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Therapy for Late-Phase Acute Respiratory Distress Syndrome
Clin Chest Med 27 (2006) 671–677
Therapy for Late-Phase Acute Respiratory Distress Syndrome Leonard D. Hudson, MD*, Catherine Lee Hough, MD, MSc Division of Pulmonary and Critical Care Medicine, Harborview Medical Center, University of Washington, 325 Ninth Avenue, Box 359762, Seattle, WA 98122, USA
The acute respiratory distress syndrome (ARDS) has arbitrarily been considered as having an early and a late phase. The early phase is characterized by an inflammatory injury with disruption of the alveolar-capillary barrier resulting in leak of protein-rich edema fluid containing neutrophils into the alveolar spaces. The late phase, or so-called ‘‘fibroproliferative’’ phase, is characterized by organization and collagen deposition with remodeling [1,2]. The timing of these phases is variable and somewhat arbitrary, in part because of the lack of a large data set of morphology at various points in time in the injury/inflammation/progression/repair process. Recently, the term ‘‘persistent ARDS’’ has been used and arbitrarily defined as meeting the criteria for ARDS and requiring mechanical ventilation 7 or more days after onset of the syndrome [3]. Biochemical evidence of fibroproliferation is present early in the injury process. Procollagen peptide III (PIIIP) is a marker of the fibrotic process in a number of disease entities. One study of ARDS found significant levels of PIIIP in bronchoalveolar lavage (BAL) fluid on day 3 following ARDS onset [4]. A subsequent study identified PIIIP in lung edema fluid from patients with ARDS on the first day after onset [5]. The predominant type of collagen deposited in the lungs of victims with ARDS studied at autopsy is type III collagen, interestingly identical to the predominant collagen type in patients with idiopathic pulmonary fibrosis [6]. A marked difference between these
* Corresponding author. E-mail address: [email protected] (L.D. Hudson).
two disease syndromes is that the collagen in ARDS survivors presumably clears. There are a few instances with lung morphology to assure this, but studies of pulmonary function in survivors show improvement with return to near-normal to normal levels by 6 to 12 months of follow-up [7,8]. In this article we review the studies of corticosteroid treatment for late ARDS in detail, for this is the only therapy that has been tested by randomized controlled trial in this population. We discuss management and prognosis of patients with late ARDS, and then conclude with an agenda for future research.
History of studies of corticosteroids for early and late acute respiratory distress syndrome Rationale The question of whether persistent ARDS with its fibroproliferative predominance warrants different treatment strategies than ARDS at its onset has been a vexing one. At its heart has been the hypothesis that the antifibrotic properties of corticosteroids will benefit patients with persistent ARDS. Presumably, the same or similar argument could be made for corticosteroid treatment of early ARDS based on the anti-inflammatory effects of steroids. Definitive answers have been difficult because of the variety of dose, duration, and tapering strategies and regimens used. The approach that has been best studied is the use of high doses of corticosteroids administered early in ARDS for 1 or 2 days. This regimen does not improve outcomes and may worsen them both in patients with established ARDS [9–11] or in patients at high risk for ARDS (septic shock) [11–13].
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Case series Corticosteroids were first proposed and systematically administered in patients with persistent ARDS by Ashbaugh and Maier [14]. They performed open lung biopsies in 10 patients both to establish that inflammatory fibrosis was present and to rule out infection. They then administered a prolonged course of moderate doses of corticosteroids as methylprednisolone given intravenously. Eight of these 10 patients survived, a number higher than expected based on overall survival rates for patients with ARDS at that time. This series was followed by publication of several other similar uncontrolled series (although without lung biopsies) with similar overall results; survival was between 70% and 80% [15–19]. This high survival rate was impressive to most ARDS ‘‘experts’’ but the expected outcome of patients with persistent ARDS was unknown at the time of publication of these series. We will return to this issue later. First randomized, controlled trial of corticosteroids for persistent acute respiratory distress syndrome These encouraging results led Meduri and coworkers [20] to conduct a randomized controlled trial of corticosteroids in patients with persistent ARDS. They randomized patients in a 2:1 ratio to either methylprednisolone or placebo. The dose of methylprednisolone was 2 mg/kg initially, followed by 2 mg/kg/day in divided doses for 14 days, followed by 1 mg/kg/day in divided doses for another 7 days, followed by 0.5 mg/kg/day in divided doses for another 7 days, followed by a final taper over 4 days. The authors considered clinical improvement as being a one-point decrease in the Lung Injury Score at or before 10 days of treatment. The study design included a provision to crossover to the alternative treatment if that criterion for improvement was not met by 10 days. Twenty-four patients were included in the study. All 16 patients in the steroid-treated group met the criterion for clinical improvement, whereas only 2 of the 8 patients randomized to placebo improved. However, four of the patients randomized to placebo were subsequently treated with corticosteroids under the crossover scheme; the other two unimproved patients died before crossover. The intention-to-treat analysis demonstrated that randomization to corticosteroids was associated with a statistically significant improvement in survival. This survival benefit was no
longer statistically significant, however, if analyzed by actual treatment (comparing the outcome of the 20 subjects who received corticosteroids with the 4 subjects who did not). This study and its results were controversial based on its small size and unconventional methodology, including multiple interim analyses and the use of the crossover design, which made survival difficult to interpret. Nonetheless, the clear demonstration of clinical improvement by day 10 was certainly encouraging.
National Institutes of Health National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome Clinical Trials Network study of corticosteroids for persistent acute respiratory distress syndrome Study design Based on these favorable but uncertain outcomes, the National Institutes of Health–sponsored National Heart, Lung, and Blood Institute ARDS Clinical Trials Network (ARDSnet) decided to conduct a trial of corticosteroids in patients with persistent ARDS, defined as meeting ARDS criteria with continuous need for endotracheal intubation and mechanical ventilation for at least 7 days and no more than 28 days after the onset of ARDS [3]. Corticosteroid administration was similar to the regimen used by Meduri and colleagues [20], but with a few differences. The regimens were identical for the first 21 days. Meduri and coworkers continued treatment for 28 days before beginning a taper; the ARDSnet study began tapering corticosteroids on study day 21. The final taper of both studies occurred over 4 days: study days 29 to 32 in the Meduri protocol, study days 22 to 26 in the ARDSnet protocol. Additionally, subjects who achieved 48 hours of unassisted breathing were rapidly tapered in the ARDSnet protocol, but not in the Meduri protocol. The primary outcome variable in the ARDSnet study was mortality 60 days after study entry. Since enrollment was slow over the first 2 years, the study was re-sized to detect a 20% decrease in mortality (40% to 20%) with 85% power and a two-sided significance of 5%. It took 7 years for 10 university centers to enroll the required 180 patients, a finding that may suggest that patients meeting this definition of persistent ARDS are less common than initially suspected. It is possible that current treatment of ARDS, especially lungprotective ventilation, has decreased the
THERAPY FOR LATE-PHASE ARDS
prevalence of persistent ARDS, but there are no firm data to support or refute this hypothesis. Study results The ARDSnet study found no difference in mortality between corticosteroids and placebo, but demonstrated clinical and physiologic benefits from corticosteroid treatment. Patients randomized to steroid treatment were liberated from mechanical ventilation considerably earlier than patients in the placebo group, with a median of 14.1 days of mechanical ventilation compared with 23.6 days (P ¼ .006). Although more steroid-treated patients required return to assisted breathing (20 versus 6 in the placebo group), the methylprednisolone group still had significantly fewer ventilator-free days than the placebo group. This difference was seen at 28 days, as well as 60 and 180 days. The methylprednisolone group also had fewer days alive and free of intensive care during the first 28 days of the study. Patients in the steroid-treated group had significant improvements in cardiopulmonary physiology, with higher PaO2:FIO2 ratios, lower plateau pressures, higher values of respiratory system compliance, and more days without shock than patients in the placebo group. There were no differences in days of other organ failures between the study groups. Mortality at 60 days was essentially identical in the two groups: 29.2% in the steroid group and 28.6% in the placebo group (P ¼ 0.99). Since nearly one third of study subjects remained hospitalized 60 days after study entry, including some requiring mechanical ventilation, mortality was also analyzed at 180 days. No differences emerged at this later time point; the mortality in the steroid group was 31.5%, and in the placebo group it was 31.9% (P ¼ 0.99). Subgroup analyses There were eight subgroup analyses of this study that were hypothesis driven and prospectively planned. Two of these eight analyses had intriguing results. When patients with ARDS onset before study entry of 7 to 13 days were compared with those of 14 days or more, patients with onset of 14 days or more had higher mortality when treated with methylprednisolone compared with placebo (44% versus 12%, respectively, P ¼ .01). There were imbalances in these groups favoring placebo, including age and lung injury score, but the mortality difference remained significant after controlling for these factors in the statistical
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analysis. This should be cautiously interpreted in light of the relatively small sample size, the multiple comparisons performed in the many subgroup analyses that increase the likelihood of false-positive findings, and the extraordinarily low mortality in the placebo-treated patients (12%). A second subgroup analysis looked for effect modification between methylprednisolone treatment and concentration of PIIIP in BAL fluid at study entry. The hypothesis was that patients with higher levels of PIIIP would have more active fibrosis and would therefore be more responsive to corticosteroid therapy, an issue of biological interest and importance. For this analysis, study subjects were stratified as ‘‘high PIIIP’’ if measured PIIIP in baseline BAL fluid was above the median, and ‘‘low PIIIP’’ if below the median. Patients with ‘‘high PIIIP’’ who were treated with corticosteroids had a lower mortality than ‘‘high PIIIP’’ patients who were treated with placebo (4% versus 24%, P ¼ .05). This suggests the possibility of detecting biologic differences in profibrotic activity that would allow identification of patients more apt to benefit from steroid treatment. Such an approach would require performance of bronchoalveolar lavage and rapid testing for PIIIP; currently no such rapid test is available. Interpretation of study results How can this disparity between findings of clinical and physiologic benefits but no differences in mortality be explained? The study authors considered the possibility that early beneficial results were counterbalanced by later adverse effects. No data suggest an increase in infections in steroid-treated patients as a possible explanation; in fact, infections were less frequent in the steroid group, although potential differences in detection of infections between the study groups must be considered. Critics of the ARDSnet study have raised the possibility that the rapid taper of steroids may have contributed to the loss of benefit from corticosteroid treatment. There are no data from the study to support or refute this hypothesis. One possibility is that more steroid patients developed neuromuscular pathology with clinical weakness (presumably predominantly myopathy) than those treated with placebo. Prospective testing of patients for weakness and its causes was not performed in this study. However, development of clinically apparent weakness was tracked through adverse event reporting, and through systematic chart review, as is described
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in the article in this issue by Hough of neuromuscular sequelae in survivors of acute lung injury. A higher incidence of severe neuromyopathy in steroid-treated patients was suggested by the report of nine adverse events of neuromyopathy in the steroid group compared with none in the placebo group. However, there were no differences in overall clinically suspected neuromyopathy between the groups as identified by chart review. Here the presence of potentially competing risks must be considered. Corticosteroids may induce neuromyopathy directly via toxic effect to the muscle [21] as well as indirectly by elevating serum glucose, a known risk factor for neuromyopathy [22–25]. On the other hand, treatment with placebo is associated with prolonged mechanical ventilation, which is also a risk factor for neuromyopathy [26,27]. The authors of the ARDSnet study concluded ‘‘our results do not provide support for the routine use of methylprednisolone in patients with persistent ARDS.’’ How can this cautious interpretation be justified in light of another ARDSnet study recommending a conservative fluid strategy with similar findings of no mortality benefit but an increase (less pronounced than in the steroid study) in ventilator-free days [28]? One reason is that in the fluid conservative strategy there was a statistically significant decrease in intensive care unit days, a difference that was not found in the 180day analysis in the ARDSnet corticosteroid trial. Furthermore, there was a 2.9% lower mortality in the fluid conservative strategy treatment group although this difference did not reach statistical significance. In the steroid trial, mortality was virtually identical at 60 and 180 days. The contribution of treatment of corticosteroids to long-term disability after ARDS remains unknown. It is possible that steroid-treated patients suffer from persistent myopathy with potentially significant detriments to quality of life. While the ARDSnet study did not measure these important endpoints, we know from Herridge and colleague’s [8] landmark study of sequelae of patients surviving an episode of ARDS that after 1 year, all patients suffered from fatigue, weakness (primarily proximal), or loss of muscle bulk. This finding, along with neuropsychologic and neurocognitive abnormalities [29–31], appears to be the prime candidate in explaining the consistently observed decrement in health-related quality of life in ARDS survivors [7,8,32,33], as reviewed by Hopkins and Herridge in this issue. Because of the disparity in neuromyopathy
reported as serious adverse events between the steroid and placebo groups in the ARDSnet study, and the unknown but possible relationship between acute steroid-induced myopathy and persistent myopathy and muscle-related complaints at 1 year and beyond, it seems prudent to be cautious in recommending corticosteroids. The issue can be rephrased with the question, ‘‘Would a patient choose fewer days of mechanical ventilation if it came at the price of more severe and persistent weakness and fatigue?’’ Much more information about the multifactorial causes of critical illness neuromyopathy and its relation to persistent functional disability and perceived health-related quality of life impairments in ARDS survivors must be generated to inform this question, and to help decide if the question is relevant.
Care of patients with late acute respiratory distress syndrome Mechanical ventilation Besides steroids, are any other differences in treatment strategy warranted in the late compared with the early phase of ARDS? For example, should the mechanical ventilation strategy vary in these two stages given the differences in underlying lung pathology? Existing experimental data are inadequate to address this question substantively. On one hand, one could argue that the fibrotic areas of the lung are less vulnerable to injury. On the other hand, patchy areas of fibrosis are apt to result in marked differences in regional or local compliance, making relatively preserved lung areas at increased risk of barotrauma and, perhaps, biotrauma. Two lines of argument support continuing a lung-protective strategy in persistent ARDS, unchanged from that used in early ARDS. First, the ARDSnet study of lung-protective ventilation that limited tidal volume and plateau pressure continued that strategy until specific criteria were met that suggested imminent ability to wean from mechanical ventilation [34]. There was no instruction for patients to be released from lung-protective ventilation based solely on duration of mechanical ventilation. One could argue that, until better rationale or data are available, the ARDSnet protocol should be followed to attain the benefits of lower mortality and morbidity found in that study.
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THERAPY FOR LATE-PHASE ARDS
Second, there are no compelling reasons to abandon that strategy for this cohort of patients. Other ancillary studies from ARDSnet centers have demonstrated no adverse effects of the low tidal volume strategy in terms of the amount of sedation used or other effects [35,36]. Unless there is a compelling reason in an individual patient, the ARDSnet protocol of lung-protective ventilation is recommended in late ARDS, and generally appears to be well tolerated. Epidemiology of late acute respiratory distress syndrome One of the surprising findings in the ARDSnet study of corticosteroids for persistent ARDS was the relatively low mortality in both groups [3]. A widely held supposition has been that patients still meeting oxygenation criteria for ARDS after 7 or more days and requiring prolonged mechanical ventilation would have a mortality substantially higher than ARDS patients as a whole. Although much has been learned about the incidence and outcomes of acute lung injury and ARDS, particularly through population-based studies conducted over the past decade [37,38], we still know little about the epidemiology of persistent ARDS. We may be tempted to extrapolate from the ARDSnet study and to conclude that persistent
ARDS is uncommon and no more fatal than all ARDS. It is important to note that this randomized, controlled trial was not a population-based study. Only 5% of the patients meeting persistent ARDS criteria were enrolled; as such, this cohort was highly selected and in many ways not representative of all persistent ARDS patients. Nonetheless, the mortality of persistent ARDS patients was very similar to the mortality of all other patients in the ARDSnet studies who enrolled within the first 48 hours of acute lung injury (Table 1) [28,34,39,40]. Recently presented data from the countywide study of acute lung injury in King County, Washington [38], demonstrated that more than one third of patients continue to require mechanical ventilation 7 days after acute lung injury onset [41]. It is unknown what percentage of these patients met the definition for persistent lung injury, for arterial blood gases were often not obtained on day 7 and afterward. However, the mortality of patients requiring 7 or more days of mechanical ventilation was not significantly different from those ventilated for less than 1 week (Table 1). While much more remains to be learned about the epidemiology and outcomes of persistent ARDS and prolonged mechanical ventilation after acute lung injury, there is currently no compelling evidence that persistent respiratory failure is an indicator of increased mortality.
Table 1 Mortality of patients with acute lung injury in Acute Respiratory Distress Syndrome Clinical Trials Network randomized, controlled trials and contemporary population-based study Study
Type
Enrollment dates
Tidal volume: 6 ml/kg [34] (ARDSnet)a Tidal volume: 12 ml/kg [34] (ARDSnet)a PEEP [39] (ARDSnet) Steroids for persistent ARDS [3] (ARDSnet) Fluid and catheter treatment trial (ARDSnet) [28,40] King County Lung Injury Project (all subjects) [38] King County Lung Injury Project (ventilated R7 days) [41]
RCT
1996–1999
No. of subjects 432
Mortality (%) 31
RCT
1996–1999
429
40
RCT RCT
1999–2002 1996–2003
549 180
26 29
RCT
2000–2005
1001
27
Population-based
1999–2000
1113
39
Population-based
1999–2000
430
37
Abbreviations: ARDSnet, Acute Respiratory Distress Syndrome Clinical Trials Network; RCT, randomized controlled trials. a Mortality is presented by study arm for the tidal volume study. All other RCTs are presented with both study arms combined, since these interventions did not significantly affect mortality.
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This has important implications for clinical care. Clinicians should take care not to infer that persistent respiratory failure is associated with increased mortality. Instead, we must look toward survival as we focus on delivering the highest quality care to these patients, minimizing complications of intensive care, and recognizing and providing support for sequelae of ARDS during recovery.
Summary Decades after initial reports of pathology and treatment, there remains little known about late ARDS. Is late or ‘‘fibroproliferative’’ ARDS truly its own entity, with unique physiology, ideal treatment, and distinctive outcomes? If so, how is late ARDS defined, what is its incidence, and how are these patients best managed to improve both early and late outcomes? Population-based epidemiologic studies, longitudinal cohort studies of survivors, and additional interventional studies that include both short- and long-term outcomes are all needed to answer these questions. Based on current knowledge, there are no specific therapies that have been proven to improve mortality or other patient-centered outcomes of persistent ARDS. The best available evidence does not support corticosteroid treatment of persistent ARDS at this time; however, it remains possible that additional research may discover a protocol and patient population in which the physiological responses seen with corticosteroid therapy translate to true clinical improvement. In the meantime, optimal therapy for late ARDS involves providing the same highquality critical care that we strive to provide for all patients with acute lung injury, recognizing that prolonged respiratory failure does not connote an increased mortality, and supporting survivors and their families through protracted convalescence and recovery. References [1] Lamy M, Fallat RJ, Koeniger E, et al. Pathologic features and mechanisms of hypoxemia in adult respiratory distress syndrome. Am Rev Respir Dis 1976;114:267–84. [2] Tomashefski JF Jr. Pulmonary pathology of the adult respiratory distress syndrome. Clin Chest Med 1990;11:593–619. [3] Steinberg KP, Hudson LD, Goodman RB, et al. Efficacy and safety of corticosteroids for persistent
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[18]
acute respiratory distress syndrome. N Engl J Med 2006;354:1671–84. Clark JG, Milberg JA, Steinberg KP, et al. Elevated lavage levels of N-terminal peptide of type III procollagen are associated with increased fatality in adult respiratory distress syndrome. Chest 1994; 105:126S–7S. Chesnutt AN, Matthay MA, Tibayan FA, et al. Early detection of type III procollagen peptide in acute lung injury. Pathogenetic and prognostic significance. Am J Respir Crit Care Med 1997;156: 840–5. Raghu G, Striker LJ, Hudson LD, et al. Extracellular matrix in normal and fibrotic human lungs. Am Rev Respir Dis 1985;131:281–9. McHugh LG, Milberg JA, Whitcomb ME, et al. Recovery of function in survivors of the acute respiratory distress syndrome. Am J Respir Crit Care Med 1994;150:90–4. 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: 683–93. Bone RC, Fisher CJ Jr, Clemmer TP, et al. Early methylprednisolone treatment for septic syndrome and the adult respiratory distress syndrome. Chest 1987;92:1032–6. Bernard GR, Luce JM, Sprung CL, et al. High-dose corticosteroids in patients with the adult respiratory distress syndrome. N Engl J Med 1987;317:1565–70. Weigelt JA, Norcross JF, Borman KR, et al. Early steroid therapy for respiratory failure. Arch Surg 1985;120:536–40. Sprung CL, Caralis PV, Marcial EH, et al. The effects of high-dose corticosteroids in patients with septic shock. A prospective, controlled study. N Engl J Med 1984;311:1137–43. Luce JM, Montgomery AB, Marks JD, et al. Ineffectiveness of high-dose methylprednisolone in preventing parenchymal lung injury and improving mortality in patients with septic shock. Am Rev Respir Dis 1988;138:62–8. Ashbaugh DG, Maier RV. Idiopathic pulmonary fibrosis in adult respiratory distress syndrome. Diagnosis and treatment. Arch Surg 1985;120:530–5. Hooper RG, Kearl RA. Established ARDS treated with a sustained course of adrenocortical steroids. Chest 1990;97:138–43. Meduri GU, Belenchia JM, Estes RJ, et al. Fibroproliferative phase of ARDS. Clinical findings and effects of corticosteroids. Chest 1991;100: 943–52. Braude S, Haslam P, Hughes D, et al. Chronic adult respiratory distress syndromeda role for corticosteroids? Crit Care Med 1992;20:1187–9. Biffl WL, Moore FA, Moore EE, et al. Are corticosteroids salvage therapy for refractory acute respiratory distress syndrome? Am J Surg 1995;170:591–5 [discussion 595–596].
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[19] Keel JB, Hauser M, Stocker R, et al. Established acute respiratory distress syndrome: benefit of corticosteroid rescue therapy. Respiration (Herrlisheim) 1998;65:258–64. [20] 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;280:159–65. [21] Kuncl RW, George EB. Toxic neuropathies and myopathies. Curr Opin Neurol 1993;6:695–704. [22] van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically ill patients. N Engl J Med 2001;345:1359–67. [23] Van den Berghe G, Wouters PJ, Bouillon R, et al. Outcome benefit of intensive insulin therapy in the critically ill: insulin dose versus glycemic control. Crit Care Med 2003;31:359–66. [24] Van den Berghe G, Schoonheydt K, Becx P, et al. Insulin therapy protects the central and peripheral nervous system of intensive care patients. Neurology 2005;64:1348–53. [25] De Jonghe B, Sharshar T, Lefaucheur JP, et al. Paresis acquired in the intensive care unit: a prospective multicenter study. JAMA 2002;288:2859–67. [26] Leijten FS, Harinck-de Weerd JE, Poortvliet DC, et al. The role of polyneuropathy in motor convalescence after prolonged mechanical ventilation. JAMA 1995;274:1221–5. [27] Maher J, Rutledge F, Remtulla H, et al. Neuromuscular disorders associated with failure to wean from the ventilator. Intensive Care Med 1995;21: 737–43. [28] Wiedemann HP, Wheeler AP, Bernard GR, et al. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med 2006;354: 2564–75. [29] Hopkins RO, Weaver LK, Collingridge D, et al. Two-year cognitive, emotional, and quality-of-life outcomes in acute respiratory distress syndrome. Am J Respir Crit Care Med 2005;171:340–7. [30] Hopkins RO, Weaver LK, Pope D, et al. Neuropsychological sequelae and impaired health status in survivors of severe acute respiratory distress syndrome. Am J Respir Crit Care Med 1999;160:50–6.
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[31] Schelling G, Stoll C, Haller M, et al. Health-related quality of life and posttraumatic stress disorder in survivors of the acute respiratory distress syndrome. Crit Care Med 1998;26:651–9. [32] Weinert CR, Gross CR, Kangas JR, et al. Health-related quality of life after acute lung injury. Am J Respir Crit Care Med 1997;156:1120–8. [33] Davidson TA, Caldwell ES, Curtis JR, et al. Reduced quality of life in survivors of acute respiratory distress syndrome compared with critically ill control patients. JAMA 1999;281:354–60. [34] The Acute Respiratory Distress Syndrome. 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;342:1301–8. [35] Kahn JM, Andersson L, Karir V, et al. Low tidal volume ventilation does not increase sedation use in patients with acute lung injury. Crit Care Med 2005;33:766–71. [36] Cheng IW, Eisner MD, Thompson BT, et al. Acute effects of tidal volume strategy on hemodynamics, fluid balance, and sedation in acute lung injury. Crit Care Med 2005;33:63–70 [discussion 239–240]. [37] Luhr OR, Antonsen K, Karlsson M, et al. Incidence and mortality after acute respiratory failure and acute respiratory distress syndrome in Sweden, Denmark, and Iceland. The ARF Study Group. Am J Respir Crit Care Med 1999;159:1849–61. [38] Rubenfeld GD, Caldwell E, Peabody E, et al. Incidence and outcomes of acute lung injury. N Engl J Med 2005;353:1685–93. [39] Brower RG, Lanken PN, MacIntyre N, et al. Higher versus lower positive enddexpiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med 2004;351:327–36. [40] Wheeler AP, Bernard GR, Thompson BT, et al. Pulmonary-artery versus central venous catheter to guide treatment of acute lung injury. N Engl J Med 2006;354:2213–24. [41] Hough CL, Steinberg KP, Caldwell E, et al. Duration of mechanical ventilation is not associated with hospital mortality in patients with acute lung injury. Am J Respir Crit Care Med 2006;3:A831.
Therapy for Late-Phase Acute Respiratory Distress Syndrome Leonard D. Hudson, MD*, Catherine Lee Hough, MD, MSc Division of Pulmonary and Critical Care Medicine, Harborview Medical Center, University of Washington, 325 Ninth Avenue, Box 359762, Seattle, WA 98122, USA
The acute respiratory distress syndrome (ARDS) has arbitrarily been considered as having an early and a late phase. The early phase is characterized by an inflammatory injury with disruption of the alveolar-capillary barrier resulting in leak of protein-rich edema fluid containing neutrophils into the alveolar spaces. The late phase, or so-called ‘‘fibroproliferative’’ phase, is characterized by organization and collagen deposition with remodeling [1,2]. The timing of these phases is variable and somewhat arbitrary, in part because of the lack of a large data set of morphology at various points in time in the injury/inflammation/progression/repair process. Recently, the term ‘‘persistent ARDS’’ has been used and arbitrarily defined as meeting the criteria for ARDS and requiring mechanical ventilation 7 or more days after onset of the syndrome [3]. Biochemical evidence of fibroproliferation is present early in the injury process. Procollagen peptide III (PIIIP) is a marker of the fibrotic process in a number of disease entities. One study of ARDS found significant levels of PIIIP in bronchoalveolar lavage (BAL) fluid on day 3 following ARDS onset [4]. A subsequent study identified PIIIP in lung edema fluid from patients with ARDS on the first day after onset [5]. The predominant type of collagen deposited in the lungs of victims with ARDS studied at autopsy is type III collagen, interestingly identical to the predominant collagen type in patients with idiopathic pulmonary fibrosis [6]. A marked difference between these
* Corresponding author. E-mail address: [email protected] (L.D. Hudson).
two disease syndromes is that the collagen in ARDS survivors presumably clears. There are a few instances with lung morphology to assure this, but studies of pulmonary function in survivors show improvement with return to near-normal to normal levels by 6 to 12 months of follow-up [7,8]. In this article we review the studies of corticosteroid treatment for late ARDS in detail, for this is the only therapy that has been tested by randomized controlled trial in this population. We discuss management and prognosis of patients with late ARDS, and then conclude with an agenda for future research.
History of studies of corticosteroids for early and late acute respiratory distress syndrome Rationale The question of whether persistent ARDS with its fibroproliferative predominance warrants different treatment strategies than ARDS at its onset has been a vexing one. At its heart has been the hypothesis that the antifibrotic properties of corticosteroids will benefit patients with persistent ARDS. Presumably, the same or similar argument could be made for corticosteroid treatment of early ARDS based on the anti-inflammatory effects of steroids. Definitive answers have been difficult because of the variety of dose, duration, and tapering strategies and regimens used. The approach that has been best studied is the use of high doses of corticosteroids administered early in ARDS for 1 or 2 days. This regimen does not improve outcomes and may worsen them both in patients with established ARDS [9–11] or in patients at high risk for ARDS (septic shock) [11–13].
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Case series Corticosteroids were first proposed and systematically administered in patients with persistent ARDS by Ashbaugh and Maier [14]. They performed open lung biopsies in 10 patients both to establish that inflammatory fibrosis was present and to rule out infection. They then administered a prolonged course of moderate doses of corticosteroids as methylprednisolone given intravenously. Eight of these 10 patients survived, a number higher than expected based on overall survival rates for patients with ARDS at that time. This series was followed by publication of several other similar uncontrolled series (although without lung biopsies) with similar overall results; survival was between 70% and 80% [15–19]. This high survival rate was impressive to most ARDS ‘‘experts’’ but the expected outcome of patients with persistent ARDS was unknown at the time of publication of these series. We will return to this issue later. First randomized, controlled trial of corticosteroids for persistent acute respiratory distress syndrome These encouraging results led Meduri and coworkers [20] to conduct a randomized controlled trial of corticosteroids in patients with persistent ARDS. They randomized patients in a 2:1 ratio to either methylprednisolone or placebo. The dose of methylprednisolone was 2 mg/kg initially, followed by 2 mg/kg/day in divided doses for 14 days, followed by 1 mg/kg/day in divided doses for another 7 days, followed by 0.5 mg/kg/day in divided doses for another 7 days, followed by a final taper over 4 days. The authors considered clinical improvement as being a one-point decrease in the Lung Injury Score at or before 10 days of treatment. The study design included a provision to crossover to the alternative treatment if that criterion for improvement was not met by 10 days. Twenty-four patients were included in the study. All 16 patients in the steroid-treated group met the criterion for clinical improvement, whereas only 2 of the 8 patients randomized to placebo improved. However, four of the patients randomized to placebo were subsequently treated with corticosteroids under the crossover scheme; the other two unimproved patients died before crossover. The intention-to-treat analysis demonstrated that randomization to corticosteroids was associated with a statistically significant improvement in survival. This survival benefit was no
longer statistically significant, however, if analyzed by actual treatment (comparing the outcome of the 20 subjects who received corticosteroids with the 4 subjects who did not). This study and its results were controversial based on its small size and unconventional methodology, including multiple interim analyses and the use of the crossover design, which made survival difficult to interpret. Nonetheless, the clear demonstration of clinical improvement by day 10 was certainly encouraging.
National Institutes of Health National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome Clinical Trials Network study of corticosteroids for persistent acute respiratory distress syndrome Study design Based on these favorable but uncertain outcomes, the National Institutes of Health–sponsored National Heart, Lung, and Blood Institute ARDS Clinical Trials Network (ARDSnet) decided to conduct a trial of corticosteroids in patients with persistent ARDS, defined as meeting ARDS criteria with continuous need for endotracheal intubation and mechanical ventilation for at least 7 days and no more than 28 days after the onset of ARDS [3]. Corticosteroid administration was similar to the regimen used by Meduri and colleagues [20], but with a few differences. The regimens were identical for the first 21 days. Meduri and coworkers continued treatment for 28 days before beginning a taper; the ARDSnet study began tapering corticosteroids on study day 21. The final taper of both studies occurred over 4 days: study days 29 to 32 in the Meduri protocol, study days 22 to 26 in the ARDSnet protocol. Additionally, subjects who achieved 48 hours of unassisted breathing were rapidly tapered in the ARDSnet protocol, but not in the Meduri protocol. The primary outcome variable in the ARDSnet study was mortality 60 days after study entry. Since enrollment was slow over the first 2 years, the study was re-sized to detect a 20% decrease in mortality (40% to 20%) with 85% power and a two-sided significance of 5%. It took 7 years for 10 university centers to enroll the required 180 patients, a finding that may suggest that patients meeting this definition of persistent ARDS are less common than initially suspected. It is possible that current treatment of ARDS, especially lungprotective ventilation, has decreased the
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prevalence of persistent ARDS, but there are no firm data to support or refute this hypothesis. Study results The ARDSnet study found no difference in mortality between corticosteroids and placebo, but demonstrated clinical and physiologic benefits from corticosteroid treatment. Patients randomized to steroid treatment were liberated from mechanical ventilation considerably earlier than patients in the placebo group, with a median of 14.1 days of mechanical ventilation compared with 23.6 days (P ¼ .006). Although more steroid-treated patients required return to assisted breathing (20 versus 6 in the placebo group), the methylprednisolone group still had significantly fewer ventilator-free days than the placebo group. This difference was seen at 28 days, as well as 60 and 180 days. The methylprednisolone group also had fewer days alive and free of intensive care during the first 28 days of the study. Patients in the steroid-treated group had significant improvements in cardiopulmonary physiology, with higher PaO2:FIO2 ratios, lower plateau pressures, higher values of respiratory system compliance, and more days without shock than patients in the placebo group. There were no differences in days of other organ failures between the study groups. Mortality at 60 days was essentially identical in the two groups: 29.2% in the steroid group and 28.6% in the placebo group (P ¼ 0.99). Since nearly one third of study subjects remained hospitalized 60 days after study entry, including some requiring mechanical ventilation, mortality was also analyzed at 180 days. No differences emerged at this later time point; the mortality in the steroid group was 31.5%, and in the placebo group it was 31.9% (P ¼ 0.99). Subgroup analyses There were eight subgroup analyses of this study that were hypothesis driven and prospectively planned. Two of these eight analyses had intriguing results. When patients with ARDS onset before study entry of 7 to 13 days were compared with those of 14 days or more, patients with onset of 14 days or more had higher mortality when treated with methylprednisolone compared with placebo (44% versus 12%, respectively, P ¼ .01). There were imbalances in these groups favoring placebo, including age and lung injury score, but the mortality difference remained significant after controlling for these factors in the statistical
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analysis. This should be cautiously interpreted in light of the relatively small sample size, the multiple comparisons performed in the many subgroup analyses that increase the likelihood of false-positive findings, and the extraordinarily low mortality in the placebo-treated patients (12%). A second subgroup analysis looked for effect modification between methylprednisolone treatment and concentration of PIIIP in BAL fluid at study entry. The hypothesis was that patients with higher levels of PIIIP would have more active fibrosis and would therefore be more responsive to corticosteroid therapy, an issue of biological interest and importance. For this analysis, study subjects were stratified as ‘‘high PIIIP’’ if measured PIIIP in baseline BAL fluid was above the median, and ‘‘low PIIIP’’ if below the median. Patients with ‘‘high PIIIP’’ who were treated with corticosteroids had a lower mortality than ‘‘high PIIIP’’ patients who were treated with placebo (4% versus 24%, P ¼ .05). This suggests the possibility of detecting biologic differences in profibrotic activity that would allow identification of patients more apt to benefit from steroid treatment. Such an approach would require performance of bronchoalveolar lavage and rapid testing for PIIIP; currently no such rapid test is available. Interpretation of study results How can this disparity between findings of clinical and physiologic benefits but no differences in mortality be explained? The study authors considered the possibility that early beneficial results were counterbalanced by later adverse effects. No data suggest an increase in infections in steroid-treated patients as a possible explanation; in fact, infections were less frequent in the steroid group, although potential differences in detection of infections between the study groups must be considered. Critics of the ARDSnet study have raised the possibility that the rapid taper of steroids may have contributed to the loss of benefit from corticosteroid treatment. There are no data from the study to support or refute this hypothesis. One possibility is that more steroid patients developed neuromuscular pathology with clinical weakness (presumably predominantly myopathy) than those treated with placebo. Prospective testing of patients for weakness and its causes was not performed in this study. However, development of clinically apparent weakness was tracked through adverse event reporting, and through systematic chart review, as is described
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in the article in this issue by Hough of neuromuscular sequelae in survivors of acute lung injury. A higher incidence of severe neuromyopathy in steroid-treated patients was suggested by the report of nine adverse events of neuromyopathy in the steroid group compared with none in the placebo group. However, there were no differences in overall clinically suspected neuromyopathy between the groups as identified by chart review. Here the presence of potentially competing risks must be considered. Corticosteroids may induce neuromyopathy directly via toxic effect to the muscle [21] as well as indirectly by elevating serum glucose, a known risk factor for neuromyopathy [22–25]. On the other hand, treatment with placebo is associated with prolonged mechanical ventilation, which is also a risk factor for neuromyopathy [26,27]. The authors of the ARDSnet study concluded ‘‘our results do not provide support for the routine use of methylprednisolone in patients with persistent ARDS.’’ How can this cautious interpretation be justified in light of another ARDSnet study recommending a conservative fluid strategy with similar findings of no mortality benefit but an increase (less pronounced than in the steroid study) in ventilator-free days [28]? One reason is that in the fluid conservative strategy there was a statistically significant decrease in intensive care unit days, a difference that was not found in the 180day analysis in the ARDSnet corticosteroid trial. Furthermore, there was a 2.9% lower mortality in the fluid conservative strategy treatment group although this difference did not reach statistical significance. In the steroid trial, mortality was virtually identical at 60 and 180 days. The contribution of treatment of corticosteroids to long-term disability after ARDS remains unknown. It is possible that steroid-treated patients suffer from persistent myopathy with potentially significant detriments to quality of life. While the ARDSnet study did not measure these important endpoints, we know from Herridge and colleague’s [8] landmark study of sequelae of patients surviving an episode of ARDS that after 1 year, all patients suffered from fatigue, weakness (primarily proximal), or loss of muscle bulk. This finding, along with neuropsychologic and neurocognitive abnormalities [29–31], appears to be the prime candidate in explaining the consistently observed decrement in health-related quality of life in ARDS survivors [7,8,32,33], as reviewed by Hopkins and Herridge in this issue. Because of the disparity in neuromyopathy
reported as serious adverse events between the steroid and placebo groups in the ARDSnet study, and the unknown but possible relationship between acute steroid-induced myopathy and persistent myopathy and muscle-related complaints at 1 year and beyond, it seems prudent to be cautious in recommending corticosteroids. The issue can be rephrased with the question, ‘‘Would a patient choose fewer days of mechanical ventilation if it came at the price of more severe and persistent weakness and fatigue?’’ Much more information about the multifactorial causes of critical illness neuromyopathy and its relation to persistent functional disability and perceived health-related quality of life impairments in ARDS survivors must be generated to inform this question, and to help decide if the question is relevant.
Care of patients with late acute respiratory distress syndrome Mechanical ventilation Besides steroids, are any other differences in treatment strategy warranted in the late compared with the early phase of ARDS? For example, should the mechanical ventilation strategy vary in these two stages given the differences in underlying lung pathology? Existing experimental data are inadequate to address this question substantively. On one hand, one could argue that the fibrotic areas of the lung are less vulnerable to injury. On the other hand, patchy areas of fibrosis are apt to result in marked differences in regional or local compliance, making relatively preserved lung areas at increased risk of barotrauma and, perhaps, biotrauma. Two lines of argument support continuing a lung-protective strategy in persistent ARDS, unchanged from that used in early ARDS. First, the ARDSnet study of lung-protective ventilation that limited tidal volume and plateau pressure continued that strategy until specific criteria were met that suggested imminent ability to wean from mechanical ventilation [34]. There was no instruction for patients to be released from lung-protective ventilation based solely on duration of mechanical ventilation. One could argue that, until better rationale or data are available, the ARDSnet protocol should be followed to attain the benefits of lower mortality and morbidity found in that study.
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Second, there are no compelling reasons to abandon that strategy for this cohort of patients. Other ancillary studies from ARDSnet centers have demonstrated no adverse effects of the low tidal volume strategy in terms of the amount of sedation used or other effects [35,36]. Unless there is a compelling reason in an individual patient, the ARDSnet protocol of lung-protective ventilation is recommended in late ARDS, and generally appears to be well tolerated. Epidemiology of late acute respiratory distress syndrome One of the surprising findings in the ARDSnet study of corticosteroids for persistent ARDS was the relatively low mortality in both groups [3]. A widely held supposition has been that patients still meeting oxygenation criteria for ARDS after 7 or more days and requiring prolonged mechanical ventilation would have a mortality substantially higher than ARDS patients as a whole. Although much has been learned about the incidence and outcomes of acute lung injury and ARDS, particularly through population-based studies conducted over the past decade [37,38], we still know little about the epidemiology of persistent ARDS. We may be tempted to extrapolate from the ARDSnet study and to conclude that persistent
ARDS is uncommon and no more fatal than all ARDS. It is important to note that this randomized, controlled trial was not a population-based study. Only 5% of the patients meeting persistent ARDS criteria were enrolled; as such, this cohort was highly selected and in many ways not representative of all persistent ARDS patients. Nonetheless, the mortality of persistent ARDS patients was very similar to the mortality of all other patients in the ARDSnet studies who enrolled within the first 48 hours of acute lung injury (Table 1) [28,34,39,40]. Recently presented data from the countywide study of acute lung injury in King County, Washington [38], demonstrated that more than one third of patients continue to require mechanical ventilation 7 days after acute lung injury onset [41]. It is unknown what percentage of these patients met the definition for persistent lung injury, for arterial blood gases were often not obtained on day 7 and afterward. However, the mortality of patients requiring 7 or more days of mechanical ventilation was not significantly different from those ventilated for less than 1 week (Table 1). While much more remains to be learned about the epidemiology and outcomes of persistent ARDS and prolonged mechanical ventilation after acute lung injury, there is currently no compelling evidence that persistent respiratory failure is an indicator of increased mortality.
Table 1 Mortality of patients with acute lung injury in Acute Respiratory Distress Syndrome Clinical Trials Network randomized, controlled trials and contemporary population-based study Study
Type
Enrollment dates
Tidal volume: 6 ml/kg [34] (ARDSnet)a Tidal volume: 12 ml/kg [34] (ARDSnet)a PEEP [39] (ARDSnet) Steroids for persistent ARDS [3] (ARDSnet) Fluid and catheter treatment trial (ARDSnet) [28,40] King County Lung Injury Project (all subjects) [38] King County Lung Injury Project (ventilated R7 days) [41]
RCT
1996–1999
No. of subjects 432
Mortality (%) 31
RCT
1996–1999
429
40
RCT RCT
1999–2002 1996–2003
549 180
26 29
RCT
2000–2005
1001
27
Population-based
1999–2000
1113
39
Population-based
1999–2000
430
37
Abbreviations: ARDSnet, Acute Respiratory Distress Syndrome Clinical Trials Network; RCT, randomized controlled trials. a Mortality is presented by study arm for the tidal volume study. All other RCTs are presented with both study arms combined, since these interventions did not significantly affect mortality.
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This has important implications for clinical care. Clinicians should take care not to infer that persistent respiratory failure is associated with increased mortality. Instead, we must look toward survival as we focus on delivering the highest quality care to these patients, minimizing complications of intensive care, and recognizing and providing support for sequelae of ARDS during recovery.
Summary Decades after initial reports of pathology and treatment, there remains little known about late ARDS. Is late or ‘‘fibroproliferative’’ ARDS truly its own entity, with unique physiology, ideal treatment, and distinctive outcomes? If so, how is late ARDS defined, what is its incidence, and how are these patients best managed to improve both early and late outcomes? Population-based epidemiologic studies, longitudinal cohort studies of survivors, and additional interventional studies that include both short- and long-term outcomes are all needed to answer these questions. Based on current knowledge, there are no specific therapies that have been proven to improve mortality or other patient-centered outcomes of persistent ARDS. The best available evidence does not support corticosteroid treatment of persistent ARDS at this time; however, it remains possible that additional research may discover a protocol and patient population in which the physiological responses seen with corticosteroid therapy translate to true clinical improvement. In the meantime, optimal therapy for late ARDS involves providing the same highquality critical care that we strive to provide for all patients with acute lung injury, recognizing that prolonged respiratory failure does not connote an increased mortality, and supporting survivors and their families through protracted convalescence and recovery. References [1] Lamy M, Fallat RJ, Koeniger E, et al. Pathologic features and mechanisms of hypoxemia in adult respiratory distress syndrome. Am Rev Respir Dis 1976;114:267–84. [2] Tomashefski JF Jr. Pulmonary pathology of the adult respiratory distress syndrome. Clin Chest Med 1990;11:593–619. [3] Steinberg KP, Hudson LD, Goodman RB, et al. Efficacy and safety of corticosteroids for persistent
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[19] Keel JB, Hauser M, Stocker R, et al. Established acute respiratory distress syndrome: benefit of corticosteroid rescue therapy. Respiration (Herrlisheim) 1998;65:258–64. [20] 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;280:159–65. [21] Kuncl RW, George EB. Toxic neuropathies and myopathies. Curr Opin Neurol 1993;6:695–704. [22] van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically ill patients. N Engl J Med 2001;345:1359–67. [23] Van den Berghe G, Wouters PJ, Bouillon R, et al. Outcome benefit of intensive insulin therapy in the critically ill: insulin dose versus glycemic control. Crit Care Med 2003;31:359–66. [24] Van den Berghe G, Schoonheydt K, Becx P, et al. Insulin therapy protects the central and peripheral nervous system of intensive care patients. Neurology 2005;64:1348–53. [25] De Jonghe B, Sharshar T, Lefaucheur JP, et al. Paresis acquired in the intensive care unit: a prospective multicenter study. JAMA 2002;288:2859–67. [26] Leijten FS, Harinck-de Weerd JE, Poortvliet DC, et al. The role of polyneuropathy in motor convalescence after prolonged mechanical ventilation. JAMA 1995;274:1221–5. [27] Maher J, Rutledge F, Remtulla H, et al. Neuromuscular disorders associated with failure to wean from the ventilator. Intensive Care Med 1995;21: 737–43. [28] Wiedemann HP, Wheeler AP, Bernard GR, et al. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med 2006;354: 2564–75. [29] Hopkins RO, Weaver LK, Collingridge D, et al. Two-year cognitive, emotional, and quality-of-life outcomes in acute respiratory distress syndrome. Am J Respir Crit Care Med 2005;171:340–7. [30] Hopkins RO, Weaver LK, Pope D, et al. Neuropsychological sequelae and impaired health status in survivors of severe acute respiratory distress syndrome. Am J Respir Crit Care Med 1999;160:50–6.
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[31] Schelling G, Stoll C, Haller M, et al. Health-related quality of life and posttraumatic stress disorder in survivors of the acute respiratory distress syndrome. Crit Care Med 1998;26:651–9. [32] Weinert CR, Gross CR, Kangas JR, et al. Health-related quality of life after acute lung injury. Am J Respir Crit Care Med 1997;156:1120–8. [33] Davidson TA, Caldwell ES, Curtis JR, et al. Reduced quality of life in survivors of acute respiratory distress syndrome compared with critically ill control patients. JAMA 1999;281:354–60. [34] The Acute Respiratory Distress Syndrome. 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;342:1301–8. [35] Kahn JM, Andersson L, Karir V, et al. Low tidal volume ventilation does not increase sedation use in patients with acute lung injury. Crit Care Med 2005;33:766–71. [36] Cheng IW, Eisner MD, Thompson BT, et al. Acute effects of tidal volume strategy on hemodynamics, fluid balance, and sedation in acute lung injury. Crit Care Med 2005;33:63–70 [discussion 239–240]. [37] Luhr OR, Antonsen K, Karlsson M, et al. Incidence and mortality after acute respiratory failure and acute respiratory distress syndrome in Sweden, Denmark, and Iceland. The ARF Study Group. Am J Respir Crit Care Med 1999;159:1849–61. [38] Rubenfeld GD, Caldwell E, Peabody E, et al. Incidence and outcomes of acute lung injury. N Engl J Med 2005;353:1685–93. [39] Brower RG, Lanken PN, MacIntyre N, et al. Higher versus lower positive enddexpiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med 2004;351:327–36. [40] Wheeler AP, Bernard GR, Thompson BT, et al. Pulmonary-artery versus central venous catheter to guide treatment of acute lung injury. N Engl J Med 2006;354:2213–24. [41] Hough CL, Steinberg KP, Caldwell E, et al. Duration of mechanical ventilation is not associated with hospital mortality in patients with acute lung injury. Am J Respir Crit Care Med 2006;3:A831.