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: natalie.htet@gmail.com
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
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