Decision Making in Emergency Critical Care

SECTION 4 - Pulmonary Critical Care

12
Acute Respiratory Distress Syndrome

Darryl Abrams and Daniel Brodie

BACKGROUND

Acute respiratory distress syndrome (ARDS) is characterized by the rapid onset of hypoxemia and bilateral pulmonary infiltrates consistent with pulmonary edema that cannot be fully attributed to cardiac failure or fluid overload.1 The ARDS Definition Task Force has recently revised this definition, which uses the ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (PaO2 to FIO2ratio), to classify ARDS into mild (200 < PaO2/FIO2 ≤ 300), moderate (100 < PaO2/FIO2 ≤ 200), and severe (PaO2/FIO2 ≤ 100), with a positive end-expiratory pressure (PEEP) of at least 5 cm of water.2 By these criteria, there are estimated to be over 190,000 cases of ARDS in the United States annually.3 In clinical trials involving patients with ARDS, mortality remains in the range of 22% to 45%, with lower PaO2 to FIO2 ratios correlating with worse survival rates.2,49 The majority of ARDS cases are caused by bacterial or viral pneumonia, extrapulmonary sepsis, aspiration, and trauma. Less common causes include acute pancreatitis, transfusions, and drug reactions.3,10,11 Pathologically, diffuse alveolar damage results from injury to both the capillary endothelium and the lung epithelium, increasing permeability and allowing protein-rich alveolar edema to form. Surfactant production and function are impaired, promoting alveolar collapse.7,12 The result is abnormal gas exchange, with hypoxemia and impaired carbon dioxide excretion, as well as decreased lung compliance.13 The distribution of ARDS is heterogeneous within the lung. Positive pressure ventilation, although potentially lifesaving in ARDS, may cause ventilator-associated lung injury (VALI) and exacerbate the inflammatory process by overdistending less affected regions of the lung and repeatedly collapsing and reopening small bronchioles and alveoli.13,14 The use of a high fraction of inspired oxygen may also contribute to lung injury.14,15 The cornerstone of management of ARDS is treatment of the precipitating illness and minimization of VALI.4,12 This chapter discusses ARDS therapies available to the emergency physician and the rationale behind them.

MANAGEMENT GUIDELINES

Lung-Protective Ventilation

The only intervention that definitively demonstrates a survival benefit in ARDS is a volume- and pressure-limited ventilation strategy. In 2000, the ARDS Network published the results of a prospective randomized trial (ARMA) in which 861 intubated patients with ARDS were assigned to receive either (1) a tidal volume of 6 mL/kg predicted body weight (based on height) with a goal airway pressure measured after a 0.5-second pause at the end of inspiration (plateau pressure) of 30 cm of water or less or (2) a traditional tidal volume of 12 mL/kg with a goal plateau pressure of 50 cm of water or less.4Tidal volumes in each group were reduced stepwise by 1 mL/kg (minimum tidal volume 4 mL/kg) as needed to achieve the target plateau pressures, with an increase in respiratory rate as needed to maintain adequate minute ventilation up to a maximum set respiratory rate of 35 breaths/min. For the group treated with the volume- and pressure-limited strategy, results showed significantly lower mortality (31% vs. 39.8%), more ventilator-free days (12 ± 11 vs. 10 ± 11), and more days without nonpulmonary organ failure (15 ± 11 vs. 12 ± 11). Of note, the actual plateau pressures achieved in the low and traditional tidal volume groups were 25 ± 6 and 33 ± 8 cm of water, respectively. Additionally, oxygenation early in the trial was not a good predictor of outcome, as the low tidal volume group had lower PaO2 to FIO2ratios on days 1 and 3, yet this group had better survival. The results of this and two other randomized trials with similar interventions have led to the adoption of a lung-protective strategy targeting low volume (6 mL/kg predicted body weight or less) and low pressure (plateau pressures of 30 cm of water or less) as the standard of care in ventilator management in ARDS.4,16,17

PEEP Strategy

Nonaerated portions of the lung in ARDS—those not adequately exchanging gas due to alveolar edema and collapse—may contribute significantly to shunt physiology and hypoxemia; in addition, the shear forces of cyclic opening and closing of alveolar units with positive pressure ventilation may precipitate worsening inflammation and VALI.13,18 By applying PEEP via the ventilator, a portion of the collapsed alveoli may be reopened or “recruited.” With this intervention, the proportion of nonaerated lung may be reduced and arterial oxygenation goals met, with lower levels of FIO2 delivered by the ventilator. However, increased levels of PEEP may cause circulatory compromise by impeding venous return and may lead to increased regional airway pressures and lung volumes, further exacerbating VALI.

The effect of different levels of PEEP on clinical outcomes was investigated by the ARDS Clinical Trials Network in a prospective, randomized trial in which 549 intubated patients with ARDS were randomized to either a high or low PEEP strategy.5 PEEP and FIO2 were adjusted in discrete steps to maintain an arterial oxyhemoglobin saturation (measured by pulse oximetry, SpO2) of 88% to 95% or a PaO2 of 55 to 80 mm Hg. There was no difference in mortality, ventilator-free days, ICU-free days, or organ failure–free days between the two groups, despite higher PaO2 to FIO2 ratios and respiratory system compliance in the high PEEP group. A subsequent multicenter study randomized 767 subjects with ARDS to either a minimal distention strategy (moderate PEEP of 5 to 9 cm of water) or an increased recruitment strategy (a level of PEEP set to reach a plateau pressure of 28 to 30 cm of water).8 Both groups were managed with low tidal volume ventilation (6 mL/kg of predicted body weight). Mean PEEP values in the minimal distention and increased recruitment strategy groups on day 1 were 8.4 cm of water and 15.8 cm of water, respectively. The increased recruitment strategy was associated with more ventilator-free days (7 vs. 3) and organ failure–free days (6 vs. 2), but there was no difference in 28- or 60-day mortality. In meta-analyses of 2,299 individual subjects from three randomized trials of high versus low PEEP (including the two previously mentioned trials), there was no significant difference in overall mortality between PEEP strategies (adjusted relative risk 0.94), though subset analysis demonstrated a survival benefit in subjects with moderate to severe ARDS who received a higher PEEP strategy (34.1% vs. 39.1%, adjusted relative risk 0.90).5,8,1921

Based on the above results, there may be a role for higher levels of PEEP in improving surrogate outcomes (ventilator-free days, ICU-free days, organ failure–free days) in ARDS, and a high PEEP strategy may confer a survival benefit in patients with more severe cases of ARDS. However, the potential benefits of higher levels of PEEP have to be balanced against the risk of hemodynamic compromise. In the acute care setting, regardless of the PEEP strategy utilized, it is essential to institute early and appropriate standard-of-care ventilator management, which requires careful attention to tidal volumes, plateau airway pressures, and acceptable combinations of PEEP and FIO2.22

Fluid Management and Hemodynamic Monitoring

Noncardiogenic pulmonary edema in ARDS results from increased capillary permeability and is exacerbated by increased intravascular hydrostatic pressure and decreased oncotic pressure. This argues in favor of a strategy that minimizes fluid administration. However, given that mortality in ARDS is often the result of nonpulmonary organ failure, a conservative fluid strategy may worsen organ perfusion and outcomes. To help guide fluid management in ARDS, the ARDS Clinical Trials Network conducted the Fluid and Catheter Treatment Trial (FACTT), a randomized controlled trial of 1,001 patients assigned to receive either a liberal or conservative fluid strategy, guided by intravascular pressure monitoring.6 The 7-day cumulative fluid balance in the conservative-strategy group was −136 ± 491 mL, compared to 6,992 ± 502 mL in the liberal-strategy group. There was no significant difference in in-hospital mortality between groups (25.5 ± 1.9% in the conservative-strategy group, 28.4 ± 2.0% in the liberal-strategy group). However, the conservative-strategy group had significantly more ventilator-free days (14.6 vs. 12.1) and ICU-free days (13.4 vs. 11.2) than did the liberal-strategy group, without increasing the rate of nonpulmonary organ failure. Based on these data, it is generally recommended to adhere to a conservative fluid strategy to help improve lung function and minimize the duration of mechanical ventilation and intensive care. Despite the recommendation to minimize intravascular pressure, this same trial found no benefit in guiding hemodynamic management using a pulmonary artery catheter (PAC) versus a central venous catheter. PACs were, however, associated with a higher rate of atrial and ventricular arrhythmias. Based on these results, PACs are not recommended for routine use in ARDS.

Corticosteroids

ARDS is characterized by diffuse lung inflammation, which is further exacerbated by positive pressure ventilation and resulting VALI. Corticosteroids, with their anti-inflammatory properties, have been hypothesized to have a role in treating ARDS; however, multiple randomized trials have not demonstrated a clear and consistent benefit from corticosteroids in either the early or late phases of ARDS.2326One RCT found no difference in 45-day mortality, resolution of ARDS, or infectious complications among 99 patients with early ARDS (onset within 48 hours) who were randomized to either high-dose corticosteroids (methylprednisolone 30 mg/kg every 6 hours for 24 hours) or placebo.23 Another randomized trial of 24 patients demonstrated a benefit in mortality when a prolonged course of corticosteroids was administered after 7 days of persistent ARDS24; however, a subsequent multicenter trial conducted by the ARDS Clinical Trials Network (Late Steroid Rescue Study, LaSRS), randomizing 180 patients with ARDS of 7 to 28 days' duration to methylprednisolone versus placebo, showed no difference in 60-day mortality (28.6% vs. 29.2%).25 Corticosteroids were associated with increases in the number of ventilator-free days (11.2 vs. 6.8) and shock-free days (20.7 vs. 17.9), but they were also associated with significantly more episodes of neuromyopathy (9 vs. 0) and a higher mortality when steroids were started 14 or more days after ARDS onset (35% vs. 8%). Based on the existing evidence, the routine use of corticosteroids is not generally recommended for ARDS; however, this remains an area of controversy. Also, such recommendations do not apply to patients whose acute hypoxemic respiratory failure is due to an etiology for which corticosteroids are indicated, such as collagen vascular disease or acute eosinophilic pneumonia.

Neuromuscular Blocking Agents

Neuromuscular blocking agents (NMBAs) are often used in severe ARDS to decrease patient–ventilator dyssynchrony and improve oxygenation when sedation alone is insufficient. However, their use has also been associated with muscle weakness.27,28 The ACURASYS trial, a recent multicenter study from France, was conducted to evaluate the effect of NMBAs in early, severe ARDS.29 Three hundred and forty patients with ARDS for <48 hours, a PaO2 to FIO2 ratio of <150, and a Ramsey sedation score of 6 (no response on glabellar tap) were randomized to receive cisatracurium or placebo for 48 hours. Those who received cisatracurium had a significantly lower 90-day mortality (hazard ratio 0.68) after post hoc adjustments were made for the degree of hypoxemia, severity of illness, and plateau airway pressure; however, this difference did not become apparent until well after NMBAs were discontinued. There were also more ventilator-free and ICU-free days within the cisatracurium group, without a significant difference in ICU-acquired paresis. NMBAs remain an option early in the course of severe ARDS when severe gas exchange abnormalities persist despite deep sedation, but their use has yet to be widely accepted as standard of care.

Extracorporeal Membrane Oxygenation

Extracorporeal membrane oxygenation (ECMO) refers to an extracorporeal circuit that directly oxygenates and removes carbon dioxide from the blood. In most cases of ECMO for ARDS, a cannula is placed in a central vein. Blood is withdrawn into an extracorporeal circuit by a mechanical pump and passed through an oxygenator, where the blood passes along one side of a semipermeable membrane that allows for diffusion of gases. The oxygenated blood is then returned to a central vein. This technique is referred to as “venovenous” ECMO because blood is withdrawn from and returned to the venous system.1 ECMO may be considered as a rescue therapy in patients whose gas exchange abnormalities are so severe that positive pressure ventilation alone is insufficient to maintain adequate gas exchange. Additionally, ECMO may be indicated in patients who can be maintained on positive pressure ventilation only at the expense of excessively high airway pressures or in patients who cannot tolerate a lung-protective ventilation strategy because of unacceptable levels of hypercapnia and acidemia.

The results of two early, randomized controlled trials with outdated ECMO technology failed to show a survival benefit with ECMO for ARDS.30,31 However, in the interval since those trials, there have been significant advances in ECMO technology, with observational reports demonstrating higher rates of survival and fewer complications. The only controlled clinical trial using modern ECMO technology is Conventional Ventilation or ECMO for Severe Adult Respiratory Failure (CESAR), in which 180 subjects with severe but potentially reversible respiratory failure were randomized to conventional mechanical ventilation or referral to a specialized center for consideration of ECMO.32 There was a significantly lower rate of death or severe disability at 6 months in the group referred for consideration of ECMO (37% vs. 53%, relative risk 0.69). The major limitation of the study was that only 70% of the conventionally managed patients received a lung-protective ventilation strategy at any time in the study because such a strategy was not mandated despite the fact that it is the widely accepted standard of care. Regardless, the results of this trial and other observational studies (particularly those published during the influenza A (H1N1) pandemic) have given momentum to the belief that there is a role for ECMO in ARDS when gas exchange is markedly abnormal or airway pressures are excessively high. A randomized controlled trial of ECMO versus standard-of-care mechanical ventilation is needed to better define the use of this therapy in severe cases of ARDS. The initiation of ECMO should be reserved for centers with extensive experience in its use. Early referral to such a center is recommended, since the benefits of ECMO may be lessened by prolonged mechanical ventilation with plateau pressures exceeding 30 cm of water for >7 days or prolonged exposure to high FIO2.3337 Earlier initiation of ECMO has been associated with better outcomes in some, but not all, observational studies.35,3840

ADDITIONAL RESCUE THERAPIES

Prone Positioning

ARDS affects the lung heterogeneously, with more consolidation and atelectasis occurring in the dependent portions of the lung and with alveolar inflation and ventilation distributing preferentially to the nondependent lung regions. Hypoxemia results from ventilation–perfusion mismatch and from the development of physiologic shunt as blood flow remains prominent in the dependent, atelectatic lung regions. Prone positioning has been proposed as a way of improving oxygenation by improving ventilation–perfusion matching. Prone positioning achieves this through redistribution of perfusion, recruitment of previously dependent lung regions, more homogeneous distribution of ventilation, and alterations in chest wall compliance.41,42

Despite demonstrating a consistent relationship between prone positioning and improved oxygenation, multiple randomized trials and meta-analyses initially failed to show any mortality benefit,4349with prone positioning associated with a higher rate of complications, including hemodynamic instability, loss of venous access, and endotracheal tube displacement.42 However, post hoc analyses of several trials and two meta-analyses have suggested a mortality benefit in patients with the most severe forms of ARDS,50,51 leading to a multicenter randomized trial of prone versus supine positioning in 466 patients with ARDS with a PaO2 to FIO2 ratio <150.52 Twenty-eight–day mortality was significantly lower in the prone group than the supine group (16.0% vs. 32.8%, hazard ratio 0.42), a difference that persisted at 90 days. Adverse event rates were comparable between the two groups, except for a higher rate of cardiac arrests in the supine group. Based on the results of this trial, the early institution of prone positioning is not recommended for routine use in ARDS, but may be considered in cases of severe hypoxemia at centers experienced in its use.

High-Frequency Oscillatory Ventilation

The principle of high-frequency oscillatory ventilation (HFOV) is to maintain alveolar patency while avoiding low end-expiratory pressure and high peak pressures. Ventilation is achieved with an oscillating piston that creates pressure cycles around a constant mean airway pressure at a very high frequency (180 to 900/min), resulting in low tidal volumes (<2.5 mL/kg).53,54 Early randomized trials demonstrated a trend toward decreased mortality with HFOV compared to conventional mechanical ventilation.55 Two multicenter randomized controlled trials comparing HFOV to standard-of-care lung-protective ventilation, the Oscillation for Acute Respiratory Distress Syndrome Treated Early Trial (OSCILLATE) and High-Frequency Oscillation in ARDS (OSCAR), have recently been conducted.56,57OSCAR failed to show a difference from HFOV in 30-day mortality (41.7% vs. 41.1%), and OSCILLATE was terminated early by the data monitoring committee due to increased in-hospital mortality in the HFOV group (47% vs. 35%, RR 1.33). Given the findings of these studies, HFOV is not recommended for routine use in ARDS.

Inhaled Vasodilators

Inhaled vasodilator therapy delivers aerosolized vasodilator medications to the alveoli by way of a ventilator. The effect of the vasodilators will not be significant in areas of the lung where edema and atelectasis are plentiful and delivery is hampered. However, in well-ventilated portions of the lung, inhaled vasodilators may improve oxygenation in ARDS by preferentially recruiting blood flow and simultaneously diverting it from areas with high levels of shunt.

Commonly used vasodilators include inhaled nitric oxide and inhaled epoprostenol. Despite demonstrating improvements in oxygenation, randomized trials have failed to show a survival benefit from vasodilator therapy, and concerns have been raised about side effects from prolonged nitric oxide administration, including cyanide toxicity, methemoglobinemia, and worsening renal function.5860 Side effects from epoprostenol may include flushing and hypotension if there is systemic absorption of the medication.61 Both therapies may worsen hypoxemia by worsening ventilation–perfusion mismatch if systemic absorption results in vasodilation of the pulmonary vasculature in areas of the lung where ventilation is low. Inhaled vasodilators should not be used routinely in ARDS, but may be considered in cases of severe, refractory hypoxemia.

Recruitment Maneuvers

Recruitment maneuvers, often used in conjunction with high levels of PEEP, are intended to improve aeration to collapsed or fluid-filled alveoli, thus improving oxygenation, minimizing shear stress on alveoli, and increasing pulmonary compliance.54,62 A recruitment maneuver involves increasing airway pressures to levels above tidal ventilation for a brief period of time. Risks of achieving these higher airway pressures include overinflation of unaffected alveoli, increased VALI, decreased alveolar fluid clearance, and hemodynamic compromise.21,6365 In a prospective trial of 983 patients with ARDS randomized to recruitment maneuvers and high levels of PEEP (40-second breath hold at 40 cm of water followed by a PEEP of 20 cm of water) or standard-of-care lung-protective ventilation, the intervention group had lower rates of refractory hypoxemia (4.6% vs. 10.2%) and death with refractory hypoxemia (4.2% vs. 8.9%), but there was no difference in all-cause mortality (36.4% vs. 40.4%, RR, 0.90).21 Recruitment maneuvers were complicated by hypotension, worsening hypoxemia, arrhythmia, or barotrauma in 22% of the subjects in the intervention group. Similar to the results of trials evaluating high PEEP strategies, these results show that recruitment maneuvers may improve surrogate outcomes but do not demonstrate a definitive mortality benefit.21,65,66 Recruitment maneuvers may be considered in severe ARDS with refractory hypoxemia, but should be avoided in patients in shock and those with pneumothoraces or focal disease. The maneuver should be aborted if hypotension or worsening hypoxemia develops and should not be repeated if there is no improvement after the initial maneuver.54

OTHER THERAPIES

The utility of noninvasive positive pressure ventilation (NIPPV), although well established in exacerbations of chronic obstructive pulmonary disease and cardiogenic pulmonary edema, is limited in ARDS and not recommended as routine therapy.67 High failure rates have been reported in several studies of NIPPV in ARDS, with severe hypoxemia, shock, and metabolic acidosis identified as independent risk factors for NIPPV failure.68 In patients with ARDS who have lower severity of illness scores and more mild hypoxemia, there may be a role for the cautious application of NIPPV.67,69 However, such patients must be assessed frequently for signs of failure of NIPPV and for the need for prompt institution of invasive mechanical ventilation. Ventilatory strategies that have been used as rescue therapies for severe ARDS include airway pressure release ventilation, inverse-ratio ventilation, and open lung ventilation. These therapies may demonstrate a benefit in surrogate outcomes, but none has been shown to affect major clinical outcomes in ARDS favorably.21,7077

CONCLUSION

Management of ARDS should focus on treatment of the underlying etiology and application of a volume- and pressure-limited ventilation strategy. A conservative fluid management strategy is recommended, and the administration of NMBAs may be associated with decreased mortality when used early in cases of severe ARDS. In patients with refractory gas exchange abnormalities despite these interventions, other therapies, including ECMO, high levels of PEEP, prone positioning, inhaled vasodilators, and recruitment maneuvers, may be considered (Table 12.1). The use of HFOV, corticosteroids, and PACs for hemodynamic monitoring is generally not recommended. Whether to use alternative therapies depends on the preference of the treating clinician and the resources available at a given institution or in that institution's referral network, since there are no evidence-based algorithms to guide decision making.

TABLE 12.1 Therapies for ARDS

ARDS, acute respiratory distress syndrome; PEEP, positive end-expiratory pressure; NMBAs, neuromuscular blocking agents; ECMO, extracorporeal membrane oxygenation; HFOV, high-frequency oscillatory ventilation.

LITERATURE TABLE

CI, confidence interval; HR, hazard ratio; RR, relative risk; RCT, randomized controlled trial.

REFERENCES

1.Brodie D, Bacchetta M. Extracorporeal membrane oxygenation for ARDS in adults. N Engl J Med. 2011;365(20):1905–1914.

2.Ranieri VM, Rubenfeld GD, Thompson BT, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012;307(23):2526–2533.

3.Rubenfeld GD, Caldwell E, Peabody E, et al. Incidence and outcomes of acute lung injury. N Engl J Med. 2005;353(16):1685–1693.

4.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(18):1301–1308.

5.Brower RG, Lanken PN, MacIntyre N, et al. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med. 2004;351(4):327–336.

6.Wiedemann HP, Wheeler AP, Bernard GR, et al. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006;354(24):2564–2575.

7.Spragg RG, Lewis JF, Walmrath HD, et al. Effect of recombinant surfactant protein C-based surfactant on the acute respiratory distress syndrome. N Engl J Med. 2004;351(9):884–892.

8.Mercat A, Richard JC, Vielle B, et al. Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA. 2008;299(6):646–655.

9.Matthay MA, Brower RG, Carson S, et al. Randomized, placebo-controlled clinical trial of an aerosolized beta(2)-agonist for treatment of acute lung injury. Am J Respir Crit Care Med. 2011;184(5):561–568.

10.Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 2000;342(18):1334–1349.

11.Rubenfeld GD, Herridge MS. Epidemiology and outcomes of acute lung injury. Chest. 2007;131(2):554–562.

12.Matthay MA, Ware LB, Zimmerman GA. The acute respiratory distress syndrome. J Clin Invest. 2012;122(8):2731–2740.

13.Piantadosi CA, Schwartz DA. The acute respiratory distress syndrome. Ann Intern Med. 2004;141(6):460–470.

14.International consensus conferences in intensive care medicine: Ventilator-associated Lung Injury in ARDS. This official conference report was cosponsored by the American Thoracic Society, The European Society of Intensive Care Medicine, and The Societe de Reanimation de Langue Francaise, and was approved by the ATS Board of Directors, July 1999. Am J Respir Crit Care Med. 1999;160(6):2118–2124.

15.Lodato R. Oxygen toxicity. In: Tobin MJ, ed. Principles and Practice of Mechanical Ventilation. 2nd ed. New York, NY: McGraw-Hill; 2006:965–989.

16.Amato MB, Barbas CS, Medeiros DM, et al. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med. 1998;338(6):347–354.

17.Villar J, Kacmarek RM, Pérez-Méndez L, et al. A high positive end-expiratory pressure, low tidal volume ventilatory strategy improves outcome in persistent acute respiratory distress syndrome: a randomized, controlled trial. Crit Care Med. 2006;34(5):1311–1318.

18.Muscedere JG, Mullen JB, Gan K, et al. Tidal ventilation at low airway pressures can augment lung injury. Am J Respir Crit Care Med. 1994;149(5):1327–1334.

19.Briel M, Meade M, Mercat A, et al. Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis. JAMA. 2010;303(9):865–873.

20.Putensen C, Theuerkauf N, Zinserling J, et al. Meta-analysis: ventilation strategies and outcomes of the acute respiratory distress syndrome and acute lung injury. Ann Intern Med. 2009;151(8):566–576.

21.Meade MO, Cook DJ, Guyatt GH, et al. Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end-expiratory pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA. 2008;299(6):637–645.

22.Checkley W, Brower R, Korpak A, et al. Effects of a clinical trial on mechanical ventilation practices in patients with acute lung injury. Am J Respir Crit Care Med. 2008;177(11):1215–1222.

23.Bernard GR, Luce JM, Sprung CL, et al. High-dose corticosteroids in patients with the adult respiratory distress syndrome. N Engl J Med. 1987;317(25):1565–1570.

24.Meduri GU, Headley AS, Golden E, et al. Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial. JAMA. 1998;280(2):159–165.

25.Steinberg KP, Hudson LD, Goodman RB, et al. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med. 2006;354(16):1671–1684.

26.Meduri GU, Golden E, Freire AX, et al. Methylprednisolone infusion in early severe ARDS: results of a randomized controlled trial. Chest. 2007;131(4):954–963.

27.Segredo V, Caldwell JE, Matthay MA, et al. Persistent paralysis in critically ill patients after long-term administration of vecuronium. N Engl J Med. 1992;327(8):524–528.

28.Murray MJ, Coursin DB, Scuderi PE, et al. Double-blind, randomized, multicenter study of doxacurium vs. pancuronium in intensive care unit patients who require neuromuscular-blocking agents. Crit Care Med. 1995;23(3):450–458.

29.Papazian L, Forel JM, Gacouin A, et al. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010;363(12):1107–1116.

30.Zapol WM, Snider MT, Hill JD, et al. Extracorporeal membrane oxygenation in severe acute respiratory failure. A randomized prospective study. JAMA. 1979;242(20):2193–216.

31.Morris AH, Wallace CJ, Menlove RL, et al. Randomized clinical trial of pressure-controlled inverse ratio ventilation and extracorporeal CO2 removal for adult respiratory distress syndrome. Am J Respir Crit Care Med. 1994;149(2 Pt 1):295–305.

32.Peek GJ, Mugford M, Tiruvoipati R, et al. Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. Lancet.2009;374(9698):1351–1363.

33.Rouby JJ, Brochard L. Tidal recruitment and overinflation in acute respiratory distress syndrome: yin and yang. Am J Respir Crit Care Med. 2007;175(2):104–106.

34.Pugin J, Verghese G, Widmer MC, et al. The alveolar space is the site of intense inflammatory and profibrotic reactions in the early phase of acute respiratory distress syndrome. Crit Care Med. 1999;27(2): 304–312.

35.Pranikoff T, Hirschl RB, Steimle CN, et al. Mortality is directly related to the duration of mechanical ventilation before the initiation of extracorporeal life support for severe respiratory failure. Crit Care Med. 1997;25(1):28–32.

36.Jackson RM. Pulmonary oxygen toxicity. Chest. 1985;88(6):900–905.

37.Davis WB, Rennard SI, Bitterman PB, et al. Pulmonary oxygen toxicity. Early reversible changes in human alveolar structures induced by hyperoxia. N Engl J Med. 1983;309(15):878–883.

38.Beiderlinden M, Eikermann M, Boes T, et al. Treatment of severe acute respiratory distress syndrome: role of extracorporeal gas exchange. Intensive Care Med. 2006;32(10):1627–1631.

39.Mols G, Loop T, Geiger K, et al. Extracorporeal membrane oxygenation: a ten-year experience. Am J Surg. 2000;180(2):144–154.

40.Lewandowski K, Rossaint R, Pappert D, et al. High survival rate in 122 ARDS patients managed according to a clinical algorithm including extracorporeal membrane oxygenation. Intensive Care Med. 1997;23(8):819–835.

41.Pelosi P, Brazzi L, Gattinoni L. Prone position in acute respiratory distress syndrome. Eur Respir J. 2002;20(4):1017–1028.

42.Gattinoni L, Caironi P. Prone positioning: beyond physiology. Anesthesiology. 2010;113(6):262–264.

43.Taccone P, Pesenti A, Latini R, et al. Prone positioning in patients with moderate and severe acute respiratory distress syndrome: a randomized controlled trial. JAMA. 2009;302(18):1977–1984.

44.Piehl MA, Brown RS. Use of extreme position changes in acute respiratory failure. Crit Care Med. 1976;4(1):13–14.

45.Slutsky AS. The acute respiratory distress syndrome, mechanical ventilation, and the prone position. N Engl J Med. 2001;345(8):610–612.

46.Abroug F, Ouanes-Besbes L, Elatrous S, et al. The effect of prone positioning in acute respiratory distress syndrome or acute lung injury: a meta-analysis. Areas of uncertainty and recommendations for research. Intensive Care Med. 2008;34(6):1002–1011.

47.Alsaghir AH, Martin CM. Effect of prone positioning in patients with acute respiratory distress syndrome: a meta-analysis. Crit Care Med. 2008;36(2):603–609.

48.Sud S, Sud M, Friedrich JO, et al. Effect of mechanical ventilation in the prone position on clinical outcomes in patients with acute hypoxemic respiratory failure: a systematic review and meta-analysis. CMAJ. 2008;178(9):1153–1161.

49.Gattinoni L, Tognoni G, Pesenti A, et al. Effect of prone positioning on the survival of patients with acute respiratory failure. N Engl J Med. 2001;345(8):568–573.

50.Gattinoni L, Carlesso E, Taccone P, et al. Prone positioning improves survival in severe ARDS: a pathophysiologic review and individual patient meta-analysis. Minerva Anestesiol. 2010;76(6): 448–454.

51.Sud S, Friedrich JO, Taccone P, et al. Prone ventilation reduces mortality in patients with acute respiratory failure and severe hypoxemia: systematic review and meta-analysis. Intensive Care Med. 2010;36(4):585–599.

52.Guerin C, et al. Prone Positioning in Severe Acute Respiratory Distress Syndrome. N Engl J Med. 2013;368(23):2159–2168.

53.Derdak S, Mehta S, Stewart TE, et al. High-frequency oscillatory ventilation for acute respiratory distress syndrome in adults: a randomized, controlled trial. Am J Respir Crit Care Med. 2002;166(6):801–808.

54.Diaz JV, Brower R, Calfee CS, et al. Therapeutic strategies for severe acute lung injury. Crit Care Med. 2010;38(8):1644–1650.

55.Ip T, Mehta S. The role of high-frequency oscillatory ventilation in the treatment of acute respiratory failure in adults. Curr Opin Crit Care. 2012;18(1):70–79.

56.Ferguson ND, Cook DJ, Guyatt GH, et al. High-Frequency Oscillation in Early Acute Respiratory Distress Syndrome. N Engl J Med. 2013;368(9):795–805.

57.Young D, Lamb SE, Shah S, et al. High-frequency oscillation for acute respiratory distress syndrome. N Engl J Med. 2013;368(9):795–805.

58.Taylor RW, Zimmerman JL, Dellinger RP, et al. Low-dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial. JAMA. 2004;291(13):1603–1609.

59.Walmrath D, Schneider T, Schermuly R, et al. Direct comparison of inhaled nitric oxide and aerosolized prostacyclin in acute respiratory distress syndrome. Am J Respir Crit Care Med. 1996;153(3):991–996.

60.Adhikari NK, et al. Effect of nitric oxide on oxygenation and mortality in acute lung injury: systematic review and meta-analysis. BMJ. 2007;334(7597):779.

61.Barst RJ, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med. 1996;334(5):296–301.

62.Barbas CS, et al. Lung recruitment maneuvers in acute respiratory distress syndrome. Respir Care Clin N Am. 2003;9(4):401–418, vii.

63.Constantin JM, et al. Response to recruitment maneuver influences net alveolar fluid clearance in acute respiratory distress syndrome. Anesthesiology. 2007;106(5):944–951.

64.Kacmarek RM, Kallet RH. Respiratory controversies in the critical care setting. Should recruitment maneuvers be used in the management of ALI and ARDS? Respir Care. 2007;52(5):622–631; discussion 631– 635.

65.Grasso S, et al. Effects of recruiting maneuvers in patients with acute respiratory distress syndrome ventilated with protective ventilatory strategy. Anesthesiology. 2002;96(4):795–802.

66.Gattinoni L, et al. Lung recruitment in patients with the acute respiratory distress syndrome. N Engl J Med. 2006;354(17):1775–1786.

67.Hill NS, et al. Noninvasive ventilation in acute respiratory failure. Crit Care Med. 2007;35(10):2402–2407.

68.Rana S, et al. Failure of non-invasive ventilation in patients with acute lung injury: observational cohort study. Crit Care. 2006;10(3):R79.

69.Antonelli M, et al. A multiple-center survey on the use in clinical practice of noninvasive ventilation as a first-line intervention for acute respiratory distress syndrome. Crit Care Med. 2007;35(1):18–25.

70.Burchardi H. New strategies in mechanical ventilation for acute lung injury. Eur Respir J. 1996;9(5):1063–1072.

71.Maung AA, Kaplan LJ. Airway pressure release ventilation in acute respiratory distress syndrome. Crit Care Clin. 2011;27(3):501–509.

72.Daoud EG, Farag HL, Chatburn RL. Airway pressure release ventilation: what do we know? Respir Care. 2012;57(2):282–292.

73.Stawicki SP, Goyal M, Sarani B. High-frequency oscillatory ventilation (HFOV) and airway pressure release ventilation (APRV): a practical guide. J Intensive Care Med. 2009;24(4):215–229.

74.Zavala E, et al. Effect of inverse I:E ratio ventilation on pulmonary gas exchange in acute respiratory distress syndrome. Anesthesiology. 1998;88(1):35–42.

75.Marcy T. In: Tobin MJ, ed. Principles and Practice of Mechanical Ventilation. 2nd ed. New York, NY: McGraw-Hill; 2006:319–332.

76.Rasanen J. In: Tobin MJ, ed. Principles and Practice of Mechanical Ventilation. 2nd ed. New York, NY: McGraw-Hill; 2006:341–348.

77.Hodgson CL, et al. A randomised controlled trial of an open lung strategy with staircase recruitment, titrated PEEP and targeted low airway pressures in patients with acute respiratory distress syndrome. Crit Care. 2011;15(3):R133.