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1 Departments of Medicine and Anesthesia, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California
Correspondence and requests for reprints should be addressed to Michael A. Matthay, M.D., Moffitt Hospital, M-917, 505 Parnassus Avenue, San Francisco, CA 94143-0624. E-mail: michael.matthay{at}ucsf.edu
ABSTRACT
This presentation at the 2007 Aspen Lung Injury and Repair Conference provided a brief historical perspective from the 1998 Aspen Conference on Acute Lung Injury, highlighting the discussion of clinical definitions. There was also a review of the National Heart, Lung, and Blood Institute ARDS Network clinical trials, with an emphasis on the success of the lung-protective ventilation strategy in reducing mortality. In addition, there was a discussion of the recently completed fluid and catheter treatment trial, which demonstrated no benefit for pulmonary arterial catheterization over central venous catheterization for monitoring patients with acute lung injury (ALI). The trial demonstrated an increase in ventilator-free days with a fluid-conservative protocol. Finally, there was a discussion of recent experimental studies that show promise for cell-based therapy with mesenchymal stem cells for the treatment of endotoxin-induced ALI in mice. There were three objectives for this presentation at the 2007 Lung Injury, Repair, and Remodeling Conference: (1) to provide a brief historical perspective from the 1998 Aspen Conference on Acute Lung Injury; (2) to review major National Heart, Lung, and Blood Institute clinical trials conducted in the past 10 years by the ARDS Network; and (3) to review some of our promising work with cell-based therapy for experimental ALI.
Key Words: acute lung injury • pulmonary edema • mesenchymal stem cells
ASPEN ACUTE LUNG INJURY CONFERENCE, 1998
At the Aspen Acute Lung Injury Conference in 1998, there was considerable discussion of the clinical definitions and the epidemiology of acute lung injury (ALI). It was recognized that the North American–European Consensus Conference definition of acute lung injury (ALI; bilateral pulmonary infiltrates with a PaO2/FIO2 < 300) was of significant clinical value (1), although it was also recognized that this definition did not include a measure of lung compliance and did not specify the level of positive end-expiratory pressure (PEEP) that was being used when oxygenation was measured (2). In spite of these limitations, the clinical definition has been practical for enrolling patients in clinical trials. The additional requirement that patients have a pulmonary artery wedge pressure less than 18 mm Hg or that clinicians determine clinically that left-atrial hypertension is not likely to be present was accepted as an important part of the definition at that time. Also, the results of several clinical trials were reviewed, including extracorporeal membrane oxygenation, inhaled nitric oxide, glucocorticoids, and surfactant replacement. None of these treatments had improved clinical outcomes, leading some investigators to speculate whether any therapeutic approach would lower mortality. The National Heart, Lung, and Blood Institute (NHLBI) ARDS Network had just begun its phase III clinical trials, with a primary focus on testing supportive care treatments.
Incidence and Mortality in 2007
Recent data published in 2005 by Rubenfeld and colleagues have established the incidence of ALI in the United States (3). These investigators performed a prospective, population-based assessment of the incidence of ALI in Seattle, King County, Washington. The results demonstrated that the estimated incidence of ALI was 190,000 patients per year. With the aging population and increasing prevalence of a variety of medical illnesses, it is estimated that the incidence will rise to 300,000 patients per year over the next 10 years. The current mortality attributable to ALI is 74,500 patients per year.
NHLBI Clinical Trials, 1996–2007
Since the Aspen Lung Conference 9 years ago, a number of phase III, placebo-controlled clinical trials have been completed by the NHLBI ARDS Network. These trials have had a significant impact on understanding the pathogenesis of ALI, as well as providing concrete evidence-based guidelines for better treatment of patients with ALI.
The 6 versus 12 ml/kg predicted body weight tidal volume trial, with a plateau pressure limit of 30 cm H2O in the 6-ml/kg arm, resulted in the first convincing evidence that mortality could be reduced in patients with ALI with a therapeutic intervention. Patients treated with the low–tidal volume strategy had reduced mortality (40% in the control group vs. 31% in the treatment group) (4). There was also a significant increase in ventilator-free days as well as nonpulmonary organ failure–free days. The results demonstrate that a lung-directed therapy could reduce both mortality and nonpulmonary organ failure in patients with ALI. Several follow-up pathogenesis studies have demonstrated that the low–tidal volume strategy reduces the levels of inflammatory mediators in the plasma (IL-6 and IL-8, as well as soluble tumor necrosis factor receptors 1 and 2) and reduces plasma levels of surfactant protein D, a product of alveolar epithelial type II cells (5–7). This lung-protective approach has proved to be the best antiinflammatory and barrier protection strategy yet developed for patients with ALI. The results have stimulated both basic and clinical research studies to better understand the mechanisms by which mechanical forces may alter the function of the lung.
In a follow-up trial, the ARDS Network tested the potential value of increasing the level of PEEP to further improve clinical outcomes in patients treated with the low–tidal volume strategy (8). The data demonstrate that a higher level of PEEP did not improve mortality, and there was no improvement in ventilator-free days. The results of this trial have been confirmed with the completion of two other unpublished clinical trials, one from Canada and one from France, demonstrating no major benefits from higher levels of PEEP in the presence of a low–tidal volume strategy. Interestingly, mortality in both the moderate and higher PEEP groups declined to 26% in this ARDS Network trial (8), confirming that the lung-protective ventilation strategy had reduced mortality overall, in part because it was probably being used in patients in this study even before they were enrolled in this clinical trial.
The ARDS Network also completed a major trial to test the potential value of methylprednisolone for the treatment of persistent or late acute respiratory distress syndrome (9). The results of this trial in 180 patients showed no difference in 60-day mortality. Furthermore, mortality was higher in patients who were treated with high-dose methylprednisolone after Day 14. There was a small increase in ventilator-free days with methylprednisolone treatment, but this result was not matched by a significant improvement in intensive care unit or hospital stay. Further, there was an increase in neuromuscular complications in patients treated with methylprednisolone.
The ARDS Network has recently completed a major clinical trial of 1,000 patients to evaluate the optimal fluid strategy in patients with ALI, as well as to assess what type of vascular pressure monitoring should be used to optimize monitoring and administration of fluids. The use of a pulmonary artery catheter versus a central venous catheter offered no advantages for clinical outcomes, with no difference in mortality or ventilator-free days (10). However, the conservative fluid strategy proved to be beneficial in significantly increasing ventilator-free days as well as a nonsignificant trend for reduction in mortality (11). One of the interesting results of this trial was the demonstration that the pulmonary arterial wedge pressure was greater than 18 mm Hg in 29% of the patients enrolled in the pulmonary artery catheter arm of the trial. However, only 2.5% of these patients had a low cardiac output, suggesting that the majority of patients with an elevated wedge pressure did not have heart failure. In a preliminary analysis, investigators at the University of Washington in Seattle have determined that clinical outcomes were similar whether patients had an elevated or a normal pulmonary arterial wedge pressure (12). The results of these observations confirm the longstanding belief that ALI is often complicated by elevation in intravascular volume, which may be associated with resuscitation from trauma or shock (13). On balance, the use of a fluid conservative strategy in patients who had not been in shock for the preceding 12 hours resulted in tangible clinical benefits. Table 1 summarizes the most important clinical trials completed by the ARDS Network with the support of the NHLBI.
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In August 2007, the NHLBI ARDS Network began a randomized, placebo-controlled clinical trial to evaluate the potential value of an aerosolized β2-adrenergic agonist, albuterol, for the treatment of early ALI. There are several preclinical studies that support the potential value of a β2-adrenergic agonist in terms of both up-regulating the resolution of alveolar edema, as well as potentially reducing lung inflammation. A phase II clinical trial from the United Kingdom published last year indicated that intravenous albuterol (salbutamol) could decrease extravascular lung water in patients with ALI (14).
Overall, the combination of both experimental and clinical studies has advanced the field of ALI, although more work is needed to identify the molecular and cellular pathways involved in lung injury and repair (15). One recent review summarizes a number of other trials that have been done in ALI (16).
Cell-based Therapy for ALI
Cell-based therapy is a promising, novel treatment for ALI. In experimental studies, our research group recently published a study on treatment of endotoxin-induced lung injury in mice. The data indicate that the use of mesenchymal stem cells (MSCs) administered by the intrapulmonary (intratracheal) route 4 hours after the establishment of endotoxin-induced lung injury resulted in a marked decrease in mortality, primarily due to a decrease in ALI (Figure 1) (17). There are other recent mouse studies that suggest that MSCs may have value for the treatment of systemic infection and pulmonary fibrosis (18, 19). Using a novel perfused human lung preparation (20), there is also new unpublished work from our research group indicating that allogeneic human MSCs may be of value in reducing endotoxin-induced ALI in the human lung. The data in all of these studies suggest that the MSCs work in part by paracrine mechanisms. For example, in the mouse studies, the MSC-treated mice have a significant decrease in some proinflammatory cytokines and a corresponding increase in antiinflammatory cytokines. There is also some evidence that production of growth factors by MSCs may benefit injury lung. More preclinical work is needed to test the mechanisms of benefit and the potential therapeutic value of MSCs for ALI.
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Considerable progress has been made in the last decade in establishing the value of new therapies that reduce mortality in ALI. The use of a lung protective ventilation strategy with a tidal volume and plateau pressure limit has reduced mortality substantially. Use of lung recruitment maneuvers with higher levels of PEEP has not been shown to be of additional value. Glucocorticoids have not been beneficial for later-stage or persistent acute respiratory distress syndrome. The Fluid and Catheter Treatment Trial provided clear evidence that use of the pulmonary artery catheter did not improve clinical outcomes in ALI compared with the central venous catheter. However, a fluid conservative strategy was associated with significantly more ventilator-free days, probably because of a more rapid improvement in physiologic indices of lung function compared with patients treated with a fluid liberal strategy. The current NHLBI trials are testing the value of aerosolized β2-agonist therapy as well as specific nutritional strategies in patients with ALI. Finally, based on preclinical studies, cell-based therapy with MSCs is emerging as a promising approach to treating a variety of organ injuries, including ALI, acute renal failure, and acute hepatic failure. The mechanisms appear to depend primarily on paracrine effects.
ACKNOWLEDGMENTS
The author thanks Andrew Manies for his assistance in preparation of the manuscript.
FOOTNOTES
Supported in part by National Heart, Lung, and Blood Institute grants R01 HL51854 and HL51856 (M.A.M).
Conflict of Interest Statement: M.A.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
(Received in original form August 29, 2007; accepted in final form November 16, 2007)
REFERENCES
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