Next Article in Journal
Long-Term Efficacy and Safety of Guselkumab in Psoriasis Patients Who Failed Anti-IL17: A Two-Year Real-Life Study
Previous Article in Journal
Comparative Analysis of Monoaxial and Polyaxial Pedicle Screws in the Surgical Correction of Adolescent Idiopathic Scoliosis
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Systematic Review

Inconsistent Methods Used to Set Airway Pressure Release Ventilation in Acute Respiratory Distress Syndrome: A Systematic Review and Meta-Regression Analysis

Department of Surgery, SUNY Upstate Medical University, Syracuse, NY 13210, USA
Health Sciences Library, SUNY Upstate Medical University, Syracuse, NY 13210, USA
Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY 13210, USA
Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY 13210, USA
Department of Public Health and Preventive Medicine, SUNY Upstate Medical University, Syracuse, NY 13210, USA
Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA
Department of Critical Care, R Adams Cowley Shock Trauma Center, Baltimore, MD 21201, USA
Division of Pulmonary, Critical Care, and Sleep Medicine, SUNY Upstate Medical University, Syracuse, NY 13210, USA
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
These authors jointly supervised this study and are co-senior authors.
J. Clin. Med. 2024, 13(9), 2690;
Submission received: 15 February 2024 / Revised: 15 April 2024 / Accepted: 30 April 2024 / Published: 3 May 2024


Airway pressure release ventilation (APRV) is a protective mechanical ventilation mode for patients with acute respiratory distress syndrome (ARDS) that theoretically may reduce ventilator-induced lung injury (VILI) and ARDS-related mortality. However, there is no standard method to set and adjust the APRV mode shown to be optimal. Therefore, we performed a meta-regression analysis to evaluate how the four individual APRV settings impacted the outcome in these patients. Methods: Studies investigating the use of the APRV mode for ARDS patients were searched from electronic databases. We tested individual settings, including (1) high airway pressure (PHigh); (2) low airway pressure (PLow); (3) time at high airway pressure (THigh); and (4) time at low pressure (TLow) for association with PaO2/FiO2 ratio and ICU length of stay. Results: There was no significant difference in PaO2/FiO2 ratio between the groups in any of the four settings (PHigh difference −12.0 [95% CI −100.4, 86.4]; PLow difference 54.3 [95% CI −52.6, 161.1]; TLow difference −27.19 [95% CI −127.0, 72.6]; THigh difference −51.4 [95% CI −170.3, 67.5]). There was high heterogeneity across all parameters (PhHgh I2 = 99.46%, PLow I2 = 99.16%, TLow I2 = 99.31%, THigh I2 = 99.29%). Conclusions: None of the four individual APRV settings independently were associated with differences in outcome. A holistic approach, analyzing all settings in combination, may improve APRV efficacy since it is known that small differences in ventilator settings can significantly alter mortality. Future clinical trials should set and adjust APRV based on the best current scientific evidence available.

Graphical Abstract

1. Introduction

Acute respiratory distress syndrome (ARDS) is a heterogeneous disorder that arises from a variety of pulmonary and extrapulmonary insults and is uniformly associated with high mortality [1,2]. Current treatment is supportive, including mechanical ventilation, prone positioning, and extracorporeal membrane oxygenation [3]. Despite several advances in the role of mechanical ventilation in the mitigation of lung injury, incorrectly adjusted ventilator settings can lead to unintended ventilator-induced lung injury (VILI), which has been shown to increase mortality in ARDS [4].
Repetitive alveolar collapse and expansion (RACE) is the primary cause of atelectrauma, which, along with volutrauma, comprise the two main mechanical mechanisms of VILI [4,5]. Low tidal volume ventilation (LTVV) has been shown to reduce mortality in ARDS, ostensibly by limiting volutrauma in the remaining normal tissue. However, even after the application of LTVV, mortality from ARDS remains unacceptably high [6,7,8]. Therefore, there is a need for novel protective modes of ventilation that can ameliorate both volutrauma and atelectrauma [NO_PRINTED_FORM].
Airway pressure release ventilation (APRV) is a form of mechanical ventilation that has been shown to have a superior physiologic profile compared to conventional LTVV in pre-clinical studies [9]. Specifically, a time-controlled adaptive ventilation protocol for setting the APRV mode, which is personalized based on changes in respiratory system compliance (CRS), has several important plausible mechanisms to reduce the propagation of lung injury [10]. These mechanisms include: (i) a brief expiratory time personalized to lung pathophysiology (CRS) that stabilizes lung tissue via pressure and time, and (ii) the extended inspiratory time that leads to the recruitment of small volumes of lung tissue with each breath. In the first mechanism, the lung does not have time to fully depressurize, generating a time-controlled PEEP. In the second mechanism, lung tissue is gradually “ratcheted” open over time, while the brief expiratory time prevents the newly opened lung tissue from re-collapsing. These elements of the physiologic rationale for APRV stem, in part, from the literature supporting the use of higher vs. lower positive end-expiratory pressure (PEEP) strategies [11,12]. Accordingly, recent practice guidelines, supported by the American Thoracic Society (ATS), suggest using higher PEEP in moderate to severe ARDS [13]. Given the inverse ratio nature of APRV, PEEP tends to be lower, but the resulting increase in mean airway pressure approximates the goal of higher PEEP in normal ratio ventilation strategies. However, clinical trials have demonstrated mixed results, with a recent meta-analysis comparing APRV, using multiple protocols to set the mode, to LTVV, finding that APRV was associated with overall improved outcomes, albeit with relatively poor study quality [14].
One of the factors that contribute to the variability in APRV vs. LTVV clinical trials may be the lack of an optimal or even standardized protocol for initiating and adjusting APRV settings on a mechanical ventilator. We therefore sought to examine the effect of the four main APRV settings on outcomes in ARDS. The objectives of our study were to (i) identify if there were studies that used similar methods to set APRV and, if so, (ii) whether there is a method of setting APRV that was associated with an improvement in ARDS-related outcomes. We analyzed the four settings used to adjust APRV, including the highest level of pressure applied to the respiratory system (Phigh), the lowest level of pressure applied to the respiratory system (Plow), and the time spent at each pressure setting (Thigh and Tlow, respectively). We hypothesized that personalizing the four settings to lung pathophysiology (CRS) would be associated with reduced mortality and length of stay and improved oxygenation.

2. Methods

2.1. Search Strategy

This systematic review and meta-regression is reported according to the Preferred Reporting for Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. A health sciences librarian with experience in systematic reviews and literature searching developed the search strategies in consultation with the research team. Systematic search queries related to ARDS and APRV using a combination of keywords and controlled vocabulary (where available) were conducted in PubMed, Embase, Scopus, Web of Science Core Collection, and CENTRAL. The included databases are standard among medical systematic reviews and meta-analyses, and we chose not to include other, specialty-specific databases that are not representative of critical care to avoid additional publication biases. All databases and registers were searched from inception to 12 October 2023. There were no search restrictions on language, publication status, or outcomes. The details of all the search strategies, including specific terms and Boolean operators, can be found in Supplementary Materials File S1. The search identified 2131 records. Duplicates were removed using EndNote 20 (Endnote, Clarivate, available at, accessd on 1 January 2023). The remaining 1755 records were uploaded into Covidence (Covidence, Veritas Health Innovation, Melbourne, Australia; available at for title and abstract screening.

2.2. Study Inclusion Criteria and Outcomes Measured

We included all experimental studies that used APRV as a mode of ventilation within their study. All patients were adults (age ≥18 years) who underwent mechanical ventilation. We excluded case reports, literature reviews, and conference proceedings as they generally lacked the data specificity necessary for our intended analyses. There were no search restrictions on language, publication status, or outcomes. All studies were conducted on humans.
We chose to categorize ventilator settings into groups based on how each setting impacts lung physiology and their alignment with the preponderance of the basic science literature that has been shown to be lung-protective [10,15]. Specifically, we compared Phigh set by plateau pressure vs. Phigh not set by plateau pressure, Plow set to 0 vs. Plow not set to 0, Tlow set to 50–75% of peak expiratory flow rate vs. Tlow not set to 50–75% of peak expiratory flow rate, and Thigh set based on PaCO2 vs. Thigh set arbitrarily.
The primary outcomes of this study were mortality (percentage of patients surviving in the APRV group), P/F ratio (PaO2/FiO2), number of ventilator-free days, static lung compliance, and intensive care unit length of stay (LOS).

2.3. Data Extraction and Quality Assessment

All procedures were independently reviewed by three authors (JC, JK, ML) in accordance with the prespecified inclusion criteria. The general information extracted included study and subject characteristics (age, gender, etiology, study design, aim of study, inclusion and exclusion criteria, method of recruitment, ventilator mode, population size, and population characteristics), specific APRV settings, including the time at high pressure, the time at low pressure, the high pressure, and the low pressure (Thigh, Tlow, Phigh, Plow), and outcome results. Data were recorded as either percentage or mean and standard deviation. The Cochrane Risk of Bias tool was used for the quality assessments. Any disagreements regarding data collection, data extraction, and quality assessment were resolved by consensus.

2.4. Statistical Analysis

Data extracted from the individual studies are presented as published (e.g., means and standard deviations) where available; when standard deviation (SD) was unavailable, we estimated the standard deviation (SD) from the range using a previously published method [16]. Between-study heterogeneity was assessed using the Cochran Q-test and I-squared test. We performed mixed-effects meta-regression to assess the association of APRV setting strategy and clinical outcomes of interest, using the maximum likelihood (ML) estimator for mixed-effect modeling. We chose to perform a meta-regression analysis as opposed to a traditional meta-analysis given the limitations of the meta-analysis framework. Specifically, a meta-analysis does not allow for a comparison of outcomes within a single arm (i.e., Plow set to 0 vs. not set to 0) as opposed to a comparison of outcomes between an intervention and a control (i.e., Plow set to 0 vs. LTVV). To maximize statistical power, we compared strategies in individual ventilator setting parameters (i.e., Phigh, Plow, Tlow, Thigh) instead of groups of settings, because, given there is no standardized protocol and a limited number of studies available, there were several combinations of ventilator settings presented as APRV in individual studies. We similarly chose not to perform sub-group analyses due to the small number of studies across parameter combinations, which could limit the validity and interpretability of any tests of interaction between sub-groups. We defined statistical significance as a 2-sided alpha < 0.5. Statistical analysis was performed using the metafor R package in R (version 4.3.2, The R Foundation for Statistical Computation, Vienna, Austria).

3. Results

3.1. Study Selection and Characteristics

We identified 2,131 records from a systematic search of the included databases (PubMed n = 1248, Embase n = 370, Scopus n = 192, Web of Science n = 321, CENTRAL n = 43). In total, 419 duplicative records were excluded. After screening 1755 titles and abstracts, 1432 records were excluded for irrelevance. After full-text assessment, 20 studies were included in our data extraction and subsequent analysis (Figure 1). The majority of studies excluded at full-text assessment (n = 303) were for incorrect study design (i.e., the study was not a RCT or cohort study), incorrect publication type (i.e., conference proceeding, and/or incomplete data). The remaining excluded studies were for languages other than English, incorrect outcomes (i.e., did not include any of the outcomes of interest), incorrect patient population or pediatric population, incorrect intervention, incorrect clinical setting, or repeat study.
We included 9 cohort studies, 10 randomized controlled trials, and one cross-over study (Table 1) [17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36]. The average number of participants from randomized controlled trials was 37 while the average number of participants from cohort studies was 22. The included studies were published between 1994 and 2022. Six of the included studies were conducted in the United States. The other studies were performed in Australia, China, Egypt, Finland, Germany, India, Japan, Mexico, and Turkey. The sample sizes ranged from 6 to 71, for a total of 538 study participants.

3.2. Bias and Study Quality Assessment

Table 2 documents the quality assessment of the included studies as determined through the Cochrane Risk of Bias tool. While most of the studies employed adequate random sequence generation and allocation concealment, the overwhelming majority of studies lacked blinding of both participants and personnel as well as an outcome assessment. We found that there was a very heterogeneous assessment of outcomes across the included studies. Most studies had complete outcome data for PaO2/FiO2 (P/F) ratio and intensive care unit (ICU) length of stay (LOS). However, the majority of studies did not include complete data for mortality, ventilator-free days, and static lung compliance. Therefore, we were only able to perform meta-regression analyses for the P/F ratio and ICU LOS. There was limited evidence of selective reporting, and we detected a low risk of other bias.

3.3. Meta-Regression Analyses

We performed mixed model meta-regression analyses with each ventilator setting individually as the categorical independent variable and outcome measure of interest as the dependent variable with a study-level random intercept to account for between-study heterogeneity. In total, 15 studies had complete data (i.e., both mean and SD) for the P/F ratio. There was no significant difference in P/F ratio between groups defined on the basis of any of the four settings (Phigh difference −12.0 [95% CI −100.4, 86.39]; Plow difference 54.3 [95% CI −52.6, 161.1]; Tlow difference −27.19 [95% CI −127.0, 72.6]; Thigh difference −51.4 [95% CI −170.3, 67.5]). The forest plots are shown in Figure 2. There was high heterogeneity across all parameters (Phigh I2 = 99.46%, Plow I2 = 99.16%, Tlow I2 = 99.31%, Thigh I2 = 99.29%).
There were 9 studies with complete data for ICU LOS. Similarly, there was no significant difference in ICU LOS between the groups in any of the four settings (Phigh difference 2.8 days [95% CI −4.8, 10.3], Plow difference −2.0 days [95% CI −11.7, 7.7], Tlow difference −1.8 days [95% CI −9.4, 5.7], Thigh difference 3.5 days [95% CI −3.5, 10.4]). The forest plots are shown in Figure 3. As with the P/F ratio analysis, there was high heterogeneity across all four ventilator setting parameters (Phigh I2 = 99.63%, Plow I2 = 99.67%, Tlow I2 = 99.63%, Thigh I2 = 99.59%).

4. Discussion

In our systematic review and meta-regression analysis, we found no difference in oxygenation or ICU LOS between strategies in setting individual APRV-related ventilator parameters. In addition, we also demonstrate significant variability in the setting and adjustment of APRV in patients with ARDS. Taken together, these findings suggest that the most effective combination of APRV settings has not been established, and the design of existing trials comparing APRV to LTVV may be suboptimal.
The variability in APRV settings among the included studies was one of the most striking findings of our study. Among the 20 studies included in our analyses, 11 of the 16 possible combinations of the 4 ventilator settings were represented, with only 2 combinations represented by more than 2 studies each. Given the inconsistency in APRV protocols used across the studies and the limited number of studies in each combination, comparisons of APRV to LTVV are limited by study heterogeneity, and comparisons of APRV protocols are limited by the low number of studies with matching ventilator setting configurations. We attempted to address some of the between-study variability by pursuing a meta-regression analysis of single APRV arms instead of the traditional meta-analysis comparing APRV to LTVV. Given the relatively even distribution of studies within each parameter, aside from Tlow, we were similarly able to employ meta-regression analysis to circumvent some of these issues.
We categorized APRV settings based on extensive physiologic data from studying the four APRV setting categories in animal models of ARDS. Although ARDS pathophysiology is highly complex, the dynamic change in alveolar mechanics predisposes the lung to a secondary VILI. In this setting, the lung becomes time- and pressure-dependent, such that it takes more time to open lung tissue and less time to re-collapse at any given airway pressure [37]. Thus, a longer inspiratory time (THigh) and a very brief expiratory time (TLow) may rapidly stabilize and then gradually recruit collapsed lung tissue, eliminating both atelectrauma and volutrauma.
Arguably, the most important APRV setting is the TLow. If the TLow is set to be sufficiently brief, it will not allow sufficient time for the alveoli to collapse, even with very rapid collapse time constants. Preventing alveolar collapse during expiration has two important lung-protective benefits: (1) progressive lung collapse moving the lung into the “VILI Vortex” would be prevented, and (2) atelectrauma, a primary VILI mechanism, would be minimized [4,38]. The slope of the expiratory flow curve (SlopeEF) has been shown to be a measure of CRS and can be used to personalize the TLow based on changes in lung pathophysiology [39]. Importantly, the expiratory flow curve is a breath-by-breath assessment of CRS only when the Plow is set to 0 cmH2O. We have previously demonstrated that if the expiratory flow is terminated (TEF) at 75% of the peak expiratory flow (PEF) (PEF L/min x 75% = TEF L/min), alveolar collapse and dynamic heterogeneity is prevented, whereas increasing the TLow (PEF x 10%, 25%, or 50%) does not. We have further shown that using this method to set TLow is highly lung-protective both in a clinically relevant large animal model and in clinical case series [40,41,42]. Despite the volume of data supporting its use, only one study included in our present analysis used PEF 75% to set the TLow [36].
In addition, we have previously demonstrated that, when using PEF 75% to set TLow, alveoli are stabilized even when PLow was set at 0 cmH2O [43]. Interestingly, the majority of studies included in the present analysis set PLow to 0 cmH2O (Table 1). Using this method, TLow is sufficiently brief such that the lung does not have time to fully depressurize. Therefore, alveolar stability is maintained by a combination of time and pressure. While PLow is set at 0 cmH2O, the end-expiratory pressure remains approximately half of the PHigh value [44]. On the other hand, PLow set above 0 cmH2O has two negative effects: (i) the added resistance slows the expiratory flow, and the SlopeEF is no longer an accurate assessment of CRS, and (ii) the reduced rate of expiration may cause an increase in PaCO2.
APRV can be adjusted to increase PaCO2 removal using two basic methods that increase minute ventilation. The TLow could be increased to augment tidal volume (VT), but from a physiologic perspective, this is problematic. It is well known that a large VT can cause VILI, and lengthening the TLow can cause alveolar instability (atelectrauma) and alveolar duct overdistension (volutrauma) [8,43,45]. Alternatively, reducing the length of the THigh to increase respiratory rate can increase PaCO2 removal. While decreasing THigh is likely more lung protective than increasing TLow, which would increase VT and compromise alveolar stability, the shorter inspiratory time may slow progressive lung recruitment. Only three of the studies analyzed in this meta-analysis changed THigh to eliminate PaCO2 (Table 1).
One of the main limiting factors of existing clinical trials comparing APRV to LTVV has been sample size. Assuming an effect size comparable to the ARMA trial (approximately 10% reduction in mortality), α = 0.05, and 80% power, the estimated sample size needed would be over 700 individuals. Among the studies included in our analysis, the largest sample size was 71 individuals, with a total of 538 individuals across all included studies, which only makes up just above 60% of the estimated sample size of an adequately powered clinical trial. Any future trial will thus need to address these considerations to study APRV in the clinical setting appropriately.
The primary limitation of our analysis was the substantial heterogeneity in the included studies. The I2 for all the analyses was over 99%, suggesting that almost all the observed variation was due to between-study, as opposed to within-study, differences. As mentioned above, at least some and perhaps a large proportion of the heterogeneity is clearly due to the multiple combinations of parameters across the studies. However, rather than showing that all APRV protocols are the same, our study demonstrates that the optimal strategy has not yet been demonstrated. There are also likely many other unknown sources of variability due to the diverse etiologies and clinical presentations of ARDS. For example, the study by Ibarra-Estrada et al. included only individuals with ARDS secondary to the novel coronavirus disease 2019 (COVID-19). While there are several clinical and biologic similarities between COVID-19 ARDS and non-COVID-19 ARDS, there are notable pathophysiologic differences, including the severity of endothelial injury, microangiopathy, and thrombosis [46]. In addition, there is a growing body of literature delineating two molecular phenotypes that have distinct biological profiles and mortality trajectories. Post hoc analyses have not demonstrated the interaction between randomized treatment and phenotype, but future studies that are designed with these heterogeneous groups in mind are necessary to better understand the role of APRV and other management strategies in ARDS [47].
Our results further highlight heterogeneity in clinical trial design as an important barrier to scientific advancement in the practice of critical care. In particular, the lack of standardization in protocols for mechanical ventilation limits the generalizability of any given clinical trial and the comparability of clinical trials in meta-analysis. For example, despite a consistent signal toward reduced mortality and improved oxygenation with higher PEEP, the authors of the recent ATS practice guideline offered only a conditional recommendation for the use of higher PEEP due to heterogeneity noted in the meta-analyses [13]. Future trials designed to evaluate APRV as a ventilation strategy for ARDS should include a clear justification for the method of setting each individual parameter, rather than comparing ventilator modes in name only.
Despite the number of criticisms of the existing APRV trials, we acknowledge that the ideal clinical trial design is complex. There may be several viable approaches, but a multi-arm parallel-group design is likely the most familiar and straightforward method for studying the multiple parameters required for APRV [48]. In this scenario, each arm would consist of a given combination of settings for the duration of the study period. Alternatively, a stepped wedge with or without cluster randomization could achieve similar results.
The principal source of bias for the included studies was the lack of blinding for participants and personnel, which was unfortunately unavoidable due to the nature of the intervention. In addition, several of the outcomes of interest, including, notably, mortality, had missing data, precluding inclusion in our analysis. However, there was sufficient data to analyze both the P/F ratio and ICU LOS, an important physiologic outcome and an important patient-centered outcome, respectively.
In conclusion, we found no differences in outcomes in individual APRV parameter strategies. Specifically, 68% of the included studies set the expiratory time (Tlow) arbitrarily and without scientific rationale. Setting the expiratory time to a specific physiologic parameter, such as CRS, may be the most important of the four settings since, if sufficiently short, it may eliminate recruitment/derecruitment-induced atelectrama. Only one study set expiratory time to 75% of PEF; thus, we could not further assess this method in sub-group analysis. While our analysis had several strengths, including the inclusion of a wide breadth of studies and meta-regression study design, the main limitation was the profound heterogeneity between included studies. With mortality related to ARDS remaining unacceptably high, further investigation into novel ventilation strategies is imminently necessary. Understanding the physiologic impact of each setting, both individually and in combination, is critical to optimizing the lung-protective impact of APRV. Our findings suggest that future studies are needed to establish the optimal combination of APRV settings to improve ARDS-related patient outcomes.

Supplementary Materials

The following supporting information can be downloaded at:, File S1: Search Strategy Details

Author Contributions

Concept and design, M.R.L., J.C., J.R.K., G.F.N., and A.J.G.; Data Collection, M.R.L., J.C., J.R.K., and A.S.; Data Analysis, M.R.L., J.C., J.R.K., S.J.G., and A.J.G.; Manuscript Writing, M.R.L., J.C., J.R.K., S.J.G., J.D.A., P.L.A., N.M.H., G.F.N., and A.J.G. All authors have read and agreed to the published version of the manuscript.


A.J.G. is supported by U.S. National Institutes of Health K08HL168205. J.A. is supported by U.S. National Institutes of Health R21EB034562. S.J.G. is supported by U.S. National Institutes of Health R01AG064955. N.M.H. is supported by U.S. Department of Defense W81XWH-20-1-0696. G.F.N. is supported by U.S. Department of Defense W81XWH-20-1-0696 and U.S. National Institutes of Health R01HL142702.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The original data presented in the study are openly available in PubMed, Embase, Scopus, Web of Science Core Collection, and CENTRAL.

Conflicts of Interest

G.F.N. has received honoraria and/or travel reimbursement at event(s) sponsored by Dräger Medical Systems, Inc., outside of the published work. G.F.N. has lectured for Intensive Care On-line Network, Inc. (ICON). N.M.H. has an Unrestricted Educational Grant from Dräger Medical Systems, Inc. N.M.H. is the founder of ICON. N.M.H. holds patents on a method of initiating, managing, and/or weaning airway pressure release ventilation, as well as controlling a ventilator in accordance with the same.


  1. Matthay, M.A.; Zemans, R.L.; Zimmerman, G.A.; Arabi, Y.M.; Beitler, J.R.; Mercat, A.; Herridge, M.; Randolph, A.G.; Calfee, C.S. Acute respiratory distress syndrome. Nat. Rev. Dis. Primers 2019, 5, 18. [Google Scholar] [CrossRef]
  2. Bellani, G.; Laffey, J.G.; Pham, T.; Fan, E.; Brochard, L.; Esteban, A.; Gattinoni, L.; Van Haren, F.; Larsson, A.; McAuley, D.F.; et al. Epidemiology, Patterns of Care, and Mortality for Patients with Acute Respiratory Distress Syndrome in Intensive Care Units in 50 Countries. JAMA 2016, 315, 788–800. [Google Scholar] [CrossRef] [PubMed]
  3. Fan, E.; Brodie, D.; Slutsky, A.S. Acute Respiratory Distress Syndrome: Advances in Diagnosis and Treatment. JAMA 2018, 319, 698–710. [Google Scholar] [CrossRef]
  4. Slutsky, A.S.; Ranieri, V.M. Ventilator-induced lung injury. N. Engl. J. Med. 2013, 369, 2126–2136. [Google Scholar] [CrossRef] [PubMed]
  5. Seah, A.S.; Grant, K.A.; Aliyeva, M.; Allen, G.B.; Bates, J.H. Quantifying the roles of tidal volume and PEEP in the pathogenesis of ventilator-induced lung injury. Ann. Biomed. Eng. 2011, 39, 1505–1516. [Google Scholar] [CrossRef] [PubMed]
  6. Pham, T.; Serpa Neto, A.; Pelosi, P.; Laffey, J.G.; De Haro, C.; Lorente, J.A.; Bellani, G.; Fan, E.; Brochard, L.J.; Pesenti, A.; et al. Outcomes of Patients Presenting with Mild Acute Respiratory Distress Syndrome: Insights from the LUNG SAFE Study. Anesthesiology 2019, 130, 263–283. [Google Scholar] [CrossRef]
  7. Writing Group for the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial Investigators; Cavalcanti, A.B.; Suzumura, E.A.; Laranjeira, L.N.; Paisani, D.M.; Damiani, L.P.; Guimarães, H.P.; Romano, E.R.; de Moraes Regenga, M.; Taniguchi, L.N.; et al. Effect of Lung Recruitment and Titrated Positive End-Expiratory Pressure (PEEP) vs. Low PEEP on Mortality in Patients with Acute Respiratory Distress Syndrome: A Randomized Clinical Trial. JAMA 2017, 318, 1335–1345. [Google Scholar] [CrossRef] [PubMed]
  8. Acute Respiratory Distress Syndrome Network; Brower, R.G.; Matthay, M.A.; Morris, A.; Schoenfeld, D.; Thompson, B.T.; Wheeler, A. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N. Engl. J. Med. 2000, 342, 1301–1308. [Google Scholar] [CrossRef]
  9. Jain, S.V.; Kollisch-Singule, M.; Sadowitz, B.; Dombert, L.; Satalin, J.; Andrews, P.; Gatto, L.A.; Nieman, G.F.; Habashi, N.M. The 30-year evolution of airway pressure release ventilation (APRV). Intensive Care Med. Exp. 2016, 4, 11. [Google Scholar] [CrossRef]
  10. Cressoni, M.; Chiurazzi, C.; Gotti, M.; Amini, M.; Brioni, M.; Algieri, I.; Cammaroto, A.; Rovati, C.; Massari, D.; di Castiglione, C.B.; et al. Lung inhomogeneities and time course of ventilator-induced mechanical injuries. Anesthesiology 2015, 123, 618–627. [Google Scholar] [CrossRef]
  11. Briel, M.; Meade, M.; Mercat, A.; Brower, R.G.; Talmor, D.; Walter, S.D.; Slutsky, A.S.; Pullenayegum, E.; Zhou, Q.; Cook, D.; et al. Higher vs Lower Positive End-Expiratory Pressure in Patients with Acute Lung Injury and Acute Respiratory Distress Syndrome. JAMA 2010, 303, 865. [Google Scholar] [CrossRef] [PubMed]
  12. Dianti, J.; Tisminetzky, M.; Ferreyro, B.L.; Englesakis, M.; Del Sorbo, L.; Sud, S.; Talmor, D.; Ball, L.; Meade, M.; Hodgson, C.; et al. Association of Positive End-Expiratory Pressure and Lung Recruitment Selection Strategies with Mortality in Acute Respiratory Distress Syndrome: A Systematic Review and Network Meta-analysis. Am. J. Respir. Crit. Care Med. 2022, 205, 1300–1310. [Google Scholar] [CrossRef] [PubMed]
  13. Qadir, N.; Sahetya, S.; Munshi, L.; Summers, C.; Abrams, D.; Beitler, J.; Bellani, G.; Brower, R.G.; Burry, L.; Chen, J.-T.; et al. An Update on Management of Adult Patients with Acute Respiratory Distress Syndrome: An Official American Thoracic Society Clinical Practice Guideline. Am. J. Respir. Crit. Care Med. 2024, 209, 24–36. [Google Scholar] [CrossRef] [PubMed]
  14. ZZhong, X.; Wu, Q.; Yang, H.; Dong, W.; Wang, B.; Zhang, Z.; Liang, G. Airway pressure release ventilation versus low tidal volume ventilation for patients with acute respiratory distress syndrome/acute lung injury: A meta-analysis of randomized clinical trials. Ann. Transl. Med. 2020, 8, 1641. [Google Scholar] [CrossRef]
  15. Camporota, L.; Rose, L.; Andrews, P.L.; Nieman, G.F.; Habashi, N.M. Airway pressure release ventilation for lung protection in acute respiratory distress syndrome: An alternative way to recruit the lungs. Curr. Opin. Crit. Care 2024, 30, 76–84. [Google Scholar] [CrossRef] [PubMed]
  16. Wan, X.; Wang, W.; Liu, J.; Tong, T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med. Res. Methodol. 2014, 14, 135. [Google Scholar] [CrossRef]
  17. Li, R.; Wu, Y.; Zhang, H.; Wang, A.; Zhao, X.; Yuan, S.; Yang, L.; Zou, X.; Shang, Y.; Zhao, Z. Effects of airway pressure release ventilation on lung physiology assessed by electrical impedance tomography in patients with early moderate-to-severe ARDS. Crit. Care 2023, 27, 178. [Google Scholar] [CrossRef] [PubMed]
  18. Varpula, T.; Valta, P.; Niemi, R.; Takkunen, O.; Hynynen, M.; Pettilä, V. Airway pressure release ventilation as a primary ventilatory mode in acute respiratory distress syndrome. Acta Anaesthesiol. Scand. 2004, 48, 722–731. [Google Scholar] [CrossRef] [PubMed]
  19. Kaplan, L.J.; Bailey, H.; Formosa, V. Airway pressure release ventilation increases cardiac performance in patients with acute lung injury/adult respiratory distress syndrome. Crit. Care 2001, 5, 221. [Google Scholar] [CrossRef]
  20. Ibrahim, R.; Mohamed, Y.; Abd El-kader, M.; Azouz, A. Airway pressure release ventilation versus pressure-controlled ventilation in acute hypoxemic respiratory failure. Egypt. J. Chest Dis. Tuberc. 2022, 71, 74. [Google Scholar]
  21. Wrigge, H.; Zinserling, J.; Hering, R.; Schwalfenberg, N.; Stüber, F.; von Spiegel, T.; Schroeder, S.; Hedenstierna, G.; Putensen, C. Cardiorespiratory Effects of Automatic Tube Compensation during Airway Pressure Release Ventilation in Patients with Acute Lung Injury. Anesthesiology 2001, 95, 382–389. [Google Scholar] [CrossRef]
  22. Lim, J.; Litton, E.; Robinson, H.; Das Gupta, M. Characteristics and outcomes of patients treated with airway pressure release ventilation for acute respiratory distress syndrome: A retrospective observational study. J. Crit. Care 2016, 34, 154–159. [Google Scholar] [CrossRef] [PubMed]
  23. Li, J.-Q.; Li, N.; Han, G.-J.; Pan, C.-G.; Zhang, Y.-H.; Shi, X.-Z.; Xu, J.-Y.; Lu, B.; Li, M.-Q. Clinical research about airway pressure release ventilation for moderate to severe acute respiratory distress syndrome. Eur. Rev. Med. Pharmacol. Sci. 2016, 20, 2634–2641. [Google Scholar]
  24. Zhou, Y.; Jin, X.; Lv, Y.; Wang, P.; Yang, Y.; Liang, G.; Wang, B.; Kang, Y. Early application of airway pressure release ventilation may reduce the duration of mechanical ventilation in acute respiratory distress syndrome. Intensive Care Med. 2017, 43, 1648–1659. [Google Scholar] [CrossRef]
  25. Marik, P.E.; Delgado, E.M.; Baram, M.; Gradwell, G.; Romeo, S.; Dutill, B. Effect of Airway Pressure Release Ventilation (APRV) with Pressure Support. (PS) on Indices of Oxygenation and Ventilation in Patients with Severe ARDS: A Cohort Study. Crit Care Shock 2009, 12, 43–48. [Google Scholar]
  26. Küçük, M.P.; Öztürk, Ç.E.; İlkaya, N.K.; Küçük, A.O.; Ergül, D.F.; Ülger, F. The effect of preemptive airway pressure release ventilation on patients with high risk for acute respiratory distress syndrome: A randomized controlled trial. Braz. J. Anesthesiol. (Engl. Ed.) 2022, 72, 29–36. [Google Scholar] [CrossRef] [PubMed]
  27. Daoud, E.G.; Chatburn, R.L. Comparing surrogates of oxygenation and ventilation between airway pressure release ventilation and biphasic airway pressure in a mechanical model of adult respiratory distress syndrome. Respir. Investig. 2014, 52, 236–241. [Google Scholar] [CrossRef] [PubMed]
  28. Yoshida, T.; Rinka, H.; Kaji, A.; Yoshimoto, A.; Arimoto, H.; Miyaichi, T.; Kan, M. The Impact of Spontaneous Ventilation on Distribution of Lung Aeration in Patients with Acute Respiratory Distress Syndrome: Airway Pressure Release Ventilation Versus Pressure Support Ventilation. Anesth. Analg. 2009, 109, 1892–1900. [Google Scholar] [CrossRef] [PubMed]
  29. Manjunath, V.; Reddy, B.; Prasad, S. Is airway pressure release ventilation, a better primary mode of post-operative ventilation for adult patients undergoing open heart surgery? A prospective randomised study. Ann. Card. Anaesth. 2021, 24, 288. [Google Scholar]
  30. Sydow, M.; Burchardi, H.; Ephraim, E.; Zielmann, S.; Crozier, T.A. Long-term effects of two different ventilatory modes on oxygenation in acute lung injury. Comparison of airway pressure release ventilation and volume-controlled inverse ratio ventilation. Am. J. Respir. Crit. Care Med. 1994, 149, 1550–1556. [Google Scholar] [CrossRef]
  31. Liu, L.; Tanigawa, K.; Ota, K.; Tamura, T.; Yamaga, S.; Kida, Y.; Kondo, T.; Ishida, M.; Otani, T.; Sadamori, T.; et al. Practical use of airway pressure release ventilation for severe ARDS—A preliminary report in comparison with a conventional ventilatory support. Hiroshima J. Med. Sci. 2009, 58, 83–88. [Google Scholar] [PubMed]
  32. Dart, B.W.; Maxwell, R.A.; Richart, C.M.; Brooks, D.K.; Ciraulo, D.L.; Barker, D.E.; Burns, R.P. Preliminary Experience with Airway Pressure Release Ventilation in a Trauma/Surgical Intensive Care Unit. J. Trauma Inj. Infect. Crit. Care 2005, 59, 71–76. [Google Scholar] [CrossRef] [PubMed]
  33. MMaxwell, R.A.; Green, J.M.; Waldrop, J.; Dart, B.W.; Smith, P.W.; Brooks, D.; Lewis, P.L.; Barker, D.E. A Randomized Prospective Trial of Airway Pressure Release Ventilation and Low Tidal Volume Ventilation in Adult Trauma Patients with Acute Respiratory Failure. J. Trauma Inj. Infect. Crit. Care 2010, 69, 501–511. [Google Scholar] [CrossRef] [PubMed]
  34. Hirshberg, E.L.; Lanspa, M.J.; Peterson, J.; Carpenter, L.; Wilson, E.L.; Brown, S.M.; Dean, N.C.; Orme, J.; Grissom, C.K. Randomized Feasibility Trial of a Low Tidal Volume-Airway Pressure Release Ventilation Protocol Compared with Traditional Airway Pressure Release Ventilation and Volume Control Ventilation Protocols. Crit. Care Med. 2018, 46, 1943–1952. [Google Scholar] [CrossRef] [PubMed]
  35. Ibarra-Estrada, M.; García-Salas, Y.; Mireles-Cabodevila, E.; López-Pulgarín, J.A.; Chávez-Peña, Q.; García-Salcido, R.; Mijangos-Méndez, J.C.; Aguirre-Avalos, G. Use of Airway Pressure Release Ventilation in Patients with Acute Respiratory Failure Due to COVID-19: Results of a Single-Center Randomized Controlled Trial*. Crit. Care Med. 2022, 50, 586–594. [Google Scholar] [PubMed]
  36. Momtaz, O.M.; Ahmed El Hefeny, R.; Fawzy, R.M.; Fathy, A.; Khateeb, E. Study of Airway pressure release ventilation versus low tidal volume ventilation in hospital outcome of acute respiratory distress syndrome. Neuroquantology 2022, 20, 3436–3445. [Google Scholar]
  37. Nieman, G.F.; Kaczka, D.W.; Andrews, P.L.; Ghosh, A.; Al-Khalisy, H.; Camporota, L.; Satalin, J.; Herrmann, J.; Habashi, N.M. First Stabilize and then Gradually Recruit: A Paradigm Shift in Protective Mechanical Ventilation for Acute Lung Injury. J. Clin. Med. 2023, 12, 4633. [Google Scholar] [CrossRef]
  38. Marini, J.J.; Gattinoni, L. Time Course of Evolving Ventilator-Induced Lung Injury: The “Shrinking Baby Lung”. Crit. Care Med. 2020, 48, 1203–1209. [Google Scholar] [CrossRef]
  39. Habashi, N.M. Other approaches to open-lung ventilation: Airway pressure release ventilation. Crit. Care Med. 2005, 33, S228–S240. [Google Scholar] [CrossRef]
  40. Roy, S.; Habashi, N.; Sadowitz, B.; Andrews, P.; Ge, L.; Wang, G.; Roy, P.; Ghosh, A.; Kuhn, M.; Satalin, J.; et al. Early airway pressure release ventilation prevents ards—A novel preventive approach to lung injury. Shock 2013, 39, 28–38. [Google Scholar] [CrossRef]
  41. Rola, P.; Daxon, B. Airway Pressure Release Ventilation with Time-Controlled Adaptive Ventilation (TCAVTM) in COVID-19: A Community Hospital’s Experience. Front. Physiol. 2022, 13, 787231. [Google Scholar] [CrossRef] [PubMed]
  42. Janssen, M.; Meeder, J.H.; Seghers, L.; den Uil, C.A. Time controlled adaptive ventilationTM as conservative treatment of destroyed lung: An alternative to lung transplantation. BMC Pulm. Med. 2021, 21, 176. [Google Scholar] [CrossRef]
  43. Kollisch-Singule, M.; Jain, S.; Andrews, P.; Smith, B.J.; Hamlington-Smith, K.L.; Roy, S.; DiStefano, D.; Nuss, E.; Satalin, J.; Meng, Q.; et al. Effect of Airway Pressure Release Ventilation on Dynamic Alveolar Heterogeneity. JAMA Surg. 2016, 151, 64. [Google Scholar] [CrossRef] [PubMed]
  44. Kollisch-Singule, M.; Emr, B.; Jain, S.V.; Andrews, P.; Satalin, J.; Liu, J.; Porcellio, E.; Van Kenyon, V.; Wang, G.; Marx, W.; et al. The effects of airway pressure release ventilation on respiratory mechanics in extrapulmonary lung injury. Intensive Care Med. Exp. 2015, 3, 35. [Google Scholar] [CrossRef] [PubMed]
  45. Kollisch-Singule, M.; Emr, B.; Smith, B.; Ruiz, C.; Roy, S.; Meng, Q.; Jain, S.; Satalin, J.; Snyder, K.; Ghosh, A.; et al. Airway pressure release ventilation reduces conducting airway micro-strain in lung injury. J. Am. Coll. Surg. 2014, 219, 968–976. [Google Scholar] [CrossRef] [PubMed]
  46. Ackermann, M.; Verleden, S.E.; Kuehnel, M.; Haverich, A.; Welte, T.; Laenger, F.; Vanstapel, A.; Werlein, C.; Stark, H.; Tzankov, A.; et al. Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in COVID-19. N. Engl. J. Med. 2020, 383, 120–128. [Google Scholar] [CrossRef] [PubMed]
  47. Sinha, P.; Neyton, L.; Sarma, A.; Wu, N.; Jones, C.; Zhuo, H.; Liu, K.D.; Sanchez Guerrero, E.; Ghale, R.; Love, C.; et al. Molecular Phenotypes of Acute Respiratory Distress Syndrome in the ROSE Trial Have Differential Outcomes and Gene Expression Patterns That Differ at Baseline and Longitudinally over Time. Am. J. Respir. Crit. Care Med. 2024, 209, 816–828. [Google Scholar] [CrossRef]
  48. Juszczak, E.; Altman, D.G.; Hopewell, S.; Schulz, K. Reporting of Multi-Arm Parallel-Group Randomized Trials. JAMA 2019, 321, 1610. [Google Scholar] [CrossRef]
Figure 1. PRISMA flowchart.
Figure 1. PRISMA flowchart.
Jcm 13 02690 g001
Figure 2. P/F ratio forest plots. Forest plots of P/F ratio analysis by APRV setting. (A) Phigh forest plot. (B) Plow forest plot. (C) Tlow forest plot. (D) Thigh forest plot [17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36].
Figure 2. P/F ratio forest plots. Forest plots of P/F ratio analysis by APRV setting. (A) Phigh forest plot. (B) Plow forest plot. (C) Tlow forest plot. (D) Thigh forest plot [17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36].
Jcm 13 02690 g002aJcm 13 02690 g002b
Figure 3. ICU LOS forest plots. Forest plots of ICU LOS analysis by APRV setting. (A) Phigh forest plot. (B) Plow forest plot. (C) Tlow forest plot. (D) Thigh forest plot [17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36].
Figure 3. ICU LOS forest plots. Forest plots of ICU LOS analysis by APRV setting. (A) Phigh forest plot. (B) Plow forest plot. (C) Tlow forest plot. (D) Thigh forest plot [17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36].
Jcm 13 02690 g003aJcm 13 02690 g003b
Table 1. Characteristics from included studies.
Table 1. Characteristics from included studies.
StudyDesignSample Size of APRV GroupTlow (%)Plow Set to 0Thigh Adjusted for PCO2Phigh Set Based on PplatOutcomes
Momtaz 2022 [36]RCT-75NoNoYes1
Li 2023 [17]Cohort study1250–75YesYesYes1,2
Varpula 2004 [18]RCT30ArbitraryNoNoNo1, 2, 3
Kaplan 2001 [19]Cohort study12Arbitrary-No-2
Ibrahim 2022 [20]RCT30ArbitraryYesNoNo1, 4, 5
Wrigge 2001 [21]Cohort study14ArbitraryNoNoNo2
Lim 2016 [22]Cohort study50ArbitraryNoNoNo1, 2, 5
Li 2016 [23]RCT26ArbitraryYesNoNo1, 2, 3, 4, 5
Zhou 2017 [24]RCT7150–75NoYesYes1, 2, 3, 5
Marik 2009 [25]Cohort study22ArbitraryNoNoYes1, 2
Kucuk 2022 [26]RCT32ArbitraryYesNoYes1, 2, 3, 5
Daoud 2013 [27]Cohort study650–75YesNoYes2
Yoshida 2009 [28]Cohort study950–75YesNoNo2
Manjunath 2021 [29]RCT30ArbitraryYesNoNo2, 4, 5
Sydow 1994 [30]Cross-over study18ArbitraryNoNoNo1
Liu 2009 [31]Cohort study19ArbitraryYesNoNo1, 2, 5
Dart 2005 [32]Cohort study46ArbitraryYesYesNo1, 2, 3
Hirshberg 2018 [34]RCT3550–75YesYesNo1, 2, 3, 5
Maxwell 2010 [33]Cohort study31ArbitraryYesNoYes1, 5
Ibarra-Estrada 2022 [35]RCT4550–75YesNoYes1, 2, 3, 5
Outcomes: 1—mortality (percentage of patients surviving in the APRV group); 2—P/F ratio (PaO2/FiO2); 3—number of ventilator-free days; 4—static lung compliance; 5—intensive care unit length of stay.
Table 2. Quality assessment of included studies.
Table 2. Quality assessment of included studies.
Study IDSequence Generation (Selection Bias)Allocation Concealment (Selection Bias)Blinding of Participants and Personnel (Performance Bias)Blinding of Outcome Assessment (Detection Bias)Incomplete Outcome Data (Attrition Bias)Selective Reporting (Reporting Bias)Other Sources of Bias
Momtaz 2022 [36]LowLowLowLowLowLowLow
Li 2023 [17]LowUnsureLowLowLowLowLow
Varpula 2004 [18]LowLowHighUnsureLowLowLow
Kaplan 2001 [19]UnsureHighHighHighHighUnsureLow
Ibrahim 2022 [20]LowLowHighHighLowLowLow
Wrigge 2001 [21]UnsureUnsureHighHighHighUnsureLow
Lim 2016 [22]LowLowUnsureUnsureLowHighLow
Li 2016 [23]LowLowUnsureUnsureUnsureLowLow
Zhou 2017 [24]LowLowHighUnsureLowLowLow
Marik 2009 [25]UnsureHighHighHighHighHighLow
Küçük 2022 [26]LowLowHighHighLowLowLow
Daoud 2013 [27]HighHighLowHighLowLowLow
Yoshida 2009 [28]HighHighHighHighHighUnsureLow
Manjunath 2021 [29]UnsureLowHighHighHighLowLow
Sydow 1994 [30]LowUnsureHighUnsureLowUnsureLow
Liu 2009 [31]LowHighUnsureUnsureLowLowLow
Dart 2005 [32]UnsureLowLowLowLowLowLow
Hirshberg 2018 [34]LowLowLowHighLowUnsureLow
Maxwell 2010 [33]LowLowHighUnsureLowUnsureLow
Ibarra-Estrada 2022 [35]LowLowHighHighLowLowLow
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Lutz, M.R.; Charlamb, J.; Kenna, J.R.; Smith, A.; Glatt, S.J.; Araos, J.D.; Andrews, P.L.; Habashi, N.M.; Nieman, G.F.; Ghosh, A.J. Inconsistent Methods Used to Set Airway Pressure Release Ventilation in Acute Respiratory Distress Syndrome: A Systematic Review and Meta-Regression Analysis. J. Clin. Med. 2024, 13, 2690.

AMA Style

Lutz MR, Charlamb J, Kenna JR, Smith A, Glatt SJ, Araos JD, Andrews PL, Habashi NM, Nieman GF, Ghosh AJ. Inconsistent Methods Used to Set Airway Pressure Release Ventilation in Acute Respiratory Distress Syndrome: A Systematic Review and Meta-Regression Analysis. Journal of Clinical Medicine. 2024; 13(9):2690.

Chicago/Turabian Style

Lutz, Mark R., Jacob Charlamb, Joshua R. Kenna, Abigail Smith, Stephen J. Glatt, Joaquin D. Araos, Penny L. Andrews, Nader M. Habashi, Gary F. Nieman, and Auyon J. Ghosh. 2024. "Inconsistent Methods Used to Set Airway Pressure Release Ventilation in Acute Respiratory Distress Syndrome: A Systematic Review and Meta-Regression Analysis" Journal of Clinical Medicine 13, no. 9: 2690.

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop