Reappraisal of Ventilator-Free Days in Critical Care Research

Nadir Yehya, Michael O Harhay, Martha A Q Curley, David A Schoenfeld, Ron W Reeder, Nadir Yehya, Michael O Harhay, Martha A Q Curley, David A Schoenfeld, Ron W Reeder

Abstract

Ventilator-free days (VFDs) are a commonly reported composite outcome measure in acute respiratory distress syndrome trials. VFDs combine survival and duration of ventilation in a manner that summarizes the "net effect" of an intervention on these two outcomes. However, this combining of outcome measures makes VFDs difficult to understand and analyze, which contributes to imprecise interpretations. We discuss the strengths and limitations of VFDs and other "failure-free day" composites, and we provide a framework for when and how to use these outcome measures. We also provide a comprehensive discussion of the different analytic methods for analyzing and interpreting VFDs, including Student's t tests and rank-sum tests, as well as competing risk regressions treating extubation as the primary outcome and death as the competing risk. Using simulations, we illustrate how the statistical test with optimal power depends on the relative contributions of mortality and ventilator duration on the composite effect size. Finally, we recommend a simple analysis and reporting framework using the competing risk approach, which provides clear information on the effect size of an intervention, a statistical test and measure of confidence with the ability to adjust for baseline factors and allow interim monitoring for trials. We emphasize that any approach to analyzing a composite outcome, including other "failure-free day" constructs, should also be accompanied by an examination of the components.

Keywords: ARDS; VFDs; acute respiratory distress syndrome; competing risk regression; ventilator-free days.

Figures

Figure 1.
Figure 1.
Different clinical trajectories of subjects assigned to (A) 0 or (B) 14 ventilator-free days. A criticism of ventilator-free days is that the “net effect” being reported does not adequately discriminate between these distinct patient outcomes.
Figure 2.
Figure 2.
Cumulative incidence functions for the primary event (extubation) in five ARDSNet (Acute Respiratory Distress Syndrome Clinical Network) trials. The subdistribution hazard ratio (SHR) and 95% confidence intervals are provided. Intervention (blue) and control (red) arms are displayed, and SHR greater than 1 is interpreted as greater hazard of intact extubation. ARMA (Respiratory Management in ARDS) and FACTT (Fluid and Catheter Treatment Trial) demonstrated a benefit of the intervention related to the probability of extubation, whereas OMEGA (Omega Nutritional Supplement Trial) demonstrated harm. ALTA = Albuterol for the Treatment of Acute Lung Injury; ALVEOLI = Assessment of Low Tidal Volume and Elevated End-expiratory Volume to Obviate Lung Injury; PEEP = positive end-expiratory pressure.

References

    1. 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;30:1772–1777.
    1. Schoenfeld DA, Hayden D, Oldmixon C, Ringwood N, Thompson BT. Statistical design and analysis issues for the ARDS Clinical Trials Network: the coordinating center perspective. Clin Invest. 2012;2:275–289.
    1. Bernard GR, Wheeler AP, Arons MM, Morris PE, Paz HL, Russell JA, et al. The Antioxidant in ARDS Study Group. A trial of antioxidants N-acetylcysteine and procysteine in ARDS. Chest. 1997;112:164–172.
    1. Matthay MA, Brower RG, Carson S, Douglas IS, Eisner M, Hite D, 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;184:561–568.
    1. Rice TW, Wheeler AP, Thompson BT, Steingrub J, Hite RD, Moss M, 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;307:795–803.
    1. 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, gamma-linolenic acid, and antioxidant supplementation in acute lung injury. JAMA. 2011;306:1574–1581.
    1. Steinberg KP, Hudson LD, Goodman RB, Hough CL, Lanken PN, Hyzy R, 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;354:1671–1684.
    1. Bodet-Contentin L, Frasca D, Tavernier E, Feuillet F, Foucher Y, Giraudeau B. Ventilator-free day outcomes can be misleading. Crit Care Med. 2018;46:425–429.
    1. Contentin L, Ehrmann S, Giraudeau B. Heterogeneity in the definition of mechanical ventilation duration and ventilator-free days. Am J Respir Crit Care Med. 2014;189:998–1002.
    1. Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, et al. The American-European Consensus Conference on ARDS: definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med. 1994;149:818–824.
    1. Harhay MO, Ratcliffe SJ, Small DS, Suttner LH, Crowther MJ, Halpern SD. Measuring and analyzing length of stay in critical care trials. Med Care. 2019;57:e53–e59.
    1. Stapleton RD, Wang BM, Hudson LD, Rubenfeld GD, Caldwell ES, Steinberg KP. Causes and timing of death in patients with ARDS. Chest. 2005;128:525–532.
    1. Dowell JC, Parvathaneni K, Thomas NJ, Khemani RG, Yehya N. Epidemiology of cause of death in pediatric acute respiratory distress syndrome. Crit Care Med. 2018;46:1811–1819.
    1. Spragg RG, Bernard GR, Checkley W, Curtis JR, Gajic O, Guyatt G, et al. Beyond mortality: future clinical research in acute lung injury. Am J Respir Crit Care Med. 2010;181:1121–1127.
    1. Harhay MO, Wagner J, Ratcliffe SJ, Bronheim RS, Gopal A, Green S, et al. Outcomes and statistical power in adult critical care randomized trials. Am J Respir Crit Care Med. 2014;189:1469–1478.
    1. Herridge MS, Chu LM, Matte A, Tomlinson G, Chan L, Thomas C, et al. RECOVER Program Investigators (Phase 1: towards RECOVER); Canadian Critical Care Trials Group. The RECOVER program: disability risk groups and 1-year outcome after 7 or more days of mechanical ventilation. Am J Respir Crit Care Med. 2016;194:831–844.
    1. Combes A, Costa MA, Trouillet JL, Baudot J, Mokhtari M, Gibert C, et al. Morbidity, mortality, and quality-of-life outcomes of patients requiring >or=14 days of mechanical ventilation. Crit Care Med. 2003;31:1373–1381.
    1. Unroe M, Kahn JM, Carson SS, Govert JA, Martinu T, Sathy SJ, et al. One-year trajectories of care and resource utilization for recipients of prolonged mechanical ventilation: a cohort study. Ann Intern Med. 2010;153:167–175.
    1. Hill AD, Fowler RA, Burns KE, Rose L, Pinto RL, Scales DC. Long-term outcomes and health care utilization after prolonged mechanical ventilation. Ann Am Thorac Soc. 2017;14:355–362.
    1. Varadhan R, Weiss CO, Segal JB, Wu AW, Scharfstein D, Boyd C. Evaluating health outcomes in the presence of competing risks: a review of statistical methods and clinical applications. Med Care. 2010;48(Suppl):S96–S105.
    1. 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;342:1301–1308.
    1. Wiedemann HP, Wheeler AP, Bernard GR, Thompson BT, Hayden D, deBoisblanc B, 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;354:2564–2575.
    1. Manja V, AlBashir S, Guyatt G. Criteria for use of composite end points for competing risks—a systematic survey of the literature with recommendations. J Clin Epidemiol. 2017;82:4–11.
    1. Ferreira-González I, Busse JW, Heels-Ansdell D, Montori VM, Akl EA, Bryant DM, et al. Problems with use of composite end points in cardiovascular trials: systematic review of randomised controlled trials. BMJ. 2007;334:786.
    1. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al. Collaborative Study Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851–860.
    1. Yehya N, Keim G, Thomas NJ. Subtypes of pediatric acute respiratory distress syndrome have different predictors of mortality. Intensive Care Med. 2018;44:1230–1239.
    1. Khemani RG, Smith L, Lopez-Fernandez YM, Kwok J, Morzov R, Klein MJ, et al. Pediatric Acute Respiratory Distress syndrome Incidence and Epidemiology (PARDIE) Investigators; Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network. Paediatric Acute Respiratory Distress Syndrome Incidence and Epidemiology (PARDIE): an international, observational study. Lancet Respir Med. 2019;7:115–128.
    1. Papazian L, Forel JM, Gacouin A, Penot-Ragon C, Perrin G, Loundou A, et al. ACURASYS Study Investigators. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010;363:1107–1116.
    1. Guérin C, Reignier J, Richard JC, Beuret P, Gacouin A, Boulain T, et al. PROSEVA Study Group. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med. 2013;368:2159–2168.
    1. Khimenko PL, Barnard JW, Moore TM, Wilson PS, Ballard ST, Taylor AE. Vascular permeability and epithelial transport effects on lung edema formation in ischemia and reperfusion. J Appl Physiol (1985) 1994;77:1116–1121.
    1. Palmieri TL, Enkhbaatar P, Bayliss R, Traber LD, Cox RA, Hawkins HK, et al. Continuous nebulized albuterol attenuates acute lung injury in an ovine model of combined burn and smoke inhalation. Crit Care Med. 2006;34:1719–1724.
    1. McAuley DF, Frank JA, Fang X, Matthay MA. Clinically relevant concentrations of β2-adrenergic agonists stimulate maximal cyclic adenosine monophosphate-dependent airspace fluid clearance and decrease pulmonary edema in experimental acid-induced lung injury. Crit Care Med. 2004;32:1470–1476.
    1. 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;173:281–287.
    1. Béduneau G, Pham T, Schortgen F, Piquilloud L, Zogheib E, Jonas M, et al. WIND (Weaning according to a New Definition) Study Group and the REVA (Réseau Européen de Recherche en Ventilation Artificielle) Network. Epidemiology of weaning outcome according to a new definition: the WIND study. Am J Respir Crit Care Med. 2017;195:772–783.
    1. Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999;94:496–509.
    1. Hauck WW, Anderson S, Marcus SM. Should we adjust for covariates in nonlinear regression analyses of randomized trials? Control Clin Trials. 1998;19:249–256.
    1. Raab GM, Day S, Sales J. How to select covariates to include in the analysis of a clinical trial. Control Clin Trials. 2000;21:330–342.
    1. Steingrimsson JA, Hanley DF, Rosenblum M. Improving precision by adjusting for prognostic baseline variables in randomized trials with binary outcomes, without regression model assumptions. Contemp Clin Trials. 2017;54:18–24.
    1. Brower RG, Lanken PN, MacIntyre N, Matthay MA, Morris A, Ancukiewicz M, 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;351:327–336.
    1. Thille AW, Richard JC, Brochard L. The decision to extubate in the intensive care unit. Am J Respir Crit Care Med. 2013;187:1294–1302.
    1. Ruan SY, Teng NC, Wu HD, Tsai SL, Wang CY, Wu CP, et al. Durability of weaning success for liberation from invasive mechanical ventilation: an analysis of a nationwide database. Am J Respir Crit Care Med. 2017;196:792–795.
    1. Willson DF, Thomas NJ, Markovitz BP, Bauman LA, DiCarlo JV, Pon S, et al. Pediatric Acute Lung Injury and Sepsis Investigators. Effect of exogenous surfactant (calfactant) in pediatric acute lung injury: a randomized controlled trial. JAMA. 2005;293:470–476.
    1. Curley MA, Hibberd PL, Fineman LD, Wypij D, Shih MC, Thompson JE, et al. Effect of prone positioning on clinical outcomes in children with acute lung injury: a randomized controlled trial. JAMA. 2005;294:229–237.
    1. Bein T, Weber-Carstens S, Goldmann A, Müller T, Staudinger T, Brederlau J, et al. 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. 2013;39:847–856.
    1. Annane D, Renault A, Brun-Buisson C, Megarbane B, Quenot JP, Siami S, et al. CRICS-TRIGGERSEP Network. Hydrocortisone plus fludrocortisone for adults with septic shock. N Engl J Med. 2018;378:809–818.
    1. De Backer D, Biston P, Devriendt J, Madl C, Chochrad D, Aldecoa C, et al. SOAP II Investigators. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med. 2010;362:779–789.
    1. Russell JA, Walley KR, Singer J, Gordon AC, Hébert PC, Cooper DJ, et al. VASST Investigators. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008;358:877–887.
    1. Gordon AC, Mason AJ, Thirunavukkarasu N, Perkins GD, Cecconi M, Cepkova M, et al. VANISH Investigators. Effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock: the VANISH randomized clinical trial. JAMA. 2016;316:509–518.
    1. Semler MW, Self WH, Wanderer JP, Ehrenfeld JM, Wang L, Byrne DW, et al. SMART Investigators and the Pragmatic Critical Care Research Group. Balanced crystalloids versus saline in critically ill adults. N Engl J Med. 2018;378:829–839.
    1. Page VJ, Casarin A, Ely EW, Zhao XB, McDowell C, Murphy L, et al. Evaluation of early administration of simvastatin in the prevention and treatment of delirium in critically ill patients undergoing mechanical ventilation (MoDUS): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2017;5:727–737.
    1. Dulhunty JM, Roberts JA, Davis JS, Webb SA, Bellomo R, Gomersall C, et al. BLING II Investigators for the ANZICS Clinical Trials Group. A multicenter randomized trial of continuous versus intermittent β-lactam infusion in severe sepsis. Am J Respir Crit Care Med. 2015;192:1298–1305.
    1. Agus MS, Wypij D, Hirshberg EL, Srinivasan V, Faustino EV, Luckett PM, et al. HALF-PINT Study Investigators and the PALISI Network. Tight glycemic control in critically ill children. N Engl J Med. 2017;376:729–741.
    1. Self WH, Semler MW, Wanderer JP, Wang L, Byrne DW, Collins SP, et al. SALT-ED Investigators. Balanced crystalloids versus saline in noncritically ill adults. N Engl J Med. 2018;378:819–828.

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