Download PDF
Semin Respir Crit Care Med 2013; 34(04): 516-521
DOI: 10.1055/s-0033-1351120
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Clinical Trial Design in Acute Lung Injury—Issues and Controversies

Maureen O. Meade
1   Department of Medicine, McMaster University, Hamilton, Ontario, Canada
2   Department of Clinical Epidemiology and Biostatistics, Faculty of Health Sciences, Health Sciences Centre, Hamilton, Ontario, Canada
,
Francois Lamontagne
3   Department of Medicine, Universite de Sherbrooke, Faculte de medicine et des sciences de la santé, Sherbrooke, Quebec, Canada
› Author Affiliations
Further Information

Publication History

Publication Date:
11 August 2013 (online)

    Permissions and Reprints

Abstract

The evolution of scientific investigation in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is replete with examples of effective bench-to-bedside transitions, pioneering research methodology, and international collaboration. This article highlights for clinicians a selection of challenges and controversies of clinical trial design in ALI and ARDS. A section on Patient Selection highlights controversial trade-offs between homogeneous and heterogeneous study populations. A section on Clinical Protocols covers blinding, process-of-care interventions, usual-care control groups, and standardized protocols for adjunctive care. The third section discusses the quest for ideal Study Outcomes. The final section presents Interpretation Controversies, such as early stopping of clinical trials.

Keywords

acute lung injury - acute respiratory distress syndrome - clinical trial designs - research methodology - patient selection
 

  • 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 (18) 1301-1308
    CrossrefPubMedGoogle Scholar
  • 2 Frank AJ, Thompson BT. Pharmacological treatments for acute respiratory distress syndrome. Curr Opin Crit Care 2010; 16 (1) 62-68
    CrossrefPubMedGoogle Scholar
  • 3 Gattinoni L, Caironi P. Refining ventilatory treatment for acute lung injury and acute respiratory distress syndrome. JAMA 2008; 299 (6) 691-693
    CrossrefPubMedGoogle Scholar
  • 4 Ferguson ND, Meade MO, Hallett DC, Stewart TE. High values of the pulmonary artery wedge pressure in patients with acute lung injury and acute respiratory distress syndrome. Intensive Care Med 2002; 28 (8) 1073-1077
    CrossrefPubMedGoogle Scholar
  • 5 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 (8) 795-803
    CrossrefPubMedGoogle Scholar
  • 6 Mercat A, Richard JC, Vielle B , et al; Expiratory Pressure (Express) Study Group. Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA 2008; 299 (6) 646-655
    CrossrefPubMedGoogle Scholar
  • 7 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
    CrossrefPubMedGoogle Scholar
  • 8 Meade MO, Cook DJ, Guyatt GH , et al; Lung Open Ventilation Study Investigators. 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 2008; 299 (6) 637-645
    CrossrefPubMedGoogle Scholar
  • 9 Villar J, Kacmarek RM, Pérez-Méndez L, Aguirre-Jaime A. A high positive end-expiratory pressure, low tidal volume ventilatory strategy improves outcome in persistent acute respiratory distress syndrome: a randomized, controlled trial. Crit Care Med 2006; 34 (5) 1311-1318
    CrossrefPubMedGoogle Scholar
  • 10 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
    CrossrefPubMedGoogle Scholar
  • 11 Meade MO, Cook DJ. The aetiology, consequences and prevention of barotrauma: a critical review of the literature. Clin Intensive Care 1995; 6 (4) 166-173
    PubMedGoogle Scholar
  • 12 Derdak S, Mehta S, Stewart TE , et al; Multicenter Oscillatory Ventilation For Acute Respiratory Distress Syndrome Trial (MOAT) Study Investigators. High-frequency oscillatory ventilation for acute respiratory distress syndrome in adults: a randomized, controlled trial. Am J Respir Crit Care Med 2002; 166 (6) 801-808
    CrossrefPubMedGoogle Scholar
  • 13 Ferguson ND, Kacmarek RM, Chiche JD , et al. Screening of ARDS patients using standardized ventilator settings: influence on enrollment in a clinical trial. Intensive Care Med 2004; 30 (6) 1111-1116
    CrossrefPubMedGoogle Scholar
  • 14 Brochard L, Roudot-Thoraval F, Roupie E , et al. Tidal volume reduction for prevention of ventilator-induced lung injury in acute respiratory distress syndrome. The Multicenter Trail Group on Tidal Volume reduction in ARDS. Am J Respir Crit Care Med 1998; 158 (6) 1831-1838
    CrossrefPubMedGoogle Scholar
  • 15 Adhikari NJK, Bashir AO, Lamontagne F , et al. High frequency oscillation in adults: a retrospective cohort study. Crit Care Med 2011; 39: 2631-2644
    PubMedGoogle Scholar
  • 16 Ferguson ND, Cook DJ, Guyatt GH , et al. High frequency oscillation in early acute respiratory distress syndrome. N Engl J Med 2013; 368: 795-805
    CrossrefPubMedGoogle Scholar
  • 17 Li G, Malinchoc M, Cartin-Ceba R , et al. Eight-year trend of acute respiratory distress syndrome: a population-based study in Olmsted County, Minnesota. Am J Respir Crit Care Med 2011; 183 (1) 59-66
    CrossrefPubMedGoogle Scholar
  • 18 Levy MM. PEEP in ARDS—how much is enough?. N Engl J Med 2004; 351 (4) 389-391
    CrossrefPubMedGoogle Scholar
  • 19 Cook DJ, McDonald E, Smith O , et al. Coenrolment of critically ill patients into multiple studies; patterns, predictors and consequences. Crit Care 2013; 17: R1
    CrossrefPubMedGoogle Scholar
  • 20 The ARDS Network. Ketoconazole for early treatment of acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA 2000; 283 (15) 1995-2002
    CrossrefPubMedGoogle Scholar
  • 21 Dellinger RP, Zimmerman JL, Taylor RW , et al; Inhaled Nitric Oxide in ARDS Study Group. Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Crit Care Med 1998; 26 (1) 15-23
    CrossrefPubMedGoogle Scholar
  • 22 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
    CrossrefPubMedGoogle Scholar
  • 23 Chiche JD, Angus DC. Testing protocols in the intensive care unit: complex trials of complex interventions for complex patients. JAMA 2008; 299 (6) 693-695
    CrossrefPubMedGoogle Scholar
  • 24 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
    CrossrefPubMedGoogle Scholar
  • 25 Meduri GU, Golden E, Freire AX , et al. Methylprednisolone infusion in early severe ARDS: results of a randomized controlled trial. Chest 2007; 131 (4) 954-963
    CrossrefPubMedGoogle Scholar
  • 26 Amato MBP, Barbas CSV, Medeiros DM , et al. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 1998; 338 (6) 347-354
    CrossrefPubMedGoogle Scholar
  • 27 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 (4) 327-336
    CrossrefPubMedGoogle Scholar
  • 28 Peek GJ, Mugford M, Tiruvoipati R , et al; CESAR trial collaboration. Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. Lancet 2009; 374 (9698) 1351-1363
    CrossrefPubMedGoogle Scholar
  • 29 Tobin MJ. Culmination of an era in research on the acute respiratory distress syndrome. N Engl J Med 2000; 342 (18) 1360-1361
    CrossrefPubMedGoogle Scholar
  • 30 Burns KEA, Adhikari NKJ, Slutsky AS , et al. Pressure and volume limited ventilation for the ventilatory management of patients with acute lung injury: a systematic review and meta-analysis. PLoS ONE 2011; 6 (1) e14623
    CrossrefPubMedGoogle Scholar
  • 31 The 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: 561-568
    CrossrefPubMedGoogle Scholar
  • 32 Slutsky AS. Neuromuscular blocking agents in ARDS. N Engl J Med 2010; 363 (12) 1176-1180
    CrossrefPubMedGoogle Scholar
  • 33 Mehta S, Burry L, Fischer S , et al; Canadian Critical Care Trials Group. Canadian survey of the use of sedatives, analgesics, and neuromuscular blocking agents in critically ill patients. Crit Care Med 2006; 34 (2) 374-380
    CrossrefPubMedGoogle Scholar
  • 34 Gainnier M, Roch A, Forel JM , et al. Effect of neuromuscular blocking agents on gas exchange in patients presenting with acute respiratory distress syndrome. Crit Care Med 2004; 32 (1) 113-119
    CrossrefPubMedGoogle Scholar
  • 35 Forel JM, Roch A, Marin V , et al. Neuromuscular blocking agents decrease inflammatory response in patients presenting with acute respiratory distress syndrome. Crit Care Med 2006; 34 (11) 2749-2757
    CrossrefPubMedGoogle Scholar
  • 36 Rubenfeld GD. How much PEEP in acute lung injury. JAMA 2010; 303 (9) 883-884
    CrossrefPubMedGoogle Scholar
  • 37 Schoenfeld DA, Bernard GR. ARDS Network. Statistical evaluation of ventilator-free days as an efficacy measure in clinical trials of treatments for acute respiratory distress syndrome. Crit Care Med 2002; 30 (8) 1772-1777
    CrossrefPubMedGoogle Scholar
  • 38 Bernard GR. PEEP guided by esophageal pressure—any added value?. N Engl J Med 2008; 359 (20) 2166-2168
    CrossrefPubMedGoogle Scholar
  • 39 Adhikari NK, Burns KEA, Friedrich JO, Granton JT, Cook DJ, Meade MO. Effect of nitric oxide on oxygenation and mortality in acute lung injury: systematic review and meta-analysis. BMJ 2007; 334 (7597) 779
    CrossrefPubMedGoogle Scholar
  • 40 Schoenfeld DA. Pro/con clinical debate: It is acceptable to stop large multicentre randomized controlled trials at interim analysis for futility. Pro: Futility stopping can speed up the development of effective treatments. Crit Care 2005; 9 (1) 34-36 , discussion 34–36
    PubMedGoogle Scholar
  • 41 Meade MO. Pro/con clinical debate: It is acceptable to stop large multicentre randomized controlled trials at interim analysis for futility. Con: the hazards of stopping for futility. Crit Care 2004; 9 (1) 34-36
    CrossrefPubMedGoogle Scholar
  • 42 Montori VM, Devereaux PJ, Adhikari NK , et al. Randomized trials stopped early for benefit: a systematic review. JAMA 2005; 294 (17) 2203-2209
    CrossrefPubMedGoogle Scholar
  • 43 Bassler D, Ferreira-Gonzalez I, Briel M , et al. Systematic reviewers neglect bias that results from trials stopped early for benefit. J Clin Epidemiol 2007; 60 (9) 869-873
    CrossrefPubMedGoogle Scholar
  • 44 Duffett M, Burns KE, Kho ME , et al; Academy of Critical CAre: Development, Evaluation, and MethodologY (ACCADEMY); Canadian Critical Care Trials group. Consent in critical care trials: a survey of Canadian research ethics boards and critical care researchers. J Crit Care 2011; 26 (5) 533e11-e22
    PubMedGoogle Scholar
  • 45 Arnold DM, Burns KEA, Adhikari NKJ, Kho ME, Meade MO, Cook DJ. McMaster Critical Care Interest Group. The design and interpretation of pilot trials in clinical research in critical care. Crit Care Med 2009; 37 (1, Suppl): S69-S74
    CrossrefPubMedGoogle Scholar
  • 46 Shure D. Pulmonary-artery catheters—peace at last?. N Engl J Med 2006; 354 (21) 2273-2274
    CrossrefPubMedGoogle Scholar