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Acute respiratory distress syndrome

Acute respiratory distress syndrome
Synonyms Respiratory distress syndrome (RDS), adult respiratory distress syndrome, shock lung
Chest x-ray of person with severe ARDS demonstrating widespread "ground-glass" appearing opacities in both lungs
Specialty Critical care medicine

Acute respiratory distress syndrome (ARDS) is a medical condition occurring in critically ill or critically wounded patients characterized by widespread inflammation in the lungs. ARDS is not a particular disease; rather, it is a clinical condition triggered by various pathologies such as trauma, pneumonia, and sepsis.

The hallmark of ARDS is diffuse injury to cells which form the barrier of the microscopic air sacs of the lungs, surfactant dysfunction, activation of the innate immune system response, and dysfunction of the body's regulation of clotting and bleeding.[1] In effect, ARDS impairs the lungs' ability to exchange oxygen and carbon dioxide with the blood across a thin layer of the lungs' microscopic air sacs known as alveoli.

The syndrome is associated with a death rate between 20 and 50%.[2] The risk of death varies based on severity, the person's age, and the presence of other underlying medical conditions.

Although the terminology of "adult respiratory distress syndrome" has at times been used to differentiate ARDS from "infant respiratory distress syndrome" in newborns, the international consensus is that "acute respiratory distress syndrome" is the best term because ARDS can affect people of all ages.[3]

Signs and symptoms

The signs and symptoms of ARDS often begin within two hours of an inciting event, but can occur after 1–3 days. Signs and symptoms may include shortness of breath, fast breathing, and a low oxygen level in the blood due to abnormal ventilation.[4][5]


Diffuse compromise of the pulmonary system resulting in ARDS generally occurs in the setting of critical illness. ARDS may be seen in the setting of severe pulmonary (pneumonia) or systemic infection (sepsis), following trauma, multiple blood transfusions (TRALI), severe burns, severe inflammation of the pancreas (pancreatitis), near-drowning or other aspiration events, drug reactions, or inhalation injuries.[6] Some cases of ARDS are linked to large volumes of fluid used during post-trauma resuscitation.[7]


A chest x-ray of transfusion-related acute lung injury which lead to ARDS

Diagnostic criteria for ARDS have changed over time as understanding of the pathophysiology has evolved. The international consensus criteria for ARDS were most recently updated in 2012 and are known as the "Berlin definition".[8][9] In addition to generally broadening the diagnostic thresholds, other notable changes from the prior 1994 consensus criteria[3] include discouraging the term "acute lung injury," and defining grades of ARDS severity according to degree of decrease in the oxygen content of the blood.

According to the 2012 Berlin definition, ARDS is characterized by the following:

  • lung injury of acute onset, within 1 week of an apparent clinical insult and with progression of respiratory symptoms
  • bilateral opacities on chest imaging (chest radiograph or CT) not explained by other lung pathology (e.g. effusion, lobar/lung colapse, or nodules)
  • respiratory failure not explained by heart failure or volume overload
  • decreased PaO
    ratio (a decreased PaO
    ratio indicates reduced arterial oxygenation from the available inhaled gas):
    • mild ARDS: 201 – 300 mmHg (≤ 39.9 kPa)
    • moderate ARDS: 101 – 200 mmHg (≤ 26.6 kPa)
    • severe ARDS: ≤ 100 mmHg (≤ 13.3 kPa)
    • Note that the Berlin definition requires a minimum positive end expiratory pressure (PEEP) of 5 cmH
      for consideration of the PaO
      ratio. This degree of PEEP may be delivered noninvasively with CPAP to diagnose mild ARDS.

Note that the 2012 "Berlin criteria" are a modification of the prior 1994 consensus conference definitions (see history).[10]

Medical imaging

Radiologic imaging has long been a criterion for diagnosis of ARDS. While original definitions of ARDS specified that correlative chest X-ray findings were required for diagnosis, the diagnostic criteria have been expanded over time to accept CT and ultrasound findings as equally contributory. Generally, radiographic findings of fluid accumulation (pulmonary edema) affecting both lungs and unrelated to increased cardiopulmonary vascular pressure (such as in heart failure) may be suggestive of ARDS. Ultrasound findings suggestive of ARDS include the following:

  • Anterior subpleural consolidations
  • Absence or reduction of lung sliding
  • “Spared areas” of normal parenchyma
  • Pleural line abnormalities (irregular thickened fragmented pleural line)
  • Nonhomogeneous distribution of B-lines (a characteristic ultrasound finding suggestive of fluid accumulation in the lungs)[11]


Micrograph of diffuse alveolar damage, the histologic correlate of ARDS. H&E stain.

ARDS is a form of fluid accumulation in the lungs not explained by heart failure (noncardiogenic pulmonary edema). It is typically provoked by an acute injury to the lungs that results in flooding of the lungs' microscopic air sacs responsible for the exchange of gases such as oxygen and carbon dioxide with capillaries in the lungs.[12] Additional common findings in ARDS include partial collapse of the lungs (atelectasis) and low levels of oxygen in the blood (hypoxemia). The clinical syndrome is associated with pathological findings including pneumonia, eosinophilic pneumonia, cryptogenic organizing pneumonia, acute fibrinous organizing pneumonia, and diffuse alveolar damage (DAD). Of these, the pathology most commonly associated with ARDS is DAD, which is characterized by a diffuse inflammation of lung tissue. The triggering insult to the tissue usually results in an initial release of chemical signals and other inflammatory mediators secreted by local epithelial and endothelial cells.

Neutrophils and some T-lymphocytes quickly migrate into the inflamed lung tissue and contribute in the amplification of the phenomenon. Typical histological presentation involves diffuse alveolar damage and hyaline membrane formation in alveolar walls. Although the triggering mechanisms are not completely understood, recent research has examined the role of inflammation and mechanical stress.


Inflammation, such as that caused by sepsis, causes endothelial cell dysfunction, fluid leakage from capillaries and impairs drainage of fluid from the lungs. Elevated inspired oxygen concentration often becomes necessary at this stage, and may facilitate a 'respiratory burst' in immune cells. In a secondary phase, endothelial cell dysfunction causes cells and inflammatory exudate to enter the alveoli. This pulmonary edema increases the thickness of the layer separating the blood in the capillary from the space in the air sacs, which increases the distance the oxygen must diffuse to reach the blood. This impairs gas exchange and leads to hypoxia, increased work of breathing, and eventually induces scarring of the air sacs of the lungs.

Fluid accumulation in the lungs and decreased surfactant production by type II pneumocytes may cause whole air sacs to collapse or to completely fill with fluid. This loss of aeration contributes further to the right-to-left shunt in ARDS. A traditional right-to-left shunt refers to blood passing from the right side of the heart to the left side without traveling to the capillaries of the lung for more oxygen (e.g., as seen in a patent foramen ovale). In ARDS, a lung right-to-left shunting occurs within the lungs since some blood from the right side of the heart will enter capillaries which cannot exchange gas with damaged air sacs that are full of fluid and debris from ARDS. As the alveoli contain progressively less gas, the blood flowing through the alveolar capillaries is progressively less oxygenated, resulting in massive shunting within the lung. The collapse of the air sacs and small airways interferes with the process of normal gas exchange. It is common to see patients with a PaO
of 60 mmHg (8.0 kPa) despite mechanical ventilation with 100% inspired oxygen.

The loss of aeration may follow different patterns depending upon the nature of the underlying disease and other factors. These are usually distributed to the lower lobes of the lungs, in their posterior segments, and they roughly correspond to the initial infected area. In sepsis or trauma-induced ARDS, infiltrates are usually more patchy and diffuse. The posterior and basal segments are always more affected, but the distribution is even less homogeneous. Loss of aeration also causes important changes[vague] in lung mechanical properties that are fundamental in the process of inflammation amplification and progression to ARDS in mechanically ventilated patients.

Mechanical stress

As the loss of aeration and the underlying disease progress, the end tidal volume grows to a level incompatible with life. Thus, mechanical ventilation is initiated to relieve muscles responsible for supporting breathing (respiratory muscles) of their work and to protect the affected person's airway. However, mechanical ventilation may constitute a risk factor for the development—or the worsening—of ARDS.[10] Aside from the infectious complications arising from invasive ventilation with endotracheal intubation, positive-pressure ventilation directly alters lung mechanics during ARDS. When these techniques are used the result is higher mortality through barotrauma.[10]

In 1998, Amato et al. published a paper showing substantial improvement in the outcome of patients ventilated with lower tidal volumes (Vt) (6 mL·kg−1).[10][13] This result was confirmed in a 2000 study sponsored by the NIH.[14] Both studies were widely criticized for several reasons, and the authors were not the first to experiment with lower-volume ventilation, but they increased the understanding of the relationship between mechanical ventilation and ARDS.

This form of stress is thought to be applied by the transpulmonary pressure (gradient) (Pl) generated by the ventilator or, better, its cyclical variations. The better outcome obtained in individuals ventilated with a lower Vt may be interpreted as a beneficial effect of the lower Pl.

The way Pl is applied on the alveolar surface determines the shear stress to which alveoli are exposed. ARDS is characterized by a usually heterogeneous reduction of the airspace, and thus by a tendency towards higher Pl at the same Vt, and towards higher stress on less diseased units. The heterogeneity of alveoli at different stages of disease is further increased by the gravitational gradient to which they are exposed and the different perfusion pressures at which blood flows through them.

The different mechanical properties of alveoli in ARDS may be interpreted as having varying time constants—the product of alveolar compliance × resistance. Slow alveoli are said to be "kept open" using PEEP, a feature of modern ventilators which maintains a positive airway pressure throughout the whole respiratory cycle. A higher mean pressure cycle-wide slows the collapse of diseased alveoli, but it has to be weighed against the corresponding elevation in Pl/plateau pressure. Newer ventilatory approaches attempt to maximize mean airway pressure for its ability to "recruit" collapsed alveoli while minimizing the shear stress caused by frequent openings and closings of aerated units.

Stress Index

Stress Index of an ARDS patient with different values of PEEP

Mechanical ventilation can worsen the inflammatory response in people with ARDS by inducing hyperinflation of the alveoli and/or increased shear stress with frequent opening and closing of collapsible alveoli.[15] The stress index is measured during constant-flow volume assist-control mechanical ventilation without changing the baseline ventilatory pattern. Identifying the steadiest portion of the inspiratory flow (F) waveform fit the corresponding portion of the airway pressure (Paw) waveform in the following power equation:

Paw = a × tb + c where the coefficient b—the Stress Index—describes the shape of the curve. The Stress Index depicts a constant compliance if the value is around 1, an increasing compliance during the inspiration if the value is below 1, and a decreasing compliance if the value is above 1. Ranieri, Grasso, et al. set a strategy guided by the stress index with the following rules:

  • Stress Index below 0.9, PEEP was increased
  • Stress Index between 0.9 and 1.1, no change was made
  • Stress Index above 1.1 PEEP was decreased.

Alveolar hyperinflation in patients with focal ARDS ventilated with the ARDSnet protocol is attenuated by a physiologic approach to PEEP setting based on the stress index measurement.[16]


If the underlying disease or injurious factor is not removed, the quantity of inflammatory mediators released by the lungs in ARDS may result in a systemic inflammatory response syndrome (SIRS) or sepsis if there is lung infection.[10] The evolution towards shock or multiple organ dysfunction syndrome follows paths analogous to the pathophysiology of sepsis. This leads to the impaired oxygenation, which is the central problem of ARDS, as well as to respiratory acidosis. Respiratory acidosis in ARDS is often caused by ventilation techniques such as permissive hypercapnia, which attempt to limit ventilator-induced lung injury in ARDS. The result is a critical illness in which the 'endothelial disease' of severe sepsis or SIRS is worsened by the lung dysfunction, which further impairs oxygen delivery to cells.


Acute respiratory distress syndrome is usually treated with mechanical ventilation in the intensive care unit (ICU). Mechanical ventilation is usually delivered through a rigid tube which enters the oral cavity and is secured in the airway (endotracheal intubation), or by tracheostomy when prolonged ventilation (≥2 weeks) is necessary. The role of non-invasive ventilation is limited to the very early period of the disease or to prevent worsening respiratory distress in individuals with atypical pneumonias, lung bruising, or major surgery patients, who are at risk of developing ARDS. Treatment of the underlying cause is crucial. Appropriate antibiotic therapy must be administered as soon as microbiological culture results are available, or clinical infection is suspected (whichever is earlier). Empirical therapy may be appropriate if local microbiological surveillance is efficient. The origin of infection, when surgically treatable, must be removed. When sepsis is diagnosed, appropriate local protocols should be enacted.

Mechanical ventilation

The overall goal of mechanical ventilation is to maintain acceptable gas exchange to meet the body's metabolic demands and to minimize adverse effects in its application. The parameters PEEP (positive end-expiratory pressure, to keep alveoli open), mean airway pressure (to promote recruitment (opening) of easily collapsible alveoli and predictor of hemodynamic effects) and plateau pressure (best predictor of alveolar overdistention) are used.[17]

Previously, mechanical ventilation aimed to achieve tidal volumes (Vt) of 12–15 ml/kg (where the weight is ideal body weight rather than actual weight). Recent studies have shown that high tidal volumes can overstretch alveoli resulting in volutrauma (secondary lung injury). The ARDS Clinical Network, or ARDSNet, completed a clinical trial that showed improved mortality when people with ARDS were ventilated with a tidal volume of 6 ml/kg compared to the traditional 12 ml/kg. Low tidal volumes (Vt) may cause a permitted rise in blood carbon dioxide levels and collapse of alveoli[10] because of their inherent tendency to increase shunting within the lung. Physiologic dead space cannot change as it is ventilation without perfusion. A shunt is perfusion without ventilation.

Low tidal volume ventilation was the primary independent variable associated with reduced mortality in the NIH-sponsored ARDSnet trial of tidal volume in ARDS. Plateau pressure less than 30 cm H
was a secondary goal, and subsequent analyses of the data from the ARDSnet trial and other experimental data demonstrate that there appears to be no safe upper limit to plateau pressure; regardless of plateau pressure, individuals with ARDS fare better with low tidal volumes.[18]

Airway pressure release ventilation

No particular ventilator mode is known to improve mortality in acute respiratory distress syndrome (ARDS).[citation needed]

Some practitioners favor airway pressure release ventilation when treating ARDS. Well documented advantages to APRV ventilation[19] include decreased airway pressures, decreased minute ventilation, decreased dead-space ventilation, promotion of spontaneous breathing, almost 24-hour-a-day alveolar recruitment, decreased use of sedation, near elimination of neuromuscular blockade, optimized arterial blood gas results, mechanical restoration of FRC (functional residual capacity), a positive effect on cardiac output[20] (due to the negative inflection from the elevated baseline with each spontaneous breath), increased organ and tissue perfusion and potential for increased urine output secondary to increased kidney perfusion.

A patient with ARDS, on average, spends between 8 and 11 days on a mechanical ventilator; APRV may reduce this time significantly and conserve valuable resources.

Positive end-expiratory pressure

Positive end-expiratory pressure (PEEP) is used in mechanically ventilated patients with ARDS to improve oxygenation. In ARDS, three populations of alveoli can be distinguished. There are normal alveoli which are always inflated and engaging in gas exchange, flooded alveoli which can never, under any ventilatory regime, be used for gas exchange, and atelectatic or partially flooded alveoli that can be "recruited" to participate in gas exchange under certain ventilatory regimens. The recruitable alveoli represent a continuous population, some of which can be recruited with minimal PEEP, and others which can only be recruited with high levels of PEEP. An additional complication is that some alveoli can only be opened with higher airway pressures than are needed to keep them open, hence the justification for maneuvers where PEEP is increased to very high levels for seconds to minutes before dropping the PEEP to a lower level. PEEP can be harmful; high PEEP necessarily increases mean airway pressure and alveolar pressure, which can damage normal alveoli by overdistension resulting in DAD. A compromise between the beneficial and adverse effects of PEEP is inevitable.

The 'best PEEP' used to be defined as 'some' cmH
above the lower inflection point (LIP) in the sigmoidal pressure-volume relationship curve of the lung. Recent research has shown that the LIP-point pressure is no better than any pressure above it, as recruitment of collapsed alveoli—and, more importantly, the overdistension of aerated units—occur throughout the whole inflation. Despite the awkwardness of most procedures used to trace the pressure-volume curve, it is still used by some[who?] to define the minimum PEEP to be applied to their patients. Some new ventilators can automatically plot a pressure-volume curve.

PEEP may also be set empirically. Some authors[who?] suggest performing a 'recruiting maneuver'—a short time at a very high continuous positive airway pressure, such as 50 cmH
(4.9 kPa)—to recruit or open collapsed units with a high distending pressure before restoring previous ventilation. The final PEEP level should be the one just before the drop in PaO
or peripheral blood oxygen saturation during a step-down trial.

Intrinsic PEEP (iPEEP) or auto-PEEP—first described by John Marini of St. Paul Regions Hospital—is a potentially unrecognized contributor to PEEP in intubated individuals. When ventilating at high frequencies, its contribution can be substantial, particularly in people with obstructive lung disease such as asthma or chronic obstructive pulmonary disease (COPD). iPEEP has been measured in very few formal studies on ventilation in ARDS patients, and its contribution is largely unknown. Its measurement is recommended in the treatment of people who have ARDS, especially when using high-frequency (oscillatory/jet) ventilation.

Prone position

The position of lung infiltrates in acute respiratory distress syndrome is non-uniform. Repositioning into the prone position (face down) might improve oxygenation by relieving atelectasis and improving perfusion. If this is done early in the treatment of severe ARDS, it confers a mortality benefit of 26% compared to supine ventilation.[21]

Fluid management

Several studies have shown that pulmonary function and outcome are better in people with ARDS who lost weight or whose pulmonary wedge pressure was lowered by diuresis or fluid restriction.[10]


An NIH-sponsored multicenter ARDSnet study of corticosteroids that ran from August 1997 to November 2003 titled LaSRS for ARDS demonstrated that despite an improvement in cardiovascular physiology, methylprednisone is not efficacious in treatment for ARDS.[22][23]

Nitric oxide

Inhaled nitric oxide (NO) selectively widens the lung's arteries which allows for more blood flow to open alveoli for gas exchange. Despite evidence of increased oxygenation status, there is no evidence that inhaled nitric oxide decreases morbidity and mortality in people with ARDS.[24] Furthermore, nitric oxide may cause kidney damage and is not recommended as therapy for ARDS regardless of severity.[25]

Surfactant therapy

To date, no prospective controlled clinical trial has shown a significant mortality benefit of exogenous surfactant in adult ARDS.[10]

Extracorporeal membrane oxygenation

Extracorporeal membrane oxygenation (ECMO) is mechanically applied prolonged cardiopulmonary support. There are two types of ECMO: Venovenous which provides respiratory support and venoarterial which provides respiratory and hemodynamic support. People with ARDS who do not require cardiac support typically undergo venovenous ECMO. Multiple studies have shown the effectiveness of ECMO in acute respiratory failure.[26][27][28] Specifically, the CESAR (Conventional ventilatory support versus Extracorporeal membrane oxygenation for Severe Acute Respiratory failure) trial[29] demonstrated that a group referred to an ECMO center demonstrated significantly increased survival compared to conventional management (63% to 47%).[30]


Since ARDS is an extremely serious condition which requires invasive forms of therapy it is not without risk. Complications to be considered include the following:[10]


The annual incidence of ARDS is 13–23 people per 100,000 in the general population.[31] Its incidence in the mechanically ventilated population in intensive care units is much higher. According to Brun-Buisson et al (2004), there is a prevalence of acute lung injury (ALI) of 16.1% percent in ventilated patients admitted for more than 4 hours.

Worldwide, severe sepsis is the most common trigger causing ARDS.[32] Other triggers include mechanical ventilation, sepsis, pneumonia, Gilchrist's disease, drowning, circulatory shock, aspiration, trauma—especially pulmonary contusion—major surgery, massive blood transfusions,[33] smoke inhalation, drug reaction or overdose, fat emboli and reperfusion pulmonary edema after lung transplantation or pulmonary embolectomy. However, the majority of these patients with all these conditions mentioned do not develop ARDS.It is not clear why some people with the mentioned factors above don't get ARDS and some do.

Pneumonia and sepsis are the most common triggers, and pneumonia is present in up to 60% of patients and may be either causes or complications of ARDS. Alcohol excess appears to increase the risk of ARDS.[34] Diabetes was originally thought to decrease the risk of ARDS, but this has shown to be due to an increase in the risk of pulmonary edema.[35][36] Elevated abdominal pressure of any cause is also probably a risk factor for the development of ARDS, particularly during mechanical ventilation.[citation needed]

The death rate varies from 25–40% in centers using up-to-date ventilatory strategies and up to 58% in all centers.[37][38][39][40]


Acute respiratory distress syndrome was first described in 1967 by Ashbaugh et al.[10][41] Initially there was no clearly established definition, which resulted in controversy regarding the incidence and death of ARDS.

In 1988, an expanded definition was proposed, which quantified physiologic respiratory impairment.

1994 American-European Consensus Conference

In 1994, a new definition was recommended by the American-European Consensus Conference Committee [3][10] which recognized the variability in severity of pulmonary injury.[42]

The definition required the following criteria be met:

  • acute onset, persistent dyspnea
  • bilateral infiltrates on chest radiograph consistent with pulmonary edema
  • hypoxemia, defined as PaO
    < 200 mmHg (26.7 kPa)
  • absence of left atrial (LA) hypertension

If PaO
< 300 mmHg (40 kPa), then the definitions recommended a classification as "acute lung injury" (ALI). Note that according to these criteria, arterial blood gas analysis and chest X-ray were required for formal diagnosis. Limitations of these definitions include lack of precise definition of acuity, nonspecific imaging criteria, lack of precise definition of hypoxemia with regards to PEEP (affects arterial oxygen partial pressure), arbitrary PaO
thresholds without systematic data.[43]

2012 Berlin definition

In 2012, the Berlin Definition of ARDS was devised by the European Society of Intensive Care Medicine, and was endorsed by the American Thoracic Society and the Society of Critical Care Medicine. These recommendations were an effort to both update classification criteria in order to improve clinical usefulness, and to clarify terminology. Notably, the Berlin guidelines discourage the use of the term "acute lung injury" or ALI, as the term was commonly being misused to characterize a less severe degree of lung injury. Instead, the committee proposes a classification of ARDS severity as mild, moderate or severe according to arterial oxygen saturation.[8] The Berlin definitions represent the current international consensus guidelines for both clinical and research classification of ARDS.

Research directions

There is ongoing research on the treatment of ARDS by interferon (IFN) beta-1a to aid in preventing leakage of vascular beds. Traumakine (FP-1201-lyo), is a recombinant human IFN beta-1a drug developed by Faron pharmaceuticals, is undergoing international phase-III clinical trials after an open-label, early-phase trial showed a 81% reduction-in-odds of 28-day mortality in ICU patients with ARDS.[44] The drug is known to function by enhancing lung CD73 expression and increasing production of anti-inflammatory adenosine, such that vascular leaking and escalation of inflammation are reduced.[45]

See also


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