4. Mutlu GM, Factor P. Alveolar epithelial beta2-adrenergic receptors.Am J Respir Cell Mol Biol 2008;38:127–134.

5. Paolillo S, Pellegrino R, Salvioni E, Contini M, Iorio A, Bovis F, AntonelliA, Torchio R, Gulotta C, Locatelli A, et al. Role of alveolar b2-adrenergic receptors on lung fluid clearance and exercise ventilationin healthy humans. PLoS ONE 2013;8:e61877.

6. Snyder EM, Beck KC, Turner ST, Hoffman EA, Joyner MJ, Johnson BD.Genetic variation of the beta2-adrenergic receptor is associatedwith differences in lung fluid accumulation in humans. J Appl Physiol(1985) 2007;102:2172–2178.

7. Johnson MW, Taylor BJ, Hulsebus ML, Johnson BD, Snyder EM.Hypoxia induced changes in lung fluid balance in humans isassociated with beta-2 adrenergic receptor density on lymphocytes.Respir Physiol Neurobiol 2012;183:159–165.

8. Matthay MA, Brower RG, Carson S, Douglas IS, Eisner M, Hite D, HoletsS, Kallet RH, Liu KD, MacIntyre N, et al. National Heart, Lung andBlood Institute Acute Respiratory Distress Syndrome Clinical TrialsNetwork. Randomized, placebo-controlled clinical trial of anaerosolized b2-agonist for treatment of acute lung injury. Am JRespir Crit Care Med 2011;184:561–568.

9. Gao Smith F, Perkins GD, Gates S, Young D, McAuley DF, Tunnicliffe W,Khan Z, Lamb SE; BALTI-2 study investigators. Effect of intravenousb-2 agonist treatment on clinical outcomes in acute respiratorydistress syndrome (BALTI-2): a multicentre, randomised controlledtrial. Lancet 2012;379:229–235.

10. Rosenberg AL, Dechert RE, Park PK, Bartlett RH, NIH NHLBI ARDSNetwork. Review of a large clinical series: association of cumulativefluid balance on outcome in acute lung injury: a retrospective reviewof the ARDSnet tidal volume study cohort. J Intensive Care Med2009;24:35–46.

11. Wiedemann HP, Wheeler AP, Bernard GR, Thompson BT, Hayden D,deBoisblanc B, Connors AF Jr, Hite RD, Harabin AL; National Heart,Lung, and Blood Institute Acute Respiratory Distress Syndrome(ARDS) Clinical Trials Network. Comparison of two fluid-managementstrategies in acute lung injury. N Engl J Med 2006;354:2564–2575.

12. Snyder EM, Wong EC, Foxx-Lupo WT, Wheatley CM, Cassuto NA,Patanwala AE. Effects of an inhaled b2-agonist on cardiovascularfunction and sympathetic activity in healthy subjects.Pharmacotherapy 2011;31:748–756.

Copyright © 2014 by the American Thoracic Society

Reply

From the Authors:

We thank Drs. Snyder and Johnson for their insightful interestin our recent trial article (1). We agree with them that thereare many potentially important nonbronchodilator effects ofb-agonists, including stimulation of alveolar fluid clearance, effectsupon inflammatory cells, and potentially promoting alveolarepithelial repair responses via MMP-9 (2–5). The wealth ofsupporting data from translational and animal/preclinical studiesdrove the hypothesis that b-agonists might work as a therapeuticor preventative agent in patients with or at risk of acute respiratorydisease (ARDS). Unfortunately, as has been so often the casewith developing new strategies for therapy in ARDS, translationof these findings into clinical benefits has been unsuccessful, withthe BALTI-2 study finding an increased risk of death in patientswith ARDS treated with intravenous b-agonists (6).

In their elegant discussion, Snyder and Johnson suggestthat deleterious effects of b-agonists upon the kidney may havecounteracted any beneficial effects of b-agonists upon alveolarfluid clearance in patients with ARDS. We agree that the effectsof b2-agonists upon renal sodium handling are important to

consider. We reported no difference in daily fluid balance in thephase 2 BALTI-1 paper (7) but have no additional unpublished datafrom BALTI-2 (6) or BALTI-prevention (1) to help shed light on thisaction. However, we note that when intravenous b2-adrenergicagonists were used for tocolysis during pregnancy, they have beenassociated with reduced sodium, potassium, and water excretion,leading to a reduced hematocrit and intravascular hypervolemia (8, 9)and development of maternal pulmonary edema (10).

Finally, we suggest that, although our BALTI-preventiontrial did not reduce the incidence of ARDS, we did demonstratesome findings worthy of future study. We found that inhaledsalmeterol resulted in a reduction in systemic inflammation,which resulted in reduced alveolar epithelial barrier dysfunctionperioperatively. The magnitude of the effects was not sufficientto prevent postoperative ARDS but did significantly reduce theincidence of reported postoperative pneumonia

We suggest, therefore, that salmeterol protected the alveolarepithelium in patients undergoing esophagectomy by reducinginflammatory and epithelial damage during injurious one-lungventilation. We agree with Snyder and Johnson that combinationtherapies, targeting different mechanisms implicated in thedevelopment of ARDS, are likely to be needed to successfullytreat and prevent ARDS. n

Author disclosures are available with the text of this letter atwww.atsjournals.org.

David R. Thickett, M.B., D.M.University of BirminghamBirmingham, United KingdomandUniversity Hospitals BirminghamBirmingham, United Kingdom

Daniel F. McAuley, M.B., M.D.Queen’s University of BelfastBelfast, United KingdomandRoyal Victoria HospitalBelfast, United Kingdom

Gavin D. Perkins, M.B., M.D.Heart of England NHS Foundation TrustBirmingham, United KingdomandUniversity of WarwickCoventry, United Kingdom

References

1. 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 controlledtrial. Am J Respir Crit Care Med 2014;189:674–683.

2. Perkins GD, McAuley DF, Richter A, Thickett DR, Gao F. Bench-to-bedside review: beta2-agonists and the acute respiratory distresssyndrome. Crit Care 2004;8:25–32.

3. Perkins GD, Nathani N, McAuley DF, Gao F, Thickett DR. In vitro andin vivo effects of salbutamol on neutrophil function in acute lung injury.Thorax 2007;62:36–42.

4. Perkins GD, Gao F, Thickett DR. In vivo and in vitro effects of salbutamolon alveolar epithelial repair in acute lung injury. Thorax 2008;63:215–220.

5. O’Kane CM, McKeown SW, Perkins GD, Bassford CR, Gao F, Thickett DR,McAuley DF. Salbutamol up-regulates matrix metalloproteinase-9in the alveolar space in the acute respiratory distress syndrome.Crit Care Med 2009;37:2242–2249.

CORRESPONDENCE

Correspondence 1447

6. Gates S, Perkins GD, Lamb SE, Kelly C, Thickett DR, Young JD,McAuley DF, Snaith C, McCabe C, Hulme CT, et al. Beta-AgonistLung injury TrIal-2 (BALTI-2): a multicentre, randomised, double-blind,placebo-controlled trial and economic evaluation of intravenousinfusion of salbutamol versus placebo in patients with acute respiratorydistress syndrome. Health Technol Assess 2013;17:v–vi, 1–87.

7. Perkins GD, McAuley DF, Thickett DR, Gao F. The beta-agonist lunginjury trial (BALTI): a randomized placebo-controlled clinical trial.Am J Respir Crit Care Med 2006;173:281–287.

8. Grospietsch G, Fenske M, Girndt J, Uhlich E, Kuhn W. The renin-angiotensin-aldosterone system, antidiuretic hormone levels andwater balance under tocolytic therapy with fenoterol and verapamil.Int J Gynaecol Obstet 1980;17:590–595.

9. Grospietsch G, Ulbrich R, Saul U, Fenske M, Ensink FB, Kuhn W. Urinaryexcretion, osmolarity and electrolytes after bolus-injection of fenoterolin female rabbits. Gynecol Obstet Invest 1984;17:317–325.

10. Bader AM, Boudier E, Martinez C, Langer B, Sacrez J, Cherif Y, MessierM, Schlaeder G. Etiology and prevention of pulmonary complicationsfollowing beta-mimetic mediated tocolysis. Eur J Obstet GynecolReprod Biol 1998;80:133–137.

Copyright © 2014 by the American Thoracic Society

Reply: b2-Agonists and Acute RespiratoryDistress Syndrome

From the Editorialists*:

In their letter, Snyder and Johnson propose a mechanism to explainwhy the clinical trials evaluating b2-agonists as a treatment orpreventive therapy for acute respiratory distress syndrome (ARDS)have failed. They suggest that extrapulmonary effects of b2-agonistson renal Na1 handling and the cardiovascular system mighthave caused an increase in total body water content, offsettingtheir beneficial effects on alveolar fluid clearance. Activation ofb2-adrenergic receptors (b2ARs) may lead to increased total bodywater content by decreasing renal Na1 excretion (1). In addition,engagement of b2ARs on the vasculature may cause a dropin systemic vascular resistance, necessitating the increasedadministration of fluids and an increase in total body water content.

Several factors argue against this hypothesis. Although thesystemic administration of b2-agonists in the BALTI 2 trial (2) mayhave affected renal Na1 handling and cardiovascular responses, theinhalation administration of b2-agonist is unlikely to have doneso (3–5). Indeed, Perkins and colleagues found that b2-agonist therapydecreased extracellular lung water content in a subgroup of patientsreceiving inhaled b2-agonists in the BALTI prevention trial (4).Snyder and Johnson point out that patients receiving b2-agonisttherapy received more cumulative fluids compared with those who didnot in the ALTA trial (2,988 6 6,614 ml in the albuterol group vs.1,905 6 6,388 ml in the control group; not significant) (5). Althoughthis may be due to the effect of b2-agonists on renal Na1 excretionand caon the rdiovascular system, this disparity more likely reflects theinclusion of more patients with shock in the ALTA trial comparedwith the previous study (approximately one half vs. one third) (5, 6).

In summary, we agree with Johnson and Snyder that manymechanisms likely play a role in the unexpected outcomes with the

use of b2-agonists for the treatment or prevention of ARDS (7).However, we think the bulk of the evidence from these trials andothers suggests that b2-agonist therapy reduces lung water content.Despite this improvement, these agents failed to improve or preventARDS. Perhaps this is because only a fraction of patients with ARDSdie directly as a result of hypoxemia. The majority of deaths occur dueto development of multiple organ dysfunction, and only patientswith severe ARDS benefit from therapies improving oxygenation (8, 9).Alternatively, the activation of b2ARs in other cells in the lungmay negate the beneficial effects of their activation in the alveolarepithelium. For example, we have recently shown that b2-agonisttherapy worsens lung inflammation in a murine model of lung injuryvia engagement of b2ARs on macrophages (10). We agree with theauthors that additional studies will be needed to distinguish thebeneficial effects of b2ARs from their unwanted and harmful effects.n

Author disclosures are available with the text of this letter atwww.atsjournals.org.

G. R. Scott Budinger, M.D.Gokhan M. Mutlu, M.D.Northwestern University Feinberg School of MedicineChicago, Illinois

References

1. DiBona GF, Kopp UC. Neural control of renal function. Physiol Rev 1997;77:75–197.

2. Gao Smith F, Perkins GD, Gates S, Young D, McAuley DF, Tunnicliffe W,Khan Z, Lamb SE; BALTI-2 study investigators. Effect of intravenousb-2 agonist treatment on clinical outcomes in acute respiratorydistress syndrome (BALTI-2): a multicentre, randomised controlledtrial. Lancet 2012;379:229–235.

3. Perkins GD, McAuley DF, Thickett DR, Gao F. The beta-agonist lunginjury trial (BALTI): a randomized placebo-controlled clinical trial. Am JRespir Crit Care Med 2006;173:281–287.

4. 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 (BALTI) prevention: a randomizedcontrolled trial. Am J Respir Crit Care Med 2014;189:674–683.

5. Matthay MA, Brower RG, Carson S, Douglas IS, Eisner M, Hite D, HoletsS, Kallet RH, Liu KD, MacIntyre N, et al. National Heart, Lung andBlood Institute Acute Respiratory Distress Syndrome Clinical TrialsNetwork. Randomized, placebo-controlled clinical trial of anaerosolized beta(2)-agonist for treatment of acute lung injury.Am J Respir Crit Care Med 2011;184:561–568.

6. Wiedemann HP, Wheeler AP, Bernard GR, Thompson BT, Hayden D,deBoisblanc B, Connors AF Jr, Hite RD, Harabin AL; National Heart,Lung, and Blood Institute Acute Respiratory Distress Syndrome(ARDS) Clinical Trials Network. Comparison of two fluid-managementstrategies in acute lung injury. N Engl J Med 2006;354:2564–2575.

7. Budinger GR, Mutlu GM. b2-Agonists and acute respiratory distresssyndrome [editorial]. Am J Respir Crit Care Med 2014;189:624–625.

8. Guerin C, Reignier J, Richard JC, Beuret P, Gacouin A, Boulain T,Mercier E, Badet M, Mercat A, Baudin O, et al.; PROSEVA StudyGroup. Prone positioning in severe acute respiratory distresssyndrome. N Engl J Med 2013;368:2159–2168.

9. Briel M, Meade M, Mercat A, Brower RG, Talmor D, Walter SD, SlutskyAS, Pullenayegum E, Zhou Q, Cook D, et al. Higher vs lowerpositive end-expiratory pressure in patients with acute lung injury andacute respiratory distress syndrome: systematic review and meta-analysis. JAMA 2010;303:865–873.

10. Chiarella SE, Soberanes S, Urich D, Morales-Nebreda L, Nigdelioglu R,Green D, Young JB, Gonzalez A, Rosario C, Misharin AV, et al.b2-adrenergic agonists augment the air pollution-induced IL-6release and thrombosis. J Clin Invest (In press)

Copyright © 2014 by the American Thoracic Society

*Drs. Budinger and Mutlu wrote an editorial (7) on the article by Perkins et al.

This work was supported by National Institutes of Health grants ES015024,ES013995, and HL071643.

CORRESPONDENCE

1448 American Journal of Respiratory and Critical Care Medicine Volume 189 Number 11 | June 1 2014