Top

Published in:

01-05-2016 | Conference Reports and Expert Panel

Personalized medicine for ARDS: the 2035 research agenda

Authors: Jeremy R. Beitler, Ewan C. Goligher, Matthieu Schmidt, Peter M. Spieth, Alberto Zanella, Ignacio Martin-Loeches, Carolyn S. Calfee, Alexandre B. Cavalcanti, The ARDSne(x)t Investigators

Published in: Intensive Care Medicine | Issue 5/2016

Abstract

In the last 20 years, survival among patients with acute respiratory distress syndrome (ARDS) has increased substantially with advances in lung-protective ventilation and resuscitation. Building on this success, personalizing mechanical ventilation to patient-specific physiology for enhanced lung protection will be a top research priority for the years ahead. However, the ARDS research agenda must be broader in scope. Further understanding of the heterogeneous biology, from molecular to mechanical, underlying early ARDS pathogenesis is essential to inform therapeutic discovery and tailor treatment and prevention strategies to the individual patient. The ARDSne(x)t research agenda for the next 20 years calls for bringing personalized medicine to ARDS, asking simultaneously both whether a treatment affords clinically meaningful benefit and for whom. This expanded scope necessitates standard acquisition of highly granular biological, physiological, and clinical data across studies to identify biologically distinct subgroups that may respond differently to a given intervention. Clinical trials will need to consider enrichment strategies and incorporate long-term functional outcomes. Tremendous investment in research infrastructure and global collaboration will be vital to fulfilling this agenda.

Acute Respiratory Distress Syndrome Network (2000) 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 342:1301–1308. doi:10.1056/NEJM200005043421801 CrossRef

Definition Task Force ARDS, Ranieri VM, Rubenfeld GD et al (2012) Acute respiratory distress syndrome: the Berlin definition. JAMA 307:2526–2533. doi:10.1001/jama.2012.5669

Thille AW, Esteban A, Fernández-Segoviano P et al (2013) Comparison of the Berlin definition for acute respiratory distress syndrome with autopsy. Am J Respir Crit Care Med 187:761–767. doi:10.1164/rccm.201211-1981OC CrossRefPubMed

Villar J, Pérez-Méndez L, López J et al (2007) An early PEEP/FIO2 trial identifies different degrees of lung injury in patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 176:795–804. doi:10.1164/rccm.200610-1534OC CrossRefPubMed

Villar J, Pérez-Méndez L, Blanco J et al (2013) A universal definition of ARDS: the PaO₂/FiO₂ ratio under a standard ventilatory setting—a prospective, multicenter validation study. Intensive Care Med 39:583–592. doi:10.1007/s00134-012-2803-x CrossRefPubMed

Rubenfeld GD, Caldwell E, Granton J et al (1999) Interobserver variability in applying a radiographic definition for ARDS. Chest 116:1347–1353CrossRefPubMed

Baldi G, Gargani L, Abramo A et al (2013) Lung water assessment by lung ultrasonography in intensive care: a pilot study. Intensive Care Med 39:74–84. doi:10.1007/s00134-012-2694-x CrossRefPubMed

Costa E, Borges JB, Melo A et al (2009) Bedside estimation of recruitable alveolar collapse and hyperdistension by electrical impedance tomography. Intensive Care Med 35:1132–1137. doi:10.1007/s00134-009-1447-y CrossRefPubMed

Victorino JA, Borges JB, Okamoto VN et al (2004) Imbalances in regional lung ventilation: a validation study on electrical impedance tomography. Am J Respir Crit Care Med 169:791–800. doi:10.1164/rccm.200301-133OC CrossRefPubMed

10.

Berkowitz DM, Danai PA, Eaton S et al (2008) Accurate characterization of extravascular lung water in acute respiratory distress syndrome. Crit Care Med 36:1803–1809. doi:10.1097/CCM.0b013e3181743eeb CrossRefPubMedPubMedCentral

11.

Calfee CS, Delucchi K, Parsons PE et al (2014) Subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials. Lancet Respir Med 2:611–620. doi:10.1016/S2213-2600(14)70097-9 CrossRefPubMedPubMedCentral

12.

Calfee CS, Janz DR, Bernard GR et al (2015) Distinct molecular phenotypes of direct vs indirect ARDS in single-center and multicenter studies. Chest 147:1539–1548. doi:10.1378/chest.14-2454 CrossRefPubMed

13.

Vincent JL, Santacruz C (2016) Do we need ARDS? Intensive Care Med 42:282–283. doi:10.1007/s00134-015-4120-7 CrossRefPubMed

14.

Li G, Malinchoc M, Cartin-Ceba R et al (2011) Eight-year trend of acute respiratory distress syndrome: a population-based study in Olmsted County, Minnesota. Am J Respir Crit Care Med 183:59–66. doi:10.1164/rccm.201003-0436OC CrossRefPubMedPubMedCentral

15.

Bellani G, Laffey JG, Pham T et al (2016) Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA 315:788–800. doi:10.1001/jama.2016.0291 CrossRefPubMed

16.

Riviello ED, Kiviri W, Twagirumugabe T et al (2016) Hospital incidence and outcomes of the acute respiratory distress syndrome using the Kigali modification of the Berlin definition. Am J Respir Crit Care Med 193:52–59. doi:10.1164/rccm.201503-0584OC CrossRefPubMed

17.

Thille AW, Esteban A, Fernández-Segoviano P et al (2013) Chronology of histological lesions in acute respiratory distress syndrome with diffuse alveolar damage: a prospective cohort study of clinical autopsies. Lancet Respir Med 1:395–401. doi:10.1016/S2213-2600(13)70053-5 CrossRefPubMed

18.

Tejera P, Meyer NJ, Chen F et al (2012) Distinct and replicable genetic risk factors for acute respiratory distress syndrome of pulmonary or extrapulmonary origin. J Med Genet 49:671–680. doi:10.1136/jmedgenet-2012-100972 CrossRefPubMedPubMedCentral

19.

Rubenfeld GD, Cooper C, Carter G et al (2004) Barriers to providing lung-protective ventilation to patients with acute lung injury. Crit Care Med 32:1289–1293. doi:10.1097/01.CCM.0000127266.39560.96 CrossRefPubMed

20.

Koenig HC, Finkel BB, Khalsa SS et al (2011) Performance of an automated electronic acute lung injury screening system in intensive care unit patients. Crit Care Med 39:98–104. doi:10.1097/CCM.0b013e3181feb4a0 CrossRefPubMed

21.

Gajic O, Dabbagh O, Park PK et al (2011) Early identification of patients at risk of acute lung injury: evaluation of lung injury prediction score in a multicenter cohort study. Am J Respir Crit Care Med 183:462–470. doi:10.1164/rccm.201004-0549OC CrossRefPubMedPubMedCentral

22.

Levitt JE, Calfee CS, Goldstein BA et al (2013) Early acute lung injury: criteria for identifying lung injury prior to the need for positive pressure ventilation. Crit Care Med 41:1929–1937. doi:10.1097/CCM.0b013e31828a3d99 CrossRefPubMedPubMedCentral

23.

Bouhemad B, Brisson H, Le-Guen M et al (2011) Bedside ultrasound assessment of positive end-expiratory pressure-induced lung recruitment. Am J Respir Crit Care Med 183:341–347. doi:10.1164/rccm.201003-0369OC CrossRefPubMed

24.

Zhao Z, Möller K, Steinmann D et al (2009) Evaluation of an electrical impedance tomography-based global inhomogeneity index for pulmonary ventilation distribution. Intensive Care Med 35:1900–1906. doi:10.1007/s00134-009-1589-y CrossRefPubMed

25.

Talmor D, Sarge T, Malhotra A et al (2008) Mechanical ventilation guided by esophageal pressure in acute lung injury. N Engl J Med 359:2095–2104. doi:10.1056/NEJMoa0708638 CrossRefPubMedPubMedCentral

26.

Beitler JR, Majumdar R, Hubmayr RD et al (2016) Volume delivered during recruitment maneuver predicts lung stress in acute respiratory distress syndrome. Crit Care Med 44:91–99. doi:10.1097/CCM.0000000000001355 CrossRefPubMed

27.

Chiumello D, Carlesso E, Cadringher P et al (2008) Lung stress and strain during mechanical ventilation for acute respiratory distress syndrome. Am J Respir Crit Care Med 178:346–355. doi:10.1164/rccm.200710-1589OC CrossRefPubMed

28.

Akoumianaki E, Maggiore SM, Valenza F et al (2014) The application of esophageal pressure measurement in patients with respiratory failure. Am J Respir Crit Care Med 189:520–531. doi:10.1164/rccm.201312-2193CI CrossRefPubMed

29.

Katzenelson R, Perel A, Berkenstadt H et al (2004) Accuracy of transpulmonary thermodilution versus gravimetric measurement of extravascular lung water. Crit Care Med 32:1550–1554. doi:10.1097/01.CCM.0000130995.18334.8B CrossRefPubMed

30.

Craig TR, Duffy MJ, Shyamsundar M et al (2010) Extravascular lung water indexed to predicted body weight is a novel predictor of intensive care unit mortality in patients with acute lung injury. Crit Care Med 38:114–120. doi:10.1097/CCM.0b013e3181b43050 CrossRefPubMed

31.

Levitt JE, Bedi H, Calfee CS et al (2009) Identification of early acute lung injury at initial evaluation in an acute care setting prior to the onset of respiratory failure. Chest 135:936–943. doi:10.1378/chest.08-2346 CrossRefPubMedPubMedCentral

32.

Agrawal A, Matthay MA, Kangelaris KN et al (2013) Plasma angiopoietin-2 predicts the onset of acute lung injury in critically ill patients. Am J Respir Crit Care Med 187:736–742. doi:10.1164/rccm.201208-1460OC CrossRefPubMedPubMedCentral

33.

Chew MS, Ihrman L, During J et al (2012) Extravascular lung water index improves the diagnostic accuracy of lung injury in patients with shock. Crit Care 16:R1. doi:10.1186/cc10599 CrossRefPubMedPubMedCentral

34.

Serpa Neto A, Cardoso SO, Manetta JA et al (2012) Association between use of lung-protective ventilation with lower tidal volumes and clinical outcomes among patients without acute respiratory distress syndrome: a meta-analysis. JAMA 308:1651–1659. doi:10.1001/jama.2012.13730 CrossRefPubMed

35.

Lellouche F, Bouchard P-A, Simard S et al (2013) Evaluation of fully automated ventilation: a randomized controlled study in post-cardiac surgery patients. Intensive Care Med 39:463–471. doi:10.1007/s00134-012-2799-2 CrossRefPubMed

36.

The PROVE Network Investigators, For the Clinical Trial Network of the European Society of Anaesthesiology (2014) High versus low positive end-expiratory pressure during general anaesthesia for open abdominal surgery (PROVHILO trial): a multicentre randomised controlled trial. Lancet. doi:10.1016/S0140-6736(14)60416-5

37.

Frat J-P, Thille AW, Mercat A et al (2015) High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure. N Engl J Med. doi:10.1056/NEJMoa1503326

38.

Beitler JR, Schoenfeld DA, Thompson BT (2014) Preventing ARDS: progress, promise, and pitfalls. Chest 146:1102–1113. doi:10.1378/chest.14-0555 CrossRefPubMedPubMedCentral

39.

Pelosi P, D’Andrea L, Vitale G et al (1994) Vertical gradient of regional lung inflation in adult respiratory distress syndrome. Am J Respir Crit Care Med 149:8–13. doi:10.1164/ajrccm.149.1.8111603 CrossRefPubMed

40.

Amato MBP, Meade MO, Slutsky AS et al (2015) Driving pressure and survival in acute respiratory distress syndrome. N Engl J Med 372:747–755CrossRefPubMed

41.

Martin-Loeches I, de Haro C, Dellinger RP et al (2013) Effectiveness of an inspiratory pressure-limited approach to mechanical ventilation in septic patients. Eur Respir J 41:157–164. doi:10.1183/09031936.00221611 CrossRefPubMed

42.

Heart National, Lung, and Blood Institute ARDS Clinical Trials Network (2004) Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med 351:327–336. doi:10.1056/NEJMoa032193 CrossRef

43.

Meade MO, Cook DJ, Guyatt GH et al (2008) Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end-expiratory pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA 299:637–645. doi:10.1001/jama.299.6.637 CrossRefPubMed

44.

Caironi P, Cressoni M, Chiumello D et al (2010) Lung opening and closing during ventilation of acute respiratory distress syndrome. Am J Respir Crit Care Med 181:578–586. doi:10.1164/rccm.200905-0787OC CrossRefPubMed

45.

Goligher EC, Kavanagh BP, Rubenfeld GD et al (2014) Oxygenation response to positive end-expiratory pressure predicts mortality in acute respiratory distress syndrome: a secondary analysis of the LOVS and ExPress Trials. Am J Respir Crit Care Med 190:70–76. doi:10.1164/rccm.201404-0688OC CrossRefPubMed

46.

Suzumura EA, Figueiró M, Normilio-Silva K et al (2014) Effects of alveolar recruitment maneuvers on clinical outcomes in patients with acute respiratory distress syndrome: a systematic review and meta-analysis. Intensive Care Med 40:1227–1240. doi:10.1007/s00134-014-3413-6 CrossRefPubMed

47.

Cressoni M, Cadringher P, Chiurazzi C et al (2014) Lung inhomogeneity in patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 189:149–158. doi:10.1164/rccm.201308-1567OC PubMed

48.

Goligher EC, Kavanagh BP, Rubenfeld GD, Ferguson ND (2015) Physiologic responsiveness should guide entry into randomized controlled trials. Am J Respir Crit Care Med 192:1416–1419. doi:10.1164/rccm.201410-1832CP CrossRefPubMed

49.

Kacmarek RM, Villar J, Sulemanji D et al (2016) Open lung approach for the acute respiratory distress syndrome: a pilot, randomized controlled trial. Crit Care Med 44:32–42. doi:10.1097/CCM.0000000000001383 CrossRefPubMed

50.

Grasso S, Stripoli T, De Michele M et al (2007) ARDSnet ventilatory protocol and alveolar hyperinflation: role of positive end-expiratory pressure. Am J Respir Crit Care Med 176:761–767. doi:10.1164/rccm.200702-193OC CrossRefPubMed

51.

Mercat A, Richard J-CM, Vielle B et al (2008) Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA 299:646–655. doi:10.1001/jama.299.6.646 CrossRefPubMed

52.

Amato MB, Barbas CS, Medeiros DM et al (1998) Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 338:347–354. doi:10.1056/NEJM199802053380602 CrossRefPubMed

53.

Spieth PM, Carvalho AR, Pelosi P et al (2009) Variable tidal volumes improve lung protective ventilation strategies in experimental lung injury. Am J Respir Crit Care Med 179:684–693. doi:10.1164/rccm.200806-975OC CrossRefPubMed

54.

Goligher EC, Fan E, Herridge MS et al (2015) Evolution of diaphragm thickness during mechanical ventilation: impact of inspiratory effort. Am J Respir Crit Care Med 192:1080–1088. doi:10.1164/rccm.201503-0620OC CrossRefPubMed

55.

Yoshida T, Torsani V, Gomes S et al (2013) Spontaneous effort causes occult pendelluft during mechanical ventilation. Am J Respir Crit Care Med 188:1420–1427. doi:10.1164/rccm.201303-0539OC CrossRefPubMed

56.

Pohlman MC, McCallister KE, Schweickert WD et al (2008) Excessive tidal volume from breath stacking during lung-protective ventilation for acute lung injury. Crit Care Med 36:3019–3023. doi:10.1097/CCM.0b013e31818b308b CrossRefPubMed

57.

Papazian L, Forel JM, Gacouin A et al (2010) Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med 363:1107–1116. doi:10.1056/NEJMoa1005372 CrossRefPubMed

58.

Peek GJ, Mugford M, Tiruvoipati R et al (2009) Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. Lancet 374:1351–1363. doi:10.1016/S0140-6736(09)61069-2 CrossRefPubMed

59.

Schmidt M, Zogheib E, Rozé H et al (2013) The PRESERVE mortality risk score and analysis of long-term outcomes after extracorporeal membrane oxygenation for severe acute respiratory distress syndrome. Intensive Care Med 39:1704–1713. doi:10.1007/s00134-013-3037-2 CrossRefPubMed

60.

Bein T, Weber-Carstens S, Goldmann A et al (2013) Lower tidal volume strategy (≈3 ml/kg) combined with extracorporeal CO2 removal versus “conventional” protective ventilation (6 ml/kg) in severe ARDS: the prospective randomized Xtravent-study. Intensive Care Med 39:847–856. doi:10.1007/s00134-012-2787-6 CrossRefPubMedPubMedCentral

61.

Terragni PP, Del Sorbo L, Mascia L et al (2009) Tidal volume lower than 6 ml/kg enhances lung protection: role of extracorporeal carbon dioxide removal. Anesthesiology 111:826–835. doi:10.1097/ALN.0b013e3181b764d2 CrossRefPubMed

62.

Abrams DC, Brenner K, Burkart KM et al (2013) Pilot study of extracorporeal carbon dioxide removal to facilitate extubation and ambulation in exacerbations of chronic obstructive pulmonary disease. Ann Am Thorac Soc 10:307–314. doi:10.1513/AnnalsATS.201301-021OC CrossRefPubMed

63.

Hoeper MM, Wiesner O, Hadem J et al (2013) Extracorporeal membrane oxygenation instead of invasive mechanical ventilation in patients with acute respiratory distress syndrome. Intensive Care Med 39:2056–2057. doi:10.1007/s00134-013-3052-3 CrossRefPubMed

64.

Zanella A, Mangili P, Redaelli S et al (2014) Regional blood acidification enhances extracorporeal carbon dioxide removal: a 48-hour animal study. Anesthesiology 120:416–424. doi:10.1097/ALN.0000000000000099 CrossRefPubMed

65.

Zanella A, Castagna L, Salerno D et al (2015) Respiratory electrodialysis: a novel, highly efficient extracorporeal CO₂ removal technique. Am J Respir Crit Care Med 192:719–726. doi:10.1164/rccm.201502-0289OC CrossRefPubMed

66.

Duggal A, Ganapathy A, Ratnapalan M, Adhikari NK (2015) Pharmacological treatments for acute respiratory distress syndrome: systematic review. Minerva Anestesiol 81:567–588PubMed

67.

Spieth PM, Zhang H (2014) Pharmacological therapies for acute respiratory distress syndrome. Curr Opin Crit Care 20:113–121. doi:10.1097/MCC.0000000000000056 CrossRefPubMed

68.

Wilson JG, Liu KD, Zhuo H et al (2015) Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial. Lancet Respir Med 3:24–32. doi:10.1016/S2213-2600(14)70291-7 CrossRefPubMedPubMedCentral

69.

Guerin C, Reignier J, Richard J-C et al (2013) Prone positioning in severe acute respiratory distress syndrome. N Engl J Med 368:2159–2168. doi:10.1056/NEJMoa1214103 CrossRefPubMed

70.

Beitler JR, Guerin C, Ayzac L et al (2015) PEEP titration during prone positioning for acute respiratory distress syndrome. Crit Care 19:436. doi:10.1186/s13054-015-1153-9 CrossRefPubMedPubMedCentral

71.

Graf J, Marini JJ (2008) Do airway secretions play an underappreciated role in acute respiratory distress syndrome? Curr Opin Crit Care 14:44–49. doi:10.1097/MCC.0b013e3282f2f4cb CrossRefPubMed

72.

Zanella A, Cressoni M, Epp M et al (2012) Effects of tracheal orientation on development of ventilator-associated pneumonia: an experimental study. Intensive Care Med 38:677–685. doi:10.1007/s00134-012-2495-2 CrossRefPubMed

73.

Zanella A, Bellani G, Pesenti A (2010) Airway pressure and flow monitoring. Curr Opin Crit Care 16:255–260. doi:10.1097/MCC.0b013e328337f209 CrossRefPubMed

74.

Mehta C, Gao P, Bhatt DL et al (2009) Optimizing trial design: sequential, adaptive, and enrichment strategies. Circulation 119:597–605. doi:10.1161/CIRCULATIONAHA.108.809707 CrossRefPubMed

75.

Herridge MS, Tansey CM, Matte A et al (2011) Functional disability 5 years after acute respiratory distress syndrome. N Engl J Med 364:1293–1304. doi:10.1056/NEJMoa1011802 CrossRefPubMed

76.

Mikkelsen ME, Christie JD, Lanken PN et al (2012) The adult respiratory distress syndrome cognitive outcomes study: long-term neuropsychological function in survivors of acute lung injury. Am J Respir Crit Care Med 185:1307–1315. doi:10.1164/rccm.201111-2025OC CrossRefPubMedPubMedCentral

77.

Becker LB, Aufderheide TP, Geocadin RG et al (2011) Primary outcomes for resuscitation science studies: a consensus statement from the American Heart Association. Circulation 124:2158–2177. doi:10.1161/CIR.0b013e3182340239 CrossRefPubMedPubMedCentral

Title: Personalized medicine for ARDS: the 2035 research agenda
Authors: Jeremy R. Beitler
Ewan C. Goligher
Matthieu Schmidt
Peter M. Spieth
Alberto Zanella
Ignacio Martin-Loeches
Carolyn S. Calfee
Alexandre B. Cavalcanti
The ARDSne(x)t Investigators
Publication date: 01-05-2016
Publisher: Springer Berlin Heidelberg
Published in: Intensive Care Medicine / Issue 5/2016
Print ISSN: 0342-4642
Electronic ISSN: 1432-1238
DOI: https://doi.org/10.1007/s00134-016-4331-6

At a glance: The STEP trials

Springer Medicine

Personalized medicine for ARDS: the 2035 research agenda

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 5/2016

Prolonged glucocorticoid treatment is associated with improved ARDS outcomes: analysis of individual patients’ data from four randomized trials and trial-level meta-analysis of the updated literature

Venovenous extracorporeal membrane oxygenation for acute respiratory failure

Our study 20 years on: UK collaborative randomised trial of neonatal extracorporeal membrane oxygenation

The ten studies that should be done in ARDS

Ten things that nurses should know about ECMO

Steroids in ARDS: to be or not to be