• Information
  1. Features
  2. Definition and Symptoms
  3. Risk Factors
  4. Causes by Pathology (
  5. Differential Diagnosis of ALI (Panel 3, Ref
  6. Clinical Course
  7. Systemic Capillary Leak Syndrome (SCLS)

• PATHOLOGY AND PATHOPHYSIOLOGY
  1. Histopathologic Changes in ARDS
  2. Pathophysiology Overview
  3. Pulmonary Edema
  4. Role of Neutrophils
  5. Effects on Gas Exchange
  6. Lung Mechanics
  7. Supportive Care
  8. Mechanical Ventilation
  9. Management of Volume Status
  10. Other Therapies
  11. Futher Evaluation

A. Features

1. Acute syndrome of hypoxemic (usually normocarbic) respiratory failure
2. Characterized by breakdown of normal barrier between capillaries and alveoli
3. This barrier normally prevents leakage of fluid out of pulmonary capillaries into alveoli
4. ARDS is a non-specific result of acute lung injury (ALI), probably endothelial damage
5. Intermittant systemic capillary leak syndromes have also been described (see below)
6. Epidemiology [1,4]
   1. ARDS: 1.5-12.9 cases per 100,000 people annually depending on definition
   2. Mortality 30-50%
   3. ALI (see below): ~79 per 100,000 annually
   4. Incidence of ALI in US extrapolated to ~200,000 cases per year
   5. Overall mortality is dropping mainly in patients <60yrs old with sepsis (~40%)
   6. ARDS associated with trauma has a mortailty rate slighly decreasing
   7. Recent studies suggest a mortality of 35-40% overall [4]
7. Most deaths within 10 days of illness
8. Previously called adult respiratory distress syndrome

B. Definition and Symptoms

1. ARDS is a subset of ALI
2. ALI and ARDS are characterized by onset of marked respiratory distress
3. Definitions Based on Lung's Ability to Oxygenate Blood
   1. Normal PaO2/FiO2 (arterial to fraction of inspired oxygen) is ~500mm Hg ~ 100mm/0.2
   2. Thus, normal arterial O2 (PaO2) ~ 100mmHg and FiO2 ~ 0.2 (20% oxygen in room air)
   3. ALI is defined broadly as PaO2/FiO2 < 300mm Hg
   4. ARDS is defined as PaO2/FiO2 < 200mm Hg
   5. Most definitions of ARDS also require absence of congestive heart failure (CHF)
   6. Lack of CHF is usually expressed as a pulmonary capillary wedge pressure of <18cm H2O
4. Diffuse bilateral alveolar infiltrates on chest radiograph (CXR)
   1. Most patients have bilateral "whiteout" on CXR - does not correlate with gas exchange
   2. Unlike cardiogenic pulmonary infiltrates, there is equal upper and lower lung infiltrates
   3. CT scan shows areas of normal and affected lung - correlates well with gas exchange
   4. Decreased pulmonary compliance
5. Marked hypoxemia usually without hypercarbia
6. Part of multisystem organ failure syndrome (MOFS)

C. Risk Factors [4]

1. Shock Syndromes
   1. Sepsis and related syndromes are most common cause of ARDS
   2. Sepsis > hypovolemic >> cardiogenic shock as causes
2. Diffuse Infectious Pneumonia / Sepsis
   1. Bacterial pneumonia, particularly in elderly
   2. Viral - respiratory syncytial virus, influenza virus
   3. Mycoplasma pneumonia
   4. Legionella pneumophilia
   5. Pneumocystis carinii
3. Gastric Aspiration - may be more common than trauma associated ARDS
4. Trauma - pulmonary or extra-pulmonary (abdominal), multiple fractures
5. Near Drowning
6. Drugs
   1. Overdose (such as heroin)
   2. Idiopathic Reactions
   3. Transfusion Related Acute Lung Injury
7. Metabolic Events: Pancreatitis >> Uremia
8. Toxic Fume Inhalation
9. Disease states that result in systemic release of inflammatory mediators
   1. Burns
   2. Extrapulmonary infections
   3. Disseminated intravascular coagulopathy (DIC) - severe sepsis
   4. Anaphylaxis
   5. Cardiopulmonary bypass
   6. Transfusion reaction
   7. Solid organ transplantation
10. Chronic alcohol abuse increases risk of developing ARDS in setting of other risks

D. Causes by Pathology ([1] and Table 4, Ref [3])

1. Diffuse alveolar damage (such as smoke or toxic gas inhalation injury)
2. Infectious pneumonia
3. Gastric Aspiration
4. Bronchiolitis obliterans with organizing pneumonia (BOOP)
5. Hemorrhage (capillaritis)
6. Pulmonary edema (alveolar or interstitial)
7. Drowning
8. Acute eosinophilic pneumonia
9. Emboli - thromboemboli, fat, foreign material, tumor
10. Bronchioalveolar carcinoma
11. Pulmonary alveolar proteinosis
12. Acute transplant rejection

E. Differential Diagnosis of ALI (Panel 3, Ref [1])

1. Left ventricular (LV) failure
2. Intravascular volume overload
3. Mitral stenosis
4. Veno-occlusive disease
5. Lymphangitic carcinoma
6. Interstitial and Airway Diseases (as above)
   1. Hypersensitivity pneumonitis
   2. Acute eosinophilic pneumonia
   3. BOOP

F. Clinical Course

1. Clinical Phases of Illness
   1. First: dyspnea, tachypnea, normal PaO2, hyperventilatory repiratory alkalosis
   2. Second: 12-24 hours after onset, lung injury present, radiographic changes
   3. Third: progressive respiratory failure, mechanical ventilation, pulmonary shunting
   4. Fourth: endstage fibrosis (>90% mortality)
2. Patients with more than one risk factor have much increased chance of developing ARDS
3. Death usually from underlying injury, not respiratory failure
4. Mortality of ~35% overall (mortality lower in younger patients) [1]
5. One Year Outcomes in Survivors [7]
   1. Pulmonary volumes and FEV1 normalized within 6 months of discharge
   2. Diffusion limit Carbon Monoxide (DLCO) still abnormal at 12 months
   3. Fatigue and muscle weakness causing functional limitation prominant at 12 months
   4. Average age of survivors 45 years
   5. Average intensive care unit stay 25 days for survivors
   6. Survivors lost average of 18% body weight

G. Systemic Capillary Leak Syndrome (SCLS) [8]

1. Episodic attacks usually lasting 24-48 hours of unexplained capillary permeability
2. Permeability increase has protein and fluid extravasation leading to hypovolemia
   1. Hypotension can occur and may be life-threatening
   2. Secondary hyperaldosteronism leads to fluid retention and edema
   3. Result is anasarca, weight gain, and renal failure (due to hypoperfusion)
   4. Serum albumin drops and hematocrit increases
3. Fewer than 40 cases reported, usually age 30-40
4. Etiology
   1. Etiology is unclear
   2. Nearly all patients have a monoclonal gammopathy and some have frank myeloma
   3. Association with IgG paraproteinemia but unclear if this is pathogenic
   4. No clear direct role for monoclonal component in pathogenesis of disease
   5. More likely that immune dysregulation with systemic lymphocyte activation is involved
   6. Increased circulating interleukin 2 levels may be involved
   7. Interleukin 2 infusions can cause a similar syndrome
   8. Activation of classical complement pathway
5. Treatment
   1. Highly variable and previously disappointing responses
   2. Combination extended release oral terbutaline + theophylline very effective [9]
   3. These agents, particularly in combination, are not tolerated very well
   4. Theophylline levels should be maintained >10µg/L
   5. Glucocorticoids - high doses are sometimes effective (poor long term tolerance)
   6. Plasma exchange - particularly if monoclonal gammopathy is present
   7. Intravenous immunoglobulin (IVIg)
6. Generally high mortality rates

1. Exudative Phase (1-4 days)
   1. Alveolar and interstitial edema (high protein content fluid leakage)
   2. Capillary Congestion - platelets and leukocyte aggregates trapped in microcirculation
   3. Type 1 alveolar cell destruction
   4. Inflammatory cell infiltrate
   5. "White Out" with fluffy interstitial infiltates on chest radiograph
   6. These areas signify alveolar collapse
   7. CT Scan shows discrete areas of normal and affected lung, correlates with O2 exchange
2. Proliferative Phase (3-10 days)
   1. Type II alveolar cell proliferation
   2. Cellular infiltration
   3. Organization of hyalin membranes
   4. Increased pulmonary vascular resistance
   5. Decreased lung compliance, increased dead space
3. Late Fibrotic Phase (7-10 days)
   1. Fibrosis of hyalin membranes
   2. Alveolar septa fibrosis
   3. Repair processes may actually allow return of normal lung function

B. Pathophysiology Overview [1]

1. Injury to Alveoli
   1. Pulmonary endothelium are damaged and activated
   2. Increased endothelial adhesion molecule expression: ICAM-1, VCAM-1, other selectins
   3. Pulmonary epithelium is damaged: types 1 and 2 pneumocytes
   4. Damage to epithelial-endothelial membrane leads to fluid influx into alveoli
   5. Stimulates production of fibrotic molecules in lung
2. Initiation of Inflammatory Cascade
   1. Bacterial products bind to specific receptors and initiate inflammatory cascade
   2. CD14 on host cells binds bacterial lippoplysaccharide (LPS)
   3. Toll-like receptor 4 (TLR4) binds pathogen-host complexes (including LPS-CD14 complexes)
   4. Engagement of TLR4 and other TLRs activates pro-inflammatory transcription factors
   5. Major transcription factors are nuclear factor kappa B (NFkB), activator protein 1 (AP1)
   6. Complement proteins C5a and C3a may be earliest initiators of neutrophil activation
   7. Platelet activating factor (PAF) and interleukin (IL) 8 are also released early
   8. These proteins mediate neutrophil recruitment and activation
3. Cytokine Production
   1. Macrophage inhibitory factor (MIF) found in elevated levels in BAL fluid
   2. MIF increasses production of proinflammatory cytokines and antagonizes glucocorticoids
   3. Interleukin 8 - stimulates neutrophil chemotaxis
   4. Interleukin 1
   5. Tumor necrosis factor alpha (TNFa)
4. Inhibition of cytokine regulators
   1. Reduced levels of soluble TNF receptor
   2. Reduced levels of IL1 receptor antagonist
   3. Reduced levels of anti-inflammatory cytokines IL10 and IL11

C. Pulmonary Edema [1,24]

1. Normally, pulmonary edema fluid is cleared by lymphatics
   1. Increased fluid will increase lymphatic clearance
   2. Eventually, increased fluid will overcome lymphatics
   3. Fluid initially accumulates in interstitium, then spills over into alveoli
   4. This is called "non-cardiogenic" pulmonary edema
   5. Non-cardiogenic pulmonary edema is protein-rich
2. Early in lung injury, protein-rich edema fluid flows into air spaces
   1. This is due to primarily to increased permeability of alveolar-capillary barrier
   2. Endothelial injury and increased vascular permeability is central to this disorder
   3. In this way, ARDS is very different from congestive heart failure (CHF)
   4. CHF may be present ("cardiogenic" pulmonary edema), but cannot be major cause
   5. Therefore, ARDS requires that Pulmonary Capillary Wedge Pressure < 18cm H2O
3. Loss of epithelial integrity also contributes to fluid
   1. Type 1 pneumocytes make up the major barrier to fluid transit in normal lung
   2. Type 1 pneumocytes are relatively susceptible to injury (compared with type II)
   3. Type 2 pneumocytes normally play a major role in alveolar ion transport
   4. Damage to type 2 pneumocytes leads to abnormal ion transport and fluid retention

D. Role of Neutrophils

1. Animal models use PMNs activated with phorbol esters to induce ARDS-like syndrome
2. Oxygen radicals are critical
   1. PMNs from chronic granulomatous disease (CGD) do not cause ARDS in animals
   2. CGD PMNs do not have a "respiratory burst" and do not make toxic oxygen radicals
3. Majority of patients with ARDS have >70% of neutrophils in broncheolar lavage fluid
   1. Normal BAL fluid <5% neutrophils
   2. Some patients will have eosinophils in BAL fluid
4. Complement system activation appears to play a major role in neutrophil activation
   1. Role for complement (C') implicated
   2. Activated Complement leads to C5a production
   3. C5a is a chemoattractant and activator of Neurophils (PMNs)
   4. Thromboxanes may play a critical role as well
5. Products of PMNs Involved in ARDS [10]
   1. Reactive Oxygen Species: peroxide (H2O2), superoxide (O2-), hydroxide radical (OH·)
   2. Proteases: elastase, collagenase
   3. Arachidonic acid metabolites: prostaglandins, leukotrienes and thromboxanes
   4. Note however, that neutropenic patients can develop ARDS
6. Patients with respiratory failure given G-CSF to increase neutrophils do not have increased risk for ARDS
7. Very possible that neutrophils are the result of lung injury, rather than a cause

E. Effects on Gas Exchange

1. Severe hypoxemia as a result of increased shunt fraction (V/Q = 0) and VQ Mismatch
2. Thus, correction of hypoxemia is refractory to increased FiO2
3. High respiratory rate contributes to hypocapnia (reduced arterial pCO2) [11]
   1. Leads to respiratory alkalosis
   2. Causes generalized vasoconstriction which exacerbates tissue ischemia
   3. Increases pulmonary shunting which exacerbates hypoxemia
4. Alveolar flooding and collapse (atelectasis) - likely due to loss of surfactant
5. Diffusion impairment does not contribute to hypoxia (that is, no decrease in DLCO)
6. Degree of hypoxemia estimated from PaO2÷ FiO2 ratio [1]
   1. Normal ratio >450 = ~90/0.2
   2. Acute lung injury ratio <300
   3. ARDS ratio <200

F. Lung Mechanics

1. ARDS: smaller and stiffer lungs (restrictive defects predominate)
2. Decreased functional residual capacity (FRC)
3. Secondary alterations in surfactant function leading to decreased lung compliance
4. Later phase increased production of profibrotic collagens, reducing compliance
5. Increased pulmonary vascular resistance with pulmonary hypertension
6. Net result is much increased work of breathing

1. Oxygen to maintain PaO2 ~60 mm or 90% saturation
2. If fever or acidosis is present, hemoglobin saturation is shifted and 90% saturation requires about ~80mm Hg instead of the usual ~60mm
3. Antioxidants should be considered
   1. 100mg selenium per day
   2. 1gm ascorbic acid per day
   3. 400 IU vitamin E per day
4. Oxygen Toxicity
   1. Pulmonary parenchymal toxicity occurs at any O2 level
   2. Especially marked at FiO2 > ~70% (worse at higher FiO2)
   3. Attempt to adjust parameters to maintain FiO2 <50%
5. Blood transfusion generously indicated to increase O2 carrying capacity.
6. "Catastrophic" ARDS may be defined as arterial pO2 <80mm Hg despite 100% FiO2 and PEEP of 15cm H2O (see below)
7. Optimized mechanical ventilation is mandatory in ARDS
8. Only minimization of barotrauma with mechanical ventilation has been shown to reduce mortality in ARDS and ALI [1]

B. Mechanical Ventilation [12,13]

1. Goals
   1. Optimizing venilator settings in patients with ARDS improves mortality
   2. Oxygenation is usually the greatest problem due to airway collapse
   3. Portions of lung are collapsed but may be recruited by elevating lung (inflation) pressures
   4. ARDS lungs are especially susceptible to damage by high pressures, called "barotrauma"
   5. Minimizing barotrauma is usually achieved by reducing plateau (mean lung) pressures but maintaining elevated pressure at end of expiration to keep alveoli open
   6. Thus, positive end expiratory pressure (PEEP) prevents alveolar collapse [16]
   7. Tidal volumes ~6mL/kg and mean plateau pressures <30cm strongly advocated [1,12]
   8. Increasing mean plateau pressures <40cm does not improve outcomes [32]
   9. Weight (kg) is calculated as appropriate weight, not actual weight (see below) [13]
   10. Initially 18-22 breaths per minute; hypercapnea may occur
   11. Increased PEEP added to low tidal volumes may provide optimal lung protection [33]
2. End Expiratory Pressure and Recruitable Lung [29]
   1. PEEP maintains open airways (recruited lung) and reduces alveolar fluid [1]
   2. PEEP improves oxygenation and allows reduction of mean airway pressures
   3. The percentage of potentially recruitable lung is extremely variable in ARDS
   4. A mean (±SD) of 13±11% of potentially recruitable lung was found in 65 ARDS patients
   5. Patients with >9% of potentially recruitable lung had poorer oxygenation, respiratory system compliance, higher dead space, and higher death rates [29]
   6. Likely that low tidal volumes (>6cc/kg) with "high" PEEP (~14cm) minimizes trauma [16]
   7. However, PEEP of 8cm versus 13cm show no differences in clinical outcomes [28]
   8. With tidal volume 6cc/kg, PEEP set to reach plateau pressure 28-30cm superior to PEEP set at 5-9cm on oxygenation, duration of mechanical ventilation and organ failure [33]
   9. Response to PEEP of 15cm or 5cm dependent upon recruitable lung space [29]
3. Ventilatory Modes in ARDS
   1. Mechanical ventilation rates of 20-24 often needed to maintain pH and CO2 levels due to increased in dead space in ARDS
   2. Auto-PEEP and high pulmonary pressures may occur at these rates
   3. Maintain plateau pressures >30cm and probably no higher than 40cm [32,33]
   4. If pH cannot be maintained, then sodium bicarbonate drip can be used for pH <7.2
   5. Permissive hypercapnea is likely safe in ARDS and helps avoid barotrauma
   6. If oxygenation not maintained with PEEP <15cm, consider inverse-ratio ventilation
   7. Pressure controlled ventilation may be preferable to standard volume; data pending
4. Prone Positioning
   1. Prone positioning in acute lung injury and ARDS can improve oxygenation in short term
   2. However, prone positioning does not improve mortality in acute respiratory failure [5,14,15]
   3. Prone positioning did not improve clinical outcomes in children with ALI [5]
5. Optimal Mechanical Ventilation in ARDS [1,13]
   1. "Protective" ventilation has been developed for use in ARDS [16]
   2. Overdistension of lungs leads to significant inflammatory / cytokine responses [21]
   3. These inflammatory responses likely exacerbate pulmonary dysfunction
   4. Protective ventilation uses low tidal volums, permissive hypercapnia, preference for pressure limited ventilatory modes and other changes
   5. Protective ventilation had better in 28 day survival and weaning from mechanical ventilation
   6. Tidal volumes ~6mL/kg and mean plateau pressures <25-30cm are essential [12,13,16]
   7. Weight used is predicted body weight (PDW)based on height
   8. PDW(men)=50.0+0.91*(height in cm-152.4); PDW(women)=45.5+0.91*(height cm-152.4)
   9. Increasing ventilator rates and use of bicarbonate to correct acidosis advocated [12,13]
   10. Ventilation at 6mL/kg had improved survival and reduced need for ventilation versus standard 12mL/kg [18]
   11. Percentage of recruitable lung space should guide selection of PEEP levels, with more PEEP for higher percentage of recruitable lung space [29]
6. Other Measures
   1. Diuresis may be helpful in elevated left atrial (pulmonary catheter occlusion) pressure
   2. Prone position should be considered when diuresis does not improve oxygenation but there is no documented mortality benefit to prone positioning (see above)
   3. Inhaled prostacyclin can increase pulmonary arterial vasodilation and improve pO2
   4. Inhaled nitric oxide improves oxygenation, may permit reduction in support levels, but has no effect on ventilation time, ICU stay, or mortality [27]
   5. Inhaled nitric oxide may be most beneficial when pulmonary shunting is present
   6. High dose glucocorticoids have had variable effects on outcomes [18,19]
   7. Extracorporeal Membrane Oxygenation (ECMO) after all other methods fail
   8. These methods should be considered particularly with "catastrophic" ARDS (see above)
   9. Pulmonary artery catheter (PAC) may be useful for optimizing cardiovascular parameters but randomized studies have shown no outcome benefits to PAC use
7. Non-Invasive Ventilation
   1. Ventilator may be connected to a well-secured face mask
   2. Probably only useful in very early and/or mild ARDS
   3. NIPPV did not improve outcomes in acute hypoxemic nonhypercapnic respiratory failure [20]
   4. NIPPV is superior to endotracheal intubation in solid organ transplant patients with acute hypoxemic respiratory failure [21]
   5. In general, endotracheal intubation with standard mechanical ventilation preferred over NIPPV in ARDS and most ALI

C. Management of Volume Status

1. Volume overload may increase fluid in lungs leading to worsening oxygenation
2. Hypovolemia may cause renal and liver dysfunction, brain damage, other problems
3. Optimal Fluid Management [31]
   1. Conservative and liberal strategies of fluid management were compared (1000 patients)
   2. Similar rates of death at 60 days
   3. Conservative management had reduced duration of mechanical ventilation and ICU stay
   4. Both strategies had similar rates of non-pulmonary organ failure
   5. Conservative fluid management strategy is generally recommended
4. PEEP may make optimization of LV filling difficult
5. Patients are often more easily managed with Pulmonary Artery Catheter (PAC) [30]
   1. The effects of changing PEEP on Cardiac Output can be readily monitored
   2. Volume status (filling pressures) can be monitored closely
   3. Especially indicated if patient is oliguric or if there is pre-existing cardiac disease
   4. PAC did not improve clinical outcomes and increased complications in ALI [30]
6. Many experts recommend maintaining wedge pressure in 12-18cm range
7. Albumin infusions should be considered to increase hydrostatic forces where appropiate

D. Other Therapies

1. Antibiotics not routinely recommended unless sepsis or aspiration is underlying condition
2. Glucocorticoids
   1. Should not be used routinely in patients with persistent ARDS [18,19]
   2. Should be used in all patients with high lung eosinophils documented on lavage
   3. Useful in some infections such as pneumocystis pneumonia, miliary tuberculosis
   4. However, before use, infections should be well characterized
   5. Prolonged methylprednisolone, 2mg/kg/day IV, begun after day 7, greatly improved extubation rate [18,19] and mortality [18] in patients with resistant ARDS
   6. Methylprednislone begun after at least 7 days of ARDS had no overall mortality benefit at 2 and 6 months [19]
   7. Methylprednisolone begun after 14 days of ARDS increased 2- and 6-month mortality [19]
   8. Methylprednisolone after 7 days increase number of ventilator-free and shock-free days within the first 28 days (improved oxygenation but not mortality) [19]
   9. Methylprednisolone blunts fever response but has not affected infection rates [18,19]
   10. Most trials have been negative for overall benefit, so routine use of glucocorticoids in ARDS is not supported by evidence [1]
3. Ketoconazole [22]
   1. Inhibits thromboxane generation; blocks thromboxane synthesis
   2. Also inhibits 5-lipoxygenase and reduces leukotriene synthesis
   3. Decreases Leukotriene B4, a major neutrophil chemoattractant
   4. No clinical benefit in patients with acute lung injury (234 patient study)
4. Nitric Oxide [23]
   1. May also be helpful in improving oxygenation in some patients
   2. Especially useful in patients with increased pulmonary vascular resistance
   3. Improves oxygenation in ARDS but may not affect overall mortality
   4. Concentration of 5 parts per million (ppm) may be optimal
   5. Nitric oxide is recommended in patients who are difficult to oxygenate
5. Not Helpful
   1. Exogenous surfactant [26]
   2. Ibuprofen
   3. N-acetylcysteine (NAC)
   4. Pentoxifylline
   5. Antiendotoxin or anti-cytokine antibodies not helpful
   6. Alprostadil (prostaglandin)
   7. Procysteine
   8. Lisofylline
6. Anti-Oxidants - most are under investigation
   1. Glutathione
   2. Superoxide dismutase
   3. ß-carotene should probably be avoided
   4. Vitamins C and E
   5. Selenium
   6. The vitamins and minerals are probably safe, efficacy under investigation
7. New modes of Ventilation
   1. Extra corporeal membrane oxygenation (ECMO)
   2. Extra corporeal carbon dioxide removal (ECCO2R)
   3. Partial Liquid Ventilation
8. ECMO
   1. Blood is oxygenated outside of the body
   2. Most commonly used to support mature newborn infants
   3. Study in neonates >34 weeks with respiratory failure showed mortality benefit [25]
   4. Method is complex and costly but confers a substantial survival benefit in infants
   5. Use in other populations is experimental
9. Calfactant (Infasurf®), a natural surfactant with high levels of surfactant-specific protein B, appears to reduce mortality and improve oxygenation in pediatric acute lung injury [6]

E. Futher Evaluation

1. Bronchealveolar lavage (BAL) may be useful early in course to rule out infection, characterize pulmonary inflammatory cells
2. Eosinophilia in BAL fluid should prompt early use of corticosteroids (2-4mg/kg/day)
3. Pneumocystis carinii infection may also benefit from corticosteroids
4. Thin Section CT scan of lungs rarely aids in diagnosis unless underlying process suspected
   1. Mass Lesion
   2. Abscess / Empyema

References

1. Wheeler AP and Bernard GR. 2007. Lancet. 369(9572):1553
2. Piantadosi CA and Schwartz DA. 2004. Ann Intern Med. 141(6):460
3. Waxman AB, Shepard JO, Mark EJ. 2003. NEJM. 348(19):1902 (Case Record)
4. Rubenfeld GD, Caldwell E, Peabody E, et al. 2005. NEJM. 353(16):1685
5. Curley MAQ, Hibberd PL, Fineman LD, et al. 2005. JAMA. 294(2):229
6. Medoff BD, Shepard JO, Smith RN, Kratz A. 2005. NEJM. 352(23):2425 (Case Report)
7. Herridge MS, Cheung AM, Tansey CM, et al. 2003. 348(8):683
8. Stirling CM, Boulton-Jones JM, Simpson K. 1998. Lancet. 352(9126):450
9. Tahirkheli NK and Greipp PR. 1999. Ann Intern Med. 130(11):905
10. Babior BM. 2000. Am J Med. 109(1):33
11. Laffey JG and Kavanagh BP. 2002. NEJM. 347(1):43
12. Acute Respiratory Distress Syndrome Network. 2000. NEJM. 342(18):1301
13. Malhotra A. 2007. NEJM. 357(11):1113
14. Gattinoni L, Tognoni G, Pesenti A, et al. 2001. NEJM. 345(8):568
15. Guerin C, Gaillard S, Lemasson S, et al. 2004. JAMA. 292(19):2379
16. Amato MBP, Barbas CSV, Medeiros DM, et al. 1998. NEJM. 338(6):341
17. Weg JG, Anzueto A, Balk RA, et al. 1998. NEJM. 338(6):341
18. Meduri GU, Headley AS, Golden E, et al. 1998. JAMA. 280(2):159
19. National Heart Lung and Blood Institute ARDS Trials Network. 2006. NEJM. 354(16):1671
20. Delclaux C, L'Her E, Alberti C, et al. 2000. JAMA. 284(18):2352
21. Antonelli M, Conti G, Bufi M, et al. 2000. JAMA. 283(2):235
22. ARDS Network Authors. 2000. JAMA. 283(15):1995
23. Dellinger RP, Zimmerman JL, Taylor RW, et al. 1998. Crit Care Med. 26:15
24. Ware LB and Matthay MA. 2005. NEJM. 353(26):2788
25. UK Collaborative ECMO Trial Group. 1996. Lancet. 348:75
26. Spragg RG, Lewis JF, Walmrath HD, et al. 2004. NEJM. 351(9):884
27. Taylor RW, Zimmerman JL, Dellinger RP, et al. 2004. JAMA. 291(13):1603
28. NHLBI ARDS Clinical Trials Network. 2004. NEJM. 351(4):327
29. Gattinoni L, Caironi P, Cressoni M, et al. 2006. NEJM. 354(17):1775
30. NHLBI ARDS Clinical Trials Network. 2006. NEJM. 354(21):2213
31. NHLBI ARDS Clinical Trials Network. 2006. NEJM. 354(24):2564
32. Meade MO, Cook DJ, Guyatt GH, et al. 2008. JAMA. 299(6):637
33. Mercat A, Richard CJ, Vielle B, et al. 2008. JAMA. 299(6):646