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Acute Respiratory Distress

Syndrome
Updated: Oct 17, 2018
Author: Eloise M Harman, MD; Chief Editor: Michael R Pinsky, MD, CM, Dr(HC), FCCP, FAPS, MCCM

Overview

Background
Since World War I, it has been recognized that some patients with nonthoracic injuries, severe pancreatitis, massive
transfusion, sepsis, and other conditions develop respiratory distress, diffuse lung infiltrates, and respiratory failure,
sometimes after a delay of hours to days. Ashbaugh et al described 12 such patients in 1967, using the term “adult
respiratory distress syndrome” to describe this condition.[1]

Before research into the pathogenesis and treatment of this syndrome could proceed, it was necessary to formulate a
clear definition of the syndrome. Such a definition was developed in 1994 by the American-European Consensus
Conference (AECC) on acute respiratory distress syndrome (ARDS).[2] The term “acute respiratory distress
syndrome” was used instead of “adult respiratory distress syndrome” because the syndrome occurs in both adults and
children.

ARDS was recognized as the most severe form of acute lung injury (ALI), a form of diffuse alveolar injury. The AECC
defined ARDS as an acute condition characterized by bilateral pulmonary infiltrates and severe hypoxemia in the
absence of evidence for cardiogenic pulmonary edema. The severity of hypoxemia necessary to make the diagnosis of
ARDS was defined by the ratio of the partial pressure of oxygen in the patient’s arterial blood (PaO2) to the fraction of
oxygen in the inspired air (FiO2). ARDS was defined by a PaO2/FiO2 ratio of less than 200, and in ALI, less than 300.

This definition was further refined in 2011 by a panel of experts and is termed the Berlin definition of ARDS.[3] ARDS is
defined by timing (within 1 wk of clinical insult or onset of respiratory symptoms); radiographic changes (bilateral
opacities not fully explained by effusions, consolidation, or atelectasis); origin of edema (not fully explained by cardiac
failure or fluid overload); and severity based on the PaO2/FiO2 ratio on 5 cm of continuous positive airway pressure
(CPAP). The 3 categories are mild (PaO2/FiO2 200-300), moderate (PaO2/FiO2 100-200), and severe (PaO2/FiO2
≤100).
DEFINITION
Go to Barotrauma and Mechanical Ventilation and Pediatric Acute Respiratory Distress Syndrome for complete
information on these topics.

Pathophysiology
ARDS is associated with diffuse alveolar damage (DAD) and lung capillary endothelial injury. The early phase is
described as being exudative, whereas the later phase is fibroproliferative in character.

Early ARDS is characterized by an increase in the permeability of the alveolar-capillary barrier, leading to an influx of
fluid into the alveoli. The alveolar-capillary barrier is formed by the microvascular endothelium and the epithelial lining
of the alveoli. Hence, a variety of insults resulting in damage either to the vascular endothelium or to the alveolar
epithelium could result in ARDS.

The main site of injury may be focused on either the vascular endothelium (eg, sepsis) or the alveolar epithelium (eg,
aspiration of gastric contents). Injury to the endothelium results in increased capillary permeability and the influx of
protein-rich fluid into the alveolar space.

Injury to the alveolar lining cells also promotes pulmonary edema formation. Two types of alveolar epithelial cells exist.
Type I cells, which make up 90% of the alveolar epithelium, are injured easily. Damage to type I cells allows both
increased entry of fluid into the alveoli and decreased clearance of fluid from the alveolar space.

Type II alveolar epithelial cells are relatively more resistant to injury. However, type II cells have several important
functions, including the production of surfactant, ion transport, and proliferation and differentiation into type l cells after
cellular injury. Damage to type II cells results in decreased production of surfactant with resultant decreased
compliance and alveolar collapse. Interference with the normal repair processes in the lung may lead to the
development of fibrosis.

Neutrophils are thought to play a key role in the pathogenesis of ARDS, as suggested by studies of bronchoalveolar
lavage (BAL) and lung biopsy specimens in early ARDS. Despite the apparent importance of neutrophils in this
syndrome, ARDS may develop in profoundly neutropenic patients, and infusion of granulocyte colony-stimulating factor
(G-CSF) in patients with ventilator-associated pneumonia (VAP) does not promote its development. This and other
evidence suggests that the neutrophils observed in ARDS may be reactive rather than causative.

Cytokines (tumor necrosis factor [TNF], leukotrienes, macrophage inhibitory factor, and numerous others), along with
platelet sequestration and activation, are also important in the development of ARDS. An imbalance of
proinflammatory and anti-inflammatory cytokines is thought to occur after an inciting event, such as sepsis. Evidence
from animal studies suggests that the development of ARDS may be promoted by the positive airway pressure
delivered to the lung by mechanical ventilation. This is termed ventilator-associated lung injury (VALI). Studies (2017)
on the ARDSNet patient cohort have identified at least two major subgroups based on immune response and
physiologic presentation.[4] Type one reflects primarily acute lung injury without antecedent systemic processes like
sepsis or pancreatitis. Type two is acute lung injury with an overwhelming systemic insult like sepsis. Important to note,
type one patients benefit from a fluid-restrictive management strategy (infra vide), while type two patients benefit from
a fluid-liberal approach. Regrettably, as of now, the prospective early separation of ARDS patients into these two types
remains unresolved.

ARDS expresses itself as an inhomogeneous process. Relatively normal alveoli, which are more compliant than
affected alveoli, may become overdistended by the delivered tidal volume, resulting in barotrauma (pneumothorax and
interstitial air). Alveoli already damaged by ARDS may experience further injury from the shear forces exerted by the
cycle of collapse at end-expiration and reexpansion by positive pressure at the next inspiration (so-called volutrauma).

In addition to the mechanical effects on alveoli, these forces promote the secretion of proinflammatory cytokines with
resultant worsening inflammation and pulmonary edema. The use of positive end-expiratory pressure (PEEP) to
diminish alveolar collapse and the use of low tidal volumes and limited levels of inspiratory filling pressures appear to
be beneficial in diminishing the observed VALI.

ARDS causes a marked increase in intrapulmonary shunting, leading to severe hypoxemia. Although a high FiO2 is
required to maintain adequate tissue oxygenation and life, additional measures, like lung recruitment with PEEP, are
often required. Theoretically, high FiO2 levels may cause DAD via oxygen free radical and related oxidative stresses,
collectively called oxygen toxicity. Generally, oxygen concentrations higher than 65% for prolonged periods (days) can
result in DAD, hyaline membrane formation, and, eventually, fibrosis.

ARDS is uniformly associated with pulmonary hypertension. Pulmonary artery vasoconstriction likely contributes to
ventilation-perfusion mismatch and is one of the mechanisms of hypoxemia in ARDS. Normalization of pulmonary
artery pressures occurs as the syndrome resolves. The development of progressive pulmonary hypertension is
associated with a poor prognosis. pulmonary ipertension
The acute phase of ARDS usually resolves completely. Less commonly, residual pulmonary fibrosis occurs, in which
the alveolar spaces are filled with mesenchymal cells and new blood vessels. This process seems to be facilitated by
interleukin (IL)-1. Progression to fibrosis may be predicted early in the course by the finding of increased levels of
procollagen peptide III (PCP-III) in the fluid obtained by BAL. This and the finding of fibrosis on biopsy correlate with an
increased mortality rate.

Etiology
Multiple risk factors exist for ARDS. Approximately 20% of patients with ARDS have no identified risk factor. ARDS risk
factors include direct lung injury (most commonly, aspiration of gastric contents), systemic illnesses, and injuries. The
most common risk factor for ARDS is sepsis..

Given the number of adult studies, major risk factors associated with the development of ARDS include the following:

Bacteremia

Sepsis

Trauma, with or without pulmonary contusion

Fractures, particularly multiple fractures and long bone fractures

Burns

Massive transfusion

Pneumonia

Aspiration

Drug overdose

Near drowning

Postperfusion injury after cardiopulmonary bypass

Pancreatitis

Fat embolism

General risk factors for ARDS have not been prospectively studied using the 1994 EACC criteria. However, several
factors appear to increase the risk of ARDS after an inciting event, including advanced age, female sex (noted only in
trauma cases), cigarette smoking,[5] and alcohol use. For any underlying cause, increasingly severe illness as
predicted by a severity scoring system such as the Acute Physiology And Chronic Health Evaluation (APACHE)
increases the risk of development of ARDS.

Genetic factors

A study by Glavan et al examined the association between genetic variations in the FAS gene and ALI susceptibility.
The study identified associations between four single nucleotide polymorphisms and increased ALI susceptibility.[6]
Further studies are needed to examine the role of FAS in ALI.

Epidemiology
The incidence of ARDS varies widely, partly because studies have used different definitions of the disease. Moreover,
to determine an accurate estimate of its incidence, all cases of ARDS in a given population must be found and
included. Although this may be problematic, recent data are available from the United States and international studies
that may clarify the true incidence of this condition.

United States statistics

In the 1970s, when a National Institutes of Health (NIH) study of ARDS was being planned, the estimated annual
frequency was 75 cases per 100,000 population. Subsequent studies, before the development of the AECC definitions,
reported much lower figures. For example, a study from Utah showed an estimated incidence of 4.8-8.3 cases per
100,000 population.

Data obtained more recently by the NIH-sponsored ARDS Study Network suggest that the incidence of ARDS may
actually be higher than the original estimate of 75 cases per 100,000 population. A prospective study using the 1994
AECC definition was performed in King County, Washington, from April 1999 through July 2000 and found that the
age-adjusted incidence of ALI was 86.2 per 100,000 person-years.[7] Incidence increased with age, reaching 306 per
100,000 person-years for people in aged 75-84 years.

On the basis of these statistics, it is estimated that 190,600 cases exist in the United States annually and that these
cases are associated with 74,500 deaths.

International statistics

The first study to use the 1994 AECC definitions was performed in Scandinavia, which reported annual rates of 17.9
cases per 100,000 population for ALI and 13.5 cases per 100,000 population for ARDS.[8]

Age-related differences in incidence

ARDS may occur in people of any age. Its incidence increases with advancing age, ranging from 16 cases per 100,000
person-years in those aged 15-19 years to 306 cases per 100,000 person-years in those between the ages of 75 and
84 years. The age distribution reflects the incidence of the underlying causes.

Sex-related differences in incidence

For ARDS associated with sepsis and most other causes, no differences in the incidence between males and females
appear to exist. However, in trauma patients only, the incidence of the disease may be slightly higher among females.

Prognosis
Until the 1990s, most studies reported a 40-70% mortality rate for ARDS. However, 2 reports in the 1990s, one from a
large county hospital in Seattle and one from the United Kingdom, suggested much lower mortality rates, in the range
of 30-40%.[9, 10] Possible explanations for the improved survival rates may be better understanding and treatment of
sepsis, recent changes in the application of mechanical ventilation, and better overall supportive care of critically ill
patients.

Note that most deaths in ARDS patients are attributable to sepsis (a poor prognostic factor) or multiorgan failure rather
than to a primary pulmonary cause, although the recent success of mechanical ventilation using smaller tidal volumes
may suggest a role of lung injury as a direct cause of death.

Mortality in ARDS increases with advancing age. A study performed in King County, Washington, found mortality rates
of 24% in patients between ages 15 and 19 years and 60% in patients aged 85 years and older. The adverse effect of
age may be related to underlying health status.

Indices of oxygenation and ventilation, including the PaO2/FiO2 ratio, do not predict the outcome or risk of death. The
severity of hypoxemia at the time of diagnosis does not correlate well with survival rates. However, the failure of
pulmonary function to improve in the first week of treatment is a poor prognostic factor.

Peripheral blood levels of decoy receptor 3 (DcR3), a soluble protein with immunomodulatory effects, independently
predict 28-day mortality in ARDS patients. In a study comparing DcR3, soluble triggering receptor expressed on
myeloid cells (sTREM)-1, TNF-alpha, and IL-6 in ARDS patients, plasma DcR3 levels were the only biomarker to
distinguish survivors from nonsurvivors at all time points in week 1 of ARDS.[11] Nonsurvivors had higher DcR3 levels
than survivors, regardless of APACHE II scores, and mortality was higher in patients with higher DcR3 levels.

Morbidity is considerable. Patients with ARDS are likely to have prolonged hospital courses, and they frequently
develop nosocomial infections, especially ventilator-associated pneumonia (VAP). In addition, patients often have
significant weight loss and muscle weakness, and functional impairment may persist for months after hospital
discharge.[12]

Severe disease and prolonged duration of mechanical ventilation are predictors of persistent abnormalities in
pulmonary function. Survivors of ARDS have significant functional impairment for years following recovery.

In a study of 109 survivors of ARDS, 12 patients died in the first year. In 83 evaluable survivors, spirometry and lung
volumes were normal at 6 months, but diffusing capacity remained mildly diminished (72%) at 1 year.[12] ARDS
survivors had abnormal 6-minute walking distances at 1 year, and only 49% had returned to work. Their health-related
quality of life was significantly below normal. However, no patient remained oxygen dependent at 12 months.
Radiographic abnormalities had also completely resolved.

A study of this same group of patients 5 years after recovery from ARDS (9 additional patients had died and 64 were
evaluated) showed continued exercise impairment and decreased quality of life related to both physical and
neuropsychological factors.[13]
A study examining health-related quality of life (HRQL) after ARDS determined that ARDS survivors had poorer overall
HRQL than the general population at 6 months after recovery.[14] This included lower scores in mobility, energy, and
social isolation.

Patient Education
For patient education resources, see the Lung and Airway Center, the Procedures Center, and the Bacterial and Viral
Infections Center, as well as Acute Respiratory Distress Syndrome, Bronchoscopy, and Severe Acute Respiratory
Syndrome (SARS).

Presentation

History
Acute respiratory distress syndrome (ARDS) is characterized by the development of acute dyspnea and hypoxemia
within hours to days of an inciting event, such as trauma, sepsis, drug overdose, massive transfusion, acute
pancreatitis, or aspiration. In many cases, the inciting event is obvious, but, in others (eg, drug overdose), it may be
harder to identify.

Patients developing ARDS are critically ill, often with multisystem organ failure, and they may not be capable of
providing historical information. Typically, the illness develops within 12-48 hours after the inciting event, although, in
rare instances, it may take up to a few days.

With the onset of lung injury, patients initially note dyspnea with exertion. This rapidly progresses to severe dyspnea at
rest, tachypnea, anxiety, agitation, and the need for increasingly high concentrations of inspired oxygen.

Physical Examination
Physical findings often are nonspecific and include tachypnea, tachycardia, and the need for a high fraction of inspired
oxygen (FiO2) to maintain oxygen saturation. The patient may be febrile or hypothermic. Because ARDS often occurs
in the context of sepsis, associated hypotension and peripheral vasoconstriction with cold extremities may be present.
Cyanosis of the lips and nail beds may occur.

Examination of the lungs may reveal bilateral rales. Rales may not be present despite widespread involvement.
Because the patient is often intubated and mechanically ventilated, decreased breath sounds over 1 lung may indicate
a pneumothorax or endotracheal tube down the right main bronchus.

Manifestations of the underlying cause (eg, acute abdominal findings in the case of ARDS caused by pancreatitis) are
present.

In a septic patient without an obvious source, pay careful attention during the physical examination to identify potential
causes of sepsis, including signs of lung consolidation or findings consistent with an acute abdomen. Carefully
examine sites of intravascular lines, surgical wounds, drain sites, and decubitus ulcers for evidence of infection. Check
for subcutaneous air, a manifestation of infection or barotrauma.

Because cardiogenic pulmonary edema must be distinguished from ARDS, carefully look for signs of congestive heart
failure or intravascular volume overload, including jugular venous distention, cardiac murmurs and gallops,
hepatomegaly, and edema.
Complications
Patients with ARDS often require high-intensity mechanical ventilation, including high levels of positive end-expiratory
pressure (PEEP) or continuous positive airway pressure (CPAP) and, possibly, high mean airway pressures; thus,
barotrauma may occur. Patients present with pneumomediastinum, pneumothorax, or both. Other potential
complications that may occur in these mechanically ventilated patients include accidental extubation and right
mainstem intubation.

If prolonged mechanical ventilation is needed, patients may eventually require tracheostomy. With prolonged intubation
and tracheostomy, upper airway complications may occur, most notably postextubation laryngeal edema and subglottic
stenosis.

Because patients with ARDS often require prolonged mechanical ventilation and invasive hemodynamic monitoring,
they are at risk for serious nosocomial infections, including ventilator-associated pneumonia (VAP) and line sepsis.
The incidence of VAP in ARDS patients may be as high as 55% and appears to be higher than that in other
populations requiring mechanical ventilation. Preventive strategies including elevation of head of the bed, use of
subglottic suction endotracheal tubes, and oral decontamination.

Other potential infections include urinary tract infection (UTI) related to the use of urinary catheters and sinusitis
related to the use of nasal feeding and drainage tubes. Patients may also develop Clostridium difficile colitis as a
complication of broad-spectrum antibiotic therapy. Patients with ARDS, because of the extended intensive care unit
(ICU) stay and treatment with multiple antibiotics, may also develop infections with drug-resistant organisms such as
methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE).

In a study of survivors of ARDS, significant functional impairment was noted at 1 year, primarily related to muscle
wasting and weakness.[12] Corticosteroid treatment and use of neuromuscular blockade are risk factors for muscle
weakness and poor functional recovery.

Patients may have difficulty weaning from mechanical ventilation. Strategies to facilitate weaning, such as daily
interruption of sedation,[15] early institution of physical therapy, attention to maintaining nutrition, and use of weaning
protocols, may decrease the duration of mechanical ventilation and facilitate recovery.

Renal failure is a frequent complication of ARDS, particularly in the context of sepsis. Renal failure may be related to
hypotension, nephrotoxic drugs, or underlying illness. Fluid management is complicated in this context, especially if the
patient is oliguric. Multisystem organ failure, rather than respiratory failure alone, is usually the cause of death in
ARDS.

Other potential complications include ileus, stress gastritis, and anemia. Stress ulcer prophylaxis is indicated for these
patients. Anemia may be prevented by the use of growth factors (erythropoietin).

Although not mentioned often, survivors of ARDs often suffer from posttraumatic stress disorder (PTSD), prolonged
myopathy limiting activities of daily living, and increased long-term mortality after apparent recovery.[16] These major
postillness complications usually linger a minimum of 3 months, but several patients have persistent neurocognitive
dysfunction 1-2 years afterward, independent of physiologic status and cardiopulmonary reserve. The management of
these complications is primarily supportive and aided by the clinician having a keen awareness that such PTSD
symptoms persist.

DDx

Diagnostic Considerations
Other conditions to be considered include the following:

Pulmonary hemorrhage

Near drowning

Drug reaction

Noncardiogenic pulmonary edema

Hamman-Rich syndrome
 Retinoic acid syndrome

Acute hypersensitivity pneumonitis

Transfusion-related acute lung injury (TRALI)

Acute eosinophilic pneumonia

Reperfusion injury

Leukemic infiltration

Fat embolism syndrome

Differential Diagnoses
Aspiration Pneumonitis and Pneumonia

Bacterial Pneumonia

Bacterial Sepsis

Goodpasture Syndrome

Hemorrhagic Shock

Heroin Toxicity

Hypersensitivity Pneumonitis

Mechanical Ventilation

Multiple Organ Dysfunction Syndrome in Sepsis

Noninvasive Ventilation

Hospital-Acquired Pneumonia (Nosocomial Pneumonia) and Ventilator-Associated Pneumonia

Perioperative Pulmonary Management

Pneumocystis jiroveci Pneumonia (PJP)

Pulmonary Eosinophilia

Respiratory Failure

Salicylate Toxicity

Septic Shock

Toxic Shock Syndrome

Transfusion Reactions

Tumor Lysis Syndrome

Ventilator-Associated Pneumonia

Viral Pneumonia

Workup

Workup
Approach Considerations
Acute respiratory distress syndrome (ARDS) is defined by the acute onset of bilateral pulmonary infiltrates and severe
hypoxemia in the absence of evidence of cardiogenic pulmonary edema. Workup includes selected laboratory tests,
diagnostic imaging, hemodynamic monitoring, and bronchoscopy. ARDS is a clinical diagnosis, and no specific
laboratory abnormalities are noted beyond the expected disturbances in gas exchange and radiographic findings.

Laboratory Tests
In ARDS, if the partial pressure of oxygen in the patient’s arterial blood (PaO2) is divided by the fraction of oxygen in
the inspired air (FiO2), the result is 300 or less. For patients breathing 100% oxygen, this means that the PaO2 is less
than 300.

In addition to hypoxemia, arterial blood gases often initially show a respiratory alkalosis. However, in ARDS occurring
in the context of sepsis, a metabolic acidosis with or without respiratory compensation may be present.

As the condition progresses and the work of breathing increases, the partial pressure of carbon dioxide (PCO2) begins
to rise and respiratory alkalosis gives way to respiratory acidosis. Patients on mechanical ventilation for ARDS may be
allowed to remain hypercapnic (permissive hypercapnia) to achieve the goals of low tidal volume and limited plateau
pressure ventilator strategies aimed at limiting ventilator-associated lung injury.

To exclude cardiogenic pulmonary edema, it may be helpful to obtain a plasma B-type natriuretic peptide (BNP) value
and echocardiogram. A BNP level of less than 100 pg/mL in a patient with bilateral infiltrates and hypoxemia favors the
diagnosis of ARDS/acute lung injury (ALI) rather than cardiogenic pulmonary edema. The echocardiogram provides
information about left ventricular ejection fraction, wall motion, and valvular abnormalities.[17]

Other abnormalities observed in ARDS depend on the underlying cause or associated complications and may include
the following:

Hematologic - In septic patients, leukopenia or leukocytosis may be noted. Thrombocytopenia may be observed
in septic patients in the presence of disseminated intravascular coagulation (DIC). Von Willebrand factor (VWF)
may be elevated in patients at risk for ARDS and may be a marker of endothelial injury.

Renal - Acute tubular necrosis (ATN) often ensues in the course of ARDS, probably from ischemia to the
kidneys. Renal function should be closely monitored.

Hepatic - Liver function abnormalities may be noted in either a pattern of hepatocellular injury or cholestasis.

Cytokines - Multiple cytokines, such as interleukin (IL)–1, IL-6, and IL-8, are elevated in the serum of patients at
risk for ARDS.

Radiography
ARDS is defined by the presence of bilateral pulmonary infiltrates. The infiltrates may be diffuse and symmetric or
asymmetric, especially if superimposed upon preexisting lung disease or if the insult causing ARDS was a pulmonary
process, such as aspiration or lung contusion.

The pulmonary infiltrates usually evolve rapidly, with maximal severity within the first 3 days. Infiltrates can be noted on
chest radiographs almost immediately after the onset of gas exchange abnormalities. They may be interstitial,
characterized by alveolar filling, or both.

Initially, the infiltrates may have a patchy peripheral distribution, but soon they progress to diffuse bilateral involvement
with ground glass changes or frank alveolar infiltrates (see the image below).
Anteroposterior portable chest radiograph in patient who had been in respiratory failure for 1 week with diagnosis of
acute respiratory distress syndrome. Image shows endotracheal tube, left subclavian central venous catheter in
superior vena cava, and bilateral patchy opacities in mostly middle and lower lung zones.

The correlation between radiographic findings and severity of hypoxemia is highly variable. In addition, diuresis tends
to improve infiltrates and volume overload tends to worsen them, irrespective of improvement or worsening in
underlying ARDS.

For patients who begin to improve and show signs of resolution, improvement in radiographic abnormalities generally
occurs over 10-14 days; however, more protracted courses are common.

Computed Tomography
In general, clinical evaluation and routine chest radiography are sufficient in patients with ARDS. However, computed
tomography (CT) scanning may be indicated in some situations. CT scanning is more sensitive than plain chest
radiography in detecting pulmonary interstitial emphysema, pneumothoraces and pneumomediastinum, pleural
effusions, cavitation, and mediastinal lymphadenopathy. The heterogeneity of alveolar involvement is often apparent
on CT scan even in the presence of diffuse homogeneous infiltrates on routine chest radiograph.

In some instances, the discovery of unexpected pulmonary pathology, such as a pneumothorax, may be lifesaving.
However, this potential benefit must be weighed against the risk associated with transporting a critically ill patient on
high-intensity mechanical ventilation out of the intensive care unit (ICU) to the CT scan equipment.

Echocardiography
As part of the workup, patients with ARDS should undergo 2-dimensional echocardiography for the purpose of
screening. If findings are suggestive of patent foramen ovale shunting, 2-dimensional echocardiography should be
followed up with transesophageal echocardiography.[18]

Because patients with severe ARDS often require prolonged prone positioning due to refractory hypoxemia, a study
assessed the use of transesophageal echocardiography (TEE) in patients in the prone position.[19] The study
determined that TEE can be safely and efficiently performed in patients with severe ARDS in the prone position.
Invasive Hemodynamic Monitoring
Because avoiding fluid-overload may be beneficial in the management of ARDS, the use of a central venous catheter
or pulmonary artery catheter may facilitate appropriate fluid management in these patients in whom judging
intravascular volume status on clinical grounds may be difficult or impossible. This may be especially helpful in patients
who are hypotensive or those with associated renal failure.

Although pulmonary artery catheters provide considerable information, their use is not without controversy. The ARDS
Clinical Trials Network studied whether a difference in mortality could be found in ARDS patients whose fluid
management was guided by pulmonary artery catheter versus central venous catheter after initial resuscitation.[20]
The study found no difference in mortality, ventilator days, ICU days, or need for pressors or dialysis The pulmonary
artery catheter group had twice as many catheter-related complications, primarily arrhythmias. Still, more patients were
excluded from the study because they had already received a pulmonary artery catheter than were randomized into
both groups combined. And, when the nonrandomized patients were studied, their mortality was similar to both control
groups.

Another large retrospective study of critically ill patients monitored with pulmonary artery catheters in the first 24 hours
of ICU admission showed that patients with pulmonary artery catheters had an increased mortality rate, hospital cost,
and length of stay compared with a retrospectively developed matched patient group managed without them.[21] Thus,
use of the generic pulmonary artery catheter past the time of initial resuscitation confers no survival benefit and
possibly has an adverse effect on survival.

In addition, accurate measurement of hemodynamic parameters with the pulmonary artery catheter requires skill and
care. This is especially difficult in patients either on mechanical ventilation or with forced spontaneous inspirations
because the pressure tracing is affected by intrathoracic pressure. PCWP should be measured at end-expiration and
from the tracing rather than from digital displays on the bedside monitor.

Bronchoscopy
Bronchoscopy may be considered to evaluate the possibility of infection, alveolar hemorrhage, or acute eosinophilic
pneumonia in patients acutely ill with bilateral pulmonary infiltrates. Culture material may be obtained by wedging the
bronchoscope in a subsegmental bronchus and collecting the fluid suctioned after instilling large volumes of
nonbacteriostatic saline (bronchoalveolar lavage; BAL). The fluid is analyzed for cell differential, cytology, silver stain,
and Gram stain and is quantitatively cultured.

Ten thousand organisms per milliliter is generally considered significant in a patient not previously treated with
antibiotics. As noted (see above), early ARDS is characterized by the presence of neutrophils in the BAL fluid, so the
presence of intracellular organisms and the use of quantitative culture are important in establishing infection.

An alternative means of obtaining a culture is by means of a protected specimen brush, which is passed through the
bronchoscope into a segmental bronchus. Subsequently, the brush is cut off into 1 mL of sterile nonbacteriostatic
saline. Culture of 1000 organisms is considered significant.

Analysis of the types of cells present in the BAL fluid may be helpful in the differential diagnosis of patients with ARDS.
For example, the finding of a high percentage of eosinophils (>20%) in the BAL fluid is consistent with the diagnosis of
acute eosinophilic pneumonia. The use of high-dose corticosteroids in these patients may be lifesaving.

A high proportion of lymphocytes may be observed in acute hypersensitivity pneumonitis, sarcoidosis, or bronchiolitis
obliterans-organizing pneumonia (BOOP). Red cells and hemosiderin-laden macrophages may be observed in
pulmonary hemorrhage. Lipid laden macrophages are suggestive of aspiration or lipoid pneumonia.

Cytologic evaluation of the BAL fluid may also be helpful in the differential diagnosis of ARDS. This may reveal viral
cytopathic changes, for example. Silver stain may be helpful in diagnosing an infection, such as Pneumocystis.

The use of bronchoscopy as an adjunct to surfactant therapy has been reported. In 10 adults with ARDS, sequential
bronchopulmonary segmental lavage with a dilute synthetic was safe, well tolerated, and associated with a decrease in
oxygen requirements.[22] To the authors’ knowledge, no study has been performed to compare the use of surfactant
with or without bronchoscopy in the setting of ARDS.

Histologic Findings
The histologic changes in ARDS are those of diffuse alveolar damage. An exudative phase occurs in the first several
days and is characterized by interstitial edema, alveolar hemorrhage and edema, alveolar collapse, pulmonary
capillary congestion, and hyaline membrane formation (see the image below). These histologic changes are
nonspecific and do not provide information that would allow the pathologist to determine the cause of the ARDS.

Photomicrograph from patient with acute respiratory distress syndrome (ARDS). Image shows ARDS in exudative
stage. Note hyaline membranes and loss of alveolar epithelium in this early stage of ARDS.

A biopsy performed after several days shows the beginning of organization of the intra-alveolar exudate and repair, the
proliferative phase of ARDS, which is characterized by the growth of type 2 pneumocytes in the alveolar walls and the
appearance of fibroblasts, myofibroblasts, and collagen deposition in the interstitium.

The final phase of ARDS is fibrotic. Alveolar walls are thickened by connective tissue rather than edema or cellular
infiltrate.

Treatment

Approach Considerations
No drug has proved beneficial in the prevention or management of acute respiratory distress syndrome (ARDS). Early
administration of corticosteroids to septic patients does not prevent the development of ARDS. A study by Martin-
Loeches et al concluded that the early use of corticosteroids was also ineffective in patients with the pandemic H1N1
influenza A infection, resulting in an increased risk of superinfections.[23] This finding was also echoed in a study by
Brun-Buisson et al, who found no evidence of benefit associated with corticosteroids in patients with ARDS secondary
to influenza pneumonia but did find that early corticosteroid therapy may be harmful.[24]

Numerous pharmacologic therapies, including the use of inhaled synthetic surfactant, intravenous (IV) antibody to
endotoxin, ketoconazole, simvastatin, and ibuprofen, have been tried and are not effective.[25]

A study that examined the use and outcomes associated with rescue therapies in patients with ARDS determined that
these therapies offered no survival benefit.[26] The study also determined that rescue therapies are most often used in
younger patients with more severe oxygenation deficits.

Inhaled nitric oxide (NO), a potent pulmonary vasodilator, seemed promising in early trials, but in larger controlled
trials, it did not change mortality rates in adults with ARDS.[27, 28] A systematic review, meta-analysis, and trial
sequential analysis of 14 randomized controlled trials, including 1303 patients, found that inhaled nitric oxide did not
reduce mortality and results in only a transient improvement in oxygenation.[29]

Although no specific therapy exists for ARDS, treatment of the underlying condition is essential, along with supportive
care, noninvasive ventilation or mechanical ventilation using low tidal volumes, and conservative fluid management.
Because infection is often the underlying cause of ARDS, early administration of appropriate antibiotic therapy broad
enough to cover suspected pathogens is essential, along with careful assessment of the patient to determine potential
infection sources. In some instances, removal of intravascular lines, drainage of infected fluid collections, or surgical
debridement or resection of an infected site (eg, the ischemic bowel) may be necessary because sepsis-associated
ARDS does not resolve without such management. In addition, preventing complications associated with prolonged
mechanical ventilation and ICU stay can include deep venous thrombosis (DVT) prophylaxis, stress ulcer prophylaxis,
early mobilization, minimizing sedation, turning and skin care, and strategies to prevent ventilator-induced pneumonia,
such as elevation of the head of the bed and use of a subglottic suction device.

With the development of the National Institutes of Health (NIH)–sponsored ARDS Clinical Trials Network, several large
well-controlled trials of ARDS therapies have been completed. Thus far, the only treatment found to improve survival in
ARDS is a mechanical ventilation strategy using low tidal volumes (6 mL/kg based upon ideal body weight).

The main concerns are missing a potentially treatable underlying cause or complication of ARDS. In these critically ill
patients, pay careful attention to early recognition of potential complications in the intensive care unit (ICU), including
pneumothorax, IV line infections, skin breakdown, inadequate nutrition, arterial occlusion at the site of intra-arterial
monitoring devices, DVT and pulmonary embolism (PE), retroperitoneal hemorrhage, gastrointestinal (GI) hemorrhage,
erroneous placement of lines and tubes, and the development of muscle weakness.

In situations where the patient requires the use of paralyzing agents to allow certain modes of mechanical ventilation,
take meticulous care to ensure that an adequate alarm system is in place to alert staff to mechanical ventilator
disconnection or malfunction. In addition, adequate sedation is important in most patients on ventilators and is
essential when paralytic agents are in use.

As in all situations in which patients are critically ill, family and friends are under stress and likely have many questions
and concerns. Keep them informed and allow them to be at the bedside as much as possible. Caretakers should
assume that even though sedated, the patient may be capable of hearing and understanding all conversations in the
room and may experience pain. Keeping this in mind, all conversation at the bedside should be appropriate and all
procedures should be performed with local anesthesia and pain medication.

Fluid Management
Distinguishing between initial fluid resuscitation, as used for therapy of septic shock, and maintenance fluid therapy is
important. Early aggressive resuscitation for associated circulatory shock and its associated remote organ injury are
central aspects of initial management. However, several small trials have demonstrated improved outcome for ARDS
in patients treated with diuretics or dialysis to promote a negative fluid balance in the first few days. Thus, distinction
between primary ARDS due to aspiration, pneumonia, or inhalational injury, which usually can be treated with fluid
restriction, from secondary ARDS due to remote infection or inflammation that requires initial fluid and potential
vasoactive drug therapy is central in directing initial treatments to stabilize the patient.

An ARDS Clinical Trials Network study of a fluid-conservative strategy versus a fluid-liberal strategy in the
management of patients with ARDS or acute lung injury (ALI) found no statistically significant difference in 60-day
mortality between the two groups 72 hours after presentation with ARDS.[30] However, patients treated with the fluid-
conservative strategy had an improved oxygenation index and lung injury score and an increase in ventilator-free days,
without an increase in nonpulmonary organ failures.

It is worth noting that the fluid-conservative group actually had an even rather than a negative fluid balance over the
first 7 days, which raises the possibility that the benefit may have been underestimated. Patients whose fluids were
managed conservatively did not have an increased need for vasopressors or dialysis.[31]

The use of a conservative fluid management approach has been called into question by the long-term followup of a
subset of survivors of the Fluid and Catheter Treatment Trial (FACTT). Although mortality in the survivors was similar
regardless of fluid management strategy, and the conservative fluid management group required about 18 hours less
mechanical ventilatory support, cognitive function was markedly impaired in the conservative fluid group compared
with the liberal fluid group, with an adjusted odds ratio of 3.35.[31]
Cognitive impairment was defined as impairment in memory, verbal fluency, or executive function. Although all those
were more common in the conservative fluid management group, only the decrement in executive function reached
statistical significance (p=0.001). Lower partial pressure of arterial oxygen during the trial was also independently
associated with cognitive impairment.

Maintaining a low-normal intravascular volume may be facilitated by hemodynamic monitoring with a central venous or
pulmonary artery (Swan-Ganz) catheter, aimed at achieving a central venous pressure (CVP) or pulmonary capillary
wedge pressure (PCWP) at the lower end of normal. The ARDS clinical trials network of pulmonary artery catheter
versus CVP to guide fluid management in ARDS showed no difference in mortality or ventilator-free days, regardless
of whether fluid status was monitored by pulmonary artery catheter or CVP.

Closely monitor urine output and administer diuretics to facilitate a negative fluid balance. In oliguric patients,
hemodialysis with ultrafiltration or continuous veno-venous hemofiltration/dialysis (CVVHD) may be required.

A study by Lakhal et al determined that respiratory pulse pressure variation fails to predict fluid responsiveness in
patients with ARDS.[32] Careful fluid challenges may be a safer alternative.

Noninvasive Ventilation and High-Flow Nasal Cannula

Because intubation and mechanical ventilation may be associated with an increased incidence of complications, such
as barotrauma and nosocomial pneumonia, alternatives to mechanical ventilation such as a high-flow nasal cannula or
noninvasive positive-pressure ventilation (NIPPV) may be beneficial in patients with ARDS. High-flow nasal cannula
uses a system of heated humidification and large-bore nasal prongs to deliver oxygen at flows of up to 50 L/min. This
is usually used in conjunction with an oxygen blender, allowing delivery of precise inspired oxygen concentrations.
High-flow nasal cannula is usually well tolerated and allows the patient to talk, eat, and move around. NIPPV is usually
given by full facemask. Sometimes, continuous positive airway pressure (CPAP) alone may be sufficient to improve
oxygenation. In a 2015 study on hypoxemic, nonhypercapnic patients comparing standard oxygen, high-flow nasal
cannula, and NIPPV,[33] all three modes had the same incidence of need for intubation/mechanical ventilation, but
high-flow nasal cannula resulted in improved 90-day mortality.

Noninvasive ventilation has been studied best in patients with hypercapnic respiratory failure caused by chronic
obstructive pulmonary disease (COPD) or neuromuscular weakness.

Patients who have a diminished level of consciousness, vomiting, upper GI bleeding, or other conditions that increase
aspiration risk are not candidates for NIPPV. Other relative contraindications include hemodynamic instability, agitation,
and inability to obtain good mask fit.

Mechanical Ventilation
The goals of mechanical ventilation in ARDS are to maintain oxygenation while avoiding oxygen toxicity and the
complications of mechanical ventilation. Generally, this involves maintaining oxygen saturation in the range of 85-90%,
with the aim of reducing the fraction of inspired oxygen (FiO2) to less than 65% within the first 24-48 hours. Achieving
this aim almost always necessitates the use of moderate-to-high levels of positive end-expiratory pressure (PEEP).

Experimental studies have shown that mechanical ventilation may promote a type of acute lung injury termed
ventilator-associated lung injury. A protective ventilation strategy using low tidal volumes and limited plateau pressures
improves survival when compared with conventional tidal volumes and pressures.

In an ARDS Network study, patients with ALI and ARDS were randomized to mechanical ventilation either at a tidal
volume of 12 mL/kg of predicted body weight and an inspiratory pressure of 50 cm water or less or at a tidal volume of
6 mL/kg and an inspiratory pressure of 30 cm water or less; the study was stopped early after interim analysis of 861
patients demonstrated that subjects in the low-tidal-volume group had a significantly lower mortality rate (31% versus
39.8%).[34]

Whereas previous studies employing low tidal volumes allowed patients to be hypercapnic (permissive hypercapnia)
and acidotic to achieve the protective ventilation goals of low tidal volume and low inspiratory airway pressure, the
ARDS Network study allowed increases in respiratory rate and administration of bicarbonate to correct acidosis. This
may account for the positive outcome in this study as compared with earlier studies that had failed to demonstrate a
benefit.

Thus, mechanical ventilation with a tidal volume of 6 mL/kg predicted body weight is recommended, with adjustment of
the tidal volume to as low as 4 mL/kg if needed to limit the inspiratory plateau pressure to 30 cm water or less.
Increase the ventilator rate and administer bicarbonate as needed to maintain the pH at a near normal level (7.3).

In the ARDS Network study, patients ventilated with lower tidal volumes required higher levels of PEEP (9.4 vs 8.6 cm
water) to maintain oxygen saturation at 85% or more. Some authors have speculated that the higher levels of PEEP
may also have contributed to the improved survival rates. However, a subsequent ARDS Network trial of higher versus
lower PEEP levels in patients with ARDS showed no benefit from higher PEEP levels in terms of either survival or
duration of mechanical ventilation.[35]

The lack of efficacy of higher levels of PEEP may have been related to the fact that the recommended levels of PEEP
in the ARDS Network study were based on oxygenation, and not individualized based on lung mechanics. ARDS is an
inhomogeneous process and patients may have different lung injury patterns and different chest wall mechanics.
Measuring esophageal pressures with an esophageal balloon catheter allows estimation of transpulmonary pressure.
Basing ventilator strategy on these pressures as PEEP is titrated might allow determination of “best PEEP” levels for
improving oxygenation and minimizing volutrauma and atelectasis.[36]

Using the protective ventilation strategy of lower tidal volumes, limited plateau pressure, and higher PEEP improves
survival in ARDS. Amato et al,[37] through a retrospective review of more than 3500 patients with ARDS reported in
nine prior studies, found that the most important ventilation variable in determining survival is delta P (plateau pressure
minus PEEP). Delta P is a reflection of lung compliance and is reliable for predicting survival in patients with ARDS
who are not spontaneously breathing. In these patients, lower levels of delta P improved survival. Higher levels of
PEEP and lower tidal volumes did not improve survival, unless they were associated with lower levels of delta P.

Patients with severe ARDS may also benefit from the early use of neuromuscular blocking agents. In a group of patient
with severe ARDS (PaO2/FiO2< 120) diagnosed within 48 hours, paralysis with cisatracurium for the next 48 hours
was shown to improve 90-day mortality, when compared with placebo (31.6% for cisatracurium vs 40.7% for placebo);
increase ventilator-free days; and reduced barotrauma. There was no increased incidence of prolonged muscle
weakness in the group that was paralyzed.[38] Use of neuromuscular blocking agents should be used selectively.
These agents may be beneficial in patients with very severe ARDS, those who have problems synchronizing breathing
with the ventilator, and patients with poor lung compliance.

Managing physicians should not use paralytics in all cases; rather, they should use them only in those where length of
ventilation is expected to exceed a few hours. Patients should not remain ventilated for longer than it takes for the
paralytics to have their effect. The duration of paralysis will depend upon the condition.[38]

A study by Jaber et al examined diaphragmatic weakness during mechanical ventilation along with the relationship
between mechanical ventilation duration and diaphragmatic injury or atrophy.[39] The study determined that longer
periods of mechanical ventilation were associated with significantly greater ultrastructural fiber injury, increased
ubiquitinated proteins, higher expression of p65 nuclear factor-kB, greater levels of calcium-activated proteases, and
decreased cross-sectional area of muscle fibers in the diaphragm. The conclusion was that weakness, injury, and
atrophy can occur rapidly in the diaphragms of patients on mechanical ventilation and are significantly correlated with
the duration of ventilator support.

Go to Barotrauma and Mechanical Ventilation for complete information on this topic.

Positive end-expiratory pressure and continuous positive airway pressure

ARDS is characterized by severe hypoxemia. When oxygenation cannot be maintained despite high inspired oxygen
concentrations, the use of CPAP or PEEP usually promotes improved oxygenation, allowing the FiO2 to be tapered.

With PEEP, positive pressure is maintained throughout expiration, but when the patient inhales spontaneously, airway
pressure decreases to below zero to trigger airflow. With CPAP, a low-resistance demand valve is used to allow
positive pressure to be maintained continuously. Positive-pressure ventilation increases intrathoracic pressure and
thus may decrease cardiac output and blood pressure. Because mean airway pressure is greater with CPAP than
PEEP, CPAP may have a more profound effect on blood pressure.

In general, patients tolerate CPAP well, and CPAP is usually used rather than PEEP. The use of appropriate levels of
CPAP is thought to improve the outcome in ARDS. By maintaining the alveoli in an expanded state throughout the
respiratory cycle, CPAP may decrease shear forces that promote ventilator-associated lung injury.

The best method for finding the optimal level of CPAP in patients with ARDS is controversial. Some favor the use of
just enough CPAP to allow reduction of the FiO2 below 65%.
Another approach, favored by Amato et al, is the so-called open lung approach, in which the appropriate level is
determined by the construction of a static pressure volume curve.[40] This is an S-shaped curve, and the optimal level
of PEEP is just above the lower inflection point. Using this approach, the average PEEP level required is 15 cm water.

However, as noted above, an ARDS Network study of higher versus lower PEEP levels in ARDS patients did not find
higher PEEP levels advantageous.[35] In this study, PEEP level was determined by how much inspired oxygen was
required to achieve a goal oxygen saturation of 88-95% or a target partial pressure of oxygen (PO2) of 55-80 mm Hg.
The PEEP level averaged 8 in the lower PEEP group and 13 in the higher PEEP group. No difference was shown in
duration of mechanical ventilation or survival to hospital discharge.

A 2010 review by Briel et al found that treatment with higher of PEEP demonstrated no advantage over treatment with
lower levels in patients with ALI or ARDS; however, among patients with ARDS, higher levels were associated with
improved survival.[41]

A study by Bellani et al found that in patients with ALI managed with relatively high PEEP, metabolic activity of aerated
regions was associated with plateau pressure and regional tidal volume that was normalized by end-expiratory lung
gas volume; no association was found between cyclic recruitment/derecruitment and increased metabolic activity.[42]

Pressure-controlled ventilation and high-frequency ventilation

If high inspiratory airway pressures are required to deliver even low tidal volumes, pressure-controlled ventilation
(PCV) may be initiated. In this mode of mechanical ventilation, the physician sets the level of pressure above CPAP
(delta P) and the inspiratory time (I-time) or inspiratory/expiratory (I:E) ratio. The resultant tidal volume depends on
lung compliance and increases as ARDS improves. PCV may also result in improved oxygenation in some patients not
doing well on volume-controlled ventilation (VCV).

If oxygenation is a problem, longer I-times, such that inspiration is longer than expiration (inverse I:E ratio ventilation)
may be beneficial; ratios as high as 7:1 have been used. PCV, using lower peak pressures, may also be beneficial in
patients with bronchopleural fistulae, facilitating closure of the fistula.

Evidence indicates that PCV may be beneficial in ARDS, even without the special circumstances noted. In a
multicenter controlled trial comparing VCV with PCV in ARDS patients, Esteban found that PCV resulted in fewer
organ system failures and lower mortality rates than VCV, despite use of the same tidal volumes and peak inspiratory
pressures.[43] A larger trial is needed before a definite recommendation is made.

High-frequency ventilation (jet or oscillatory) is a ventilator mode that uses low tidal volumes and high respiratory rates.
Given that distention of alveoli is known to one of the mechanisms promoting ventilator-associated lung injury, high-
frequency ventilation would be expected to be beneficial in ARDS. Results of clinical trials comparing this approach
with conventional ventilation in adults have generally demonstrated early improvement in oxygenation but no
improvement in survival.

The largest randomized controlled trial, in which 148 adults with ARDS were randomized to conventional ventilation or
high-frequency oscillatory ventilation (HFOV), found that the HFOV group had early improvement in oxygenation that
did not persist beyond 24 hours.[44] The 30-day mortality in the HFOV group was 37%, compared with 52% in the
conventional ventilation group, but this difference was not statistically significant. HFOV may be the most useful for
patients with bronchopleural fistulae.

Partial liquid ventilation has also been tried in ARDS. A randomized controlled trial that compared it with conventional
mechanical ventilation determined that partial liquid ventilation resulted in increased morbidity (pneumothoraces,
hypotension, and hypoxemic episodes), and a trend toward higher mortality.[45]

Prone positioning

Some 60-75% of patients with ARDS have significantly improved oxygenation when turned from the supine to the
prone position. The improvement in oxygenation is rapid and often substantial enough to allow reductions in FIO2 or
level of CPAP. The prone position is safe, with appropriate precautions to secure all tubes and lines, and does not
require special equipment. The improvement in oxygenation may persist after the patient is returned to the supine
position and may occur on repeat trials in patients who did not respond initially.

Possible mechanisms for the improvement noted are recruitment of dependent lung zones, increased functional
residual capacity (FRC), improved diaphragmatic excursion, increased cardiac output, and improved ventilation-
perfusion matching.

Despite improved oxygenation with the prone position, early randomized controlled trials of the prone position in ARDS
did not demonstrate improved survival. In an Italian study, the survival rate to discharge from the ICU and the survival
rate at 6 months were unchanged compared with patients who underwent care in the supine position, despite a
significant improvement in oxygenation.[46] This study was criticized because patients were kept in the prone position
for an average of only 7 hours per day. In addition, a subsequent French study, in which patients were in the prone
position for at least 8 hours per day, did not document a benefit from the prone position in terms of 28- or 90-day
mortality, duration of mechanical ventilation, or development of ventilator-associated pneumonia (VAP).[47] However, a
subsequent randomized controlled trial in which patients with severe ARDS were placed in the prone position early
and for at least 16 hours a day showed a significant mortality benefit.[48] In this study, patients with severe ARDS
(PaO2/FiO2 of < 150) were randomized to prone position after 12-24 hours of stabilization. The 28-day mortality rate
was 16% in the prone group and 32.8% in the supine group. Patients were turned manually. A specialized bed was not
required.

Tracheostomy
In patients requiring prolonged mechanical ventilation, tracheostomy allows the establishment of a more stable airway,
which may allow for mobilization of the patient and, in some instances, may facilitate weaning from mechanical
ventilation. Tracheostomy, may be performed in the operating room or percutaneously at the bedside. Timing of the
procedure should be individualized, but it is generally performed after about 2 weeks of mechanical ventilation.

Extracorporeal Membrane Oxygenation

A large multicenter trial in the 1970s demonstrated that extracorporeal membrane oxygenation (ECMO) did not
improve the mortality rate in ARDS patients. A later trial using extracorporeal carbon dioxide removal along with
inverse-ratio ventilation also did not improve survival in ARDS.[49] However, during the H1N1 flu epidemic in 2009,
ECMO appeared to improve survival in patients with H1N1-associated ARDS who could not be oxygenated with
conventional mechanical ventilation.[50] This led to a 2018 study of venovenous ECMO for ARDS.[51] In this study,
patients with very severe ARDS (PaO2/FiO2 of < 50) were randomized to venovenous ECMO or conventional
management with ECMO rescue for refractory hypoxemia. Although there was a trend toward lower mortality (35%
EMCO vs 46% control), there was no statistically significant difference in 60-day mortality. Extracorporeal carbon
dioxide removal may also be an option for ARDS. Extracorporeal carbon dioxide removal uses a less invasive system
than venovenous ECMO, similar to hemodialysis. Carbon dioxide removal would allow lower-intensity mechanical
ventilation and possibly less ventilator-associated lung injury. This is currently under study.

Nutritional Support
Institution of nutritional support after 48-72 hours of mechanical ventilation usually is recommended. Enteral nutrition
via a feeding tube is preferable to IV hyperalimentation unless it is contraindicated because of an acute abdomen,
ileus, GI bleeding, or other conditions.

A low-carbohydrate high-fat enteral formula including anti-inflammatory and vasodilating components

(eicosapentaenoic acid and linoleic acid) along with antioxidants has been demonstrated in some studies to improve
outcome in ARDS.[52, 53] In a prospective, randomized study of ARDS patients in Brazil given an enteral formula
containing antioxidants, eicosapentaenoic acid, and gamma-linoleic acid compared with a standard isocaloric formula,
Pontes-Arruda demonstrated improved survival and oxygenation with the specialized diet.[53]

The ARDSNet completed a trial of feeding in ARDS (the EDEN-OMEGA study), in which patients were randomized to
supplements containing omega-3 fatty acid and antioxidants versus placebo. This study was terminated early for
futility, but the full results have not yet been published.[54]

An open-label, multicenter trial (the EDEN study) randomized 1000 adult patients who required mechanical ventilation
within 48 hours of developing acute lung injury to receive either trophic or full enteral feeding for the first 6 days. Initial
lower-volume trophic enteral feeding did not improve ventilator-free days, 60-day mortality, or infectious complications
compared with initial full enteral feeding, but it was associated with less gastrointestinal intolerance.[55]
Activity Restriction
Patients with ARDS are on bed rest. Frequent position changes should be started immediately, as should passive—
and, if possible, active—range-of-motion activities of all muscle groups. Elevation of the head of the bed to a 45° angle
is recommended to diminish the development of VAP. Recently, increased interest in minimizing sedation and earlier
ambulation has been proposed. Such approaches are associated with less posttraumatic stress disorder in survivors
and was the preferred approach by patients’ families. If at all possible, use of minimal sedation, sedation holidays, and
more ambulation appear to be the goals of management once severe cardiovascular insufficiency, if present, has
resolved.

Transfer Considerations
Once the acute phase of ARDS resolves, patients may require a prolonged period to be weaned from mechanical
ventilation and to regain muscle strength lost after prolonged inactivity. This may necessitate transfer to a rehabilitation
facility once the acute phase of the illness is resolved.

Transfer of the ARDS patient to a tertiary care facility may be indicated in some situations, provided that safe transport
can be arranged. Transfer may be indicated if the FIO2 cannot be lowered to less than 0.65 within 48 hours.

Other patients who may potentially benefit from transfer include those who have experienced pneumothorax and have
persistent air leaks, patients who cannot be weaned from mechanical ventilation, patients who have upper airway
obstruction after prolonged intubation, or those with a progressive course in which an underlying cause cannot be
identified.

If ARDS develops in a patient who previously has undergone organ or bone marrow transplantation, transfer to an
experienced transplant center is essential for appropriate management.

Prevention
Although multiple risk factors for ARDS are known, no successful preventive measures have been identified. Careful
fluid management in high-risk patients may be helpful. Because aspiration pneumonitis is a risk factor for ARDS, taking
appropriate measures to prevent aspiration (eg, elevating the head of the bed and evaluating swallowing mechanics
before feeding high-risk patients) may also prevent some ARDS cases.

In patients without ARDS on mechanical ventilation, the use of high tidal volumes appears to be a risk factor for the
development of ARDS, and, therefore, the use of lower tidal volumes in all patients on mechanical ventilation may
prevent some cases on ARDS.[56]

Consultations
Treatment of patients with ARDS requires special expertise with mechanical ventilation and management of critical
illness. Accordingly, it is appropriate to consult a physician specializing in pulmonary medicine or critical care.

Medication
Medication Summary
No drug has proved beneficial in the prevention or management of acute respiratory distress syndrome (ARDS). Early
administration of corticosteroids to septic patients does not prevent the development of ARDS. Numerous
pharmacologic therapies, including the use of inhaled or instilled synthetic surfactant, intravenous (IV) antibody to
endotoxin, ketoconazole, and ibuprofen, have been tried and are not effective. Statins, which also appeared to have
promise in small studies, also did not show benefit in a recently published randomized trial in 60 patients with acute
lung injury (ALI).[57]

Small sepsis trials suggest a potential role for antibody to tumor necrosis factor (TNF) and recombinant interleukin
(IL)–1 receptor antagonist. Inhaled nitric oxide (NO), a potent pulmonary vasodilator, seemed promising in early trials,
but in larger controlled trials, it did not change mortality rates in adults with ARDS. A systematic review, meta-analysis,
and trial sequential analysis of 14 randomized controlled trials, including 1303 patients, found that inhaled nitric oxide
did not reduce mortality and results in only a transient improvement in oxygenation.[29] Inhaled prostacycline also has
not been shown to improve survival.

Because of apparent benefit in small trials, it was thought that there might be a role for high-dose corticosteroid
therapy in patients with late (fibroproliferative phase) ARDS.[58] However, an ARDS Study Network trial of
methylprednisolone for patients with ARDS persisting for at least 7 days demonstrated no benefit in terms of 60-day
mortality.[59] Patients treated later in the course of ARDS, 14 days after onset, had worsened mortality with
corticosteroid therapy.

Although no survival advantage was shown in patients treated with methylprednisolone, short-term clinical benefits
included improved oxygenation and increased ventilator-free and shock-free days. Patients treated with corticosteroids
were more likely to experience neuromuscular weakness, but the rate of infectious complications was not increased.

Corticosteroids

Class Summary
Development of the late phase of ARDS may represent continued uncontrolled inflammation, and corticosteroids may
be considered a form of rescue therapy that may improve oxygenation and hemodynamics but does not change
mortality (except that corticosteroids increase mortality in patients who have had ARDS for >14 d).

Methylprednisolone (Solu-Medrol)
High-dose methylprednisolone has been used in trials of patients with ARDS who have persistent pulmonary infiltrates,
fever, and high oxygen requirement despite resolution of pulmonary or extrapulmonary infection. Pulmonary infection is
assessed with bronchoscopy and bilateral bronchoalveolar lavage (BAL) and quantitative culture.

Questions & Answers

Overview

What is the origin of acute respiratory distress syndrome (ARDS)?

How is acute respiratory distress syndrome (ARDS) defined?

What is the role of diffuse alveolar damage (DAD) in the pathogenesis of acute respiratory distress syndrome (ARDS)?

How is early acute respiratory distress syndrome (ARDS) characterized?

What are the injuries that result in acute respiratory distress syndrome (ARDS)?

What injuries to the alveolar epithelium result in acute respiratory distress syndrome (ARDS)?

What are characteristics of type II alveolar cells involved in the pathogenesis of acute respiratory distress syndrome
(ARDS)?

What is the role of neutrophils in the pathogenesis of acute respiratory distress syndrome (ARDS)?

What is the role of the immune system in the pathogenesis of acute respiratory distress syndrome (ARDS)?

How does acute respiratory distress syndrome (ARDS) progress following injury to alveoli?

How does acute respiratory distress syndrome (ARDS) cause hypoxemia?

What is the role of pulmonary hypertension in the pathogenesis of acute respiratory distress syndrome (ARDS)?

What factors lead to mortality in acute phase of acute respiratory distress syndrome (ARDS)?

What are the common risk factors for acute respiratory distress syndrome (ARDS)?

What are the major risk factors for acute respiratory distress syndrome (ARDS)?

Which patient groups are at increased risk for the development of acute respiratory distress syndrome (ARDS)?

What are the genetic risk factors of acute respiratory distress syndrome (ARDS)?

Why is the incidence of acute respiratory distress syndrome (ARDS) difficult to quantify?

What is the incidence of acute respiratory distress syndrome (ARDS) in the US?

What is the global incidence of acute respiratory distress syndrome (ARDS)?

What are the age-related differences in incidence for acute respiratory distress syndrome (ARDS)?

How does the incidence of acute respiratory distress syndrome (ARDS) vary by sex?

What are the mortality rates for acute respiratory distress syndrome (ARDS)?

Which factors increase the mortality risk of acute respiratory distress syndrome (ARDS)?

What are the morbidities associated with acute respiratory distress syndrome (ARDS)?

What is the effect of acute respiratory distress syndrome (ARDS) on quality of life following recovery?

What are some patient education resources for acute respiratory distress syndrome (ARDS)?

Presentation

What are the signs and symptoms of acute respiratory distress syndrome (ARDS)?

Which physical findings are characteristic of acute respiratory distress syndrome (ARDS)?

Which lung exam findings are characteristic of acute respiratory distress syndrome (ARDS)?

What should be the focus of the physical exam in a septic patient with suspected acute respiratory distress syndrome
(ARDS)?

How is cardiogenic pulmonary edema distinguished from acute respiratory distress syndrome (ARDS)?

What complications may occur in mechanically ventilated patients with acute respiratory distress syndrome (ARDS)?

When is a tracheostomy indicated in the management of acute respiratory distress syndrome (ARDS)?

Which nosocomial infections are patients with acute respiratory distress syndrome (ARDS) at increased risk of
contracting?

Which secondary infections are common in acute respiratory distress syndrome (ARDS)?

Which treatments for acute respiratory distress syndrome (ARDS) may cause muscle weakness and poor functional
recovery?

How are patients with acute respiratory distress syndrome (ARDS) weaned from mechanical ventilation?

Why is renal failure a frequent complication of acute respiratory distress syndrome (ARDS)?
What are potential complications of acute respiratory distress syndrome (ARDS)?

What are the long-term sequelae of acute respiratory distress syndrome (ARDS)?

DDX

Which medical conditions should be included in the differential diagnoses of acute respiratory distress syndrome
(ARDS)?

What are the differential diagnoses for Acute Respiratory Distress Syndrome?

Workup

How is acute respiratory distress syndrome (ARDS) diagnosed?

What is the expected partial pressure of oxygen in the arterial blood (PaO2) in acute respiratory distress syndrome
(ARDS)?

What is the role of arterial blood gases in the evaluation of acute respiratory distress syndrome (ARDS)?

What happens to the partial pressure of carbon dioxide (PCO2) as acute respiratory distress syndrome (ARDS)
progresses?

How is cardiogenic pulmonary edema differentiated from acute respiratory distress syndrome (ARDS)?

Which abnormalities of acute respiratory distress syndrome (ARDS) are related to the underlying etiology?

What is the role of radiography in the evaluation of acute respiratory distress syndrome (ARDS)?

When are signs of recovery from acute respiratory distress syndrome (ARDS) seen on radiographs?

What is the role of CT scanning in the diagnosis of acute respiratory distress syndrome (ARDS)?

What is the role of echocardiography in the diagnosis of acute respiratory distress syndrome (ARDS)?

What is the role of a blood vessel catheter in the management of acute respiratory distress syndrome (ARDS)?

What is the role of pulmonary artery catheters in the diagnosis and management of acute respiratory distress
syndrome (ARDS)?

What is the role of bronchoscopy in the diagnosis of acute respiratory distress syndrome (ARDS)?

Which BAL fluid finding is characteristic of acute respiratory distress syndrome (ARDS)?

How is a culture obtained for the diagnosis of acute respiratory distress syndrome (ARDS)?

What is the role of cytologic evaluation of the bronchoalveolar lavage (BAL) fluid in the diagnosis of acute respiratory
distress syndrome (ARDS)?

How is bronchoscopy used in surfactant therapy for the diagnosis of acute respiratory distress syndrome (ARDS)?

What are the histologic changes associated with acute respiratory distress syndrome (ARDS)?

Which biopsy findings are characteristic of acute respiratory distress syndrome (ARDS)?

Which histologic findings are characteristic of the final phase of acute respiratory distress syndrome (ARDS)?

Treatment

What is the role of corticosteroids in the treatment of acute respiratory distress syndrome (ARDS)?

What are the pharmacologic therapies used for the treatment of acute respiratory distress syndrome (ARDS)?

What is the role of rescue therapies in the treatment of acute respiratory distress syndrome (ARDS)?

What is the role of inhaled nitric oxide (NO) in the treatment of acute respiratory distress syndrome (ARDS)?

How are the underlying causes of acute respiratory distress syndrome (ARDS) managed?
What is the role of mechanical ventilation in the treatment of acute respiratory distress syndrome (ARDS)?

Which complications of acute respiratory distress syndrome (ARDS) should be monitored for in the ICU?

What is the management required for patients with acute respiratory distress syndrome (ARDS) taking paralyzing
agents?

What is included in the management of critically ill patients with acute respiratory distress syndrome (ARDS)?

How is initial fluid resuscitation distinguished from maintenance fluid therapy in the treatment of acute respiratory
distress syndrome (ARDS)?

What are the differences in efficacy between fluid-conservative strategies and the fluid-liberal strategies for the
treatment of acute respiratory distress syndrome (ARDS)?

What are the disadvantages of a fluid-conservative therapy for the treatment of acute respiratory distress syndrome
(ARDS)?

How is a low-normal intravascular volume maintained during the treatment of acute respiratory distress syndrome
(ARDS)?

How is a negative fluid balance facilitated in acute respiratory distress syndrome (ARDS)?

What is the role of e respiratory pulse pressure variation in the treatment of acute respiratory distress syndrome
(ARDS)?

What is the role of noninvasive positive-pressure ventilation (NIPPV) in the treatment of acute respiratory distress
syndrome (ARDS)?

In which patients with acute respiratory distress syndrome (ARDS) has noninvasive ventilation been studied?

When is noninvasive positive-pressure ventilation (NIPPV) contraindicated for the treatment of acute respiratory
distress syndrome (ARDS)?

What are the goals of mechanical ventilation for the treatment of acute respiratory distress syndrome (ARDS)?

How is ventilator-associated lung injury prevented during the treatment of acute respiratory distress syndrome
(ARDS)?

What is the benefit of mechanical ventilation with low tidal volumes for the treatment of acute respiratory distress
syndrome (ARDS)?

What is the recommended tidal volume for mechanical ventilation in the treatment of patients with acute respiratory
distress syndrome (ARDS)?

What is the role of PEEP in the treatment of acute respiratory distress syndrome (ARDS) when patients ventilate with
lower tidal volumes?

When is the use of paralytics indicated for the treatment of acute respiratory distress syndrome (ARDS)?

What are the disadvantages to mechanical ventilation in the treatment of acute respiratory distress syndrome (ARDS)?

How is hypoxemia treated in acute respiratory distress syndrome (ARDS)?

What are the differences between positive end-expiratory pressure (PEEP) and continuous positive airway pressure
(CPAP) measures for the treatment of acute respiratory distress syndrome (ARDS)?

How is the optimal level of continuous positive airway pressure (CPAP) determined for the treatment of acute
respiratory distress syndrome (ARDS)?

What is the role of the open lung approach in the treatment of acute respiratory distress syndrome (ARDS)?

What are the benefits to higher positive end-expiratory pressure (PEEP) for the treatment of acute respiratory distress
syndrome (ARDS)?

What is the role of pressure-controlled ventilation (PCV) in the treatment of acute respiratory distress syndrome
(ARDS)?

What are the benefits of using pressure-controlled ventilation (PCV) to treat acute respiratory distress syndrome
(ARDS)?

What is the role of high-frequency ventilation (jet or oscillatory) for the treatment of acute respiratory distress syndrome
(ARDS)?

What is the role of partial liquid ventilation for the treatment of acute respiratory distress syndrome (ARDS)?

What is the difference in oxygenation from the supine to the prone position in patients with acute respiratory distress
syndrome (ARDS)?

What are possible mechanisms for the improvement of prone position oxygenation in acute respiratory distress
syndrome (ARDS)?

What is the role of a tracheostomy in the treatment of acute respiratory distress syndrome (ARDS)?

What are the benefits of using extracorporeal membrane oxygenation (ECMO) in the treatment of acute respiratory
distress syndrome (ARDS)?

When is the institution of nutritional support recommended for in the treatment of acute respiratory distress syndrome
(ARDS)?

Which nutritional components have demonstrated improved outcomes in patients with acute respiratory distress
syndrome (ARDS)?

What is the role of lower-volume trophic enteral feeding in the treatment of acute respiratory distress syndrome
(ARDS)?

What activity restrictions are used in the treatment of acute respiratory distress syndrome (ARDS)?

What are the transfer considerations for patients with acute respiratory distress syndrome (ARDS)?

How is acute respiratory distress syndrome (ARDS) prevented?

Which specialist consultations are needed for the management of acute respiratory distress syndrome (ARDS)?

Medications

What is the role of medications in the treatment of acute respiratory distress syndrome (ARDS)?

Which medications are used in the treatment of acute respiratory distress syndrome (ARDS)?

What are the benefits of methylprednisolone in the treatment of acute respiratory distress syndrome (ARDS)?

Which medications in the drug class Corticosteroids are used in the treatment of Acute Respiratory Distress
Syndrome?

Contributor Information and Disclosures

Author

Eloise M Harman, MD Staff Physician and MICU Director, Pulmonary Division, Gainesville Veterans Affairs Medical
Center

Eloise M Harman, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Chest
Physicians, American Medical Women's Association, American Thoracic Society, Phi Beta Kappa, Sigma Xi

Disclosure: Nothing to disclose.

Chief Editor

Michael R Pinsky, MD, CM, Dr(HC), FCCP, FAPS, MCCM Professor of Critical Care Medicine, Bioengineering,
Cardiovascular Disease, Clinical and Translational Science and Anesthesiology, Vice-Chair of Academic Affairs,
Department of Critical Care Medicine, University of Pittsburgh Medical Center, University of Pittsburgh School of
Medicine

Michael R Pinsky, MD, CM, Dr(HC), FCCP, FAPS, MCCM is a member of the following medical societies: American
College of Chest Physicians, American College of Critical Care Medicine, American Thoracic Society, European
Society of Intensive Care Medicine, Society of Critical Care Medicine

Disclosure: Received income in an amount equal to or greater than $250 from: Masimo, Edwards Lifesciences,
Cheetah Medical, Exostat<br/>Received honoraria from LiDCO Ltd for consulting; Received intellectual property rights
from iNTELOMED for board membership; Received honoraria from Edwards Lifesciences for consulting; Received
honoraria from Masimo, Inc for board membership.

Acknowledgements

Francisco Talavera, PharmD, PhD

Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape
Drug Reference

Disclosure: Medscape Salary Employment

Rajat Walia, MD

Assistant Professor of Medicine, Division of Pulmonary and Critical Care Medicine, University of Florida College of
Medicine

Disclosure: Nothing to disclose.

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