Acute Respiratory Distress Syndrome- Etiology, Pathogenesis, and Summary on Management

Analytic Review
Acute Respiratory Distress Syndrome:
Etiology, Pathogenesis, and Summary
on Management
Journal of Intensive Care Medicine
1-15
ª The Author(s) 2019
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DOI: 10.1177/0885066619855021
journals.sagepub.com/home/jic
Shawn Kaku, MD1,*, Christopher D. Nguyen, MD2,*,
Natalie N. Htet, MD, MS1,* , Dominic Tutera, MD2, Juliana Barr, MD1,3,
Harman S. Paintal, MBBS2,3, and Ware G. Kuschner, MD2,3
Abstract
The acute respiratory distress syndrome (ARDS) has multiple causes and is characterized by acute lung inflammation and
increased pulmonary vascular permeability, leading to hypoxemic respiratory failure and bilateral pulmonary radiographic opacities. The acute respiratory distress syndrome is associated with substantial morbidity and mortality, and effective treatment
strategies are limited. This review presents the current state of the literature regarding the etiology, pathogenesis, and management strategies for ARDS.
Keywords
acute respiratory distress syndrome, sepsis, aspiration, mechanical ventilation, critical care medicine
Introduction
Acute respiratory distress syndrome (ARDS) was first
described by Ashbaugh et al in the 1960s as the development of acute hypoxic respiratory failure in adults associated with a variety of etiologies (eg, infection, trauma,
pancreatitis), leading to pulmonary inflammation and the
development of nonhydrostatic pulmonary edema in
patients.1 Worldwide estimates of the incidence of ARDS
range from 7.2 to 34 cases per 100 000 person-years.2-4
Historically, the ARDS case fatality rate was reported to
be around 60%.5-7 Over the past 2 decades, there has been
a progressive improvement in survival from ARDS, with
current mortality rates ranging between 26% and 35%.5-7
This improved survival is attributable to both advances in
general critical care management and in the specific management of patients with ARDS, especially the use of low
tidal volume mechanical ventilation. Nevertheless, ARDS
remains a lethal disease, resulting in nearly 75 000 deaths
annually in the United States.7 Worldwide, ARDS affects
nearly 3 million people annually and accounts for 10% of
all intensive care unit (ICU) admissions and 23% of ICU
patients requiring mechanical ventilation.8
The clinical definition of ARDS was first made in 1994
by the American-European Consensus Conference (AECC),9
and replaced in 2012 by the Berlin definition.10,11 The
AECC defined the criteria for ARDS and acute lung injury
(ALI), with ARDS being a more severe hypoxic subset of
ALI.9 The Berlin definition for ARDS removes the category
of ALI, and instead categorizes ARDS as mild (200 mm Hg
<PaO2/FiO2 300 mm Hg), moderate (100 mm Hg <PaO2/
FiO2 200 mm Hg), and severe (PaO2 /FiO 2 100 mm
Hg).11 The Berlin definition retains the general case definition criteria about the disease being acute in onset (1 week
or less), with diffuse bilateral opacities on chest radiographs, which are not attributed to congestive heart failure
or intravascular (IV) volume overload. Additionally, the
patient should be receiving a minimum positive endexpiratory pressure (PEEP) of 5 cm H2O, which can be
delivered either invasively or noninvasively, depending on
the severity of disease. The Berlin definition has significantly greater predictive validity for mortality from ARDS
than the AECC definition.
1
Department of Anesthesiology, Perioperative, and Pain Medicine, Stanford
University School of Medicine, Stanford, CA, USA
2
Division of Pulmonary and Critical Care Medicine, Department of Medicine,
Stanford University School of Medicine, Stanford, CA, USA
3
Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA
*Authors have contributed equally
Received August 30, 2018. Received revised May 13, 2019. Accepted May
15, 2019.
Corresponding Author:
Natalie N. Htet, Washington Hospital, 2000 Mowry Ave, Fremont, CA 94538,
USA.
Email: [email protected]
2
Pathophysiology of ARDS
The acute respiratory distress syndrome is characterized by
diffuse alveolar damage (DAD) and increased capillary
permeability.12,13 Both the capillary endothelial and alveolar
epithelial surfaces are affected, with disruption of the
alveolar-capillary membrane. This is followed by the leakage
of protein-rich fluid, the recruitment of neutrophils and
macrophages into the alveolar space, and hyaline membrane
formation.13-16 Further damage to the lung and propagation of
inflammation occurs as a result of cytokine activation and the
release of pro-inflammatory mediators such as tumor necrosis
factor and interleukins IL-1 and IL-6.12,17 Activated neutrophils release toxic mediators causing oxidative cell damage.17
Damage to the alveolar-capillary membrane results in the
accumulation of protein-rich fluid in the pulmonary parenchymal interstitium, inactivation of surfactant, atelectasis, and
impaired gas exchange.13,17 Clinically, this early or exudative
phase of ARDS is characterized by marked hypoxemia and
decreased lung compliance.3 This acute phase may resolve
completely, or it may progress to the fibroproliferative phase
with persistent hypoxemia, increased dead space, further loss
of lung compliance, lung fibrosis, and neovascularization of
the lung.17
The diagnostic criteria for ARDS do not include the histopathological diagnosis of DAD, and the correlation between the
clinical diagnosis of ARDS and pathologic findings of DAD
varies. Studies comparing postmortem or open-lung biopsy
evidence of DAD with clinical criteria for ARDS show only
a 50% to 88% correlation using the AECC definition,18-21 and
only a 45% to 56% correlation using the Berlin definition.22
Clinicians should be mindful of the poor concordance between
ARDS diagnosed by clinical criteria and the finding of DAD on
lung biopsy or autopsy; however, the clinical significance of
this observation will, in most practice settings, be limited.23
Etiology and Risk Factors
Of the more than 50 disorders associated with the development
of ARDS, sepsis, pneumonia, aspiration, trauma, and multiple
blood transfusions are responsible for the majority of cases.24,25
Nearly 20% of ARDS cases have no clear risk factors.26
Although there may be a genetic predisposition to the development and severity of ARDS, a genetic link has not been
clearly established.27-30
The most common etiology of ARDS is sepsis, accounting
for approximately 40% of cases.24,25 Approximately 6% to 7%
of patients with sepsis develop ARDS with lower rates
observed among patients with nonpulmonary causes and milder
forms of sepsis and higher rates and worse outcomes reported
among patients with septic shock.31-34 A pulmonary source of
sepsis appears to carry a higher risk of ARDS, resulting from
both direct (ie, local inflammation) and indirect (ie, systemic
inflammatory response) sources of ALI.7,35,36
Pneumonia is also a common cause of ARDS, especially in
hospitalized pneumonia patients with culture-positive
Journal of Intensive Care Medicine XX(X)
microbiologic diagnosis.37 Gram-positive and Gram-negative
bacteria have similar rates of ARDS.37 Although viral and
fungal pathogens are less frequent causes of pneumonia, these
pathogens are associated with a higher risk of ARDS than
bacterial pneumonia; this is especially true for Pneumocystis
jiroveci and Blastomyces.37
Aspiration of gastric contents is an important cause of
ARDS, accounting for up to 30% of cases in some studies.25,38
Aspiration leads to ARDS in patients more frequently and is
more severe than ARDS due to other causes, with higher mortality rates (ie, 3-fold higher).38 Risk factors for developing
ARDS following aspiration include male gender, a history of
alcohol abuse, a lower Glasgow Coma Scale, and admission
from a nursing home.38
Up to 25% of ARDS cases result from severe trauma.24 The
incidence of ARDS in trauma patients admitted to an ICU is
approximately 12%.39 Although ARDS in trauma patients is
associated with longer ICU stays, it does not predict a higher
mortality rate in these patients.39 After adjusting for age, severity of illness, and comorbid conditions, patients with traumaassociated ARDS have higher survival rates compared to
ARDS cases due to other causes.39 In the ARDS Network
study, trauma patients with ARDS had lower risk-adjusted odds
of death at 90 days (odds ratio [OR], 0.44; 95% confidence
interval [CI], 0.24-0.82; P ¼ .01), compared to patients with
ARDS due to other causes.40 This outcome difference may be
explained, in part, by less severe lung epithelial and endothelial
injury in trauma-related ARDS.40,41
Multiple blood transfusions account for 25% to 40% of
ARDS cases. 24-26 Transfusion-related acute lung injury
(TRALI) is defined as ALI that develops within 6 hours after
a completed infusion of 1 or more plasma-containing or
plasma-derived blood products.42 Initial studies evaluating
transfusions showed that massive transfusion of more than 22
units of blood in 12 hours and more than 15 units of blood in
24 hours was a significant risk factor for subsequent development
of ARDS.24-26 Transfusion of packed red blood cells (PRBCs) in
critically ill patients is independently associated with the development of ARDS in a dose–response relationship.43 The acute
respiratory distress syndrome is more likely to develop in
patients who received fresh-frozen plasma and platelet transfusions than in those who receive only PRBC transfusions.44
ARDS Scoring Systems
In 2011, the US Critical Illness and Injury Trials Group created
and validated a risk model, the Lung Injury Prediction Score
(LIPS), to identify patients at high risk for developing ALI and
ARDS prior to the onset of injury.32 This model was validated
in a prospective, multicenter, observational cohort study of
5584 patients with 1 or more ALI/ARDS risk factors, of whom
377 (6.8%) developed ALI/ARDS. These patients were evaluated during the first 6 hours after initial emergency department
evaluation, or preoperatively at the time of hospital admission
for high-risk elective surgery. The goal was to identify those
patients at high risk for ALI/ARDS who were early in their
Kaku et al
course of illness and prior to ICU admission. By identifying
these patients as early as possible, clinical interventions, strategies, and modifications of care could be implemented to prevent patients from subsequently developing ALI/ARDS. At a
cutoff LIPS score of >4, considered the optimal cutoff point by
area under the curve analysis, the negative and positive predictive values for developing ALI/ARDS were 0.97 and 0.18,
and the sensitivity and specificity were 69% and 78%, respectively. In practice, LIPS may be a useful tool for identifying
patients at low risk for developing ALI/ARDS (ie, those
patients with an LIPS score less than or equal to 4). But the
low positive predictive value and the complexity of the LIPS
worksheet limit its utility.
Levitt and colleagues conducted a prospective cohort study
to identify variables that would predict progression to positive
pressure ventilation in patients with radiographic evidence of
ALI (ie, bilateral lung opacities for <7 days) without isolated
left atrial hypertension.45 Tachypnea, immune suppression, and
increasing oxygen requirements were found to independently
predict progression to ALI/ARDS and were used to create an
early acute lung injury (EALI) score. The 3-component EALI
score (ie, 1 point for an O2 requirement of 2-6 L/min or 2 points
for >6 L/min, and 1 point each for a respiratory rate 30 and
immune suppression) accurately identified patients who progressed to ALI requiring positive pressure ventilation. An
EALI score of 2 identifies patients with mild ARDS who will
require positive pressure ventilation with an 89% sensitivity
and a 75% specificity. Median time to requiring positive pressure ventilation was 20 hours. The positive and negative predictive values of the EALI score were 53% and 95%,
respectively. The EALI score may be a useful triage tool to
identify those patients at risk of developing ARDS and requiring mechanical ventilation, although it has yet to be validated
in an external cohort of patients.
Diagnostic Biomarkers for ARDS
Given the limitations of ARDS diagnostic criteria and predictive scoring systems, there is a growing interest in ARDS biomarkers. Exhaled biomarkers of ARDS are particularly
attractive because they may reflect events occurring in the lung
with greater fidelity than circulating biomarkers. Investigated
breath biomarkers include volatile organic compounds, cytokines, hydrogen peroxide, nitric oxide, acidity, lipid peroxidation byproducts, and cytokeratins.46 However, none of these
markers is yet ready for clinical use.
Other ARDS biomarkers from bronchial alveolar lavage
specimens and serum have been studied. Bronchial alveolar
lavage concentrations of IL-8 in high-risk patients are significantly higher in patients who subsequently go on to develop
ARDS.47 Villar and colleagues found that a higher level of
serum lipopolysaccharide-binding protein in patients with sepsis was associated with the development of sepsis-induced
ARDS and predicted a worse clinical outcome.48 Elevated levels of serum angiopoietin-2 have been shown to be associated
with increased development of ALI in critically ill patients.49
3
A recent systematic review and meta-analysis identified 20
viable serum biomarkers used for the diagnosis of ARDS in
high-risk populations.50
The limitation of biomarkers is that no single biomarker can
adequately predict the progression to or outcome of ARDS in
patients. Recent studies have demonstrated the usefulness of
combining multiple biomarkers with clinical data, such as the
Acute Physiology, Age, Chronic Health Evaluation
(APACHE)-III scoring system, to improve risk prediction.51,52
The future of ARDS biomarkers may be in their utility to
improve predictive scoring systems rather than as isolated diagnostic tests.
Prevention and Management of ARDS
The lung injury that characterizes ARDS can be viewed as a
maladaptive response to an initial insult, such as sepsis, pneumonia, or aspiration. But only a subset of these patients will go
on to develop ARDS. This has led to a growing interest in
identifying early pathophysiologic events that lead to ARDS
and effective interventions that will abort that injurious
response. The acute respiratory distress syndrome prevention
strategies that have been tested in high-risk patients include
early goal-directed therapy in sepsis, IV fluid management,
blood transfusion strategies, lung-protective ventilation (LPV)
strategies, and nutritional management.
Sepsis Management
Sepsis accounts for nearly 40% of all cases of ARDS. Although
there is no specific modality to prevent the development of
ARDS in patients with sepsis, delaying treatment in sepsis
increases the risk of ARDS.53 In particular, delayed goaldirected resuscitation and the delayed administration of appropriate antibiotics increase the odds of patients with sepsis
developing ARDS by 3.6- and 2.4-fold, respectively. Early
identification and treatment of sepsis can reduce the risk of
ARDS in patients.
Fluid Management
A hallmark of ARDS is increased capillary permeability, capillary fluid leakage, and an increase in extravascular lung water.
It would seem reasonable that a conservative IV fluid management strategy may prevent ARDS in high-risk patients. Jia and
colleagues demonstrated that a high net positive fluid balance
in patients who were mechanically ventilated for more than
48 hours was associated with an OR of 1.3 for the development
of ARDS, suggesting a role for conservative fluid management
in the prevention of ARDS.54 Perioperative studies of patients
undergoing major surgery have also shown that positive fluid
balance is an independent risk factor for the development of
ARDS. In open thoracotomy patients, a positive fluid balance
on postoperative day 1 was associated with increased risk of
patients developing ARDS.55 A recent meta-analysis of thoracic surgery patients undergoing lung resection demonstrated
4
that a liberal perioperative fluid management strategy, which
amounted to an average of 2.6 mL/kg/h during and for the first
24 hours after the operations, was associated with a higher
incidence of postoperative ARDS.56 In surgical ICU patients
with hypoxemic respiratory failure requiring mechanical ventilation postoperatively, patients who received >20 mL/kg/h of
IV fluids intraoperatively had almost a 4-fold increased risk of
developing ARDS than those who received <10 mL/kg/h.57
While definitive data are lacking for the optimal fluid strategy
to prevent ARDS, avoidance of excessive IV fluids may be
considered as a reasonable strategy to mitigate the risk of
ARDS in high-risk patients.
In patients who have already developed ARDS, the Fluids
and Catheters Treatment Trial (FACTT) showed that a conservative IV fluid management strategy shortens the duration of
mechanical ventilation and ICU length of stay (LoS), and
improves oxygenation in these patients.58 In this study, patients
with ARDS in the conservative IV fluids group were given IV
fluids to maintain lower central venous pressures and pulmonary capillary wedge pressures than in the liberal IV fluids
group. In a secondary analysis of the ARDSNet Trial data,
cumulative negative IV fluid balance on day 4 of the study was
associated with an independently lower hospital mortality (OR,
0.50; 95% CI, 0.28-0.89; P < .001) and more ventilator and
intensive care unit-free days in patients with ARDS.59 Thus,
limiting IV fluid intake and achieving controlled diuresis may
lead to beneficial outcomes in patients with ARDS.60
Blood Transfusion Management
The dose–response relationship between the amount of blood
products transfused in patients and their risk of developing
ARDS suggests that restrictive transfusion policies may reduce
the incidence of ARDS in these patients.43,44,61 In a large randomized trial conducted by the Canadian Critical Care Trials
Group, a restrictive strategy for red blood cell (RBC) transfusions (target hemoglobin ¼ 7-9 g/dL), was associated with a
lower incidence of ARDS compared with a liberal transfusion
strategy (target hemoglobin ¼ 10-12 g/dL; ie, 7.7% vs
11.4%).62 Extra caution should also be used with the transfusion of platelets and fresh-frozen plasma, as these blood products are associated with a higher risk of ARDS than with RBC
transfusions.44 Even in modern combat care, once the hemorrhaging is controlled, a more conservative transfusion strategy
for blood products has been advocated in order to decrease the
risk of ARDS in these patients.63
Granulocyte or HLA-specific antibodies from donor blood
may also play a role in the pathogenesis of transfusion-related
ARDS, through complement activation and subsequent pulmonary injury.64,65 Universal screening of donors for specific
antibodies has been theorized as a potential way to help
decrease the incidence of TRALI.66 But the exact cutoff for
antibody levels and the cost-benefits of routine antibody testing
in blood donors have not been established.66 The association
between multiparity and the formation of human leukocyte
antigen (HLA) antibodies in women has also raised concerns
Journal of Intensive Care Medicine XX(X)
about the safety of blood from female donors. Several studies
have shown an increased risk of TRALI and worse clinical
outcomes in patients receiving whole blood or plasma transfusions from female donors.67,68 To reduce the risk of TRALI, the
American Association of Blood Banks recommends that high
plasma volume blood components (ie, plasma, platelets, or
whole blood) shall be obtained either from males, females who
have never been pregnant, or females who have tested negative
for HLA antibodies.66,69 Similar recommendations have been
established internationally, resulting in a two-thirds reduction
in the number of TRALI cases reported.70
There is some evidence to suggest an association between
blood storage time and the risk of TRALI. As stored PRBCs
age, activation of neutrophil toxic metabolites occurs, which
was thought to contribute to the development of TRALI,
thereby raising concerns about the safety of older blood products.71 An in vivo bovine model also raised this concern.72 But
multiple studies of blood transfusions in humans have not
shown an association between the transfusion of older blood
products and TRALI.67,68,73-75 Currently, there are not enough
data to advocate for the use of newer blood products in highrisk patients.
Mechanical Ventilation Management
Lung-protective ventilation strategies represent the greatest
advancement in the management of ARDS over the past
50 years. Strategies to reduce volutrauma and atelectrauma with
the use of low tidal volumes, low inspiratory and plateau pressures, and prone positioning have been shown to improve outcomes in patients with ARDS and are strongly recommended by
the major critical care societies in their most recent ARDS
guidelines.76-78 These guidelines recommend that LPV strategies be used for all patients with ARDS, defined as targeting:
(1) a tidal volume of 4 to 8 mL/kg (based on predicted body
weight) and (2) a plateau pressure of <30 cm H2O, using lower
inspiratory pressures. The guidelines do not recommend the routine use of high-frequency oscillatory ventilation (HFOV) in
patients with ARDS. 77 The OSCILLATE trial found an
increased 28-day mortality risk with HFOV (relative risk,
1.41; 95% CI, 1.12-1.79),79 and other pragmatic HFOV trials
have found no benefit in patients with ARDS.80,81 Additional
studies are needed to determine the safety and efficacy of using
extracorporeal membrane oxygenation (ECMO) in patients with
severe ARDS.77 In a recent randomized controlled trial, patients
with severe ARDS (PaO2/FiO2< 80 mm Hg for more than 6
hours) who received an immediate veno-venous ECMO did not
have a significant change in mortality compared to those who
received conventional mechanical ventilation (35% vs 46%).82
However, 28% of patients who received conventional mechanical ventilation crossed over to ECMO, making it difficult to
draw conclusions regarding the utility of ECMO in ARDS.
These guidelines also made 2 conditional recommendations
for using higher PEEP and recruitment maneuvers in patients
with moderate-to-severe ARDS.77 These recommended treatment strategies were based on the notion that high PEEP and
Kaku et al
recruitment maneuvers may be effective in opening collapsed
alveoli and improving lung compliance and gas exchange. But
a recent large randomized trial found that a strategy of recruitment maneuvers with higher PEEP titration (vs standard, lower
PEEP care) in patients with ARDS resulted in an increased
28-day mortality in these patients (hazard ratio 1.20; 95% CI,
1.01-1.42).83 In an analysis of 3562 patients with ARDS from 9
previous trials, decreases in driving pressure, calculated as tidal
volume divided by respiratory system compliance or the plateau pressure minus PEEP in patients not making inspiratory
efforts, were associated with increased survival.84 This finding
may explain why benefits of PEEP are found in patients with
greater lung recruitability,85 and potential harm can happen
when PEEP causes overdistention.86,87
Various modes of mechanical ventilation have been studied
in patients with ARDS. Airway pressure release ventilation
(APRV) is a mode of mechanical ventilation that switches
between 2 levels of continuous positive airway pressure, while
allowing for spontaneous breathing in any phase of the
mechanical ventilatory cycle. Early small studies of APRV in
patients with ARDS showed improvement in cardiac output,
gas exchange, lung compliance, and sedation requirements and
length of mechanical ventilation compared to conventional
mechanical ventilation (which did not include LPV strategies
of low tidal volumes and inspiratory pressures).88,89 Animal
studies have also shown that APRV can prevent ARDS in both
high-risk models and in normal lungs.90,91 In high-risk animal
models, APRV is associated with a reduction in lung edema
and preservation of lung E-cadherin and surfactant protein,
suggesting it attenuates lung permeability, edema, and surfactant degradation compared with animals ventilated with low
tidal volumes.90 In normal lung populations, APRV prevented
the development of ALI and resulted in higher PaO2/FiO2
ratios (478 vs 242, respectively, P < .5), compared to animals
receiving continuous mandatory ventilation with tidal volumes
of 10 cc/kg.91 In a systemic review of observational data from
trauma patients, early application of APRV in high-risk trauma
patients decreased the incidence of ARDS; however, the
authors were unable to determine whether the comparator
group used a low tidal volume ventilation strategy.92 More
recent studies comparing APRV to ventilation strategies targeting tidal volumes 8 to 10 mL/kg have failed to demonstrate a
clear benefit of using APRV in patients with ARDS.93-95 However, a recent single-center, randomized controlled trial comparing early APRV (initiated <48 hours after the onset of
mechanical ventilation) to low tidal volume ventilation in
138 patients with ARDS with PaO2/FiO2 <250 showed benefit
in terms of ventilator-free days, extubation, tracheostomy, and
ICU mortality.96 These patients receiving APRV also required
fewer proning episodes, less neuromuscular blockade (NMB),
and received fewer recruitment maneuvers. It’s important to
note that the APRV protocol used in this study avoided high
peak pressures and high tidal volumes, which could have conferred a greater degree of lung protection in the APRV group.
Given the conflicting data, there is no clear evidence to support
a recommendation for the use of APRV in patients with ARDS.
5
Inverse ratio ventilation (IRV) is another mode of mechanical ventilation that has been trialed in patients with ARDS.
Inverse ratio ventilation aims to reverse the normal inspiratory
to expiratory time ratio, making the inspiratory period longer
than the expiratory period during mechanical ventilation. This
theoretically raises mean airway pressure and helps with
recruitment of collapsed alveoli. Inverse ratio ventilation can
be implemented in either pressure-controlled or volumecontrolled modes of mechanical ventilation. The downside of
IRV is that it can lead to significant air trapping and auto-PEEP
in the lungs, especially in patients with obstructive lung disease. Few well-conducted trials have examined the role of IRV
in ARDS. These studies have shown that IRV has a minimal
effect on oxygenation, cardiac output, or CO2 elimination compared to conventional ventilation and may worsen gas
exchange, volutrauma, and hemodynamics.97-100
Given their poor lung function, patients with ARDS are
particularly prone to the development of air trapping and
auto-PEEP, regardless of the mode of mechanical ventilation
used. Esophageal manometry has been proposed as a way to
detect auto-PEEP and to help guide clinicians in optimizing
ventilator settings to minimize transpulmonary pressures, and
to improve gas exchange in patients with ARDS.101-104 In a
randomized controlled trial of 61 patients with ARDS, Talmor
and colleagues examined the clinical effects of PEEP titration
based on pleural pressures obtained from esophageal manometry.105 In the esophageal manometry group, whose PEEP levels
were set to achieve a transpulmonary pressure of 0 to 10 cm
H2O at end expiration, patients had significantly better oxygenation and compliance. Soroksy and colleagues used esophageal manometry to titrate tidal volume in patients with ARDS
and found that severe hypercapnia could successfully be treated
using this modality.106 However, Chiumello and colleagues
found that PEEP titration using esophageal manometry did not
reliably predict lung recruitment in ARDS, as measured by
computed tomography scan algorithms.107 A recent study did
not find a significant difference in death or days free from
mechanical ventilation among patients with ARDS who were
randomized to get PEEP titration guided by esophageal pressure measurement, compared with an empirical high PEEPFiO2 strategy.108 More definitive studies are needed before
esophageal manometry becomes a standard of care in patients
with ARDS. A large, randomized trial (the Esophageal
Pressure-Guided Ventilation 2 study) is currently underway
to assess the effects of using esophageal manometry in patients
with ARDS on relevant clinical outcomes (eg, mortality,
ventilator-free days).109
Positioning
For patients with severe ARDS (ie, a PaO2/FiO2 ratio <100),
these patients should be placed in the prone position for at least
12 h/d.77 Based on the results from the Proning Severe ARDS
Patients (PROSEVA) trial, prone positioning in patients with
severe ARDS reduced 28-day mortality by more than 50%.110
Prone positioning represents a significant practice change for
6
many ICUs and clinicians and can be logistically challenging. In
addition, prone positioning may carry additional risks to patients,
such as malpositioning or dislodgement of endotracheal tubes,
the need for increased sedation, less opportunity for early mobilization, and a higher risk of pressure ulcers in patients.
Nutritional Management
Patients with ARDS are intensely catabolic and adequate nutritional support is necessary to offset their caloric and protein
losses while minimizing the risk of fluid overload.111 The initial trophic vs. full enteral feeding in patients with acute lung
injury (EDEN) trial attempted to address the amount of nutrition required in patients with ARDS by comparing clinical
outcomes between patients receiving trophic enteral feeds
(ie, 20 kcal/h) versus full enteral feeds (ie, 25-30 kcal/kg/d of
nonprotein calories, plus 1.2-1.6 g/kg/d of protein) for their first
6 days of mechanical ventilation, after which full enteral nutrition was the goal in both groups.112 They found no difference in
ventilator-free days, short- or long-term mortality, long-term
physical function, or secondary complications between the 2
groups.113,114 However, in the full enteral feeds group, patients
experienced higher rates of vomiting, gastric residuals, hyperglycemia, and constipation than the trophic feeds group.112
The preferred route of administering nutrition to patients
with ARDS remains unclear. There has been a concern that
parenteral nutrition containing large quantities of intravenous
(IV) fat emulsions may worsen alveolar epithelial inflammation. Lekka et al compared the effects of administering lipid
containing total parenteral nutrition versus placebo to patients
with ARDS.115 The patients with ARDS receiving lipid administration experienced worsening oxygenation, decreased pulmonary compliance, and increased pulmonary vascular
resistance compared to those receiving placebo infusions.
Similarly, Suchner et al examined the clinical effects of lipid
infusion rates in patients with ARDS and noted that rapid infusion of fat emulsions (ie, over 6 hours) was associated with
worsening oxygenation compared to slower infusions over 24
hours.116 Thus, IV lipid infusions may be harmful in patients
with ARDS. Yet a randomized controlled trial (CALORIES
Trial) by Harvey et al examining 2400 critically ill patients
(including patients with ARDS), who were randomly assigned
to full parenteral versus enteral nutrition demonstrated no significant difference in 30- and 90-day mortality, or in infection
rates.117 Further studies are needed to address the optimal route
of nutrition in critically ill patients with ARDS.
In terms of the composition of feeding preparations, the
literature is mixed with regard to clinical efficacy of nutritional
antioxidant supplementation to reduce pulmonary inflammation in patients with ARDS. Two separate studies (N ¼ 146
and 100, respectively) evaluated the effects of eicosapentaenoic acid, gamma-linolenic acid, and antioxidants (ie, components of an immune-modulating diet) in patients with ARDS;
both studies demonstrated improved oxygenation and less time
on mechanical ventilation in patients receiving the immunemodulating supplements.118,119 However, a more recent study
Journal of Intensive Care Medicine XX(X)
by Rice et al administering o-3 fatty acids, g-linolenic acid,
and antioxidants to patients with ARDS was discontinued early
because of clinical futility.120 In addition, Stapleton and colleagues evaluated the use of fish oil versus placebo in 90
patients with ARDS and found no difference in pulmonary
biomarkers or clinical outcomes in these patients.121 Given the
small sample sizes and conflicting results of these studies,
further research is needed to determine the efficacy of
immune-modulating diets in patients with ARDS.
Pharmacologic Management in Patients With ARDS
Sedation. Sedation is a key component in the management of
mechanically ventilated patients with ARDS. Studies looking
specifically at sedation strategies in patients with ARDS are
limited, but sedation management in these patients can be
extrapolated from the general ICU literature. The clinical practice guidelines for sedation and analgesia for adult ICU patients
are applicable to patients ARDS.122 Sedation and analgesia
help to reduce energy expenditure and improve ventilator compliance and synchrony in patients ARDS.123,124 However,
oversedation to the point of unconsciousness can prolong
mechanical ventilation and ICU and hospital LoS, and increase
the risks of patients developing ICU delirium and severe deconditioning.125-129 This, in turn, can lead to higher mortality rates,
and long-term physical and cognitive dysfunction in these
patients.130-133 Minimizing sedation can facilitate ventilator
weaning and early mobility, thereby hastening their recovery
and improving their clinical outcomes.126,128,134,135 Lungprotective strategies for mechanical ventilation can be
employed in patients with ARDS without the use of deep sedation.136-141 But deep sedation and analgesia is required in
patients with severe ARDS who require prolonged NMB to
improve gas exchange and ventilator tolerance, in order to
eliminate awareness, discomfort, and recall in these patients.128
Sedation with benzodiazepines should generally be avoided in
critically ill patients, as sedation with benzodiazepines is associated with increased ICU delirium, ICU and hospital LoS,
duration of mechanical ventilation, and mortality in
patients.142-146 Additional studies of sedation strategies in
patients with ARDS are needed, particularly during prone
positioning of patients. In patients with ARDS who do
require sedation, an analgesia-first sedation strategy should
be employed (ie, treat pain first before initiating or
increasing sedation), using nonbenzodiazepine sedatives
(ie, propofol, dexmedetomidine) to optimize patient outcomes.122,126,128,143,147-149
Neuromuscular blockade. Neuromuscular blockade is used in
patients with severe ARDS (ie, PaO2/FiO2 ratio <150) to
improve gas exchange and to facilitate ventilator synchrony.
Neuromuscular blockade administered for up to 48 hours early
on in the course of ARDS has been shown to improve oxygenation and reduce mortality in patients with ARDS. Gainnier
and colleagues showed that compared to conventional therapy,
the addition of 48 hours of NMB in severe patients with ARDS
Kaku et al
resulted in higher PaO2/FiO2 ratios up to 120 hours after randomization.150 Forel and colleagues demonstrated a decrease in
the pro-inflammatory responses with the early use of NMB.151
In the ACCURASYS trial, Papazian and colleagues found that
treatment with 48 hours of NMB was associated with improved
oxygenation and reduced 90-day mortality compared to placebo in patients with ARDS who were deeply sedated.152 A
recent meta-analysis demonstrated that cisatracurium infusions
administered for up to 48 hours in patients with severe ARDS
was associated with a lower hospital mortality and a lower risk
of barotrauma in patients.153 However, the recently published
Reevaluation of Systemic Early Neuromuscular Blockade
(ROSE) trial did not find a difference in 90-day mortality in
patients with moderate-severe ARDS who received a 48-hour
continuous infusion of NMB with deep sedation (intervention
group) or a usual-care approach with light sedation and without
routine NMB (control group).154 Prolonged NMB in patients
with ARDS is also associated with severe deconditioning, myopathy, and weakness in these patients.155 Based on this evidence, NMB should not be used routinely in patients with
moderate-severe ARDS, and when NMB is used by clinicians,
it should be instituted early on in their course, but limited to no
more than 48 hours of treatment.
Pulmonary artery vasodilators. Inhaled nitric oxide (iNO) is a pulmonary arterial vasodilator that can potentially improve V/Q
matching and oxygenation in patients with ARDS. Numerous
case series and randomized trials of iNO in patients with ARDS
have shown its benefit in improving PaO2/FiO2 ratios compared
to conventional therapy, but this improvement is often transient
and has not translated to improved clinical outcomes (eg, survival, LoS, duration of mechanical ventilation).156-161
Two studies examining the long-term effects of iNO showed
conflicting results. In their follow-up of a randomized trial of
385 patients with ARDS, Angus et al showed that iNO was not
associated with improvements in 1-year survival, LoS, quality
of life, or functional status.162 Dellinger et al found that
patients treated with iNO had some improved measures of
pulmonary function at 6 months.163 A recent systematic review
concluded that iNO does not reduce mortality in adults or children with ARDS, regardless of the degree of hypoxemia.164
Although iNO may transiently improve oxygenation, the lack
of sustained positive outcomes and its expense preclude the
routine use in the management of ARDS.
Inhaled prostacyclin agonists (eg, epoprostenol, iloprost) are
pulmonary arterial vasodilators that improve V/Q matching in
the same manner as iNO. In patients with ARDS, inhaled prostacyclins have been shown to improve oxygenation and PaO2/
FiO2 ratios.165-167 Head-to-head comparisons of iNO and
inhaled epoprostenol in patients with ARDS have shown
equivalence in their effects on oxygenation and hemodynamics.168,169 But these studies have not assessed their effects
on meaningful outcomes in patients with ARDS, such as survival and duration of mechanical ventilation. Further study is
needed before determining the role of prostacyclin in the treatment of ARDS.
7
Sildenafil is an oral pulmonary arterial vasodilator used in
the treatment of non–group II pulmonary hypertension. In a
prospective cohort study of patients with ARDS, administration of sildenafil was found to reduce mean pulmonary arterial
pressure, but did not improve pulmonary arterial oxygen tension.170 The drug also led to significant reductions in systemic
mean arterial pressure. Given the lack of meaningful outcomes
data and its effects on blood pressure, sildenafil is not recommended for the routine management of ARDS.
Corticosteroids. Corticosteroids have been extensively studied in
patients with ARDS. Both high- and low-dose systemic steroid
therapy along with optimal timing have been evaluated.
Patients treated with high-dose steroids show no improvement
in terms of duration of ventilation, level of PEEP, or FiO2 but
do experience higher infection rates and higher mortality
rates.171-173 Moderate-dose steroid therapy in ARDS is associated with improved oxygenation and more ventilator-free days,
but has no effect on mortality early on in the course of the
disease and increases mortality in patients with ARDS longer
than 2 weeks.173 In 2008, a systematic review and metaanalysis failed to demonstrate any benefit of systemic steroids
in patients with ARDS.174,175
A subsequent study on low-dose corticosteroids (methylprednisolone) started within 72 hours of the onset of ARDS
and continued for up to 28 days (prolonged use) showed a
reduction in duration of mechanical ventilation, ICU LoS, and
mortality.176 Two subsequent meta-analyses demonstrated that
low-dose systemic steroids were associated with reduced morbidity and mortality in ARDS.177,178 But adequately powered
studies are still needed to determine the safety and efficacy of
systemic steroids in ARDS.
A recent analysis of the LIPS cohort showed that the prehospital use of inhaled corticosteroids in patients with at least 1
ARDS risk factor was associated with a decreased risk of
ARDS.179 But 69% of patients in this trial who were using
inhaled corticosteroids were also using inhaled b agonists, versus just 8% in the control cohort. When adjusting for inhaled b
agonist use, there was no longer a significant protective effect
with inhaled corticosteroids in these patients.
Other pharmacologic therapies for ARDS. The role of surfactant to
prevent alveolar collapse and its anti-inflammatory properties
makes it a potential therapy for ARDS. But the data on surfactant therapy in patients with ARDS have been mixed. Smaller
studies have shown possible improvements in oxygenation
without any mortality benefit,180-182 and a meta-analysis has
confirmed these results.183 But a larger study of 418 adult
patients with ARDS showed that patients treated with porcine
surfactant demonstrated a trend toward increased mortality and
adverse effects,184 while another study by Wilson and colleagues using surfactant in infants, children, and adolescents
with ALI showed improvements in oxygenation and decreased
mortality.185 These inconsistencies may be due to the variability in the type and dose of surfactant used, the population
studied, and the cause of the ARDS.186-188 More studies are
8
needed to identify the ideal type and dose of surfactant, and the
specific type of patients with ARDS who may respond to surfactant supplementation.
Several other pharmacologic agents have been studied for the
treatment of ARDS, including lisofylline (antioxidant),189 Nacetylcysteine (antioxidant),190-194 macrolide antibiotics (antiinflammatory and antimicrobial properties),195 ketoconazole
(thromboxane synthase inhibitor),196-198 angiotensin receptor
blockers, and angiotensin-converting enzyme inhibitors (antiinflammatory properties).199-202 Large, well-designed studies are
either lacking or have failed to demonstrate any outcome benefit
with any of these agents in patients with ARDS.
The latest area of research interest in the treatment of ARDS
is mesenchymal stem cell (MSC) therapy.203 Based on animal
and in vitro studies, MSCs have been shown to possess antiinflammatory properties and also to preserve vascular endothelial and alveolar epithelial barrier function.204-207 These effects
have been studied and replicated in an ex vivo isolated perfused
human lung model.208 Zheng and colleagues prospectively randomized 12 adult patients with ARDS to receive either a single
dose of MSCs or placebo. The treatment group had significantly lower circulating blood levels of IL-8, and a trend
toward lower levels of IL-6 (biomarkers of ALI) than the control group.209 But there was no difference in ventilator-free or
ICU-free days between the 2 groups. Wilson and colleagues
published the results of a phase 1 clinical trial involving 9
patients with ARDS who received IV MSCs, demonstrating
no serious adverse events.210 They are now moving toward a
phase 2 trial in patients with moderate-to-severe ARDS. Stem
cell therapy remains a promising area of investigation in the
treatment of patients with ARDS.
Summary
The acute respiratory distress syndrome remains a significant
public health burden worldwide with persistently high morbidity and mortality rates, in spite of significant improvements in
the delivery of critical care medicine and in the specific management of ARDS. Research in recent decades has helped to
better define the disease and to elucidate its underlying pathophysiology. As a result, identification of at-risk patients and
detection rates for ARDS has improved. Yet the prevention of
ARDS remains a challenge. Early detection and treatment of
sepsis, conservative IV fluid administration and blood product
transfusion, and the use of LPV strategies and early prone
positioning show the greatest promise for preventing and slowing the progression of ARDS. Minimizing sedation, except in
the case of NMB use, is essential to avoid the short- and longterm complications from oversedation and immobility in these
patients. NMB treatment shall not be routinely used in all
patients. But large, well-designed trials are either lacking or
show no benefit for most other potential drug treatments. Additional large high-quality studies are needed to better define
optimal nutritional management strategies in patients with
ARDS. Stem cell therapy may be the next frontier in the battle
to improve outcomes in patients with ARDS.
Journal of Intensive Care Medicine XX(X)
Authors’ Note
Shawn Kaku, MD, Christopher D. Nguyen, MD, and Natalie N. Htet,
MD, contributed equally to this work.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
ORCID iD
Natalie N. Htet, MD, MS
https://orcid.org/0000-0001-7813-8905
References
1. Ashbaugh D, Bigelow DB, Petty T, Levine B. Acute respiratory
distress in adults. Lancet. 1967;290(7511):319-323.
2. Luhr OR, Antonsen K, Karlsson M, et al. Incidence and mortality
after acute respiratory failure and acute respiratory distress syndrome in Sweden, Denmark, and Iceland. Am J Respir Crit Care
Med. 1999;159(6):1849-1861.
3. Villar J. What is the acute respiratory distress syndrome? Respir
Care. 2011;56(10):1539-1545.
4. Bersten AD, Edibam C, Hunt T, et al. Incidence and mortality of
acute lung injury and the acute respiratory distress syndrome in
three Australian States. Am J Respir Crit Care Med. 2002;165(4):
443-448.
5. Stapleton RD, Wang BM, Hudson LD, Rubenfeld GD, Caldwell
ES, Steinberg KP. Causes and timing of death in patients with
ARDS. Chest. 2005;128(2):525-532.
6. Erickson SE, Martin GS, Davis JL, Matthay MA, Eisner MD,
Network NNA. Recent trends in acute lung injury mortality:
1996–-2005. Crit Care Med. 2009;37(5):1574-1579.
7. Rubenfeld GD, Caldwell E, Peabody E, et al. Incidence and outcomes of acute lung injury. N Engl J Med. 2005;353(16):
1685-1693.
8. Bellani G, Laffey JG, Pham T, et al. Epidemiology, patterns of
care, and mortality for patients with acute respiratory distress
syndrome in intensive care units in 50 countries. JAMA. 2016;
315(8):788-800.
9. Bernard GR, Artigas A, Brigham KL, et al. The AmericanEuropean Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J
Respir Crit Care Med. 1994;149(3 pt 1):818-824.
10. Ranieri VM, Rubenfeld GD, Thompson BT, et al; ARDS Definition Task Force. Acute respiratory distress syndrome: the Berlin
definition. JAMA. 2012;307(23):2526-2533.
11. Ferguson ND, Fan E, Camporota L, et al. The Berlin definition of
ARDS: an expanded rationale, justification, and supplementary
material. Intensive Care Med. 2012;38(10):1573-1582.
12. Katzenstein AL, Bloor CM, Leibow AA. Diffuse alveolar damage
– the role of oxygen, shock, and related factors. A review. Am J
Pathol. 1976;85(1):209-228.
13. Piantadosi CA, Schwartz DA. The acute respiratory distress syndrome. Ann Intern Med. 2004;141(6):460-470.
Kaku et al
14. Anderson WR, Thielen K. Correlative study of adult respiratory
distress syndrome by light, scanning, and transmission electron
microscopy. Ultrastruct Pathol. 1992;16(6):615-628.
15. Pratt PC, Vollmer RT, Shelburne JD, Crapo JD. Pulmonary morphology in a multihospital collaborative extracorporeal membrane oxygenation project. I. Light microscopy. Am J Pathol.
1979;95(1):191-214.
16. Bachofen M, Weibel ER. Alterations of the gas exchange apparatus in adult respiratory insufficiency associated with septicemia.
Am Rev Respir Dis. 1977;116(4):589-615.
17. Pierrakos C, Karanikolas M, Scolletta S, Karamouzos V, Velissaris D. Acute respiratory distress syndrome: pathophysiology
and therapeutic options. J Clin Med Res. 2012;4(1):7-16.
18. de Hemptinne Q, Remmelink M, Brimioulle S, Salmon I, Vincent
JL. ARDS: a clinicopathological confrontation. Chest. 2009;
135(4):944-949.
19. Sarmiento X, Guardiola JJ, Almirall J, et al. Discrepancy between
clinical criteria for diagnosing acute respiratory distress syndrome
secondary to community acquired pneumonia with autopsy findings of diffuse alveolar damage. Respir Med. 2011;105(8):
1170-1175.
20. Esteban A, Fernández-Segoviano P, Frutos-Vivar F, et al. Comparison of clinical criteria for the acute respiratory distress syndrome with autopsy findings. Ann Intern Med. 2004;141(6):
440-445.
21. Pinheiro BV, Muraoka FS, Assis RVC, et al. Accuracy of clinical
diagnosis of acute respiratory distress syndrome in comparison
with autopsy findings. J Bras Pneumol. 2007;33(4):423-428.
22. Kao KC, Hu HC, Chang CH, et al. Diffuse alveolar damage
associated mortality in selected acute respiratory distress syndrome patients with open lung biopsy. Crit Care. 2015;19(1):
228.
23. Thompson BT, Michael AM. The Berlin definition of ARDS
versus pathological evidence of diffuse alveolar damage. Am J
Respir crit Care Med. 2013;187(7):675-677.
24. Hudson LD, Milberg JA, Anardi D, Maunder RJ. Clinical risks for
development of the acute respiratory distress syndrome. Am J
Respir crit Care Med. 1995;151(2 pt 1):293-301.
25. Pepe PE, Potkin RT, Reus DH, Hudson LD, Carrico CJ. Clinical
predictors of the adult respiratory distress syndrome. Am J Surg.
1982;144(1):124-130.
26. Eworuke E, Major JM, Gilbert McClain LI. National incidence
rates for acute respiratory distress syndrome (ARDS) and ARDS
cause-specific factors in the United States (2006-2014). J Crit
Care. 2018;47:192-197.
27. Marshall RP, Webb S, Hill MR, Humphries SE, Laurent GJ.
Genetic polymorphisms associated with susceptibility and outcome in ARDS. Chest. 2002;121(3 suppl):68S-69S.
28. Marshall RP, Webb S, Bellingan GJ, et al. Angiotensin converting
enzyme insertion/deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome.
Am J Respir crit Care Med. 2002;166(5):646-650.
29. Copland IB, Kavanagh BP, Engelberts D, McKerlie C, Belik J,
Post M. Early changes in lung gene expression due to high tidal
volume. Am J Respir crit Care Med. 2003;168(9):1051-1059.
9
30. Grigoryev DN, Finigan JH, Hassoun P, Garcia JGN. Science
review: searching for gene candidates in acute lung injury. Crit
Care. 2004;8(6):440.
31. Mikkelsen ME, Shah CV, Meyer NJ, et al. The epidemiology of
acute respiratory distress syndrome in patients presenting to the
emergency department with severe sepsis. Shock. 2013;40(5):
375-381.
32. Gajic O, Dabbagh O, Park PK, et al. Early identification of
patients at risk of acute lung injury: evaluation of lung injury
prediction score in a multicenter cohort study. Am J Respir crit
Care Med. 2011;183(4):462-470.
33. Ferguson ND, Frutos-Vivar F, Esteban A, et al. Clinical risk
conditions for acute lung injury in the intensive care unit and
hospital ward: a prospective observational study. Crit Care.
2007;11(5):R96.
34. Fein AM, Calalang-Colucci MG. Acute lung injury and acute
respiratory distress syndrome in sepsis and septic shock. Crit
Care Clin. 2000;16(2):289-317.
35. Pelosi P, D’Onofrio D, Chiumello D, et al. Pulmonary and extrapulmonary acute respiratory distress syndrome are different. Eur
Respir J Suppl. 2003;42:48s-56s.
36. Sheu CC, Gong MN, Zhai R, et al. The influence of infection sites
on development and mortality of ARDS. Intensive Care Med.
2010;36(6):963-970.
37. Kojicic M, Li G, Hanson AC, et al. Risk factors for the development of acute lung injury in patients with infectious pneumonia.
Crit Care. 2012;16(2):R46.
38. Lee A, Festic E, Park PK, et al. Characteristics and outcomes of
patients hospitalized following pulmonary aspiration. Chest.
2014;146(4):899-907.
39. Treggiari MM, Hudson LD, Martin DP, Weiss NS, Caldwell E,
Rubenfeld G. Effect of acute lung injury and acute respiratory
distress syndrome on outcome in critically ill trauma patients. Crit
Care Med. 2004;32(2):327-331.
40. Calfee CS, Eisner MD, Ware LB, et al. Trauma-associated lung
injury differs clinically and biologically from acute lung injury
due to other clinical disorders. Crit Care Med. 2007;35(10):
2243-2250.
41. Moss M, Gillespie MK, Ackerson L, Moore FA, Moore EE, Parsons PE. Endothelial cell activity varies in patients at risk for the
adult respiratory distress syndrome. Crit Care Med. 1996;24(11):
1782-1786.
42. Toy P, Popovsky MA, Abraham E, et al. Transfusion-related
acute lung injury: definition and review. Crit Care Med. 2005;
33(4):721-726.
43. Zilberberg MD, Carter C, Lefebvre P, et al. Red blood cell transfusions and the risk of acute respiratory distress syndrome among
the critically ill: a cohort study. Crit Care. 2007;11(3):R63.
44. Khan H, Belsher J, Yilmaz M, et al. Fresh-frozen plasma and
platelet transfusions are associated with development of acute
lung injury in critically ill medical patients. Chest. 2007;131(5):
1308-1314.
45. Levitt JE, Calfee CS, Goldstein BA, Vojnik R, Matthay MA.
Early acute lung injury: criteria for identifying lung injury prior
to the need for positive pressure ventilation*. Crit Care Med.
2013;41(8):1929-1937.
10
46. Crader KM, Repine DJJ, Repine JE. Breath biomarkers and the
acute respiratory distress syndrome. J Pulm Respir Med. 2012;
2(1):1-9.
47. Donnelly SC, Strieter RM, Kunkel SL, et al. Interleukin-8 and
development of adult respiratory distress syndrome in at-risk
patient groups. Lancet. 1993;341(8846):643-647.
48. Villar J, Pérez-Méndez L, Espinosa E, et al. Serum lipopolysaccharide binding protein levels predict severity of lung injury and
mortality in patients with severe sepsis. PLoS One. 2009;4(8):
e6818.
49. Agrawal A, Matthay MA, Kangelaris KN, et al. Plasma
angiopoietin-2 predicts the onset of acute lung injury in critically
ill patients. Am J Respir Crit Care Med. 2013;187(7):736-742.
50. Terpstra ML, Aman J, van Nieuw Amerongen GP, Groeneveld
ABJ. Plasma biomarkers for acute respiratory distress syndrome:
a systematic review and meta-analysis*. Crit Care Med. 2014;
42(3):691-700.
51. Calfee CS, Ware LB, Glidden DV, et al. Use of risk reclassification with multiple biomarkers improves mortality prediction in
acute lung injury. Crit Care Med. 2011;39(4):711-717.
52. Ware LB, Koyama T, Billheimer DD, et al. Prognostic and pathogenetic value of combining clinical and biochemical indices in
patients with acute lung injury. Chest. 2010;137(2):288-296.
53. Iscimen R, Cartin-Ceba R, Yilmaz M, et al. Risk factors for the
development of acute lung injury in patients with septic shock: an
observational cohort study. Crit Care Med. 2008;36(5):
1518-1522.
54. Jia X, Malhotra A, Saeed M, Mark RG, Talmor D. Risk factors for
ARDS in patients receiving mechanical ventilation for greater
than 48 hours. Chest. 2008;133(4):853-861.
55. Yao S, Mao T, Fang W, Xu M, Chen W. Incidence and risk factors
for acute lung injury after open thoracotomy for thoracic diseases.
J Thorac Dis. 2013;5(4):455-460.
56. Evans RG, Naidu B. Does a conservative fluid management strategy in the perioperative management of lung resection patients
reduce the risk of acute lung injury? Interact Cardiovasc Thorac
Surg. 2012;15(3):498-504.
57. Hughes CG, Weavind L, Banerjee A, Mercaldo ND, Schildcrout
JS, Pandharipande PP. Intraoperative risk factors for acute
respiratory distress syndrome in critically ill patients. Anesth
Analg. 2010;111(2):464-467.
58. Wiedemann HP, Wheeler AP, Bernard GR, et al. Comparison of
two fluid-management strategies in acute lung injury. N Engl J
Med. 2006;354(24):2564-2575.
59. Rosenberg AL, Dechert RE, Park PK, Bartlett RH, Network
NNA. Review of a large clinical series: association of cumulative
fluid balance on outcome in acute lung injury: a retrospective
review of the ARDSnet tidal volume study cohort. J Intensive
Care Med. 2009;24(1):35-46.
60. Seeley EJ. Fluid therapy during acute respiratory distress syndrome: less is more, simplified*. Crit Care Med. 2015;43(2):
477-478.
61. Gong MN, Thompson BT, Williams P, Pothier L, Boyce PD,
Christiani DC. Clinical predictors of and mortality in acute
respiratory distress syndrome: potential role of red cell transfusion. Crit Care Med. 2005;33(6):1191-1198.
Journal of Intensive Care Medicine XX(X)
62. Hébert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion requirements in critical care investigators,
canadian critical care trials group. N Engl J Med. 1999;340(6):
409-417.
63. Park PK, Cannon JW, Ye W, et al. Transfusion strategies and
development of acute respiratory distress syndrome in combat
casualty care. J Trauma Acute Care Surg. 2013;75(2 suppl 2):
S238-S246.
64. Popovsky MA, Moore SB. Diagnostic and pathogenetic considerations in transfusion-related acute lung injury. Transfusion.
1985;25(6):573-577.
65. Curtis BR, McFarland JG. Mechanisms of transfusion-related
acute lung injury (TRALI): anti-leukocyte antibodies. Critical
care medicine. 2006;34(5 suppl):S118-S123.
66. Vlaar AP, Juffermans NP. Transfusion-related acute lung injury: a
clinical review. Lancet. 2013;382(9896):984-994.
67. Toy P, Gajic O, Bacchetti P, et al. Transfusion-related acute lung
injury: incidence and risk factors. Blood. 2012;119(7):1757-1767.
68. Gajic O, Rana R, Winters JL, et al. Transfusion-related acute lung
injury in the critically ill: prospective nested case–control study.
Am J Respir Crit Care Med. 2007;176(9):886-891.
69. Price TH. Standards for Blood Banks and Transfusion Services.
Bethesda, MD: AABB; 2008.
70. Eder AF, Herron R, Strupp A, et al. Transfusion-related acute
lung injury surveillance (2003-2005) and the potential impact of
the selective use of plasma from male donors in the American Red
Cross. Transfusion. 2007;47(4):599-607.
71. Silliman CC, Thurman GW, Ambruso DR. Stored blood components contain agents that prime the neutrophil NADPH oxidase
through the platelet-activating-factor receptor. Vox Sanguinis.
1992;63(2):133-136.
72. Tung JP, Fraser JF, Nataatmadja M, et al. Age of blood and
recipient factors determine the severity of transfusion-related
acute lung injury (TRALI). Crit Care. 2012;16(1):R19.
73. Vlaar APJ, Binnekade JM, Prins D, et al. Risk factors and outcome of transfusion-related acute lung injury in the critically ill: a
nested case–control study. Crit Care Med. 2010;38(3):771-778.
74. Middelburg RA, Borkent-Raven BA, Borkent B, et al. Storage
time of blood products and transfusion-related acute lung injury.
Transfusion. 2012;52(3):658-667.
75. Kor DJ, Kashyap R, Weiskopf RB, et al. Fresh red blood cell
transfusion and short-term pulmonary, immunologic, and coagulation status: a randomized clinical trial. Am J Respir Crit Care
Med. 2012;185(8):842-850.
76. Fan E, Brodie D, Slutsky AS. Acute respiratory distress syndrome: advances in diagnosis and treatment. JAMA. 2018;
319(7):698-710.
77. Howell MD, Davis AM. Management of ARDS in adults. JAMA.
2018;319(7):711-712.
78. Fan E, Del Sorbo L, Goligher EC, et al. An official American
Thoracic Society/European Society of Intensive Care Medicine/
Society of Critical Care Medicine clinical practice guideline:
mechanical ventilation in adult patients with acute respiratory
distress syndrome. Am J Respir Crit Care Med. 2017;195(9):
1253-1263.
Kaku et al
79. Ferguson ND, Cook DJ, Guyatt GH, et al. High-frequency oscillation in early acute respiratory distress syndrome. N Engl J Med.
2013;368(9):795-805.
80. Lall R, Hamilton P, Young D, et al. A randomised controlled trial
and cost-effectiveness analysis of high-frequency oscillatory ventilation against conventional artificial ventilation for adults with
acute respiratory distress syndrome. The OSCAR (OSCillation in
ARDS) study. Health Technol Assess. 2015;19(23):1-177, vii.
81. Sud S, Sud M, Friedrich JO, et al. High-frequency oscillatory
ventilation versus conventional ventilation for acute respiratory
distress syndrome. Cochrane Database Syst Rev. 2016;(4):
CD004085.
82. Combes A, Hajage D, Capellier G, et al. Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome.
N Engl J Med. 2018;378(21):1965-1975.
83. Cavalcanti AB, Suzumura EA, Laranjeira LN, et al. Effect of lung
recruitment and titrated positive end-expiratory pressure (PEEP)
vs low PEEP on mortality in patients with acute respiratory distress syndrome: a randomized clinical trial. JAMA. 2017;318(14):
1335-1345.
84. Amato MB, Meade MO, Slutsky AS, et al. Driving pressure and
survival in the acute respiratory distress syndrome. N Engl J Med.
2015;372(8):747-755.
85. Grasso S, Fanelli V, Cafarelli A, et al. Effects of high versus low
positive end-expiratory pressures in acute respiratory distress syndrome. Am J Respir Crit Care Med. 2005;171(9):1002-1008.
86. Vieira SR, Puybasset L, Lu Q, et al. A scanographic assessment of
pulmonary morphology in acute lung injury. Significance of the
lower inflection point detected on the lung pressure-volume
curve. Am J Respir Crit Care Med. 1999;159(5 pt 1):1612-1623.
87. Gattinoni L, Caironi P, Cressoni M, et al. Lung recruitment in
patients with the acute respiratory distress syndrome. N Engl J
Med. 2006;354(17):1775-1786.
88. Putensen C, Mutz NJ, Putensen-Himmer G, Zinserling J. Spontaneous breathing during ventilatory support improves ventilationperfusion distributions in patients with acute respiratory distress
syndrome. Am J Respir Crit Care Med. 1999;159(4 pt 1):
1241-1248.
89. Putensen C, Zech S, Wrigge H, et al. Long-term effects of spontaneous breathing during ventilatory support in patients with acute
lung injury. Am J Respir Crit Care Med. 2001;164(1):43-49.
90. Roy S, Habashi N, Sadowitz B, et al. Early airway pressure
release ventilation prevents ARDS – a novel preventive approach
to lung injury. Shock. 2013;39(1):28.
91. Emr B, Gatto LA, Roy S, et al. Airway pressure release ventilation prevents ventilator-induced lung injury in normal lungs.
JAMA Surg. 2013;148(11):1005-1012.
92. Andrews PL, Shiber JR, Jaruga-Killeen E, et al. Early application
of airway pressure release ventilation may reduce mortality in
high-risk trauma patients: a systematic review of observational
trauma ARDS literature. J Trauma Acute Care Surg. 2013;75(4):
635-641.
93. Varpula T, Valta P, Niemi R, Takkunen O, Hynynen M, Pettila
VV. Airway pressure release ventilation as a primary ventilatory
mode in acute respiratory distress syndrome. Acta Anaesthesiol
Scand. 2004;48(6):722-731.
11
94. Maxwell RA, Green JM, Waldrop J, et al. A randomized prospective trial of airway pressure release ventilation and low tidal
volume ventilation in adult trauma patients with acute respiratory failure. J Trauma. 2010;69(3):501-510; discussion 511.
95. Gonzalez M, Arroliga AC, Frutos-Vivar F, et al. Airway pressure release ventilation versus assist-control ventilation: a comparative propensity score and international cohort study.
Intensive Care Med. 2010;36(5):817-827.
96. Zhou Y, Jin X, Lv Y, et al. Early application of airway pressure
release ventilation may reduce the duration of mechanical ventilation in acute respiratory distress syndrome. 2017;43(11):
1648-1659.
97. Mercat A, Titiriga M, Anguel N, Richard C, Teboul JL. Inverse
ratio ventilation (I/E ¼ 2/1) in acute respiratory distress syndrome: a six-hour controlled study. Am J Respir Crit Care Med.
1997;155(5):1637-1642.
98. Lessard MR, Guerot E, Lorino H, Lemaire F, Brochard L.
Effects of pressure-controlled with different I:E ratios versus
volume-controlled ventilation on respiratory mechanics, gas
exchange, and hemodynamics in patients with adult respiratory
distress syndrome. Anesthesiology. 1994;80(5):983-991.
99. Mancebo J, Vallverdu I, Bak E, et al. Volume-controlled ventilation and pressure-controlled inverse ratio ventilation: a comparison of their effects in ARDS patients. Monaldi Arch Chest
Dis 1994;49(3):201-207.
100. Huang CC, Shih MJ, Tsai YH, Chang YC, Tsao TC, Hsu KH.
Effects of inverse ratio ventilation versus positive endexpiratory pressure on gas exchange and gastric intramucosal
PCO(2) and pH under constant mean airway pressure in acute
respiratory distress syndrome. Anesthesiology. 2001;95(5):
1182-1188.
101. Soroksky A, Esquinas A. Goal-directed mechanical ventilation:
are we aiming at the right goals? A proposal for an alternative
approach aiming at optimal lung compliance, guided by esophageal pressure in acute respiratory failure. Crit Care Res Pract.
2012. doi:10.1155/2012/597932.
102. Chiumello D, Cressoni M, Colombo A, et al. The assessment of
transpulmonary pressure in mechanically ventilated ARDS
patients. Intensive Care Med. 2014;40(11):1670-1678.
103. Chiumello D, Guerin C. Understanding the setting of PEEP from
esophageal pressure in patients with ARDS. Intensive Care Med.
2015;41(8):1465-1467.
104. Talmor D, Sarge T, O’Donnell CR, et al. Esophageal and transpulmonary pressures in acute respiratory failure. Crit Care Med.
2006;34(5):1389-1394.
105. Talmor D, Sarge T, Malhotra A, et al. Mechanical ventilation
guided by esophageal pressure in acute lung injury. N Engl J
Med. 2008;359(20):2095-2104.
106. Soroksky A, Kheifets J, Girsh Solomonovich Z, Tayem E, Gingy
Ronen B, Rozhavsky B. Managing hypercapnia in patients with
severe ARDS and low respiratory system compliance: the role of
esophageal pressure monitoring –a case–cohort study. Bio Med
Res Int. 2015;2015:385042.
107. Chiumello D, Cressoni M, Carlesso E, et al. Bedside selection of
positive end-expiratory pressure in mild, moderate, and severe
12
108.
109.
110.
111.
112.
113.
114.
115.
116.
117.
118.
119.
120.
121.
Journal of Intensive Care Medicine XX(X)
acute respiratory distress syndrome. Crit Care Med. 2014;42(2):
252-264.
Beitler JR, Sarge T, Banner-Goodspeed VM, et al. Effect of
titrating positive end-expiratory pressure (PEEP) with an esophageal pressure-guided strategy vs an empirical high PEEPFiO2 strategy on death and days free from mechanical ventilation among patients with acute respiratory distress syndrome: a
randomized clinical trial. JAMA. 2019;321(9):846-857.
Fish E, Novack V, Banner-Goodspeed VM, Sarge T, Loring S,
Talmor D. The esophageal pressure-guided ventilation 2
(EPVent2) trial protocol: a multicentre, randomised clinical trial
of mechanical ventilation guided by transpulmonary pressure.
BMJ Open. 2014;4(9):e006356.
Guerin C, Reignier J, Richard JC, et al. Prone positioning in
severe acute respiratory distress syndrome. N Engl J Med.
2013;368(23):2159-2168.
Martindale RG, McClave SA, Vanek VW, et al. Guidelines for
the provision and assessment of nutrition support therapy in the
adult critically ill patient: society of critical care medicine and
american society for parenteral and enteral nutrition: executive
summary. Crit Care Med. 2009;37(5):1757-1761.
Rice TW, Wheeler AP, Thompson BT, et al. Initial trophic vs
full enteral feeding in patients with acute lung injury: the EDEN
randomized trial. JAMA. 2012;307(8):795-803.
Needham DM, Dinglas VD, Bienvenu OJ, et al. One year outcomes in patients with acute lung injury randomised to initial
trophic or full enteral feeding: prospective follow-up of EDEN
randomised trial. BMJ. 2013;346:f1532.
Needham DM, Dinglas VD, Morris PE, et al. Physical and cognitive performance of patients with acute lung injury 1 year after
initial trophic versus full enteral feeding. EDEN trial follow-up.
Am J Respir Crit Care Med. 2013;188(5):567-576.
Lekka ME, Liokatis S, Nathanail C, Galani V, Nakos G. The
impact of intravenous fat emulsion administration in acute lung
injury. Am J Respir Crit Care Med. 2004;169(5):638-644.
Suchner U, Katz DP, Furst P, et al. Effects of intravenous fat
emulsions on lung function in patients with acute respiratory
distress syndrome or sepsis. Crit Care Med. 2001;29(8):
1569-1574.
Harvey SE, Parrott F, Harrison DA, et al. Trial of the route of
early nutritional support in critically ill adults. N Engl J Med.
2014;371(18):1673-1684.
Singer P, Theilla M, Fisher H, Gibstein L, Grozovski E, Cohen J.
Benefit of an enteral diet enriched with eicosapentaenoic acid
and gamma-linolenic acid in ventilated patients with acute lung
injury. Crit Care Med. 2006;34(4):1033-1038.
Gadek JE, DeMichele SJ, Karlstad MD, et al. Effect of enteral
feeding with eicosapentaenoic acid, gamma-linolenic acid, and
antioxidants in patients with acute respiratory distress syndrome.
Enteral Nutrition in ARDS Study Group. Crit Care Med. 1999;
27(8):1409-1420.
Rice TW, Wheeler AP, Thompson BT, et al. Enteral omega-3
fatty acid, gamma-linolenic acid, and antioxidant supplementation in acute lung injury. JAMA. 2011;306(14):1574-1581.
Stapleton RD, Martin TR, Weiss NS, et al. A phase II randomized placebo-controlled trial of omega-3 fatty acids for the
122.
123.
124.
125.
126.
127.
128.
129.
130.
131.
132.
133.
134.
135.
136.
137.
138.
treatment of acute lung injury. Crit Care Med. 2011;39(7):
1655-1662.
Devlin JW, Skrobik Y, Gélinas C, et al. Clinical Practice Guidelines for the Prevention and Management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients
in the ICU. Crit Care Med. 2018;46(9):e825-e873.
Hansen-Flaschen J.Improving patient tolerance of mechanical
ventilation. Challenges ahead. Crit Care Clin. 1994;10(4):
659-671.
Swinamer DL, Phang PT, Jones RL, Grace M, King EG. Effect
of routine administration of analgesia on energy expenditure in
critically ill patients. Chest. 1988;93(1):4-10.
Shah FA, Girard TD, Yende S. Limiting sedation for patients
with acute respiratory distress syndrome – time to wake up. Curr
Opin Crit Care. 2017;23(1):45-51.
Kress JP, Pohlman AS, O’Connor MF, Hall JB. Daily interruption of sedative infusions in critically ill patients undergoing
mechanical ventilation. N Engl J Med. 2000;342(20):1471-1477.
Takala J. Of delirium and sedation. Am J Respir Crit Care Med.
2014;189(6):622-624.
Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines
for the management of pain, agitation, and delirium in adult
patients in the intensive care unit. Crit Care Med. 2013;41(1):
263-306.
Wilhelm W, Kreuer S. The place for short-acting opioids: special emphasis on remifentanil. Crit Care. 2008;12(suppl 3):S5.
Shehabi Y, Bellomo R, Reade MC, et al. Early intensive care
sedation predicts long-term mortality in ventilated critically ill
patients. Am J Respir Crit Care Med. 2012;186(8):724-731.
Tanaka LM, Azevedo LC, Park M, et al. Early sedation and
clinical outcomes of mechanically ventilated patients: a prospective multicenter cohort study. Crit Care. 2014;18(4):R156.
Treggiari MM, Romand JA, Yanez ND, et al. Randomized trial
of light versus deep sedation on mental health after critical illness. Crit Care Med. 2009;37(9):2527-2534.
Jackson JC, Girard TD, Gordon SM, et al. Long-term cognitive
and psychological outcomes in the awakening and breathing
controlled trial. Am J Respir Crit Care Med. 2010;182(2):
183-191.
Girard TD, Jackson JC, Pandharipande PP, et al. Delirium as a
predictor of long-term cognitive impairment in survivors of critical illness. Crit Care Med. 2010;38(7):1513-1520.
Brook AD, Ahrens TS, Schaiff R, et al. Effect of a nursingimplemented sedation protocol on the duration of mechanical
ventilation. Crit Care Med. 1999;27(12):2609-2615.
Kahn JM, Andersson L, Karir V, Polissar NL, Neff MJ, Rubenfeld GD. Low tidal volume ventilation does not increase sedation
use in patients with acute lung injury. Crit Care Med. 2005;
33(4):766-771.
Wolthuis EK, Veelo DP, Choi G, et al. Mechanical ventilation
with lower tidal volumes does not influence the prescription of
opioids or sedatives. Crit Care. 2007;11(4):R77.
Serpa Neto A, Simonis FD, Barbas CS, et al. Association
between tidal volume size, duration of ventilation, and sedation
needs in patients without acute respiratory distress syndrome: an
Kaku et al
139.
140.
141.
142.
143.
144.
145.
146.
147.
148.
149.
150.
151.
152.
individual patient data meta-analysis. Intensive Care Med. 2014;
40(7):950-957.
Arroliga AC, Thompson BT, Ancukiewicz M, et al. Use of
sedatives, opioids, and neuromuscular blocking agents in
patients with acute lung injury and acute respiratory distress
syndrome. Crit Care Med. 2008;36(4):1083-1088.
Mehta S, Cook DJ, Skrobik Y, et al. A ventilator strategy combining low tidal volume ventilation, recruitment maneuvers, and
high positive end-expiratory pressure does not increase sedative,
opioid, or neuromuscular blocker use in adults with acute
respiratory distress syndrome and may improve patient comfort.
Ann Intensive Care. 2014;4:33.
Cheng IW, Eisner MD, Thompson BT, Ware LB, Matthay MA.
Acute effects of tidal volume strategy on hemodynamics, fluid
balance, and sedation in acute lung injury. Crit Care Med. 2005;
33(1):63-70; discussion 239-240.
Pandharipande P, Shintani A, Peterson J, et al. Lorazepam is an
independent risk factor for transitioning to delirium in intensive
care unit patients. Anesthesiology. 2006;104(1):21-26.
Lonardo NW, Mone MC, Nirula R, et al. Propofol is associated
with favorable outcomes compared with benzodiazepines in
ventilated intensive care unit patients. Am J Respir Crit Care
Med. 2014;189(11):1383-1394.
Riker RR, Shehabi Y, Bokesch PM, et al. Dexmedetomidine vs
midazolam for sedation of critically ill patients: a randomized
trial. JAMA. 2009;301(5):489-499.
Jakob SM, Ruokonen E, Grounds RM, et al. Dexmedetomidine
vs midazolam or propofol for sedation during prolonged
mechanical ventilation: two randomized controlled trials. JAMA.
2012;307(11):1151-1160.
Pandharipande PP, Pun BT, Herr DL, et al. Effect of sedation
with dexmedetomidine vs lorazepam on acute brain dysfunction
in mechanically ventilated patients: the MENDS randomized
controlled trial. JAMA. 2007;298(22):2644-2653.
Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines
for the management of pain, agitation, and delirium in adult
patients in the intensive care unit: executive summary. Am J
Health-Syst Pharm. 2013;70(1):53-58.
Devabhakthuni S, Armahizer MJ, Dasta JF, Kane-Gill SL.
Analgosedation: a paradigm shift in intensive care unit sedation
practice. Ann Pharmacother. 2012;46(4):530-540.
Strom T, Martinussen T, Toft P. A protocol of no sedation for
critically ill patients receiving mechanical ventilation: a randomised trial. Lancet. 2010;375(9713):475-480.
Gainnier M, Roch A, Forel JM, et al. Effect of neuromuscular
blocking agents on gas exchange in patients presenting with
acute respiratory distress syndrome. Crit Care Med. 2004;
32(1):113-119.
Forel JM, Roch A, Marin V, et al. Neuromuscular blocking
agents decrease inflammatory response in patients presenting
with acute respiratory distress syndrome. Crit Care Med.
2006;34(11):2749-2757.
Papazian L, Forel JM, Gacouin A, et al. Neuromuscular blockers
in early acute respiratory distress syndrome. N Engl J Med.
2010;363(12):1107-1116.
13
153. Alhazzani W, Alshahrani M, Jaeschke R, et al. Neuromuscular
blocking agents in acute respiratory distress syndrome: a systematic review and meta-analysis of randomized controlled
trials. Crit Care. 2013;17(2):R43.
154. Moss M, Huang DT, Brower RG, et al. Early neuromuscular
blockade in the acute respiratory distress syndrome. The New
England Journal of Medicine. 2019;380(21):1997-2008.
155. Watling SM, Dasta JF. Prolonged paralysis in intensive care unit
patients after the use of neuromuscular blocking agents: a review
of the literature. Crit Care Med. 1994;22(5):884-893.
156. Westphal K, Strouhal U, Byhahn C, Hommel K, Behne M. Inhalation of nitric oxide in severe lung failure. Anaesthesiol Reanim.
1998;23(6):144-148.
157. Johannigman JA, Davis K Jr, Campbell RS, Luchette F, Hurst
JM, Branson RD. Inhaled nitric oxide in acute respiratory distress syndrome. J Trauma. 1997;43(6):904-909; discussion 909910.
158. Dellinger RP, Zimmerman JL, Taylor RW, et al. Effects of
inhaled nitric oxide in patients with acute respiratory distress
syndrome: results of a randomized phase II trial. Inhaled Nitric
Oxide in ARDS Study Group. Crit Care Med. 1998;26(1):15-23.
159. Michael JR, Barton RG, Saffle JR, et al. Inhaled nitric oxide
versus conventional therapy: effect on oxygenation in ARDS.
Am J Respir Crit Care Med. 1998;157(5 pt 1):1372-1380.
160. Taylor RW, Zimmerman JL, Dellinger RP, et al. Inhaled nitric
oxide in ASG. Low-dose inhaled nitric oxide in patients with
acute lung injury: a randomized controlled trial. JAMA. 2004;
291(13):1603-1609.
161. Dupont H, Le Corre F, Fierobe L, Cheval C, Moine P, Timsit JF.
Efficiency of inhaled nitric oxide as rescue therapy during severe
ARDS: survival and factors associated with the first response. J
Crit Care. 1999;14(3):107-113.
162. Angus DC, Clermont G, Linde-Zwirble WT, et al. Healthcare
costs and long-term outcomes after acute respiratory distress
syndrome: a phase III trial of inhaled nitric oxide. Crit Care
Med. 2006;34(12):2883-2890.
163. Dellinger RP, Trzeciak SW, Criner GJ, et al. Association
between inhaled nitric oxide treatment and long-term pulmonary
function in survivors of acute respiratory distress syndrome. Crit
Care. 2012;16(2):R36.
164. Adhikari NK, Dellinger RP, Lundin S, et al. Inhaled nitric oxide
does not reduce mortality in patients with acute respiratory distress syndrome regardless of severity: systematic review and
meta-analysis. Crit Care Med. 2014;42(2):404-412.
165. Dunkley KA, Louzon PR, Lee J, Vu S. Efficacy, safety, and
medication errors associated with the use of inhaled epoprostenol for adults with acute respiratory distress syndrome: a pilot
study. Ann Pharmacother. 2013;47(6):790-796.
166. Sawheny E, Ellis AL, Kinasewitz GT. Iloprost improves gas
exchange in patients with pulmonary hypertension and ARDS.
Chest. 2013;144(1):55-62.
167. Dahlem P, van Aalderen WM, de Neef M, Dijkgraaf MG, Bos
AP. Randomized controlled trial of aerosolized prostacyclin
therapy in children with acute lung injury. Crit Care Med.
2004;32(4):1055-1060.
14
168. Walmrath D, Schneider T, Schermuly R, Olschewski H, Grimminger F, Seeger W. Direct comparison of inhaled nitric oxide
and aerosolized prostacyclin in acute respiratory distress syndrome. Am J Respir Crit Care Med. 1996;153(3):991-996.
169. Torbic H, Szumita PM, Anger KE, Nuccio P, LaGambina S,
Weinhouse G. Inhaled epoprostenol vs inhaled nitric oxide for
refractory hypoxemia in critically ill patients. J Crit Care. 2013;
28(5):844-848.
170. Cornet AD, Hofstra JJ, Swart EL, Girbes AR, Juffermans NP.
Sildenafil attenuates pulmonary arterial pressure but does not
improve oxygenation during ARDS. Intensive Care Med.
2010;36(5):758-764.
171. Weigelt JA, Norcross JF, Borman KR, Snyder WH 3rd. Early
steroid therapy for respiratory failure. Arch Surg. 1985;120(5):
536-540.
172. Bone RC, Fisher CJ Jr., Clemmer TP, Slotman GJ, Metz CA.
Early methylprednisolone treatment for septic syndrome and the
adult respiratory distress syndrome. Chest. 1987;92(6):
1032-1036.
173. Steinberg KP, Hudson LD, Goodman RB, et al.; Blood Institute
Acute Respiratory Distress Syndrome Clinical Trials N. Efficacy
and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med. 2006;354(16):1671-1684.
174. Deal EN, Hollands JM, Schramm GE, Micek ST. Role of corticosteroids in the management of acute respiratory distress syndrome. Clin Ther. 2008;30(5):787-799.
175. Peter JV, John P, Graham PL, Moran JL, George IA, Bersten A.
Corticosteroids in the prevention and treatment of acute respiratory distress syndrome (ARDS) in adults: meta-analysis. BMJ.
2008;336(7651):1006-1009.
176. Meduri GU, Golden E, Freire AX, et al. Methylprednisolone
infusion in early severe ARDS results of a randomized controlled trial. 2007. Chest. 2009;136(5 suppl):e30.
177. Tang BM, Craig JC, Eslick GD, Seppelt I, McLean AS. Use of
corticosteroids in acute lung injury and acute respiratory distress
syndrome: a systematic review and meta-analysis. Crit Care
Med. 2009;37(5):1594-1603.
178. Meduri GU, Bridges L, Shih MC, Marik PE, Siemieniuk RA,
Kocak M. Prolonged glucocorticoid treatment is associated with
improved ARDS outcomes: analysis of individual patients’ data
from four randomized trials and trial-level meta-analysis of the
updated literature. Intensive Care Med. 2016;42(5):829-840.
179. Ortiz-Diaz E, Li G, Kor D. Preadmission use of inhaled corticosteroids is associated with a reduced risk of direct acute lung
injury/acute respiratory distress syndrome. Chest. 2011;140:
912A.
180. Weg JG, Balk RA, Tharratt RS, et al. Safety and potential efficacy of an aerosolized surfactant in human sepsis-induced adult
respiratory distress syndrome. JAMA. 1994;272(18):1433-1438.
181. Anzueto A, Baughman RP, Guntupalli KK, et al. Aerosolized
surfactant in adults with sepsis-induced acute respiratory distress
syndrome. Exosurf acute respiratory distress syndrome sepsis
study group. N Engl J Med. 1996;334(22):1417-1421.
182. Spragg RG, Lewis JF, Walmrath HD, et al. Effect of recombinant surfactant protein C-based surfactant on the acute respiratory distress syndrome. N Engl J Med. 2004;351(9):884-892.
Journal of Intensive Care Medicine XX(X)
183. Davidson WJ, Dorscheid D, Spragg R, Schulzer M, Mak E, Ayas
NT. Exogenous pulmonary surfactant for the treatment of adult
patients with acute respiratory distress syndrome: results of a
meta-analysis. Crit Care. 2006;10(2):R41.
184. Kesecioglu J, Beale R, Stewart TE, et al. Exogenous natural
surfactant for treatment of acute lung injury and the acute
respiratory distress syndrome. Am J Respir Crit Care Med.
2009;180(10):989-994.
185. Willson DF, Thomas NJ, Markovitz BP, et al. Effect of exogenous surfactant (calfactant) in pediatric acute lung injury: a randomized controlled trial. JAMA. 2005;293(4):470-476.
186. Taut FJ, Rippin G, Schenk P, et al. A Search for subgroups of
patients with ARDS who may benefit from surfactant replacement therapy: a pooled analysis of five studies with recombinant
surfactant protein-C surfactant (Venticute). Chest. 2008;134(4):
724-732.
187. Spragg RG, Taut FJ, Lewis JF, et al. Recombinant surfactant
protein C-based surfactant for patients with severe direct lung
injury. Am J Respir Crit Care Med. 2011;183(8):1055-1061.
188. Park SY, Kim HJ, Yoo KH, et al. The efficacy and safety of
prone positioning in adults patients with acute respiratory distress syndrome: a meta-analysis of randomized controlled trials.
J Thorac Dis. 2015;7(3):356-367.
189. Randomized, placebo-controlled trial of lisofylline for early
treatment of acute lung injury and acute respiratory distress
syndrome. Crit Care Med. 2002;30(1):1-6.
190. Jepsen S, Herlevsen P, Knudsen P, Bud MI, Klausen NO. Antioxidant treatment with N-acetylcysteine during adult respiratory
distress syndrome: a prospective, randomized, placebocontrolled study. Crit Care Med. 1992;20(7):918-923.
191. Bernard GR, Wheeler AP, Arons MM, et al. A trial of antioxidants N-acetylcysteine and procysteine in ARDS. The
Antioxidant in ARDS Study Group. Chest. 1997;112(1):
164-172.
192. Suter PM, Domenighetti G, Schaller MD, Laverriere MC, Ritz
R, Perret C. N-acetylcysteine enhances recovery from acute lung
injury in man. A randomized, double-blind, placebo-controlled
clinical study. Chest. 1994;105(1):190-194.
193. Domenighetti G, Suter PM, Schaller MD, Ritz R, Perret C.
Treatment with N-acetylcysteine during acute respiratory distress syndrome: a randomized, double-blind, placebocontrolled clinical study. J Crit Care. 1997;12(4):177-182.
194. Moradi M, Mojtahedzadeh M, Mandegari A, et al. The role of
glutathione-S-transferase polymorphisms on clinical outcome of
ALI/ARDS patient treated with N-acetylcysteine. Respir Med.
2009;103(3):434-441.
195. Walkey AJ, Wiener RS. Macrolide antibiotics and survival in
patients with acute lung injury. Chest. 2012;141(5):1153-1159.
196. Yu M, Tomasa G. A double-blind, prospective, randomized trial
of ketoconazole, a thromboxane synthetase inhibitor, in the prophylaxis of the adult respiratory distress syndrome. Crit Care
Med. 1993;21(11):1635-1642.
197. Slotman GJ, Burchard KW, D’Arezzo A, Gann DS. Ketoconazole prevents acute respiratory failure in critically ill surgical
patients. J Trauma. 1988;28(5):648-654.
Kaku et al
198. Ketoconazole for early treatment of acute lung injury and acute
respiratory distress syndrome: a randomized controlled trial. The
ARDS Network. JAMA. 2000;283(15):1995-2002.
199. Ortiz-Diaz E, Festic E, Gajic O, Levitt JE. Emerging pharmacological therapies for prevention and early treatment of acute lung
injury. Semin Respir Crit Care Med. 2013;34(4):448-458.
200. Boyle AJ, Mac Sweeney R, McAuley DF. Pharmacological
treatments in ARDS: a state-of-the-art update. BMC Med.
2013;11:166.
201. Trillo-Alvarez CA, Kashyap R, Kojicic M, Li G, Thakur S.
Chronic use of angiotensin pathway inhibitors is associated with
a decreased risk of acute respiratory distress syndrome. Am J
Respir Crit Care Med. 2009;179(1):A4638.
202. Watkins TR, Lemos-Filho LB, Dabbagh O, Chang SY, Park PK.
Use of angiotensin converting enzyme inhibitors or angiotensin
receptor blockers and clinical outcomes among patients at-risk
for acute lung injury. In American Thoracic Society International Conference, 2011, Denver, CO.
203. Walter J, Ware LB, Matthay MA. Mesenchymal stem cells:
mechanisms of potential therapeutic benefit in ARDS and sepsis.
Lancet Respir Med. 2014;2(12):1016-1026.
204. Rojas M, Xu J, Woods CR, et al. Bone marrow-derived
mesenchymal stem cells in repair of the injured lung. Am J
Respir Cell Mol Biol. 2005;33(2):145-152.
15
205. Serikov VB, Mikhaylov VM, Krasnodembskay AD, Matthay
MA. Bone marrow-derived cells participate in stromal remodeling of the lung following acute bacterial pneumonia in mice.
Lung. 2008;186(3):179-190.
206. Gupta N, Su X, Popov B, Lee JW, Serikov V, Matthay MA.
Intrapulmonary delivery of bone marrow-derived mesenchymal stem cells improves survival and attenuates endotoxininduced acute lung injury in mice. J Immunol. 2007;179(3):
1855-1863.
207. McIntyre LA, Moher D, Fergusson DA, et al. Efficacy of
mesenchymal stromal cell therapy for acute lung injury in preclinical animal models: a systematic review. PloS one. 2016;
11(1):e0147170.
208. Lee JW, Krasnodembskaya A, McKenna DH, Song Y, Abbott J,
Matthay MA. Therapeutic effects of human mesenchymal stem
cells in ex vivo human lungs injured with live bacteria. Am J
Respir Crit Care Med. 2013;187(7):751-760.
209. Zheng G, Huang L, Tong H, et al. Treatment of acute respiratory
distress syndrome with allogeneic adipose-derived mesenchymal stem cells: a randomized, placebo-controlled pilot study.
Respir Res. 2014;15:39.
210. Wilson JG, Liu KD, Zhuo H, et al. Mesenchymal stem (stromal)
cells for treatment of ARDS: a phase 1 clinical trial. Lancet
Respir Med. 2015;3(1):24-32.