2012 Research Highlights

Acute respiratory distress syndrome: from TRALI to trials

Although acute respiratory distress syndrome (ARDS) can occur in various well described clinical settings such as sepsis or severe trauma,1 the entity of transfusionrelated acute lung injury (TRALI) is less well understood. 2012 began with publication of a large, well designed, two-centre prospective observational study to determine the incidence and risk factors for this important cause of ARDS.2 Through active surveillance of patients attending hospital, 89 patients with TRALI were identied and matched with 164 transfused controls. Transfusion of plasma or whole blood (not packed red-blood cells) from female donors and volume of HLA class II antibodies and anti-human neutrophil antigen antibodies transfused were independent risk factors for TRALI. Recipient factors also aected risk of this injury, including alcohol misuse, smoking status, shock, peak airway pressures, positive uid balance, liver surgery, and interleukin 8 levels. The nding that both donor and recipient factors contribute to the risk of TRALI supports the hypothesis that development of TRALI is a two-stage process in which an underlying predisposition in the recipient is potentiated by transfusion of blood products. Antibodies to HLA II or human neutrophils in transfused blood seem to be a major potentiator of underlying risk. The overall incidence of TRALI declined during the study,2 probably because of reduced transfusion of plasma from female donors. Incidence decreased by more than 50% from 257 cases per 10 000 transfused units in 2006 to 081 cases per 10 000 transfused units in 2009. This sharp reduction in TRALI incidence shows how a better understanding of the pathogenetic mechanisms of ARDS can lead to targeted interventions for eective prevention. Several large multicentre clinical trials in ARDS were published in 2012. The -agonist lung injury trial (BALTI-2)3 was a randomised placebo-controlled trial of an intravenous 2 adrenergic agonist, salbutamol (also known as albuterol), in patients with ARDS. This study was based on a large body of preclinical evidence suggesting that 2 adrenergic agonists can accelerate the rate of alveolar uid clearance and enhance the resolution of pulmonary oedema and encouraging data from a small phase 2 clinical trial of intravenous salbutamol that showed signicant reductions in extravascular lung water and plateau pressure in patients with ARDS.4 In BALTI-2, 162 patients with
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ARDS were randomly allocated salbutamol and 164 patients were randomly allocated placebo before recruitment was stopped because of safety concerns. Salbutamol signicantly increased 28-day mortality compared with placebo (55 [34%] patients died in the salbutamol group vs 38 [23%] in the placebo group; risk ratio 147, 95% CI 103208). These ndings are concordant with the US National Heart Lung and Blood Institutes ARDS Clinical Trials Network multicentre randomised trial of aerosolised salbutamol versus placebo in 282 patients with acute lung injury and ARDS5 that was published in 2011, which also showed no clinical benet for salbutamol compared with placebo (mortality 230% vs 177%; p=030). Also published in 2012, a randomised trial of early versus delayed enteral nutrition in 1000 patients with ARDS showed no clinical benet from either feeding strategy.6 Although both feeding strategies were well tolerated, the early full-feeding group had more episodes of vomiting, elevated gastric residual volumes, and constipation and higher plasma glucose values and average hourly insulin administration. Although 2012 was another disappointing year in ARDS clinical trials, new therapies on the horizon are a cause for optimism. In particular, cell-based therapy for ARDS might hold promise. Mesenchymal stem cells (MSCs) are broblast-like stem cells derived from the stroma that are increasingly understood to have

Published Online January 14, 2013 http://dx.doi.org/10.1016/ S2213-2600(13)70004-3

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Volker Steger/Science Photo Library

2012 Research Highlights

potent immunomodulatory and reparative properties.7 MSCs are already in clinical trials for cardiovascular and neurological diseases, diabetes, graft versus host disease, and a number of lung diseases. Early phase studies suggest that MSCs are hypoimmunogenic and have few toxic eects. MSCs might be ecacious in ARDS and sepsis through various mechanisms, including enhanced endothelial and epithelial function and repair and modulation of innate immunity.7 Moreover, several additional protective mechanisms of MSCs were reported in 2012. Bacterial clearance and survival were improved in a mouse model of Escherichia coli pneumonia by intratracheal administration of MSCs.8 Bacterial clearance and survival were also improved in a mouse model of gram-negative peritonitis by intravenous administration of MSCs, in part by enhancing the phagocytic activity of blood monocytes.9 In addition to enhanced bacterial clearance, new evidence also suggests that mitochondrial transfer from MSCs can rescue endotoxin-injured lung epithelium by restoring normal bioenergetics, with an improvement in epithelial barrier properties and the capacity to secrete surfactant.10 The growing list of potential benecial eects of MSCs in sepsis and ARDS suggests that such stem cells could provide multimodal therapy for these complex clinical syndromes. Phase 1 clinical trials of MSCs are currently in the planning stages for ARDS and sepsis to establish safety of this treatment in the setting of critical illness. Finally, new denitions for ARDS in 2012 should be noted. Since the acute respiratory distress syndrome (ARDS) was rst described in 1967, clinicians and researchers have wrestled with how to dene this complex clinical syndrome. In 1994, the AmericanEuropean consensus conference (AECC)11 established diagnostic criteria based on oxygenation and chest radiographic ndings that substantially improved standardisation in clinical trials. Because of perceived shortcomings in the AECC denitions, the Berlin study group met several times in 2011 to rene the AECC denitions culminating with the publication in 2012 of the Berlin denition of ARDS.12 Modications to the AECC criteria include denition of the acuity as onset within

1 week of presentation, and establishment of minimum requirements for invasive or non-invasive ventilator settings. The term acute lung injury, previously used for mild cases of disease, has been abandoned in favour of the term ARDS for all patients with an arterial-toinspired oxygen ratio less than or equal to 300 mm Hg, with severity now assessed by the degree of hypoxaemia and categorised as mild, moderate, or severe. Severity as dened by these categorisations was shown in several retrospective cohorts to correlate with clinical outcomes, a nding that might be useful in selection of patients for clinical trials. Lorraine B Ware
Departments of Medicine and Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232-2650, USA Lorraine.ware@vanderbilt.edu
I declare that I have no conicts of interest. 1 2 3 Matthay MA, Ware LB, Zimmerman GA. The acute respiratory distress syndrome. J Clin Invest 2012; 122: 273140. Toy P, Gajic O, Bacchetti P, et al. Transfusion-related acute lung injury: incidence and risk factors. Blood 2012; 119: 175767. Gao Smith F, Perkins GD, Gates S, et al. Eect of intravenous beta-2 agonist treatment on clinical outcomes in acute respiratory distress syndrome (BALTI-2): a multicentre, randomised controlled trial. Lancet 2012; 379: 22935. 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: 28187. Matthay MA, Brower RG, Carson S, et al. Randomized, placebo-controlled clinical trial of an aerosolized beta(2)-agonist for treatment of acute lung injury. Am J Respir Crit Care Med 2011; 184: 56168. Rice TW, Wheeler AP, Thompson BT, et al. Initial trophic vs full enteral feeding in patients with acute lung injury: the EDEN randomized trial. JAMA 2012; 307: 795803. Gotts JE, Matthay MA. Mesenchymal stem cells and acute lung injury. Crit Care Clin 2011; 27: 71933. Gupta N, Krasnodembskaya A, Kapetanaki M, et al. Mesenchymal stem cells enhance survival and bacterial clearance in murine Escherichia coli pneumonia. Thorax 2012; 67: 53339. Krasnodembskaya A, Samarani G, Song Y, et al. Human mesenchymal stem cells reduce mortality and bacteremia in gram-negative sepsis in mice in part by enhancing the phagocytic activity of blood monocytes. Am J Physiol Lung Cell Mol Physiol 2012; 302: L100313. Islam MN, Das SR, Emin MT, et al. Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat Med 2012; 18: 75965. Bernard GR, Artigas A, Brigham KL, et al. The American-European Consensus Conference on ARDS. Denitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994; 149: 81824. Ranieri VM, Rubenfeld GD, Thompson BT, et al. Acute respiratory distress syndrome: the Berlin Denition. JAMA 2012; 307: 252633.

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