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. Author manuscript; available in PMC: 2017 Sep 1.
Published in final edited form as: Crit Care Med. 2014 Oct;42(10):2278–2289. doi: 10.1097/CCM.0000000000000504

Tidal Volume and Plateau Pressure Use for Acute Lung Injury from 2000 to Present: A Systematic Literature Review

Dharmvir S Jaswal 1,3, Janice M Leung 1,3, Junfeng Sun 1, Xizhong Cui 1, Yan Li 1, Steven Kern 1, Judith Welsh 2, Charles Natanson 1, Peter Q Eichacker 1
PMCID: PMC5579487  NIHMSID: NIHMS895627  PMID: 25098333

Abstract

Objective

Since publication of the ARMA trial in 2000, use of tidal volumes (VT) ≤6 mL/kg predicted body weight (PBW) with corresponding plateau airway pressures (PPlat) ≤30 cmH2O has been advocated for acute lung injury (ALI). However, compliance with these recommendations is unknown. We therefore investigated VT (mL/kg PBW) and PPlat (cmH2O) practices reported in studies of ALI since ARMA using a systematic literature review (i.e. not a meta-analysis).

Data Sources

PubMed, Scopus, and EMBASE.

Study Selection

Randomized controlled trials (RCTs) and non-randomized studies (NRS) enrolling ALI patients from May 2000 to June 2013 and reporting VT.

Data Extraction

Whether the study was an RCT or NRS and performed or not at an ARDSNetwork center; in RCTs, the pre- and post-randomization VT (mL/kg PBW) and PPlat (cmH2O) and whether a VT protocol was used post-randomization; in NRSs, baseline VT and PPlat.

Data Synthesis

Twenty-two RCTs and 71 NRSs were included. Since 2000 at ARDSNetwork centers, routine VT was similar comparing RCTs and NRSs (p=0.25) and unchanged over time (p=0.75) with a mean value of 6.81(95%CI: 6.45,7.18). At non-ARDSNetwork centers routine VT was also similar when comparing RCTs and NRSs (p=0.71), but decreased (p=0.001); the most recent estimate for it was 6.77(6.22,7.32). All VT estimates were significantly >6 (p≤0.02). In RCTs employing VT protocols, routine VT was reduced in both ARDSNetwork (n=4) and non-ARDSNetwork (n=11) trials (p≤0.01 for both), but even post-randomization was >6 [6.47(6.29,6.65) and 6.80(6.42,7.17), respectively; p≤0.0001 for both)]. In 59 studies providing data, routine PPlat, averaged across ARDSNetwork or non-ARDSNetwork centers was significantly <30 (p≤0.02).

Conclusion

For clinicians treating ALI since 2000, achieving VT ≤6 mL/kg PBW may not have been as attainable or important as PPlat ≤30 cmH2O.. If so, there may be equipoise to test if VT ≤6 mL/kg PBW are necessary to improve ALI outcome.

Keywords: acute respiratory distress syndrome, acute lung injury, mechanical ventilation, tidal volume, ARDS

Introduction

Mechanical ventilation, although a lifesaving therapy for acute lung injury (ALI), including the adult respiratory distress syndrome (ARDS), can also aggravate injury.1–3 During the 1990s, randomized controlled trials (RCTs) studied different tidal volume (VT) levels to minimize such injury.4–8 The largest trial (ARMA), conducted by the ARDS Network (ARDSNet), reported that a protocol reducing VT to 4 to 6 mL/kg predicted body weight (PBW) and plateau pressures (PPlat) to ≤30 cmH2O, significantly decreased mortality from 40 to 31% when compared to a protocol targeting a “traditional” control VT of 12 mL/kg PBW (See Appendix 1 for the methods used in patients randomized to the low tidal volume arm of the ARMA trial).9 Since the ARMA trial was published in 2000, this low VT (LVT) protocol10,11 (also referred to as the lung protective ventilation protocol12) has been advocated by the ARDSNet (Appendix 2), as well as the Surviving Sepsis Campaign Guidelines (SSC) 13, the Institute for Healthcare Improvement,14 and the German Sepsis Society.15 Adherence to mechanical ventilation with VT ≤6 mL/kg PBW has also been stipulated for use in RCTs testing new therapies for ALI and has even been recommended for mechanically ventilated patients without ALI.16,17

Despite these recommendations, evidence suggests that physicians have not routinely maintained VT ≤6 mL/kg PBW in patients with ALI. Surveys in the United States (US),18 Ireland,19 Finland,20 Mexico,21 and Canada22 over the past ten years reported routine VT (±SD) in ALI patients greater than 6 mL/kg PBW (7.0±1.6, 8.4±2.0, 8.6±1.9, 8.3±3.0, and 9.0±2.5, respectively). Recently published RCTs of ALI/ARDS from the US and Europe beginning enrollment in 2006 also reported routine VT ≥6 mL/kg PBW (7.3±1.5 and 8.1±1.8, respectively averaged over study groups).23,24 However, routine PPlat in these studies were ≤30 cmH2O. We therefore hypothesized that since publication of the ARMA trial, although widely advocated, VT ≤6 mL/kg PBW have not routinely been used in patients. To test this hypothesis, we performed a systematic literature review (i.e. not a meta-analysis) and analyzed VT and accompanying PPlat used for ALI in RCTs and non-randomized studies (NRS) conducted since ARMA.

Materials and Methods

Literature Search

PubMed, Scopus, and EMBASE databases were searched employing the search terms and strategy summarized in Appendix 3. The search was limited to human subjects, the English language, and publication dates from May 2000 until June 2013. References from retrieved reports were examined for additional studies. Both RCTs and NRSs (i.e. observational studies or uncontrolled treatment studies) were analyzed if the patient population studied met diagnostic criteria for ALI 25; the date of initial enrollment followed publication of the ARMA trial (May 4, 2000); and the average routine VT for the population studied were reported. Two authors (DJ and PQE) independently reviewed all citations and abstracts followed by relevant full text articles to determine study suitability. Disagreements were resolved by consensus. This study was reviewed by local IRB and was deemed exempt from approval.

Data Extraction

Extracted data from selected studies included the following: the number of enrolled patients; patient ages and sex; VT (in mL/kg PBW); PPlat; risk factors for ALI; baseline PaO2:FiO2 ratios; and Acute Physiology and Chronic Health Evaluation II scores (APACHE-II), Lung Injury scores (LIS), and Simplified Acute Physiology scores (SAPS II); reported mortality rates; exclusion criteria; whether the trial took place at a single center or multiple centers; geographic location; location of the trial at either an ARDSNet or non-ARDSNet center; and for RCTs, whether an LVT protocol based on the ARMA trial or similar criteria was employed following patient randomization. For RCTs VT pre-randomization and the first VT reported post-randomization (if available) were recorded whereas for NRSs the baseline VT was recorded. For studies providing data for individual patients, group mean values were calculated. Pre-randomization and baseline VT and PPlat were considered routine ones. For studies in which VT were provided in mL/kg or total mL only, attempts were made to contact corresponding authors to obtain VT in mL/kg PBW. Tidal volumes based on ideal body weight (IBW) were considered comparable to ones based on PBW.9,26–34 If only VT in mL/kg total body weight was available, then a conversion factor was applied based on previous literature documenting a difference of +1.55 mL/kg between VT per PBW and VT per total body weight.20 This conversion was necessary for one RCT and nine non-RCTs.35–44 For 56 studies providing VT in mL only, investigators from 4 subsequently provided it in mL/kg PBW or mL/kg IBW. 29,35,39,45 Remaining studies were excluded.

Data Analysis

All analyses were done using R packages meta and metafor unless stated otherwise. For studies with more than one group, VT and PPlat data were first combined to generate study level summary statistics.26–28,30,31,46–51 This was justified because there was little difference between treatment groups within each study. Random-effect meta-analysis and meta-regression were performed with inverse-variance weighting and estimated using restricted maximum likelihood. While these were the most appropriate methods for our analysis, this is not a standard meta-analysis since tidal volume is not the experimental treatment or outcome, and it is similar across treatment groups. The month and year of initial enrollment for studies were used for analysis. For two RCTs and six NRSs only initial years of enrollment were available for analysis (Tables E1 and E2).38,43,51–56 The 95% confidence bands were estimated and plotted in Figures 2 and 4. The change in VT (pre- versus post-randomization) were analyzed via a special bivariate meta-analysis random effect model57 using SAS version 9.3. Two-sided p-values ≤0.05 were considered significant.

Figure 2.

Figure 2

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Mean tidal volume (VT) for the various types of centers and trials are shown. The area of each circle is proportional to the inverse of the variance associated with each mean VT value. The solid diagonal line in each panel represents the weighted regression line and the dashed lines represent the 95% CIs for the relationship between baseline VT and the date of initial enrollment into trials in each group. Equations for the weighted regression lines and p-values for the slope of the line are shown for each group of studies. A horizontal line denoting a 6 mL/kg PBW VT is shown in each panel for reference to the VT targeted in the ARDSNet LVT protocol. Panels E and F show data post-randomization VT in RCTs employing low VT protocols.

Figure 4.

Figure 4

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Mean plateau pressure (PPlat) for the various types of centers and trials are shown. The area of each circle is proportional to the inverse of the variance associated with each mean PPlat value. The solid diagonal line in each panel represents the weighted regression line and the dashed lines represent the 95% CIs for the relationship between baseline PPlat and the year of the start of enrollment for each group of trials. Equations for the weighted regression lines and p-values for the slope of the line are shown. These equations were available for all groups of studies except for nonrandomized studies at ARDSNet centers (Panel B) in which there were too few studies to fit a regression line. A horizontal line denoting a PPlat of 30 cmH2O is included for reference. Panels E and F show data post-randomization PPlat in RCTs employing low VT protocols.

Results

Literature Search and Study Characteristics

A literature search yielded 3,328 references. After independent review and subsequent discussion, the authors assessing individual studies (DSJ and PQE) were in agreement that 93 of these studies met inclusion criteria (Figure 1). Of these, 22 were RCTs23,24,43,52,58–75 (totaling 7,503 patients) and 71 were NRSs 19–22,26–42,44–51,53–56,76–113 (totaling 5,376 patients). Characteristics of these trials and studies are listed in Tables E1 and E2 in the electronic supplement while patient baseline data are listed in Tables E3 to E6.

Figure 1.

Figure 1

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This figure is a flow chart that summarizes the results of the literature search employed and the selection of trials for analysis in this study. From 3,328 references, 93 studies (22 randomized controlled trials and 71 non-randomized studies) met criteria for inclusion.

Routine Tidal Volumes

We first examined the mean VT (ml/kg PBW) routinely prescribed for patients in four groups of studies: pre-randomization in RCTs or at baseline in NRSs at ARDSNet (Figure 2, Panels A and B, respectively) or non-ARDSNet centers (Figure 2, Panels C and D, respectively). The area of each circle in Figure 2 is proportional to the inverse of the variance associated with the mean VT value for each study. A weighted regression line with 95% confidence intervals (CI) for the relationship over the study period (May 2000 to June 2013) between VT and date of initial study enrollment is shown for each of the four groups of trials. Baseline VT was not significantly associated with baseline PaO2:FiO2 or PPlat (each p=ns) (Tables E5 and E6). Other baseline measures of disease severity were reported in fewer than 50% of studies and were not analyzed. Across the study period, routine mean VT were >6 ml/kg PBW in 87 of the 93 studies analyzed. At ARDSNet centers, while the value of routinely prescribed VT decreased over the study period in a pattern that approached significance for RCTs [rate of annual change in VT (mL/kg PBW) (95% CI)] [−0.07 (−0.14, 0.006), p=0.07], routine VT did not change significantly in NRSs [0.06 (−0.40, 0.52), p=0.81]. At non-ARDSNet centers, routine VT did not change significantly in RCTs [−0.07 (−0.25, 0.10), p=0.40] but did decrease significantly in NRSs [−0.14 (−0.22, −0.05), p=0.002]. Since changes in VT comparing RCTs versus NRSs at either ARDSNet or non-ARDSNet centers were not significantly different (p=0.60 and 0.58, respectively), we calculated common slopes to increase the detection of significant reductions over time. After combining RCTs and NRSs, the mean annual VT change over the study period was still not significant for ARDSNet centers [−0.03 (−0.21, 0.15), p=0.75] but was for non-ARDSNet centers [−0.13 (−0.20, −0.05), p=0.001].

We then compared routine VT at ARDSNet and non-ARDSNet centers to the widely recommended goal of 6 mL/kg PBW. At ARDSNet centers, where routine VT have not changed significantly over the study period, VT was significantly higher than 6 mL/kg PBW [6.81 (6.45, 7.18), p≤0.0001]. Furthermore, at non-ARDSNet centers, where there have been significant decreases in VT over the study period, even the estimated mean VT (95% CI) at the time of the most recent study did not meet this goal and was significantly greater than 6 mL/kg PBW [6.77 (6.22, 7.32); p=0.006].

Changes in Tidal Volumes Following Randomization in RCTs

We next examined how VT changed from pre- to post-randomization in RCTs. Four of 5 ARDSNet and 11 of the 14 non-ARDSNet center RCTs reported post-randomization VT and also stipulated use of a LVT protocol during the post-randomization period (Table E1). Three non-ARDSNet center RCTs that reported post-randomization VT did not stipulate such a protocol (Table E1). For RCTs stipulating an LVT protocol, all ARDSNet23,59,64,71,73 and four non-ARDSNet centers24,58,63,67 described employing the ARDSNet LVT protocol while five non-ARDSNet centers targeted a VT of 6 mL/kg PBW52,60,61,72,74 and five non-ARDSNet centers targeted a VT of 6 to 8 mL/kg PBW.62,65,68,69,75 Figure 3 shows mean (±SE) VT pre- and post-randomization for ARDSNet RCTs (Figure 3A) and for non-ARDSNet RCTs that either did (Figure 3B) or did not (Figure 3C) stipulate the use of an LVT protocol. In RCTs employing an LVT protocol, post-randomization VT increased over time at ARDSNet centers [slope: 0.04 (0.02, 0.07), p=0.0003] but not at non-ARDSNet centers [slope: 0.01 (−0.15, 0.18), p=0.86] (Figure 2, Panels E and F). Across RCTs, mean (95% CI) changes in VT from pre- to post-randomization were highly significant for ARDSNet and non-ARDSNet RCTs employing an LVT protocol [−0.67 (−1.206, −0.14), p=.01, and −0.66 (−0.96, −0.36), p<0.0001, respectively] but not for non-ARDSNet trials not reporting using a protocol [0.03 (−0.56, 0.62), p=0.91]. Despite significant reductions in VT in RCTs stipulating an LVT protocol, the mean (95% CI) post-randomization VT at ARDSNet [6.47 (6.29, 6.65)] and non-ARDSNet [6.80 (6.42, 7.17)] centers were still significantly greater than 6 mL/kg PBW over the study period (both p≤0.0001).

Figure 3.

Figure 3

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This figure compares mean tidal volumes (VT, ±SE) pre-randomization (open circles) and post-randomization (closed circles) in RCTs at ARDSNet centers (Figure 3A) and at non-ARDSNet centers that either did (Figure 3B) or did not (Figure 3C) stipulate the use of a low VT protocol for patients after randomization. The figures in the insets in each panel show the estimated mean pre- and post-randomization VT in each group of trials with p-values reflecting the significance for the change in VT.

Routine Plateau Pressures

Eighteen RCTs and 41 NRSs reported PPlat. Figure 4 shows the routine mean PPlat in patients pre-randomization in RCTs and at baseline in NRSs at ARDSNet (Panels A and B, respectively) and non-ARDSNet (Panels C and D, respectively) centers. Routine PPlat were ≤30 cmH2O in 48 out of 59 studies. In ARDSNet RCTs, although routine PPlat was already ≤30 cmH2O at the start of the decade (26.4, (25.8,26.9) p<0.0001), it decreased further across the years studied [rate of annual change in PPlat (cmH2O) (95% CI)] [−0.33 (−0.42, −0.25), p<0.0001]. In ARDSNet NRSs, and in non-ARDSNet RCTs and NRSs, routinely prescribed PPlat did not change significantly [−0.30 (−2.36, 1.76), p=0.78; 0.16 (−0.62, 0.94), p=0.69; and 0.20 (−0.37, 0.76), p=0.49, respectively] and the mean values over the study period were all significantly <30 cmH2O [26.6(23.7,29.6), p=0.02; 26.8(25.1,28.6), p=0.0003; and 27.2(25.6,28.8); p≤0.0007, respectively].

In RCTs that stipulated use of an LVT protocol, PPlat post-randomization decreased over the study period at ARDSNet [−0.31(−0.55, −0.08), p=0.009) but not at non-ARDSNet centers [0.53(−0.29,1.34), p=0.20] (Figure 4, Panels E and F). Post-randomization mean PPlat were ≤30 cmH2O in all but two of these trials.

Discussion

Since the ARMA trial, routine VT administered to ALI patients at academic centers has decreased significantly at non-ARDSNet but not at ARDSNet centers. However, when routine VT were either averaged over this time period for ARDSNet centers [mean (95%CI) mL/kg PBW] [6.81 (6.45, 7.18)], or estimated at the time of the most recent RCTs or NSRs at non-ARDSNet centers [6.77 (6.22, 7.32)], these remained 10 to 15% significantly greater than the 6 mL/kg PBW VT widely recommended based on the ARDSNetwork LVT protocol.9 Highlighting differences between actual and recommended practice, in RCTs at both ARDSNet and non-ARDSNet centers stipulating an LVT protocol post-randomization, enrolled patients on average have had their routine VT reduced significantly. However, even after these reductions, VT in these trials [6.47 (6.29, 6.65) and 6.80 (6.42, 7.17) respectively] remained significantly greater than 6 mL/kg PBW.

Failure to routinely employ the ARDSNet LVT and to achieve its stated VT goal has frequently been invoked as evidence that physicians do not effectively incorporate clinical research results and thereby potentially jeopardize patient care.114,115 In 2009, investigators at the University of Washington noted “…since the publication of the landmark randomized trial demonstrating the efficacy of lung protective ventilation (LPV), a large proportion of patients with ALI still receive mechanical ventilation with tidal volumes above the goal of 6 mL/kg predicted body weight. Barriers to the delivery of LPV include concern about adverse effects of low tidal volumes, inadequate knowledge of the LPV protocol, under-recognition of ALI, and an unwillingness of the bedside physician to relinquish control of the ventilator.”11 However, there are alternative explanations for this discrepancy.

One explanation is that rather than targeting a specific VT level, physicians adjust VT based on airway pressures such as a PPlat ≤30 cmH2O. 84,116 Titrating to such a PPlat does not always necessitate the level of VT recommended with the LVT protocol. In the absence of higher airway pressures, physicians may be more concerned about the potential adverse effects of lower VT (e.g. patient-ventilator dyssynchrony, hypercapnia, and hypoxemia).12 Analysis of physician practice including ARMA trial pre-randomization data, suggests that physicians have routinely adjusted VT based on airway pressures or measures of lung compliance.117–120 Notably, the widely advocated SSC sepsis bundles,121 (in contrast to the SSC guidelines), directed titration of VT to achieve a PPlat ≤30 cmH2O but did not recommend a specific VT level. This component of the bundles has been well adhered.122,123 Consistent with such practice, in the present study, although baseline VT were greater than those targeted in the ARDSNet LVT protocol, baseline PPlat were ≤30 cmH2O in the majority of studies.

Concerns regarding the design and interpretation of the ARMA trial may have also limited acceptance of the LVT protocol. At the trial’s publication, questions were raised as to whether it had demonstrated benefit with low VT as opposed to introducing harm with the high “traditional” control VT of 12 mL/kg PBW.124 Post-randomization airway pressures (mean±SE) in these controls (34.1±0.4 cmH2O) were greater than before randomization in these subjects (30.3±0.6 cmH2O) as well as in control patients not having their VT raised after randomization in other VT trials (≤30 cmH2O).120 Such differences have confounded meta-analyses of VT trials and prevented a definitive conclusion about the benefit of the ARDSNet LVT protocol.125 By not including a control group in ARMA representing conventional therapy, the trial was unable to demonstrate that the LVT protocol improved survival compared to routine care.126 A recent large observational study did report that adherence to the ARDSNet LVT protocol based on reductions in VT and PPlat alone or together, was associated with reduced mortality in ALI patients.127 However, this study’s observational design and use of both VT and PPlat to assess adherence to the ARDSNet protocol potentially complicate its interpretation.

In contrast to routine care, our findings suggest that application of LVT protocols are frequently stipulated in RCTs investigating new therapies for ALI and that their use was associated with patients receiving significantly lower VT after enrollment than before. On the one hand, these reductions suggest that the presence and use of LVT protocols may increase prescription of lower tidal volumes.128 However, this discrepancy in VT use comparing pre- and post-randomization periods also raises concerns. First, administration of VT during the investigation of a new therapy that on average differ from routine ones may confound interpretation of that therapy’s effects during later clinical use. Such discrepancies may have the greatest impact for new therapies related to ventilator management. For example, maneuvers to promote airway recruitment might result in greater improvements in oxygenation in the setting of lower VT, which increases the potential for atelectasis, compared to higher VT. The second concern relates to the potential for practice misalignments to develop.120 As noted above, several lines of evidence indicates that physicians routinely titrate VT based on airway pressures (e.g. PPlat) and the underlying severity of lung injury as reflected by lung compliance. Patients with less severe lung injury and better lung compliance receive higher VT than patients with more severe disease and lower compliance. Prior analysis of the ARMA trial showed that randomizing patients into fixed treatment groups (i.e. low or high VT groups) disrupted this relationship between routinely applied VT and the severity of disease and created practice misalignments.120 Stipulating use of the ARDSNet LVT protocol or a similar one in trials would introduce this same risk and further confound extrapolation of trial results clinically.

The findings that both routine VT as well as post-enrollment ones in RCTs employing LVT protocols have remained greater than 6 mL/kg PBW raises the possibility that this widely advocated goal may be unachievable in many ALI patients. Even at ARDSNet centers where routine adoption of LVT protocols might be most expected, routine and post-enrollment VT did not change after ARMA and remained on average between 6.5 and 7.0 mL/kg PBW. While VT has decreased over the past decade at non-ARDSNet centers, they started at higher levels (p=0.01) than at ARDSNet centers and, based on the most recent estimates, remain significantly greater than 6 mL/kg PBW.

This study has limitations. First, while we extracted recorded pre-randomization and baseline VT for both RCTs and NRSs, it is possible that with routine care these may have decreased following admission and reached those targeted by the LVT protocol. However, such reductions have not occurred in other studies that examined use of the LVT protocol at later time points.128 Second, inability of most ventilators to allow adjustment of VT in mL/kg PBW may have resulted in the application VT different from 6 mL/kg PBW for some patients in which this level was in fact intended. However, the fact that average VT were significantly greater than 6 mL/kg PBW for all comparisons made, suggests that these differences were not related to obstacles arising from ventilator calibration alone. Third, in the present study PPlat data were unavailable in several trials. It is possible that in these trials, PPlat were sufficiently >30 cmH2O to raise concern regarding the routine VT that was being employed. However, mean PPlat was consistently ≤30 cmH2O in the majority of trials providing data. The absence of reported PPlat from some trials may also suggest that parameters other than airway pressure were employed to manage VT. However this absence does not necessarily mean that PPlat was not measured and employed by clinicians. Fourth, it is unclear why in ARDSNetwork RCTs post-randomization VT increased while PPlat decreased overtime. Although a decrease in the severity of lung injury of patients post-randomization in these trials over time might explain this pattern, there was insufficient data to explore this. Finally, it is possible that our search strategy, that included English language publications only, may have omitted relevant studies for analysis. However, the terminology we employed was broad and yielded more than 3300 studies for review.

Conclusions

Minimizing injury related to mechanical ventilation during management of patients with ALI is important. However, more than a decade has passed since ARMA was published and adherence to the ARDSNet LVT protocol and application of VT of ≤6 mL/kg PBW are still not routine despite being advocated as the standard of care. Physicians do however routinely employ VT associated with PPlat ≤30 cmH2O. One interpretation of these findings is that clinicians caring for patients with ALI are more focused on limiting PPlat – and if PPlat is ≤30 cmH2O, they are less focused on limiting VT. Ultimately, studies employing mixed methods (e.g. surveys, focus groups, cross-sectional audits of barriers/facilitators) may be needed to fully understand why VT ≤6 mL/kg PBW is not being employed by clinicians. However, if there is equipoise among clinicians regarding the need for VT ≤6 mL/kg PBW to improve the outcome of patients with ALI, but this strategy is being advocated for all cases, then a trial testing it is necessary. Such a trial would be needed not only to guide future care but also because a VT ≤6 mL/kg PBW has not yet been compared to routine care.

Supplementary Material

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Acknowledgments

This research was supported by the Division of Intramural Research of the Clinical Center at the National Institutes of Health. There are no conflicts of interests to report for the authors.

Drs. Eichacker, Jaswal, Li, and Natanson received support for article research from NIH and disclosed government work. Dr. Leung lectured for Astra-Zeneca (Speaking Honoraria). Dr. Sun disclosed government work. Dr. Cui received support for article research from NIH. Dr. Kern received support for article research from NIH.

Appendix 1

In the group treated with lower tidal volumes, the tidal volume was reduced to 6 ml per kilogram of predicted body weight within four hours after randomization and was subsequently reduced stepwise by 1 ml per kilogram of predicted body weight if necessary to maintain plateau pressure at a level of no more than 30 cm of water. The minimal tidal volume was 4 ml per kilogram of predicted body weight. If plateau pressure dropped below 25 cm of water, tidal volume was increased in steps of 1 ml per kilogram of predicted body weight until the plateau pressure was at least 25 cm of water or the tidal volume was 6 ml per kilogram of predicted body weight. For patients with severe dyspnea, the tidal volume could be increased to 7 to 8 ml per kilogram of predicted body weight if the plateau pressure remained 30 cm of water or less. Plateau pressures were measured with a half-second inspiratory pause at four-hour intervals and after changes in the tidal volume or positive end-expiratory pressure. Plateau pressures of more than 50 cm of water in the patients in the group treated with traditional tidal volumes and of more than 30 cm of water in patients in the group treated with lower tidal volumes were allowed if the tidal volume was 4 ml per kilogram of predicted body weight or if arterial pH was less than 7.15.

Appendix 2

NIH NHLBI ARDS Clinical Network

Mechanical Ventilation Protocol Summary

INCLUSION CRITERIA

Acute onset of

  1. PaO2/FiO2 ≤300 (corrected for altitude)

  2. Bilateral (patchy, diffuse, or homogeneous) infiltrates consistent with pulmonary edema

  3. No clinical evidence of left atrial hypertension

PART I: VENTILATOR SETUP AND ADJUSTMENT

  1. Calculate predicted body weight (PBW) Males = 50 + 2.3 [height (inches) – 60] Females = 45.5 + 2.3 [height (inches) – 60]

  2. Select any ventilator mode

  3. Set ventilator settings to achieve initial VT = 8 mL/kg PBW

  4. Reduce VT by 1 ml/kg at intervals ≤2 hours until VT = 6 mL/kg PBW.

  5. Set initial rate to approximate baseline minute ventilation (not >35 bpm).

  6. Adjust VT and RR to achieve pH and plateau pressure goals below.

PLATEAU PRESSURE GOAL: ≤30 cmH2O

  • Check PPlat (0.5 second inspiratory pause), at least q4h and after each change in PEEP or VT.

  • If PPlat >30 cmH2O: decrease VT by 1mL/kg steps (minimum = 4 mL/kg).

  • If PPlat <25 cmH2O and VT <6 mL/kg, increase VT by 1 ml/kg until PPlat >25 cmH2O or VT = 6mL/kg.

  • If PPlat <30 cmH2O and breath stacking or dyssynchrony occurs: may increase VT in 1 mL/kg increments to 7 or 8 mL/kg if PPlat remains <30 cmH2O

Appendix 3: Search terms and strategies for the three data bases employed (i.e. Pubmed, EMBASE and Scopus)

PubMed

“respiratory distress syndrome, adult” [majr] OR “acute lung injury”[majr] OR “acute respiratory distress syndrome”[tiab] OR “adult respiratory distress syndrome”[tiab] OR “acute lung injury”[tiab] OR ARDS[tiab] OR ALI[tiab] Filters: Clinical Trial; Comparative Study; Meta-Analysis; Publication date from 2000/01/01; Humans; English; Adult: 19+ years

(“respiratory distress syndrome, adult”[majr] OR “acute lung injury”[majr] OR “acute respiratory distress syndrome”[tiab] OR “adult respiratory distress syndrome”[tiab] OR “acute lung injury”[tiab] OR ARDS[tiab] OR ALI[tiab]) AND (“clinical trials as topic”[mesh] OR “meta-analysis as topic”[mesh] OR “epidemiologic studies”[mesh]) Filters: Publication date from 2000/01/01; Humans; English; Adult: 19+ years

(“respiratory distress syndrome, adult”[majr] OR “acute lung injury”[majr] OR “acute respiratory distress syndrome”[tiab] OR “adult respiratory distress syndrome”[tiab] OR “acute lung injury”[tiab] OR ARDS[tiab] OR ALI[tiab]) AND (“non-randomized” OR nonrandomized OR “non-randomised”) Filters: Publication date from 2000/01/01; Humans; English; Adult: 19+ years

EMBASE

adult respiratory distress syndrome’/exp/mj OR ‘acute lung injury’/exp/mj AND (‘clinical study’/exp OR ‘comparative study’/exp OR ‘meta analysis’/exp OR ‘meta analysis (topic)’/exp) AND ([adult]/lim OR [aged]/lim) AND [humans]/lim AND [english]/lim AND [2000–2014]/py

‘adult respiratory distress syndrome’/exp/mj OR ‘acute lung injury’/exp/mj AND ([cochrane review]/lim OR [controlled clinical trial]/lim OR [meta analysis]/lim OR [randomized controlled trial]/lim OR [systematic review]/lim) AND ([adult]/lim OR [aged]/lim) AND [humans]/lim AND [english]/lim AND [2000–2014]/py

Scopus

(TITLE(“adult respiratory distress syndrome” OR “acute respiratory distress syndrome” OR “acute lung injury”) OR ABS(“adult respiratory distress syndrome” OR “acute respiratory distress syndrome” OR “acute lung injury”) AND TITLE-ABS-KEY(“clinical trial”)) AND PUBYEAR > 1999 AND (LIMIT-TO(LANGUAGE, “English”)) AND (LIMIT-TO(EXACTKEYWORD, “Human”)) AND (LIMIT-TO(EXACTKEYWORD, “Adult”))

(TITLE(“adult respiratory distress syndrome” OR “acute respiratory distress syndrome” OR “acute lung injury”) OR ABS(“adult respiratory distress syndrome” OR “acute respiratory distress syndrome” OR “acute lung injury”) AND TITLE-ABS-KEY(randomized trial OR randomised trial)) AND PUBYEAR > 1999 AND (LIMIT-TO(LANGUAGE, “English”)) AND (LIMIT-TO(EXACTKEYWORD, “Human”)) AND (LIMIT-TO(EXACTKEYWORD, “Adult”))

(TITLE(“adult respiratory distress syndrome” OR “acute respiratory distress syndrome” OR “acute lung injury”) OR ABS(“adult respiratory distress syndrome” OR “acute respiratory distress syndrome” OR “acute lung injury”) AND TITLE-ABS-KEY(controlled trial)) AND PUBYEAR > 1999 AND (LIMIT-TO(LANGUAGE, “English”)) AND (LIMIT-TO(EXACTKEYWORD, “Human”)) AND (LIMIT-TO(EXACTKEYWORD, “Adult”))

(TITLE(“adult respiratory distress syndrome” OR “acute respiratory distress syndrome” OR “acute lung injury”) OR ABS(“adult respiratory distress syndrome” OR “acute respiratory distress syndrome” OR “acute lung injury”) AND TITLE-ABS-KEY(multicenter OR “multi-center”)) AND PUBYEAR > 1999 AND (LIMIT-TO(LANGUAGE, “English”)) AND (LIMIT-TO(EXACTKEYWORD, “Human”)) AND (LIMIT-TO(EXACTKEYWORD, “Adult”))

(TITLE(“adult respiratory distress syndrome” OR “acute respiratory distress syndrome” OR “acute lung injury”) OR ABS(“adult respiratory distress syndrome” OR “acute respiratory distress syndrome” OR “acute lung injury”) AND TITLE-ABS-KEY(meta-analysis)) AND PUBYEAR > 1999 AND (LIMIT-TO(LANGUAGE, “English”)) AND (LIMIT-TO(EXACTKEYWORD, “Human”)) AND (LIMIT-TO(EXACTKEYWORD, “Adult”))

(TITLE(“adult respiratory distress syndrome” OR “acute respiratory distress syndrome” OR “acute lung injury”) OR ABS(“adult respiratory distress syndrome” OR “acute respiratory distress syndrome” OR “acute lung injury”) AND TITLE-ABS-KEY(“comparative study”)) AND PUBYEAR > 1999 AND (LIMIT-TO(LANGUAGE, “English”)) AND (LIMIT-TO(EXACTKEYWORD, “Human”)) AND (LIMIT-TO(EXACTKEYWORD, “Adult”))

(TITLE(“adult respiratory distress syndrome” OR “acute respiratory distress syndrome” OR “acute lung injury”) OR ABS(“adult respiratory distress syndrome” OR “acute respiratory distress syndrome” OR “acute lung injury”) AND TITLE-ABS-KEY(“non-randomized” OR nonrandomized OR “non-randomised”)) AND PUBYEAR > 1999 AND (LIMIT-TO(LANGUAGE, “English”)) AND (LIMIT-TO(EXACTKEYWORD, “Human”)) AND (LIMIT-TO(EXACTKEYWORD, “Adult”))

Footnotes

Copyright form disclosures: Dr. Welsh disclosed that she does not have any potential conflicts of interest.

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