Acute respiratory distress syndrome
|Acute respiratory distress syndrome|
|Classification and external resources|
Chest x-ray of patient with ARDS
||This article needs additional citations for verification. (November 2012)|
Acute respiratory distress syndrome (ARDS), also known as respiratory distress syndrome (RDS) or adult respiratory distress syndrome (in contrast with IRDS) is a life-threatening reaction to injuries or acute infection to the lung. ARDS is a severe lung syndrome (not a disease) with direct and indirect causes. Inflammation of the lung parenchyma leads to impaired gas exchange with systemic release of inflammatory mediators, causing inflammation, hypoxemia and frequently multiple organ failure. This condition has a 90% death rate in untreated patients. With treatment, usually mechanical ventilation in an intensive care unit, the death rate is 50%. A less severe form is called acute lung injury (ALI).
ARDS formerly most commonly signified adult respiratory distress syndrome to differentiate it from infant respiratory distress syndrome in premature infants. However, as this type of pulmonary edema also occurs in children, ARDS has gradually shifted to mean acute rather than adult. The differences with the typical infant syndrome remain.
Signs and symptoms 
ARDS mostly occurs about 72 hours after the trigger, such as an injury (trauma, burns, aspiration, massive blood transfusion, drug/alcohol abuse) or an acute illness (infectious pneumonia, sepsis, acute pancreatitis).
- Acute onset
- Bilateral infiltrates on chest radiograph sparing costophrenic angles
- Pulmonary artery wedge pressure < 18 mmHg (obtained by pulmonary artery catheterization), if this information is available; if unavailable, then lack of clinical evidence of left atrial hypertension
- if PaO2:FiO2 < 300 mmHg (40 kPa) acute lung injury (ALI) is considered to be present
- if PaO2:FiO2 < 200 mmHg (26.7 kPa) acute respiratory distress syndrome (ARDS) is considered to be present
The PaO2:FiO2 ratios above refer to the gradient between the inspired oxygen level and the oxygen that is present in the blood. The lower the ratio, the less inspired oxygen is getting into the blood, and so the worse the patient's condition — so ARDS represents a more severe progression of disease from ALI by these diagnostic criteria.
To summarize and simplify, ARDS is an acute (rapid onset) syndrome (collection of symptoms) that affects the lungs widely and results in a severe oxygenation defect, but is not due to heart failure.
Three clinical settings account for 75% of ARDS cases:
1. Sepsis syndrome - most important cause
2. Severe multiple trauma
3. Aspiration of saliva/gastric contents and it could also be a complication of pneumonia if left untreated known as aspiration pneumonia.
4. Necrotizing pancreatitis
Some cases of ARDS are linked to large volumes of fluid used during resuscitation post trauma. Other causes include shock, near-drowning, multiple transfusions and inhalation of irritants or toxic fumes that damage the alveolar epithelium.
An arterial blood gas analysis and chest X-ray allow formal diagnosis by the below mentioned criteria. Although severe hypoxemia is generally included, the appropriate threshold defining abnormal PaO2 has never been systematically studied. Note though, that a severe oxygenation defect is not synonymous with ventilatory support. Any PaO2 below 100 (generally saturation less than 100%) on a supplemental oxygen fraction of 50% meets criteria for ARDS. This can easily be achieved by high flow oxygen supplementation without ventilatory support.
Any cardiogenic cause of pulmonary edema should be excluded. This can be done by placing a pulmonary artery catheter for measuring the pulmonary artery wedge pressure. However, this is not necessary and is now rarely done as abundant evidence has emerged demonstrating that the use of pulmonary artery catheters does not lead to improved patient outcomes in critical illness including ARDS.
Plain chest X-rays are sufficient to document bilateral alveolar infiltrates in the majority of cases. While CT scanning leads to more accurate images of the pulmonary parenchyma in ARDS, it has little utility in the clinical management of patients with ARDS, and remains largely a research tool.
Four main criteria for ARDS:
- Acute onset
- Chest X-Ray: Bilateral diffuse infiltrates of the lungs
- No cardiovascular lesion
- No evidence of left atrial hypertension: PaO2/FiO2 ratio equal to or less than 200 mmHg.
The criteria for diagnosis of Acute Lung Injury (ALI) are similar except that PaO2/FiO2 ratio is ≤300.
ARDS is a clinical syndrome associated with a variety of pathological findings. These include 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.
DAD is characterized by a diffuse inflammation of lung parenchyma. The triggering insult to the parenchyma usually results in an initial release of cytokines and other inflammatory mediators, secreted by local epithelial and endothelial cells.
Although the triggering mechanisms are not completely understood, recent research has examined the role of inflammation and mechanical stress.
Inflammation alone, as in sepsis, causes endothelial dysfunction, fluid extravasation from the capillaries and impaired drainage of fluid from the lungs. Dysfunction of type II pulmonary epithelial cells may also be present, with a concomitant reduction in surfactant production. Elevated inspired oxygen concentration often becomes necessary at this stage, and may facilitate a 'respiratory burst' in immune cells.
In a secondary phase, endothelial dysfunction causes cells and inflammatory exudate to enter the alveoli. This pulmonary edema increases the thickness of the alveolo-capillary space, increasing the distance the oxygen must diffuse to reach blood. This impairs gas exchange leading to hypoxia, increases the work of breathing, eventually induces fibrosis of the airspace.
Moreover, edema and decreased surfactant production by type II pneumocytes may cause whole alveoli to collapse, or to completely flood. This loss of aeration contributes further to the right-to-left shunt in ARDS. As the alveoli contain progressively less gas, the blood flowing through the alveolar capillaries is progressively less oxygenated, resulting in massive intrapulmonary shunting.
The loss of aeration may follow different patterns according to the nature of the underlying disease, and other factors. In pneumonia-induced ARDS, for example, large, more commonly causes relatively compact areas of alveolar infiltrates. These are usually distributed to the lower lobes, 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 in lung mechanical properties. These alterations are fundamental in the process of inflammation amplification and progression to ARDS in mechanically ventilated patients.
Mechanical stress 
Mechanical ventilation is an essential part of the treatment of ARDS. As loss of aeration (and the underlying disease) progress, the end tidal volume eventually grows to a level incompatible with life. Thus, mechanical ventilation is initiated to relieve respiratory muscles of their work, and to protect the usually obtunded patient's airways.
However, mechanical ventilation may constitute a risk factor for the development, or the worsening, of ARDS.
Aside from the infectious complications arising from invasive ventilation with tracheal intubation, positive-pressure ventilation directly alters lung mechanics during ARDS. The result is higher mortality, i.e. through baro-trauma, when these techniques are used.
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). This result was confirmed in a 2000 study sponsored by the NIH. Although both these studies were widely criticized for several reasons, and although the authors were not the first to experiment lower-volume ventilation, they shed new light on the relationship between mechanical ventilation and ARDS.
One opinion is that the forces applied to the lung by the ventilator may work as a lever to induce further damage to lung parenchyma. It appears that shear stress at the interface between collapsed and aerated units may result in the breakdown of aerated units, which inflate asymmetrically due to the 'stickiness' of surrounding flooded alveoli. The fewer such interfaces around an alveolus, the lesser the stress.
Indeed, even relatively low stress forces may induce signal transduction systems at the cellular level, thus inducing the release of inflammatory mediators.
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 patients ventilated with lower Vt may be interpreted as a beneficial effect of the lower Pl. Transpulmonary pressure, is an indirect function of the Vt setting on the ventilator, and only trial patients with plateau pressures (a surrogate for the actual Pl) were less than 32 cmH2O (3.1 kPa) had improved survival.
The way Pl is applied on alveolar surface determines the shear stress to which lung units are exposed. ARDS is characterized by a usually inhomogeneous 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 inhomogeneity 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. Finally, abdominal pressure exerts an additional pressure on inferoposterior lung segments, favoring compression and collapse of those units.
The different mechanical properties of alveoli in ARDS may be interpreted as having varying time constants (the product of alveolar compliance × resistance). A long time constant indicates an alveolus which opens slowly during tidal inflation, as a consequence of contrasting pressure around it, or altered water-air interface inside it (loss of surfactant, flooding).
Slow alveoli are said to be 'kept open' using positive end-expiratory pressure, 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 units, 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 lung units while minimizing the shear stress caused by frequent openings and closings of aerated units.
The prone position also reduces the inhomogeneity in alveolar time constants induced by gravity and edema. If clinically appropriate, mobilization of the ventilated patient can assist in achieving the same goal.
Stress Index 
Mechanical ventilation can exacerbate the inflammatory response in patients with ARDS by including cyclic tidal alveolar hyperinflation and/or recruiting/derecruiting. Stress index is measured during constant-flow 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 depict 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.
- Adjustment of PEEP was suspended if any one of the following conditions ensued: plateau pressure > 30 cmH2O, SaO2 < 88%, or hemodynamic instability.
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.
If the underlying disease or injurious factor is not removed, the amount of inflammatory mediators released by the lungs in ARDS may result in a systemic inflammatory response syndrome (or sepsis if there is lung infection). The evolution towards shock and/or multiple organ failure follows paths analogous to the pathophysiology of sepsis.
This adds up to the impaired oxygenation which is the central problem of ARDS, as well as to respiratory acidosis, which 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/SIRS is worsened by the pulmonary dysfunction, which further impairs oxygen delivery.
Acute respiratory distress syndrome is usually treated with mechanical ventilation in the Intensive Care Unit. Ventilation is usually delivered through oro-tracheal intubation, or tracheostomy whenever prolonged ventilation (≥2 weeks) is deemed inevitable.
The possibilities of non-invasive ventilation are limited to the very early period of the disease or, better, to prevention in individuals at risk for the development of the disease (atypical pneumonias, pulmonary contusion, major surgery patients).
Treatment of the underlying cause is imperative, as it tends to maintain the ARDS picture.
Appropriate antibiotic therapy must be administered as soon as microbiological culture results are available. Empirical therapy may be appropriate if local microbiological surveillance is efficient. More than 60% ARDS patients experience a (nosocomial) pulmonary infection either before or after the onset of lung injury.
Commonly used supportive therapy includes particular techniques of mechanical ventilation and pharmacological agents whose effectiveness with respect to the outcome has not yet been proven. It is now debated whether mechanical ventilation is to be considered mere supportive therapy or actual treatment, since it may substantially affect survival.
Survivors of ARDS have an increased risk of lower quality of life, persistent cognitive impairment, depression and posttraumatic stress disorder.
Mechanical ventilation 
The overall goal is to maintain acceptable gas exchange and to minimize adverse effects in its application. Three parameters are used: PEEP (positive end-expiratory pressure, to maintain maximal recruitment of alveolar units), mean airway pressure (to promote recruitment and predictor of hemodynamic effects) and plateau pressure (best predictor of alveolar overdistention).
Conventional therapy aimed at tidal volumes (Vt) of 12–15 ml/kg. 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 landmark trial that showed improved mortality when ventilated with a tidal volume of 6 ml/kg compared to the traditional 12 ml/kg. Low tidal volumes (Vt) may cause hypercapnia and atelectasis due to their inherent tendency to increase physiologic shunt. 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 H2O was a secondary goal, and subsequent analyses of the data from the ARDSnet trial (as well as other experimental data) demonstrate that there appears to be NO safe upper limit to plateau pressure; that is, regardless of plateau pressure, patients fare better with low tidal volumes (see Hager et al., American Journal of Respiratory and Critical Care Medicine, 2005).
Airway pressure release ventilation 
It is often said that no particular ventilator mode is known to improve mortality in airway pressure release ventilation (APRV). The ARDSNet trial used a volume controlled mode comparing delivered tidal volumes of 6 ml/kg with 12 ml/kg and showed decrease mortality with smaller volumes and typically higher set rates. However, other modes of ventilation, like airway pressure release ventilation (APRV), have not been directly compared to volume controlled ventilation*.
Some practitioners favor airway pressure release ventilation when treating ARDS. Well documented advantages to APRV ventilation 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 (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 renal 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.
- A proposed study to compare APRV to the ARDSNet Protocol is set for December 2011.
- January 2013 - Animal studies show that ventilation with APRV immediately following injury prevents development of ARDS, when compared to current published ARDS Network guidelines (6 mL/kg).
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 aveoli 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 or perhaps most 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. Finally, PEEP can be harmful. High PEEP necessarily increases mean airway pressure and alveolar pressure. This in turn can damage normal alveoli by overdistension resulting in DAD.
The 'best PEEP' used to be defined as 'some' cmH2O 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 to define the minimum PEEP to be applied to their patients. Some of the newest ventilators have the ability to automatically plot a pressure-volume curve. The possibility of having an 'instantaneous' tracing trigger might produce renewed interest in this analysis.
PEEP may also be set empirically. Some authors suggest performing a 'recruiting maneuver' (i.e., a short time at a very high continuous positive airway pressure, such as 50 cmH2O (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 PaO2 (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 patients. When ventilating at high frequencies, its contribution can be substantial, particularly in patients with obstructive lung disease. 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 ARDS patients, especially when using high-frequency (oscillatory/jet) ventilation.
A compromise between the beneficial and adverse effects of PEEP is inevitable.
Prone position 
Distribution 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. However, although the hypoxemia is overcome there seems to be no effect on overall survival.
Fluid management 
A Meduri et al. study has found significant improvement in ARDS using modest doses of corticosteroids.The initial regimen consists of methylprednisolone 2 mg/kg daily. After 3–5 days a response must be apparent. In 1–2 weeks the dose can be tapered to methylprednisolone 0.5–1.0 mg daily. But high dose steroid therapy has no effect on ARDS when given within 24 hours of the onset of illness. This was a study involving a small number of patients in one center. A recent NIH-sponsored multicenter ARDSnet LAZARUS study of corticosteroids for ARDS demonstrated that they are not efficacious in ARDS. The benefit of steroids in late ARDS may be explained by the ability of steroids to promote breakdown and inhibit fibrosis.
Nitric oxide 
Inhaled nitric oxide (NO) potentially acts as selective pulmonary vasodilator. Rapid binding to hemoglobin prevents systemic effects. It should increase perfusion of better ventilated areas. There are no large studies demonstrating positive results. Therefore its use must be considered individually.
Almitrine bismesylate stimulates chemoreceptors in carotic and aortic bodies. It has been used to potentiate the effect of NO, presumably by potentiating hypoxia-induced pulmonary vasoconstriction. In case of ARDS it is not known whether this combination is useful.
Surfactant therapy 
Since ARDS is an extremely serious condition which requires invasive forms of therapy it is not without risk. Complications to be considered are:
- Pulmonary: barotrauma (volutrauma), pulmonary embolism (PE), pulmonary fibrosis, ventilator-associated pneumonia (VAP).
- Gastrointestinal: hemorrhage (ulcer), dysmotility, pneumoperitoneum, bacterial translocation.
- Cardiac: arrhythmias, myocardial dysfunction.
- Renal: acute renal failure (ARF), positive fluid balance.
- Mechanical: vascular injury, pneumothorax (by placing pulmonary artery catheter), tracheal injury/stenosis (result of intubation and/or irritation by endotracheal tube.
- Nutritional: malnutrition (catabolic state), electrolyte deficiency.
The annual incidence of ARDS is 13–23 people per 100,000 in the general population. Its incidence in the intensive care unit (ICU), mechanically ventilated population is much higher. Brun-Buisson et al. (2004) reported a prevalence of acute lung injury (ALI) (see below) of 16.1% percent in ventilated patients admitted for more than 4 hours. More than half these patients may develop ARDS.
Mechanical ventilation, sepsis, pneumonia, shock, aspiration, trauma (especially pulmonary contusion), major surgery, massive transfusions, smoke inhalation, drug reaction or overdose, fat emboli and reperfusion pulmonary edema after lung transplantation or pulmonary embolectomy may all trigger ARDS. Pneumonia and sepsis are the most common triggers, and pneumonia is present in up to 60% of patients. Pneumonia and sepsis may be either causes or complications of ARDS. Alcohol excess appears to increase the risk of ARDS. 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 oedema.
Elevated abdominal pressure of any cause is also probably a risk factor for the development of ARDS, particularly during mechanical ventilation.
The mortality rate varies from 25-40% in centers using up to date ventilatory strategies and up to 58% in all centers. Usually, randomized controlled trials in the literature show lower death rates than observational studies, both in control and treatment patients. This is thought to be due to stricter enrollment criteria.
Acute respiratory distress syndrome was first described in 1967 by Ashbaugh et al. Initially there was no definition, resulting in controversy over incidence and mortality. In 1988 an expanded definition was proposed which quantified physiologic respiratory impairment.
In 1994 a new definition was recommended by the American-European Consensus Conference Committee. It had two advantages: first, it recognizes that severity of pulmonary injury varies, and secondly, it is simple to use.
ARDS was defined as the ratio of arterial partial oxygen tension (PaO2) as fraction of inspired oxygen (FiO2) below 200 mmHg in the presence of bilateralinfiltrates on the chest x-ray. These infiltrates may appear similar to those of left ventricular failure, but the cardiac silhouette appears normal in ARDS. Also, the pulmonary capillary wedge pressure is normal (less than 18 mmHg) in ARDS, but raised in left ventricular failure.
A PaO2/FiO2 ratio less than 300 mmHg with bilateral infiltrates indicatesacute lung injury (ALI). Although formally considered different from ARDS, ALI is usually just a precursor to ARDS.
In 2012 the Berlin Definition of ARDS was published. This did away with the ALI/ARDS differentiation. It opts instead to classify ARDS as mild, moderate or severe.
See also 
- Irwin RS, Rippe JM (2003). Irwin and Rippe's Intensive Care Medicine (5th ed.). Lippincott Williams & Wilkins. ISBN 0-7817-3548-3.
- Bernard G, Artigas A, Brigham K, Carlet J, Falke K, Hudson L, Lamy M, Legall J, Morris A, Spragg R (1994). "The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination". Am J Respir Crit Care Med 149 (3 Pt 1): 818–24. PMID 7509706.
- Cherkas, David (Nov 2011). "Traumatic Hemorrhagic Shock: Advances In Fluid Management". Emergency Medicine Practice 13 (11).
- Amato M, Barbas C, Medeiros D, Magaldi R, Schettino G, Lorenzi-Filho G, Kairalla R, Deheinzelin D, Munoz C, Oliveira R, Takagaki T, Carvalho C (1998). "Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome". N Engl J Med 338 (6): 347–54. doi:10.1056/NEJM199802053380602. PMID 9449727.
- MacIntyre N (2000). "Mechanical ventilation strategies for lung protection". Semin Respir Crit Care Med 21 (3): 215–22. doi:10.1055/s-2000-9850. PMID 16088734.
- Slutsky AS (May 2005). "Ventilator-induced lung injury: from barotrauma to biotrauma". Respir Care 50 (5): 646–59. PMID 15912625.
- Grasso S, Stripoli T, De Michele M, et al. (October 2007). "ARDSnet ventilatory protocol and alveolar hyperinflation: role of positive end-expiratory pressure". Am. J. Respir. Crit. Care Med. 176 (8): 761–7. doi:10.1164/rccm.200702-193OC. PMID 17656676.
- Malhotra A (2007). "Low-tidal-volume ventilation in the acute respiratory distress syndrome". N Engl J Med 357 (11): 1113–20. doi:10.1056/NEJMct074213. PMC 2287190. PMID 17855672.
- a positive effect on cardiac output
- Comparison study APRV to ARDSNet
- Gattinoni L, Tognoni G, Pesenti A, Taccone P, Mascheroni D, Labarta V, Malacrida R, Di Giulio P, Fumagalli R, Pelosi P, Brazzi L, Latini R (2001). "Effect of prone positioning on the survival of patients with acute respiratory failure". N Engl J Med 345 (8): 568–73. doi:10.1056/NEJMoa010043. PMID 11529210.
- Meduri G, Tolley E, Chrousos G, Stentz F (2002). "Prolonged methylprednisolone treatment suppresses systemic inflammation in patients with unresolving acute respiratory distress syndrome: evidence for inadequate endogenous glucocorticoid secretion and inflammation-induced immune cell resistance to glucocorticoids". Am J Respir Crit Care Med 165 (7): 983–91. PMID 11934726.
- Lewandowski K, Lewandowski M. Epidemiology of ARDS. Minerva Anestesiol. 2006 Jun;72(6):473-7.
- Vlaar AP, Binnekade JM, Prins D, et al. (2010). "Risk factors and outcome of transfusion-related acute lung injury in the critically ill: a nested case-control study.". Crit Care Med 38 (3): 771–8. PMID 20035217.
- Moss M, Bucher B, Moore FA, Moore EE, Parsons PE. (1996). "The role of chronic alcohol abuse in the development of acute respiratory distress syndrome in adults.". JAMA 275 (1): 50–4.
- Moss M, Guidot DM, Steinberg KP, et al. (2000). "Diabetic patients have a decreased incidence of acute respiratory distress syndrome.". Crit Care Med 28 (7): 2187–92.
- Koh GC, Vlaar AP, Hofstra JJ, et al. (2012). "In the critically ill patient, diabetes predicts mortality independent of statin therapy but is not associated with acute lung injury: A cohort study". Crit Care Med 40 (6): 1835–1843. PMID 22488007.
- The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000;342:1301–1308.
- Wiedemann HP, Wheeler AP, Bernard GR, et al; National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006;354:2564–2575.
- Wheeler AP, Bernard GR, Thompson BT, et al; National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Pulmonary-artery versus central venous catheter to guide treatment of acute lung injury. N Engl J Med. 2006;354:2213–2224.
- Brun-Buisson C, Minelli C, Bertolini G, et al; ALIVE Study Group. Epidemiology and outcome of acute lung injury in European intensive care units. Results from the ALIVE study. Intensive Care Med. 2004;30:51–61.
- Ashbaugh D, Bigelow D, Petty T, Levine B (1967). "Acute respiratory distress in adults". Lancet 2 (7511): 319–23. doi:10.1016/S0140-6736(67)90168-7. PMID 4143721.
- Ware L, Matthay M (2000). "The acute respiratory distress syndrome". N Engl J Med 342 (18): 1334–49. doi:10.1056/NEJM200005043421806. PMID 10793167.
- CV. Marco Ranieri, MD (2012). "The ARDS Definition Task Force*. Acute Respiratory Distress Syndrome: The Berlin Definition". JAMA 307 (23): 2526–2533. doi:10.1001/jama.2012.5669.
Further reading 
- Marino, Paul L. (1998). The ICU book. Baltimore: Williams & Wilkins. ISBN 0-683-05565-8.
- Martin GS, Moss M, Wheeler AP, Mealer M, Morris JA, Bernard GR (2005). "A randomized, controlled trial of furosemide with or without albumin in hypoproteinemic patients with acute lung injury". Crit. Care Med. 33 (8): 1681–7. doi:10.1097/01.CCM.0000171539.47006.02. PMID 16096441.
- Jackson WL, Shorr AF (2005). "Blood transfusion and the development of acute respiratory distress syndrome: more evidence that blood transfusion in the intensive care unit may not be benign". Crit. Care Med. 33 (6): 1420–1. doi:10.1097/01.CCM.0000167073.99222.50. PMID 15942365.
- Mortelliti MP, Manning HL (May 2002). "Acute respiratory distress syndrome". Am Fam Physician 65 (9): 1823–30. PMID 12018805.
- Metnitz PG, Bartens C, Fischer M, Fridrich P, Steltzer H, Druml W (February 1999). "Antioxidant status in patients with acute respiratory distress syndrome". Intensive Care Med 25 (2): 180–5. PMID 10193545.
- ARDSNet — the NIH / NHLBI ARDS Network
- ARDS Support Center — information and support for patients with ARDS and their loved ones
- ARDS Foundation — a charitable organization offers support to families/victims of Acute Respiratory Distress Syndrome
- Respiratory mechanics monitor — a monitor capable of measuring Stress Index