Comments
Abstract
Systematic reviews have considerable potential to provide evidence-based data to aid clinical decision-making. However, there is growing recognition that trials involving mechanical ventilation lack consistency in the definition and measurement of ventilation outcomes, creating difficulties in combining data for meta-analyses. To address the inconsistency in outcome definitions, international standards for trial registration and clinical trial protocols published recommendations, effectively setting the “gold standard” for reporting trial outcomes. In this Critical Care Perspective, we review the problems resulting from inconsistent outcome definitions and inconsistent reporting of outcomes (outcome sets). We present data highlighting the variability of the most commonly reported ventilation outcome definitions. Ventilation outcomes reported in trials over the last 6 years typically fall into four domains: measures of ventilator dependence; adverse outcomes; mortality; and resource use. We highlight the need, first, for agreement on outcome definitions and, second, for a minimum core outcome set for trials involving mechanical ventilation. A minimum core outcome set would not restrict trialists from measuring additional outcomes, but would overcome problems of variability in outcome selection, measurement, and reporting, thereby enhancing comparisons across trials.
Many interventions applied in the critically ill influence the duration of mechanical ventilation. Measures of ventilator dependence, such as duration of ventilation, are frequently used as primary and secondary outcomes. However, variations in outcome definitions lead to differences in estimates of treatment effects and in a systematic review this “artifactual difference” may dilute the real effect (1). As such, it is highly desirable that standardized outcome definitions be used in trials examining interventions likely to affect duration of mechanical ventilation. This will enable treatment effects to be compared in an unbiased, reliable, and robust manner.
Consistency in the measurement and reporting of trial outcomes is lacking. Williamson and colleagues noted that the most accessed and cited Cochrane reviews in 2009 all described inconsistencies in trial outcomes (2). Two systematic reviews of the effectiveness of protocolized weaning highlighted inconsistencies in measurement time points for ventilation outcomes (3, 4). Current international standards for trial registration (Consolidated Standards of Reporting Trials [CONSORT], World Health Organization [WHO] Registry) and the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) 2013 recommendations for writing clinical trial protocols stress that investigators should report the specific measurement variable and time frame for each outcome measure when registering trials (5–7). However, analysis of a cohort of records from the ClinicalTrials.gov database indicated that 36% of trials registered a domain only and lacked definition of the specific measure, metric used, or method of aggregation of results (8). Furthermore, outcomes included in trial protocols are not always reported in trial publications (9, 10).
In addition to the need for consistency in outcome definitions, Williamson and colleagues called for the development and use of core outcome sets (2), defined as an “agreed, standardized collection of outcomes measured and reported in all trials for a specific clinical area” (11). Agreement on a core outcome set should avoid problems associated with selective reporting of outcomes. The Core Outcome Measures in Effectiveness Trials (COMET) database has registered more than 260 references of planned work in developing core outcome sets and among them there are three studies exploring ventilation outcomes, long-term outcomes in acute respiratory failure, and rehabilitation after critical illness (12).
Little is known about how ventilation outcomes are defined and measured. To investigate this we sought to, first, identify trials involving mechanically ventilated adults and children that reported ventilation outcomes and describe how these outcomes were reported; and second, explore how trials specifically evaluating ventilation interventions reported ventilation outcomes and whether these might reveal a core outcome set.
We included trials published in the top-ranked journals between January 2007 and December 2012 in general medicine (New England Journal of Medicine, Lancet, Journal of the American Medical Association, and Pediatrics) and critical care (American Journal of Respiratory and Critical Care Medicine, Critical Care Medicine, Intensive Care Medicine, and Pediatric Critical Care Medicine). We specifically chose top-ranked journals because of the likelihood of locating high-quality trial reports. Rankings were based on the impact factors in the Web of Knowledge and Journal Citation Reports 2011 (Thomson Reuters). Our review included only randomized controlled trials involving adults or children receiving invasive mechanical ventilation and measuring outcomes pertaining to the duration of ventilation and its discontinuation. Three authors (B.B., L.R., P.J.McG.) divided the journals and independently searched, screened, and extracted data. Titles and abstracts of papers in the journals were reviewed: full texts including supplementary material, published protocols, or protocol registrations of all potentially relevant trials were retrieved. Details of the trials’ aims, primary and secondary outcome measures, and their definitions were extracted onto prepiloted data extraction forms (see the online supplement, Appendix 1). These forms were reviewed by the three authors to confirm inclusion: a fourth author (D.F.McA.) acted as arbitrator.
We included 66 reports of randomized trials (13–78) and associated documentation (59 trial registrations; 34 electronic supplementary materials; 13 published protocols) (Figure 1). Interventions addressed management of ventilation, sedation, physiotherapy, nutrition, renal/fluid management, medications, and infection prevention. The 66 trials reported 30 different primary outcomes. Primary outcomes reported by more than 1 trial and secondary outcomes reported by more than 10 trials are shown in Figure 2.
Figure 1. Flowchart of search and inclusion of trials. AJRCCM = American Journal of Respiratory and Critical Care Medicine; CCM = Critical Care Medicine; ICM = Intensive Care Medicine; JAMA = Journal of the American Medical Association; NEJM = New England Journal of Medicine; PCCM = Pediatric Critical Care Medicine; PP = published protocols; SM = supplementary material; TR = trial registrations.
[More] [Minimize]
Figure 2. Most reported primary and secondary outcomes in 66 trials involving mechanically ventilated patients. ICU = intensive care unit; LOS = length of stay; MV = mechanical ventilation; VAP = ventilatory-associated pneumonia; VFD = ventilator-free days.
[More] [Minimize]Nine ventilation outcomes were reported across included trials, reflecting measures of ventilator dependence or occurrence of events (typically adverse outcomes) (Table 1). Duration of ventilation was the most commonly reported outcome, yet only 12 trials (25%) provided a definition (20, 24, 30, 32, 35, 42–44, 61, 64, 71, 73) with substantial variation in time point measures. Twenty-five trials reported ventilator-free days as an outcome; 9 (36%) (18, 19, 23, 51, 53, 62, 63, 72, 73) provided no definition, and variable start and end points were reported in the 16 (64%) providing a definition (24, 26, 31, 45, 50, 52, 54, 57, 58, 65, 66, 68–70, 72, 76) (Table 2). Three trials reporting weaning duration as a secondary outcome (24, 62, 76) and only one provided a definition (24). When reintubation was reported as a trial outcome (four trials), follow-up was measured at 24 hours (73), 48 hours (49, 61), or 7 days (32). When reintubation was recorded as an adverse event (four trials) (31, 40, 55, 71), the follow-up period within which this was measured was not provided.
| Outcome | No. of Trials | Reported as Primary Outcome | Reported as Adverse Event | Definition Provided [n (%)] |
|---|---|---|---|---|
| Measure of ventilation dependence | ||||
| Duration of ventilation | 48 | 9 | — | 12 (25%) |
| Ventilator-free days | 25 | 4 | — | 16 (64%) |
| Weaning time | 3 | — | — | 1 (33%) |
| Time to separation potential | 1 | 1 | — | 1 (100%) |
| Occurrence of events | ||||
| Reintubation | 8 | 2 | 4 | 4 (50%) |
| Extubation failure | 4 | 1 | 1 | 2 (50%) |
| Use of postextubation NIV | 4 | — | 3 | 1 (25%) |
| Weaning failure | 1 | 1 | — | 1 (100%) |
| Successful extubation | 1 | — | — | 0 |
| Start Point | End Point |
|---|---|
| Duration of mechanical ventilation | |
| Commencement of IMV (20, 30, 71) | First extubation (24, 30, 44, 61, 64) |
| Intubation (43) | Successful extubation (35, 61, 64) |
| Randomization (24, 35, 42, 44, 61, 64, 73) | Successful extubation: UAB for 24 h (73), 48 h (43, 44), or 72 h (24) |
| First SBT (64) | |
| Successful SBT (61, 64) | |
| Successful extubation (24 h) or successful SBT (UAB for 48 h) (42) | |
| Ventilator free (71) | |
| Free from IMV or NIV (for 48 h) (35) | |
| Extubation from IMV and NIV stop or reintubation for NIV group (32) | |
| Ventilation time within 28 d (64) | |
| Successful weaning (20, 61) | |
| VFD | |
| Day 1 (50, 54) | Day 28 (24, 31, 45, 50, 52, 58, 65, 66, 68–70, 76) |
| Intubation (50) | Day 60 (24) |
| Randomization (24, 30, 40, 46, 49, 51, 52, 81) | Day 90 (57) |
| Not specifically stated (26, 65, 69, 70, 76) | Days 28 and 90 (54) |
| Not specifically stated (72) | |
Twelve trials tested a ventilation intervention including sedation and ventilation weaning methods (20, 30, 31, 43, 44, 49, 68), ventilator modes (27, 78), automated systems to facilitate ventilator weaning (61, 64), and early noninvasive ventilation after invasive ventilation (32). Primary and secondary outcomes reported in these trials are presented in Figure 3. Outcome measures reflected four domains: measures of ventilator dependence (e.g., duration of ventilation, duration of weaning, separation potential), adverse outcomes (e.g., ventilatory-associated pneumonia, reintubation, self-extubation), mortality and survival outcomes (e.g., survival, intensive care unit [ICU] mortality, hospital mortality), and resource use (e.g., ICU length of stay, hospital length of stay, clinical workload).
Figure 3. Type and number of primary and secondary outcomes reported in 12 trials specifically evaluating a ventilation intervention. Reference numbers before and after the double forward slash indicate primary and secondary outcome references, respectively. ICU = intensive care unit; LOS = length of stay; MV = mechanical ventilation; NIV = noninvasive ventilation; VAP = ventilator-associated pneumonia; VFD = ventilator-free days.
[More] [Minimize]There was considerable variation in measuring primary outcomes. Ventilation trials reported either duration of mechanical ventilation or ventilator-free days, but not both. Start and end points are shown in Table 3. In secondary outcomes, mortality was reported for different follow-up periods that included ICU (20, 49, 68, 78), hospital (20, 68, 78), 28 days (31, 64), 30 days (30), 90 days (31), and before ventilator separation potential and extubation (61). One trial did not define the follow-up period (27) and one trial did not measure mortality (43). Two trials measured survival, at 1 year (31) and at an undefined time point (32).
| Start Point | End Point |
|---|---|
| Duration of mechanical ventilation | |
| Commencement of IMV (20, 30) | First extubation (30, 61, 64) |
| Intubation (43, 61) | Successful extubation (61) |
| Randomization (39, 76, 77) | Extubation or a tracheostomy mask for 48 h (43, 44) |
| Extubation from IMV and NIV stop or reintubation for NIV group (32) | |
| First SBT (32) | |
| Successful SBT (32) | |
| Successful weaning (20) | |
| VFD | |
| Intubation (68) | Day 28 (31, 68) |
| Randomization (31, 68) | |
We found substantial variation in the outcome sets used. Outcome definitions differed among trials, often measuring different time points and different follow-up periods. Furthermore, a large number of trials lacked detail in their outcome definitions.
It is important to highlight the effect related to the competing risk of death in using duration of ventilation as an outcome measure. Various statistical methods have tried to address this issue. Egleston and colleagues (79) point out that by using a basic approach of examining outcomes in survivors only it is possible that a harmful intervention will increase mortality in a vulnerable population. These remaining healthier survivors may have a reduced duration of ventilation, giving the impression that the intervention has a beneficial effect (79). Therefore it is important to consider the duration of ventilation as an outcome in the context of mortality. Measuring ventilator-free days (i.e., a composite outcome of mortality and duration of ventilation) is one method to address competing risks (80). Our work has demonstrated that ventilator-free days are often poorly defined or not reported.
Cause-specific hazard models that fail to take into account the competing event (death) result in the patient being censored from the analysis and may falsely make the intervention appear beneficial (81). When a subdistribution hazard model is employed patients are not censored despite the occurrence of the competing event. When events are mutually exclusive, such as death or unassisted breathing and discharge home, a parametric mixture survival model may be the most appropriate method to determine the true effect of an intervention (82).
The issue of competing risk is complex and does not apply just to mortality. An intervention intended to reduce the duration of mechanical ventilation may potentially lead to complications, making it unclear whether the treatment causes the complication or results in more patients being alive to develop the complication. Statistical approaches such as cause-specific hazard, cumulative incidence function, and event-free survival are used to detect the true effect of an intervention. However, their ability to do so varies depending on whether the competing risk is affected in the same or opposite manner as the primary event being studied (83). Regardless of these issues our finding of variability in mechanical ventilation outcome measures is important.
The outcome “duration of mechanical ventilation” was reported by 73% of all trials and was measured from either intubation or initiation of ventilation (which may or may not occur simultaneously). It is generally interpreted as intubation and initiation of mechanical ventilation occurring on ICU admission. However, initiation may occur in the operating room or emergency department and the start time point may be difficult to obtain or inconsistently recorded. Furthermore, some trials reported randomization as the start point for “duration of mechanical ventilation.” First, the criteria for randomization vary between trials. Second, enrollment in some trials, for example, investigating weaning methods, are dependent on physician assessment and are prone to bias. Finally, randomization may be delayed by the process of gaining consent, with consent windows up to 24 hours.
We found the end time point for measuring duration of mechanical ventilation was reported as either “free from mechanical ventilation” or extubation. Free from mechanical ventilation was defined as either freedom from invasive ventilation or both invasive and noninvasive ventilation. Timing of extubation may be influenced by organizational issues such as workload and staff availability (84, 85). These organizational issues may vary widely between institutions and across trials. This wide variability in outcome definitions regarding start and end points of mechanical ventilation will not be problematic within a trial provided both arms are equally affected. However, it may lead to systemic variations when comparing trials, highlighting the need for agreed outcome definitions.
In the 12 trials specifically evaluating a ventilation intervention, there was also time point variation in secondary outcomes. When reporting mortality, it is reasonable to choose a longer duration of follow-up when delayed effects are expected, such as in acute respiratory distress syndrome or severe sepsis (86). However, consensus on duration of follow-up is required if trials are to be compared. Length of stay (ICU and hospital) was frequently measured as a secondary outcome. Length of stay is an important health care resource use outcome. However, it has limitations, particular in comparing trials across countries with different health care funding models and resource availability. Furthermore, contextual differences in end-of-life care practices may also affect duration of ventilation and length of stay.
Although this article is the first to provide data showing substantial variation in outcome definitions in ventilation trials, it is not the first to call for improvements in standardizing outcomes in critical care trials. A workshop convened by the National Heart, Lung, and Blood Institute (87) recommended standardization in describing and collecting end points to facilitate meta-analyses of acute lung injury trials; and a Society of Critical Care Medicine stakeholder conference (88) highlighted the necessity of gaining consensus on a standard set of outcome measures for long-term outcomes after ICU discharge.
Our analysis indicates that outcomes reported in trials of ventilation interventions typically measure outcomes in a number of domains: measures of ventilator dependence, adverse outcomes, mortality and survival outcomes, and resource use. For ICU patients, being free from ventilation and survival are clearly important outcomes, but length of stay may not be. Longer term outcomes such as cognitive and physical function and quality of life are often underreported (87, 88). However, the effects of critical illness impacts on patients long after hospital discharge and these longer term outcomes are increasingly being recognized by investigators as being important (89–91). The optimal duration of long-term follow-up remains to be determined.
The common domains that are addressed give rise to the possibility of obtaining agreement on outcome definitions and a core outcome set. A core outcome set would not restrict trialists from measuring additional outcomes, but would overcome problems of variability in outcome selection, measurement, and reporting, thereby enhancing valid comparisons across trials. To address this, we are undertaking a study that will use the Delphi technique to achieve international consensus on core outcome definitions and a core outcome set for use in trials involving mechanical ventilation (http://www.comet-initiative.org/studies/details/292?result=true). We will liaise closely with the International Forum for Acute Care Trialists (InFACT) and the Delphi panel will draw on relevant stakeholders including patient groups, professional societies, clinical trial groups, and industry.
Our search for trials was restricted to a short, but recent, time period and a small number of journals. It does not provide a full, comprehensive overview of ventilation outcomes in trials across a longer time period and a wider range of journals; however, we are confident that we have presented sufficient data to demonstrate significant variability in outcome reporting in recent trials accepted for publication in high-impact journals.
We show substantial variation in the choice of outcome measures and their definition in randomized trials evaluating interventions likely to influence the duration of ventilation. We anticipate that the recent SPIRIT 2013 statement (7) outlining guidance for reporting clinical trial protocols will help investigators provide clear definitions enabling more appropriate comparisons. Expert consensus on, and implementation of, standardized outcome definitions and core outcome sets is fundamental to reducing bias when comparing effects across trials.
| 1. | Glasziou PP, Sanders SL. Investigating causes of heterogeneity in systematic reviews. Stat Med 2002;21:1503–1511. |
| 2. | Williamson PR, Altman DG, Blazeby JM, Clarke M, Devane D, Gargon E, Tugwell P. Developing core outcome sets for clinical trials: issues to consider. Trials 2012;13:132. |
| 3. | Blackwood B, Alderdice F, Burns KE, Cardwell CR, Lavery G, O’Halloran P. Protocolized versus non-protocolized weaning for reducing the duration of mechanical ventilation in critically ill adult patients. Cochrane Database Syst Rev 2010;5:CD006904. |
| 4. | Blackwood B, Murray M, Chisakuta A, Cardwell CR, O’Halloran P. Protocolized versus non-protocolized weaning for reducing the duration of invasive mechanical ventilation in critically ill paediatric patients. Cochrane Database Syst Rev 2013;7:CD009082. |
| 5. | Consolidated Standards of Reporting Trials (CONSORT) [accessed 2013 Sep 1]. Available from: http://www.consort-statement.org/ |
| 6. | World Health Organization. The WHO Registry Network [accessed 2013 Sep 1]. Available from: http://www.who.int/ictrp/network/en/ |
| 7. | Chan AW, Tetzlaff JM, Gøtzsche PC, Altman DG, Mann H, Berlin JA, Dickersin K, Hróbjartsson A, Schulz KF, Parulekar WR, et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ 2013;346:e7586. |
| 8. | Zarin DA, Tse T, Williams RJ, Califf RM, Ide NC. The ClinicalTrials.gov results database—update and key issues. N Engl J Med 2011;364:852–860. |
| 9. | Chan AW, Hróbjartsson A, Haahr MT, Gøtzsche PC, Altman DG. Empirical evidence for selective reporting of outcomes in randomized trials: comparison of protocols to published articles. JAMA 2004;291:2457–2465. |
| 10. | Chan AW, Krleza-Jeric K, Schmid I, Altman DG. Outcome reporting bias in randomized trials funded by the Canadian Institutes of Health Research. CMAJ 2004;171:735–740. |
| 11. | Clarke M. Standardising outcomes for clinical trials and systematic reviews. Trials 2007;8:39. |
| 12. | Core Outcome Measures in Effectiveness Trials (COMET). The COMET database [accessed 2013 Sep 1]. Available from: http://www.comet-initiative.org/ |
| 13. | Agus MS, Steil GM, Wypij D, Costello JM, Laussen PC, Langer M, Alexander JL, Scoppettuolo LA, Pigula FA, Charpie JR, et al.; SPECS Study Investigators. Tight glycemic control versus standard care after pediatric cardiac surgery. N Engl J Med 2012;367:1208–1219. |
| 14. | Bellomo R, Cass A, Cole L, Finfer S, Gallagher M, Lo S, McArthur C, McGuinness S, Myburgh J, Norton R, et al.; RENAL Replacement Therapy Study Investigators. Intensity of continuous renal-replacement therapy in critically ill patients. N Engl J Med 2009;361:1627–1638. |
| 15. | Bjelland TW, Dale O, Kaisen K, Haugen BO, Lydersen S, Strand K, Klepstad P. Propofol and remifentanil versus midazolam and fentanyl for sedation during therapeutic hypothermia after cardiac arrest: a randomised trial. Intensive Care Med 2012;38:959–967. |
| 16. | Blot F, Similowski T, Trouillet JL, Chardon P, Korach JM, Costa MA, Journois D, Thiéry G, Fartoukh M, Pipien I, et al. Early tracheotomy versus prolonged endotracheal intubation in unselected severely ill ICU patients. Intensive Care Med 2008;34:1779–1787. |
| 17. | Boussekey N, Chiche A, Faure K, Devos P, Guery B, d’Escrivan T, Georges H, Leroy O. A pilot randomized study comparing high and low volume hemofiltration on vasopressor use in septic shock. Intensive Care Med 2008;34:1646–1653. |
| 18. | Brunkhorst FM, Engel C, Bloos F, Meier-Hellmann A, Ragaller M, Weiler N, Moerer O, Gruendling M, Oppert M, Grond S, et al.; German Competence Network Sepsis (SepNet). Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 2008;358:125–139. |
| 19. | Brunkhorst FM, Oppert M, Marx G, Bloos F, Ludewig K, Putensen C, Nierhaus A, Jaschinski U, Meier-Hellmann A, Weyland A, et al.; German Study Group Competence Network Sepsis (SepNet). Effect of empirical treatment with moxifloxacin and meropenem vs meropenem on sepsis-related organ dysfunction in patients with severe sepsis: a randomized trial. JAMA 2012;307:2390–2399. |
| 20. | Bucknall TK, Manias E, Presneill JJ. A randomized trial of protocol-directed sedation management for mechanical ventilation in an Australian intensive care unit. Crit Care Med 2008;36:1444–1450. |
| 21. | Carcillo JA, Dean JM, Holubkov R, Berger J, Meert KL, Anand KJ, Zimmerman J, Newth CH, Harrison R, Burr J, et al.; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Collaborative Pediatric Critical Care Research Network (CPCCRN). The randomized comparative pediatric critical illness stress-induced immune suppression (CRISIS) prevention trial. Pediatr Crit Care Med 2012;13:165–173. |
| 22. | Casaer MP, Mesotten D, Hermans G, Wouters PJ, Schetz M, Meyfroidt G, Van Cromphaut S, Ingels C, Meersseman P, Muller J, et al. Early versus late parenteral nutrition in critically ill adults. N Engl J Med 2011;365:506–517. |
| 23. | Craig TR, Duffy MJ, Shyamsundar M, McDowell C, O’Kane CM, Elborn JS, McAuley DF. A randomized clinical trial of hydroxymethylglutaryl-coenzyme A reductase inhibition for acute lung injury (the HARP Study). Am J Respir Crit Care Med 2011;183:620–626. |
| 24. | Mekontso Dessap A, Roche-Campo F, Kouatchet A, Tomicic V, Beduneau G, Sonneville R, Cabello B, Jaber S, Azoulay E, Castanares-Zapatero D, et al. Natriuretic peptide–driven fluid management during ventilator weaning: a randomized controlled trial. Am J Respir Crit Care Med 2012;186:1256–1263. |
| 25. | Davies AR, Morrison SS, Bailey MJ, Bellomo R, Cooper DJ, Doig GS, Finfer SR, Heyland DK; ENTERIC Study Investigators; ANZICS Clinical Trials Group. A multicenter, randomized controlled trial comparing early nasojejunal with nasogastric nutrition in critical illness. Crit Care Med 2012;40:2342–2348. |
| 26. | De Backer D, Biston P, Devriendt J, Madl C, Chochrad D, Aldecoa C, Brasseur A, Defrance P, Gottignies P, Vincent JL; SOAP II Investigators. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med 2010;362:779–789. |
| 27. | Duman N, Tuzun F, Sutcuoglu S, Yesilirmak CD, Kumral A, Ozkan H. Impact of volume guarantee on synchronized ventilation in preterm infants: a randomized controlled trial. Intensive Care Med 2012;38:1358–1364. |
| 28. | Fernandez R, Trenchs X, Klamburg J, Castedo J, Serrano JM, Besso G, Tirapu JP, Santos A, Mas A, Parraga M, et al. Prone positioning in acute respiratory distress syndrome: a multicenter randomized clinical trial. Intensive Care Med 2008;34:1487–1491. |
| 29. | Finfer S, Chittock DR, Su SY, Blair D, Foster D, Dhingra V, Bellomo R, Cook D, Dodek P, Henderson WR, et al.; NICE-SUGAR Study Investigators. Intensive versus conventional glucose control in critically ill patients. N Engl J Med 2009;360:1283–1297. |
| 30. | Foronda FK, Troster EJ, Farias JA, Barbas CS, Ferraro AA, Faria LS, Bousso A, Panico FF, Delgado AF. The impact of daily evaluation and spontaneous breathing test on the duration of pediatric mechanical ventilation: a randomized controlled trial. Crit Care Med 2011;39:2526–2533. |
| 31. | Girard TD, Kress JP, Fuchs BD, Thomason JW, Schweickert WD, Pun BT, Taichman DB, Dunn JG, Pohlman AS, Kinniry PA, et al. Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial. Lancet 2008;371:126–134. |
| 32. | Girault C, Bubenheim M, Abroug F, Diehl JL, Elatrous S, Beuret P, Richecoeur J, L’Her E, Hilbert G, Capellier G, et al.; VENISE Trial Group. Noninvasive ventilation and weaning in patients with chronic hypercapnic respiratory failure: a randomized multicenter trial. Am J Respir Crit Care Med 2011;184:672–679. |
| 33. | Hough CL, Steinberg KP, Taylor Thompson B, Rubenfeld GD, Hudson LD. Intensive care unit–acquired neuromyopathy and corticosteroids in survivors of persistent ARDS. Intensive Care Med 2009;35:63–68. |
| 34. | Jack T, Boehne M, Brent BE, Hoy L, Köditz H, Wessel A, Sasse M. In-line filtration reduces severe complications and length of stay on pediatric intensive care unit: a prospective, randomized, controlled trial. Intensive Care Med 2012;38:1008–1016. |
| 35. | Jakob SM, Ruokonen E, Grounds RM, Sarapohja T, Garratt C, Pocock SJ, Bratty JR, Takala J; Dexmedetomidine for Long-Term Sedation Investigators. Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials. JAMA 2012;307:1151–1160. |
| 36. | Jansen TC, van Bommel J, Schoonderbeek FJ, Sleeswijk Visser SJ, van der Klooster JM, Lima AP, Willemsen SP, Bakker J; LACTATE Study Group. Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial. Am J Respir Crit Care Med 2010;182:752–761. |
| 37. | Knight DJ, Gardiner D, Banks A, Snape SE, Weston VC, Bengmark S, Girling KJ. Effect of synbiotic therapy on the incidence of ventilator associated pneumonia in critically ill patients: a randomised, double-blind, placebo-controlled trial. Intensive Care Med 2009;35:854–861. |
| 38. | Kollef MH, Afessa B, Anzueto A, Veremakis C, Kerr KM, Margolis BD, Craven DE, Roberts PR, Arroliga AC, Hubmayr RD, et al.; NASCENT Investigation Group. Silver-coated endotracheal tubes and incidence of ventilator-associated pneumonia: the NASCENT randomized trial. JAMA 2008;300:805–813. |
| 39. | Gupta K, Gupta VK, Jayashree M, Singhi S. Randomized controlled trial of interrupted versus continuous sedative infusions in ventilated children. Pediatric Crit Care Med 2012;13:131–135. |
| 40. | Lacherade JC, De Jonghe B, Guezennec P, Debbat K, Hayon J, Monsel A, Fangio P, Appere de Vecchi C, Ramaut C, Outin H, et al. Intermittent subglottic secretion drainage and ventilator-associated pneumonia: a multicenter trial. Am J Respir Crit Care Med 2010;182:910–917. |
| 41. | Manzanares W, Biestro A, Torre MH, Galusso F, Facchin G, Hardy G. High-dose selenium reduces ventilator-associated pneumonia and illness severity in critically ill patients with systemic inflammation. Intensive Care Med 2011;37:1120–1127. |
| 42. | Meade MO, Cook DJ, Guyatt GH, Slutsky AS, Arabi YM, Cooper DJ, Davies AR, Hand LE, Zhou Q, Thabane L, 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;299:637–645. |
| 43. | Mehta S, Burry L, Martinez-Motta JC, Stewart TE, Hallett D, McDonald E, Clarke F, Macdonald R, Granton J, Matte A, et al.; Canadian Critical Care Trials Group. A randomized trial of daily awakening in critically ill patients managed with a sedation protocol: a pilot trial. Crit Care Med 2008;36:2092–2099. |
| 44. | Mehta S, Burry L, Cook D, Fergusson D, Steinberg M, Granton J, Herridge M, Ferguson N, Devlin J, Tanios M, et al.; SLEAP Investigators; Canadian Critical Care Trials Group. Daily sedation interruption in mechanically ventilated critically ill patients cared for with a sedation protocol: a randomized controlled trial. JAMA 2012;308:1985–1992. |
| 45. | Mercat A, Richard JC, Vielle B, Jaber S, Osman D, Diehl JL, Lefrant JY, Prat G, Richecoeur J, Nieszkowska A, 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;299:646–655. |
| 46. | Mesnil M, Capdevila X, Bringuier S, Trine PO, Falquet Y, Charbit J, Roustan JP, Chanques G, Jaber S. Long-term sedation in intensive care unit: a randomized comparison between inhaled sevoflurane and intravenous propofol or midazolam. Intensive Care Med 2011;37:933–941. |
| 47. | Morrow LE, Kollef MH, Casale TB. Probiotic prophylaxis of ventilator-associated pneumonia: a blinded, randomized, controlled trial. Am J Respir Crit Care Med 2010;182:1058–1064. |
| 48. | Myburgh JA, Finfer S, Bellomo R, Billot L, Cass A, Gattas D, Glass P, Lipman J, Liu B, McArthur C, et al.; CHEST Investigators; Australian and New Zealand Intensive Care Society Clinical Trials Group. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med 2012;367:1901–1911. |
| 49. | Navalesi P, Frigerio P, Moretti MP, Sommariva M, Vesconi S, Baiardi P, Levati A. Rate of reintubation in mechanically ventilated neurosurgical and neurologic patients: evaluation of a systematic approach to weaning and extubation. Crit Care Med 2008;36:2986–2992. |
| 50. | Nguyen NQ, Besanko LK, Burgstad C, Bellon M, Holloway RH, Chapman M, Horowitz M, Fraser RJ. Delayed enteral feeding impairs intestinal carbohydrate absorption in critically ill patients. Crit Care Med 2012;40:50–54. |
| 51. | Nseir S, Zerimech F, Fournier C, Lubret R, Ramon P, Durocher A, Balduyck M. Continuous control of tracheal cuff pressure and microaspiration of gastric contents in critically ill patients. Am J Respir Crit Care Med 2011;184:1041–1047. |
| 52. | Paine R III, Standiford TJ, Dechert RE, Moss M, Martin GS, Rosenberg AL, Thannickal VJ, Burnham EL, Brown MB, Hyzy RC. A randomized trial of recombinant human granulocyte-macrophage colony stimulating factor for patients with acute lung injury. Crit Care Med 2012;40:90–97. |
| 53. | Pandharipande PP, Pun BT, Herr DL, Maze M, Girard TD, Miller RR, Shintani AK, Thompson JL, Jackson JC, Deppen SA, et al. Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial. JAMA 2007;298:2644–2653. |
| 54. | Papazian L, Forel JM, Gacouin A, Penot-Ragon C, Perrin G, Loundou A, Jaber S, Arnal JM, Perez D, Seghboyan JM, et al.; ACURASYS Study Investigators. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med 2010;363:1107–1116. |
| 55. | Patman S, Jenkins S, Stiller K. Physiotherapy does not prevent, or hasten recovery from, ventilator-associated pneumonia in patients with acquired brain injury. Intensive Care Med 2009;35:258–265. |
| 56. | Payen JF, Dupuis C, Trouve-Buisson T, Vinclair M, Broux C, Bouzat P, Genty C, Monneret D, Faure P, Chabre O, et al. Corticosteroid after etomidate in critically ill patients: a randomized controlled trial. Crit Care Med 2012;40:29–35. |
| 57. | Perner A, Haase N, Guttormsen AB, Tenhunen J, Klemenzson G, Åneman A, Madsen KR, Møller MH, Elkjær JM, Poulsen LM, 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;367:124–134. |
| 58. | Rice TW, Mogan S, Hays MA, Bernard GR, Jensen GL, Wheeler AP. Randomized trial of initial trophic versus full-energy enteral nutrition in mechanically ventilated patients with acute respiratory failure. Crit Care Med 2011;39:967–974. |
| 59. | Riker RR, Shehabi Y, Bokesch PM, Ceraso D, Wisemandle W, Koura F, Whitten P, Margolis BD, Byrne DW, Ely EW, et al.; SEDCOM (Safety and Efficacy of Dexmedetomidine Compared with Midazolam) Study Group. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA 2009;301:489–499. |
| 60. | Röhm KD, Wolf MW, Schöllhorn T, Schellhaass A, Boldt J, Piper SN. Short-term sevoflurane sedation using the Anaesthetic Conserving Device after cardiothoracic surgery. Intensive Care Med 2008;34:1683–1689. |
| 61. | Rose L, Presneill JJ, Johnston L, Cade JF. A randomised, controlled trial of conventional versus automated weaning from mechanical ventilation using SmartCare/PS. Intensive Care Med 2008;34:1788–1795. |
| 62. | Ruokonen E, Parviainen I, Jakob SM, Nunes S, Kaukonen M, Shepherd ST, Sarapohja T, Bratty JR, Takala J; “Dexmedetomidine for Continuous Sedation” Investigators. Dexmedetomidine versus propofol/midazolam for long-term sedation during mechanical ventilation. Intensive Care Med 2009;35:282–290. |
| 63. | Russell JA, Walley KR, Singer J, Gordon AC, Hébert PC, Cooper DJ, Holmes CL, Mehta S, Granton JT, Storms MM, et al.; VASST Investigators. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008;358:877–887. |
| 64. | Schädler D, Engel C, Elke G, Pulletz S, Haake N, Frerichs I, Zick G, Scholz J, Weiler N. Automatic control of pressure support for ventilator weaning in surgical intensive care patients. Am J Respir Crit Care Med 2012;185:637–644. |
| 65. | Schweickert WD, Pohlman MC, Pohlman AS, Nigos C, Pawlik AJ, Esbrook CL, Spears L, Miller M, Franczyk M, Deprizio D, et al. Early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomised controlled trial. Lancet 2009;373:1874–1882. |
| 66. | Gao Smith F, Perkins GD, Gates S, Young D, McAuley DF, Tunnicliffe W, Khan Z, Lamb SE; 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;379:229–235. |
| 67. | Spies C, Macguill M, Heymann A, Ganea C, Krahne D, Assman A, Kosiek HR, Scholtz K, Wernecke KD, Martin J. A prospective, randomized, double-blind, multicenter study comparing remifentanil with fentanyl in mechanically ventilated patients. Intensive Care Med 2011;37:469–476. |
| 68. | Strøm T, Martinussen T, Toft P. A protocol of no sedation for critically ill patients receiving mechanical ventilation: a randomised trial. Lancet 2010;375:475–480. |
| 69. | Taccone P, Pesenti A, Latini R, Polli F, Vagginelli F, Mietto C, Caspani L, Raimondi F, Bordone G, Iapichino G, et al.; Prone-Supine II Study Group. Prone positioning in patients with moderate and severe acute respiratory distress syndrome: a randomized controlled trial. JAMA 2009;302:1977–1984. |
| 70. | Talmor D, Sarge T, Malhotra A, O’Donnell CR, Ritz R, Lisbon A, Novack V, Loring SH. Mechanical ventilation guided by esophageal pressure in acute lung injury. N Engl J Med 2008;359:2095–2104. |
| 71. | Templeton M, Palazzo MG. Chest physiotherapy prolongs duration of ventilation in the critically ill ventilated for more than 48 hours. Intensive Care Med 2007;33:1938–1945. |
| 72. | Terragni PP, Antonelli M, Fumagalli R, Faggiano C, Berardino M, Pallavicini FB, Miletto A, Mangione S, Sinardi AU, Pastorelli M, et al. Early vs late tracheotomy for prevention of pneumonia in mechanically ventilated adult ICU patients: a randomized controlled trial. JAMA 2010;303:1483–1489. |
| 73. | Thomas NJ, Guardia CG, Moya FR, Cheifetz IM, Markovitz B, Cruces P, Barton P, Segal R, Simmons P, Randolph AG; PALISI Network. A pilot, randomized, controlled clinical trial of lucinactant, a peptide-containing synthetic surfactant, in infants with acute hypoxemic respiratory failure. Pediatr Crit Care Med 2012;13:646–653. |
| 74. | Treggiari MM, Romand JA, Yanez ND, Deem SA, Goldberg J, Hudson L, Heidegger CP, Weiss NS. Randomized trial of light versus deep sedation on mental health after critical illness. Crit Care Med 2009;37:2527–2534. |
| 75. | Tsangaris I, Galiatsou E, Kostanti E, Nakos G. The effect of exogenous surfactant in patients with lung contusions and acute lung injury. Intensive Care Med 2007;33:851–855. |
| 76. | Vaschetto R, Turucz E, Dellapiazza F, Guido S, Colombo D, Cammarota G, Della Corte F, Antonelli M, Navalesi P. Noninvasive ventilation after early extubation in patients recovering from hypoxemic acute respiratory failure: a single-centre feasibility study. Intensive Care Med 2012;38:1599–1606. |
| 77. | Welzing L, Oberthuer A, Junghaenel S, Harnischmacher U, Stützer H, Roth B. Remifentanil/midazolam versus fentanyl/midazolam for analgesia and sedation of mechanically ventilated neonates and young infants: a randomized controlled trial. Intensive Care Med 2012;38:1017–1024. |
| 78. | Xirouchaki N, Kondili E, Vaporidi K, Xirouchakis G, Klimathianaki M, Gavriilidis G, Alexandopoulou E, Plataki M, Alexopoulou C, Georgopoulos D. Proportional assist ventilation with load-adjustable gain factors in critically ill patients: comparison with pressure support. Intensive Care Med 2008;34:2026–2034. |
| 79. | Egleston BL, Scharfstein DO, Freeman EE, West SK. Causal inference for non-mortality outcomes in the presence of death. Biostatistics 2007;8:526–545. |
| 80. | Sevransky JE, Checkley W, Martin GS. Critical care trial design and interpretation: a primer. Crit Care Med 2010;38:1882–1889. |
| 81. | Lau B, Cole SR, Gange SJ. Competing risk regression models for epidemiologic data. Am J Epidemiol 2009;170:244–256. |
| 82. | Checkley W, Brower RG, Muñoz A; NIH Acute Respiratory Distress Syndrome Network Investigators. Inference for mutually exclusive competing events through a mixture of generalized gamma distributions. Epidemiology 2010;21:557–565. |
| 83. | 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(6 Suppl):S96–S105. |
| 84. | Blackwood B, Wilson-Barnett J, Trinder J. Protocolized weaning from mechanical ventilation: ICU physicians’ views. J Adv Nurs 2004;48:26–34. |
| 85. | Krishnan JAMD, Moore D, Robeson C, Rand CS, Fessler HE. A prospective, controlled trial of a protocol-based strategy to discontinue mechanical ventilation. Am J Respir Crit Care Med 2004;169:673–678. |
| 86. | Rubenfeld GD, Angus DC, Pinsky MR, Curtis JR, Connors AF Jr, Bernard GR; Members of the Outcomes Research Workshop. Outcomes research in critical care: results of the American Thoracic Society Critical Care Assembly Workshop on Outcomes Research. Am J Respir Crit Care Med 1999;160:358–367. |
| 87. | Spragg RG, Bernard GR, Checkley W, Curtis JR, Gajic O, Guyatt G, Hall J, Israel E, Jain M, Needham DM, et al. Beyond mortality: future clinical research in acute lung injury. Am J Respir Crit Care Med 2010;181:1121–1127. |
| 88. | Needham DM, Davidson J, Cohen H, Hopkins RO, Weinert C, Wunsch H, Zawistowski C, Bemis-Dougherty A, Berney SC, Bienvenu OJ, et al. Improving long-term outcomes after discharge from intensive care unit: report from a stakeholders’ conference. Crit Care Med 2012;40:502–509. |
| 89. | Needham DM, Dinglas VD, Bienvenu OJ, Colantuoni E, Wozniak AW, Rice TW, Hopkins RO; NIH NHLBI ARDS Network. One year outcomes in patients with acute lung injury randomised to initial trophic or full enteral feeding: prospective follow-up of EDEN randomised trial. BMJ 2013;346:f1532. |
| 90. | Needham DM, Dinglas VD, Morris PE, Jackson JC, Hough CL, Mendez-Tellez PA, Wozniak AW, Colantuoni E, Ely EW, Rice TW, et al.; NIH NHLBI ARDS Network. Physical and cognitive performance of patients with acute lung injury 1 year after initial trophic versus full enteral feeding: EDEN trial follow-up. Am J Respir Crit Care Med 2013;188:567–576. |
| 91. | Peek GJ, Mugford M, Tiruvoipati R, Wilson A, Allen E, Thalanany MM, Hibbert CL, Truesdale A, Clemens F, Cooper N, 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;374:1351–1363. |
Author Contributions: B.B., L.R., D.F.M., and M.C. have been involved in the conception and design of the study; B.B., P.J.M., and L.R. have been involved in data acquisition and data extraction; B.B., L.R., D.F.M., J.C.M., and M.C. have been involved in analysis and interpretation of the data; all authors have contributed to writing the article before submission.
This article has an online supplement, which is accessible from this issue’s table of contents online at www.atsjournals.org
Originally Published in Press as DOI: 10.1164/rccm.201309-1645PP on February 10, 2014
Author disclosures are available with the text of this article at www.atsjournals.org.
