Acute respiratory distress syndrome (ARDS) is a life-threatening condition triggered by various causes (e.g., pneumonia, sepsis, trauma) and associated with substantial morbidity and mortality (1 , 2). A recently published global epidemiologic study reported that ARDS represented 10.4% of total ICU admissions and 23.4% of all intubated patients (3). Furthermore, it is still underrecognized among clinicians (3). Despite ongoing research, there are no definitive treatments for ARDS, and strategies for management are limited to supportive care, including mechanical ventilation. Lung protective ventilation using low tidal volume, higher positive end-expiratory pressure (PEEP), and low plateau pressure is the only ventilatory strategy associated with improved survival in patients with ARDS (4 , 5).
The driving pressure of the respiratory system is defined as the difference between plateau pressure and PEEP and can also be expressed as the ratio of tidal volume to respiratory system compliance (6). A retrospective analysis of patient-level randomized controlled trials (RCTs) data demonstrated that driving pressure is the variable that is most strongly associated with mortality in ARDS and that lower driving pressure is associated with lower mortality (6). However, since it was a single study, further data were required to more clearly understand the importance of driving pressure for ARDS treatment. That is, it is still unknown whether a strategy in which mechanical ventilation is set to limit driving pressure is superior to the current approach (7), and if so, what the appropriate target driving pressure should be.
Given the potential importance of driving pressure in patients with ARDS, we conducted a systematic review and meta-analysis to determine the association of driving pressure with mortality in mechanically ventilated patients with ARDS. In addition, other objectives of this study were to identify the target driving pressure, compare driving pressure with plateau pressure or respiratory system compliance for predicting mortality, and determine whether transpulmonary driving pressure is superior to driving pressure of the respiratory system for predicting mortality.
MATERIALS AND METHODS
This systematic review was conducted on the basis of the Cochrane Collaboration approach (8). The results were reported following the “Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocols (PRISMA-P) 2015 statement” (9).
Criteria for Considering Studies for This Review
Types of Studies.
Inclusion and exclusion criteria are summarized in Appendix A (Supplemental Digital Content 1, http://links.lww.com/CCM/D24). We included RCTs, controlled studies, cohort studies, and case-control studies that investigated driving pressure of mechanically ventilated patients with ARDS. No language restrictions were applied.
Types of Participants.
We included studies of adults (age ≥ 18 yr) with ARDS receiving mechanical ventilation in the ICU.
Types of Interventions.
We included studies that compared different levels of driving pressure or compared driving pressure with other respiratory measurements (i.e., plateau pressure, lung compliance, or elastance).
Types of Outcome Measures.
Our primary outcome was hospital mortality. If not available, we used mortality at the latest reported time point. Prespecified secondary outcomes included total duration of mechanical ventilation, length of ICU and hospital stay, ventilator-associated complication (e.g., barotrauma, ventilator-associated pneumonia), use of adjunctive/rescue therapies (e.g., neuromuscular blockade, inhaled vasodilators, prone positioning, extracorporeal life support), physiologic measurements (e.g., oxygenation, compliance, plateau pressure, PEEP, tidal volume), and any adverse events (e.g., organ failure).
Search Methods for Identification of Studies
We performed an electronic search of MEDLINE, Medline In-Process/ePubs Ahead of Print, EMBASE, and Cochrane CENTRAL (via the Ovid search interface), PubMed (via the National Library of Medicine and excluding Medline records), and CINAHL (via EbscoHost), from their inception dates to February 10, 2017, using a sensitive search strategy (Appendix B, Supplemental Digital Content 2, http://links.lww.com/CCM/D25). We used controlled vocabulary terms (when available), text words, and keywords. Blocks of terms per concept were created (i.e., driving pressure [with related synonyms] AND intensive care/mechanical ventilation [with related synonyms] AND ARDS [with related synonyms] AND a block of selected study types was added). Where possible, the search results were limited to human adults. The Web of Science Core Collection (Clarivate Analytics) was used for citation searching of selected eligible studies and also bibliography searching of selected eligible studies as well.
Data Collection and Analysis
Selection of Studies.
Title and abstract screen were conducted for all relevant records based on the electronic literature search. Full-text review was done for potentially relevant records. A standardized, piloted data collection form designed for this systematic review was developed for data extraction. The study selection and data extraction were independently conducted by two authors (H.A., T.P.). Cohen’s kappa was reported for agreement between the two reviewers. Any disagreement and discrepancies were resolved by adjudication of a third reviewer (E.F.) or discussion of whole group (H.A., T.P., E.F.).
Assessment of Risk of Bias in Included Studies.
The risk of bias was assessed for each outcome in all included studies using the Cochrane Systematic Review Handbook for Randomized Controlled Studies (8) and the Newcastle-Ottawa scale for Nonrandomized Controlled Studies (10). A maximum of nine points were awarded based on cohort selection (maximum four points), the comparability of the cohort design and analysis (maximum two points), and the adequacy of outcome measures (maximum three points); the number of star greater than equal to six points was considered high quality (10).
Assessment of Reporting Biases.
Among eligible studies for meta-analyses described below, reporting bias was assessed with a funnel plot.
Means and SDs were used to describe normally distributed continuous variables, whereas median and interquartile ranges (IQRs) were used for nonnormally distributed data as appropriate. Categorical variables were expressed as counts and proportions.
Meta-analysis for pooled estimate of each outcome was planned. To incorporate the heterogeneity between trials, we used a random effects model to calculate risk ratios (RRs) and 95% CIs for each outcome (11 , 12). The statistical heterogeneity was assessed using I2, the percentage of variability that is due to heterogeneity rather than sampling error (13 , 14) and considered moderate when I2 equals to 50–74% and high for I2 greater than or equal to 75%. To determine statistical significance, a two-sided p value of less than 0.05 was employed. All statistical analyses were undertaken using RevMan, version 5.1 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) and SAS 9.4 (SAS Institute, Cary, NC).
Subgroup and Sensitivity Analyses.
Sensitivity analyses were planned, restricted to RCTs or studies of higher methodological quality (low risk of bias) or different cutoff of driving pressure. Subgroup analyses were planned according to severity of ARDS (Berlin Definition) (2), if appropriate.
We conducted electronic searches that retrieved a total of 5,196 records (Fig. 1). We identified 16 potentially relevant articles after full-text search. Of these, nine did not meet our inclusion criteria (Appendix C, Supplemental Digital Content 3, http://links.lww.com/CCM/D26). We eventually included seven studies in this review (3 , 6 , 15–19). There was near-perfect agreement on study inclusion between two reviewers (kappa = 0.997).
Included Studies and Participants
We included seven observational studies (6,062 patients) (Table 1; and Appendix D, Supplemental Digital Content 4, http://links.lww.com/CCM/D27). Five (5,333 patients) were secondary analysis of previous RCTs and cohort studies (6 , 15 , 17–19). Two studies (729 patients) were results from the same parent study (LUNG SAFE) (3 , 16); therefore, the results of these two studies were collapsed to one study for further analysis.
The included studies recruited adults with a median (IQR) age of 55 years (52–59 yr). The number of participants in each study ranged from 56 to 3,652 (Table 1). There was no uniform severity score (e.g., Acute Physiology and Chronic Health Evaluation II) among the studies. However, the included studies had reported similar mortality and distributions of ARDS severity. Only four studies (1,771 patients) investigated variables of respiratory mechanics (i.e., lung compliance and elastance) (15 , 17–19). When other respiratory variables related to mechanical ventilation were not available in the secondary analysis of previous studies, the original study was assessed to obtain these variables (Table 2). Median (IQR) mortality of included studies was 34% (32–38%), although eligible studies employed different time points to determine mortality (Table 1). All studies had low risk of bias according to the Newcastle-Ottawa scale (Table 1; and Appendix D, Supplemental Digital Content 4, http://links.lww.com/CCM/D27). Visual inspection of the funnel plot revealed some asymmetry, suggesting potential publication bias (Appendix E, Supplemental Digital Content 5, http://links.lww.com/CCM/D28).
All included studies demonstrated an association between higher driving pressure and higher mortality (3 , 6 , 15–19). In addition, all included studies evaluated the association of higher versus lower driving pressure with mortality, except one study using esophageal balloon catheter to evaluate transpulmonary driving pressure (defined as driving pressure without chest wall compliance whereas driving pressure of the respiratory system includes the effect of chest wall compliance) (19). However, each study employed different cutoff of driving pressure for each group (lower vs higher) based on median driving pressure derived from whole cohort of the study (Table 1). The median (IQR) cutoff of driving pressure from all studies was 15 (14–16) cm H2O (Table 1).
Effects of Driving Pressure on Outcomes
In a meta-analysis of four studies (3,252 patients) out of six eligible studies, higher driving pressure was significantly associated with increased mortality among mechanically ventilated ARDS patients (pooled RR, 1.44; 95% CI, 1.11–1.88; I 2 = 85%) (Fig. 2A) (3 , 6 , 15–17). One study was not included in this meta-analysis because actual number of events was not shown in the article (18). The other study was not included because of no comparison of higher with lower driving pressure in the study (19).Since no study investigated the association of driving pressure with barotrauma and other outcomes, meta-analysis of secondary outcomes was not conducted.
Since all eligible studies were nonrandomized clinical trials with a low risk of bias (Table 1), a prespecified sensitivity analysis based on methodological criteria was not conducted. A sensitivity analysis restricted to the three studies (2,774 patients) with similar cutoff of driving pressure (13–15 cm H2O) showed robust finding of pooled estimate of RR for high driving pressure on mortality (pooled RR, 1.28; 95% CI, 1.14–1.43; I 2 = 0%) (Fig. 2B) (3 , 6 , 16 , 17). Finally, no subgroup analyses were conducted because of limited data on ARDS severity among included studies.
Our systematic review and meta-analysis of seven studies, including 6,062 patients, demonstrated that higher driving pressure was significantly associated with a higher mortality in mechanically ventilated patients with ARDS. This result was robust when restricted to studies with a similar driving pressure cutoff and suggests that a target driving pressure for ventilated ARDS patients could exist between 13 and 15 cm H2O.
Lung protective ventilation remains the cornerstone of supportive treatment for ARDS and has traditionally focused on inspiratory plateau pressure and tidal volume limitation (7). The potential importance of driving pressure in the ventilation strategy for ARDS patients was first proposed in 1998 (4). More recently, a secondary analysis of previous RCTs of ventilation management for ARDS demonstrated that driving pressure is the variable that is most strongly associated with mortality in ARDS after multivariate adjustment (RR, 1.41; 95% CI, 1.31–1.51) (6). The current study is the first meta-analysis of driving pressure in mechanically ventilated ARDS patients, confirming the results of other prior individual studies for the association of higher driving pressure with higher mortality (3 , 15–19). However, it is unclear what is the optimal strategy for reducing driving pressure. For instance, one study showed no significant differences in driving pressure among three groups of patients ventilated with different tidal volume (i.e., ≤ 6.5, > 6.5 to < 7.5, and ≥ 7.5 mL/kg with predicted body weight) (15). Furthermore, the included studies reported conflicting results regarding predictive performance of driving pressure in comparison to plateau pressure. Two studies concluded that the plateau pressure was the same as or slightly better predictor than the driving pressure (15 , 18). Of these two studies, hazard ratios from the Cox models and area under the receiver operator curve were 1.05 (95% CI, 1.02–1.08) and 0.704 (95% CI, 0.667–0.741) for driving pressure, and 1.05 (95% CI, 1.01–1.08) and 0.724 (95% CI, 0.686–0.761) for plateau pressure, respectively. Although none of the included studies reported on our predefined secondary outcomes (e.g., barotrauma), an individual patient data meta-analysis of driving pressure in postoperative patients demonstrated an association between higher driving pressure and a greater number of pulmonary complications (20). Finally, our study is not able to conclude whether driving pressure or plateau pressure is superior for predicting mortality in ARDS patients due to inconsistent results among included studies (6 , 15 , 17 , 18). Since these studies employed different approaches to evaluate the prognostic ability of driving pressure and plateau pressure (6 , 15 , 17 , 18), we were unable to compare pooled estimates for their association with mortality.
The inconsistencies in the included studies may be due to a number of important factors. The interpretation of observational studies of physiologic targets, such as that by Amato et al (6), requires certain considerations. Physiologic variables, such as tidal volume, plateau pressure, and PEEP, are inter-related in a number of ways—they are both mathematically and physiologically coupled (21). These relationships and interdependence may result in their collective association with mortality, with changes to any one variable leading to unpredictable changes in the other dependent variables. Furthermore, important predictors could have nonsignificant associations due to confounding by other predictors or nuances in the dataset being used (22). Finally, it remains unclear whether an intervention targeting a physiologic profile (e.g., high driving pressure) will necessarily lead to reduced mortality (21).
Of note, Amato et al (6) only referred to driving pressure including the effect of chest wall compliance (i.e., the driving pressure of the respiratory system) (23). There was only one study comparing transpulmonary driving pressure (i.e., driving pressure without chest wall compliance) with driving pressure of the respiratory system for predicting mortality. This study concluded that both driving pressures seem to be similar, but it is still unclear which is superior because of lack of statistical power (19). Transpulmonary driving pressure may be more reasonable to be measured in “stiff” lungs such as severe ARDS potentially because it represents the pressure actually applied to the lungs (19). One study compared transpulmonary driving pressure with driving pressure of respiratory system to predict lung stress (i.e., the pressure generated into the lung), but not mortality (17). Thus, no study has investigated the prognostic value of transpulmonary driving pressure on mortality in patients with ARDS (17 , 19).
Strengths and Weaknesses of the Study
This study has several strengths. We used robust methods for our systematic review and meta-analysis as recommended by the Cochrane Collaboration and reported our results based on PRISMA-P (8 , 9). Second, the meta-analysis used a random effects model with generic inverse variance, so that pooled estimate of RR for driving pressure on mortality could be computed, although some studies reported only RR and its SE without specifying actual number of the dichotomous outcome. Last, our prespecified sensitivity analysis assessed and confirmed the robustness of results of the meta-analysis and suggests that a driving pressure target 13–15 cm H2O could be a starting point for future research (3 , 6 , 16 , 17).
This study has important limitations. First, although our results suggest a potential target of driving pressure, the optimal driving pressure cutoff could not be calculated due to the use of published study-level data. Second, the lack of enough information comparing driving pressure of the respiratory system with plateau pressure, respiratory system compliance, or transpulmonary driving pressure does not allow us to conclude which respiratory variable has the best predictive performance for mortality (15 , 17). Third, there were no RCTs to include in this meta-analysis, although all included observational studies had a low risk of bias. Finally, although there was significant statistical heterogeneity, which is mainly due to the use of different cutoff of driving pressure among included studies, our sensitivity analysis confirmed the robustness of the findings.
Unanswered Questions and Future Research
Currently, these results are hypothesis-generating and there is insufficient data to support the clinical use of driving pressure in any ventilatory strategy among ARDS patients. Future studies need to compare the predictive performance of driving pressure versus plateau pressure for ARDS, and mortality needs to be investigated in prospective nature. These studies are better to use esophageal balloon to compute transpulmonary pressure because transpulmonary driving pressure may be better than driving pressure of the respiratory system for predicting mortality among patients with stiff lung (i.e., severe ARDS). Thus, such studies need to ascertain the optimal target of driving pressure and the subgroup of ARDS patients who could have most benefit from ventilatory strategies targeting driving pressure. A safety and feasibility trial is also needed to understand how a protocol targeting driving pressure can be developed and implemented by bedside clinicians (e.g., adjustment of tidal volume or other ventilatory variables, lung recruitment with PEEP), and whether there are any adverse effects of such as strategy as compared to convention mechanical ventilation strategies. Finally, well-designed randomized clinical trials are necessary to support clinical practice recommendations at the level of evidence-based guideline to compare a driving pressure-based ventilation strategy versus the current lung protective ventilation strategy (7).
In mechanically ventilated adult patients with ARDS, higher driving pressure is associated with higher mortality. Our study proposes a target range of driving pressure that may be evaluated in future clinical trials. Further effort is needed to ascertain whether ventilatory strategies in patients with ARDS targeting driving pressure are superior to current regimens targeting inspiratory pressure- and volume-limited ventilation.
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