EDITORIALS 12. Brummel NE, Ely EW. Sedation level and the prevalence of delirium. Intensive Care Med 2014;40:135. 13. Patel SB, Poston JT, Pohlman A, Hall JB, Kress JP. Rapidly reversible, sedation-related delirium versus persistent delirium in the ICU. Am J Respir Crit Care Med 2014;189:658–665. 14. Barr J, Egan TD, Sandoval NF, Zomorodi K, Cohane C, Gambus PL, Shafer SL. Propofol dosing regimens for ICU sedation based upon

an integrated pharmacokinetic-pharmacodynamic model. Anesthesiology 2001;95:324–333. 15. Page VJ, Davis D, Zhao XB, Norton S, Casarin A, Brown T, Ely EW, McAuley DF. Statin use and risk of delirium in the critically ill. Am J Respir Crit Care Med 2014;189:666–673.

Copyright © 2014 by the American Thoracic Society

b2-Agonists and Acute Respiratory Distress Syndrome Recent advances in the supportive care of patients with acute respiratory distress syndrome (ARDS) have resulted in significant reductions in mortality (1–4). However, pharmacologic therapies specific for ARDS have remained elusive, and mortality remains unacceptably high (4, 5). The resolution of ARDS requires the removal of excess lung edema fluid and acute inflammatory cells accompanied by repair of the injured alveolar epithelium (5, 6). The absorption of excess alveolar fluid is an active, ATP-dependent process that involves the vectorial transport of sodium ions out of alveolar air spaces via the apical sodium and chloride channels and basolateral Na-K-ATPases in the alveolar epithelium (6–8). Confirming a wealth of preclinical data suggesting an important role for the removal of edema fluid, Ware and Matthay found that alveolar fluid clearance is impaired in the majority of patients with ARDS and that preservation of normal clearance is associated with better outcomes (9). In animal models and human cells, the stimulation of b2-adrenergic receptors (b2ARs) increases the vectorial transport of sodium across the alveolar epithelium to improve edema clearance (6–8, 10–13). The efficacy of b2-agonist therapy in lung edema clearance in humans was confirmed in a clinical trial where the administration of the long-acting b2-agonist salmeterol reduced the incidence of high-altitude pulmonary edema in a high-risk group of travelers (14). These promising findings were the basis for clinical trials of b2-agonists for the treatment of ARDS. Encouraging results from a small phase II trial, the b-Agonist Lung Injury (BALTI)-1 trial (15), prompted two large-scale randomized control trials (16, 17). Unfortunately, both trials were terminated due to futility and safety concerns. In the Albuterol to Treat Acute Lung Injury (ALTA) study, patients with ARDS were randomized to receive either nebulized albuterol or placebo every 4 hours (16). There was no significant difference in the primary outcome of ventilator-free days or in the secondary outcomes of death before hospital discharge or toxicity. The concern that albuterol administered via inhalation may not have been delivered to the regions of the lung with the most severe edema was addressed in the second large, randomized control study, BALTI-2, in which patients with ARDS were randomized to receive a continuous intravenous infusion of salbutamol at the maximal dose that did not result in an increase in arrhythmias in critically ill patients (17). This study was terminated after an interim analysis showed an increase in 28-day mortality in the patients treated with salbutamol compared with placebo (34% vs. 23%).

Supported by National Institute of Health grants ES015024, ES013995, and HL071643.

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The combined results of the ALTA and BALTI-2 trials do not support the use of b2-agonists for the treatment of ARDS and suggest that intravenous administration of b2-agonists may be harmful. However, it remains possible that b2-agonists might be useful to prevent the development of ARDS in high-risk patients. In this issue of the Journal, Perkins and colleagues (pp. 674–683) tested this hypothesis in patients undergoing elective esophagectomy, a procedure that carries a high risk for the development of postoperative ARDS (18). They examined the rates of postoperative ARDS in patients randomized to receive either inhaled salmeterol or placebo in the first 72 hours after surgery. Unfortunately, the results were negative; the rates of ARDS as well as the secondary outcomes, which included organ failure, survival, or health-related quality of life, were similar irrespective of b2-agonist therapy. Although study-specific concerns might have masked a small effect—the intraoperative tidal volume in the patients receiving b2-agonists was higher and the drug was given only 2 hours prior to the operation—the overall findings of the study do not support a role for b2-agonist therapy to prevent ARDS. These results leave us asking why b2-agonist therapy has been ineffective in improving or preventing ARDS. Measures of extravascular lung water were reduced in patients receiving b2-agonists in the BALTI-1 trial and in a subgroup of patients included in the most recent BALTI prevention trial, making it less likely that the drugs failed to improve vectorial sodium transport. One potential explanation is that pulmonary edema, although an important consequence of ARDS, is not a major driver of mortality. Only a minority of patients with ARDS die as a result of acute hypoxemia (the majority of deaths are attributable to the development of multiple organ dysfunction later in the course of the critical illness), and only patients with severe lung injury and hypoxemia have benefited from therapies for ARDS that improve oxygenation (2, 19). Another explanation is that although the systemic cardiovascular effects of b2-agonists are small, they might offset their potential benefits on lung edema clearance. This would explain why increased mortality was observed in the BALTI-2 but not the ALTA trial. Finally, b2-agonists may have detrimental off-target effects on other cells present in the injured lung. Indeed, b2-adrenergic receptors are expressed not only on the alveolar epithelial cells but also on other cells within the lung, including resident and recruited inflammatory cells (20). Although several short-term studies suggest that stimulation of b2ARs down-regulates inflammation, there are hints from the sepsis literature that the opposite may be the case. The b-blockers may be useful in the treatment of sepsis due to their beneficial effects on metabolism, glucose homeostasis, cytokine expression, and

American Journal of Respiratory and Critical Care Medicine Volume 189 Number 6 | March 15 2014

EDITORIALS cardiac function, and in contrast, the use of drugs that stimulate bARs may be associated with detrimental effects and worsened outcomes (21–24). Interestingly, much of the preclinical data supporting the use of b2-agonists was performed in sterile models of ARDS (hyperoxia, ischemia reperfusion, or LPS), and b2agonists were effective in patients at risk for high-altitude pulmonary edema, which results in edema with minimal inflammation. What can we learn from the failure of b2-agonists in these trials? First, the available data suggest that even in the injured lung, agents that drive vectorial sodium transport can reduce extravascular lung water, potentially improving edema clearance. Moving forward, we need to look for mechanisms to selectively stimulate these pathways without the potential offtarget effects of b2-agonists. Second, we need to understand more about the potential harmful effects of b2-agonists in patients with ARDS. Are these effects limited to those on the cardiovascular system, or do b2ARs on cells present in the injured lung play a role in the pathophysiology of ARDS, and might these pathways be targeted for therapy? Third, we need to improve our preclinical models of ARDS. Studies in sterile lung injury models need to be complemented by more clinically relevant models (e.g., viral or bacterial pneumonia). Finally, we need to develop biomarkers that identify specific populations of patients with ARDS who might benefit from selected therapies and understand why our surrogate markers for outcomes in phase II trials failed to predict the outcome of these large clinical trials. Improved selection of patients for targeted therapies and better markers to predict the response to novel therapies in phase II trials will speed the flow of new agents for ARDS from the bench to bedside. n Author disclosures are available with the text of this article at www.atsjournals.org. G. R. Scott Budinger, M.D. Gokhan ¨ M. Mutlu, M.D. Pulmonary and Critical Care Medicine Northwestern University Feinberg School of Medicine Chicago, Illinois

References 1. 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;342:1301–1308. 2. Guerin ´ C, Reignier J, Richard JC, Beuret P, Gacouin A, Boulain T, Mercier E, Badet M, Mercat A, Baudin O, et al.; PROSEVA Study Group. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med 2013;368:2159–2168. 3. Papazian L, Forel JM, Gacouin A, Penot-Ragon C, Perrin G, Loundou A, Jaber S, Arnal JM, Perez D, Seghboyan JM, et al.; ACURASYS Study Investigators. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med 2010;363:1107–1116. 4. Li G, Malinchoc M, Cartin-Ceba R, Venkata CV, Kor DJ, Peters SG, Hubmayr RD, Gajic O. Eight-year trend of acute respiratory distress syndrome: a population-based study in Olmsted County, Minnesota. Am J Respir Crit Care Med 2011;183:59–66. 5. Matthay MA, Ware LB, Zimmerman GA. The acute respiratory distress syndrome. J Clin Invest 2012;122:2731–2740. 6. Mutlu GM, Sznajder JI. Mechanisms of pulmonary edema clearance. Am J Physiol Lung Cell Mol Physiol 2005;289:L685–L695.

Editorials

7. Bertorello AM, Komarova Y, Smith K, Leibiger IB, Efendiev R, Pedemonte CH, Borisy G, Sznajder JI. Analysis of Na1,K1-ATPase motion and incorporation into the plasma membrane in response to G proteincoupled receptor signals in living cells. Mol Biol Cell 2003;14: 1149–1157. 8. Mutlu GM, Adir Y, Jameel M, Akhmedov AT, Welch L, Dumasius V, Meng FJ, Zabner J, Koenig C, Lewis ER, et al. Interdependency of beta-adrenergic receptors and CFTR in regulation of alveolar active Na1 transport. Circ Res 2005;96:999–1005. 9. Ware LB, Matthay MA. Alveolar fluid clearance is impaired in the majority of patients with acute lung injury and the acute respiratory distress syndrome. Am J Respir Crit Care Med 2001;163:1376–1383. 10. Mutlu GM, Dumasius V, Burhop J, McShane PJ, Meng FJ, Welch L, Dumasius A, Mohebahmadi N, Thakuria G, Hardiman K, et al. Upregulation of alveolar epithelial active Na1 transport is dependent on beta2-adrenergic receptor signaling. Circ Res 2004;94: 1091–1100. 11. Mutlu GM, Koch WJ, Factor P. Alveolar epithelial beta 2-adrenergic receptors: their role in regulation of alveolar active sodium transport. Am J Respir Crit Care Med 2004;170:1270–1275. 12. Mutlu GM, Factor P. Alveolar epithelial beta2-adrenergic receptors. Am J Respir Cell Mol Biol 2008;38:127–134. 13. Sznajder JI. Alveolar edema must be cleared for the acute respiratory distress syndrome patient to survive. Am J Respir Crit Care Med 2001;163:1293–1294. 14. Sartori C, Allemann Y, Duplain H, Lepori M, Egli M, Lipp E, Hutter D, Turini P, Hugli O, Cook S, et al. Salmeterol for the prevention of high-altitude pulmonary edema. N Engl J Med 2002;346:1631–1636. 15. Perkins GD, McAuley DF, Thickett DR, Gao F. The beta-agonist lung injury trial (BALTI): a randomized placebo-controlled clinical trial. Am J Respir Crit Care Med 2006;173:281–287. 16. Matthay MA, Brower RG, Carson S, Douglas IS, Eisner M, Hite D, Holets S, Kallet RH, Liu KD, MacIntyre N, et al.; National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Randomized, placebo-controlled clinical trial of an aerosolized b₂-agonist for treatment of acute lung injury. Am J Respir Crit Care Med 2011;184:561–568. 17. Gao Smith F, Perkins GD, Gates S, Young D, McAuley DF, Tunnicliffe W, Khan Z, Lamb SE; BALTI-2 study investigators. Effect of intravenous b-2 agonist treatment on clinical outcomes in acute respiratory distress syndrome (BALTI-2): a multicentre, randomised controlled trial. Lancet 2012;379:229–235. 18. Perkins GD, Gates S, Park D, Gao F, Knox C, Holloway B, McAuley DF, Ryan J, Marzouk J, Cooke MW, et al.; BALTI-Prevention Collaborators. The Beta Agonist Lung Injury Trial Prevention: a randomized controlled trial. Am J Respir Crit Care Med 2014;189:674–683. 19. Briel M, Meade M, Mercat A, Brower RG, Talmor D, Walter SD, Slutsky AS, Pullenayegum E, Zhou Q, Cook D, et al. Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis. JAMA 2010;303:865–873. 20. Tan KS, Nackley AG, Satterfield K, Maixner W, Diatchenko L, Flood PM. Beta2 adrenergic receptor activation stimulates pro-inflammatory cytokine production in macrophages via PKA- and NF-kappaBindependent mechanisms. Cell Signal 2007;19:251–260. 21. Novotny NM, Lahm T, Markel TA, Crisostomo PR, Wang M, Wang Y, Ray R, Tan J, Al-Azzawi D, Meldrum DR. beta-Blockers in sepsis: reexamining the evidence. Shock 2009;31:113–119. 22. Morelli A, Donati A, Ertmer C, Rehberg S, Kampmeier T, Orecchioni A, D’Egidio A, Cecchini V, Landoni G, Pietropaoli P, et al. Microvascular effects of heart rate control with esmolol in patients with septic shock: a pilot study. Crit Care Med 2013;41:2162–2168. 23. Hayes MA, Timmins AC, Yau EH, Palazzo M, Hinds CJ, Watson D. Elevation of systemic oxygen delivery in the treatment of critically ill patients. N Engl J Med 1994;330:1717–1722. 24. Russell JA, Walley KR, Singer J, Gordon AC, Hebert ´ PC, Cooper DJ, Holmes CL, Mehta S, Granton JT, Storms MM, et al.; VASST Investigators. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008;358: 877–887.

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β2-agonists and acute respiratory distress syndrome.

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