Translational Research in Intensive Care Unit: Novel Approaches for Drug Development and Personalized Medicine

Romit J. Samanta; Charlotte Summers

doi:10.1055/s-0039-1698407

Seminars in Respiratory and Critical Care Medicine, Inhaltsverzeichnis

Semin Respir Crit Care Med 2019; 40(05): 687-698
DOI: 10.1055/s-0039-1698407

Review Article

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Translational Research in Intensive Care Unit: Novel Approaches for Drug Development and Personalized Medicine

Autor*innen

Romit J. Samanta

¹Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom
Charlotte Summers

¹Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom

Abstract

The major clinical presentations seen by critical care physicians are sepsis and acute respiratory distress syndrome (ARDS), both of which are heterogeneous clinical syndromes rather than specific diagnoses. The current diagnostic criteria provide little insight into the mechanisms underlying these heterogeneous syndromes and minimal progress has been made with regard to the development of therapies, despite many large randomized controlled trials being undertaken. This review outlines the advances made in improved characterization of critically-ill patients, using ARDS as an exemplar, and highlights the need for this improved patient characterization to be coupled with mechanistic science to develop therapies that target specific pathomechanisms.

Keywords

acute respiratory distress syndrome - sepsis - phenotype - endotype - biomarker - transcriptome

Volltext

Referenzen

References
1 Thompson BT, Chambers RC, Liu KD. Acute respiratory distress syndrome. N Engl J Med 2017; 377 (06) 562-572
2 Singer M, Deutschman CS, Seymour CW. , et al. The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA 2016; 315 (08) 801-810
3 Iwashyna TJ, Netzer G. The burdens of survivorship: an approach to thinking about long-term outcomes after critical illness. Semin Respir Crit Care Med 2012; 33 (04) 327-338
4 Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults. Lancet 1967; 2 (7511): 319-323
5 Bernard GR, Artigas A, Brigham KL. , et al. The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994; 149 (3, Pt 1): 818-824
6 Ranieri VM, Rubenfeld GD, Thompson BT. , et al; ARDS Definition Task Force. Acute respiratory distress syndrome: the Berlin definition. JAMA 2012; 307 (23) 2526-2533
7 Rubenfeld GD, Herridge MS. Epidemiology and outcomes of acute lung injury. Chest 2007; 131 (02) 554-562
8 Bellani G, Laffey JG, Pham T. , et al; LUNG SAFE Investigators; ESICM Trials Group. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA 2016; 315 (08) 788-800
9 Thiagarajan RR, Barbaro RP, Rycus PT. , et al; ELSO member centers. Extracorporeal life support organization registry international report 2016. ASAIO J 2017; 63 (01) 60-67
10 Herridge MS, Cheung AM, Tansey CM. , et al; Canadian Critical Care Trials Group. One-year outcomes in survivors of the acute respiratory distress syndrome. N Engl J Med 2003; 348 (08) 683-693
11 Cheung AM, Tansey CM, Tomlinson G. , et al. Two-year outcomes, health care use, and costs of survivors of acute respiratory distress syndrome. Am J Respir Crit Care Med 2006; 174 (05) 538-544
12 Herridge MS, Moss M, Hough CL. , et al. Recovery and outcomes after the acute respiratory distress syndrome (ARDS) in patients and their family caregivers. Intensive Care Med 2016; 42 (05) 725-738
13 Dowdy DW, Eid MP, Dennison CR. , et al. Quality of life after acute respiratory distress syndrome: a meta-analysis. Intensive Care Med 2006; 32 (08) 1115-1124
14 Herridge MS, Tansey CM, Matté A. , et al; Canadian Critical Care Trials Group. Functional disability 5 years after acute respiratory distress syndrome. N Engl J Med 2011; 364 (14) 1293-1304
15 Johnson P, Chaboyer W, Foster M, van der Vooren R. Caregivers of ICU patients discharged home: what burden do they face?. Intensive Crit Care Nurs 2001; 17 (04) 219-227
16 Kamdar BB, Sepulveda KA, Chong A. , et al. Return to work and lost earnings after acute respiratory distress syndrome: a 5-year prospective, longitudinal study of long-term survivors. Thorax 2018; 73 (02) 125-133
17 Brower RG, Matthay MA, Morris A, Schoenfeld D, Thompson BT, Wheeler A. ; 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 (18) 1301-1308
18 Cardinal-Fernández P, Lorente JA, Ballén-Barragán A, Matute-Bello G. Acute respiratory distress syndrome and diffuse alveolar damage new insights on a complex relationship. Ann Am Thorac Soc 2017; 14 (06) 844-850
19 Summers C, Singh NR, White JF. , et al. Pulmonary retention of primed neutrophils: a novel protective host response, which is impaired in the acute respiratory distress syndrome. Thorax 2014; 69 (07) 623-629
20 Matthay MA, Zemans RL, Zimmerman GA. , et al. Acute respiratory distress syndrome. Nat Rev Dis Primers 2019; 5 (01) 18
21 Marshall RP, Bellingan G, Webb S. , et al. Fibroproliferation occurs early in the acute respiratory distress syndrome and impacts on outcome. Am J Respir Crit Care Med 2000; 162 (05) 1783-1788
22 Guérin C, Reignier J, Richard JC. , et al; PROSEVA Study Group. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med 2013; 368 (23) 2159-2168
23 Moss M, Huang DT, Brower RG. , et al; National Heart, Lung, and Blood Institute PETAL Clinical Trials Network. Early neuromuscular blockade in the acute respiratory distress syndrome. N Engl J Med 2019; 380 (21) 1997-2008
24 Asfar P, Meziani F, Hamel JF. , et al; SEPSISPAM Investigators. High versus low blood-pressure target in patients with septic shock. N Engl J Med 2014; 370 (17) 1583-1593
25 Gordon AC, Perkins GD, Singer M. , et al. Levosimendan for the prevention of acute organ dysfunction in sepsis. N Engl J Med 2016; 375 (17) 1638-1648
26 Zarbock A, Kellum JA, Schmidt C. , et al. Effect of early vs delayed initiation of renal replacement therapy on mortality in critically ill patients with acute kidney injury: the ELAIN randomized clinical trial. JAMA 2016; 315 (20) 2190-2199
27 Thiele H, Zeymer U, Neumann FJ. , et al; IABP-SHOCK II Trial Investigators. Intraaortic balloon support for myocardial infarction with cardiogenic shock. N Engl J Med 2012; 367 (14) 1287-1296
28 Ranieri VM, Thompson BT, Barie PS. , et al; PROWESS-SHOCK Study Group. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med 2012; 366 (22) 2055-2064
29 Perner A, Haase N, Guttormsen AB. , et al; 6S Trial Group; Scandinavian Critical Care Trials Group. Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis. N Engl J Med 2012; 367 (02) 124-134
30 Blondonnet R, Constantin JM, Sapin V, Jabaudon M. A Pathophysiologic approach to biomarkers in acute respiratory distress syndrome. Dis Markers 2016; 2016: 3501373
31 Ware LB, Zhao Z, Koyama T. , et al. Derivation and validation of a two-biomarker panel for diagnosis of ARDS in patients with severe traumatic injuries. Trauma Surg Acute Care Open 2017; 2 (01) e000121
32 Agrawal A, Matthay MA, Kangelaris KN. , et al. Plasma angiopoietin-2 predicts the onset of acute lung injury in critically ill patients. Am J Respir Crit Care Med 2013; 187 (07) 736-742
33 Terpstra ML, Aman J, van Nieuw Amerongen GP, Groeneveld AB. Plasma biomarkers for acute respiratory distress syndrome: a systematic review and meta-analysis. Crit Care Med 2014; 42 (03) 691-700
34 Ware LB, Koyama T, Billheimer DD. , et al; NHLBI ARDS Clinical Trials Network. Prognostic and pathogenetic value of combining clinical and biochemical indices in patients with acute lung injury. Chest 2010; 137 (02) 288-296
35 Zhao Z, Wickersham N, Kangelaris KN. , et al. External validation of a biomarker and clinical prediction model for hospital mortality in acute respiratory distress syndrome. Intensive Care Med 2017; 43 (08) 1123-1131
36 Ware LB, Koyama T, Zhao Z. , et al. Biomarkers of lung epithelial injury and inflammation distinguish severe sepsis patients with acute respiratory distress syndrome. Crit Care 2013; 17 (05) R253
37 Calfee CS, Janz DR, Bernard GR. , et al. Distinct molecular phenotypes of direct vs indirect ARDS in single-center and multicenter studies. Chest 2015; 147 (06) 1539-1548
38 Sweeney TE, Thomas NJ, Howrylak JA, Wong HR, Rogers AJ, Khatri P. Multicohort analysis of whole-blood gene expression data does not form a robust diagnostic for acute respiratory distress syndrome. Crit Care Med 2018; 46 (02) 244-251
39 Kangelaris KN, Prakash A, Liu KD. , et al. Increased expression of neutrophil-related genes in patients with early sepsis-induced ARDS. Am J Physiol Lung Cell Mol Physiol 2015; 308 (11) L1102-L1113
40 Howrylak JA, Dolinay T, Lucht L. , et al. Discovery of the gene signature for acute lung injury in patients with sepsis. Physiol Genomics 2009; 37 (02) 133-139
41 Chen Y, Shi JX, Pan XF, Feng J, Zhao H. DNA microarray-based screening of differentially expressed genes related to acute lung injury and functional analysis. Eur Rev Med Pharmacol Sci 2013; 17 (08) 1044-1050
42 Dolinay T, Kim YS, Howrylak J. , et al. Inflammasome-regulated cytokines are critical mediators of acute lung injury. Am J Respir Crit Care Med 2012; 185 (11) 1225-1234
43 Juss JK, House D, Amour A. , et al. Acute respiratory distress syndrome neutrophils have a distinct phenotype and are resistant to phosphoinositide 3-kinase inhibition. Am J Respir Crit Care Med 2016; 194 (08) 961-973
44 Christie JD, Wurfel MM, Feng R. , et al; Trauma ALI SNP Consortium (TASC) investigators. Genome wide association identifies PPFIA1 as a candidate gene for acute lung injury risk following major trauma. PLoS One 2012; 7 (01) e28268
45 Bime C, Pouladi N, Sammani S. , et al. Genome-wide association study in African Americans with acute respiratory distress syndrome identifies the selectin P ligand gene as a risk factor. Am J Respir Crit Care Med 2018; 197 (11) 1421-1432
46 Cooke CR, Shah CV, Gallop R. , et al; National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome Network. A simple clinical predictive index for objective estimates of mortality in acute lung injury. Crit Care Med 2009; 37 (06) 1913-1920
47 Brown LM, Calfee CS, Matthay MA, Brower RG, Thompson BT, Checkley W. ; National Institutes of Health Acute Respiratory Distress Syndrome Network Investigators. A simple classification model for hospital mortality in patients with acute lung injury managed with lung protective ventilation. Crit Care Med 2011; 39 (12) 2645-2651
48 Villar J, Fernández RL, Ambrós A. , et al; Acute Lung Injury Epidemiology and Natural history Network. A clinical classification of the acute respiratory distress syndrome for predicting outcome and guiding medical therapy. Crit Care Med 2015; 43 (02) 346-353
49 Bos LD, Cremer OL, Ong DS. , et al; MARS consortium. External validation confirms the legitimacy of a new clinical classification of ARDS for predicting outcome. Intensive Care Med 2015; 41 (11) 2004-2005
50 Wang CY, Calfee CS, Paul DW. , et al. One-year mortality and predictors of death among hospital survivors of acute respiratory distress syndrome. Intensive Care Med 2014; 40 (03) 388-396
51 Bos LDJ, Scicluna BP, Ong DSY, Cremer O, van der Poll T, Schultz MJ. Understanding heterogeneity in biologic phenotypes of acute respiratory distress syndrome by leukocyte expression profiles. Am J Respir Crit Care Med 2019; 200 (01) 42-50
52 Hinks TSC, Brown T, Lau LCK. , et al. Multidimensional endotyping in patients with severe asthma reveals inflammatory heterogeneity in matrix metalloproteinases and chitinase 3-like protein 1. J Allergy Clin Immunol 2016; 138 (01) 61-75
53 Dawood S, Hu R, Homes MD. , et al. Defining breast cancer prognosis based on molecular phenotypes: results from a large cohort study. Breast Cancer Res Treat 2011; 126 (01) 185-192
54 Tamimi RM, Baer HJ, Marotti J. , et al. Comparison of molecular phenotypes of ductal carcinoma in situ and invasive breast cancer. Breast Cancer Res 2008; 10 (04) R67
55 Barker AD, Sigman CC, Kelloff GJ, Hylton NM, Berry DA, Esserman LJ. I-SPY 2: an adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy. Clin Pharmacol Ther 2009; 86 (01) 97-100
56 Das S, Lo AW. Re-inventing drug development: A case study of the I-SPY 2 breast cancer clinical trials program. Contemp Clin Trials 2017; 62: 168-174
57 Gobat N, Amuasi J, Yazdanpanah Y. , et al. Advancing preparedness for clinical research during infectious disease epidemics. ERJ Open Res 2019; 5 (02) 00227-2018
58 Scicluna BP, van Vught LA, Zwinderman AH. , et al; MARS consortium. Classification of patients with sepsis according to blood genomic endotype: a prospective cohort study. Lancet Respir Med 2017; 5 (10) 816-826
59 Davenport EE, Burnham KL, Radhakrishnan J. , et al. Genomic landscape of the individual host response and outcomes in sepsis: a prospective cohort study. Lancet Respir Med 2016; 4 (04) 259-271
60 Burnham KL, Davenport EE, Radhakrishnan J. , et al. Shared and distinct aspects of the sepsis transcriptomic response to fecal peritonitis and pneumonia. Am J Respir Crit Care Med 2017; 196 (03) 328-339
61 Rautanen A, Mills TC, Gordon AC. , et al; ESICM/ECCRN GenOSept Investigators. Genome-wide association study of survival from sepsis due to pneumonia: an observational cohort study. Lancet Respir Med 2015; 3 (01) 53-60
62 Seymour CW, Kennedy JN, Wang S. , et al. Derivation, validation, and potential treatment implications of novel clinical phenotypes for sepsis. JAMA 2019; 321 (20) 2003-2017
63 Calfee CS, Delucchi K, Parsons PE, Thompson BT, Ware LB, Matthay MA. ; NHLBI ARDS Network. Subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials. Lancet Respir Med 2014; 2 (08) 611-620
64 Famous KR, Delucchi K, Ware LB. , et al; ARDS Network. Acute respiratory distress syndrome subphenotypes respond differently to randomized fluid management strategy. Am J Respir Crit Care Med 2017; 195 (03) 331-338
65 Calfee CS, Delucchi KL, Sinha P. , et al; Irish Critical Care Trials Group. Acute respiratory distress syndrome subphenotypes and differential response to simvastatin: secondary analysis of a randomised controlled trial. Lancet Respir Med 2018; 6 (09) 691-698
66 Sinha P, Delucchi KL, Thompson BT, McAuley DF, Matthay MA, Calfee CS. ; NHLBI ARDS Network. Latent class analysis of ARDS subphenotypes: a secondary analysis of the statins for acutely injured lungs from sepsis (SAILS) study. Intensive Care Med 2018; 44 (11) 1859-1869
67 Reilly JP, Bellamy S, Shashaty MG. , et al. Heterogeneous phenotypes of acute respiratory distress syndrome after major trauma. Ann Am Thorac Soc 2014; 11 (05) 728-736
68 Ketoconazole for Early Treatment of Acute Lung Injury and Acute Respiratory Distress Syndrome: a randomized controlled trial. The ARDS Network. JAMA 2000; 283 (15) 2831995
69 The ARDS Network. Randomized, placebo-controlled trial of lisofylline for early treatment of acute lung injury and acute respiratory distress syndrome. Crit Care Med 2002; 30 (01) 1-6
70 Brower RG, Lanken PN, MacIntyre N. , et al; National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med 2004; 351 (04) 327-336
71 Taylor RW, Zimmerman JL, Dellinger RP. , et al; Inhaled Nitric Oxide in ARDS Study Group. Low-dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial. JAMA 2004; 291 (13) 1603-1609
72 Steinberg KP, Hudson LD, Goodman RB. , et al; National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med 2006; 354 (16) 1671-1684
73 Wiedemann HP, Wheeler AP, Bernard GR. , et al; National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med 2006; 354 (24) 2564-2575
74 Papazian L, Forel JM, Gacouin A. , et al; ACURASYS Study Investigators. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med 2010; 363 (12) 1107-1116
75 Rice TW, Wheeler AP, Thompson BT, deBoisblanc BP, Steingrub J, Rock P. ; NIH NHLBI Acute Respiratory Distress Syndrome Network of Investigators. Enteral omega-3 fatty acid, γ-linolenic acid, and antioxidant supplementation in acute lung injury. JAMA 2011; 306 (14) 1574-1581
76 Matthay MA, Brower RG, Carson S. , et al; National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Randomized, placebo-controlled clinical trial of an aerosolized β₂-agonist for treatment of acute lung injury. Am J Respir Crit Care Med 2011; 184 (05) 561-568
77 Gao Smith F, Perkins GD, Gates S. , et al; BALTI-2 study investigators. Effect of intravenous β-2 agonist treatment on clinical outcomes in acute respiratory distress syndrome (BALTI-2): a multicentre, randomised controlled trial. Lancet 2012; 379 (9812): 229-235
78 Rice TW, Wheeler AP, Thompson BT. , et al; National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Initial trophic vs full enteral feeding in patients with acute lung injury: the EDEN randomized trial. JAMA 2012; 307 (08) 795-803
79 McAuley DF, Laffey JG, O'Kane CM. , et al; HARP-2 Investigators; Irish Critical Care Trials Group. Simvastatin in the acute respiratory distress syndrome. N Engl J Med 2014; 371 (18) 1695-1703
80 Young D, Lamb SE, Shah S. , et al; OSCAR Study Group. High-frequency oscillation for acute respiratory distress syndrome. N Engl J Med 2013; 368 (09) 806-813
81 Ferguson ND, Cook DJ, Guyatt GH. , et al; OSCILLATE Trial Investigators; Canadian Critical Care Trials Group. High-frequency oscillation in early acute respiratory distress syndrome. N Engl J Med 2013; 368 (09) 795-805
82 Truwit JD, Bernard GR, Steingrub J. , et al; National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. Rosuvastatin for sepsis-associated acute respiratory distress syndrome. N Engl J Med 2014; 370 (23) 2191-2200
83 Kor DJ, Carter RE, Park PK. , et al; US Critical Illness and Injury Trials Group: Lung Injury Prevention with Aspirin Study Group (USCIITG: LIPS-A). Effect of aspirin on development of ARDS in at-risk patients presenting to the emergency department: the LIPS-A randomized clinical trial. JAMA 2016; 315 (22) 2406-2414
84 McAuley DF, Cross LM, Hamid U. , et al. Keratinocyte growth factor for the treatment of the acute respiratory distress syndrome (KARE): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Respir Med 2017; 5 (06) 484-491
85 Combes A, Hajage D, Capellier G. , et al; EOLIA Trial Group, REVA, and ECMONet. Extracorporeal membrane oxygenation for acute respiratory distress syndrome in adults. N Engl J Med 2018; 378 (21) 1965-1975