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Temporal Changes in Ventilator Settings in Patients With Uninjured Lungs: A Systematic Review

Schaefer, Maximilian S. MD*; Serpa Neto, Ary MD, MSc, PhD†,‡; Pelosi, Paolo MD, FERS§; Gama de Abreu, Marcelo MD, MSc, PhD, DESA; Kienbaum, Peter MD*; Schultz, Marcus J. MD, PhD; Meyer-Treschan, Tanja Astrid MD*

doi: 10.1213/ANE.0000000000003758
Critical Care and Resuscitation

In patients with uninjured lungs, increasing evidence indicates that tidal volume (VT) reduction improves outcomes in the intensive care unit (ICU) and in the operating room (OR). However, the degree to which this evidence has translated to clinical changes in ventilator settings for patients with uninjured lungs is unknown. To clarify whether ventilator settings have changed, we searched MEDLINE, Cochrane Central Register of Controlled Trials, and Web of Science for publications on invasive ventilation in ICUs or ORs, excluding those on patients <18 years of age or those with >25% of patients with acute respiratory distress syndrome (ARDS). Our primary end point was temporal change in VT over time. Secondary end points were changes in maximum airway pressure, mean airway pressure, positive end-expiratory pressure, inspiratory oxygen fraction, development of ARDS (ICU studies only), and postoperative pulmonary complications (OR studies only) determined using correlation analysis and linear regression. We identified 96 ICU and 96 OR studies comprising 130,316 patients from 1975 to 2014 and observed that in the ICU, VT size decreased annually by 0.16 mL/kg (−0.19 to −0.12 mL/kg) (P < .001), while positive end-expiratory pressure increased by an average of 0.1 mbar/y (0.02–0.17 mbar/y) (P = .017). In the OR, VT size decreased by 0.09 mL/kg per year (−0.14 to −0.04 mL/kg per year) (P < .001). The change in VTs leveled off in 1995. Other intraoperative ventilator settings did not change in the study period. Incidences of ARDS (ICU studies) and postoperative pulmonary complications (OR studies) also did not change over time. We found that, during a 39-year period, from 1975 to 2014, VTs in clinical studies on mechanical ventilation have decreased significantly in the ICU and in the OR.

From the *Department of Anesthesiology, Düsseldorf University Hospital, Düsseldorf, Germany

Department of Critical Care Medicine, Hospital Israelita Albert Einstein, São Paulo, Brazil

Program of Post-Graduation, Innovation and Research, Faculdade de Medicina do ABC, Santo Andre, Brazil

§Department of Surgical Sciences and Integrated Diagnostics, San Martino Policlinico Hospital, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) for Oncology, Genoa, Italy

Department of Anesthesiology and Intensive Care Therapy, Pulmonary Engineering Group, University Hospital Carl Gustav Carus, Dresden, Germany

Department of Intensive Care, Academic Medical Center, University of Amsterdam, the Netherlands.

Published ahead of print 26 July 2018.

Accepted for publication July 26, 2018.

Funding: Institutional.

The authors declare no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website.

Reprints will not be available from the authors.

Address correspondence to Tanja Astrid Meyer-Treschan, MD, Department of Anesthesiology, Institution Düsseldorf University Hospital, Moorenstr 5, 40225 Düsseldorf, Germany. Address e-mail to

Every year, millions of critically ill patients worldwide receive invasive mechanical ventilation in intensive care units (ICUs), and hundreds of millions of patients undergo mechanical ventilation for major surgical procedures in operating rooms (ORs).1 For many years, ventilation with high tidal volumes (VTs) has been applied to counterbalance the formation of atelectasis and to avoid the use of higher fractions of inspired oxygen (Fio2).2,3 In ICU patients with acute respiratory distress syndrome (ARDS), low VT ventilation has been recognized as an important factor in minimizing ventilator-induced lung injury and improving mortality.4–6 However, growing evidence suggests that large VTs may also induce lung injury in patients without lung injury.7–9 A randomized controlled trial from 2010 in ICU patients with uninjured lungs10 and 2 randomized controlled trials in 2013 in patients during general anesthesia for surgery11,12 found that ventilation with low VTs improves pulmonary outcomes.8,13,14 However, translation of research results into daily practice may occur slowly and be difficult to detect.15 To clarify whether research results on lower VTs have translated into daily practice, we reviewed relevant observational studies and control arms of randomized trials reporting VT to determine whether VT settings have changed over time. Our primary hypothesis was that VT size has decreased in both patient groups. We also hypothesized that changes in VT size are associated with a reduced incidence of ARDS in mechanically ventilated ICU patients and with fewer postoperative pulmonary complications in surgical patients.

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This systematic review, referred to as the “Evolution of Ventilation in Intensive Care Units and Operating Rooms” study, focused on changes in VT size in the ICU and OR from 1975 to 2014, but was limited to the extent possible to patients with uninjured lungs, defined as patients not experiencing acute lung injury or ARDS.

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Search Strategy

Based on our review protocol (described in Supplemental Digital Content 1, Document 1,, 2 investigators (M.S.S., T.A.M.-T.) performed the literature search following a sensitive search strategy consisting of medical subject headings and the keywords “tidal volume” and “mechanical ventilation” in MEDLINE (PubMed), Web of Science, and the Cochrane Central Register of Controlled Trials, each without restrictions on publication year. We screened recently published systematic reviews and meta-analyses to identify additional publications.8,13,16,17

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Selection of Clinical Investigations

Publications were eligible for inclusion if VT size was documented, reported either as an absolute value (ie, in mL) or relative to ideal body weight or actual body weight (ABW) (ie, in mL/kg); ideal body weight was treated as synonymous to predicted body weight (PBW). Of trials that randomized to different VTs, data were analyzed from the study arms representing the current standard of care as defined by the authors. In contrast, randomized controlled trials were excluded if VT was not characterized as the “standard of care” by the authors. Finally, study cohorts from observational studies differentiating cohorts from different time periods were included separately in the analysis. Publications on studies in patients <18 years of age and publications in a language other than English were excluded. Furthermore, we excluded publications on studies in which >25% of the patients were reported to have ARDS at the onset of ventilation. Investigations of high-frequency oscillation, 1-lung ventilation, ventilation after lung transplantation, ventilation during cardiopulmonary resuscitation, noninvasive ventilation, or studies focusing on the weaning process or on ventilation outside the ICU or OR were also excluded.

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Data Extraction

The following data were extracted if present: investigation type (observational or interventional), study setting (ICU or OR), and year of data collection (begin and end of data collection or, if this was not reported, the reported year of article submission). Ventilator settings collected included VT size, maximum airway pressure (Pmax), peak airway pressure, plateau pressure (Pplat), mean airway pressures (Pmean), level of positive end-expiratory pressure (PEEP), and Fio2. Pmax and peak airway pressures were treated as equivalent and are referred to as Pmax throughout this article.

If available, we collected data on the development of ARDS or, in publications that did not yet use the Berlin definition of ARDS,18 acute lung injury or ARDS (in ICU investigations) and postoperative pulmonary complications (in OR investigations) which included postoperative pneumonia, acute lung injury or ARDS, atelectasis, and barotrauma.

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Calculation of VT Size

If VT size was expressed in milliliters, the average VT of the groups in mL/kg PBW was calculated using the formula19: PBW in kg = (50 × [fraction males] + 45.5 × [fraction females]) + 0.91 × (average group height in cm − 152.4). If height was not available, VT was calculated from group average VT and group average weight and expressed as mL/kg ABW.

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Study End Points

The primary study end point was the mean VT per patient cohort, and we specifically analyzed the evolution of this parameter during the years covered by the selected investigations, either in the ICU or OR. Secondary end points included temporal changes in ventilation parameters Pmax, Pmean, Pplat, PEEP, and Fio2, and temporal changes in the development of new ARDS onset in ICU studies and postoperative pulmonary complications in OR studies. In an exploratory analysis, we investigated the association between the average VT size and Pmax of the studies.

Our primary hypothesis was that VT size decreased in both ICU and OR patients during the study period. We therefore expected a negative correlation between VT and years as indicated by a correlation coefficient ≤−0.3.

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Analysis Plan and Statistical Analysis

Data from studies on ventilation in the ICU were analyzed separately from studies on ventilation in the OR. To plot VT size for a specific study on a time graph, we chose the middle of the period during which data collection for the study was performed or, in case this information was not available, the date of study report submission. Associations were assessed with Spearman correlation and linear regression analyses for all primary and secondary variables. Confidence intervals were calculated for Spearman ρ as well as the regression coefficient b (ie, the slope of the regression line). In addition, P values were derived from the linear regression analyses. Scatter graphs were then plotted. When linear regression reached statistical significance, an additional regression line with the corresponding 95% confidence interval was drawn. To explore nonlinear relationships, we conducted a secondary analysis calculating local regression (LOESS) lines for all graphs involving >10 data points. These are provided in Supplemental Digital Content 2, Figures,

To estimate VTs during current practice, we calculated the median VT for all studies within the interval from 2010 to end of data (2014). A 2-sided α was set to .05. To account for 2 main outcome parameters, Bonferroni correction was applied, and a P < .025 was considered statistically significant for VT size in the ICU or OR. All graphs were plotted with SigmaPlot 13.0 (SYSTAT Software, Inc, San Jose, CA). Linear regression analyses were performed with SPSS Statistics 25 (IBM Corporation, Armonk, NY), and confidence intervals for Spearman ρ were calculated using Stata IC 10.1 (Statacorp, College Station, TX) with bootstrapping.

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Figure 1.

Figure 1.

Our systematic search yielded a total of 12,437 publications (Figure 1). Three additional publications were identified by screening recently published reviews. For the analysis, we selected 192 publications from a period of 39 years including >130,000 patients in 59 countries. Of the publications, 96 reported on studies of ventilation in the ICU10,20–114 and 96 on studies of ventilation in the OR.11,12,115–208 Some of these studies included >1 patient cohort. We were able to separate these according to distinctly different time periods during which patients were recruited resulting in 108 ICU patient cohorts and 100 OR patient cohorts eligible for analysis; key characteristics of the 208 selected cohorts are summarized in Supplemental Digital Content 3, Table 1,

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Temporal Changes in VT Size

Median VT at the start of the review period was 13.8 mL/kg ABW in the ICU cohort and 13 mL/kg ABW in the OR cohort. In the ICU studies, VT size declined over time with an average reduction of 0.16 mL/kg per year (−0.19 to −0.12 mL/kg per year; Figure 2) to a median of 8.0 mL/kg (interquartile range, 7.5–8.7 mL/kg) in the 20 studies conducted between 2010 and 2014. Visual inspection of LOESS regression revealed that the decline in VT size primarily occurred until around 1995, and subsequent changes in VT have been minimal (Supplemental Digital Content 2, Figure 1, These findings were also seen in our subanalyses of studies reporting VT as mL and in studies reporting VT as mL/kg ABW, but not in studies reporting VT as mL/kg PBW (Figure 2).

Figure 2.

Figure 2.

Figure 3.

Figure 3.

In OR studies, VT size declined over time with an average reduction of 0.09 mL/kg per year (−0.14 to −0.04 mL/kg per year; Figure 3). This association was also significant when studies reporting VT as mL/kg ABW and mL/kg PBW were analyzed separately. Twenty studies reporting VT as absolute mL did not show a reduction over time (P = .05; r = −0.44; Figure 3). Median VT for the 17 studies conducted between 2010 and 2014 was 8.0 mL/kg (7.1–9.0 mL/kg).

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Changes in Other Ventilator Settings

In ICU patients, Pmax decreased over time (–0.52 mbar/y [–0.84 to −0.19 mbar/y]; Figure 4). PEEP increased on average by 0.1 mbar/y (0.02–0.17 mbar/y) (Supplemental Digital Content 2, Figure 5A, Pplat, Pmean, and Fio2 did not change in ICU patients over time (Supplemental Digital Content 2, Figure 5B–D,

Figure 4.

Figure 4.

In OR patients, neither Pmax (Figure 5) nor PEEP, Pplat, Pmean, or Fio2 changed over time (Supplemental Digital Content 2, Figure 6A–D,

Figure 5.

Figure 5.

Finally, we found a significant association between VT size and corresponding Pmax in studies in the ICU (2.3 [1.1–3.6] mbar increase per mL/kg; Supplemental Digital Content 2, Figure 7,, but not in the OR (Supplemental Digital Content 2, Figure 8,

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Development of Lung Injury

Development of ARDS as an outcome was reported in 14 ICU studies, while the occurrence of postoperative pulmonary complications was reported in 7 OR studies. Reported incidences of ARDS and postoperative pulmonary complications varied between studies (Supplemental Digital Content 2, Figures 9–10, Due to the limited number of studies and the short time frame these studies cover, statistical assessment of associations between temporal changes in VT size and incidences of ARDS development or postoperative pulmonary complications was not conducted.

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In this systematic review of 192 studies and >120,000 patients with uninjured lungs, we found that prescribed VTs during clinical studies of mechanical ventilation decreased in both ICU and OR during the period from 1975 to 2014.

Although the specific intent behind the decrease in VT size in studies of ICU patients is unknown, we speculate that physicians have begun to believe that effects of VT reduction in patients with ARDS may be extrapolated to patients with uninjured lungs. However, several concerns have been raised against unselected use of low VT in ICU patients, including the risk of more atelectasis209 and increase in ventilator–patient asynchrony.210,211 Also, because low VTs mandate the use of higher respiratory rates, VT reduction might result in increased carbon dioxide retention, a greater need for sedation,212 and an increase in delirium.213,214 However, other studies disagree.7,9 We consider it impressive that VT for mechanical ventilation of patients with uninjured lungs has decreased over time in the OR and ICU without milestone trials showing clear benefits, as was the case for ICU patients with ARDS.6

In a large international cohort study, Esteban et al48 investigated ventilator parameters including VT size and clinical outcomes for ICU patients. They found that the reduction in VT size was associated with a decrease in mortality. To go beyond these findings, we analyzed all published studies retrieved from major databases during an extended 40-year period. Based on data in the literature, high-quality evidence is scarce regarding the benefit of low VTs in ICU patients with uninjured lungs.17,213

VT size declined in OR patients as well. This finding deserves mention because short-term intraoperative ventilation (ie, ventilation for several hours) is unlikely to be as harmful as ventilation in ICU patients which usually lasts longer.8 Of note, trials investigating the effects of lung-protective ventilation rarely studied the sole effects of ventilation with lower VT,215 but rather mostly combined low VTs with higher levels of PEEP and/or recruitment maneuvers.11,12,216

Our main findings are consistent with 3 reports from 2015 investigating the development of intraoperative ventilation patterns in single or a small number of centers over time.217–219 All found a decrease in VT size during the last 7–20 years. Furthermore, in contrast to our data, in 2 of these studies,217,219 the proportion of patients in whom PEEP was applied has increased significantly since 2005219 and 2008.217 Despite theoretically beneficial effects, large investigations have so far failed to prove any positive effect on patient outcome when groups were only randomized to different PEEP values in patients experiencing ARDS220 or in surgical patients,115 which may explain the large heterogeneity in PEEP levels in our review.

We identified only few studies reporting Pplat, especially before 2007. This lack of data may explain why we were unable to find temporal changes in Pplat. Pplat is an important determinant of driving pressure, which plays an important role in lung injury in patients with ARDS.221

We did not find a temporal change in clinical outcomes, which were the development of ARDS in the ICU and incidences of postoperative pulmonary complications in the OR. Incidences of pulmonary injury varied widely in the analyzed studies, suggesting either heterogeneity of study populations or incomplete or imprecise reporting of pulmonary complications in some observational and retrospective studies. Of note, 11 ICU studies35–37,45,58,61,63,67,73,88,114 and 11 OR studies117,142,144,146,147,158,161,178,188,192,201 reported a VT size of ≤7 mL/kg (Figures 2–3). In a recent meta-analysis of individual patient data, VTs of 7 mL/kg PBW or less, but not 7–10 mL/kg PBW, reduced pulmonary complications in ICU patients without ARDS.7 Thus, the lack of studies with such low VT might be another reason for the lack of changes in the development of ARDS and postoperative pulmonary complications.

Our approach has some strengths. First, our nonrestrictive search strategy maximized the number of included investigations. Consequently, the analysis reflects ventilation practice in a large number of cohorts of patients worldwide over a long period of time. Second, rather than reporting original data from individual institutions,218,219 we chose to analyze temporal change of reported VT in published literature. We preferred this approach because ventilation practice might differ significantly between individual institutions.217 Consequently, observations at single centers, or even in individual countries, might substantially differ from general practice patterns. We therefore believe that our approach might give a better estimate of general ventilation patterns than single-center or single-country studies.

Our analysis also exhibits some limitations. Only including publications reporting VT sizes may have caused some bias because investigators who report on this ventilation setting may be more aware of the potential benefit of VT reduction in patients without ARDS. Furthermore, several trials added >1 cohort to our analysis. Thus, there is a small fraction of data points that are not independent from each other. We decided against extracting and analyzing data on mode of ventilation (ie, volume-controlled versus pressure-controlled ventilation) because modes of ventilation were often mixed and not clearly distinguishable making an appropriate analysis unfeasible. We included groups from randomized controlled trials in our primary analysis that were defined to reflect ventilation practice at the time the study was conducted. In turn, we had to exclude from our primary analysis any randomized controlled trials in which no group was defined as reflecting the standard of care. However, defining the standard of care is not the same as assessment in observational studies, and therefore, we cannot be certain if the included groups from randomized trials actually reflected daily care. Finally, because the aim of our analysis was to assess the use of low VTs in patients with healthy lungs in either the ICU or OR setting, several studies were excluded for including more than one-quarter of patients experiencing ARDS, or investigating 1-lung ventilation, or ventilation after lung transplantation or during cardiopulmonary resuscitation; investigations outside the ICU or OR were also excluded. “Uninjured lungs” were defined as “no acute lung injury or ARDS.” However, this definition did not exclude patients who experienced other pulmonary diseases, such as chronic obstructive pulmonary disease or fibrosis. Therefore, no conclusions can be made regarding these important patient groups and separate investigations are required to assess the use of potentially harmful ventilation strategies in these patients.

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We included data from a total of >120,000 patients spanning a period of 40 years. Although this seems to be a very large number of patients, it covers only approximately 3000 patients per year. Many more patients receive mechanical ventilation every day on ICUs or in the ORs. Thus, our results only depict a very small proportion of patients receiving mechanical ventilation. It is possible that clinical practice differs from the studies we reviewed.

In summary, we found during a 40-year span ending in 2014 that VT decreased in studies of ICU and OR patients with uninjured lungs. For both patient populations, evidence of the benefits of low VTs was scarce. More work is needed to better understand how literature findings cause clinicians to change their behavior. In addition, further studies are warranted on the development of VT size in clinical practice in ICUs and in the ORs and on the effects of VT size and outcome in patients with uninjured lungs.222 When designing new ventilation trials, control groups are expected to reproduce current daily practice.223 When designing such trials, the findings of this investigation will help to plan ventilation strategies for control patients.

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The authors wish to thank Renate Babian and Julia Övermöhle for their help with data collection, and Anne Berwanger for language editing.

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Name: Maximilian S. Schaefer, MD.

Contribution: This author helped plan the study, perform the search for data, extract, analyze, and interpret the data, write parts of the manuscript, and approve the final version to be published.

Name: Ary Serpa Neto, MD, MSc, PhD.

Contribution: This author helped design the study, gave advice on data analysis, and helped revise the manuscript critically for important intellectual content, and approve the final version.

Name: Paolo Pelosi, MD, FERS.

Contribution: This author helped design the study, gave advice on data analysis, and helped revise the manuscript critically for important intellectual content, and approve the final version.

Name: Marcelo Gama de Abreu, MD, MSc, PhD, DESA.

Contribution: This author helped design the study, gave advice on data analysis, and helped revise the manuscript critically for important intellectual content, and approve the final version.

Name: Peter Kienbaum, MD.

Contribution: This author helped design the study, gave advice on data analysis, and helped revise the manuscript critically for important intellectual content, and approve the final version.

Name: Marcus J. Schultz, MD, PhD.

Contribution: This author helped design the study, gave advice on data analysis, and helped revise the manuscript critically for important intellectual content, and approve the final version.

Name: Tanja Astrid Meyer-Treschan, MD.

Contribution: This author helped extract and interpret the data, write parts of the manuscript, and approve the final version to be published.

This manuscript was handled by: Avery Tung, MD, FCCM.

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