest imaging, bilateral hilum is
58 T. Kishaba
positioned center between apex and dome of diaphragm. If position of hilum is

shifted to diaphragm with adequate inspiration, we could judge it volume loss.
Atelectasis resembles volume loss. Therefore, accurate distinction between these
two process is difficult by chest radiograph alone. Gas exchange usually worse in
volume loss and late inspiratory crackles are audible in volume loss [14]. On the
other hand, decreased breath sound is evident in atelectasis. From normal volume to
volume loss, ARDS phase might be changed exudative to fibroproliferation. In addi-
tion to persistent volume loss and hypoxemia, ARDS patients will show poor prog-
nosis with reflection of pathological diffuse alveolar damage (DAD). In evaluating
diffuse reticulation, ARDS patients more often show homogeneous distribution of
reticulation compared with idiopathic pulmonary fibrosis (IPF). ARDS patients
tend to show more central distribution of reticulation rather than IPF. More exten-
sive consolidation or reticulation with significant volume loss is associated with
poor prognosis.
3 Chest HRCT
Chest HRCT has advantages for anatomical evaluation of main findings and estima-
tion of extent. Standardization of definition of each imaging findings is quite impor-
tant. I show definition of major imaging findings of ARDS based on the Fleischner
Society [15].
Air bronchogram: An air bronchogram is a pattern of air-filled (low-attenuation)
bronchi on a background of opaque (high-attenuation) airless lung. The sign implies
(a) patency of proximal airways and (b) evacuation of alveolar air by means of
absorption (atelectasis) or replacement (e.g., pneumonia) or a combination of these
processes.
Consolidation: Consolidation appears as a homogeneous increase in pulmonary
parenchymal attenuation that obscures the margins of vessels and airway walls.
Consolidation refers to an exudate or other product of disease that replaces alveolar
air, rendering the lung solid.
Ground-glass opacity (GGO): It appears as hazy increased opacity of lung, with
preservation of bronchial and vascular margins. It is caused by partial filling of air-
spaces, interstitial thickening (due to fluid, cells, and/or fibrosis), partial collapse of
alveoli, increased capillary blood volume, or a combination of these, the common
factor being the partial displacement of air.
Honeycombing: the appearance is of clustered cystic air spaces, typically of
comparable diameters on the order of 3–10 mm but occasionally as large as 2.5 cm.
Honeycombing is usually subpleural and is characterized by well-defined walls.
Honeycombing represents destroyed and fibrotic lung tissue containing numerous
cystic airspaces with thick fibrous walls, representing the late stage of various lung
diseases, with complete loss of acinar architecture. The cysts range in size from a
few millimeters to several centimeters in diameter, have variable wall thickness, and
are lined by metaplastic bronchiolar epithelium.
Reticular pattern: They are interlobular septal thickening, intralobular lines, or

the cyst walls of honeycombing.
Traction bronchiectasis and traction bronchiolectasis: Traction bronchiectasis
and traction bronchiolectasis, respectively, represent irregular bronchial and bron-
chiolar dilatation caused by surrounding retractile pulmonary fibrosis. Dilated air-
ways are identified as cysts or microcysts.
Chest HRCT is useful for detection of anatomical location and more accurate
extent and distribution of parenchymal shadow rather than chest radiograph
(Table 4.1). In one study, the imaging findings provided by CT compared with chest
radiograph frequently yielded additional information (66%), with direct influence
on patient treatment in 22% of cases [16]. Therefore, HRCT plays an important role
for diagnosis, evaluation of severity, and prediction of prognosis of ARDS. ARDS
is the most severe form of lung injury. Most important differential diagnosis is
CHF. CHF patients often show interlobular septal thickening especially in ventral
area in upper lung field and peri-bronchovascular thickening in hilum portion.
Mediastinal window of chest CT shows bilateral or right predominant pleural effu-
sion in CHF patients at initial stage. In addition, CHF patients often show enlarge-
ment of right pulmonary vein because of volume overload. ARDS is divided into
early phase and late phase clinically. Usual threshold between these phases are
14 days [17].
From a pathological point of view, ARDS have three stages which consist of
exudative, fibroproliferative, and fibrotic phase.
Exudative phase has extensive inflammation with protein-rich pulmonary edema
and hemorrhage. Fibroproliferative phase shows that fibroblast develops with col-
lagen deposition. Fibrotic phase demonstrates lung remodeling with architectural
destruction and cystic changes [18]. In exudative phase, ARDS patients show exten-
sive bilateral consolidation in gravity dependent area with GGO (Fig. 4.1). This
distribution derived from large difference between intrapulmonary vessel and tissue
hydrostatic pressure in dependent area. In addition, dense posterior dependent con-
solidation can be seen as the syndrome progresses beyond the first week. In early
phase, there is air bronchogram with smooth bronchial wall not traction. If adequate
intervention is provided during this period, reversibility of consolidation or GGO
will be anticipated. When clinical status progresses despite management including
lung protective strategy, chest imaging phase shifts to late exudative and enters into
fibroproliferative phase.
Table 4.1 Comparison of Chest radiograph and HRCT

Main findings Advantage Disadvantage
Chest Bilateral infiltration without
Easy to perform Accurate distribution of
radiograph cardiomegaly Detection of volume infiltration is difficult
is more evident
Chest HRCT Bilateral dorsal consolidation Detail evaluation for Radiation exposure
with ground-glass opacity anatomical location High cost
HRCT high-resolution computed tomography
60 T. Kishaba
Fig. 4.1 Exudative phase.

Dependent airspace
consolidation. Adapted
from [18]
Fibroproliferative reaction is associated with tissue repair response histologi-

cally. This phase is an important turning point which radiological improvement or
get worse with clinical condition or gas exchange. CT signs of parenchymal archi-
tectural distortion appear with reticulation and bronchiectasis after 2 weeks of
ARDS onset. When we see GGO with reticular pattern, which is associated with
interlobular septal thickening due to drainage of exudates. Important imaging indi-
cator of transition to fibroproliferative phase is bronchiolectasis, which originates
from dilatation of membranous bronchioles. In fibroproliferative phase, chest paren-
chymal shadow gradually improves in good prognosis group, which suggests adap-
tive response. On the other hand, traction bronchiectasis within consolidation or
GGO appears in spite of treatment, which means maladaptive response and future
development of fibrotic phase (Fig. 4.2). Ichikado et al. proposed HRCT score
which focus on extent of fibrotic process during fibroproliferative phase [19]. The
HRCT score was assigned on a 6-point scale: (I) normal attenuation; (II) ground-
glass attenuation; (III) consolidation; (IV) ground-glass attenuation with traction
bronchiolectasis or bronchiectasis; (V) consolidation with traction bronchiolectasis
or bronchiectasis; and (VI) honeycombing. The presence of each of these six abnor-
malities in the upper, middle, and lower segments of each lung was independently
assessed. The extent of each abnormality was determined by visually estimating the
percentage of the affected lung parenchyma in each segment. Each abnormality
Fig. 4.2 Fibroproliferative
phase. Extensive airspace
consolidation and
ground-glass attenuation
with traction bronchiectasis
(arrows). Adapted
from [18]
score was calculated by multiplying the percentage area by each score. Scores for
the six segments were averaged to determine the total score for each abnormality.
The overall HRCT score was derived by adding the six abnormality scores. HRCT
score have been reported to predict mortality of both pulmonary and extrapulmo-
nary ARDS [20]. According to the multivariate analysis for the association between
60-day mortality and various outcome measure, HRCT score showed most strong
predictor of mortality for ARDS [Hazard ratio 1.23 (1.09–1.35), p-value <0.01].
This HRCT score also predict mortality for AE of IPF [21]. Anan et al. showed a
simple clinical scoring system consisting of the Acute Physiology and Chronic
Health Evaluation (APACHE) II score, P/F ratio, disseminated intravascular coagu-
lation and HRCT scores can predict drug associated ARDS [22]. In terms of traction
bronchiectasis, this finding is usually noticed in chronic fibrotic lung disease.
Therefore, when we see such findings in ARDS patients, we should call it bronchi-
ectasis or bronchiolectasis alone. Based on current concept, (V) should be replaced
by consolidation with bronchiolectasis or bronchiectasis of HRCT score for ARDS
patients. HRCT bronchiectasis or bronchiolectasis and lower lobe volume loss may
reflect pathological diffuse alveolar damage.
Fibrotic process progresses, ARDS patients shift to next stage, that is fibrotic
phase. When we see more central bronchiectasis, which means early stage of fibrotic
phase. In this phase, we can see more coarse reticular pattern and small cystic
changes (Fig. 4.3). These parenchymal shadows reflect irreversible process such as
62 T. Kishaba
Fig. 4.3 Fibrotic phase.

Extensive ground-glass
attenuation associated with
traction bronchiectasis
(arrows), coarse
reticulation, and cystic
changes (arrowheads).
Adapted from [18]
remodeling of lung architecture. In addition, we often see persistent GGO or small

cystic changes in ventral area. This process is due to overdistension of ventral area
with baby lung in severe ARDS [23]. Improvement of oxygenation in ARDS patients
is more evident in ventral region [24, 25]. Burnham et al. evaluated HRCT at 1 and
14 days after ARDS onset, average static respiratory compliance over 14 days had
negative association with HRCT reticular pattern (p = −0.46). Initial static respira-
tory compliance at 1 day was inversely correlated with HRCT reticulation
(p = −0.38) and was lower in ARDS patients who showed bronchiectasis on HRCT
at 14 days (p = 0.008) [26]. Another radiological scoring system showed increased
radiologic scores for reticulation were associated with a decreased total lung capac-
ity, forced vital capacity, and diffusing capacity for carbon monoxide (p < 0.002) at
180 days after ARDS. This radiological scoring consists of the following; the extent
of involvement for each pattern was assigned a numerical score, where 0 = no
involvement; 1 = <5% involvement/minimal/not normal; 2 = 5–25% involvement;

3 = 26–49% involvement; 4 = 50–75% involvement; and 5 = greater than 75%
involvement. For each radiologic pattern, the average score (range, 0–20) was cal-
culated by summing all quadrant values for each of slice, adding these values
together, and dividing by the number of slices with complete data [27]. Chung et al.
also reported that lung involvement of greater than 80%, RA/LA ratio > 1, and vari-
coid traction bronchiectasis were statistically more common in nonsurvivors than in
survivors (respective p values of 0.001, 0.008, and 0.038) [28]. Recently, Japanese
study of ARDS patients stratified Berlin criteria consists of 153 patients. The sever-
ity of this cohort was mild in 42 patients, moderate in 71, and severe in 40 patients.
Multivariate analyses revealed that elevated blood lactate level (≥ 2.0 mmol/L) and
increased HRCT scores were significantly associated with weaning failure and
30-day mortality of the patients with ARDS [29]. Elevation of lactate is associated
with tissue hypoxia and HRCT score reflects both degree of lung injury and fibrop-
roliferation changes.
Finally, we discuss about ventilator-associated complication such as pneumotho-
rax, pneumomediastinum, and ventilator-associated pneumonia. In ventilator man-
agement for ARDS patients, lung protective approach such as high PEEP with
control of plateau pressure is usually applied. Even if such strategy is introduced,
ARDS patients sometimes develop barotrauma because of reduced lung compliance
and fragile of visceral pleura associated with intermittent shear stress and persistent
inflammation. Chest HRCT provides useful information for early detection of sub-
tle pneumomediastinum to apparent pneumothorax compared to chest radiograph.
In terms of VAP, chest HRCT can demonstrate new parenchymal shadow which is
distinct from pleural effusion. Patients with the CT score < 235 had a significantly
lower incidence of barotrauma (5.0 vs 32.0%; p 0.0019) within 28 days after the
onset of ARDS than those with CT score of ≧235. The CT score was also indepen-
dently associated with the occurrence of barotraumas with an odds ratio (OR) of
1.61 by multivariate regression analysis (p = 0.018). The percentage of patients
complicated with VAP in the higher CT score group tended to be higher than those
in the lower CT score groups (51.4% and 35.4%, respectively). Multivariate analy-
sis also demonstrated that the CT score was independently associated with the com-
plication of VAP with an OR of 1.46 (p 0.0041).
4 Conclusion
In answers for opening clinical question, we can evaluate the severity of ARDS
patients with integration of Berlin criteria and chest imaging texture. Furthermore,
we are able to predict mortality of ARDS patients based on the accurate estimation
of extent of bronchiectasis or bronchiolectasis.
64 T. Kishaba
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Chapter 5
Serum Markers of ARDS: How Can
We Know the Severity and Prognosis
from the Serum Markers?
Taku Nakashima and Noboru Hattori
Abstract Acute respiratory distress syndrome (ARDS) describes a group of dis-

eases that present with severe respiratory failure and a high mortality rate. For the
management of this refractory disease, biomarkers in the early diagnostic stage of
ARDS may be a meaningful indicator for clinical diagnosis and management.
Among biomarkers overall, peripheral blood serum or plasma biomarkers are ideal
because they are less invasive and easier to repeatedly measure. In ARDS patients,
serum or plasma biomarkers associated with coagulation/fibrinolysis, inflammatory
cascade, endothelium damage, and epithelium damage are shown to be predictors of
prognosis. In addition, some of these biomarkers have shown promising results in
patients with ARDS related to coronavirus disease 2019. Clinicians should be aware
of several points in interpreting biomarkers. First, no specific single biomarker can
clearly distinguish ARDS from non-ARDS patients. Second, useful biomarkers also
vary depending on the phase of ARDS. Finally, some biomarkers are reliable only
in some diseases in the spectrum of ARDS manifestations with specific underlying
causes. Because the mortality rate of ARDS remains high, the discovery of more
innovative biomarkers and the development of useful biomarkers, regardless of the
cause of ARDS, are urgently needed.
Keywords Biomarker · Serum · Plasma · Prognosis · COVID-19 · KL-6
T. Nakashima (*) · N. Hattori

Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health
Sciences, Hiroshima University, Minami-ku, Hiroshima, Japan
e-mail: tnaka@hiroshima-u.ac.jp

Ltd. 2022
https://doi.org/10.1007/978-981-16-8371-8_5
68 T. Nakashima and N. Hattori
1 Introduction
Acute respiratory distress syndrome (ARDS) describes a group of diseases with a

high mortality rate, despite current medical advances. An indicator that can accu-
rately predict the prognosis for ARDS patients at diagnosis would be very useful.
The indicators that can be obtained in the clinical course of ARDS include the fol-
lowing types of test data: clinical, such as ventilator setting and oxygenation index;
physiologic, such as pulmonary function; radiologic, such as chest computed
tomography; pathologic, such as lung biopsy; and biomarkers, primarily protein
from biomaterials, such as blood, urine, sputum, and bronchoalveolar lavage fluid.
Because ARDS patients are in a critical condition, it is practically difficult to per-
form repeated highly invasive examinations such as lung function tests, bronchoal-
veolar lavage, or lung biopsies. Biomarkers are defined by the National Institutes of
Health Biomarkers Definitions Working Group as “a characteristic that is objec-
tively measured and evaluated as an indicator of normal biological processes, patho-
genic processes, or pharmacologic responses to a therapeutic intervention” [1].
Among the various indicators just described, serum or plasma biomarkers from
peripheral blood are ideal because they are less invasive and easier to repeatedly
measure. However, some important points must be noted in the evaluation of ARDS
biomarkers obtained from peripheral blood. First, no specific ARDS biomarker
exists that can clearly distinguish ARDS from non-ARDS patients. Second, the
pathologic course of ARDS is characterized by temporal changes, namely the exu-
dative, proliferative, and fibrotic phases. Therefore, useful biomarkers also vary,
depending on the phase of ARDS. In addition, according to the definition of ARDS,
diagnosis requires the presence of a wide range of underlying heterogeneous dis-
eases that cause ARDS, which can be classified as direct or indirect lung injury,
which is why some serum biomarkers are reliable only in manifestations of ARDS
with specific types of underlying cause [2]. Particular attention should be paid to the
interpretation of whether the serum biomarker of interest is “useful for whole
ARDS” or “useful only for ARDS with some specific underlying injury” [2]. This
chapter focuses on serum and plasma biomarkers in ARDS which can serve as prog-
nostic indicators when measured early in the clinical course of ARDS. This chapter
excludes the predictive biomarkers for ARDS development in patients who do not
have a disease but are at risk.
2 Serum Biomarkers Associated with Prognosis in ARDS
Table 5.1 summarizes biomarkers associated with the prognosis in patients with
ARDS. The detailed significance of each biomarker is described in the follow-
ing text.
5 Serum Markers of ARDS: How Can We Know the Severity and Prognosis… 69
Table 5.1 Prognostic blood biomarkers in acute respiratory distress syndrome

Status associated with
Classification Biomarker poor prognosis Ref.
Coagulation and
fibrinolysis
Plasminogen activator inhibitor-1 ↑ [5, 6]
Protein C ↓ [5, 6]
Soluble thrombomodulin ↑ [6, 7]
Inflammatory cascade
Interleukins (IL-1β, 2, 4, 6, 6R, 8, ↑ [2,
10, 18) 8–10]
TNF-α and soluble TNFR ↑ [9, 11,
12]
C-reactive protein ↓ [13]
High-mobility group box 1 ↑ [14]
Granulocyte colony-stimulating ↑ [15]
factor
Activin-A ↑ [16]
Decoy receptor 3 ↑ [17]
Neutrophil elastase ↑ [18]
Peptidase inhibitor 3 ↓ [18]
Soluble suppression of ↑ [19]
tumorigenicity-2
Heparin-binding protein ↑ [20]
Endothelium damage
von Willebrand factor ↑ [2, 21,
22]
Soluble intercellular adhesion ↑ [6, 23]
molecule-1
Angiopoietin-2 ↑ [2, 22]
Endocan ↑ [24]
Growth differentiation factor-15 ↑ [25]
Epithelium damage
Krebs von den Lungen-6 ↑ [27, 28]
Surfactant protein-D ↑ [31]
Receptor for advanced glycation ↑ [2, 33]
end products
Club cell protein 16 ↑ [34]
IL-6R interleukin-6 receptor, TNFR tumor necrosis factor receptor
2.1 Biomarkers Associated with Coagulation and Fibrinolysis
In patients with ARDS, the balance of the coagulation and fibrinolysis is disrupted
in the alveolar lumen [3, 4]. Specifically, it has been observed that the balance shifts
to a hypercoagulable/antifibrinolytic state, which contributes to the pathogenesis of
ARDS, such as impaired gas exchange in the alveolar lumen. Plasminogen activator
inhibitor-1 (PAI-1) is a hypercoagulation/antifibrinolytic protein that suppresses the

fibrinolytic system by inhibiting tissue plasminogen activator activity, consequently
inhibiting fibrinolysis. Protein C is an anticoagulation factor synthesized in the liver
in a vitamin K-dependent manner, and a decrease in protein C leads to a hyperco-
agulation/antifibrinolytic balance in the body. Compared with patients with cardio-
genic pulmonary edema, ARDS patients had higher concentrations of plasma PAI-1
and lower concentrations of plasma protein C [5]. Higher plasma PAI-1 and lower
plasma protein C concentrations were associated with higher mortality in ARDS
patients [5, 6]. Thrombomodulin, an activator of protein C, is also known as a
marker of endothelial cytotoxicity. Patients with high plasma concentrations of sol-
uble thrombomodulin at the onset of ARDS had a significantly poorer prognosis
than those with low concentrations [6, 7].
2.2 Biomarkers Associated with the Inflammatory Cascade
Systemic inflammatory responses are induced through increased proinflammatory

cytokine expression and decreased anti-inflammatory cytokine expression in the
early onset of ARDS. Serum or plasma proinflammatory cytokine interleukin
(IL)-1β, IL-2, IL-4, IL-6, IL-6 receptor, IL-8, IL-10, and IL-18 at the onset of ARDS
were significantly higher in nonsurvivors than survivors [2, 8–10]. Similarly, higher
concentrations of tumor necrosis factor (TNF)-α, and soluble TNF receptor were
associated with poorer prognosis in ARDS patients [9, 11, 12]. Among them, IL-1β,
IL-6, IL-8, and TNF-α concentrations were higher in septic versus nonseptic ARDS
[9]. Furthermore, a multicenter study revealed that IL-6 and IL-8 were higher in
ARDS patients with underlying indirect injury such as sepsis than in those with
direct injury such as pneumonia [2]. These results suggest that serum concentrations
of proinflammatory cytokines are more likely to be elevated in patients with ARDS
caused by indirect injury than in those caused by direct injury.
The production of C-reactive protein (CRP) in the liver is induced by proinflam-
matory cytokines, such as IL-6, IL-1, and TNF-α. Among these CRP-inducible pro-
inflammatory cytokines, IL-6 is the strongest inducer in the CRP production. As
previously described, a higher concentration of IL-6 is associated with poor out-
comes in ARDS patients; therefore, it is easy to predict that a higher concentration
of CRP is also associated with poor prognosis in ARDS patients. Interestingly, how-
ever, higher serum CRP concentrations within 48 h after ARDS onset were associ-
ated with better survival rates [13].
High-mobility group box 1 (HMGB1) is a known mediator of acute lung injury
through the acceleration of proinflammatory signaling. Serum HMGB1 concentra-
tion at the diagnosis of ARDS is an independent predictor for intensive care unit
mortality [14]. Another indicator may be the granulocyte colony-stimulating factor
(G-CSF), which is a neutrophilic growth and release factor. Several lines of evi-
dence suggest the role of G-CSF in the pathogenesis of ARDS. High baseline
plasma concentrations of G-CSF are associated with an increased risk of death and
a decreased ventilator-free and organ failure-free days in patients with ARDS, espe-
cially in sepsis-related ARDS [15].
Activin-A, a member of the transforming growth factor-β (TGF-β) superfamily,
is a pleiotropic regulator of cell development and function in both acute and chronic
inflammation. Serum activin-A was elevated in ARDS patients compared with
healthy controls and non-ARDS sepsis patients [16]. Serum activin-A also showed
statistically significant correlation with in-hospital mortalities [16]. Decoy receptor
3 (DcR3) is a member of the TNF receptor superfamily, existing as a soluble recep-
tor for the Fas ligand. High plasma DcR3 concentrations correlate with the develop-
ment of multiple-organ dysfunction and independently predict 28-day mortality in
patients with ARDS [17].
The release of inflammatory mediators and cytokines from accumulated poly-
morphonuclear neutrophils plays crucial roles in the pathophysiology of
ARDS. Among the mediators, neutrophil elastase is one of the most important
organ- and tissue-destructive proteases, which is inhibited by endogenous protein-
ase inhibitors, such as peptidase inhibitor 3 (PI3)/elafin. Higher plasma concentra-
tions of neutrophil elastase and lower concentrations of PI3 at the diagnosis of
ARDS were associated with higher 28-day and 60-day mortality in ARDS
patients [18].
Suppression of tumorigenicity-2 (ST2) is an IL-1 receptor family member that
exists in both a transmembrane and a soluble isoform. The functional ligand for ST2
is IL-33, and ST2/IL-33 signaling was first described as a mediator of inflammation
and immunity. Higher soluble ST2 concentrations are associated with worse out-
comes in ARDS patients [19].
Finally, heparin-binding protein (HBP), an antimicrobial protein stored in neu-
trophil granules, has a broad spectrum of antimicrobial activity, mainly against
Gram-negative bacteria. Patients with ARDS had significantly higher plasma con-
centrations of HBP compared with patients with cardiogenic pulmonary edema and
healthy controls. The plasma HBP concentrations at the diagnosis of ARDS were
significantly higher in nonsurvivors than in survivors [20].
2.3 Biomarkers Associated with Endothelium Damage
Obvious or latent vascular endothelial cell injury is associated with both systemic
inflammation and disease progression in the clinical course of ARDS. Therefore,
factors related to vascular endothelial cytotoxicity may be prognostic indicators.
The von Willebrand factor (vWF) is a high molecular weight antigen produced
exclusively by vascular endothelial cells, and its release into the blood flow reflects
endothelial cells activation and injury. Plasma vWF concentrations at the diagnosis
of ARDS were significantly higher in nonsurvivors than in survivors, even after
adjusting for the severity of illness, sepsis, and ventilator strategy. Higher vWF
concentrations were also significantly associated with fewer organ failure-free days
[2, 21, 22].
Intercellular adhesion molecule-1 (ICAM-1), an adhesion molecule expressed

on alveolar epithelial and vascular endothelial cells, plays an important role in the
migration and aggregation of neutrophils into the lung. Soluble ICAM-1 concentra-
tions were significantly higher in ARDS patients than in non-ARDS patients with
pulmonary edema; in addition, patients with high concentrations of soluble ICAM-1
at the diagnosis of ARDS demonstrated a poorer prognosis than those with low
concentrations [6, 23].
Angiopoietin-2 is a proinflammatory mediator of endothelial injury in animal
models. Increased plasma angiopoietin-2 concentrations are associated with poor
outcomes in patients with sepsis-associated ARDS, but not pneumonia-associated
ARDS [2, 22]. Another endothelial marker is endocan, also called endothelial cell-
specific molecule-1. Endocan is a soluble 50 kDa dermatan sulfate proteoglycan
that is secreted from pulmonary and kidney vascular endothelial cells. Endocan
inhibits leukocyte–endothelial cell adhesion and reduces excessive leukocyte
recruitment into the lungs. Plasma endocan concentrations in patients with ARDS
were significantly correlated with the Acute Physiologic Assessment and Chronic
Health Evaluation II score, and were higher in nonsurvivors than in survivors [24].
The growth differentiation factor-15 (GDF-15) is a stress-responsive cytokine
and member of the TGF-β superfamily. The expression of GDF-15 has been shown
to be a biomarker for pulmonary vascular disorders. In patients with ARDS, higher
concentrations of GDF-15 are significantly associated with poor outcomes [25].
Finally, similar to biomarkers associated with the inflammatory cascade, biomark-
ers associated with endothelium damage, such as vWF and angiopoietin-2, have
been reported to be significantly higher in ARDS patients with indirect injury than
in those with direct injury; therefore, particular attention should be paid to the inter-
pretation of these biomarkers [2].
2.4 Biomarkers Associated with Epithelium Damage
The main pathologic finding in patients with ARDS is diffuse alveolar damage,
which is identical to the pathologic findings seen in acute exacerbation of interstitial
pneumonia. Thus, many biomarkers that reflect alveolar epithelial cells injury are
shared with ARDS and other types of interstitial pneumonia. Krebs von den
Lungen-6 (KL-6) is a high molecular weight mucin-like glycoprotein that belongs
to the MUC1 mucin family [26]. Exclusively expressed on type II alveolar epithelial
cells and respiratory bronchiolar epithelial cells in the lung, KL-6 is thought to be
oversecreted into the alveolar cavity during alveolar epithelial injury and regenera-
tion and then transferred to the bloodstream. Plasma KL-6 concentrations in patients
with ARDS were significantly higher than in healthy controls and patients with
cardiogenic pulmonary edema [27]. In addition, KL-6 concentrations in the plasma
and fluid in the alveolar epithelial lining at the diagnosis of ARDS were signifi-
cantly higher in nonsurvivors than in survivors [27, 28].
It is important to note that the complication of disseminated intravascular coagu-

lation (DIC) with underlying disease leads to high mortality in ARDS patients. In
fact, the prognosis in patients with ARDS complicated by DIC during their clinical
course was significantly worse than that of patients without DIC, with a mortality
rate of 79–83% versus 22–32%, respectively [29, 30]. Unfortunately, it is currently
impossible to determine the complication of DIC using a single biomarker; how-
ever, serum concentrations of KL-6 and its submolecule (carrying selectin ligands
such as Sialyl Lewisa/CA19–9 and Sialyl Lewisx) at the diagnosis of ARDS have
been shown to be predictive biomarkers for the development of DIC in ARDS
patients [29, 30]. If the complication of DIC is suspected during the clinical course
of ARDS, treatment should be initiated immediately.
Surfactant protein-A and -D (SP-A and SP-D) are mainly produced by type II
alveolar epithelial cells and are thought to be involved in the immune response of
the lungs. Higher baseline plasma concentrations of SP-D, but not SP-A, were asso-
ciated with a greater risk of mortality, fewer ventilator-free days, and fewer organ
failure-free days in ARDS patients [31]. Interestingly, contrary to KL-6, the concen-
trations of SP-A and SP-D in the alveolar space tended to be lower in patients with
ARDS than in controls [32]. The molecular weight of SP-A, SP-D, and KL-6 is
28–36 kDa, 43 kDa, and >200 kDa, respectively. This difference in molecular size
and weight may contribute to the opposite pattern in alveolar and blood
concentrations.
The receptor for advanced glycation end products (RAGE) is a pattern-
recognition receptor expressed on multiple cell types, but is constitutively expressed
at its highest concentrations on alveolar type I epithelial cells. Higher baseline
plasma concentrations of RAGE were associated with increased severity of lung
injury, mortality, fewer ventilator-free days, and fewer organ failure-free days in
ARDS patients [2, 33].
Finally, club cell protein 16 (CC-16, formerly known as Clara cell secretory
protein) is secreted by bronchiolar Clara cells in a region commonly affected by
ARDS related diffuse alveolar damage. Higher initial CC-16 serum concentrations
in patients with ARDS are associated with increased risk of mortality, fewer
ventilator-free days, and increased frequency of nonpulmonary multiple-organ fail-
ure [34]. Contrary to the biomarkers associated with inflammatory cascade and
endothelium damage, biomarkers associated with epithelium damage tend to be
higher in ARDS patients with direct injury than in those with indirect injury [2].
3 W
hat Is the Useful Biomarker for Coronavirus Disease
2019 (COVID-19)-Related ARDS?
The rapid outbreak of COVID-19 caused by severe acute respiratory syndrome

coronavirus 2 (SARS-COV-2) has become a pandemic. Although most cases remain
mild to moderate, about 15% of patients develop severe pneumonia, and 5%
Table 5.2 Median or mean concentrations of serum KL-6 (U/mL) in patients with or without
COVID-19
Control subjects COVID-19
Severe
Author Healthy condition Nonsevere Severe Whole Ref.
Xue et al. – 174 (n = 43) 241 (n = 6) 677 – [35]
(n = 15)
d’Alessandro et al. 239 – 293 1021 – [36]
(n = 22) (n = 10) (n = 12)
Awano et al. – – 223 338 – [37]
(n = 33) (n = 21)
Frix et al. 254 – – – 405 [38]
(n = 70) (n = 83)
Japan ECMOnet for – – – 333 – [39]
COVID-19 (n = 26)
COVID-19 Coronavirus disease 2019, KL-6 Krebs von den Lungen-6
progress to severe respiratory failure, sepsis, multiple-organ failure, and other fatal
conditions. One of the main causes of COVID-19-related mortality is ARDS, and it
is triggered by a cytokine storm that damages the respiratory epithelium. In this
context, biomarkers associated with epithelium damage may also serve as a reliable
biomarker in patients with ARDS related to COVID-19. Among the epithelium
damage biomarkers, KL-6 is one of the promising candidates because SARS-COV-2
infects type II alveolar epithelial cells, which secrete KL-6. In fact, as shown in
Table 5.2, several reports suggested that serum KL-6 concentrations at the diagnosis
of COVID-19 were significantly higher in patients with severe clinical conditions
than in patients with nonsevere conditions [35–38]. These reports concluded that
serum concentrations of KL-6 may be a useful prognostic biomarker for severe
COVID-19. More recently, however, the working group of the Japan extracorporeal
membrane oxygenation (ECMO) network (ECMONet) for COVID-19 suggested
that patients with type L, but not type H, COVID-19 do not display increased serum
concentrations of KL-6 [39]. Thus, careful attention should be paid to the use of
KL-6 as a potential biomarker for the management of COVID-19 patients.
4 Conclusion
Biomarkers obtained from peripheral blood in the early diagnostic stage of ARDS
can serve as indicators of both disease severity and prognosis for patients with
ARDS. Furthermore, promising biomarkers have been reported in ARDS patients
related to COVID-19. Notably, some ARDS biomarkers are reliable only in ARDS
manifestations with specific types of underlying causes. Because the mortality rate
of ARDS remains high, the discovery of more innovative markers and the develop-
ment of useful biomarkers, regardless of the cause of ARDS, are urgently needed.
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Part III
Management
Chapter 6
Ventilatory Management for Patients
with ARDS: Established and Rapidly
Evolving Strategies
Yasuhiro Norisue
Abstract The main goal of ventilatory management for patients with ARDS is to
prevent further injury of intact alveoli while maintaining adequate oxygenation and
ventilation. This chapter will review established and evolving approaches in ventila-
tory management, as well as the underlying pathophysiology. Considerations in
managing ARDS secondary to COVID-19 infection (CARDS) will also be dis-
cussed in this chapter.
Keywords Ventilatory management · Ventilator-induced lung injury · VILI

Patient self-inflicted lung injury · P-SILI · COVID-19
1 Introduction
Although mechanical ventilation is essential for managing patients with acute respi-
ratory distress syndrome (ARDS), it does not “treat” the lungs. The main goal of
ventilatory management for patients with ARDS is to prevent further injury of
remaining alveoli while maintaining adequate oxygenation and ventilation. Several
new concepts of a “lung-protective strategy” have emerged during the last decade.
This chapter will review established and evolving approaches to ARDS manage-
ment, as well as the underlying pathophysiology. Management of ARDS secondary
to COVID-19 infection (CARDS) will also be discussed.
Y. Norisue (*)
Department of Pulmonary Medicine, Department of Emergency and Critical Care Medicine,
Tokyo Bay Urayasu Ichikawa Medical Center, Urayasu, Chiba, Japan

Ltd. 2022
https://doi.org/10.1007/978-981-16-8371-8_6
82 Y. Norisue
2 Ventilator-Induced Lung Injury
Although mechanical ventilators can provide adequate gas exchange, they may also
promote progression of lung injury, known as ventilator-induced lung injury (VILI)
[1]. The main processes responsible for VILI are overdistension and atelectasis of
alveoli [2–4]. Because lungs with severe ARDS usually have only a small region
with intact, open alveoli (and thus limited functional residual capacity), a tidal vol-
ume set on the basis of lung volume in the absence of ARDS may lead to regional
overdistension and injury of alveoli due to exaggerated stress and strain. During
mechanical ventilation, atelectasis alone can induce lung injury by cyclic reopening
(recruitment) of alveoli [5]. Repetition of the re-collapse upon expiration and
reopening upon inspiration results in regional “atelectrauma,” because of high
mechanical stress on the epithelial surface of alveoli. In addition, the interface
between adjacent collapsed and non-collapsed alveoli is believed to be exposed to
high stress and strain [6].
3 “ Classical,” or Established, Recommendations

in Ventilatory Settings
3.1 L
imiting Tidal Volume on the Basis of Predicted Body
Weight and Plateau Airway Pressure
Current guidelines and expert statements recommend low tidal ventilation, about
4–6 mL/kg. The value is based on predicted body weight (PBW) and limiting pla-
teau airway pressure (Pplat) to ≤30 cm H2O, to prevent excessive strain and stress
on alveoli [7]. On the basis of findings from laboratory research [8–10], several
small randomized controlled trials (RCTs) investigated the hypothesis that limiting
lung strain and stress produced by mechanical ventilation could improve mortality.
A subsequent larger randomized controlled trial conducted by the ARDS Network
showed that a ventilatory strategy targeting a tidal volume of 6 mL/kg PBW and a
Pplat of ≤30 cm H2O was associated with lower mortality than a strategy targeting
a tidal volume of 12 mL/kg PBW and a Pplat of ≤50 cm H2O in patients with ARDS
[2]. Although limiting tidal volume on the basis of PBW is simple and remains the
mainstay of lung protective strategy, this method is limited by the fact that lung
strain and stress are dependent variables of functional residual capacity (FRC), not
of PBW. Therefore, a tidal volume adjusted for PBW may not prevent VILI, espe-
cially in patients with severe ARDS and low FRC. Determination of acceptable tidal
volume in relation to driving pressure (ΔP) is an emerging standard that may over-
come this limitation, as explained below.
6 Ventilatory Management for Patients with ARDS: Established and Rapidly Evolving… 83
3.2 S
electing Positive End-Expiratory Pressure from Positive
End-Expiratory Pressure/FiO2 Tables
Use of an adequate level of positive end-expiratory pressure (PEEP) to improve

oxygenation has been an essential in ventilatory management for patients with
ARDS. PEEP/FiO2 tables proposed by the ARDS Network (Table 6.1) are com-
monly used for selecting PEEP. With this method, PEEP is based on the FiO2
required to maintain adequate oxygenation. Meta-analyses of trials comparing
higher versus lower PEEP strategies [7] suggest that a higher PEEP/FiO2 table is
generally recommended for patients with a PaO2/FiO2 of <200.
Use of the PEEP/FiO2 table to set PEEP is justified if we assume that a patient
who requires high FiO2 to maintain oxygenation has large lung regions with col-
lapsed alveoli that are recruitable with high airway pressure. Obviously, this
assumption is untrue for hypoxic patients without significant recruitable atelectasis,
such as those with early COVID-19, COPD, interstitial lung disease, or non-
recruitable atelectasis. Therefore, application of the PEEP/FiO2 table without patient
individualization could cause harm from the adverse hemodynamic effects of PEEP
and yield no benefit. A potentially useful method to individualize the effect of PEEP
is to adjust PEEP in accordance with respiratory and hemodynamic parameters,
such as oxygenation, ventilation, respiratory system compliance, and cardiac output
before and after increasing or decreasing PEEP.
3.3 Prone Positioning
Prone positioning is currently the most effective intervention for managing patients
with moderate to severe ARDS. As previously mentioned, increasing FRC reduces
lung strain. By altering the anatomical characteristics of the thorax and mediasti-
num, prone positioning is believed to increase FRC by reducing heterogeneity of
alveoli. Clinical trials have consistently shown that prone positioning for at least
16 h a day improved survival for patients with moderate to severe ARDS [11, 12],
and current guidelines and expert statements recommend prone positioning of
ARDS patients with a P/F of <150 mm Hg [13].
Table 6.1 PEEP/FiO2 tables

Low PEEP/FiO2 table
FiO2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
PEEP 5 5–8 8–10 10 10–12 12–14 18 18–24
High PEEP/FiO2 table
FiO2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
PEEP 5–14 14–16 16–18 18–20 18–20 20–22 22 22–24
84 Y. Norisue
4 E
merging Strategies in Lung Protection
and Underlying Pathophysiology
4.1 U
sing Driving Pressure (ΔP) to Identify an Individualized
Acceptable Tidal Volume
Volutrauma is provoked by strain during alveolar distention. Strain is defined as:
Strain = tidal volume / FRC
The most important implication of this equation for lung protective ventilation
is that tidal volume is not the only variable in determining volutrauma; FRC is
equally important. That is, lower FRC is associated with greater strain, and vice
versa. It has been suggested that, to prevent volutrauma, a strain of >1 should be
avoided [14]. However, it is neither easy nor practical in daily practice to measure
FRC in patients who are mechanically ventilated. Instead, Amato et al. used big
data from previous trials to evaluate the hypothesis that because respiratory system
compliance (Crs) reflects “functional FRC,” strain would be positively, linearly
correlated with ΔP (Pplat − PEEP), which is tidal volume divided by Crs, and that
higher ΔP would be associated with greater mortality. Indeed, they found a strong
association between a ΔP of >15 cm H2O and high mortality [15]. A clinical impli-
cation of this finding is that tidal volume should be less than that gained with a ΔP
of ≤15 cm H2O. In patients on pressure control ventilation without spontaneous
breathing, the tidal volume gained with an inspiratory pressure of ≤15 cm H2O with
an inspiratory time sufficient for end-inspiratory flow to be zero is permitted. In
patients on volume control ventilation without spontaneous breathing, the set tidal
volume should be limited so that ΔP (Pplat − PEEP) is ≤15 cm H2O, regardless of
PBW. Future RCTs will need to verify this strategy, although it seems physiologi-
cally sound and plausible.
4.2 T
ranspulmonary Pressure and Esophageal
Pressure Monitoring
The true pressure that causes alveoli to expand or collapse is not the absolute value
of the airway pressure but the pressure gradient between the airway pressure, i.e.,
the pressure inside alveoli, and pleural pressure, the pressure outside alveoli. The
pressure gradient is referred to as transpulmonary pressure (PL). An intuitive way to
interpret PL is to see it as the force required to expand alveoli. Alveoli begin to
inflate only when PL is positive, and alveoli are compressed when PL is negative.
Esophageal pressure is measured as a surrogate for pleural pressure at the bedside.
Although there are several clinical applications of PL, the most potentially useful
utilization of PL in ventilatory management is in determining the PEEP that is
adequate for avoiding alveolar collapse and confirming that absolute airway pres-
sure and ΔP are not in ranges that provoke VILI. PL can be especially useful when
a patient has conditions that increase the discrepancy between airway pressure and
PL, i.e., conditions that increase pleural pressure, such as obesity and abdominal
compartment syndrome and conditions that cause substantial negative pleural pres-
sure because of a strong inspiratory effort. Although evidence to support the use of
esophageal pressure monitoring during mechanical ventilation is limited, esopha-
geal manometry for selected patients is an evolving standard [13]. Table 6.2 shows
the target values for PL, which are based on expert opinion regarding mechanically
ventilated patients without spontaneous breathing [16, 17].
4.3 P
atient Self-Inflicted Lung Injury and Controlling
Patients’ Inspiratory Effort
As part of daily practice to avoid diaphragmatic atrophy and dysfunction and pos-
sibly to “prevent atelectasis,” clinicians commonly seek to maintain patients’ inspi-
ratory effort and partially assisted ventilation, even in patients with moderate to
severe ARDS. However, a rapidly emerging concept suggests that inspiratory effort
alone might provoke lung injury, particularly because of negative pleural pressure
leading to high PL and tidal volume and negative pressure pulmonary edema, espe-
cially in patients with severe ARDS. This phenomenon is referred to as patient self-
inflicted lung injury (P-SILI) [18].
Concerns regarding possible worsening of lung injury due to P-SILI led some
experts to recommend early intubation when swings in esophageal pressure increase
[19], as well as control of patient inspiratory effort by esophageal pressure monitor-
ing during mechanical ventilation (Table 6.3) [13, 16, 17]. However, there is no
consensus, especially on target dynamic pressures without end-inspiratory pause. In
addition, evidence that controlling inspiratory effort improves important outcomes
Table 6.2 Target values in Values Target

patients without
End-expiratory PL Above 0 cm H2O
spontaneous breathing
End-inspiratory PL Below 20 cm H2O
Tidal ΔPL Below 12 cm H2O
Table 6.3 Target values in Values Target

patients with spontaneous
Esophageal pressure swing Below 10 cm H2O
breathing
End-expiratory PL Above 0 cm H2O
End-inspiratory PLa Below 20 cm H2O
Tidal ΔPL Below 12 cm H2O
a
End-inspiratory PL needs to be measured with end-
inspiratory pause on pressure support ventilation
86 Y. Norisue
is limited. In a multicenter RCT, Papazian et al. reported that, as compared with

deep sedation without paralysis, 48 h of neuromuscular blockade yielded better-
adjusted survival in patients with moderate to severe ARDS [20]. Although the
improvement in mortality with paralytic use is often attributed to reduction of
P-SILI by paralytic-induced silencing of patient respiratory effort, such a conclu-
sion remains speculative because esophageal pressure was not monitored in the
trial. Tobin and colleagues expressed their concern in a letter to the editor, in which
they maintained that guiding intubation and mechanical ventilation on the basis of
a non-proven concept is not scientifically sound and could be harmful to patients
[21]. Gattinoni and colleagues are world leading experts on mechanical ventilation,
and believers in P-SILI. They argue against this criticism in their response letter,
which maintains that P-SILI has been demonstrated and that ignoring it could be the
more harmful course [22]. Nevertheless, control of inspiratory effort to prevent
P-SILI remains controversial and thus the practice varies among institutions.
5 C
onsiderations for Managing ARDS Patients
with COVID-19
5.1 P
oor Correlation Between Hypoxia Severity
and Reduction in FRC
COVID-19 patients with ARDS (CARDS) often present with severe hypoxia, with or
without a minimal area of alveolar collapse on chest CT (Type-L). As the disease pro-
gresses, infiltrates and atelectasis evolves acutely in the lung fields (Type-H) [23]. The
pathophysiology of hypoxia without atelectasis or infiltrates on chest images is mainly
attributed to microthrombosis and dysfunction of hypoxic vasoconstriction of capillar-
ies [24]. As mentioned above, the PEEP/FiO2 table is used with the assumption that a
patient who requires high FiO2 to maintain oxygenation has a large lung area with col-
lapsed alveoli that are recruitable with high airway pressure. Similarly, the rationale for
prone positioning is to increase FRC in patients with moderate to severe ARDS. However,
the use of a high PEEP or prone positioning for a patient with hypoxia caused by
microthrombi and dysfunction hypoxic vasoconstriction of capillaries with preserved
FRC is not theoretically appropriate, and some experts recommend against high PEEP
and prone positioning in patients with type-L CARDS [19, 23].
5.2 P
ersistent Strong Inspiratory Effort and High Incidence
of Re-intubation
Inspiratory effort tends to be stronger and more persistent in patients with CARDS
than in those with ARDS due to other causes. CARDS patients have a high inci-
dence of extubation failure (up to 50%) [22]. Some researchers have suggested that
the high incidence of extubation failure is due in part to progressive P-SILI second-
ary to strong inspiratory effort and that premature extubation should be avoided [19,
22]. Because of the possibility of worsening of ARDS secondary to P-SILI, it may
be reasonable to control inspiratory effort by using adequate sedation, and neuro-
muscular blockade if necessary, at least during the acute phase of CARDS. However,
the decision whether, and how long, to control inspiratory effort is a tradeoff
between lung protection and the risk of post-intensive care syndrome, such as ICU-
acquired weakness. Some researchers doubt that P-SILI is an actual disease entity,
and there is no direct evidence indicating a benefit for controlling inspiratory effort
in CARDS. Because of the non-negligible adverse effects of deep sedation and neu-
romuscular blockade, the decision to suppress inspiratory effort in daily practice
should be made cautiously.
6 Conclusions
This chapter has reviewed established and evolving strategies for ventilatory man-
agement, as well as the pathophysiology of the causative conditions. Although some
strategies improve survival, other approaches require further study and validation
before they become established strategies. Clinicians must make choices on apply-
ing and implementing these evolving strategies only after cautious individualized
assessment of patients and critical appraisal of new evidence.
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Society of Intensive Care Medicine/Society of Critical Care Medicine clinical practice guide-
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9. Dreyfuss D, Saumon G. Ventilator-induced lung injury: lessons from experimental studies. Am

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11. Guerin C, Reignier J, Richard JC, et al. Prone positioning in severe acute respiratory distress
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tion on mortality among patients with acute respiratory distress syndrome: a systematic review
and meta-analysis. CMAJ. 2014;186(10):E381–90.
13. Menk M, Estenssoro E, Sahetya SK, et al. Current and evolving standards of care for patients
with ARDS. Intensive Care Med. 2020;46(12):2157–67.
14. Modesto IAV, Aguar Carrascosa M, Medina VA. Stress, strain and mechanical power:

is material science the answer to prevent ventilator induced lung injury? Med Intensiva.
2019;43(3):165–75.
15. Amato MB, Meade MO, Slutsky AS, et al. Driving pressure and survival in the acute respira-
tory distress syndrome. N Engl J Med. 2015;372(8):747–55.
16. Bertoni M, Spadaro S, Goligher EC. Monitoring patient Respiratory effort during mechanical
ventilation: lung and diaphragm-protective ventilation. Crit Care. 2020;24(1):106.
17. Mauri T, Yoshida T, Bellani G, et al. Esophageal and transpulmonary pressure in the clinical
setting: meaning, usefulness and perspectives. Intensive Care Med. 2016;42(9):1360–73.
18. Brochard L, Slutsky A, Pesenti A. Mechanical ventilation to minimize progression of lung
injury in Acute Respiratory failure. Am J Respir Crit Care Med. 2017;195(4):438–42.
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not lead to a “typical” acute respiratory distress syndrome. Am J Respir Crit Care Med.
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Chapter 7
Noninvasive Ventilation and High-Flow
Oxygen Therapy for ARDS: Does
Noninvasive Ventilatory Management
Improve the Outcome of ARDS Patients?
Toshiki Yokoyama and Yasuhiro Kondoh
Abstract The purpose of noninvasive respiratory management, such as noninva-

sive ventilation (NIV) and high-flow nasal cannula (HFNC) oxygen therapy, is to
prevent unnecessary intubation and worsening of the disease severity. The lung pro-
tective strategy, mainly including low tidal ventilation, is important in the respira-
tory management of ARDS. The effect of NIV and HFNC for ARDS can be limited
because of the lack of strict limitation of tidal volume. However, there is a possibil-
ity that both NIV and HFNC are effective as respiratory management in mild and
early ARDS based on their unique mechanism, but sufficient evidence has not been
established. Further examinations are expected in future.
Keywords NIV · HFNC · CPAP · PEEP · Lung protective strategy
1 Introduction
A lung protective strategy focusing on low tidal volume ventilation is important in

respiratory management of acute respiratory distress syndrome (ARDS) [1], and is
based on intubation and mechanical ventilation.
T. Yokoyama
Department of Respiratory Medicine and Allergy, Tosei General Hospital, Seto, Japan
Department of Critical Care and Intensive Care Medicine, Tosei General Hospital,
Seto, Japan
Y. Kondoh (*)
Department of Respiratory Medicine and Allergy, Tosei General Hospital, Seto, Japan
e-mail: kondoh@tosei.or.jp

Ltd. 2022
https://doi.org/10.1007/978-981-16-8371-8_7
90 T. Yokoyama and Y. Kondoh
Use of noninvasive respiratory management, such as noninvasive ventilation

(NIV) and high-flow nasal cannula (HFNC) oxygen therapy, is limited to mild cases
of ARDS. The Berlin definition recommends that mild ARDS be treated [2]. The
purpose of noninvasive respiratory management is to prevent unnecessary intuba-
tion and worsening of the disease severity.
2 Noninvasive Ventilation
2.1 Background
NIV is mechanical ventilation without intubation, mainly positive airway pressure

ventilation via facemask to the upper airway. Respiratory assistance by biphasic
pressure via cuirass to the chest wall is also included in NIV. NIV can help to avoid
mechanical ventilation and ventilator associated pneumonia, and in most cases NIV
can be managed without excessive sedation or rest. Recent NIV devices have been
improved and are easy to remove and easy to restart.
The history of NIV is very old; the iron lung, also known as a tank ventilator, was
used from middle nineteenth century as a type of negative pressure ventilator. It is a
mechanical respirator which encloses most of a person’s body, and assists them in
breathing in the enclosed space [3]. Biphasic cuirass ventilation is a refinement of
the iron lung. The old iron lung was used commonly until the polio pandemic in the
1950s. However, insufficient airway management with iron lungs led to poor prog-
nosis in the management of polio [4], and the innovation of endotracheal intubation
has become the main form of mechanical ventilation since then. In the 1990s, NIV
again attracted attention as means of respiratory management. Based on continuous
positive airway pressure (CPAP) for the management of sleep apnea syndrome, a
new noninvasive positive pressure respiratory management via nasal or facemask
was developed. In the “new NIV,” conventional mechanical ventilation was con-
nected directly to a facemask, without going through endotracheal intubation
(Fig. 7.1). From the evidence established in cardiogenic pulmonary edema [5–7]
and exacerbation of COPD [8–10], the indications for NIV were expanded to vari-
ous areas, including ARDS [11, 12].
2.2 Mechanism
The most important point in respiratory management in ARDS is appropriate lung

protective ventilation, according to the ARMA study in 2000 [1]. NIV together with
spontaneous breath without strict limitation of tidal volume cannot necessarily be
applied in a lung protective strategy. In general, NIV is mechanical ventilation with-
out endotracheal intubation, and today it is primarily positive airway pressure ven-
tilation via a specialized interface, a facemask. The main modes are CPAP and
7 Noninvasive Ventilation and High-Flow Oxygen Therapy for ARDS: Does… 91
Full-face
mask
Fig. 7.1 NIV via face mask
pressure support ventilation (PSV), and sedative-agents are commonly either not
used, or minimized. Therefore, it is difficult to limit tidal volume to strictly meet
target tidal volume in NIV.
However, NIV can be used for lung protection based on sufficient settings, espe-
cially PEEP. Higher PEEP can increase patients’ functional residual capacity (FRC)
and raise the end-expiratory position. Increased FRC decreases tidal volume as a
result. The lung protective mechanism of NIV is indirect limitation of excessive
tidal volume based on the appropriate use of PEEP. Control of excessive exhalation
decreases excessive tidal volume and keeps the lung alveoli opened (Fig. 7.2).
Although tidal volume cannot be directly limited to 6 mL/kg, the target tidal volume
in the ARMA study, sufficient use of PEEP and NIV can limit excessive ventilation
volume. NIV may be useful for lung protective management in ARDS as a concept.
However, it cannot limit to strict low tidal volume, as lung protective strategy.
Therefore, the clinical effect of NIV can be restrictive in patients with severe ARDS,
because NIV cannot limit tidal volume strictly to 6 mL/kg. It is suggested that NIV
should not be used in patients with severe ARDS, and the use of NIV for ARDS
should be confined to the early stage or mild cases. It is important to prevent the
progression of ventilator induced lung injury. The direct purpose of NIV is not to
cure ARDS, but to avoid exacerbation to severe ARDS and endotracheal intubation.
Some current consensus indicates that NIV for ARDS should be limited to mild/
early cases [2].
PEEP
exhalation
exhalation
PEEP effect
inhalation
inhalation
Decrease tidal volume
Fig. 7.2 PEEP effect and tidal volume limitation in NIV
On the other hand, attention also should be paid to avoiding endotracheal intuba-
tion. Intubated mechanical ventilation tends to require a sedative agent and exces-
sive rest. Prolonged endotracheal intubation can cause a secondary infection,
ventilator associated pneumonia (VAP). Prolonged intubated ventilatory manage-
ment can be harmful for many patients because of the high mortality with VAP. It is
expected that using NIV to avoid endotracheal intubation may improve ARDS
patients’ prognosis, especially immunocompromised patients who may be adversely
affected by VAP. The benefit of NIV in avoiding intubation may be greater in immu-
nocompromised patients with ARDS.
2.3 Evidence
2.3.1 Comparison with Intubation and Mechanical Ventilation
A report by Antonelli et al. in 1998 showed a comparison between intubated

mechanical ventilation and NIV in patients with acute hypoxemic respiratory fail-
ure including ARDS [12]. There was a similar improvement of oxygenation and
prognosis in both groups. However, serious complications, including secondary
pneumonia, and duration of ICU stay were decreased in the NIV group.
Matic et al. reported a study with a total of 387 ICU patients divided into two
groups, which compared NIV and intubated mechanical ventilation [13]. They
reported that the number of ICU deaths was 15 (26%) in the NIV group vs. 21
(25%) in the intubated mechanical ventilation group. While the ICU mortality was
not significantly different, the NIV group had a significantly lower rate of
tracheostomy and shorter ICU duration. They reported better outcomes in cases
with high lung compliance. Therefore, NIV may be more beneficial in mild cases.
Honrubia et al. compared 21 patients with noninvasive ventilation and 33 patients
with conventional mechanical ventilation [14]. In their study, although NIV reduced
the need for intubation, there was a nonsignificant trend for reduction in ICU stay
and hospital mortality, together with fewer complications during ICU stay.
Based on these several studies, it seems that NIV can reduce the need for intuba-
tion and complications, such as pneumonia, but a benefit was not demonstrated in
terms of prognosis.
2.3.2 Comparison with Oxygen Therapy
A 1999 report by Confalonieri et al. compared NIV and regular oxygen therapy for
acute respiratory failure. Their study looked at respiratory failure due to pneumonia,
which may differ strictly from ARDS. They were better able to avoid tracheal intu-
bation with the use of NIV than with oxygen therapy, and the time in the ICU was
shorter [15].
Antonelli et al. conducted an RCT in patients undergoing solid organ transplan-
tation [16]. In that study, 40 acute hypoxemic respiratory failure patients among 238
patients undergoing solid organ transplantation were randomized to an NIV or con-
ventional group. The use of NIV was associated with a significant reduction in the
rate of endotracheal intubation (20% vs. 70%; P = 0.002) and ICU mortality (20%
vs. 50%; P = 0.05); however, hospital mortality did not differ.
Hilbert evaluated the efficacy of NIV in immunocompromised patients [17].
They conducted a prospective, randomized trial of NIV, as compared with standard
treatment with supplemental oxygen and no ventilatory support, in 52 immunosup-
pressed patients with acute respiratory failure. They showed that fewer patients in
the NIV group than in the standard treatment group required endotracheal intuba-
tion (12 vs. 20, P = 0.03), died in the ICU (10 vs. 18, P = 0.03), or died in the hos-
pital (13 vs. 21, P = 0.02).
A few systematic review and meta-analysis have been performed [18, 19]. David-
João et al. reviewed nine studies and showed a significant protective effect of NIV
especially in immunosuppressed patients [18]. Ping Xu et al. reviewed 11 studies
and showed that NIV decreased endotracheal intubation rates and hospital mortality
in acute hypoxemic nonhypercapnic respiratory failure, excluding COPD exacerba-
tion and cardiogenic pulmonary edema [19].
Various past reports show that NIV is effective in avoiding tracheal intubation,
but whether or not it improves prognosis differs depending on the report. A higher
effect is often seen in comparatively mild cases or immunocompromised patients. It
may be that prognosis is improved with the use of NIV in immunocompromised
patients in particular. Antonelli et al. reported that in expert centers, intubation was
avoided in 54% of treated patients in whom NIV was applied as first-line interven-
tion in ARDS [11] (Table 7.1).
Table 7.1 Past studies of NIV for acute respiratory failure

Author Year Design Findings
Comparison with intubation and mechanical ventilation
Antonelli, et al. [12] 1998 RCT Similar improvement of oxygenation and prognosis,
but serious complication and ICU duration were
decreased in the NIV group
Matric, et al. [13] 2007 RCT ICU mortality was no significant difference.
Tracheostomy rate and ICU stay were decreased in
NIV group.
Honrubia, et al. [14] 2005 RCT Hospital mortality and ICU duration was no significant
difference. Intubation rate was decreased in NIV
group
Comparison with oxygen therapy
Confalonieri, et al. [15] 1999 RCT Intubation rate and ICU duration were decreased in
NIV group.
Antonelli, et al. [16] 2000 RCT Intubation rate and ICU mortality were decreased in
NIV group. Hospital mortality was no significant
difference.
Hilbert, et al. [17] 2001 RCT Intubation rate, ICU mortality, and Hospital mortality
were decreased in NIV group.
2.4 Actual Setting Method of NIV
2.4.1 Indications for NIV
Application of NIV is considered in cases when oxygenation cannot be maintained

even with the use of general oxygen therapy, and in cases when dyspnea does not
improve.
2.4.2 Initial Settings and Method of Introduction of NIV
CPAP mode is generally started from about 4–5 cmH2O. The effectiveness of PEEP
differs depending on the patient’s condition, and so PEEP should preferably be
raised while watching the movement in oxygenation and dyspnea. The trachea and
esophagus cannot be isolated with NIV, and PEEP of about 12–15 cmH2O is thought
to be the limit, although individual patient tolerances differ.
It has been previously indicated that with NPPV in ARDS, oxygenation trends
soon after the start of NIV and severity are associated with the success rate [11], and
so very careful management is needed for a time after the start of NIV. Delayed
tracheal intubation has been reported to be associated with increased mortality and
ARDS is not a condition for which the effectiveness of NIV has been established.
Therefore, when indicated, tracheal intubation should be done at an early stage. It
should be noted that patients with ARDS often meet the general precautions for
NIV, such as shock, multiple organ failure, restlessness, or copious airway secretions.
2.4.3 Types of NIV
There are various types of NIV. The external mechanical ventilation typified by the
iron lung that was long in use is also NIV. Today, it has evolved to mechanical ven-
tilation in which an interface called a cuirass is attached from the abdomen to the
chest, and respiratory assistance is performed using negative pressure.
The main form of NIV today is positive pressure ventilation using a face mask,
but this also has two types: one using a ventilator specifically for NIV and one using
an ICU ventilator. The NIV-specific ventilator uses a leak-type face mask and a
single circuit. An intentional leak is permitted, and the tolerance is good because the
mask can be connected loosely, but expiratory ventilation cannot be measured so
strict monitoring cannot be done. Most ICU ventilators use a double circuit and a
non-leak type face mask, and so fundamentally management is done in a closed
circuit. This enables strict measurement of ventilation and strict monitoring.
However, since large air leaks cannot be permitted with ICU ventilators, the mask
should be fitted tightly and patient tolerance is not necessarily good.
2.5 New Era of NIV in ARDS
In recent years, NIV with a helmet has been gaining attention (Fig. 7.3). A type of
interface that covers the entire head is fixed using the shoulders. When this is
attached to a ventilator, positive pressure ventilation is possible. Helmet NIV
requires fewer fine adjustments than face mask NIV, and patient tolerance is rela-
tively stable. However, attaching and removing the helmet is time-consuming in
itself, and so it may not be suited to long-term management. Helmet NIV is the
preferred method mainly in Europe.
Brambilla et al. reported a comparison of helmet CPAP vs. oxygen therapy to
reduce the risk of meeting the criteria for endotracheal intubation [20]. In that study,
40 patients were randomized to helmet CPAP and 41 to Venturi mask. The propor-
tion of patients meeting endotracheal intubation criteria in the helmet CPAP group
was significantly lower compared to those in the control group (6/40 = 15% vs.
26/41 = 63%, respectively, P = 0.001). The helmet CPAP group showed a faster and
greater improvement in oxygenation in comparison to controls (P = 0.001).
Patel et al. evaluated whether helmet NIV improved the intubation rate among
patients with ARDS compared with conventional facemask NIV [21]. Eighty-three
patients were included in the analysis, and the intubation rate was 61.5% (n = 24)
for the face mask group and 18.2% (n = 8) for the helmet group (P < 0.001). Among
patients with ARDS, treatment with helmet NIV reduced intubation rates with a
significant difference. There was also a statistically significant reduction in 90-day
mortality with helmet NIV.
Information on helmet NIV for ARDS is lacking, and there have been few sys-
tematic reviews. Among studies performed with a variety of diseases including
Access port
Inspiratory
limb
Expiratory
limb
Underarm
strap
Fig. 7.3 Helmet NIV
ARDS, there is a systematic review of 11 studies including the two studies men-
tioned above. Compared with conventional NIV, helmet NIV was associated with
reduced hospital mortality and intubation requirement [22].
3 High-Flow Nasal Cannula Oxygen Therapy
3.1 Background
Recently, newly introduced HFNC is expected to not only provide sufficient humid-
ification and accurate oxygen concentration, but also more comfortable manage-
ment with a PEEP-like effect and reduced breathing work. Compared with
conventional oxygen therapy, HFNC is a ground-breaking system that achieves dra-
matic advances. Using a special dedicated nasal cannula, it is an oxygen therapy
that can deliver very high-flow mixed oxygen at up to 60 L/min. The oxygen deliv-
ery system comprises an oxygen blender, mixed oxygen delivery circuit, and nasal
cannula [23].
First, the mixed oxygen is formed in the oxygen blender. The pure mixed oxygen
flow rate and the inspiratory oxygen fraction can be set. It can generally be set up to
60 L/min, but the maximum flow differs depending on the blender performance.
The mixed oxygen delivery circuit used is the same as in an artificial respiration
circuit. It is equipped with a humidifier, and so sufficient heating and humidification
is possible. With the use of highly humidified mixed oxygen, oxygen can be deliv-
ered at a high flow rate than was previously impossible.
The oxygen cannula is somewhat larger than the nasal cannulas used in low-flow
systems, and a dedicated device is used. It is generally fixed to the face with straps
in two locations. Since it is a special large bore cannula, there are cases in which
loads are applied on certain sections depending on patient movement, and there
have been cases of breakage with long-term use.
Structurally, it is formed of the three parts mentioned above and can deliver
mixed oxygen at high flow rates that were previously impossible (Fig. 7.4).
Purified water
Flow meter
Air-oxygen
blender
Special large
bore cannula
Heated inspiratory circuit
Active humidifier
Fig. 7.4 HFNC
3.2 Mechanism
In respiratory management in ARDS, lung protective ventilation centered on tidal

volume limitation is important. Because ventilatory volume cannot be monitored
during the management of HFNC, tidal volume limitation cannot be adequately
achieved. However, it has several advantages over regular oxygen therapy in terms
of respiratory management due to the special effect of delivering oxygen at a high
flow rate.
3.2.1 Maintenance of Airway Mucociliary Clearance
As mentioned above, since the heater/humidifier is the same as that used in ventila-
tors, the system boasts a very high humidification performance. Theoretically, a
relative humidity of 100% at 37 °C is possible, and an environment nearly equiva-
lent to that within the living lungs can be created. By preventing dryness and main-
taining ciliary function, it is thought that the mobility of secretions is maintained
and the risk of respiratory infection is decreased. In addition, the water for humidi-
fication is not directly discharged as in the nebulizers often used in previous high-
flow oxygen therapy, and so even if microbes arise in the stored water the possibility
that they will transmitted to the patient is low. The level of safety in managing infec-
tions is thought to be high. It is also true, however, that much about the mechanism
is largely theoretical, and there is little verification with clinical data.
3.2.2 Effect of Washing Out Anatomical Dead Space
It is frequently experienced that when HFNC is used in patients with some hyper-
capnia, the patient’s PaCO2 decreases. This is based on the fact that turbulence
forms from the administration of mixed oxygen at very high flow rate, and a blow-
out effect occurs in the anatomical dead space. Especially in patients with low pul-
monary function, the proportion of anatomical dead space is relatively high, and so
the distribution of CO2 that remains in the anatomical dead space on exhalation is
thought to be large. The gas with a high CO2 concentration that accumulates in ana-
tomical dead spaces is blown out, from which reduction in accumulated CO2 in the
patient’s body can be expected.
However, the number of past investigations reporting improvements in carbon
dioxide accumulation is limited [24, 25]. There is also a report that HFNC was
effective for acute type II respiratory failure due to neuromuscular disease [26]. It is
possible that the effectiveness of reduced carbon dioxide concentration is influenced
by several factors, such as the actual anatomical formation of the nasal cavity, the
flow rate of administered oxygen, and ventilation status of the individual patient,
and that it is not something that fits all patients. As mentioned above, HFNC has the
advantage that the inspiratory oxygen fraction can be accurately set, and so it is
thought to be the next best measure in cases avoiding NIV and intubation and
mechanical ventilation. Future investigations that examine the kinds of diseases or
conditions in which the effectiveness of reduced CO2 is high are awaited.
Since patients’ breathing workload can be alleviated by reducing the amount of
anatomical dead space, the possibility has also been indicated that there will be an
effect in alleviating respiratory muscle fatigue. The proportion of anatomical dead
space is relatively high especially in cases of low pulmonary function, and so it is
thought that alleviation of the breathing workload by washing out the dead spaces
will also be greater. In a report by Vargas et al., pressure in the esophagus was mea-
sured and compared with the level of breathing effort with HFNC, oxygen therapy,
and CPAP in 12 patients with acute respiratory failure [27]. HFNC was thought to
alleviate the work of breathing more than oxygen therapy, equivalent to CPAP.
3.2.3 A
ccurate Setting of Inspiratory Oxygen Fraction at
High Concentrations
Different from a regular nasal cannula, the fraction of inspired oxygen (FiO2) can be
set at high concentrations without being affected by the tidal volume or respiratory
rate of the patient. Ritchie et al. reported that with flow rates of 30 L/min or higher
at rest, there was not a big difference between the FiO2 setting and the actual FiO2
[28]. For the FiO2 setting, however, there is a possibility that the performance differs
depending on the type of equipment. The more recent types can measure and dis-
play actual measured oxygen fraction values, and so more accurate monitoring can
be done.
3.2.4 PEEP-Like Effect and Alveolar Recruitment
Because of the high flow, airway pressure rises on expiration in accordance with the
flow rate, but unlike the PEEP set in mechanical ventilation the airway pressure
rises early in the expiratory phase, and the pressure decreases through the end of
expiration. The degree of airway pressure is said to rise depending on the level of
the flow rate [29]. Moreover, Parke et al. reported that in healthy people with their
mouths closed, airway pressure was 1.93 cmH2O at a flow rate of 30 L/min and rose
to 3.31 cmH2O at 50 L/min [30]. It is also said that the degree of airway pressure
differs with the mouth open and the mouth closed, and with the mouth open it is
thought that airway pressure does not sufficiently rise [31].
Corley et al. reported that the end-expiratory lung volume increased in correla-
tion with the rise in airway pressure with the use of HFNC in cardiac surgery patients
[32], and it is said that this may improve alveolar collapse and oxygenation.
3.3 Evidence
HFNC does not have a long history, and sufficient evidence has not been accumu-
lated. With HFNC in ARDS, in addition to improved oxygenation from a PEEP-like
effect and increased FRC, alleviation of breathing workload leads to a lower respira-
tory rate. There is a possibility that it will act to limit tidal volume from the inhibition
of excessive ventilatory effort. Theoretically, therefore, it is thought to be effective
as lung protective ventilation, but this is not clear because of the difficulty in moni-
toring, as mentioned above. In severe ARDS that requires strict management, tra-
cheal intubation is necessary and management with HFNC is not recommended.
As a prospective study of acute type I respiratory failure, Roca et al. reported an
investigation of 20 cases of HFNC for hypoxemic respiratory failure that did not
improve with regular oxygen administration [33]. When a switch was made from
face mask oxygen administration to HFNC (FiO2 50%, flow rate 20–30 L/min), a
significant improvement in oxygenation and a decrease in respiratory rate were
reported. A report by Parke et al. compared face masks and HFNC for respiratory
failure mainly in 60 patients after surgery for cardiovascular disease [34]. A com-
parison of the results for 30 patients in the face mask group and 30 patients in the
HFNC group showed a significantly higher success rate in the HFNC group.
Compared with the face mask group, the proportion who reached NIV introduction
was very small although not statistically significant. As in these reports, HFNC has
been shown to have high efficacy for acute type I respiratory failure compared with
conventional oxygen therapy.
Frat et al. conducted a multi-center randomized controlled trial comparing
HFNC, regular oxygen masks, and NIV for acute type I respiratory failure due to
ARDS, with the intubation rate as the primary endpoint [35]. No significant differ-
ences were seen in the intubation rate between the three groups, but when limited to
serious cases of PaO2/FiO2 < 200 the intubation rate was found to be significantly
lower in the HFNC group. The 90-day mortality rate was 12% in the HFNC group,
23% in the mask group, and 28% in the NIV group, a result showing a significantly
better prognosis in the HFNC group.
Similar to NIV, HFNC has also attracted attention in acute respiratory failure with
underlying immunodeficiency, wherein the advantages of avoiding tracheal intuba-
tion are large. There is also a report, although it was an observational study, that
HFNC is effective in acute respiratory failure with underlying immunodeficiency
[36], and that in a sub-analysis of the abovementioned report by Frat et al. [37],
HFNC had high efficacy in acute respiratory failure with underlying immunodefi-
ciency. On the other hand, Azoulay et al. reported the effect of HFNC vs. standard
oxygen in immunocompromised patients with acute respiratory failure in the HIGH
randomized trial [38]. In that study, 776 adult immunocompromised patients with
acute respiratory failure were included and randomized to continuous HFNC
(n = 388) or to standard oxygen therapy (n = 388). The results showed that HFNC did
not significantly decrease 28th day mortality compared with standard oxygen therapy.
Theoretically, the possibility has been suggested that HFNC is effective against
mild ARDS, but sufficient evidence has not been established. We look forward to
further progress in future investigations.
3.4 Actual Setting Method of HFNC
3.4.1 Indications for HFNC
As with NIV, when oxygenation cannot be maintained even with general oxygen
therapy, the use of HFNC is considered when there is no improvement in dyspnea.
3.4.2 Initial HFNC Settings and Method of Introduction
Today, HFNC is commonly started with a moderate flow rate of 30–40 L/min. The
flow rate is increased or decreased while watching tolerability and oxygenation.
Heater/humidifier settings are taken to be the same as for invasive mechanical ven-
tilation, and efforts should be made for sufficient heat and humidity.
Because a delay in tracheal intubation has been reported to be associated with
increased mortality, as in NIV, tracheal intubation should be done immediately if
indicated. General NIV precautions such as shock, multiple organ failure, restless-
ness, and copious airway secretions should also be noted in the HFNC. As methods
to predict the success or failure of HFNC, there are reports that high severity
(APACHE, SOFA) and the failure to improve oxygenation for a short time after the
start of HFNC are useful predictors of intubation [39], and that the respiratory rate
is important [40]. These things are also the same as with NIV. Another recent report
found that ROX score, defined as the ratio of oxygen saturation as measured by
pulse oximetry/FiO2 to respiratory rate, is useful [41].
4 Conclusion
This article reviewed noninvasive respiratory management devices in ARDS. There

is a possibility that both NIV and HFNC are effective as respiratory management in
mild and early ARDS, but sufficient evidence has not been established. It is also
likely that failure of noninvasive respiratory management is linked to worsening
prognosis, and careful management is necessary. Further findings are awaited.
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Chapter 8
Fluid and Nutritional Management
of ARDS: What Is the Ideal Fluid
and Nutritional Management for an ARDS
Patient?
Shinichiro Ohshimo
Abstract Acute respiratory distress syndrome (ARDS) is a life-threatening condi-

tion with complicated pathogenesis. Adequate fluid and nutritional managements
would have potentials to improve outcome of ARDS. Conservative fluid manage-
ment would be preferable compared with liberal fluid management in terms of pre-
venting severe pulmonary edema and improving a resultant poor prognosis.
However, potential risk of cognitive impairment should be noted in conservative
fluid management. Central venous pressure and pulmonary artery occlusion pres-
sure can be useful surrogates for achieving adequate fluid management. Combined
use of diuretics and albumin would be an alternative option to improve fluid bal-
ance, oxygenation, and hemodynamic stability. Regarding nutritional management,
if oral intake is not possible, early enteral nutrition initiated within 48 h is recom-
mended rather than delaying enteral nutrition or any parenteral nutrition. Target
energy can be calculated by using indirect calorimetry or eight-based equations
(i.e., 20–25 kcal/kg/day). Gradual increase in providing feeding would be prefera-
ble for avoiding refeeding syndrome. Insulin can be used for achieving the target
concentration of blood glucose level of 6–8 mmol/L (108–144 mg/dL). Omega-3
fatty acid is likely to be beneficial for treating ARDS, although the results of ran-
domized controlled trials remain controversial. Further studies are necessary to con-
firm the beneficial effects of adequate fluid and nutritional managements on ARDS.
Keywords Conservative · Liberal · Central venous pressure · Omega-3 fatty acid

Refeeding syndrome
S. Ohshimo (*)
Department of Emergency and Critical Care Medicine, Graduate School of Biomedical and
Health Sciences, Hiroshima University, Hiroshima, Japan
e-mail: ohshimos@hiroshima-u.ac.jp
Ltd. 2022
https://doi.org/10.1007/978-981-16-8371-8_8
106 S. Ohshimo
Abbreviations
ARDS Acute respiratory distress syndrome

BALF Bronchoalveolar lavage fluid
CI Confidence interval
CNS Central nervous system
COVID-19 Coronavirus disease 2019
CVP Central venous pressure
DHA Docosahexaenoic acid
EN Enteral nutrition
EPA Eicosapentaenoic acid
ESPEN European Society for Clinical Nutrition and Metabolism
EVLW Extravascular lung water
FIO2 Fraction of inspiratory oxygen
GLA Gamma-linolenic acid
HR Hazard ratio
ICU Intensive care unit
IL Interleukin
OR Odds ratio
PaO2 Partial pressure of arterial oxygen
PAOP Pulmonary artery occlusion pressure
PEEP Positive end-expiratory pressure
PN Parenteral nutrition
RCT Randomized, control trial
REE Resting energy expenditure
SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2
SMD Standardized mean difference
SOFA Sequential organ failure assessment
VCO2 Carbon dioxide production
VO2 Oxygen consumption
1 Introduction
Acute respiratory distress syndrome (ARDS) is a life-threatening condition with

complicated pathogenesis. Currently, no specific curative therapies have been devel-
oped for this condition.
The predominant pathology of ARDS is diffuse alveolar damage and a resultant
injury in the alveolar–capillary membrane (Fig. 8.1). This damage in the capillary-
endothelial barrier allows the leakage of protein-rich fluid into alveoli and intersti-
tium, resulting in alveolar and interstitial edema. Endothelial damage can induce a
lot of inflammatory changes including neutrophil accumulation and activation, pro-
motion of thrombosis and coagulation, and increase in reactive oxygen species. The
imbalance in pro-inflammatory and anti-inflammatory cytokines can also promote
8 Fluid and Nutritional Management of ARDS: What Is the Ideal Fluid and… 107
Fig. 8.1 Mechanisms of fluid and nutritional management in ARDS. Excessive fluid administra-
tion can induce alveolar and interstitial edema, through the injury of capillary-endothelial barrier.
Omega-3 fatty acids can have a potential to block reactive oxygen species, interleukin-1beta, -6,
and -8. TNF tumor necrosis factor, IL interleukin, FA fatty acid, ROS reactive oxygen species,
NETs neutrophil extracellular traps
inflammation. These complicated inflammatory processes would be associated with

the development of pulmonary edema in ARDS [1]. Although ARDS alone can be
fatal, deaths in patients with ARDS are frequently due to the failure of non-
pulmonary organs [2]. Therefore, the adequate management of hydrostatic and
oncotic pressures, organ perfusion, and cytokine production are essential for
improving the outcome of patients with ARDS.
2 Fluid Balance
The current practice seems widely ranging. Most physicians weigh the risks and
benefits of conservative and liberal fluid managements. Conservative fluid manage-
ment strategy aims to decrease pulmonary edema, shorten the duration of mechani-
cal ventilation, and improve survival. However, this strategy might have a risk of
decrease in cardiac output and subsequent decrease in non-pulmonary organ perfu-
sion. Liberal fluid management strategy reverses these potential benefits and risks.
108 S. Ohshimo
2.1 Animal Studies
Previous studies have investigated the effects of fluid managements in animal mod-
els of ARDS. Ali et al. [3] developed canine models of pulmonary capillary leak
induced by intravenous oleic acid. They demonstrated that administration of furose-
mide (1 mg/kg) significantly reduced the pulmonary shunt in canine models,
whereas the same models not given furosemide increased the pulmonary shunt.
Other group [4] also investigated the canine models of acute lung injury induced by
intravenous oleic acid, and demonstrated that continuous administration of furose-
mide (0.2 mg/kg/h) improved partial pressure of arterial oxygen (PaO2)/fraction of
inspiratory oxygen (FIO2) ratio, lung injury score, and pulmonary shunt, whereas
decreased positive end-expiratory pressure (PEEP) requirements. These data sug-
gest that the conservative fluid management strategy with the use of diuretics is
likely to improve the pathophysiology of ARDS lungs.
2.2 Current Evidences
Mitchell et al. [5] conducted a prospective randomized control trial (RCT) to evalu-
ate the effects of fluid restriction management as well as diuretics on outcomes in
critically ill patients with pulmonary edema. They included a total of 101 patients
and demonstrated that the fluid restriction management was associated with
decreased extravascular lung water (EVLW), shorter ventilator days, and shorter
intensive care unit (ICU) stay. The fluid restriction management did not increase
any adverse events.
Wiedemann et al. [6] investigated the optimal fluid management in patients with
ARDS (Fluids and Catheters Treatment Trial: FACTT). They compared effects of a
conservative and a liberal fluid management strategy for 7 days in 1000 patients
with ARDS. Patients in the conservative-strategy group received furosemide or flu-
ids to achieve a central venous pressure (CVP) of <4 mmHg and a pulmonary artery
occlusion pressure (PAOP) <8 mmHg. Patients in the liberal-strategy group were
managed to achieve a CVP of 10–14 mmHg and a PAOP of 14–18 mmHg. The
cumulative fluid balance during the 7 days was −136 mL in the conservative-
strategy group, whereas +6992 mL in the liberal-strategy group. The primary out-
come of 60-day mortality was not significantly different between the groups (26%
vs. 28%), but ventilator-free days (15 vs. 12 days), ICU-free days (13 vs. 11 days),
and central nervous system (CNS)-failure-free days (19 vs. 17 days) were better in
the conservative-strategy group compared with the liberal-strategy group.
These results support the potential benefit of the conservative strategy of fluid
management in patients with ARDS. However, the actual CVP over time in the
conservative-strategy group was higher than 8 mmHg, and the actual PAOP over
time was higher than 12 mmHg, suggesting that a CVP <4 mmHg and a PAOP
<8 mmHg were the difficult target ranges to be safely achieved. The secondary
analysis of the FACTT demonstrated that conservative fluid management decreased

mortality in patients with a baseline CVP of <8 mmHg, whereas conservative fluid
management had no significant prognostic benefit in patients with a baseline CVP
of >8 mmHg [7]. These results suggest that the benefit of conservative fluid man-
agement might depend on the baseline fluid balance in patients with ARDS.
2.3 S
ignificant Considerations for Conservative
Fluid Management
Increasing number of studies indicated that neuropsychological impairment would

be an important and potentially manageable outcome among survivors of ARDS
[8]. Mikkelsen et al. [9] conducted a telephone-based neuropsychological test, and
investigated the cognitive and psychiatric morbidity in the FACTT cohort. Of 1001
patients studied in FACTT, a total of 406 patients have survived. As a consequence,
they evaluated a total of 122 patients at least once, and among them 102 patients at
12 months of follow-up. Cognitive impairment was observed in 55% of patients at
12 months, which was significantly associated with the presence of psychiatric
symptoms, specifically anxiety. Memory, verbal fluency, and executive function
were impaired in 13%, 16%, and 49% of patients in the conservative-strategy group
at 12 months, respectively. Executive function was impaired in 57% of patients.
Risk factors for long-term cognitive impairment included lower PaO2 (adjusted
odds ratio (OR), 1.51 [95% confidence interval (CI), 1.01–2.26] to 1.68 [95%CI,
1.14–2.49]), and enrollment in the conservative fluid management strategy group
(adjusted OR, 3.35 [95%CI, 1.16–9.70] to 5.46 [95%CI, 1.92–15.53]).
2.4 Recent Advances
Recent studies further investigated the optimal fluid balance for the adequate man-
agement of ARDS. The RADAR-2 (Role of Active Deresuscitation After
Resuscitation-2) trial [10] investigated the benefit of conservative fluid management
and deresuscitation in patients with various etiologies requiring mechanical ventila-
tion in ICU. A total of 33% of the cohort had respiratory etiologies with the lowest
PaO2/FIO2 ratio of 175 (95%CI, 118–258) on admission. Deresuscitation was
defined as removal of fluid using diuretics or renal replacement therapy. They
included a total of 400 patients, and demonstrated that the positive fluid balance on
day 3 was an independent risk factor for 30-day mortality (OR, 1.26/L [95%CI,
1.07–1.46]). In addition, the largest amount of fluid input was medication diluents
and maintenance fluid rather than resuscitation fluid. This study suggested that phy-
sicians should be aware of that the fluid balance can be practice-driven and a modifi-
able variable.
110 S. Ohshimo
While the FACTT failed to demonstrate a 60-day survival benefit of conservative

fluid management strategy in patients with ARDS, van Mourik et al. [11] retrospec-
tively investigated the association between cumulative fluid balance, length on
mechanical ventilation and mortality in patients with ARDS. They included a total
of 600 patients with ARDS, of whom 156 (26%) died within 28 days. They demon-
strated that a higher cumulative fluid balance was associated with increased 28-day
and 90-day mortalities in a non-linear dose-response relationship manner. Higher
cumulative fluid balance was also associated with longer time on mechanical venti-
lation and a longer length of ICU stay.
Sepsis is one of the most major and fatal causes of ARDS. Approximately 40%
of ARDS incidence can be associated with sepsis. Fluid resuscitation is the main-
stay for treating sepsis. A recent meta-analysis [12] showed that a conservative
fluid management was associated with increased ventilator-free days and decreased
length of ICU stay in patients with sepsis/ARDS compared with a liberal fluid
management strategy or standard management. However, the optimal fluid man-
agement in patients with sepsis/ARDS remains unknown. Wang et al. [13] investi-
gated a total of 322 patients with sepsis, among whom 84 (26%) patients were
diagnosed as having ARDS within 72 h from the onset of sepsis. They demon-
strated that survived patients showed daily negative net fluid balance during the
7-day period except for the first day, while non-survivors showed daily positive net
fluid balance every day during the 7-day period (p < 0.01). They concluded that
early negative fluid balance since day 2 was independently associated with lower
mortality rate in patients with ARDS secondary to sepsis. Early sufficient fluid
resuscitation and a subsequent restricted fluid management might be beneficial for
this type of cohort.
Diabetes might be associated with decreased development of ARDS [14]. The
mechanism of diabetes developing ARDS remains unclear. Since inflammation
is one of the key pathogenesis of ARDS, decreased cytokine release and neutro-
phil dysfunction in diabetes might be associated with lower incidence of
ARDS. Several pathways including peroxisome proliferator-activated receptor
gamma, nuclear factor-kappa B, insulin-like growth factor-1, leptin, and
advanced glycation end products might be involved in the mechanisms of ARDS
complicated by diabetes.
The secondary analysis of the FACTT [15] evaluated the impact of diabetes on
the fluid strategy in patients with ARDS. They analyzed a total of 956 patients using
a propensity score matching approach, and found that diabetes had no impact on
ventilator-free days and 60-day mortality in patients with ARDS, when a conserva-
tive fluid management strategy was applied as compared to a liberal fluid manage-
ment strategy. This study suggested that fluid management should not be altered
according to the presence or absence of diabetes.
2.5 Combined Use of Diuretics and Albumin
Combined use of furosemide and albumin may be an alternative option to improve

fluid balance, oxygenation, and hemodynamic stability [16], especially in hypopro-
teinemic patients [17]. Martin et al. [16] investigated a total of 37 patients with
acute lung injury requiring mechanical ventilation concomitant with serum total
protein of less than 5.0 g/dL in a prospective RCT. They prescribed continuous
intravenous furosemide (1 mg/mL) with 25 g of 25% intravenous albumin every 8 h
for 5 days. The treatment cohort demonstrated a significantly greater reduction in
body weight by day 5 (mean weight loss, 10.0 vs. 4.7 kg, p = 0.04), whereas the
control cohort showed no significant difference in the weight loss. Oxygenation was
rapidly improved in the treatment cohort compared with that in the control cohort
(mean change in PaO2/FIO2 ratio during the first 24 h, 64 vs. 5 mmHg, p = 0.003).
Heart rate decreased over time from 110 to 95 beats/min in the treatment cohort
(p = 0.008), while mean arterial pressure was not changed.
The same group [17] further investigated the utility of furosemide with or with-
out albumin in hypoproteinemic patients with ARDS. They included a total of 40
patients in this study. The treatment cohort received 25 g of 25% intravenous albu-
min and immediately followed by a loading dose of intravenous furosemide (20 mg)
and a continuous infusion of furosemide (1 mg/mL) for 3 days. Albumin was subse-
quently administered every 8 h for 3 days. The cumulative fluid loss during the
study period was greater in the treatment cohort compared with the control cohort
(net fluid balance at day 3, −5480 vs. −1490 mL, p < 0.01). Oxygenation signifi-
cantly increased in the treatment cohort (mean change in PaO2/FIO2 ratio during the
first 24 h, 43 vs. −24 mmHg, p < 0.01) and remained higher compared with the
control cohort throughout the observation period.
Figure 8.2 summarizes the recommended fluid management in ARDS.
3 Nutrition
Since patients with ARDS are frequently catabolic, optimal nutritional support is
important for improving catabolic losses. Adequate nutrition might promote benefi-
cial immune responses and decrease oxidative stress [18]. In patients with intact
gastrointestinal tract, enteral feedings are recommended. Possible advantages of the
enteral feedings would be less frequencies of gastrointestinal bleeding, intestinal
mucosal impairment, bacterial translocation, and catheter-related blood stream
infections. Adequate nutrition has a potential to modify the immune system, which
might reduce lung inflammation and oxidative stress in patients with ARDS [19].
112 S. Ohshimo
Admission of patients with

ARDS
Yes MAP 60 without No

vasopressors
• Use vasopressors
• Fluid bolus
Evaluate CVP
(± PAOP)
CVP >8 CVP 4-8 CVP <4

(PAOP >12) (PAOP 8-12) (PAOP <8)
UV 0.5 UV >0.5
mL/kg/hr mL/kg/hr
Yes No Yes No
No
Furosemide* Furosemide* Fluid bolus Fluid bolus
intervention
Fig. 8.2 Flowchart of the recommended fluid management in ARDS. Fluid management for
ARDS can be modified, according to the hemodynamics, CVP and/or PAOP, and urine volume.
ARDS acute respiratory distress syndrome, MAP mean arterial pressure, CVP central venous pres-
sure, PAOP pulmonary artery occlusion pressure, UV urine volume
3.1 Current Guidelines
The European Society for Clinical Nutrition and Metabolism (ESPEN) updated the
recommendation of the enteral nutrition (EN) and parenteral nutrition (PN) in adult
critically ill patients in 2019 [20]. Although this guideline is not specific for ARDS,
most recommendations seem suitable for ARDS. Oral intake may be preferred over
EN or PN in patients with ARDS who can eat. If oral intake is not possible (e.g.,
uncontrolled shock, uncontrolled acidosis, uncontrolled upper gastrointestinal
bleeding, gastric aspirate of >500 mL/6 h, bowel ischemia, bowel obstruction,
abdominal compartment syndrome, and severe fistula), early EN (within 48 h) is
recommended rather than delaying EN or early PN. In case of contraindications to

oral intake and EN, PN is recommended to start within 3–7 days.
3.2 Target Energy
Energy expenditure should be estimated by using indirect calorimetry; otherwise,

the balance between oxygen consumption (VO2) from pulmonary arterial catheter
and carbon dioxide production (VCO2) derived from the ventilator would be prefer-
able to estimate the target energy. Resting energy expenditure (REE) can be calcu-
lated by the following formula: REE = VCO2 × 8.19. In the absence of indirect
calorimetry, VO2 and VCO2 measurements, or weight-based equations (i.e.,
20–25 kcal/kg/day) would be good alternatives. In the early phase of ARDS, hypo-
caloric nutrition of <70% of energy expenditure should be provided. After day 3,
total calorie can be gradually increased up to 80–100% of predicted energy expen-
diture. Early full feeding can increase the risk of refeeding, which should be avoided.
The target glucose administration should not exceed 5 mg/kg/min. Excessive glu-
cose administration can induce enhanced carbon dioxide production, which has
negative effect for ARDS. Intravenous lipid should not exceed 1.0–1.5 g/kg/day.
Since propofol contains 1.1 kcal/mL of fatty acid, special attention should be paid
to avoid providing excessive nutritional support.
3.3 Management of Blood Glucose Level
Optimal control of blood glucose level is important for improving patients’ out-
come. A number of previous studies confirmed that severe hyperglycemia (>180 mg/
dL, 10 mmol/L), increased variability of blood glucose (coefficient of variation
>20%), mild hypoglycemia (<70 mg/dL, 3.9 mmol/L) were associated with
increased mortality. The target concentration of blood glucose level would be
6–8 mmol/L (108–144 mg/dL). Hyperglycemia should be adjusted by using insulin
in case of glucose levels of >10 mmol/L (180 mg/dL). However, previous prospec-
tive studies remain inconclusive to define the optimal target range of blood glucose
for achieving best prognosis in ARDS.
3.4 Avoiding Refeeding Syndrome
Refeeding syndrome is defined as the severe shifts of electrolytes occurring in

patients with malnutrition receiving excessive feeding. In patients with malnutri-
tion, therefore, energy supply should be restricted for initial 48 h and subsequently
gradually increased to avoid refeeding syndrome. Repeated measurements of
114 S. Ohshimo
phosphorus, potassium, and magnesium are important to detect refeeding syndrome

during the beginning of feeding.
The INTACT trial [21] is the single-center RCT to evaluate the effect of intensive
medical nutrition therapy compared with standard nutrition support in patients with
ARDS. This trial was stopped early because of significantly greater hospital mortal-
ity in the intervention cohort (40% vs. 16%, p = 0.017). A post hoc analysis of the
INTACT trial [22] demonstrated that higher energy intake during days 1–7 was
significantly associated with increased mortality (hazard ratio (HR), 1.17; 95%CI,
1.07–1.28), whereas higher energy intake after day 8 was beneficial for decreasing
mortality (HR, 0.91; 95%CI, 0.83–1.0). These findings might be explained by the
effect of refeeding syndrome.
3.5 Current Evidences for Omega-3 Fatty Acids
Omega-3 fatty acids, also known as eicosapentaenoic acid (EPA) and docosahexae-
noic acid (DHA), are included in fish oils, which may have an anti-inflammatory
and immunomodulatory properties. These dietary nutrients may have a potential to
modify the immune system, including inhibition of neutrophil accumulation in
lungs, reduction of alveolar permeability, and suppression of pro-inflammatory
cytokines.
Pontes-Arruda et al. [23] investigated the benefit of an inflammation-modulating
diet enriched with EPA and/or gamma-linolenic acid (GLA) by a meta-analysis.
They included a total of 411 patients with ARDS requiring mechanical ventilation,
and evaluated in-hospital mortality, ventilator-free days, ICU-free days, and the
development of new organ failures. They demonstrated that the administration of
EPA and GLA reduced the risk of mortality (OR, 0.40; 95%CI, 0.24–0.68;
p = 0.001), the risk of new organ failures (OR, 0.17; 95%CI, 0.08–0.34; p < 0.0001),
duration of mechanical ventilation (standardized mean difference [SMD], 0.56;
95%CI, 0.32–0.79; p < 0.0001), and length of ICU stay (SMD, 0.51; 95%CI,
0.27–0.74; p < 0.0001).
Conversely, however, Stapleton et al. [24] failed to demonstrate the benefit of
enteral administration of omega-3 fatty acid for reducing pulmonary inflammation
in patients with ARDS. They included a total of 90 patients with ARDS requiring
mechanical ventilation. The treatment cohort received enteral fish oil of 7.5 mL
every 6 h (i.e., equivalent to 9.75 g EPA and 6.75 g DHA daily) for 14 days or until
death, ICU discharge, or 48 h of unassisted breathing, whichever occurred first. The
treatment cohort showed an increased serum concentration of EPA. However, the
use of enteral fish oil did not reduce the concentration of interleukin (IL)-8 in bron-
choalveolar lavage fluid (BALF). Similarly, there were no differences in plasma
IL-8, IL-6, surfactant protein-D, or von Willebrand factor between the two groups.
There were also no significant differences in the clinical outcomes including
ventilator-free days, ICU-free days, length of hospital stay, multiple organ dysfunc-
tion score, in-hospital mortality, or 60-day mortality between the groups.
The OMEGA study [25] was a multicenter, double-blind RCT that investigated
the benefit of twice-daily enteral supplementation of omega-3 fatty acids, EPA and
GLA in patients with ARDS. They included a total of 272 patients, and the omega-3
fatty acids or control supplements were enterally administered as twice-daily
boluses of 120 mL. Feeding continued until the earliest of 21 days, 48 h of unas-
sisted breathing, or extubation. The use of omega-3 fatty acids was associated with
shorter ventilator-free days (14.0 vs. 17.2; p = 0.02), shorter ICU-free days (14.0 vs.
16.7; p = 0.04), and shorter non-pulmonary organ failure-free days (12.3 vs. 15.5;
p = 0.02). Accordingly, this study was stopped early for futility of omega-3
fatty acids.
Parish et al. [26] conducted an RCT including 58 patients with ARDS in two
ICUs to investigate the effect of omega-3 fatty acid supplementation. Patients
received 25 kcal/kg/day of enteral feeding. The treatment cohort received omega-3
soft gels of 2160 mg/day including 1080 mg of EPA and 720 mg of DHA in addition
to standard treatment. They demonstrated that enteral supplementation of omega-3
fatty acids improved PaO2, lung compliance and resistance. These conflicting results
regarding the benefit of omega-3 fatty acids were likely to be associated with the
etiologies of patients. In this study, high proportion of patients suffered from trauma-
associated ARDS, which had less severe endothelial and alveolar epithelial injury.
Shirai et al. [27] conducted a single-center RCT including a total of 46 patients
with sepsis-induced ARDS. The treatment cohort received an enteral diet enriched
with EPA, GLA, and antioxidants (Oxepa®, Abbott Nutrition, Tokyo, Japan). The
target calories were set at 1.2× basal energy expenditure. They demonstrated that an
enteral diet enriched with EPA, GLA, and antioxidants decreased the duration of
ICU stay (HR, 2.18; 95%CI, 1.13–4.23; p = 0.015), although duration of mechani-
cal ventilation, sequential organ failure assessment (SOFA) score, and mortality
were not improved. In the OMEGA study, omega-3 fatty acids were supplemented
by bolus feeding twice daily, and the incidence of gastrointestinal complications or
diarrhea occurred as much as 29% in the treatment cohort. This bolus supplementa-
tion of omega-3 fatty acids may have associated with the conflicting results between
these two studies.
Dushianthan et al. [28] conducted a meta-analysis for investigating the effects of
immunonutrition compared with standard feeding on mechanically ventilated adult
patients with ARDS. They identified a total of 10 RCTs with 1015 participants. All
studies investigated the effects of supplemental omega-3 fatty acids (i.e., EPA,
DHA, GLA, and antioxidants). For the primary outcome, they found no differences
in all-cause mortality with the use of supplemental omega-3 fatty acids and antioxi-
dants (risk ratio [RR], 0.79; 95%CI, 0.59–1.07). For the secondary outcomes,
although some forest plots revealed significant effects of the intervention, the
authors concluded that they were uncertain whether immunonutrition with omega-3
fatty acids and antioxidants had a significant benefit for the duration of ventilator
days, length of ICU stay, or oxygenation at day 4 due to the very low quality of
evidence.
116 S. Ohshimo
3.6 Possible Benefit of Other Nutrients
Heyland et al. [29] investigated the potential benefit of glutamine and antioxidant
supplementation. They included a total of 1223 critically ill adult patients who
underwent mechanical ventilation in 40 ICUs. The treatment cohort received intra-
venous supplementation of glutamine (0.35 g/kg/day), according to ideal body
weight. In addition, antioxidant supplementation (i.e., 500 μg of intravenous sele-
nium and enteral vitamin, and oral mineral supplements) was randomly adminis-
tered. They demonstrated a trend to increase in 28-day mortality in patients who
received glutamine compared with the control cohort (32% vs. 27%; OR, 1.28;
95%CI, 1.00–1.64; p = 0.05). In addition, the use of glutamine was associated with
increased in-hospital and 6-month mortalities. Time to final discontinuation of
mechanical ventilation, time to ICU discharge, and time to hospital discharge were
also longer in patients who received glutamine compared with the control cohort.
Antioxidant supplementation showed no therapeutic benefit. Accordingly, this study
concluded that the early administration of glutamine in critically ill patients was
harmful.
Bertolini et al. [30] evaluated the potential benefit of early enteral immunonutri-
tion in critically ill patients with severe sepsis. They included a total of 237 patients,
among whom 39 had severe sepsis or septic shock. Eligible patients received either
total PN or EN containing extra l-arginine (6.8 g/L), omega-3 fatty acids (1.5 g/L),
vitamin E (29 mg/L), beta carotene (7.5 mg/L), zinc (22 mg/L), and selenium
(70 mg/L). Feeding was started within 48 h from ICU admission. Three logistic
regression models were conducted for evaluating the effects of EN containing extra
l-arginine on severe septic condition (i.e., model 1 was the unadjusted analysis;
model 2 was the planned adjusted analysis for caloric intake; model 3 was the
unplanned adjusted analysis for caloric intake and unbalanced baseline characteris-
tics). However, all three models demonstrated a significant worse outcome with EN
containing extra l-arginine (i.e., model 1, OR = 4.8; model, OR = 2.4; model 3,
OR = 3.1). This study was stopped due to futility and potential harm of the interven-
tion arm based on this interim analysis. l-arginine is an essential amino acid in
humans, which serves as a precursor for the synthesis of nitric oxide. Vasodilation
generated by nitric oxide might have affected the impairment of organ perfusion in
the intervention arm. Although this study investigated the effects of EN containing
extra l-arginine on severe sepsis, it seems preferable to avoid l-arginine in patients
with severe condition including ARDS.
Figure 8.3 summarizes the recommended nutritional management in ARDS.
Admission of patients with

ARDS
Yes No
Evaluate
malnutrition
Start EN within 48 hours Start EN

Day 1 10 kcal/kg/day Target energy 25 kcal/kg/day
Day 2 15 kcal/kg/day Target protein 1.0-1.5 g/kg/day
Day 3 20 kcal/kg/day
Day 4 25 kcal/kg/day • May include omega-3 fatty acids
Target protein 1.0-1.5 g/kg/day • Calorie in propofol should be
noted
• Gradual increase of energy to
avoid refeeding syndrome
• May include omega-3 fatty acids
• Calorie in propofol should be
noted
Monitor blood glucose and mineral levels

• Glucose range 6-8 mmol/L (108-144 mg/dL)
• Insulin can be used for adjustment
• P, K, and Mg should be monitored to avoid
refeeding syndrome
Yes No
EN intolerable
for >3 days
• PN can be considered
• Vitamins and trace elements
should be added to PN
Fig. 8.3 Flowchart of the recommended nutritional management in ARDS. Nutritional manage-

ment for ARDS can be modified, according to the presence or absence of malnutrition. Careful
attention should be paid to maintain adequate blood glucose levels, and to find refeeding syndrome
118 S. Ohshimo
3.7 Nutritional Management for COVID-19
The coronavirus disease 2019 (COVID-19) is an emerging infectious disease with

potentially fatal outcome. Five to ten percent of patients infected with severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2) may present ARDS requiring
mechanical ventilation. Nutrition is also an important factor of better care for
COVID-19, which should be integrated into the therapeutic strategy. Organ failure,
obesity, diabetes, or malignancies may be potential risk factors for the most severe
form of COVID-19. These risk factors can mask underlying malnutrition.
As usually recommended in the ICU, EN should be preferred over PN. EN
should be started within 48 h of admission to reach an energy target by day 4–6.
Polymeric standard formulas for EN should be used to calculate the target calorie.
Use of EN enriched with omega-3 fatty acids seems favorable in case of
ARDS. l-arginine should not be used in patients with COVID-19, because of a
potential harm of l-arginine for mortality [30].
Since patients with COVID-19 are often vulnerable and unwell for several days
due to fever, fatigue, reduced appetite, and energy deficit, the refeeding syndrome
should be considered. Plasma potassium and magnesium should be measured soon
after starting nutrition support, and low values should be corrected. Optimal nutri-
tional management is essential to maintain immune defenses, and avoid muscle
weakness in patients with COVID-19.
4 Conclusion
In conclusion, regarding the fluid management, a conservative fluid management

strategy would be preferable in patients with ARDS in terms of ventilator-free days
and ICU-free days. It might be reasonable to target a CVP of <4 mmHg and a PAOP
of <8 mmHg, as long as hypotension or organ hypoperfusion can be avoided.
Regarding the nutritional management, provision of optimal calorie (i.e.,
20–25 kcal/kg/day) including omega-3 fatty acids, gradual increase of energy to
avoid the risk of refeeding syndrome, and adequate management of blood glucose
level of 6–8 mmol/L (108–144 mg/dL) would be important for the better manage-
ment of ARDS.
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Chapter 9
CHDF and ECMO for ARDS: Does CHDF
and ECMO Improve the Outcome
of ARDS Patients?
Shinhiro Takeda and Keisuke Ohyama
Abstract Although a case series has reported that CHDF increased the permeabil-
ity of pulmonary blood vessels, improved oxygenation, and extended the survival
rate, its validity as scientific evidence is weak. There is little evidence to actively
recommend CHDF in patients other than ARDS patients complicated with renal
failure.
ECMO therapy for respiratory failure is gaining worldwide attention. It was
added to the Berlin definition as a treatment option for severe ARDS. ECMO is a
highly invasive treatment and should be indicated carefully. However, ECMO can
minimize lung damage from mechanical ventilation and provide a better lung envi-
ronment for recovery.
Keywords VV-ECMO · Indication · Pandemic
1 CHDF
Continuous hemodiafiltration (CHDF), one of continuous renal replacement ther-

apy (CRRT), is useful for systemic management of fluid and metabolite removal as
well as electrolyte and acid-base balance. Blood purification therapy may also be
used to eliminate blood cytokines, which are exacerbating factors for ARDS.
Today it is assumed that many mediators are involved in lung tissue damage in
ARDS [1, 2]. In ARDS, respiratory failure may result from excessive lung inflam-
mation associated with cytokine overproduction. In previous studies, HVHF signifi-
cantly reduced the inflammatory cytokine IL-6 [3, 4]. The effectiveness of CHF for
removing this mediator is also reported [5].
S. Takeda (*) · K. Ohyama

Kawaguchi Cardiovascular and Respiratory Hospital, Kawaguchi, Saitama, Japan
e-mail: shinhiro@nms.ac.jp
Ltd. 2022
https://doi.org/10.1007/978-981-16-8371-8_9
122 S. Takeda and K. Ohyama
However, in another RCT, CHDF did not change the cytokine concentration and
the number of organ failures in septic patients [6]. In addition, no previous report
examined the effect of CHDF on the survival of ARDS patients.
ARDS often results in MOF including renal failure [7]. In ARDS with renal fail-
ure, if the infusion volume is limited to improve oxygenation in the lungs, the circu-
lating plasma volume and the urine volume will decrease, further worsening the
renal function. On the other hand, if the infusion is continued to maintain the urine
volume, overflow will adversely affect oxygenation in the lungs. In such pathologi-
cal conditions, respiratory management using a mechanical ventilator and strict
fluid control are critical. Mechanical ventilation should be used to improve respira-
tory function as soon as possible. In addition, pulmonary edema should be slowly
and securely removed to maintain the oxygenation capacity without affecting the
circulatory dynamics [8]. CHDF may be effective in such cases.
There is no study showing that CHDF lowered the blood concentration of inflam-
matory cytokines in ARDS. Although a case series have reported that CHDF
increased the permeability of pulmonary blood vessels, improved oxygenation, and
extended the survival rate, its validity as scientific evidence is weak. Oxygenation
improves in some patients with ARDS accompanied by acute renal failure. However,
it is unclear whether this is the effect of fluid removal by ultrafiltration or cytokine
removal by CHDF. So far, there is little evidence to actively recommend CHDF in
patients other than ARDS patients complicated with renal failure.
2 ECMO
2.1 Establishment of ECMO for Respiratory Failure
ECMO is a mechanical assist device used for maintaining respiratory and circula-
tory systems in patients with severe respiratory or heart failure. It is categorized into
venoarterial (VA) ECMO and venovenous (VV) ECMO based on the vascular
access type. The former provides both respiratory and cardiac support, but the latter
provides only respiratory support.
The first successful ECMO for adult respiratory failure was reported in 1971 [9].
Since the first RCT in 1979 comparing ECMO with mechanical ventilation manage-
ment could not prove the usefulness of ECMO [10], ECMO was rarely used for
adult respiratory failure in the 1980s. However, some ECMO centers in Europe and
the United States continued to use ECMO for respiratory failure and improved the
performance. The RCT in 1994 using a low-flow VV-ECMO to remove CO2 (extra-
corporeal CO2 removal: ECCO2R) also could not prove the effectiveness [11]
because the ECMO flow rate was too low to supply sufficient oxygen, which not
allowed to lower the respiratory setting adequately. Since then, ECMO has fully
supported the lung function with a high flow rate while the mechanical ventilator
setting is a low pressure/low FiO2, so-called the lung rest setting. After that, superior
9 CHDF and ECMO for ARDS: Does CHDF and ECMO Improve the Outcome… 123
survival rates were continuously reported [12], and ECMO for adult respiratory
failure was reevaluated. From 2001 to 2006, a multicenter RCT, the CESAR study,
was conducted in adult patients with respiratory failure in the UK [13]. The result
showed a significant difference in the “6-month survival rate without serious dys-
function,” and the CESAR study proved the usefulness of ECMO in the treatment
of adult respiratory failure for the first time. Under such circumstances, ECMO was
used for patients with severe pneumonia during the pandemic of H1N1 influenza in
2009 and highlighted the high survival rate.
2.2 Indications of ECMO for Adult Respiratory Failure
ECMO is a highly invasive treatment. Therefore, ECMO is considered for respira-

tory failure when there is no response to conventional mechanical ventilation ther-
apy and a high risk for mortality. Another crucial point is whether the lung disorder
can be “reversible” or not. ECMO is not a curative treatment for the disease itself.
It is a treatment that keeps the body alive until recovery by supplying sufficient
oxygen with cardiopulmonary support to stabilize the systemic condition. The
Extracorporeal Life Support Organization (ELSO) guideline [14] describes the fol-
lowing criteria for indications. Given mortality risk of ECMO itself is 50%, ECMO
should be considered when the mortality risk is 50% or greater and immediately
indicated when the mortality risk is 80% or greater. Although there are no absolute
contraindications, the use of mechanical ventilation for 7 days or more at high set-
tings is considered a relative contradiction due to the possible progression of irre-
versible lung damage. For H1N1 influenza, the survival rate was 72% when ECMO
was established within 6 days after tracheal intubation, compared with 31% after
7 days [15].
2.3 Practice of ECMO Management for Respiratory Failure
ECMO for respiratory failure often requires long-term management. The average
period is 2 weeks, and not a few cases exceed 1 month. Therefore, the device must
be durable, antithrombotic, and manageable for a long period of time. Preventing
thrombus formation is also important for prolonging the circuit life.
For vascular access, VV-ECMO is usually preferred. VA-ECMO is considered if
respiratory failure occurs with cardiac dysfunction. If right heart failure develops
due to pulmonary hypertension in the course, the conversion from VV to VA should
be considered. In VV-ECMO, the right internal jugular vein and the femoral vein are
usually selected for cannulation. Blood is drained from the inferior vena cava and
reinfused into the right atrium. On the other hand, blood is drained from the right
atrium and reinfused into the inferior vena cava in some facilities because drainage
from the right atrium increases recirculation but improves blood drainage. The
124 S. Takeda and K. Ohyama
standard flow rate of ECMO is 60 ml/kg/min but should be adjusted depending on

the oxygen supply-demand balance based on SaO2 and SvO2. In VV-ECMO, SaO2
is 70–80% when pulmonary oxygenation is lost. However, if the serum Hb level and
the cardiac output are within the normal range, 70% SaO2 is sufficient and accept-
able because the oxygen supply is five times larger than the oxygen consumption in
the normal state. Even if the oxygen supply decreases to about three times for the
oxygen consumption, it can adapt by increasing the oxygen intake rate. The serum
Hb, on the contrary, should be maintained within the normal range of 12–14 g/dl by
performing blood cell transfusion. In VA-ECMO, SvO2 indicates oxygen delivery,
and 70% SvO2 or more is sufficient. In VV-ECMO, the lactate level and the pres-
ence or absence of acidosis should be assessed together, considering recirculation.
If SvO2 is 75% or greater, increased recirculation is suspected. The ventilator setting
during ECMO should be the “lung rest setting” to prevent ventilation-associated
pneumonia. Although depending on the facility, the standard settings for ECMO are
FiO2 < 0.4, PEEP < 10 cmH2O, PIP < 25 cmH2O, and RR 10–12.
Bleeding control and prevention of coagulation and fibrinolysis are essential.
Strict anticoagulation therapy using heparin is performed to minimize bleeding at
the site of catheter insertion. In our hospital, the ACT and APTT targets are
1800–200 and 60–80 s, and they are measured every 2 h and once or twice a day,
respectively. The target serum fibrinogen level is 250 mg/dl, and the platelet count
is 80,000/ml or more. FFP and platelet-rich plasma are infused for
supplementation.
The advantage of ECMO for respiratory failure is that the patient can keep awak-
ened during management. Although deep sedation is required immediately after
introduction, the dose of sedatives should reduce as much as possible to awake the
patient after the oxygen supply-demand balance becomes stable. Awakening the
patient promotes lung recovery by increasing the tidal volume, cardiac output, and
pulmonary lymphatic drainage [16].
Management of fluid balance is also important. Severely ill patients are fre-
quently overhydrated, so infusion should be limited during ARDS treatment.
Similarly, active diuresis and fluid removal are recommended to maintain dry weight
during ECMO management [17]. By stabilizing the circulatory dynamics and respi-
ratory state using ECMO, fluid balance can be corrected through fluid removal. If
the diuretic response is not sufficient, continuous hemofiltration is placed to remove
the fluid. Fluid should be removed until the normal extracellular fluid volume is
achieved according to the degree of edema and the body weight.
ECMO can be used for ARDS patients who do not respond to mechanical venti-
lation. However, it should be cautiously indicated since the procedure is highly
invasive and the device is unavailable in many facilities.
9 CHDF and ECMO for ARDS: Does CHDF and ECMO Improve the Outcome… 125
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respiratory failure. A randomized prospective study. JAMA. 1979;242:2193–6.
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respiratory failure. Ann Surg. 1997;226:544–64.
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vival in adult patients with acute respiratory distress syndrome treated by extracorporeal mem-
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2000;26:1630–7.
17. Brodie D, Bacchetta M. Extracorporeal membrane oxygenation for ARDS in adults. N Engl J
Med. 2011;365:1905–14.
Chapter 10
Physiotherapy and Early Rehabilitation
for Patients with ARDS: Does
Physiotherapy Improve the Functional
Outcome of ARDS Patients?
Ryo Kozu, Masatoshi Hanada, Masato Oikawa, Hiroki Nagura,

Rina Takeuchi, and Motohiro Sekino
Abstract While numerous studies suggest that the mortality rate for acute respira-
tory distress syndrome (ARDS) has decreased over time, the number of survivors
with persistent functional disability is increasing. The aim of physiotherapy for
patients with ARDS is to prevent physical impairments, especially muscle dysfunc-
tion due to immobilization, and improve exercise capacity, activities of daily living,
and health-related quality of life. In this chapter, we describe the clinical issues
related physical impairments in patients with ARDS, and practice and scientific
evidence of physiotherapy and early rehabilitation. Physiotherapy, including early
active exercise and mobilization, is safe and feasible, with some evidence of
improved patient outcomes. Further research is needed to establish stronger evi-
dence for the effectiveness of physiotherapy for patients with ARDS.
Keywords Acute respiratory distress syndrome · Physical function ·

Physiotherapy · Positioning · Early mobilization and exercise training
R. Kozu (*) · M. Hanada · M. Oikawa · H. Nagura

Department of Physical Therapy Science, Nagasaki University Graduate School of
Biomedical Sciences, Nagasaki, Japan
Cardiorespiratory Division, Department of Rehabilitation Medicine, Nagasaki University
Hospital, Nagasaki, Japan
e-mail: ryokozu@nagasaki-u.ac.jp
R. Takeuchi
Cardiorespiratory Division, Department of Rehabilitation Medicine, Nagasaki University
Hospital, Nagasaki, Japan
M. Sekino
Department of Anesthesiology and Intensive Care Medicine, Nagasaki University Graduate
School of Biomedical Sciences, Nagasaki, Japan
Ltd. 2022
https://doi.org/10.1007/978-981-16-8371-8_10
128 R. Kozu et al.
1 Introduction
Although many prospective studies suggest that the mortality from acute respiratory
distress syndrome (ARDS) has decreased over time [1], the number of survivors
with persistent functional disability is increasing. In intensive care, long-term func-
tional status and health-related quality of life (HRQoL) are now recognized as
important patient-centered outcomes. The aim of intensive care is to support patients
through their critical illnesses and facilitate return to daily lives before hospitaliza-
tion with complete physical and psychological well-being [2].
There is a growing need for the recognition of early rehabilitation in intensive
care. This should proceed concurrently with ARDS treatment. Physiotherapy, along
with occupational therapy and speech-language therapy, is a major therapeutic com-
ponent of the rehabilitation process and plays a central role in early rehabilitation in
intensive care.
2 Functional Disabilities in ARDS Survivors
2.1 P
hysical, Functional, and Health-Related Quality
of Life Impairments
ARDS survivors had significant morbidity and functional impairments. They con-
tinued to have persistent functional disabilities, with significant weight loss, muscle
weakness, impairment of exercise capacity (66% of predicted distance in the 6-min
walk test), and reduced HRQoL, 1 year after discharge from the ICU, and half of
them were unable to return to work [3]. Furthermore, their physical function did not
return to the normal predicted levels even after 5 years [4]. The frequency of clinical
muscle weakness has been reported in 60% of patients with ARDS [5]. At hospital
discharge, 38% of patients with ARDS had muscle weakness and were associated
with worse 5-year survival [6].
Cognitive impairments and mental health disorders such as depression and anxi-
ety were frequently observed [7], and a decline in HRQoL had been reported [7].
Cognitive sequelae occurred in about 70% of survivors at hospital discharge, and in
about 40% at 2 years post-discharge [8]. They had decreased HRQoL that persisted
for at least 2 years after hospital discharge.
These are serious problems for daily life and employment in ARDS survivors.
Physical impairment is characterized by muscle weakness, fatigue, and decreased
exercise tolerance, and is closely related to activities of daily living (ADL) and abil-
ity to return to work [3]. Thus, it is notable that physical and cognitive impairments
occurring in the acute phase of the disease trajectory affect the long-term prognosis
of patients with ARDS.
10 Physiotherapy and Early Rehabilitation for Patients with ARDS: Does… 129
2.2 Detrimental Effects of Bed Rest
Bed rest can lead to rapid deconditioning, muscle atrophy and weakness, and
increased inflammation [9]. ICU patients are routinely subjected to deep sedation
and bed rest [10]. Although bed rest is necessary for recovery from critical illnesses,
prolonged bed rest and immobility can lead to adverse effects in almost every organ
system, such as contractures, muscle weakness, orthostatic intolerance, risk of
pneumonia and atelectasis, and sleep and mental health illness [11]. In patients with
critical illnesses, bed rest and immobility are major risk factors for long-term physi-
cal disability after ICU discharge. A prospective longitudinal study showed that the
duration of bed rest during ARDS was consistently associated with muscle weak-
ness throughout the 24-month follow-up period [12]. Recognizing immobility and
inactivity due to bed rest as important risk factors is the first step in improving
patient outcomes.
2.3 ICU-Acquired Weakness
Recently, the importance of ICU-acquired weakness (ICUAW) as a cause of physi-

cal impairment in ICU patients has been recognized. ICUAW is defined as “a syn-
drome of generalized limb weakness that develops while the patient is critically ill
and for which there is no alternative explanation other than the critical illness itself
[13].” The Medical Research Council (MRC) score (ranging from 0 [no muscle
contraction] to 5 [normal strength]) is widely used for its evaluation and diagnosis
of ICUAW [14]. It is assessed in three muscle groups in each upper and lower limb
bilaterally, and a total score of less than 48/60 indicates ICUAW or significant mus-
cle weakness. Moreover, a total score below 36 indicates severe weakness [15, 16].
Assessment of the MRC score requires patients to be sufficiently awake and
cooperate.
In critically ill patients, a combination of hypermetabolism due to excessive
stress and inflammation leads to increased catabolism, rapid and marked degrada-
tion of muscle proteins, and decreased synthesis. As a result, skeletal muscle wast-
ing increases and muscle mass decreases. In critically ill patients receiving
mechanical ventilation, diaphragm atrophy begins 18–48 h after intubation [17, 18],
and in the quadriceps muscle, muscle protein degradation begins within 24 h after
ICU admission. Moreover, it has been shown that a 10% reduction in the rectus
femoris cross-sectional area occurs over 10 days [19]. The loss of muscle mass due
to increased muscle wasting combined with immobilization is an important factor in
physical impairment.
ICUAW has been recognized as a serious complication in critically ill patients.
In these patients, multiple organ failure, severity of illness, and modifiable factors
such as immobilization, hyperglycemia, corticosteroid use, and neuromuscular
blocker use are known risk factors for ICUAW [20]. It has been shown to have
130 R. Kozu et al.
important short-and long-term adverse prognostic factors for patients, including not
only prolonged functional disability, but also inability to wean from mechanical
ventilation, increased mortality, and decreased HRQoL [21].
2.4 ICU-Acquired Delirium
Other complications in critically ill patients include delirium. It is disturbance of con-

sciousness and cognition with an acute onset or fluctuating change. The high preva-
lence of delirium in ICU patients has been reported, affecting 60–80% of mechanically
ventilated patients [22–24]. Delirium is an important risk factor for cognitive decline
following ARDS, along with pre-existing cognitive impairment, sepsis, systemic
inflammation, mechanical ventilation, and prolonged exposure to sedatives [25]. It is
associated with long-term cognitive impairment after ARDS [26], and predicts longer
hospital length of stay and higher mortality [27]. Further, longer durations of delirium
predict more severe cognitive impairment at 12-month follow-up [26].
2.5 Post Intensive Care Syndrome in ARDS Patients
Critically ill patients including ARDS experienced a wide range of sequelae, which
are aggregated in the term “post intensive care syndrome” (PICS). Recently, a com-
prehensive approach has been proposed for these conditions. PICS is defined as
“new or worsening functional impairments in physical and cognitive functioning or
mental health that persist after critical illness and acute hospitalization” [28]. As
described previously, it is a major problem after recovery from ARDS, and long-
term care, including multifaceted rehabilitation, is essential.
3 Physiotherapy Program
3.1 Aim
The aim of physiotherapy for patients with ARDS is to prevent respiratory and
physical impairments, especially muscle dysfunction due to immobilization and
functional disability, and improve exercise capacity, ADL, and HRQoL during and
after hospitalization [29]. It includes prevention of and contribution to the treatment
of respiratory complications that prolong mechanical ventilation. Therefore, phys-
iotherapy should be instituted as early as possible after the patient is admitted to the
ICU. All patients with ARDS should be considered eligible for physiotherapy.
As a key target for physiotherapy is to increase physical activity during and after
critical illnesses, it comprises mainly of early mobilization and exercise. These are
essential interventions. In general, early mobilization is defined as intervention

commencing within 48–72 h of ICU admission.
3.2 Components of a Physiotherapy Program
Physiotherapy for patients with ARDS can be categorized into approaches for respi-
ratory impairment (respiratory physiotherapy) and physical impairment (early
mobilization) (Fig. 10.1). Early mobilization is essential for the prevention of long-
term functional disability and impairment of daily life and HRQoL in survivors of
ARDS. The present practical approach of early mobilization for patients with criti-
cally ill is widely accepted [9].
3.2.1 Respiratory Physiotherapy
Respiratory physiotherapy is a technique that directly improves respiratory dys-

function [30]. In the acute phase of ARDS, respiratory physiotherapy complements
mechanical ventilatory support by correcting maldistribution of ventilation,
improvement of oxygenation, resolution of atelectasis, and prevention of new devel-
opment of pulmonary complications. The goal is to facilitate early weaning from a
mechanical ventilator.
3.2.1.1 Body Positioning
Body positioning is an intervention in which a patient is maintained in a specific

position (e.g., lateral, prone, semi-prone, sitting) for several hours. This is the basis
for all respiratory physiotherapy programs, including airway clearance techniques
[31]. The goal of positioning is to resolve atelectasis and improve oxygenation,
which involves mechanisms such as increasing lung volume, enhancing mucocili-
ary clearance, improving ventilation-perfusion mismatch, and reducing the work of
breathing. For this reason, respiratory physiotherapy usually applies a position in
which the lesion site is on the upper side.
In patients with ARDS, the prone position has been shown to improve oxygen-
ation. This is due to many mechanisms, such as improving functional residual
capacity, ventilation/perfusion heterogeneity, diaphragm movement in dorsal
regions, and increasing ventilation in dependent lung regions [32, 33]. Prone posi-
tion has been shown to have significantly more ventilator-free days and is beneficial
for early mobilization. Turning from the supine to prone position requires a lot of
manpower burden, so a semi-prone position can be used instead (Fig. 10.2) [34].
The sitting position is useful for increasing lung capacity and improving oxygen-
ation with increased functional residual capacity [35], and is an important positional
control in promoting sitting tolerance and initiating early mobilization.
132 R. Kozu et al.
Instable-uncooperative respiratory physiotherapy
early mobilization Stable-cooperative
acute stable recovery
Fig. 10.1 Intervention modalities of physiotherapy according to the clinical course of ARDS
Prone position conducted for greater than 12 h/day, and studies restricted to
moderate to severe ARDS were associated with a mortality benefit (RR, 0.74; 95%
CI, 0.56–0.99) [33].
3.2.1.2 Airway Clearance Techniques
Airway clearance techniques enhance mucus clearance in ARDS patients under

mechanical ventilation who are at risk for retained airway secretions from the endo-
tracheal tube, immobility, and impaired cough. The clinical significance of this tech-
nique is airway management in patients with adverse effects associated with airway
secretion retention, with the goal of improving ventilation and oxygenation through
effective removal of secretions. In ARDS patients, endotracheal suctioning and turn-
ing are routinely used; however, if large amounts of secretions are retained in the
dependent areas, postural drainage is used. This technique uses gravity-assisted posi-
tioning to promote the transport of airway secretions. Manual or ventilator hyperin-
flation is a technique for mobilizing and removing excess bronchial secretions,
expanding collapsed alveoli, and improving oxygenation and lung compliance [36].
3.2.1.3 Inspiratory Muscle Training
Inspiratory muscle weakness, especially of the diaphragm, is highly prevalent in

critically ill patients [37]. Ventilatory management has a significant effect on dia-
phragmatic atrophy and contractile dysfunction, which is referred to as
P/F ratio PEEP

prone semi-prone/lateral lateral/sitting (cmH2O)
350
300 15
250
200 10
150
100 5
50
ICU ICU
admission tracheostomy discharge
0
X X+3 X+6 X+9 X+12 X+15 X+18 X+21
Fig. 10.2 A 60-year-old man, severe pneumonia, ARDS with septic shock. After ICU admission,
prone ventilation had been initiated because of refractory hypoxemia (PaO2/FIO2 78) and hyper-
capnia (arterial blood gas, pH 7.287; PaCO2 57.5 mmHg; PaO2 58.4 mmHg; HCO3− 26.6 mmol/L)
regardless of mechanical ventilation (A/C mode with FIO2 75%; PEEP 12 cmH2O; peak pressure
24 cmH2O; respiratory rate 18 bpm). After admission to the ICU, the patient was placed in the
prone position, followed by the semi-prone/lateral position
ventilator-induced diaphragmatic dysfunction. It is a serious complication that

occurs in around 60–80% of mechanically ventilated patients [38], and it has been
suggested that weaning from mechanical ventilation is more difficult and affects
clinical outcomes. The mechanisms of ventilator-induced diaphragmatic dysfunc-
tion include disuse atrophy from excessive ventilatory support and load-induced
injury due to eccentric contraction-insufficient ventilatory support [38]. The dia-
phragm becomes inactive and may contribute to its disuse and consequent atrophy.
It has been shown a few hours of controlled mechanical ventilation leads to rapid-
onset decreased contractile force of diaphragm [39].
Inspiratory muscle training is a technique that aims to improve inspiratory mus-
cle function by applying an inspiratory resistive load to weakened muscles. Training
for weakened muscle function may improve respiratory muscle function and wean-
ing outcomes [40]. It can be applied to enhance muscle endurance or strength with
protocols that use a threshold-loading device [41]. A systematic review showed
inspiratory muscle training in critically ill patients is feasible, well tolerated, and
improves inspiratory as well as expiratory muscle strength [42].
3.2.2 Early Mobilization
Mobilization is referred to as physical activity performed at an intensity that can

cause physiological changes [31]. Early mobilization is the application of physical
activity within the first 2–5 days of critical illness or injury [43]. There are two types
of mobilization, passive and active. Active mobilization is preferred to passive
mobilization for the prevention and improvement of physical dysfunction [44]. One
of the goals of physiotherapy for patients with ARDS is to achieve independence in
ADL, which requires improvement of physical function, muscle strength and
134 R. Kozu et al.
endurance, performance of basic activities, and improvement of respiratory and cir-

culatory adaptations. It is difficult to prevent skeletal muscle atrophy and weakness
without active mobilization by the patient’s effort, even after a long period of pas-
sive exercise.
For active mobilization, effective analgesia and light sedation, “analgesia-based
sedation,” is essential. It is also part of the Assess, Prevent, and Manage Pain, Both
Spontaneous Awakening Trials and Spontaneous Breathing Trials, Choice of
Analgesia and Sedation, Delirium: Assess, Prevent, and Manage; Early Mobility
and Exercise; and Family Engagement and Empowerment (ABCDEF) bundle [45].
Early mobilization is required to be performed together with the other components
of the bundle and proceeded according to the mobilization protocol. Because
immobility-associated muscle loss or ICUAW begins within the first 48 h of ICU
admission [46], early mobilization should be initiated within 48–72 h of ICU
admission and adapted to improve the patient’s level of function. It has been shown
to be associated with improving clinical outcomes for mechanically ventilated
patients [47]. In addition, the optimal intensity, frequency, and duration of exercise
must be identified to obtain the benefits of mobilization and improve functional
outcomes. Some devices are incorporated into the mobilization protocol, such as
neuromuscular electrical stimulation (NMES), cycle ergometer, and standing/tilt-
ing device.
3.2.2.1 Passive Mobilization
Passive mobilization, such as manual passive limb (range of motion) exercises,

semi-recumbent position with the head of bed elevated 30–45 degrees, regular
changes in body position, in-bed cycling, and NMES, may be used for patients
unable to cooperate with instructions due to unconscious or deep sedation. These
interventions are expected to maintain joint mobility and apply mechanical stimula-
tion to the muscles [48]. Passive mobilization or exercise is safe in mechanically
ventilated patients, including those with ARDS. It has been reported that these exer-
cises did not adversely affect the respiratory and circulatory systems using heart
rate, blood pressure, or oxygen saturation as measures in critically ill patients
[48, 49].
NMES and cycle ergometry are effective exercises, but they require specialized
equipment [50]. The former is a treatment modality to create a passive contraction
of the skeletal muscle through a transcutaneous electrical impulse without active
patient participation and cause cardiorespiratory instability while a patient remains
in bed. The latter is a stationary cycling equipment that can alter the work done by
the patient who is exercising, and it can be used to perform passive, active, and
resistive exercises using the lower or upper extremities. They may be an alternative
strategy to reverse muscle weakness and prevent muscle atrophy due to passive
muscle loading. The consensus on the indications and timing of initiation, time,
frequency, and duration of implementation is unclear.
Although passive mobilization alone does not prevent muscle atrophy and weak-
ness, it has been demonstrated to have antioxidant effects and alter the levels of
inflammatory cytokines [48].
3.2.2.2 Active Exercise and Progressive Mobilization
Active mobilization refers to exercise or physical activity that requires the subject’s
own effort, and includes activities such as active assistive or resistive limb exercises,
bed exercise (e.g., cycling), and tilting up. Progressive mobilization refers to sitting
on the edge of the bed, sitting to standing, standing transfers, marching on the spot,
or ambulation (either assisted or unassisted), and is usually performed according to
the protocol. Active mobilization is considered effective and is recommended in the
clinical practice guidelines [51]. When patients are able to follow instructions or
actively collaborate, active exercise can be initiated. Moreover, as the patient
becomes more interactive, they can progress to mobilization, such as standing, self-
care activities, transfer to chair, and walking.
ARDS patients are severely ill and unstable, and active mobilization is often dif-
ficult because of intubation, mechanical ventilators, other medical equipment, and
many routes and drains. In order to mobilize patients safely, these interventions
must be performed based on the recommended safety criteria for active mobiliza-
tion of mechanically ventilated critically ill patients [52, 53]. When active mobiliza-
tion is carried out according to safety criteria, reported adverse events range between
0% and 3%, and are not usually serious [44].
4 Physiotherapy Practice for Patients with ARDS
The clinical course of ARDS can be divided into four phases: acute, earlier stages in
stable, stable, and recovery phases, which allows for a better understanding of the
aim and role of physiotherapy in the management (Fig. 10.1). Physiotherapy should
be implemented according to the general condition of patients and treatment at each
stage, from the initiation of mechanical ventilatory management to hospital discharge.
4.1 Acute Phase
The acute phase is from the initiation of mechanical ventilatory management to

hemodynamic stability, generally within 24–48 h of treatment initiation. The prior-
ity in this phase is to suppress rapidly progressive hypoxemia that is refractory to
oxygen therapy and minimize the impact on organs. In addition, the oxygen demand
should be reduced by applying adequate analgesia, deep sedation, and fever reduc-
tion. As early rehabilitation, physiotherapy is started within 48 h and mainly
136 R. Kozu et al.
consists of respiratory physiotherapy and passive mobilization. The prone position

improves oxygenation and prevents ventilator-associated lung injury as lung-
protective ventilation. When the prone position is applied, appropriate limb position
and posture should be performed to avoid serious complications such as plexopathy,
peripheral nerve damage [54, 55], and skin breakdown.
Since it is not acceptable to increase the patient’s oxygen demand during this
phase, only passive limb exercises are indicated and may be useful to maintain
range of motion and muscle function as “mechanical stimulus.”
4.2 Earlier Stages in Stable Phase
In this phase, treatments for causing respiratory failure are effective, hemodynamic
stability is achieved, and catecholamines are used but do not increase. Pulmonary
gas exchange is also improving compared to ICU admission. The ventilator mode is
still assist-control ventilation, but FIO2 is often set below 0.6. Excessive sedation
should be strictly avoided because of its adverse effects, and the level of sedation
should be −2 to −1 on the Richmond Agitation Sedation Scale.
As in physiotherapy, appropriate body positioning is continued for alveolar
recruitment and airway clearance, or prevention of new development of pulmonary
complications. Passive mobilization, such as a semi-recumbent position and in-bed
active limb exercise, may be started. These tests are also performed to evaluate the
effect on the respiratory and circulatory systems due to increased oxygen demand
and load during and after mobilization.
4.3 Stable Phase
Hemodynamics is not a problem, unless new infections are involved. Sedation is

minimal, and the patient is able to communicate with staff and/or their family mem-
bers. FIO2 and the level of PEEP in ventilatory support gradually decreased and
weaning from the ventilator continued gradually.
Because the patient’s general condition is stable, it is possible to proceed with
active exercise and progressive mobilization. Patients are able to sit on the edge of
the bed, transfer to a chair, stand, march in place, and ambulate. These activities are
initiated and performed with mechanical ventilatory support. Active exercise and
progressive mobilization are beneficial not only in improving physical functioning,
but also in increasing ventilation, expanding the lungs, and preventing delirium.
Safety and patient tolerance should be assessed continuously during and after
exercise.
4.4 Recovery Phase During ICU Stay
In this phase, ventilatory support is minimal, and it is the final stage in which the
patient can be weaned from mechanical ventilation. Sedation is discontinued, and a
spontaneous breathing trial is performed. If the patient does not have any new infec-
tions, there is no hemodynamic issue. In physiotherapy, active mobilization is con-
tinued; however, the frequency of mobilization or activities and the intensity of
exercise are increased. It is also important to encourage activities such as self-care
in bed during the day in order to improve ADL faster in the general ward after ICU
discharge.
4.5 Recovery Phase After ICU Discharge
After ICU discharge, exercise training should be continued in the physiotherapy

gym, if possible. Based on a periodic functional assessment, resistance training on
extremities, general endurance training, and exercises to improve the ability to per-
form ADL should be performed at least 5 days a week with gradually increasing
exercise intensity. If patients experience desaturation during exercise, a sufficient
amount of oxygen should be administered.
Patients with complications of PICS require long-term follow-up and rehabilita-
tion after hospital discharge. Since the effects of PICS are long-lasting, physical and
cognitive functioning, and mental health need to be assessed periodically from the
acute phase during ICU stay to more than a few years after hospital discharge [56].
Medical and nursing care services and social resources in the community are needed
in addition to rehabilitation for patients to reintegrate into society. Appropriate and
continuous support in the community will be required in the future.
5 Evidence on Physiotherapy in Patients With ARDS
Physiotherapy, especially active exercise and progressive mobilization for patients

with mechanically ventilated ARDS, may have both short- and long-term benefits.
The current evidence indicates that early mobilization is safe and feasible and has
beneficial effects on short-term ICU outcomes, such as muscle strength at discharge
and functional independence [57].
Although there are only a few reports of studies limited to ARDS patients, early
mobilization has consistently been shown to be safe and feasible in the ICU setting,
even during mechanical ventilation [58, 59] and/or continuous renal replacement
therapy [60], or administration of vasopressors [61, 62]. A systematic review that
reported on patient safety during early mobilization showed 308 potential safety
events occurred from 13,974 mobilization sessions, with a 2% incidence of
138 R. Kozu et al.
potential safety events during mobilization [63]. Of these, 78 (0.6%) safety events
were reported. For adverse events such as high heart rate, low blood pressure, and
oxygen desaturation, the pooled incidence rates were all less than two per 1000
mobilization/rehabilitation sessions [63].
The reported benefits of early mobilization include reduced ICU and hospital
length of stay [61, 64, 65], shortened duration of delirium [57, 65], fewer ventilator-
dependent days [57], improved walking distance [49, 66], and functional status at
hospital discharge [49, 57, 65]. However, few studies have focused on ARDS.
In a systematic review and meta-analysis of randomized controlled trials aimed
at examining the efficacy of early mobilization in critically ill patients [67], 11 stud-
ies (including 1322 patients) were included in the meta-analysis, and the effect of
early mobilization on the primary outcome was favorable only for the length of
hospital stay. The MRC score of the early mobilization group was superior to that
of the control group. This study showed that there was no apparent difference in in-
hospital mortality and HRQoL between early mobilization and usual care.
In another systematic review and meta-analysis of different types of interven-
tions in physiotherapy [68], 43 recent randomized controlled trials (9 with cycling,
14 with NMES, and 20 with protocolized physical rehabilitation as compared to
standard of care) were identified. A total of 3548 patients were randomized, and
there were no serious adverse events due to the intervention. Exercise intervention
did not influence mortality, but reduced the duration of mechanical ventilation and
length of ICU stay. The reduction in the length of hospital stay was not significant
(−1.6 days). The effect of shortening the length of mechanical ventilation and ICU
stay was observed only in the protocolized physical rehabilitation group, and was
particularly effective in patients with longer ICU stays and lower Acute Physiology
and Chronic Health Evaluation II scores. There was no benefit from early interven-
tion initiation.
These results indicate that early mobilization interventions for critically ill
patients, including ARDS patients, do not influence mortality. In addition, the long-
term effects of early mobilization in the ICU on physical and cognitive function or
HRQoL are inconsistent.
6 Conclusion
While mortality in ARDS is decreasing, survivors frequently experience significant

disabilities, such as muscle weakness, cognitive and mental health disorders, and
reduced HRQoL [7]. In the ICU, bed rest is a common practice; mechanically ven-
tilated ARDS patients are more likely to have prolonged bed rest and increase in
complications and negative sequelae. Physiotherapy should be implemented as
early as after ICU admission to assist ventilation and oxygenation, prevent the com-
plications of immobilization, and improve functional recovery. An integrated pro-
gram with respiratory physiotherapy and exercise is needed to optimally manage
complex patient problems.
However, evidence determining optimal timing, intensity, frequency, and dura-

tion of exercises that would practice effective mobilization of patients with ARDS
is lacking. In addition, the type and timing of assessments of outcomes measures for
determining efficacy of physiotherapy are not standardized.
Physiotherapy, including early active exercise and mobilization, is safe and fea-
sible, with some evidence of improved patient outcomes. Its clinical practice has
been well-supported with randomized controlled trials, systematic reviews, and rec-
ommendations. Further research is needed to establish stronger evidence for the
effectiveness of physiotherapy for patients with ARDS.
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Part IV
Current Topics
Chapter 11
MicroRNAs and Extracellular Vesicles
for Diagnosis of ARDS: Can MicroRNAs
and Extracellular Vesicles Be Helpful
for Early Diagnosis or Risk Evaluation
of ARDS?
Mitsuhiro Yamada
Abstract The lungs are the organs which work for gas exchange. The basic struc-
ture of the lungs is an alveolus, which consists essentially of epithelial cells, endo-
thelial cells, and mesenchymal cells. Moreover, in the alveoli, various types of bone
marrow-derived cells, including alveolar macrophages, exist for various functions
including host-defense and tissue repair. Therefore, because the lungs consist of
various types of cells which have various functions, the communication between
each type of cells should play important roles for maintaining the homeostasis as
well as the pathogenesis of the diseases in the lungs. In the past decades, the
researches have focused on cytokines or adhesion molecules to reveal the intercel-
lular communication for understanding the homeostasis and the pathogenesis in the
lungs. Recent investigations have revealed that an extracellular vesicle and its com-
ponents, microRNAs can move from the cells to others for transferring substances
including microRNAs in vesicles as an intercellular messenger. MicroRNAs and
extracellular vesicles are therefore attracting increasing attentions from both trans-
lational and clinical researchers. In this chapter, I describe the microRNAs and
extracellular vesicles in terms of the question, whether microRNAs and extracellu-
lar vesicles be helpful for early diagnosis or risk evaluation of ARDS.
Keywords Extracellular vesicles · MicroRNAs · Exosome · Microparticle

Ectosome
M. Yamada (*)
Department of Respiratory Medicine, Tohoku University Graduate School of Medicine,
Sendai, Miyagi, Japan
e-mail: yamitsu@med.tohoku.ac.jp
Ltd. 2022
https://doi.org/10.1007/978-981-16-8371-8_11
148 M. Yamada
1 Introduction
The lungs are the primary organs in the respiratory system. The main function of the
lungs is gas exchange, to extract oxygen from the atmosphere and emit carbon diox-
ide from blood into the atmosphere. The basic structure of the lungs is an alveolus,
which consists of parenchymal cells including epithelial cells, endothelial cells, and
mesenchymal cells. Moreover, various types of bone marrow-derived cells, includ-
ing alveolar macrophages exist in the alveoli and worked for various functions
including host-defense and tissue repair. Therefore, because the lungs consist of
various types of cells which have various functions, the communication between
each type of cells should play important roles for maintaining the homeostasis as
well as the pathogenesis of the diseases in the lungs [1]. In the past decades, the
researches have focused on soluble factors like cytokines and growth factors and
cell adhesion molecules on cell surface to reveal the intercellular communication
between the cells for understanding the homeostasis and the pathogenesis in the
lungs. Recent investigations have revealed that an extracellular vesicle and its com-
ponents including microRNAs, mRNA, lipids, and proteins can move from the cells
to others for transferring components in vesicles as intercellular messengers.
Therefore, microRNAs and extracellular vesicles attract increasing attentions from
both translational and clinical researchers, especially who investigate biomarkers
for diagnosis and prognosis of diseases including malignant diseases as well as
inflammatory diseases like acute respiratory distress syndrome. In this chapter, I
describe the microRNAs and extracellular vesicles in terms of the question, whether
microRNAs and extracellular vesicles be helpful for early diagnosis or risk evalua-
tion of acute respiratory distress syndrome (ARDS).
2 MicroRNAs in ARDS
In human genome, over 1900 microRNAs are encoded [2]. MicroRNAs are initially
transcribed as part of one arm of an RNA stem-loop that forms part of a several
hundred nucleotide microRNA precursor termed a primary microRNA (pri-
microRNA). A pri-microRNA contains a few precursors of microRNA of which
structures are hairpin loops. These structures are composed of about 70 nucleotides.
The double-stranded RNA structure of the hairpin structures in a pri-microRNA is
recognized by a nuclear protein, DiGeorge Syndrome Critical Region 8 (DGCR8),
named because of its association with DiGeorge Syndrome. DGCR8 associates
with Drosha, the enzyme that cuts RNA [3]. After processing by this complex, pre-
microRNAs, which has a two-nucleotide overhang at its 3′ end, are produced. Pre-
microRNAs are exported from the nucleus by the nucleocytoplasmic shuttle protein,
Exportin-5. In the cytoplasm, the RNase III enzyme, Dicer, cleaves the hairpins of
pre-microRNAs hairpin [4]. This cleaving produces an imperfect
microRNA:microRNA* duplex about 22 nucleotides in length. Although either
11 MicroRNAs and Extracellular Vesicles for Diagnosis of ARDS: Can MicroRNAs… 149
strand may potentially become a functional miRNA, only one strand is usually
incorporated into the RNA-induced silencing complex (RISC) in which the
microRNA and its target mRNA are interacting. Most of microRNAs are located
within the cell, some microRNAs, as circulating microRNAs or extracellular
microRNAs, have also been found in extracellular environment including circulat-
ing blood and urine. MicroRNAs work for RNA silencing and post-transcriptional
regulation of gene expression via base-pairing with complementary sequences
within mRNA molecules. MicroRNAs suppress mRNA molecules via cleavage of
the mRNA strand, destabilization through shortening of its poly(A) tail, or interfer-
ing translation of the mRNA.
As mentioning above, although the majority of microRNAs exist inside the cells,
some microRNAs are exported in extracellular vesicles, mentioning in the later
paragraph, and stably exist in extracellular fluids like blood or epithelial lining flu-
ids. Because the amount and types of microRNAs exported into extracellular vesi-
cles may vary according to physiological and pathological conditions, the studies to
profile microRNAs in extracellular fluids of the patients have performed to seek
candidate microRNAs which can work as a biomarker for diagnosis or prognosis of
diseases. Several studies to profile microRNAs in blood of the patients with ARDS
were also performed and reported.
Zhu et al. performed the survival analysis to seek the prognostic microRNAs in
blood as part of the Molecular Epidemiology Study of ARDS (MEARDS) from the
ICU at Massachusetts General Hospital and Beth Israel Deaconess Medical Center
[5]. They collected blood samples from 78 patients with moderate and severe ARDS
and analyzed to estimate the hazards ratio of microRNA for 28-day mortality. They
revealed that 19 microRNAs were associated with survival. Among them, five miR-
NAs were most differentially expressed, miR-628.3p (HR = 1.70, p < 0.01), miR-922
(HR = 1.05, p < 0.01), miR-505* (HR = 1.65, p < 0.01), miR-130b* (HR = 1.44,
p < 0.01), and miR-624 (HR = 1.38, p < 0.01). Moreover, according to statistical
analyses, they determined the microRNA classifier to predict ARDS 28-day mortal-
ity and revealed that time to death was shorter in patients with higher eight-miRNA
classifier expression (p = 0.04).
The same group also reported the analyses to compare miRNA expression in
whole blood samples from the patients with ARDS and the critically ill at-risk con-
trol patients [6]. They revealed that the levels of miR-181a or miR-92a were posi-
tively correlated to a risk for a development of ARDS, whereas miR-424 was
negatively correlated to a risk for ARDS. Addition of these microRNAs to Lung
injury prediction Score can improve the estimation for a risk of developing
ARDS. Although these reports did not investigate the mechanisms of an increase or
decrease in the microRNA in the patients with ARDS, and some of the microRNAs
suggested in these human studies showed a different expression manner in animal
models of ARDS, these studies may suggest that circulating microRNAs are poten-
tial biomarkers for diagnosis or prognosis of ARDS.
The investigations for the role of microRNAs in the pathogenesis of ARDS have
mainly used in vitro culture models and animal models (Table 11.1). Cai et al. inves-
tigated lipopolysaccharide (LPS)-induced mouse acute lung injury model and found
150 M. Yamada
Table 11.1 The roles of microRNAs in the pathogenesis of acute lung injury
microRNA Change in acute lung injury Function References
miR-16 Decreased Suppression of IL-6 and TNF-α [7]
expression
miR-181b Decreased Suppression of importin-α3 [7, 8]
expression
inhibition of NF-κb nuclear
translocation
suppression of the expression of
target genes of NF-κb
suppression of inflammation
miR-155 Increased Suppression of SOCS1expression [9]
enhancement of cytokine signaling
miR-146a Increased Suppression of IRAK-1 and [10]
TRAF-6 expression
inhibition of NF-κb activation
suppression of expression of
inflammatory cytokines
miR-223 Increased (transferred from PMNs Suppression of PARP-1 expression [11]
to alveolar epithelial cells) inhibition of NF-κb and AP-1
activation
suppression of inflammation
that miR-214 and miR-415 were upregulated in the lungs during LPS-induced acute
lung injury, whereas miR-16, miR-23a, miR-24, miR-181a, miR-181b, and
miR-199a were significantly down-regulated [7]. They focused on miR-16, which
were the most significantly down-regulated microRNAs during LPS-induced, and
performed an over-expression of miR-16 assay in LPS-treated A549 cells, an alveo-
lar epithelial cell line. Over-expression of miR-16 significantly down-regulated the
levels of expression of IL-6 and TNF-α. They also realized that a 3′ untranslational
region (UTR) of IL-6 and TNF-α contains the binding sites of miR-16. According
to this bioinformatics information, miR-16 significantly suppressed the luciferase
activity of a reporter fusion vector with the TNF-α 3′UTR region, suggesting that
miR-16 has an anti-inflammatory function by suppressing translation of inflamma-
tory cytokines. It has been also reported that miR-181b suppressed importin-alpha3,
a protein that is required for nuclear translocation of NF-κB, and regulates the
expression adhesion molecules which were induced by inflammatory stimuli
through NF-κB [8]. This study suggests that microRNAs that can inhibit the transla-
tion of inflammatory cytokines were down-regulated during ARDS, which resulted
in aggravation of inflammation.
Rao et al. focused on miR-155, which was upregulated in the lung-infiltrating
mononuclear cells in an acute lung injury model and analyzed the role of miR-155 in
acute lung injury using miR-155 deficient mice [9]. They prepared an acute lung
injury model induced by Staphylococcal enterotoxin B (SEB) using wild-type mice
and miR-155 deficient mice. They found the decrease in infiltration of inflammatory
cells, especially T lymphocytes, in miR-155 deficient mice. Because the expression
of interferon-γ (IFN-γ) also decreased, they investigated the signaling pathway

related to IFN-γ and revealed that suppressor of cytokine signaling 1 (SOCS1), a
negative regulator of IFN-γ, was upregulated in miR-155 deficient mice. These find-
ings suggest the possibility that miR-155 suppressed the expression of SOCS1 pro-
tein and augmented the signaling induced by cytokines during acute lung injury.
It has been reported that miR-146a, which is also upregulated in a LPS-induced
acute lung injury animal model, suppresses inflammatory responses [10]. miR-146a
significantly suppressed LPS-mediated TNF-α, IL-6, and IL-1β induction in alveo-
lar macrophage cells through repressing protein expression of IRAK-1 (IL-1 recep-
tor activated kinase-1) and TRAF-6 (tumor receptor factor associated factor-6),
which results in activation of NF-κB. It was also reported that miR-146a also con-
tributed to induction of M2 macrophages, anti-inflammatory macrophages [12].
These observations may suggest that miR-146a plays a significant role in regulation
of inflammation during ARDS.
Polymorphonuclear neutrophil (PMN) is a key player for lung tissue damage
during ARDS, whereas it has been suggested that neutrophils also contribute to
resolution of inflammation and a repair of alveolar epithelial cells [13]. Neudecker
et al. reported an interesting study showing that neutrophils contributed to anti-
inflammatory functions by transferring neutrophil-derived microRNAs to pulmo-
nary epithelial cells [11]. They cocultured alveolar epithelial cells with PMNs and
analyze the changes of expression of microRNAs in the alveolar epithelial cells.
When they cocultured alveolar epithelial cells with wild-type PMNs, They found a
significant increase in miR-223 in the epithelial cells. However, when they cocul-
tured alveolar epithelial cells with miR-223-deficient PMNs, no alterlation of
miR-223 expression was observed in the epithelial cells. These findings suggested
that PMN-derived miR-223 became incorporated in the epithelial cells, not sug-
gested the induction of miR-223 in the epithelial cells by stimulation by humoral
factors derived from PMNs. MiR-223 was increased both in the lung tissues of a
ventilator-induced acute lung injury mouse model and in the bronchoalveolar lavage
fluids of ARDS. They also revealed that miR-223 deficiency induced severer lung
inflammation, whereas over-expression of miR-223 in mouse lungs resulted in pro-
tection in lung injury models. They further revealed that the target of miR-223 was
poly (adenosine diphosphate-ribose) polymerase-1 (PARP-1) that augments inflam-
matory responses via activation of NF-κB and AP-1 transcription factors, which
suggested miR-223 suppressed inflammation by downregulation of PARP-1. These
interesting findings suggest that miR-223 from neutrophils was transferred to pul-
monary epithelial cells intracellularly and weaken acute lung injury through repres-
sion of PARP-1.
Accumulating evidences including the above-mentioned studies have revealed
that microRNAs play important roles in not only the regulation of expression and
translation of the genes in the cells, but also in intercellular regulation of the expres-
sion during acute lung injury, which suggests that microRNA is an important player
in ARDS and could be a candidate of the biomarker for diagnosis and prognosis as
well as a good target molecule of new treatment for ARDS.
152 M. Yamada
3 Extracellular Vesicles in ARDS
Extracellular vesicles (EVs) are lipid bilayer-vesicles released from various types of
the cells. Various EV subtypes have been defined by size, biogenesis, transportation,
cellular source, and function, including terms like exosomes, microparticles, and
apoptotic bodies [14].
Exosomes are one of the major components of EVs [15]. Recently, EVs, includ-
ing exosomes, have been considered as novel tools for intercellular communication
[16] because EVs contain various proteins and nucleic acids including microRNAs
(Fig. 11.1). MicroRNAs in EVs can be transferred to target cells to regulate gene
expression and cell function [17–19]. EVs and enveloped microRNAs have been
shown to function in physiological and pathological conditions [20–24]. EVs and
enveloped microRNAs within biological fluids (e.g., circulating blood) have also
attracted attention as novel biomarkers of diseases such as cancer because the com-
ponents and secretion dynamics of EVs vary according to their cellular origin and
environment [25, 26]. Several studies have been reported about the changes of
microRNA expression in lung injury models and the possibility of a new treatment
strategy using exosomes for ARDS (Table 11.2).
The study reported by Zhu et al. showed that the intratracheal instillation of exo-
somes which isolated culture supernatants of human mesenchymal stem cells
(MSCs) ameliorated lung injury in an Escherichia coli-derived LPS-induced lung
injury model [27]. Instillation of the exosomes induced a reduction of pulmonary
edema and lung protein permeability as well as the influx of neutrophils. They fur-
ther investigated the mechanism and revealed that KGF mRNAs in the exosomes
play an important role for this amelioration of inflammation.
Morrison et al. focused on the paracrine effect of MSCs on macrophage polariza-
tion and the role of EV-mediated mitochondrial transfer [28]. They cocultured
human monocyte-derived macrophages (MDMs) with MSCs without direct contact.
The coculture with MSCs suppressed the production of inflammatory cytokines,
Endocytosis Exosome
• lipid bilayer-vesicles
• Diameter: 40-200nm
• Secreted from most type
of the eukaryotic cells
microRNA • Can stably exist
mRNA • Contain various molecular
protein constituents including
Early Multi- protein and microRNAs
endosome vesicular
body
Fig. 11.1 Generation of exosomes. Exosomes are derived from the endosomal compartment of
cells. It has been reported the molecules related to endocytosis including Rab small G protein fam-
ily and ESCRT (endosomal sorting complexes required for transport) are involved in generation
and secretion of exosomes, although the mechanism has not been fully elucidated
Table 11.2 Extracellular vesicles/exosomes in acute lung injury

Functional molecules/
Origin apparatus Function References
Bone-marrow KGF mRNA Suppression of inflammatory [27]
derived MSCs responses
Bone-marrow Mitochondria Modulating differentiation of [28]
derived MSCs alveolar macrophages
Lung epithelial cells Caspase 3 Activation of macrophages [29]
increased expression of the M2 macrophage marker CD206, and augmented phago-

cytic capacity of LPS-stimulated MDMs. These effects were partially mediated by
CD44-expressing EVs which include exosomes. They also found that the treatment
of MDMs with MSC-EVs induced the mitochondrial transfer from the EVs to the
MDMs. Adoptive transfer of alveolar macrophages treated with the exosomes
derived from MSCs suppressed inflammation and lung injury in a LPS-induced lung
injury model. This effect of MSCs was inhibited by blocking oxidative phosphory-
lation or generating dysfunctional mitochondria in MSCs using rhodamine-6G pre-
treatment. These findings suggest that the anti-inflammatory effects of MSC-EVs
depend on the EV-mediated mitochondrial transfer, which results in enhancement of
macrophage oxidative phosphorylation and changing macrophage phenotype in an
acute lung injury model and the ARDS environment.
On the other hand, the study by Moon et al. reported that the extracellular vesi-
cles including exosomes derived from epithelial cells activated macrophages and
augmented the inflammation in an acute lung injury model [29]. They found that,
after hyperoxia, EVs were generated and released into BALF. These hyperoxia-
induced EVs were mainly derived from lung epithelial cells because of hyperoxia-
associated endoplasmic reticulum stress. Treating alveolar macrophages with
hyperoxia-induced, epithelial cell-derived EVs induced an increased secretion of
IL-6, TNF-α, and macrophage inflammatory protein 2 (MIP-2). They further inves-
tigated the mechanism and revealed that caspase-3 in EVs was largely responsible
for the alveolar macrophage activation via the Rho-associated protein kinase
(ROCK1) pathway. These results show that hyperoxia-induced, lung epithelial cell-
derived and caspase-3 enriched EVs activate macrophages and augment the inflam-
matory responses during acute lung injury.
The evidences including the studies shown in this chapter suggest the possibility
that the EVs derived from lung parenchymal cells activate inflammatory cells
including lung macrophages, which results in exacerbation of inflammation in
ARDS. On the other hand, the reports about MSC-derived EVs including exosomes
reinforce the previous findings about the anti-inflammatory function of MSCs dur-
ing acute lung injury models and suggest that MSC-EVs could be a possible treat-
ment tool for ARDS.
Microparticles (MPs), which are also called exosomes, are the extracellular ves-
icles of which dimensions are between 0.1 and 1.0 μm [30, 31]. MPs bud off from
plasma membrane during injury, activation, or apoptosis [32, 33]. MPs have been
used as the biomarker indicating the injury of a specific type of cells because it is
154 M. Yamada
possible to identify their parent cells by analyzing the cell-specific antigen on MP

surface. Recent reports also suggested that the MPs participate in the intercellular
communication [30, 32, 34]. It has been reported that endothelial microparticles
(EMPs), which are the microparticles derived from endothelial cells, increase in
diseases accompanied with endothelial injury such as acute coronary syndrome,
renal failure, and COPD [35–41]. These reports also suggest that the number of
circulating EMPs reflects the degrees of the endothelial injury and the disease sever-
ity [37]. These facts provided us the hypothesis that the EMPs would be a marker
for pulmonary endothelial injury and ARDS. The diseases causing ARDS such as
sepsis usually provoke the severe systemic inflammation, which results in the sys-
temic endothelial cell injury. Therefore, analyzing the EMPs which expressed the
specific antigen of pulmonary microvascular endothelium is critical to distinguish
pulmonary microvascular injury from systemic capillary injury and to utilize EMPs
as the biomarker for ARDS. We focused on angiotensin-converting enzyme (ACE),
a zinc dependent metalloprotease on cell membrane [42]. Pulmonary microvascular
endothelial cells relatively express the high levels of ACE comparing with other
endothelial cells including systemic capillary endothelium [43–45]. Therefore, we
hypothesized that circulating ACE+ EMPs increase during ARDS and correlate with
the severity of lung microvascular injury, and performed the study [46].
We first examined whether exposure to an inflammatory stimulus induced the
formation of ACE+ EMPs from pulmonary microvascular endothelium. We found
that inflammatory stimuli induce the formation of ACE+ EMPs (EMPs highly
expressing ACE) from pulmonary microvascular endothelial cells, resulting in
decreased levels of cell-surface ACE expression. The experiments using inhibitors
for singling molecules showed that significant amounts of EMPs induced by TNF-α
stimulation were possibly derived from apoptosis or pyroptosis which inhibited by
Z-VAD-FMK. Because inflammatory stimulation induces the budding of ACE+
EMPs from pulmonary microvascular endothelium, we hypothesized that the circu-
lating ACE+ EMP numbers would increase during acute lung injury, which involves
injury of the pulmonary microvasculature, and the ACE+ EMP numbers correlate
with the severity of lung injury. To address this issue, we utilized different types of
injury models, including the CLP-induced injury model (CLP model; as a model of
indirect injury) and the intratracheally administered LPS-induced injury model
(LPS-IT model; as a model of direct injury). We examined circulating EMPs in the
injury models by flow cytometry. Total EMP numbers were significantly increased
compared with the respective controls (Fig. 11.2a). ACE+ EMP numbers were also
significantly increased in injury models (Fig. 11.2b). Moreover, the ACE+ EMP/
EMP ratio significantly increased in the injury models compared to the respective
controls (Fig. 11.2c), indicating that the increase in the counts of ACE+ EMPs in the
injury models was not due to the increase in total EMPs, but likely to the increase in
the ACE+ EMP numbers released from lung microvascular endothelium. We ana-
lyzed the correlation between the circulating EMPs and the severity of lung injury
and revealed that circulating ACE+ EMPs and the ACE+ EMP/EMP ratio possibly
reflected the severity of lung injury including alterations in the alveolar–capillary
barrier. These data indicate that the formation of ACE+ EMPs occurred during lung
a 500 * b 200 c 50
ACE EMPs/EMPs(%)
* * *
* *
ACE EMPs(/µL)
400 150 40
EMPs(/µL)
300 30
100
200 20
+
50
+
100 10
0 0 0
Sham CLP PBS-IT LPS-IT Sham CLP PBS-IT LPS-IT Sham CLP PBS-IT LPS-IT
d 5000 e 400 f 15
*
ACE EMPs/EMPs(%)
4000 *
ACE EMPs(/µL)
300
10
EMPs(/µL)
3000
200
+
2000
5
+
100
1000
0 0 0
without with without with without with
ARDS ARDS ARDS ARDS ARDS ARDS
Fig. 11.2 The number of circulating ACE+ EMPs and the ratio of ACE+ EMPs to total circulating
EMPs increased in both lung injury mouse models and septic patients who developed ARDS. The
counts of EMPs (a), ACE+ EMPs (b) and the ACE+ EMP/EMP ratio (c) in sham-operated mice
(sham), CLP-operated mice (CLP), intratracheal PBS-administered mice (PBS-IT), and intratra-
cheal LPS-administered mice (LPS-IT; n = 12 in each group). Box and whisker plots show the first
and third quartiles (bottom and top of the box), the median (the band inside the box), and the mini-
mum and maximum (the ends of the whiskers). *p < 0.05 between the two groups. The number of
EMPs (e), ACE+ EMPs (d) and the ACE+ EMP/EMP ratio (f) in the serum of septic patients who
developed (gray; n = 21) or who did not develop ARDS (white; n = 61). *p < 0.05 between the two
groups. ACE angiotensin-converting enzyme, CLP cecal ligation and puncture, EMPs endothelial
microparticles, LPS lipopolysaccharide, PBS phosphate-buffered saline, ARDS acute respiratory
distress syndrome
injury and resulted in both an increase in circulating ACE+ EMPs and a decrease in
ACE expression in pulmonary microvascular cells.
The animal study showed increased ACE+ EMPs and their correlation with the
severity of lung injury. To test the hypothesis that ACE+ EMPs could serve as a
prognostic indicator of ARDS development in septic patients, we examined circu-
lating ACE+ EMPs by flow cytometry in 82 septic patients recruited for the prospec-
tive observational study. Twenty-one septic patients developed ARDS (8 with direct
ARDS, 13 with indirect ARDS). The counts of circulating ACE+ EMPs on admis-
sion were significantly higher in the septic patients who developed ARDS than in
those who did not develop ARDS (Fig. 11.2e, p < 0.001), but no difference was
observed in the counts of total EMPs (Fig. 11.2d, p = 0.843). The ACE+ EMP/EMP
ratio was also significantly higher in patients who developed ARDS (Fig. 11.2f,
p < 0.001). We performed a subgroup analysis of circulating ACE+ EMPs based on
the source of injury for developing ARDS. The counts of total EMPs and ACE+
EMPs were similar in both patients that developed direct and those that developed
indirect ARDS. However, the ACE+ EMP/EMP ratio was significantly higher in the
indirect ARDS patients, possibly suggesting the presence of severer pulmonary
endothelial injury through indirect ARDS. Circulating ACE+ EMPs and the ACE+
156 M. Yamada
EMP/EMP ratio were also significantly higher in the patients that developed ARDS
than in those with hydrostatic pulmonary edema.
The results of our study suggest that ACE+ EMPs from pulmonary microvascu-
lar endothelial cells may reflect the injury of pulmonary microvascular endothelial
cells, and could be a prognostic marker for developing ARDS in septic patients as
well as a diagnostic marker for distinguishing ARDS from hydrostatic pulmo-
nary edema.
4 Conclusion
The lungs consist of various types of the cells including epithelial cells, endothelial
cells, mesenchymal cells, and bone-marrow derived cells. Therefore, for intracel-
lular communication, extracellular vesicles and encapsulated microRNAs derived
from the various types of the lung cells are involved in the pathophysiology of the
lung diseases including ARDS. Recent investigations including the above-mentioned
studies have elucidated the roles of microRNAs and extracellular vesicles in the
pathogenesis of ARDS and also suggest the possibility of circulating microRNAs
and extracellular vesicles as the biomarkers for diagnosis and prognosis of
ARDS. Further investigations including how to deliver microRNAs or extracellular
vesicles to specific target cells would provide a new treatment strategy for ARDS.
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diabetes mellitus. Atherosclerosis. 2010;208:264–9.
38. Gordon C, Gudi K, Krause A, Sackrowitz R, Harvey BG, Strulovici-Barel Y, Mezey JG,
Crystal RG. Circulating endothelial microparticles as a measure of early lung destruction in
cigarette smokers. Am J Respir Crit Care Med. 2011;184:224–32.
39. Jung C, Sorensson P, Saleh N, Arheden H, Ryden L, Pernow J. Circulating endothelial
and platelet derived microparticles reflect the size of myocardium at risk in patients with
ST-elevation myocardial infarction. Atherosclerosis. 2012;221:226–31.
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Jinnouchi H, Ogawa H. Significance of a multiple biomarkers strategy including endothelial
dysfunction to improve risk stratification for cardiovascular events in patients at high risk for
coronary heart disease. J Am Coll Cardiol. 2009;54:601–8.
41. Takahashi T, Kobayashi S, Fujino N, Suzuki T, Ota C, He M, Yamada M, Suzuki S, Yanai
M, Kurosawa S, Yamaya M, Kubo H. Increased circulating endothelial microparticles
in COPD patients: a potential biomarker for COPD exacerbation susceptibility. Thorax.
2012;67:1067–74.
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44. Danilov S, Jaspard E, Churakova T, Towbin H, Savoie F, Wei L, Alhenc-Gelas F. Structure-
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Muzykantov VR. Lung uptake of antibodies to endothelial antigens: key determinants of vas-
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M. Increase in circulating ACE-positive endothelial microparticles during acute lung injury.
Eur Respir J. 2019;54:1801188.
Chapter 12
Stem Cell Therapy and Regenerative
Medicine for ARDS: Can Stem Cell
Therapy and Regenerative Medicine
Contribute to the Protection or Recovery
of the Injured Lungs?
Makoto Ishii
Abstract Acute respiratory distress syndrome (ARDS) is a life-threatening severe

acute respiratory failure syndrome characterized by rapid onset of widespread
inflammation in the lungs and subsequent increased permeability of the pulmonary
capillary endothelial and alveolar epithelial barriers, leading to severe progressive
hypoxemia and frequent need for mechanical ventilation. Despite recent improve-
ments in the clinical management of ARDS patients, such as the use of respiratory
support and fluid input restriction, there are no established pharmacological thera-
pies, and the mortality rate of ARDS is still high. The recent global pandemic of
coronavirus disease 2019 (COVID-19), which is caused by SARS-CoV-2 and often
results in ARDS, has encouraged the rapid establishment of novel therapies. Cell-
based therapies, primarily using mesenchymal stem/stromal cells, have been exten-
sively reported in animal models and clinical studies as a promising approach for
the treatment of ARDS mainly induced by various kinds of respiratory infections,
including influenza virus and SARS-CoV-2. In this chapter, the current knowledge
and future direction of stem cell therapy for ARDS will be reviewed.
Keywords Lung stem/progenitor cells · Mesenchymal stem/stromal cells ·

Influenza virus · COVID-19
M. Ishii (*)
Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
e-mail: ishii@keio.jp
Ltd. 2022
https://doi.org/10.1007/978-981-16-8371-8_12
160 M. Ishii
1 Introduction
Acute respiratory distress syndrome (ARDS) is a syndrome of acute hypoxemic

respiratory failure that develops primarily from an increase in lung endothelial and
epithelial cell permeability, leading to the diffuse damage of these cells, mainly in
the setting of pneumonia, sepsis, aspiration of gastric contents, or severe trauma [1,
2]. In spite of recent developments in multidisciplinary approaches such as lung
protective ventilation strategies and fluid management, its mortality rate was still
found to be high at around 30–40% in most studies [1]. Development of a novel,
efficient therapy is required for overcoming ARDS.
The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) infection, was first reported in Wuhan,
China in December 2019 and subsequently spread globally, leading to a pandemic.
As of December 22, 2020, more than 77 million people worldwide had been con-
firmed to have COVID-19 infections, and more than 1.7 million patients died [3].
Although the majority of COVID-19 cases are classified as mild or asymptomatic,
approximately 17–35% of hospitalized patients with COVID-19 are treated in an
intensive care unit, most commonly due to hypoxemic respiratory failure [4]. Recent
reports suggest that up to 12% of patients hospitalized with COVID-19 require inva-
sive mechanical ventilation [5, 6], with the majority developing ARDS [7].
Treatment for patients with COVID-19 includes best practices for supportive man-
agement of acute hypoxic respiratory failure. To efficiently manage COVID-19,
various kinds of drugs for COVID-19 have been investigated and developed includ-
ing antiviral drugs (e.g., remdesivir), antibodies (e.g., hyperimmune immunoglobu-
lins, convalescent plasma), anti-inflammatory agents (e.g., dexamethasone, statins),
targeted immunomodulatory therapies (e.g., tocilizumab, sarilumab, anakinra, rux-
olitinib), and anticoagulants (e.g., heparin) [4]. Recent evidence suggests that treat-
ment of COVID-19 with dexamethasone decreased 28-day mortality in patients
who needed supplemental oxygen without mechanical ventilation as compared to
the usual care group (23.3% vs. 26.2%; rate ratio, 0.82 [95% CI, 0.72–0.94]) and in
those who received invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio,
0.64 [95% CI, 0.51–0.81]) [8], and the WHO Rapid Evidence Appraisal for
COVID-19 Therapies (REACT) Working Group confirmed by prospective meta-
analysis of clinical trials that administering systemic corticosteroids to critically ill
patients with COVID-19 was associated with lower 28-day all-cause mortality as
compared with usual care or placebo [9]. Remdesivir, an antiviral drug, shortened
time to recovery (hospital discharge or no supplemental oxygen requirement) from
15 to 10 days [10], although a recent study from the WHO Solidarity trial consor-
tium indicated that remdesivir showed little or no beneficial effects for COVID-19
[11]. However, these drugs are not enough to completely rescue patients with severe
COVID-19.
Cell-based therapies, primarily using mesenchymal stem/stromal cells (MSCs),
for ARDS and COVID-19 have been reported to be safe and effective [12, 13]. In
12 Stem Cell Therapy and Regenerative Medicine for ARDS: Can Stem Cell Therapy… 161
this chapter, we mainly focus on current knowledge of the use of MSCs in the treat-
ment of ARDS, including COVID-19-induced ARDS.
2 A
lveolar and Airway Cell Lineages in Lung Repair
and Regeneration
The lung alveolus is composed of various cell types including multiple epithelial,
endothelial, and mesenchymal cells (Fig. 12.1) [14]. In addition to these structural
cells in the alveolus, various immune cells, including alveolar macrophages, inter-
stitial macrophages, dendritic cells, and lymphocytes, each contain distinct sub-
populations in the alveolus of mice and humans [15, 16]. These alveolar constituent
cells exhibit slow turnover under steady-state conditions. On the other hand, when
the lungs were injured, these cells were able to proliferate and self-renew. Alveolar
epithelial cells consist of two major lineages: alveolar epithelial type II (AT2) cells
and type I (AT1) cells. AT1 cells are thin squamous epithelial cells that cover more
than 95% of the alveolar surface and are indispensable for gas exchange in the
lungs. AT2 cells are cuboidal epithelial cells that produce surfactant proteins in the
lungs. In adult mice, AT2 cells act as a stem cell-like population by self-renewing
and regenerating AT1 cells after lung injury [17]. In addition, human AT2 cells form
self-renewing colonies in 3D culture, suggesting that human AT2 cells are also
long-term self-renewing stem cells [17].
The proximal airway cells are the body’s first line of defense in the lungs of mice
and humans against airborne particles such as germs and pollution, which can cause
illness. The proximal airway cells mainly consist of club cells (secretory cells), cili-
ated cells, goblet cells (mucus cells), neuroendocrine cells, and basal cells (Fig. 12.2)
[14]. Basal cells are a major stem cell population, which can differentiate into club
cells, ciliated cells, and goblet cells [14]. Basal cells in humans exist in distal inter-
mediate airways, while those in mice exist in proximal airways, the trachea and
proximal main bronchi, both of which closely resemble one another. Current knowl-
edge of airway regeneration has come from the study of the mouse trachea. In mice,
various types of progenitor cell populations, such as variant club/secretory cells
[18], bronchoalveolar stem cells (BASCs), and lineage-negative epithelial progeni-
tors (LNEPs), also referred to as distal airway stem cells (DASCs), play pivotal
roles in the regeneration of proximal airway cells after lung injury. BASCs co-
express the canonical club cell marker Scgb1a1 and AT2 cell marker Sftpc, and are
located in the murine bronchioalveolar duct junction (BADJ). Recent reports dem-
onstrated that BASCs can differentiate into club cells and AT2 cells in lung injury
mouse models induced by naphthalene (mainly airway epithelial injury), bleomy-
cin, and influenza virus infection [19, 20].
162 M. Ishii
a Intermediate airways Respiratory airways Alveoli

Human
b Intermediate airways Alveoli

Mouse
Secretory Variant secretory BASC Multi-cilliated Goblet Basal Low cuboidal

cell cell (mouse) (mouse) cell cell cell epithelium (human)
Scgb1a1 Scgb1a1+Cyp2f2- Scgb1a1+Sftpc Foxj1/TubbIV Muc5ac Trp63/Krt5
Mesenchymal Mesenchymal alveolar Axin2+ myogenic Alveolar Alveolar epithelial Alveolar

support cell niche cell precursor type 2 cell progenitor type 1 cell
Lgr6+/Axin2+ Axin2+/Pdgfra+/Lrp5+ Axin2+/Pdgfrb+ Sftpc/Abca3 Axin2/Tm4sf1 Ager
Fig. 12.1 Alveolar cell lineages involved in lung repair and regeneration (Copyright from Basil
MC et al. Cell Stem Cell 2020). (a) Various types of cells in human distal airways and alveoli.
Basal cells were found in human intermediate and respiratory airways. (b) Various types of cells in
mouse distal airways and alveoli. Mice do not have respiratory bronchioles that transition from the
intermediate airways but have pseudostratified intermediate airways. Basal cells were not found in
mouse distal airways. Bronchoalveolar stem cells (BASCs), which express both the secretory cell
marker Scgb1a1 and the AT2 marker Sftpc, are located in the bronchioalveolar duct junction
(BADJ). (c) Various types of cells were found in the distal airway and alveolus of the human (a)
and mouse (b) lung
3 Mesenchymal Stem/Stromal Cells
Mesenchymal stromal cells (MSCs) are heterogeneous, multipotent fibroblast-like

cells that can be isolated from various sources, including bone marrow, adipose,
skeletal muscle, heart, umbilical cord, lung, liver, and placental tissue [21].
Large airway, pseudostratified epithelium Small airway, columnar surface epithelium Alveoli
H2-K1high
Basel cell progenitors
Club cell
Bronchioalveolar
stem cell (BASC)
Submucosal gland Submucosal gland Variant club cell

myoepithelial cell
Luminal cell Multiciliated cell Neuroendocrine cell Ionocyte Tuft/brush cell
Fig. 12.2 Airway cell lineages involved in lung repair and regeneration (Copyright from Basil MC et al. Cell Stem Cell 2020). Submucosal glands exist in
pseudostratified large airways and trachea and consist of both myoepithelial cells and other luminal secretory lineages. Smaller airways of mouse lungs consist
of various luminal secretory epithelial lineages (e.g., club cells, neuroendocrine cells) and ciliated epithelial lineages (e.g., multiciliated cells). Bronchoalveolar
12 Stem Cell Therapy and Regenerative Medicine for ARDS: Can Stem Cell Therapy…
stem cells (BASCs) and H2-K1high secretory cell subtypes, located in the smaller airways, have been reported to produce alveolar epithelium after severe injury
163
164 M. Ishii
According to the International Society for Cellular Therapy, MSCs are defined as
follows: MSCs are plastic-adherent cells; express cell surface markers of CD105,
CD73, and CD90, and the absence of CD45, CD34, CD14, CD19, CD124, and
HLA-DR, and have the capacity to differentiate into osteoblasts, adipocytes, and
chondroblasts in vitro [22].
4 P
otential Mechanisms of Mesenchymal Stem Cell
Actions in ARDS
Cell-based therapy, especially stem cell therapy, is currently a promising therapeu-

tic option for refractory and incurable diseases. Among these, MSCs are the most
studied cells, which can regenerate injured tissue and play immunomodulatory and
anti-inflammatory roles; however, the detailed mechanism of their beneficial effects
during ARDS is not fully understood.
There are multiple mechanisms of the protective effects of MSCs in ARDS
through their secretion of soluble paracrine protein factors and extracellular vesicles
(EVs), and the transfer of mitochondria. MSCs promote the repair of pulmonary
endothelial and alveolar epithelial cells; possess immunomodulatory, anti-
inflammatory, anti-apoptotic, and anti-microbial properties; enhance alveolar fluid
clearance; and inhibit pulmonary fibrosis (Fig. 12.3) [23].
An example of the immunomodulatory and anti-inflammatory effects of MSCs
during inflammation, mediated by the innate immune system, shows that MSCs are
a promising therapeutic option for various non-infectious inflammatory lung dis-
eases such as chronic obstructive pulmonary disease, interstitial pulmonary fibrosis,
and bronchiolitis obliterans syndrome [24]. MSCs have been shown to attenuate
experimental sepsis through the production of prostaglandin E2 (PGE2), which acts
on macrophages that produce the anti-inflammatory molecule interleukin (IL)-10
[12]. MSCs also play protective roles in LPS-induced acute lung injury. In addition,
treatment with MSCs was shown to improve lung function in a human ex vivo-
perfused TLR4-mediated acute lung injury model [14]. MSCs were also shown to
improve survival during experimental pneumonia caused by Escherichia coli by
secreting anti-microbial molecules, such as lipocalin 2 [15] and LL-37 [16], and
were also shown to improve resistance to Klebsiella pneumoniae [17]. We reported
the anti-inflammatory roles of MSCs in mice intratracheally infected with
Streptococcus pneumonia [25]. These results indicate that MSCs represent a prom-
ising option for cell-mediated therapies to treat pulmonary inflammatory diseases,
including ARDS [18].
Alveolus
Paracrine
factors
EVs
Mitochonria
An
e
nc
Lipids
ti-in
Ca
ara
pill Neutrophils
flam
ary
cle
mRNA
Mi
MSCs
ma
id
cro
flu
tor
RN
lar
y
FGF-7
eo
MSCs Proteins
Pro-inflammatory
Alv
HGF
Angiopoeitin-1 IL-1
EVs Anti-inflammatotry IL1 Macrophages
Na+/K+-ATPase IL-1RN IL-6
PGE2 IL-8
IL-10 IFN-
Alv
Lymphocytes
Lipoxin A4 MIP-1
eol
IL-1
Re pithe
HGF
TSG+ MIP-2
ar
TGF 1
pai
KGF
EVs TNF- MSCs
e
TIMP-1
r
MSCs PGE2
Angiopoeitin-1
lial
En
IL-1RN HGF
ce
dot
Re
EVs
En
KGF
lls
hel
pai
do
MMP-8 LL-37 Apoptosis IGF

the
ial
Lipocalin-2 IL-10
and
lial
-Defensin-2 EVs
ce
Fib
Hepcidin
epi
lls
ros
KGF
the
Bacteria
is
lial
Phagocytosis
per
Apoptosis
me
abi
lity
Phagocytosis tic
to
pop
Bacteria ti-a
An An
tim
icro
bia
l
Fig. 12.3 The mechanisms of the protective effects of mesenchymal stem/stromal cells (MSCs)
therapy in ARDS (Copyright from Qin H et al. Protein Cell, 2020). There are multiple mechanisms
of the protective effects of MSCs in ARDS through their secretion of soluble paracrine protein
factors and extracellular vesicles (EVs) and the transfer of mitochondria. MSCs promote the repair
of pulmonary endothelial and alveolar epithelial cells and possess anti-inflammatory, anti-
apoptotic, and anti-microbial properties; enhance alveolar fluid clearance; and inhibit pulmonary
fibrosis
5 MSC Clinical Trials for ARDS and COVID-19
Several MSC clinical trials for ARDS and COVID-19 are ongoing or have been
completed. As of December 20, 2020, more than 70 studies that investigated the
effects of MSCs during ARDS and/or COVID-19 were registered at Clin.Trial.com
166 M. Ishii
(https://clinicaltrials.gov/ct2/home) and the Chinese Clinical Trial Registry (http://

www.chictr.org.cn/enindex.aspx). The START study (ClinicalTrials.gov Identifier:
NCT02097641), a prospective, double-blind, multicenter, randomized phase 2a
study, reported that intravenous administration of bone-marrow-derived MSCs
resulted in improved oxygenation, although there were no significant differences
between the two groups [26]. The post-thaw viability of cryopreserved MSCs may
have contributed to the modest improvement in treatment for ARDS [13, 26].
Another clinical study demonstrated that menstrual-blood-derived MSCs signifi-
cantly improved the survival rate of severe H7N9 influenza-induced ARDS with no
adverse events (ChiCTR-OCC-15006355) [27], suggesting that MSC-based therapy
could be a possible alternative for treating COVID-19.
6 Other Stem Cell Therapies
Recent evidence indicates that lung injury can induce proliferation of multiple alve-
olar cell types, leading to restoration of alveolar structure and function when repair
is effective [14], which suggests that sub-lineages of various lung epithelial cells
have the potential to self-renew and differentiate into more mature cells. For exam-
ple, the Wnt-responsive alveolar epithelial progenitor (AEP) lineage within the AT2
cell population acts as a major facultative progenitor cell in the distal lung [28].
AEPs expand rapidly to regenerate a large proportion of the alveolar epithelium
after acute lung injury. These results suggest that administration of exogenous lung
progenitor cells likely protects against lung injury.
In fact, treatment with epithelial stem/progenitor cells of mouse or human origin
has recently been reported to play protective roles in injured mouse lungs after intra-
tracheal or intravenous delivery [14]. For example, mouse and embryonic lung cells
play protective roles in naphthalene-injured and irradiated syngeneic mice [29].
3D-expanded multipotent Sox9+ mouse lung progenitors that were transplanted into
injured lungs (naphthalene-induced or bleomycin-induced lung injury) exhibited
cell differentiation into all major airway and alveolar lineages in vivo in a region-
appropriate fashion [30]. In addition, lung bud tip progenitor cells derived from
human pluripotent stem cells were engrafted in vivo in naphthalene-injured
lungs [31].
More recent reports demonstrated that both mouse and human AT2 cells, which
can self-renew and differentiate into AT1 cells, can be transplanted into precondi-
tioned mice or injured lungs; co-transplantation of lung and hematopoietic progeni-
tors in preconditioned mice resulted in lung regeneration in different lung cell
lineages [32]. Primary mouse AT2 cells were successfully transplanted into injured
lungs induced by infection with influenza virus or bleomycin [33]. As for ARDS,
several clinical trials of stem cell therapy for ARDS are ongoing: umbilical cord
lining stem cells (ULSCs) for patients with COVID-19 ARDS (NCT04494386),
human embryonic stem cells-derived M cells (CAStem) for severe COVID-19 asso-
ciated with or without ARDS (NCT04331613), and multipotent adult progenitor
cells (MultiStem) for COVID-19-associated ARDS (NCT04367077). Collectively,

the administration of lung progenitor cells has great potential for the protection and
recovery of injured lungs.
7 Conclusion
MSCs have been shown to possess immunomodulatory and regenerative properties

in pre-clinical animal models of ARDS induced by H5N1, H9N2, and H7N9 influ-
enza virus or bacterial pneumonia. MSC-based cell therapy is a promising strategy
for the treatment of ARDS. Some clinical studies have demonstrated that MSC
therapy for ARDS patients is safe and potentially effective. In addition, because of
the urgent need to develop a novel approach against COVID-19, many clinical stud-
ies are ongoing, and the results of early published preliminary studies are promis-
ing. Therefore, the author believes that stem cell therapy such as MSCs therapy and
regenerative medicine can contribute to the protection or recovery of the injured
lungs, although data from larger-scale, long-term, multicenter, and controlled trials
will be required to further explore the therapeutic effects of MSCs as well as the
safety of MSCs.
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Chapter 13
Imaging Technique for Ventilatory
Management of ARDS Patients: Novel
Monitoring Tool—Electrical Impedance
Tomography
Atsuko Shono and Toru Kotani
Abstract Because of the large heterogeneity in lung mechanics across the patient
with ARDS, uneven distribution can be exaggerated by positive pressure ventila-
tion. A modality that can offer dynamic image of ventilation may benefit for the
individualized lung protective management. Ideal imaging technique for ventilatory
management of ARDS patients is expected to be used at bedside repeatedly at any
time given during the clinical course. Electrical impedance tomography (EIT) is a
real-time, non-invasive monitoring tool that can visualize the distribution of ventila-
tion how the lungs are ventilated. The temporal and spatial distribution and time
delay during both inspiratory and expiratory phase are not only visually recognized,
but also quantified as clinically distinctive parameters by adding subsequent analy-
sis using recorded impedance data. In clinical practice aiming at homogenous ven-
tilation to prevent further lung injury, EIT can be used to evaluate the existing
pathological condition and the real-time response to therapeutic interventions, such
as change in ventilatory settings, prone positioning, and administration of muscle
relaxant, which helps clinicians choose appropriate strategies to fit individual
patient’s needs.
Keywords Acute respiratory distress syndrome · Ventilator-associated lung injury

Regional ventilation monitoring · Electrical impedance tomography
A. Shono · T. Kotani (*)

Department of Intensive Care Medicine, Showa University School of Medicine, Tokyo, Japan
e-mail: trkotani@med.showa-u.ac.jp
Ltd. 2022
https://doi.org/10.1007/978-981-16-8371-8_13
172 A. Shono and T. Kotani
1 Introduction
Mechanical ventilation can cause ventilator-induced lung injury (VILI) that induces
multiple organ dysfunctions, the major cause of death in ARDS. ARDS network
proved the decrease of mortality rate in ARDS when mechanical ventilation was
provided with a low tidal volume ventilation strategy limiting both tidal volume and
plateau pressure. However, the mortality still remains around 30–40% [1] that is
unacceptably high. A point-of-prevalence study, the LUNGSAFE study, disclosed
that 40% of patients did not receive lung protective ventilation. Delay of diagnosis
was one of the reasons for the lack of lung protection. However, it has been pointed
out that even if ARDS is correctly diagnosed and LTV is applied according to the
guidelines, it is not enough to improve the mortality. Terragni and colleagues
reported that low tidal volume ventilation could not completely prevent overdisten-
tion of the recruited area and inflammatory cytokines was produced in the airways
if a large collapse area was left. Limiting tidal volume is a global strategy so that it
is difficult to prevent regional inhomogeneity.
Several studies report that uneven intrapulmonary gas distribution is capable of
increasing regional stress and strain [2, 3]. Achieving even distribution of ventila-
tion plays a pivotal role in preventing VILI. Lung mechanics in ARDS vary from
case to case, so the settings of mechanical ventilation should be tailored to each
case. All factors for mechanical ventilation, such as pressure, flow rate, and inspira-
tion/expiration time, influence each other. In addition, the presence or absence of
spontaneous breathing brings a complex effect on ventilation distribution. Whether
the even distribution is achieved cannot be known without monitoring by some means.
There are various restrictions on the evaluation of ventilation distribution for
critically ill patients on mechanical ventilation, unlike regular tests. Transporting
with a ventilator is a big risk, especially if the hemodynamics are unstable. If the
ventilator is not mobile, and if the ventilator needs to be replaced for ventilation
distribution testing, disconnecting the circuit, even for a moment, will significantly
change the distribution. It is no longer the evaluation of the ventilation setting that
was used in the intensive care unit. After changing the ventilation settings, it is nec-
essary to check how those affect the ventilation distribution, so there is a need for a
means that can be tested several times a day. Taken together, ideal imaging tech-
nique for ventilatory management is expected to be used at bedside repeatedly at
any time given during the clinical course.
2 Imaging Techniques
2.1 I maging Modality for Evaluation of Lung Morphology

and Function
Ventilation assessment by computed tomography (CT) is well known. Using chest

CT, the images are taken at the end of inspiration and the end of exhalation during
mechanical ventilation and classified into the following four categories based on the
13 Imaging Technique for Ventilatory Management of ARDS Patients: Novel… 173
CT number; overdistended, normally ventilated, poorly ventilated, and non-

ventilated. By classifying the gas distribution in the lungs and calculating the volume
of each, it is possible to visually confirm the gas distribution due to ventilation.
However, this method involves serious problems and risks. First, we have to
transport the very sick patients to the radiology division. It is risky and the staff
should be well trained. Second, distribution of ventilation could change during
transportation. It is not guaranteed that the ventilation distribution in ICU is iden-
tical to that in CT room even if the ventilatory settings are completely identical.
Disconnection of the circuit for any reason causes a big change of the ventilation
distribution and functional residual capacity in ARDS lungs. Third, a risk of radi-
ation exposure is a serious problem. Forth, radiation exposure limits the frequent
and repetitive testing. It is impossible to take the patient to radiology area every
time after the vent settings are changed. Fifth, CT scan is a static approach. It is
difficult to observe the time course of the changes in gas distribution using
CT scan.
Positron emission tomography (PET) imaging is a non-invasive, quantitative
method to assess regional perfusion, shunt, aeration, ventilation, and gas trapping
in vivo [4]. It requires the tracer, such as 13N2, and this is the limitation of the use.
Recently lung ultrasound (LUS) is increasingly used to evaluate lung aeration
and consolidation [5]. However, LUS examination and correct interpretation of
findings are operator-dependent and this is the major limitation. Ultrasound window
is relatively narrow, and it is impossible to detect the specific lung slice simultane-
ously. Obesity and subcutaneous emphysema interfere propagation of ultrasound
beams from skin to lung.
Electrical impedance tomography (EIT) is a recently available monitoring tool
that can visualize the distribution of ventilation by measuring the regional increase
in impedance caused by inspired air [[6–8]. Biological tissue composing of human
body (e.g., lipids, water, electrolytes) has an individual resistance to an externally
applied alternating electric current, which are generally described as “bioimped-
ance” [6]. Air hold in the thorax acts as electrical resistors and inhaled air increases
regional impedance [7]. EIT monitors these impedance changes accompanied
with respiratory cycle in real time [8]. The change in impedance is measured by
applying a small alternating current through electrodes installed in a specific EIT
belt, which is normally placed at fifth to sixth intercostal level of the patient’s
thorax. The raw impedance data are reconstructed using an algorithm as the cross-
sectional image. The constructed sequential images are projected on the EIT
screen as a real-time dynamic image of ventilation. The EIT tidal image which
shows the distribution of the inspired air during one breath is also presented on the
screen (Fig. 13.1). This image consists of 32 × 32 pixels with color-scaled based
on the tidal impedance change (TIV) that is calculated by subtracting the maxi-
mum impedance value at the peak inspiration by the minimum value at the end of
expiration. Global TIV is the sum of impedance changes in all pixels across the
whole image. It has been demonstrated that global TIV correlates well with
tidal volume.
Region of interest: 4 layers
ventral 10%
mid-ventral 38%
ventral
mid-dorsal 40%
dorsal 12%
left
right
Region of interest: quadrants
right upper 25%
dorsal right lower 30%

left upper 22%
small large left lower 23%
impedance impedance
change change
Fig. 13.1 EIT tidal image. Left, typical EIT tidal image is shown. Regional distribution of tidal
breath is visualized with a color scale based on calculated impedance changes during one breath.
Brighter color (corresponding to large impedance change) shows a well-ventilated area. Darker
color (small impedance change) shows a less ventilated area. Right, the images when region of
interests are applied with horizontal layers (upper image) and quadrants (lower image). The distri-
bution at each region (regional TIV) is expressed as a percentage of global tidal impedance varia-
tion (TIV)
2.2 EIT: The Difference from Other Modalities
The real-time EIT image on the screen can be obtained non-invasively, which
enables to evaluate ongoing ventilation and contributes to the rapid decision-making
for the therapeutic management. EIT is a roll-around device and can be used repeat-
edly as a day-by-day monitoring tool. In the special circumstances when the risk of
infectious spread is anticipated, EIT may be invaluable because of no need for trans-
portation of the patients. Regarding the functional images, EIT can provide
“dynamic” information that track the temporal and spatial changes in distribution of
ventilation, which differentiates EIT from other monitoring tool. Static images at
certain time points taken by X-ray or CT can only warrant the morphological assess-
ment of lung aeration unless specific technological setup is used. The lung ultra-
sound can exhibit real-time, dynamic images of pleural movement related to
ventilation (lung sliding, lung pulse, etc.) and artifacts reflecting the morphologic
changes of aeration (B-line, consolidation, etc.), but not dynamics of gas distribu-
tion as EIT presents [9].
Another specific characteristic of EIT monitoring is that “regional” ventilation
occurring at any sites in the entire lung can be assessed. The monitoring of esopha-
geal pressure can be used for the calculation of transpulmonary pressure enabling
the evaluation for the stress applying to the lung in ARDS patients. However, it is
presented as one specific, absolute value despite the fact that it differs from each
region in the thoracic cavity [3]. EIT can delineate this regional impedance differ-
ence clearly by dividing the whole lung area to pre-defined lung “region of interest,”
such as dependent/non-dependent region, right/left region (Fig. 13.1). Regional
impedance changes, which correspond to tidal volume delivered to each lung region,
can be measured and utilized to calculate the regional lung compliance by dividing
regional impedance change by applied driving pressure. Bikker and colleagues cal-
culated regional compliance during an incremental/decremental PEEP trial and
found a different response in regional compliance between dorsal and ventral lung
regions, and between ARDS and non-ARDS patients [10]. In this way, EIT can
show the regional information reflecting lung mechanics in both healthy and
injured lungs.
In addition, EIT can even monitor the temporal and spatial behavior of gas dis-
tribution during both inspiratory and expiratory phase and comparison between
each region is possible by tracking the change in impedance values in pixels in each
region [11–13]. Furthermore, overall dispersion in spatial distribution and time
delay can be quantified as clinically distinctive parameters by adding subsequent
analysis using recorded impedance data. Those values, calculated from the func-
tional EIT image, are called EIT measures [14–16].
3 Roles of EIT in Clinical Practice
ARDS lungs have large regional mechanical heterogeneity and its pathophysiologic
changes differ among patients in clinical course. Therefore, individualized ventila-
tory management is demanded to achieve uniform ventilation in each ARDS patient
to prevent VILI. EIT can be used to evaluate ongoing ventilation at bedside which
promotes a better understanding of the existing pathological condition and track the
clinical trajectory of disease course. In addition, assessing the real-time response to
therapeutic interventions, such as change in ventilatory settings, prone positioning,
and administration of muscle relaxant, helps clinicians choose appropriate strate-
gies to fit individual patient’s needs. Though the contribution of using EIT in the
respiratory management to outcome of ARDS has not been proved yet, many stud-
ies have demonstrated its usefulness in clinical practice aiming at lung protective
strategy [17, 18]. The benefits in using EIT in clinical practice could be summarized
as following points: (1) repeated measurements and assessment at the bedside at any
given time during the clinical course are possible, (2) functional images can be pro-
filed as EIT measures to focus on the details of regional lung mechanics, and (3)
analyzed images can be shared with involved medical staff and by taking these
results into account together with other clinical information a personalized ventila-
tion strategy can be discussed.
3.1 E
valuation of Ventilatory Settings and the Effect
of Therapeutic Interventions
3.1.1 Ventilatory Settings in ARDS
The appropriate ventilator settings of driving pressures and PEEP levels that can
provide homogeneous ventilation are prerequisite for lung protective ventilation in
ARDS. PEEP defines lung volume and plays a role to stabilize the tendency to col-
lapse by lung edema during tidal ventilation [10, 14, 16]. However, the way to set
appropriate PEEP has not been standardized in ventilatory management yet. ARDS
network PEEP/FiO2 table suggests the combination of FiO2 and both lower and
higher PEEP settings so that physicians can select PEEP from wide range of PEEP
values [19]. However, inappropriate PEEP levels can cause not only lung collapse
when chosen too low, but also overdistention that induces local lung stress leading
to volutrauma when chosen too high [20]. The previous research has demonstrated
that EIT could be used to detect an optimal PEEP level by monitoring impedance
change during PEEP trial. By analyzing changes in impedance values EIT mea-
sures, which exhibit the direct physiological responses of the lungs to the applied
ventilatory settings, can be calculated by special formulas. ODCL (Overdistension
and atelectasis/collapse) is one of EIT measures that focus on the overall balance
between collapse and overdistention which could occur simultaneously in the entire
lungs [21]. It calculates overall decrease in regional compliance from its highest
values in each pixel during PEEP trial and exhibits how much the lungs are affected
by collapse and/or overdistention resulting in reduced regional compliance. By ana-
lyzing data the user can detect the most reasonable PEEP level at which lungs are
ventilated with minimum collapse and overdistention. It has been demonstrated that
optimized PEEP detected by ODCL differed greater than 4 cm H2O from physician-
selected PEEP in 26% of ARDS patients, showing a better lung compliance and
PaO2/FiO2-ratio in EIT-guided PEEP [18]. In addition, these EIT-guided PEEP dis-
agreed with PEEP selected according to the ARDS network table. It indicates that
ventilatory settings without reliable monitoring tool might cause inappropriate sup-
port neglecting lung mechanics, from which the patients might not benefit. EIT
based individual PEEP setting might be a reliable method to minimize inhomoge-
neous ventilation in ARDS patients.
3.1.2 Therapeutic Interventions: Prone Position
Besides changing ventilatory settings, rescue therapies, such as the use of specific
ventilatory modes, prone positioning, application of extracorporeal membrane
oxygenation (ECMO) must be taken into account when gas exchange cannot be
maintained within physiologically acceptable range. The purpose of employment
of these rescue therapies is the protection of injured lungs from the development of
VILI. Prone positioning has been proved as a therapeutic strategy that can improve
survival [22]. Most important role of prone positioning attributing to better
outcome is that it can provide homogeneous ventilation and reduce regional trans-
pulmonary pressure leading to lung protection [23]. Recently published experi-
mental research showed that prone position increased aeration and ventilation of
dorsal lung and homogenized regional lung strain in ARDS model [24]. EIT can
confirm these beneficial effects of prone position on aeration and ventilation in
ARDS patient (Fig. 13.2). By liberating the dependent lung area from the gravity,
lowered transpulmonary pressure might deliver the inspired gas more homoge-
neously, which contributes on the improvement in oxygenation. In other study in
which both ventilation and perfusion were monitored during prone position in
patients with COVID-19 pneumonia, ventilation/perfusion mismatch was reduced
by prone position [25].
3.1.3 Evaluation of Therapeutic Interventions: ECMO
When all other rescue therapies cannot keep the gas exchange within physiologi-
cally relevant range, venovenous-extracorporeal membrane oxygenation
(VV-ECMO) may be conducted in severe ARDS patients. One of the main goals of
VV-ECMO is to reduce the load on the injured lungs which could enhance the pre-
vention of VILI. Though applying a so-called ultra-protective ventilation strategy,
combining significant reductions of the tidal volume and intrathoracic pressures, is
recommended to minimize the dynamic strain, PEEP selection during VV-ECMO is
Ventral
Mid-ventral
Mid-dorsal Ventral Mid-ventral Mid-dorsal Dorsal
Dorsal
20 min after 60 min after 240 min after
Supine
prone position prone position prone position
Distribution of
ventilation (%)
Fig. 13.2 Change in ventilation distribution during prone position. The fraction of distribution of
ventilation is presented as percentage contribution of global impedance change (100%) in the
entire lung at each time point
not standardized and usually at the discretion of physicians. The recent research that
investigated the optimal PEEP levels by using EIT in patients on VV-ECMO has
been reported. Franchineau et al. performed decremental PEEP trial from at 20 cm
H2O to 5 cm H2O in 5 cm H2O steps with fixed driving pressure of 14 cm H2O for
15 patients on VV-ECMO [26]. They examined the optimal PEEP level using ODCL
that provided the best compromise between overdistention and collapse (defined as
the lowest PEEP level providing collapsed area of less than 15% with least overdis-
tention). They found optimal PEEP levels highly varied among the patients, 15 cm
H2O in seven patients, 10 cm H2O in six patients, 5 cm H2O in two patients, respec-
tively. It indicates that in condition of severe ARDS large heterogeneity exists across
the patients and accounts for the need for personalized titration for ventilatory set-
tings. However, the rationale for ventilatory settings in severe ARDS during
VV-ECMO is uncertain and it is still under debate whether it should be adjusted to
keep lungs open with minimum collapse or should not.
3.2 Monitoring of Assisted Ventilation

with Spontaneous Breathing
3.2.1 Assessment of Ventilation with Respiratory Effort
In spontaneous breath, the center of ventilation, which represents a vertical shift of

the ventilation distribution along a ventro-dorsal axis, normally positions in dorsal
half of the thorax due to the predominant distribution to the dorsal parts caused by
an active movement of the diaphragm. When the patients on mechanical ventilation
are supported by assisted modes, the intensity of ventilation could be determined by
the patient respiratory drive, which swings depending on the severity of the disease
and associated inflammation. In mild and moderate ARDS, preserving spontaneous
breath is recommended to avoid muscle atrophy of the diaphragm and prevent
delayed weaning process from ventilator. However, in severe ARDS, it has been
demonstrated that preserved spontaneous breath might inflict additional lung injury
due to a high imposed pressure caused by an excess respiratory effort. The transpul-
monary driving pressure which exhibits the intensity of the force on the lungs dur-
ing a tidal breath increases concomitantly with increased respiratory effort and
leads to unregulated high tidal volume. EIT can visualize abnormal respiratory pat-
tern when a strong spontaneous effort occurs during assisted ventilation [27]. In the
early phase of inspiration, the large amount of an inspired gas distributes to the
dorsal region predominantly due to the hyperactive movement of the diaphragm. As
a result, the dorsal region receives an unphysiological high tidal volume in every
respiratory cycle. In the experimental research [28] threefold increase in airway
driving pressures was required to achieve comparable tidal volume of dependent
lung regions when the injured lungs were passively ventilated, which led to a high
transpulmonary driving pressure of 25 cm H2O in the dorsal region.
In addition, it is reported that this strong respiratory effort accompanies temporal
discordance in distribution between non-dependent and dependent region, which is
referred as pendelluft [28]. The transient inflation in the dependent lung and transient
deflation in the non-dependent lung simultaneously occur at the early phase of inspira-
tion, shifting the air from one side to the other. In EIT monitoring, this temporal shift
in distribution could be recognized visually and identified in off-line analysis by track-
ing impedance change in each pixel in the corresponding region. In Fig. 13.3, EIT
shows the images of air distribution at each time point during tidal breath in patients
with severe ARDS. It is clearly demonstrated that at the beginning of inspiration only
the dependent region received air, afterwards the non-dependent region started to be
ventilated. When focusing on impedance change in pixel in a corresponding breath,
the difference in change in impedance value between the dependent region and non-
dependent region can be found, in which the impedance value in the pixel located in
the non-dependent area firstly decreased from the baseline impedance value.
3.2.2 Therapeutic Interventions: Muscle Relaxant
Once strong respiratory effort is recognized, administration of muscle relaxant is

recommended to terminate the vicious respiratory cycles contributing to inhomoge-
neous ventilation. The use of muscle relaxant in severe ARDS has been reported to
a start of the end of the

impedance inspiration inspiration
change large
small
b c Impedance waveform
Ventral
ː
fraction of regional TIV (%)
Dorsal
start of the end of the ː

inspiration inspiration
Fig. 13.3 EIT images during one breath, change in impedance in the dependent and non-dependent
regions in patients with high respiratory drive. (a) EIT dynamic images from at the beginning of
inspiration to the end of inspiration. (b) The fraction of regional tidal impedance variation (%)
changes in the dependent (red line) and non-dependent regions (blue line) from at the beginning of
inspiration to the end of inspiration. The graph shows the predominant distribution of inspired gas
to the dependent part during an almost entire inspiratory phase. (c) EIT tidal images and imped-
ance waveforms representing the change in impedance value during a tidal breath at different
region. Red lines represent impedance changes in the pixel marked with red asterisk in the non-
dependent (upper panel) and dependent region (lower panel). Black dashed lines represent global
impedance change in the entire lung
reduce mortality when given within 48 h from the occurrence of ARDS [29]. The
even distribution temporally and quantitatively can be achieved by use of muscle
relaxant, which is captured by continuous EIT monitoring before and after adminis-
tration. Figure 13.4 shows the EIT images and impedance waveform before and
after muscle relaxant in severe ARDS patient with high respiratory drive reaching
transpulmonary driving pressure of 35 cm H2O [28]. The fraction of regional venti-
lation before administration of muscle relaxant was 25% and 75% in the non-
dependent and the dependent regions, respectively. After administration of muscle
relaxant, tidal volume was regulated and transpulmonary driving pressure decreased
to 19 cm H2O. Consequently, the fraction of distribution of tidal breath was homog-
enized to 43% and 57% in the non-dependent and the dependent regions, respec-
tively. In this way, EIT can track the course of therapeutic intervention, allowing us
to judge whether the decision on use of muscle relaxant deserves to make or not in
ARDS patients with hyperactive respiratory drive.
3.3 EIT-Guided Respiratory Management
Clinical studies have been enthusiastically conducted to confirm validity and utility
of EIT for clinical use. EIT-guided PEEP selection was frequently evaluated in pre-
vious research in comparison with methods of selecting PEEP using other parame-
ters such as dead space, static compliance, and transpulmonary pressure. However,
Impedance value
(au)
(time)
Before muscle relaxant After muscle relaxant

(tidal volume 900ml) (tidal volume 430ml)
25% 43%
75% 57%
Fig. 13.4 Impedance waveform and EIT tidal images before and after administration of muscle
relaxant. The fraction of regional tidal impedance variation was 25% and 75% in the non-dependent
and the dependent regions, respectively, before administration of rocuronium. It changed to 43%
and 57% after administration of rocuronium
there are few prospective studies that tested contribution of use of EIT on patient
outcome. In an animal model of ARDS, Wolf et al. induced lung injury in pigs by
saline lavage and investigated the respiratory mechanics, gas exchange, interleukin-
8 level, and histopathologic change in two groups, one was ventilated with EIT-
guided ventilatory settings and the other was ventilated using ARDSnet guidelines
[30]. The results showed that respiratory mechanics and gas exchange improved in
the EIT-guided group. In addition, the presence of hyaline membranes and airway
fibrin was significantly reduced in the EIT-guided group, which indicated reduced
histologic evidence of VILI. Another prospective study conducted in clinical prac-
tice was recently reported [31]. In this research including severe ARDS (arterial
oxygen partial pressure to fractional inspired oxygen ratio, PaO2/FiO2 < 100 mmHg),
24 patients were set optimal PEEP based on ODCL (EIT group) prospectively and
31 patients were set according to the pressure–volume curve (control group) retro-
spectively. It was shown that not only higher compliance and lower driving pres-
sure, but also reduced hospital survival rate and higher weaning success rate were
found in the EIT group compared to control group.
4 Conclusions
A real-time imaging technique monitoring ventilation is demanded in clinical prac-

tice to assess the ventilatory settings and therapeutic intervention for respiratory
management in ARDS. EIT can meet this demand as it can provide regional infor-
mation dynamically that other imaging techniques cannot. However, further clinical
studies are warranted to evaluate whether EIT monitoring can shorten the duration
of ventilation or improve mortality in patients with ARDS.
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Acute Respiratory Distress Syndrome 2022

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Respiratory Disease Series:

Diagnostic Tools and Disease Managements

Sadatomo Tasaka Editor

More information about this series at https://link.springer.com/bookseries/15152

Acute Respiratory Distress

ISSN 2509-5552 ISSN 2509-5560 (electronic)

associated with poor prognosis. In ARDS patients, serum or plasma biomarkers

Hirosaki, Japan Sadatomo Tasaka

Part I Definition, Epidemiology, and Pathophysiology

8 Fluid and Nutritional Management of ARDS: What Is the Ideal

Part IV Current Topics

Keywords Berlin definition · AECC definition · Clinical criteria

© The Author(s), under exclusive license to Springer Nature Singapore Pte 3

3.1 First Report of ARDS by Ashbaugh and Colleagues

Ashbaugh and colleagues described 12 patients with refractory respiratory distress

Table 1.1 Clinical It occurs from an unrelated variety of direct and

3.2 Murray’s Definition with Lung Injury Score

In 1988, Murray and colleagues reported their definition of ARDS incorporating

Table 1.2 Expanded Acute or Chronic, depending on the course mild to

4.1 AECC Definition

Table 1.3 AECC definition [12]

mild moderate severe Berlin

Table 1.4 Clinical Direct injury Indirect injury

4.2 Limitation of AECC Definition

4.3 DELPHI Definition

The Delphi technique is a group interaction method of gaining consensus on a par-

5.1 Berlin Definition; Draft Definition

Table 1.6 Berlin definition [24]

Table 1.7 Common risk Risk factors

5.3 Berlin Definition; Limitation of the Berlin Definition

5.4 Future Perspective

In general, a precise and appropriate definition is absolutely necessary to facilitate

In this chapter, the definition of ARDS was historically summarized. It is important

ARDS. Therefore, it has to be defined by a constellation of clinical and physiologi-

15. De Hemptinne Q, Remmelink M, Brimioulle S, Salmon I, Vincent JL. ARDS: a clinicopatho-

Keywords Multi-hit theory · Injurious ventilation · Transfusion-related acute lung

© The Author(s), under exclusive license to Springer Nature Singapore Pte 19

2.1 Incidence of ARDS

2.2 Clinical Risk Factors

2.3 Comorbidities and Susceptibility to ARDS

2.4 Hospital-Based Modifiable Exposures and ARDS

In addition to transfusion, the following are also independent risk factors of

2.5 Interaction of Factors as Risk Enhancement

Notably, some factors may serve as an amplifying factor in the presence of other

3.1 Mortality Related to Severity of ARDS

3.2 Mortality Related to the Cause of Lung Injury

The committee of the latest definition of ARDS, the Berlin definition, decided not

3.3 Ventilatory Strategy and Mortality

It is well known that low tidal volume ventilation as compared with conventional

3.4 Trends in Mortality

Even before the low tidal-volume ventilation strategy era, a number of single-center

3.5 Mortality Related to Organizational Factors

Raymondos et al. investigated differences in treatment and outcome of ventilated

3.6 Mortality Related to Unmodifiable Factors

3.7 Genetic Factors and ARDS

3.8 Outcomes Other than Mortality

Mortality is the essential endpoint in studies to measure the outcome of ARDS. Many

3.9 Quality of Life After ARDS

Abstract ARDS is a non-cardiogenic pulmonary edema caused by increased per-

Keywords Innate immunity · Intrapulmonary shunt · Neutrophils · Permeability

© The Author(s), under exclusive license to Springer Nature Singapore Pte 33

The acute respiratory distress syndrome (ARDS) represents a spectrum of respira-

Pathogen PAMPS PRR APC T cell

Hirosaki, Japan Sadatomo Tasaka

Part I Definition, Epidemiology, and Pathophysiology

8 Fluid and Nutritional Management of ARDS: What Is the Ideal

Part IV Current Topics

3.1 First Report of ARDS by Ashbaugh and Colleagues

3.2 Murray’s Definition with Lung Injury Score

4.1 AECC Definition

4.2 Limitation of AECC Definition

4.3 DELPHI Definition

5.1 Berlin Definition; Draft Definition

5.3 Berlin Definition; Limitation of the Berlin Definition

5.4 Future Perspective

2.1 Incidence of ARDS

2.2 Clinical Risk Factors

2.3 Comorbidities and Susceptibility to ARDS

2.4 Hospital-Based Modifiable Exposures and ARDS

2.5 Interaction of Factors as Risk Enhancement

3.1 Mortality Related to Severity of ARDS

3.2 Mortality Related to the Cause of Lung Injury

3.3 Ventilatory Strategy and Mortality

3.4 Trends in Mortality

3.5 Mortality Related to Organizational Factors

3.6 Mortality Related to Unmodifiable Factors

3.7 Genetic Factors and ARDS

3.8 Outcomes Other than Mortality

3.9 Quality of Life After ARDS

4 Cellular and Molecular Pathogenesis

4.1 Accumulation of Neutrophils in the Lungs

4.2 Neutrophil-Derived Substances

4.2.1 Reactive Oxygen Species

4.2.2 Proteolytic Enzymes

4.2.3 Neutrophil Extracellular Traps

4.3 I mpairment of Endothelial and Epithelial

5 Development of Permeability Edema

6 Changes in the Pulmonary Circulation During ARDS

6.1 Hypoxic Pulmonary Vasoconstriction

6.2 Increased Pulmonary Vascular Tone

6.3 Coagulation Abnormality

7.1 Intrapulmonary Shunt

7.2 Changes in Ventilation Mechanics

7.2.1 Decreased Lung Compliance (Hardening of the Lungs)

7.2.2 Increased Respiratory Resistance

7.3 Impaired Diffusing Capacity

7.4 Ventilation-Perfusion Mismatch

7.5 Elevated Pulmonary Vascular Resistance

7.6 Pulmonary Surfactant Dysfunction

7.6.1 Pulmonary Surfactant Dysfunction During ARDS

7.6.2 Influence of Respiratory Management on Pulmonary Surfactant

8 Assessment of Respiratory Function of ARDS Patients

8.1 Practical Assessment of Respiratory Function

8.2 Exhaled Gas Analysis

2 Serum Biomarkers Associated with Prognosis in ARDS

2.1 Biomarkers Associated with Coagulation and Fibrinolysis

2.2 Biomarkers Associated with the Inflammatory Cascade

2.3 Biomarkers Associated with Endothelium Damage