[Skip to Content]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 54.161.216.242. Please contact the publisher to request reinstatement.
Sign In
Individual Sign In
Create an Account
Institutional Sign In
OpenAthens Shibboleth
[Skip to Content Landing]
Download PDF
Figure. Typical Chest Radiograph and Computed Tomographic Scan of a Patient With Acute Respiratory Distress Syndrome
Image description not available.

A, The chest radiograph shows bilateral pulmonary infiltrates that appear to be diffuse. B, A computed tomographic scan of the thorax from the same patient demonstrates that the distribution of the bilateral infiltrates is predominantly in dependent regions with more normal-appearing lung in nondependent regions.

Table 1. Diagnostic Criteria for ARDS
Image description not available.
Table 2. Trials of Volume- and Pressure-Limited Ventilation in Acute Lung Injury and Acute Respiratory Distress Syndrome
Image description not available.
1.
Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults.  Lancet. 1967;2:319-323PubMedArticle
2.
Frutos-Vivar F, Nin N, Esteban A. Epidemiology of acute lung injury and acute respiratory distress syndrome.  Curr Opin Crit Care. 2004;10:1-6PubMedArticle
3.
Rubenfeld GD. Epidemiology of acute lung injury.  Crit Care Med. 2003;31:S276-S284PubMedArticle
4.
Esteban A, Anzueto A, Frutos F.  et al.  Characteristics and outcomes in adult patients receiving mechanical ventilation: a 28-day international study.  JAMA. 2002;287:345-355PubMedArticle
5.
Montgomery AB, Stager MA, Carrico CJ, Hudson LD. Causes of mortality in patients with the adult respiratory distress syndrome.  Am Rev Respir Dis. 1985;132:485-491PubMed
6.
Milberg JA, Davis DR, Steinberg KP, Hudson LD. Improved survival of patients with acute respiratory distress syndrome (ARDS): 1983-1993.  JAMA. 1995;273:306-309PubMedArticle
7.
Davidson TA, Caldwell ES, Curtis JR. Reduced quality of life in survivors of acute respiratory distress syndrome compared with critically ill control patients.  JAMA. 1999;281:354-360PubMedArticle
8.
Herridge MS, Cheung AM, Tansey CM.  et al.  One-year outcomes in survivors of the acute respiratory distress syndrome.  N Engl J Med. 2003;348:683-693PubMedArticle
9.
Hopkins RO, Weaver LK, Pope D, Orme JF, Bigler ED, Larsen-Lohr V. Neuropsychologiocal sequelae and impaired health status in survivors of severe acute respiratory distress syndrome.  Am J Respir Crit Care Med. 1999;160:50-56PubMedArticle
10.
Hopkins RO, Weaver LK, Collingridge D, Parkinson RB, Chan KJ, Orme JF Jr. Two-year cognitive, emotional, and quality-of-life outcomes in acute respiratory distress syndrome.  Am J Respir Crit Care Med. 2005;171:340-347PubMedArticle
11.
Petty TL, Ashbaugh DG. The adult respiratory distress syndrome: clinical features, factors influencing prognosis and principles of management.  Chest. 1971;60:233-239PubMedArticle
12.
Murray JF, Matthay MA, Luce JM, Flick MR. An expanded definition of the adult respiratory distress syndrome.  Am Rev Respir Dis. 1988;138:720-723PubMedArticle
13.
Bernard GR, Artigas A, Brigham KL.  et al.  The American-European Consensus Conference on ARDS: definitions, mechanisms, relevant outcomes, and clinical trial coordination.  Am J Respir Crit Care Med. 1994;149:818-824PubMedArticle
14.
American Thoracic Society.  International consensus conferences in intensive care medicine: ventilator-associated lung injury in ARDS.  Am J Respir Crit Care Med. 1999;160:2118-2124PubMedArticle
15.
Crimi E, Slutsky AS. Inflammation and the acute respiratory distress syndrome.  Best Pract Res Clin Anaesthesiol. 2004;18:477-492PubMedArticle
16.
Plotz FB, Slutsky AS, van Vught AJ, Heijnen CJ. Ventilator-induced lung injury and multiple system organ failure: a critical review of facts and hypotheses.  Intensive Care Med. 2004;30:1865-1872PubMedArticle
17.
Dreyfuss D, Soler P, Basset G, Saumon G. High inflation pressure pulmonary edema: respective effects of high airway pressure, high tidal volume, and positive end-expiratory pressure.  Am Rev Respir Dis. 1988;137:1159-1164PubMedArticle
18.
Slutsky AS. Lung injury caused by mechanical ventilation.  Chest. 1999;116:9S-15SPubMedArticle
19.
Tremblay LN, Slutsky AS. Ventilator-induced lung injury: from barotrauma to biotrauma.  Proc Assoc Am Physicians. 1998;110:482-488PubMed
20.
Gattinoni L, Caironi P, Pelosi P, Goodman LR. What has computed tomography taught us about the acute respiratory distress syndrome?  Am J Respir Crit Care Med. 2001;164:1701-1711PubMedArticle
21.
Gattinoni L, Pesenti A. ARDS: the non-homogeneous lung; facts and hypothesis.  Intensive Crit Care Dig. 1987;6:1-4
22.
Gattinoni L, Pesenti A. The concept of “baby lung.”  Intensive Care Med. 2005;31:776-784Article
23.
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;338:347-354PubMedArticle
24.
Brochard L, Roudot-Thoraval F, Roupie E.  et al.  Tidal volume reduction for prevention of ventilator-induced lung injury in acute respiratory distress syndrome.  Am J Respir Crit Care Med. 1998;158:1831-1838PubMedArticle
25.
Stewart TE, Meade MO, Cook DJ.  et al.  Evaluation of a ventilation strategy to prevent barotrauma in patients at high risk for acute respiratory distress syndrome: pressure and volume limited ventilation strategy group.  N Engl J Med. 1998;338:355-361PubMedArticle
26.
Brower RG, Shanholtz CB, Fessler HE.  et al.  Prospective, randomized controlled clinical trial comparing traditional versus reduced tidal volume ventilation in acute respiratory distress syndrome patients.  Crit Care Med. 1999;27:1492-1498PubMedArticle
27.
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;342:1301-1308PubMedArticle
28.
Eichacker PQ, Gerstenberger EP, Banks SM, Cui X, Natanson C. Meta-analysis of acute lung injury and acute respiratory syndrome trials testing low tidal volumes.  Am J Respir Crit Care Med. 2002;166:1510-1514PubMedArticle
29.
Petrucci N, Iacovelli W. Ventilation with smaller tidal volumes: a quantitative systematic review of randomized controlled trials.  Anesth Analg. 2004;99:193-200PubMedArticle
30.
Moran JL, Bersten AD, Solomon PJ. Meta-analysis of controlled trials of ventilator therapy in acute lung injury and acute respiratory distress syndrome: an alternative perspective.  Intensive Care Med. 2005;31:227-235PubMedArticle
31.
Brower RG, Matthay M, Schoenfeld D. Meta-analysis of acute lung injury and acute respiratory distress syndrome trials.  Am J Respir Crit Care Med. 2002;166:1515-1517PubMedArticle
32.
Laffey JG, O’Croinin D, McLoughlin P, Kavanagh BP. Permissive hypercapnia—role in lung protective ventilatory strategies.  Intensive Care Med. 2004;30:347-356PubMedArticle
33.
Kahn JM, Andersson L, Karir V, Polissar NL, Neff MJ, Rubenfeld GD. Low tidal volume ventilation does not increase sedation use in patients with acute lung injury.  Crit Care Med. 2005;33:766-771PubMedArticle
34.
Lapinsky SE, Mehta S. Bench-to-bedside review: recruitment and recruiting maneuvers.  Crit Care. 2005;9:60-65PubMedArticle
35.
Lapinsky SE, Aubin M, Mehta S, Boiteau P, Slutsky A. Safety and efficacy of a sustained inflation for alveolar recruitment in adults with respiratory failure.  Intensive Care Med. 1999;25:1297-1301PubMedArticle
36.
Pelosi P, Cadringher P, Bottino N.  et al.  Sigh in acute respiratory distress syndrome.  Am J Respir Crit Care Med. 1999;159:872-880PubMedArticle
37.
Foti G, Cereda M, Sparacino M, DeMarchi ME, Villa F, Pesenti A. Effects of periodic lung recruitment maneuvers on gas exchange and respiratory mechanics in mechanically ventilated ARDS patients.  Intensive Care Med. 2000;26:501-507PubMedArticle
38.
The ARDS Clinical Trials Network.  Effects of recruitment maneuvers in patients with acute lung injury and acute respiratory distress syndrome ventilated with high positive end-expiratory pressure.  Crit Care Med. 2003;31:2592-2597PubMedArticle
39.
Meade MO, Guyatt GH, Cook DJ.  et al.  Physiologic randomized pilot study of a lung recruitment maneuver in acute lung injury.  Am J Respir Crit Care Med. 2001;165:A683
40.
Lim SC, Adams AB, Simonson DA.  et al.  Intercomparison of recruitment maneuver efficacy in three models of acute lung injury.  Crit Care Med. 2004;32:2371-2377PubMedArticle
41.
Gattinoni L, Pelosi P, Suter PM, Pedoto A, Vercesi P, Lissoni A. Acute respiratory distress syndrome caused by pulmonary and extrapulmonary disease: different syndromes?  Am J Respir Crit Care Med. 1998;158:3-11PubMedArticle
42.
Pelosi P, D’Onofrio D, Chiumello D.  et al.  Pulmonary and extrapulmonary acute respiratory distress syndrome are different.  Eur Respir J Suppl. 2003;42:48S-56SPubMedArticle
43.
Cakar N, Akinci O, Tugrul S.  et al.  Recruitment maneuver: does it promote bacterial translocation?  Crit Care Med. 2002;30:2103-2106PubMedArticle
44.
The National Heart, Lung, and Blood Institute ARDS Clinical Trials Network.  Higher verus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome.  N Engl J Med. 2004;351:327-336PubMedArticle
45.
Levy MM. PEEP in ARDS—how much is enough?  N Engl J Med. 2004;351:389-391PubMedArticle
46.
Ritacca FV, Stewart TE. Clinical review: high frequency-oscillatory ventilation in adults—a review of the literature and practical applications.  Crit Care. 2003;7:385-390PubMedArticle
47.
Imai Y, Slutsky AS. High-frequency oscillatory ventilation and ventilator-induced lung injury.  Crit Care Med. 2005;33:S129-S134PubMedArticle
48.
Habashi NM. Other approaches to open-lung ventilation: airway pressure release ventilation.  Crit Care Med. 2005;33:S228-S240PubMedArticle
49.
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;166:801-808PubMedArticle
50.
Bollen CW, van Well GT, Sherry T.  et al.  High frequency oscillatory ventilation compared with conventional mechanical ventilation in adult respiratory distress syndrome: a randomized controlled trial.  Crit Care. 2005;9:R430-R439PubMedArticle
51.
Bryan AC. Comments of a devil's advocate.  Am Rev Respir Dis. 1974;110:143-144PubMed
52.
Pelosi P, Brazzi L, Gattinoni L. Prone position in acute respiratory distress syndrome.  Eur Respir J. 2002;20:1017-1028PubMedArticle
53.
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;345:568-573PubMedArticle
54.
Guerin C, Gaillard S, Lemasson S.  et al.  Effects of systematic prone positioning in hypoxemic acute respiratory failure: a randomized controlled trial.  JAMA. 2004;292:2379-2387PubMedArticle
55.
Mancebo J, Rialp G, Fernandez R.  et al.  Randomized multicenter trial in ARDS. Supine vs prone position.  Intensive Care Med. 2003;29:S64Article
56.
Rossaint R, Falke KJ, Lopez F, Slama K, Pison U, Zapol WM. Inhaled nitric oxide for the adult respiratory distress syndrome.  N Engl J Med. 1993;328:399-405PubMedArticle
57.
Dellinger RP, Zimmerman JL, Taylor RW.  et al.  Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial.  Crit Care Med. 1998;26:15-23PubMedArticle
58.
Michael JR, Barton RG, Saffle JR.  et al.  Inhaled nitric oxide versus conventional therapy: effect on oxygenation in ARDS.  Am J Respir Crit Care Med. 1998;157:1372-1380PubMedArticle
59.
Troncy E, Collet JP, Shapiro S.  et al.  Inhaled nitric oxide in acute respiratory distress syndrome: a pilot randomized controlled study.  Am J Respir Crit Care Med. 1998;157:1483-1488PubMedArticle
60.
Lundin S, Mang H, Smithies M, Stenqvist O, Frostell C. Inhalation of nitric oxide in acute lung injury: results of a European multicentre study.  Intensive Care Med. 1999;25:911-919PubMedArticle
61.
Mehta S, Simms HH, Levy MM.  et al.  Extended therapy with inhaled nitric oxide fails to improve oxygenation in patients with acute respiratory distress syndrome: a randomized controlled trial.  J Appl Res. 2001;1:73-84
62.
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;291:1603-1609PubMedArticle
63.
Sokol J, Jacobs SE, Bohn D. Inhaled nitric oxide for acute respiratory failure in children and adults: a meta-analysis.  Anesth Analg. 2003;97:989-998PubMedArticle
64.
Shapiro BA, Crane RD, Harrison RA, Steiner MC. Changes in intrapulmonary shunting with administration of 100 percent oxygen.  Chest. 1980;77:138-141PubMedArticle
65.
Santos C, Ferrer M, Roca J, Torres A, Hernandez C, Rodriguez-Roisin R. Pulmonary gas exchange response to oxygen breathing in acute lung injury.  Am J Respir Crit Care Med. 2000;161:26-31PubMedArticle
66.
Ferguson ND, Kacmarek RM, Chiche JD.  et al.  Screening of ARDS patients using standardized ventilator settings: influence on enrollment in a clinical trial.  Intensive Care Med. 2004;30:1111-1116PubMedArticle
67.
Rubenfeld GD, Caldwell E, Granton J, Hudson LD, Matthay MA. Interobserver variability in applying a radiographic definition for ARDS.  Chest. 1999;116:1347-1353PubMedArticle
68.
Esteban A, Fernandez-Segoviano P, Frutos-Vivar F.  et al.  Comparison of clinical criteria for the acute respiratory distress syndrome with autopsy findings.  Ann Intern Med. 2004;141:440-445PubMedArticle
69.
Kallet RH, Jasmer RM, Pittet JF.  et al.  Clinical implementation of the ARDS network protocol is associated with reduced hospital mortality compared with historical controls.  Crit Care Med. 2005;33:925-929PubMedArticle
70.
Brower RG, Thompson BT, Ancukiewicz M. Clinical trial of mechanical ventilation with traditional versus lower tidal volumes in acute lung injury and acute respiratory distress syndrome: effects on physician's practices.  Am J Respir Crit Care Med. 2004;169:A17
71.
Weinert CR, Gross CR, Marinelli WA. Impact of randomized trial results on acute lung injury ventilator therapy in teaching hospitals.  Am J Respir Crit Care Med. 2003;167:1304-1309PubMedArticle
72.
Young MP, Manning HL, Wilson DL.  et al.  Ventilation of patients with acute lung injury and acute respiratory distress syndrome: has new evidence changed clinical practice?  Crit Care Med. 2004;32:1260-1265PubMedArticle
73.
Rubenfeld GD, Cooper C, Carter G, Thompson BT, Hudson LD. Barriers to providing lung-protective ventilation to patients with acute lung injury.  Crit Care Med. 2004;32:1289-1293PubMedArticle
74.
Marini JJ, Gattinoni L. Ventilatory management of the acute respiratory distress syndrome: a consensus of two.  Crit Care Med. 2004;32:250-255PubMedArticle
75.
Hager DN, Krishnan JA, Hayden DL, Brower RG. Tidal volume reduction in patients with acute lung injury when plateau pressures are not high.  Am J Respir Crit Care Med. 2005;172:1241-1245PubMedArticle
76.
Mehta S, Granton J, MacDonald RJ.  et al.  High-frequency oscillatory ventilation in adults: the Toronto experience.  Chest. 2004;126:518-527PubMedArticle
77.
Fan E, Mehta S. High-frequency oscillatory ventilation and adjunctive therapies: inhaled nitric oxide and prone positioning.  Crit Care Med. 2005;33:S182-S187PubMedArticle
78.
Ferguson ND, Chiche JD, Kacmarek RM.  et al.  Combining high-frequency oscillatory ventilation and recruitment maneuvers in adults with early acute respiratory distress syndrome: the Treatment with Oscillation and an Open Lung Strategy (TOOLS) Trial Pilot study.  Crit Care Med. 2005;33:479-486PubMedArticle
79.
Medoff BD, Shepard JO, Smith RN, Kratz A. Case 17-2005—a 22-year old woman with back and leg pain and respiratory failure.  N Engl J Med. 2005;352:2425-2434PubMedArticle
Clinical Review
Clinician's Corner
December 14, 2005

Ventilatory Management of Acute Lung Injury and Acute Respiratory Distress Syndrome

Author Affiliations
 

Clinical Review Section Editor: Michael S. Lauer, MD. We encourage authors to submit papers for consideration as a “Clinical Review.” Please contact Michael S. Lauer, MD, at lauerm@ccf.org.

 

Author Affiliations: Interdepartmental Division of Critical Care Medicine and Department of Medicine, University of Toronto and University Health Network and Mount Sinai Hospital, Toronto, Ontario, (Drs Fan and Stewart) and Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Md (Dr Needham).

JAMA. 2005;294(22):2889-2896. doi:10.1001/jama.294.22.2889
Context

Context The acute lung injury and acute respiratory distress syndrome are critical illnesses associated with significant morbidity and mortality. Mechanical ventilation is the cornerstone of supportive therapy. However, despite several important advances, the optimal strategy for ventilation and adjunctive therapies for patients with acute lung injury and acute respiratory distress syndrome is still evolving.

Evidence Acquisition To identify reports of invasive ventilatory and adjunctive therapies in adult patients with acute lung injury and acute respiratory distress syndrome, we performed a systematic English-language literature search of MEDLINE (1966-2005) using the Medical Subject Heading respiratory distress syndrome, adult, and related text words, with emphasis on randomized controlled trials and meta-analyses. EMBASE and the Cochrane Central Register of Controlled Trials were similarly searched. The search yielded 1357 potential articles of which 53 were relevant to the study objectives and considered in this review.

Evidence Synthesis There is strong evidence to support the use of volume- and pressure-limited lung-protective ventilation in adult patients with acute lung injury and acute respiratory distress syndrome. The benefit of increased levels of positive end-expiratory pressure and recruitment maneuvers is uncertain and is being further evaluated in ongoing trials. Existing randomized controlled trials of alternative ventilation modes, such as high-frequency oscillation and adjunctive therapies, including inhaled nitric oxide and prone positioning demonstrate no significant survival advantage. However, they may have a role as rescue therapy for patients with acute respiratory distress syndrome with refractory life-threatening hypoxemia.

Conclusions Volume- and pressure-limited ventilation strategies should be used in managing adult acute lung injury and acute respiratory distress syndrome patients. Further research is needed to identify barriers to widespread adoption of this strategy, as well as the role of alternative ventilation modes and adjunctive therapies.

For nearly 4 decades since the acute respiratory distress syndrome (ARDS) was first described,1 research has been ongoing in an effort to improve the outcome of this critical illness. Quiz Ref IDAcute respiratory distress syndrome is characterized by the acute onset of hypoxemia and bilateral infiltrates on chest radiography in the absence of left atrial hypertension. Various pulmonary (eg, pneumonia) and nonpulmonary (eg, pancreatitis) risk factors are associated with ARDS.2 Mortality rates range from 26% to 74%, with most deaths attributed to associated conditions, such as sepsis and multisystem organ failure, rather than hypoxemia alone.26 Some survivors of ARDS have reduced quality of life with physical, neurocognitive, and emotional morbidity.710

The original ARDS case series1 outlined a number of clinical features that were later incorporated into more formal definitions of this syndrome (Table 1).1113 In 1994, the American-European Consensus Conference (AECC) definition was developed and is used widely by clinicians and researchers.13 Under this definition, acute lung injury (ALI) is designated for patients with significant hypoxemia (partial pressure of arterial oxygen to fraction of inspired oxygen [PaO2/FIO2] ratio <300), while ARDS represents the subset of ALI patients with the most severe lung injury (PaO2/FIO2 ratio <200). Using these definitions, ALI and ARDS are relatively common with annual incidences estimated at 20 to 50 and 15 to 30 cases per 100 000 persons, respectively.2,3

No specific pharmacologic therapy has proved effective for ALI or ARDS, and therapy is largely supportive with the use of mechanical ventilation.11 Perhaps the most important advance in ALI and ARDS research has been the recognition that mechanical ventilation, although necessary to preserve life, can potentiate or directly injure the lungs through a variety of mechanisms collectively referred to as ventilator-associated lung injury.1416 These mechanisms include exposure to high inflation pressures or overdistention (barotrauma or volutrauma),17 repetitive opening and closing of alveoli (atelectrauma),18 and mechanotransduction resulting in up-regulated cytokine release and a systemic inflammatory response (biotrauma).19 The lungs of patients with ALI or ARDS are particularly prone to ventilator-associated lung injury because they are heterogeneously affected, as demonstrated in computed tomography studies (Figure).20 As a result, some areas of the lung (often dependent regions) are atelectatic, consolidated, less compliant, and thus less available for ventilation while other areas (usually nondependent regions) appear and behave normally. Understanding this heterogeneity has led to the “baby lung” concept, which suggests that, overall, a markedly reduced volume of lung is available for ventilation in ALI or ARDS, effectively, a functionally baby-sized lung within an adult-sized body.21,22Quiz Ref IDConsequently, mechanical ventilation can result in barotrauma or volutrauma when volumes and pressures meant for the entire lung are forced into only a small portion of functional lung. In addition, shear forces at the interface between the open and closed lung units result in atelectrauma. Both of these types of injury also can lead to release of cytokines from the lung and have adverse systemic effects, contributing to the development of multisystem organ failure.18,19

This improved understanding of ALI and ARDS and ventilator-associated lung injury has been important in designing lung protective mechanical ventilation strategies aimed at attenuating ventilator-associated lung injury and improving outcomes. Such strategies for the invasive ventilatory management of adult ALI and ARDS have recently been tested in a number of important clinical trials, which we review in this article. In addition, we discuss alternative invasive ventilatory modes and adjunctive therapies, with a focus on those that we believe are widely available for clinical use in adults at the present time. We also highlight recent controversies and suggest areas for future research.

EVIDENCE ACQUISITION

To assist with this review, we systematically searched MEDLINE (1966 to September 2005), using the Medical Subject Heading respiratory distress syndrome, adult, and related text words (acute respiratory distress syndrome, acute lung injury, respiratory distress syndrome, adult respiratory distress syndrome, ALI, or ARDS). The search results were limited to English language, human subjects, randomized controlled trials, and meta-analyses. EMBASE and the Cochrane Central Register of Controlled Trials were also similarly searched. This strategy resulted in 1357 potentially relevant articles for which citations, abstracts, or both were reviewed. Bibliographies of all selected articles and review articles were hand searched for additional relevant articles. Studies evaluating noninvasive ventilation, pharmacologic therapies (not part of a mechanical ventilation strategy), and small, exploratory randomized trials (<50 patients) were excluded. To provide a focused and pragmatic review, we also excluded studies of therapies that we believed were not widely available for clinical use in adults at the present time (eg, exogenous surfactant and extracorporeal membrane oxygenation). A total of 53 articles met our criteria and were considered in this review.

EVIDENCE SYNTHESIS
Conventional Lung Protective-Ventilation

Conventional lung-protective ventilation involves strategies designed to mitigate further lung injury in patients with ALI or ARDS using a standard mechanical ventilator. Five randomized controlled trials2327 and 3 meta-analyses2830 have evaluated lung-protective ventilation compared with conventional approaches, using a variety of volume- and pressure-limited strategies (Table 2). Three of the randomized trials, with sample sizes of 52 to 120 patients, did not find a difference in mortality between the treatment and control arms.2426 One study by Amato et al23 used higher positive end-expiratory pressure (PEEP) and recruitment maneuvers in conjunction with pressure- and volume-limited ventilation in the intervention group. This study was stopped early, enrolling 53 of 58 patients, after demonstrating a significant reduction in 28-day mortality. However, there was no significant difference in mortality at hospital discharge, and a high mortality rate (71%) in the control group may have accounted for the survival difference. Nevertheless, this trial strongly suggested that ventilatory strategies could impact mortality, and the results in the intervention group generated interesting hypotheses that have been pursued in subsequent studies. Quiz Ref IDThe largest trial of volume- and pressure-limited ventilation was conducted by the ARDS Network (ARDSNet).27 This trial of 861 patients demonstrated a 9% absolute decrease in mortality (31% vs 40%; P = .007) when patients with ALI or ARDS receiving mechanical ventilation have reduced tidal volumes (target of 6 mL/kg of predicted body weight with a range of 4-8 mL/kg depending on plateau pressure and pH) and reduced pressures (plateau pressure, measured after a 0.5-second end-inspiratory pause, ≤30 cm H2O).

Three meta-analyses2830 of these 5 clinical trials have been performed.2327 The first meta-analysis concluded that the control groups of the 2 trials, which demonstrated a survival advantage,23,27 did not reflect the “standard of care” and were likely responsible for the mortality difference.28 In addition, the authors suggested that the low tidal volumes used in the intervention group of the ARDSNet trial may be harmful.28 This meta-analysis has been criticized as having important methodological flaws, such as inappropriately grouping the individual trial results.2931 In addition, its findings are contradicted by 2 subsequent meta-analyses,29,30 which suggested that volume-limited ventilation, particularly in the setting of elevated plateau pressure (>30 cm H2O), has a short-term survival benefit. One meta-analysis also concluded that decreased tidal volumes may be advantageous below a threshold level (<7.7 mL/kg predicted body weight).30

In many instances, lung-protective ventilation may lead to an elevation of arterial carbon dioxide, referred to as permissive hypercapnia. Although acute hypercapnic respiratory acidosis has many potential adverse effects, the extent to which a more controlled subacute elevation of carbon dioxide is harmful remains uncertain.32 In fact, some evidence indicates that permissive hypercapnia is relatively benign.32 At present, there are few data to inform physicians on a clinically relevant threshold of hypercapnia, acidosis, or both that require specific interventions, such as increasing effective ventilation, decreasing carbon dioxide production, or using buffer therapy (eg, bicarbonate). Of note, the ARDSNet study27 investigators used a stepwise approach of increasing respiratory rates (to a maximum of 35 breaths/min), allowing bicarbonate infusions (at the physicians' discretion), and increasing tidal volumes for the management of acidosis.

Other important consequences of lung-protective ventilation possibly include worsened oxygenation and the need for increased sedation or analgesia compared with patients receiving conventional ventilation. Of note, patients in the intervention arm of the ARDSNet study had reduced oxygenation in the first few days but improved survival.27 Furthermore, a recent analysis of a subset of the ARDSNet study revealed no significant differences in sedation or analgesia use between lung-protective and conventional mechanical ventilation groups.33 However, the effect of any potential increase in sedation or analgesia use in patients receiving lung-protective ventilation requires further study.

In addition to pressure and volume limitation, higher PEEP and the use of recruitment maneuvers may be important components of a lung-protective ventilation strategy. Recruitment refers to the dynamic process of reopening collapsed alveoli through an intentional increase in transpulmonary pressure, which may be achieved through a variety of mechanisms, such as a transient high continuous positive airway pressure (eg, 40 cm H2O for 40 seconds).34 Human studies evaluating recruitment maneuvers have yielded variable results.3539 Such factors as the type (eg, primary vs secondary) and stage (eg, early vs late) of ALI or ARDS and recruitment technique used may be important determinants of response.4042 The optimal pressure, duration, and frequency of recruitment maneuvers has not been defined and tested in clinical trials. Of note, the safety of recruitment maneuvers also requires careful evaluation. Although transient oxygen desaturation and hypotension are the most common adverse effects, other clinically significant events, such as barotrauma (eg, pneumothorax), arrhythmia, and bacterial translocation, may occur.38,43

The isolated effect of higher PEEP and recruitment maneuvers could not be determined in the small trial by Amato et al.23 A much larger study, known as the ALVEOLI trial,44 was conducted by ARDSNet to investigate this issue. This study provided volume- and pressure-limited lung-protective ventilation to all study patients and evaluated the effect on mortality of higher PEEP (12-24 cm vs 5-24 cm H2O) in the treatment group. In addition, recruitment maneuvers were conducted in patients randomized to the higher PEEP group by applying a pressure of 35 to 40 cm H2O for 30 seconds to assess the effect on oxygenation. After evaluating the first 80 patients, recruitment maneuvers demonstrated only a modest effect on oxygenation with no difference in the requirement for oxygenation support (ie, PEEP or FIO2) and were not continued for the remainder of the study.39 The study was stopped early, due to futility, after enrollment of 549 of 750 patients. There was no significant difference in in-hospital mortality, even after adjusting for important imbalances in baseline characteristics between the study groups (higher, 25.1% vs lower, 27.5% PEEP; 95% confidence interval [CI], −3.6% to 8.4%; P = .47). However, some have suggested that a true effect may have been missed due to stopping the study early.45 Alternatively, a beneficial effect of higher PEEP in some (recruitable) patients may have been negated by a detrimental effect in other (nonrecruitable) patients. These issues require further investigation.

Alternative Ventilatory Approaches to Lung Protection

Quiz Ref IDThe precise role of alternative methods of ventilation, such as high-frequency ventilation (ie, jet, oscillation, and percussive ventilation) and airway pressure release ventilation, has not been established. High-frequency ventilation allows for higher mean airway pressures that may be advantageous for lung recruitment. In addition, it also allows for markedly reduced tidal volumes (1-3 mL/kg) compared with conventional ventilation, which may further reduce ventilator-associated lung injury.46,47 Airway pressure release ventilation not only provides higher mean airway pressures but also allows for spontaneous breathing, which may be associated with better gas exchange, hemodynamics, and reduced sedation requirements.48

Of these alternative ventilatory modes, only high-frequency oscillatory ventilation (HFOV) has been studied in moderately sized randomized trials.49 In a trial of 148 patients comparing HFOV with conventional mechanical ventilation with respect to key adverse outcomes (eg, new airleak, intractable hypotension), there were no significant differences between groups. Mortality was examined as a secondary outcome, with a nonsignificant lower 30-day mortality in the HFOV group (37% vs 52%, P = .10). This finding must be interpreted with caution because the conventional ventilation protocol did not use the current standard for volume- and pressure-limited lung protective ventilation and the study was not powered to assess mortality. A second trial of 61 ARDS patients comparing HFOV with conventional mechanical ventilation also revealed no significant differences in survival without supplemental oxygen or ventilatory support (HFOV vs conventional ventilation 32% vs 38%; adjusted odds ratio, 0.80; 95% CI, 0.22-2.97; P = .79), or other secondary end points.50 However, a post hoc analysis revealed that patients with the most severe hypoxemia had a trend toward a benefit from HFOV.

Adjunctive Therapies to Lung-Protective Ventilation

Adjunctive therapies are cointerventions that may result in improved outcomes when combined with lung-protective ventilatory strategies. Prone positioning and inhaled nitric oxide are 2 adjunctive therapies that are currently widely available and have been studied in large randomized trials of adult patients with ALI or ARDS.

The use of prone positioning with mechanical ventilation was first described in 1974.51 Placing the patient in a prone position has potential physiological benefits, including the recruitment of dorsal (nondependent) atelectatic lung units, improved respiratory mechanics, decreased ventilation-perfusion mismatch, increased secretion drainage, reduced and improved distribution of injurious mechanical forces, and improved fit of the lungs within the thorax.52

There are 3 randomized trials of prone positioning in adults with ALI or ARDS.5355 In the first study, 304 patients were randomly assigned either to the supine or the prone position for at least 6 hours per day over a 10-day period.53 Although oxygenation significantly improved in the prone group, there was no significant difference in mortality or any secondary outcome. A post hoc analysis of the most severely ill patients revealed decreased mortality for patients randomly assigned to the prone position (relative risk [RR, 0.54; 95% CI, 0.32-0.90) at day 10, but this benefit did not persist beyond intensive care unit discharge. The second study randomized 791 patients (48% with ALI or ARDS) to supine or prone positioning for at least 8 hours per day and also demonstrated improved oxygenation without a survival benefit at 28 days (supine, 31.5% vs prone 32.4%; RR, 0.97; 95% CI, 0.79-1.19; P = .77).54 This second trial revealed a significantly higher rate of adverse events in the prone group, including selective (right or left mainstem bronchus) intubation, endotracheal tube obstruction, and pressure sores. The third study of prone positioning in ARDS, was stopped early (133 of 200 patients) due to problems with enrolment. It revealed a large, but statistically insignificant, difference in intensive care unit mortality between the 2 groups (supine, 58.6% vs prone, 44.4%, P = .43).55

Inhaled nitric oxide provides selective vasodilation in ventilated lung units thus improving ventilation-perfusion mismatch, hypoxemia, and pulmonary hypertension.56 This therapy has been studied in 6 randomized, placebo-controlled trials of adults with ALI or ARDS.5762 None of these studies demonstrated a sustained benefit. A Cochrane meta-analysis of more than 500 patients (80% adults) concluded that inhaled nitric oxide led to a transient improvement in oxygenation for up to 72 hours but no survival benefit (RR, 0.98; 95% CI, 0.66-1.44).63 After this meta-analysis was completed, the largest trial of inhaled nitric oxide was published.62 This study randomly assigned 385 nonseptic patients with ALI or ARDS to receive either continuous low-dose inhaled nitric oxide at 5 ppm or placebo. The results of this trial were consistent with earlier studies in demonstrating only transient improvements in oxygenation without a significant mortality benefit (nitric oxide, 23% vs placebo 20%, P = .54).

CURRENT UNRESOLVED QUESTIONS AND PERSONAL PERSPECTIVE
Current ALI and ARDS Definition and Clinical Trials

Despite a strong physiological rationale, many therapies for ALI and ARDS have not led to a significant survival benefit when tested in large clinical trials. It is possible that the case definition of ALI and ARDS may have contributed to this. The current American-European Consensus Conference definition has important limitations in its reliability and validity. First, the PaO2/FIO2 ratio that defines hypoxemia does not consider the effect of ventilatory settings (eg, PEEP) or adjunctive therapies (eg, inhaled nitric oxide), which can have an important acute influence on PaO2, nor does it consider whether a patient meets ALI or ARDS criteria.6466 Thus, variation in ventilation practices across institutions may lead to systematic differences in defining this disease entity for clinical studies and patient management. Second, there is only moderate interobserver agreement in interpreting the chest radiograph for ARDS, and ventilator settings also can influence the degree of infiltrates appearing on the radiograph.13,67 Finally, in comparison to autopsy findings of nonsurvivors, a single-center study demonstrated only moderate accuracy of the ARDS definition.68 Refinement of the current definition of ALI and ARDS to achieve more homogeneous patient populations may be beneficial in order to detect a significant treatment effect in clinical trials of ALI and ARDS therapies. However, a more restrictive definition also may exclude patients who may potentially benefit from a particular intervention. Further consideration of the current ALI and ARDS definitions are necessary before potentially important therapies are rejected as nonbeneficial.

Widespread Adoption of the ARDSNet Ventilation Protocol

Given that the ARDSNet study27 provided the only ventilation protocol that had a significant and sustained short-term mortality benefit, we believe patients with ALI or ARDS would benefit if all institutions used a lung-protective ventilation protocol based on this volume- and pressure-limited strategy. Although the ARDSnet protocol can be successfully implemented in clinical practice,69 widespread adoption has not rapidly occurred.7073 One possible explanation for this finding is a perception by caregivers that implementation could be harmful to patients,73 despite the lack of evidence to support this notion.

Some argue that adoption of the exact ARDSNet protocol (available at www.ardsnet.org) may be unnecessary and use of other modes of ventilation, which achieve similar volume and pressure limitations (ie, tidal volume 4-8 mL/kg predicted body weight and pressure <30 cm H2O), may be equally beneficial.74 Such alternate volume- and pressure-limited protocols may be easier to implement and follow, especially if they are already consistent with local practice patterns. However, the use of custom-made protocols, which may seem logical, should be approached with caution, for it remains unclear what specific aspect of the ARDSNet protocol confers the survival advantage. For instance, a secondary analysis of the ARDSNet data75 suggested that tidal volume reduction even benefited patients with safe plateau pressures of 31 cm H2O or less of water, meaning that pressure-limited ventilation, without concomitant volume-limitation, may be detrimental. Irrespective of this controversy as to whether the exact ARDSNet protocol should be adopted, the existing evidence (including 2 meta-analyses of all trials) supports that clinicians should change their practice and adopt volume- and pressure-limited ventilation for patients with ALI or ARDS. As additional evidence emerges, ongoing reassessment and evolution of these protocols will be necessary.

Role for Rescue Therapy

There are many alternative ventilatory approaches and adjunctive therapies that have some evidence of short-term physiological benefit, but no consistent evidence for a survival advantage when studied with large randomized trials. Consequently, deciding the exact role of such therapies in managing individual patients is difficult. One approach is to completely avoid all of these therapies outside of clinical trials until their efficacy has been adequately demonstrated. Assuming their physiological benefit and safety have been appropriately evaluated in prior human studies, another approach is to limit use of these therapies to well-defined rescue situations in which a patient is deemed to be failing, or at risk of harm, from conventional ventilation. In these instances, rescue therapy may be considered to potentially avoid significant morbidity or mortality. However, the controversy lies in determining which rescue therapies should be used (either alone or in combination) and at what point they should be initiated and terminated. For example, preliminary data suggest that earlier institution of HFOV may portend a better prognosis76 and that there may be synergistic benefits of combining different rescue modalities for ARDS patients with severe, life-threatening hypoxemia.77,78Quiz Ref IDAlthough some protocols have been reported,79 there is insufficient evidence to support the superiority of any particular approach to rescue therapy. Whenever possible, such patients should be considered for transfer to institutions with significant experience in ALI and ARDS management to allow further expert evaluation and treatment. Additional research is needed to build on the anecdotal evidence supporting the benefit of rescue therapies for the most severely ill patients with ALI or ARDS.

Conclusions and Future Considerations

Recognition that mechanical ventilation, although life-saving, can contribute to patient morbidity and mortality has been the most important advance in the management of patients with ALI and ARDS. Volume- and pressure-limited ventilation clearly leads to improved patient survival. The role of recruitment maneuvers, higher levels of PEEP, or both remain controversial and are the subject of 2 ongoing multicenter clinical trials (ExPress trial [France], LOVS trial [Canada, Australia, and Saudi Arabia]). At this time, use of alternative modes of ventilation (eg, HFOV) and adjunctive therapies (eg, inhaled nitric oxide and prone positioning) should be limited to future clinical trials and rescue therapy for patients with ALI or ARDS with life-threatening hypoxemia failing maximal conventional lung-protective ventilation.

Although agreement on the current definition of ALI and ARDS has been a fundamental step forward in research and clinical practice, further refinement is required to ensure that the efficacy of new and existing therapies are evaluated in the most appropriate patient population.

Finally, after decades of ALI and ARDS research, it is important to ensure widespread uptake of efficacious volume- and pressure-limited mechanical ventilation. It is critical that clinicians who treat patients with ALI or ARDS reassess their current ventilation strategies, assimilate the available evidence, and modify their practices to ensure the highest quality of care and best outcomes for their patients. Understanding the existing barriers to use of lung-protective ventilation and methods for increasing implementation of current research findings are important opportunities for future study.

Back to top
Article Information

Corresponding Author: Thomas E. Stewart, MD, University Health Network/Mount Sinai Hospital, 600 University Ave, Suite 18-206, Toronto, Ontario, Canada M5G 1X5 (tstewart@mtsinai.on.ca).

Financial Disclosures: None reported.

Funding/Support: Dr Needham is supported by the Canadian Institutes of Health Research (Clinician-Scientist Award), Royal College of Physicians and Surgeons of Canada (Detweiler Fellowship), and grant P050 HL 73994-01 from the National Institutes of Health.

Role of the Sponsor: None of the funding organizations or sponsors had any role in the design and conduct of the study; the collection, management, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript.

Acknowledgment: We thank A. Slutsky, MD, Interdepartmental Division of Critical Care Medicine and Department of Medicine, and A. Detsky, MD, PhD, Department of Medicine, both at the University of Toronto, Toronto, Ontario, and C. Soong, MD, Department of Medicine, William Osler Health Center, Etobicoke, Ontario, for their review of early drafts of this article.

REFERENCES
1.
Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults.  Lancet. 1967;2:319-323PubMedArticle
2.
Frutos-Vivar F, Nin N, Esteban A. Epidemiology of acute lung injury and acute respiratory distress syndrome.  Curr Opin Crit Care. 2004;10:1-6PubMedArticle
3.
Rubenfeld GD. Epidemiology of acute lung injury.  Crit Care Med. 2003;31:S276-S284PubMedArticle
4.
Esteban A, Anzueto A, Frutos F.  et al.  Characteristics and outcomes in adult patients receiving mechanical ventilation: a 28-day international study.  JAMA. 2002;287:345-355PubMedArticle
5.
Montgomery AB, Stager MA, Carrico CJ, Hudson LD. Causes of mortality in patients with the adult respiratory distress syndrome.  Am Rev Respir Dis. 1985;132:485-491PubMed
6.
Milberg JA, Davis DR, Steinberg KP, Hudson LD. Improved survival of patients with acute respiratory distress syndrome (ARDS): 1983-1993.  JAMA. 1995;273:306-309PubMedArticle
7.
Davidson TA, Caldwell ES, Curtis JR. Reduced quality of life in survivors of acute respiratory distress syndrome compared with critically ill control patients.  JAMA. 1999;281:354-360PubMedArticle
8.
Herridge MS, Cheung AM, Tansey CM.  et al.  One-year outcomes in survivors of the acute respiratory distress syndrome.  N Engl J Med. 2003;348:683-693PubMedArticle
9.
Hopkins RO, Weaver LK, Pope D, Orme JF, Bigler ED, Larsen-Lohr V. Neuropsychologiocal sequelae and impaired health status in survivors of severe acute respiratory distress syndrome.  Am J Respir Crit Care Med. 1999;160:50-56PubMedArticle
10.
Hopkins RO, Weaver LK, Collingridge D, Parkinson RB, Chan KJ, Orme JF Jr. Two-year cognitive, emotional, and quality-of-life outcomes in acute respiratory distress syndrome.  Am J Respir Crit Care Med. 2005;171:340-347PubMedArticle
11.
Petty TL, Ashbaugh DG. The adult respiratory distress syndrome: clinical features, factors influencing prognosis and principles of management.  Chest. 1971;60:233-239PubMedArticle
12.
Murray JF, Matthay MA, Luce JM, Flick MR. An expanded definition of the adult respiratory distress syndrome.  Am Rev Respir Dis. 1988;138:720-723PubMedArticle
13.
Bernard GR, Artigas A, Brigham KL.  et al.  The American-European Consensus Conference on ARDS: definitions, mechanisms, relevant outcomes, and clinical trial coordination.  Am J Respir Crit Care Med. 1994;149:818-824PubMedArticle
14.
American Thoracic Society.  International consensus conferences in intensive care medicine: ventilator-associated lung injury in ARDS.  Am J Respir Crit Care Med. 1999;160:2118-2124PubMedArticle
15.
Crimi E, Slutsky AS. Inflammation and the acute respiratory distress syndrome.  Best Pract Res Clin Anaesthesiol. 2004;18:477-492PubMedArticle
16.
Plotz FB, Slutsky AS, van Vught AJ, Heijnen CJ. Ventilator-induced lung injury and multiple system organ failure: a critical review of facts and hypotheses.  Intensive Care Med. 2004;30:1865-1872PubMedArticle
17.
Dreyfuss D, Soler P, Basset G, Saumon G. High inflation pressure pulmonary edema: respective effects of high airway pressure, high tidal volume, and positive end-expiratory pressure.  Am Rev Respir Dis. 1988;137:1159-1164PubMedArticle
18.
Slutsky AS. Lung injury caused by mechanical ventilation.  Chest. 1999;116:9S-15SPubMedArticle
19.
Tremblay LN, Slutsky AS. Ventilator-induced lung injury: from barotrauma to biotrauma.  Proc Assoc Am Physicians. 1998;110:482-488PubMed
20.
Gattinoni L, Caironi P, Pelosi P, Goodman LR. What has computed tomography taught us about the acute respiratory distress syndrome?  Am J Respir Crit Care Med. 2001;164:1701-1711PubMedArticle
21.
Gattinoni L, Pesenti A. ARDS: the non-homogeneous lung; facts and hypothesis.  Intensive Crit Care Dig. 1987;6:1-4
22.
Gattinoni L, Pesenti A. The concept of “baby lung.”  Intensive Care Med. 2005;31:776-784Article
23.
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;338:347-354PubMedArticle
24.
Brochard L, Roudot-Thoraval F, Roupie E.  et al.  Tidal volume reduction for prevention of ventilator-induced lung injury in acute respiratory distress syndrome.  Am J Respir Crit Care Med. 1998;158:1831-1838PubMedArticle
25.
Stewart TE, Meade MO, Cook DJ.  et al.  Evaluation of a ventilation strategy to prevent barotrauma in patients at high risk for acute respiratory distress syndrome: pressure and volume limited ventilation strategy group.  N Engl J Med. 1998;338:355-361PubMedArticle
26.
Brower RG, Shanholtz CB, Fessler HE.  et al.  Prospective, randomized controlled clinical trial comparing traditional versus reduced tidal volume ventilation in acute respiratory distress syndrome patients.  Crit Care Med. 1999;27:1492-1498PubMedArticle
27.
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;342:1301-1308PubMedArticle
28.
Eichacker PQ, Gerstenberger EP, Banks SM, Cui X, Natanson C. Meta-analysis of acute lung injury and acute respiratory syndrome trials testing low tidal volumes.  Am J Respir Crit Care Med. 2002;166:1510-1514PubMedArticle
29.
Petrucci N, Iacovelli W. Ventilation with smaller tidal volumes: a quantitative systematic review of randomized controlled trials.  Anesth Analg. 2004;99:193-200PubMedArticle
30.
Moran JL, Bersten AD, Solomon PJ. Meta-analysis of controlled trials of ventilator therapy in acute lung injury and acute respiratory distress syndrome: an alternative perspective.  Intensive Care Med. 2005;31:227-235PubMedArticle
31.
Brower RG, Matthay M, Schoenfeld D. Meta-analysis of acute lung injury and acute respiratory distress syndrome trials.  Am J Respir Crit Care Med. 2002;166:1515-1517PubMedArticle
32.
Laffey JG, O’Croinin D, McLoughlin P, Kavanagh BP. Permissive hypercapnia—role in lung protective ventilatory strategies.  Intensive Care Med. 2004;30:347-356PubMedArticle
33.
Kahn JM, Andersson L, Karir V, Polissar NL, Neff MJ, Rubenfeld GD. Low tidal volume ventilation does not increase sedation use in patients with acute lung injury.  Crit Care Med. 2005;33:766-771PubMedArticle
34.
Lapinsky SE, Mehta S. Bench-to-bedside review: recruitment and recruiting maneuvers.  Crit Care. 2005;9:60-65PubMedArticle
35.
Lapinsky SE, Aubin M, Mehta S, Boiteau P, Slutsky A. Safety and efficacy of a sustained inflation for alveolar recruitment in adults with respiratory failure.  Intensive Care Med. 1999;25:1297-1301PubMedArticle
36.
Pelosi P, Cadringher P, Bottino N.  et al.  Sigh in acute respiratory distress syndrome.  Am J Respir Crit Care Med. 1999;159:872-880PubMedArticle
37.
Foti G, Cereda M, Sparacino M, DeMarchi ME, Villa F, Pesenti A. Effects of periodic lung recruitment maneuvers on gas exchange and respiratory mechanics in mechanically ventilated ARDS patients.  Intensive Care Med. 2000;26:501-507PubMedArticle
38.
The ARDS Clinical Trials Network.  Effects of recruitment maneuvers in patients with acute lung injury and acute respiratory distress syndrome ventilated with high positive end-expiratory pressure.  Crit Care Med. 2003;31:2592-2597PubMedArticle
39.
Meade MO, Guyatt GH, Cook DJ.  et al.  Physiologic randomized pilot study of a lung recruitment maneuver in acute lung injury.  Am J Respir Crit Care Med. 2001;165:A683
40.
Lim SC, Adams AB, Simonson DA.  et al.  Intercomparison of recruitment maneuver efficacy in three models of acute lung injury.  Crit Care Med. 2004;32:2371-2377PubMedArticle
41.
Gattinoni L, Pelosi P, Suter PM, Pedoto A, Vercesi P, Lissoni A. Acute respiratory distress syndrome caused by pulmonary and extrapulmonary disease: different syndromes?  Am J Respir Crit Care Med. 1998;158:3-11PubMedArticle
42.
Pelosi P, D’Onofrio D, Chiumello D.  et al.  Pulmonary and extrapulmonary acute respiratory distress syndrome are different.  Eur Respir J Suppl. 2003;42:48S-56SPubMedArticle
43.
Cakar N, Akinci O, Tugrul S.  et al.  Recruitment maneuver: does it promote bacterial translocation?  Crit Care Med. 2002;30:2103-2106PubMedArticle
44.
The National Heart, Lung, and Blood Institute ARDS Clinical Trials Network.  Higher verus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome.  N Engl J Med. 2004;351:327-336PubMedArticle
45.
Levy MM. PEEP in ARDS—how much is enough?  N Engl J Med. 2004;351:389-391PubMedArticle
46.
Ritacca FV, Stewart TE. Clinical review: high frequency-oscillatory ventilation in adults—a review of the literature and practical applications.  Crit Care. 2003;7:385-390PubMedArticle
47.
Imai Y, Slutsky AS. High-frequency oscillatory ventilation and ventilator-induced lung injury.  Crit Care Med. 2005;33:S129-S134PubMedArticle
48.
Habashi NM. Other approaches to open-lung ventilation: airway pressure release ventilation.  Crit Care Med. 2005;33:S228-S240PubMedArticle
49.
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;166:801-808PubMedArticle
50.
Bollen CW, van Well GT, Sherry T.  et al.  High frequency oscillatory ventilation compared with conventional mechanical ventilation in adult respiratory distress syndrome: a randomized controlled trial.  Crit Care. 2005;9:R430-R439PubMedArticle
51.
Bryan AC. Comments of a devil's advocate.  Am Rev Respir Dis. 1974;110:143-144PubMed
52.
Pelosi P, Brazzi L, Gattinoni L. Prone position in acute respiratory distress syndrome.  Eur Respir J. 2002;20:1017-1028PubMedArticle
53.
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;345:568-573PubMedArticle
54.
Guerin C, Gaillard S, Lemasson S.  et al.  Effects of systematic prone positioning in hypoxemic acute respiratory failure: a randomized controlled trial.  JAMA. 2004;292:2379-2387PubMedArticle
55.
Mancebo J, Rialp G, Fernandez R.  et al.  Randomized multicenter trial in ARDS. Supine vs prone position.  Intensive Care Med. 2003;29:S64Article
56.
Rossaint R, Falke KJ, Lopez F, Slama K, Pison U, Zapol WM. Inhaled nitric oxide for the adult respiratory distress syndrome.  N Engl J Med. 1993;328:399-405PubMedArticle
57.
Dellinger RP, Zimmerman JL, Taylor RW.  et al.  Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial.  Crit Care Med. 1998;26:15-23PubMedArticle
58.
Michael JR, Barton RG, Saffle JR.  et al.  Inhaled nitric oxide versus conventional therapy: effect on oxygenation in ARDS.  Am J Respir Crit Care Med. 1998;157:1372-1380PubMedArticle
59.
Troncy E, Collet JP, Shapiro S.  et al.  Inhaled nitric oxide in acute respiratory distress syndrome: a pilot randomized controlled study.  Am J Respir Crit Care Med. 1998;157:1483-1488PubMedArticle
60.
Lundin S, Mang H, Smithies M, Stenqvist O, Frostell C. Inhalation of nitric oxide in acute lung injury: results of a European multicentre study.  Intensive Care Med. 1999;25:911-919PubMedArticle
61.
Mehta S, Simms HH, Levy MM.  et al.  Extended therapy with inhaled nitric oxide fails to improve oxygenation in patients with acute respiratory distress syndrome: a randomized controlled trial.  J Appl Res. 2001;1:73-84
62.
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;291:1603-1609PubMedArticle
63.
Sokol J, Jacobs SE, Bohn D. Inhaled nitric oxide for acute respiratory failure in children and adults: a meta-analysis.  Anesth Analg. 2003;97:989-998PubMedArticle
64.
Shapiro BA, Crane RD, Harrison RA, Steiner MC. Changes in intrapulmonary shunting with administration of 100 percent oxygen.  Chest. 1980;77:138-141PubMedArticle
65.
Santos C, Ferrer M, Roca J, Torres A, Hernandez C, Rodriguez-Roisin R. Pulmonary gas exchange response to oxygen breathing in acute lung injury.  Am J Respir Crit Care Med. 2000;161:26-31PubMedArticle
66.
Ferguson ND, Kacmarek RM, Chiche JD.  et al.  Screening of ARDS patients using standardized ventilator settings: influence on enrollment in a clinical trial.  Intensive Care Med. 2004;30:1111-1116PubMedArticle
67.
Rubenfeld GD, Caldwell E, Granton J, Hudson LD, Matthay MA. Interobserver variability in applying a radiographic definition for ARDS.  Chest. 1999;116:1347-1353PubMedArticle
68.
Esteban A, Fernandez-Segoviano P, Frutos-Vivar F.  et al.  Comparison of clinical criteria for the acute respiratory distress syndrome with autopsy findings.  Ann Intern Med. 2004;141:440-445PubMedArticle
69.
Kallet RH, Jasmer RM, Pittet JF.  et al.  Clinical implementation of the ARDS network protocol is associated with reduced hospital mortality compared with historical controls.  Crit Care Med. 2005;33:925-929PubMedArticle
70.
Brower RG, Thompson BT, Ancukiewicz M. Clinical trial of mechanical ventilation with traditional versus lower tidal volumes in acute lung injury and acute respiratory distress syndrome: effects on physician's practices.  Am J Respir Crit Care Med. 2004;169:A17
71.
Weinert CR, Gross CR, Marinelli WA. Impact of randomized trial results on acute lung injury ventilator therapy in teaching hospitals.  Am J Respir Crit Care Med. 2003;167:1304-1309PubMedArticle
72.
Young MP, Manning HL, Wilson DL.  et al.  Ventilation of patients with acute lung injury and acute respiratory distress syndrome: has new evidence changed clinical practice?  Crit Care Med. 2004;32:1260-1265PubMedArticle
73.
Rubenfeld GD, Cooper C, Carter G, Thompson BT, Hudson LD. Barriers to providing lung-protective ventilation to patients with acute lung injury.  Crit Care Med. 2004;32:1289-1293PubMedArticle
74.
Marini JJ, Gattinoni L. Ventilatory management of the acute respiratory distress syndrome: a consensus of two.  Crit Care Med. 2004;32:250-255PubMedArticle
75.
Hager DN, Krishnan JA, Hayden DL, Brower RG. Tidal volume reduction in patients with acute lung injury when plateau pressures are not high.  Am J Respir Crit Care Med. 2005;172:1241-1245PubMedArticle
76.
Mehta S, Granton J, MacDonald RJ.  et al.  High-frequency oscillatory ventilation in adults: the Toronto experience.  Chest. 2004;126:518-527PubMedArticle
77.
Fan E, Mehta S. High-frequency oscillatory ventilation and adjunctive therapies: inhaled nitric oxide and prone positioning.  Crit Care Med. 2005;33:S182-S187PubMedArticle
78.
Ferguson ND, Chiche JD, Kacmarek RM.  et al.  Combining high-frequency oscillatory ventilation and recruitment maneuvers in adults with early acute respiratory distress syndrome: the Treatment with Oscillation and an Open Lung Strategy (TOOLS) Trial Pilot study.  Crit Care Med. 2005;33:479-486PubMedArticle
79.
Medoff BD, Shepard JO, Smith RN, Kratz A. Case 17-2005—a 22-year old woman with back and leg pain and respiratory failure.  N Engl J Med. 2005;352:2425-2434PubMedArticle
×